0A4F4F9BD490A749D5437F821CF06DF1
Handbook for Good Clinical Research Practice (GCP)
http://apps.who.int/medicinedocs/documents/s14084e/s14084e.pdf
http://leaux.net/URLS/ConvertAPI Text Files/18F7161532DBE7C650B637202A4DCB66.en.txt
Examining the file media/Synopses/18F7161532DBE7C650B637202A4DCB66.html:
This file was generated: 2020-07-15 06:52:59
| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Criminal Convictions
Searching for indicator prisoners:
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p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
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p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
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p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
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Political / Indigenous
Searching for indicator indigenous:
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p.000121: http://www.med.umich.edu/irbmed/ethics/Nuremberg/NurembergCode. html
p.000121: 16. United Nations International Covenant on Civil and Political Rights. 1966.
p.000121: http://www.hrweb.org/legal/cpr.html
p.000121:
p.000121:
p.000121: Related documents
p.000121: 1. ETH. Global list of national bioethics committees with contact details. http://www.who.int/ethics/en
p.000121: 2. IVB. Ethical considerations arising from vaccine trials.
p.000121: http://www.who.int/entity/vaccine_research/documents/en/manu774. pdf
p.000121: 3. RHR. Implementation of Good Clinical Practice (GCP) guidelines in RHR re- search activities.
p.000121: http://www.who.int/reproductive-health/publications/RHR_02_05/ Section_11.PDF
p.000121: 4. RHR Guidelines for research. http://www.who.int/reproductivehealth/hrp/ ethical_issues.en.html
p.000121: http://www.who.int/reproductive health/hrp/SERG_guidelines.en.html
p.000121: 5. RHR. Guideline for obtaining informed consent for the procurement and use of human tissues, cells and fluids in
p.000121: research. http://www.who.int/reproductive-health/ hrp/SERG_guidelines.en.html
p.000121: 6. TDR Standard operating procedures for clinical investigators. TDR/TDP/ SOP/99.1
p.000121: www.who.int/tdr/publications/publications/sop.htm
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
p.000121: 8. TDR Guidelines for Ethical Clearance & TDR Ethical Clearance Checklist
p.000121: http://www.who.int/tdr/publications/
p.000121: 9. Indigenous peoples & participatory health research. http://www.who.int/ethics/indigenous_peoples/en/
p.000121: 10. UNAIDS (Joint United Nations Programme on HIV/AIDS): Ethical considera- tions in HIV preventive vaccine research.
p.000121: http://www.unaids.org/publications/documents/vaccines/index.html
p.000121:
p.000121: REFERENCES | 123
p.000121:
p.000121: 11. International guidelines for ethical review of epidemiological studies. CIOMS, Geneva, 1991 (revision
p.000121: pending). http://www.cioms.ch/
p.000121: 12. Additional Protocol to the Convention of Human Rights and Biomedicine concerning biomedical research. Council of
p.000121: Europe. European Treaty Se- ries – 195. http://www.coe.int/T/E/Legal_Affairs/
p.000121: 13. Steering Committee on Bioethics (CDBI) Restricted CDBI/INF (2002) 5. Council of Europe.
p.000121: http://www.coe.int/T/E/Legal_Affairs/
p.000121:
p.000121:
p.000121: National good clinical practice and other guidelines
p.000121: Australia
p.000121: Regulation of clinical trials in Australia: http://www.tga.gov.au
p.000121:
p.000121: Canada
p.000121: Good clinical practices.
p.000121: http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/hp_gcp_e.html
p.000121:
p.000121: European Union
p.000121: European Agency for Evaluation of Medicines (EMEA). ICH topic E6. Note for guidance on good clinical practice
p.000121: (CPMP/ICH/135/95) http://www.emea.eu.int/pdfs/human/ich/013595en.pdf
p.000121: European Clinical Trials Directive for GCP, 2001/20/EC, 04.2001
p.000121:
p.000121: India
p.000121: Ethical guidelines for biomedical research on human subjects. http://icmr.nic.in/ethical.pdf
p.000121: Japan
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Political / political affiliation
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p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
p.000121: standards. This in- cludes the investigator(s) and site staff, the sponsor and sponsor’s staff (including
p.000121: monitors and auditors), the ethics committee(s), the regulatory authority(-ies), and the individual research subjects.
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p.000121: 24 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities):
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: 2000, Section 6.2)
p.000121: Follow-Up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, 2000, Section 9)
p.000121: Ethical review of externally sponsored research (CIOMS, Interna- tional Ethical Guidelines, Guideline 3)
p.000121: For clinical investigators, refer to:
p.000121: Communications with the IRB/IEC (ICH E6, Section 4.4) Informed Consent of Trial Subjects (ICH E6, Section 4.8) Safety
p.000121: Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
p.000121: Trial Design (ICH E6, Section 5.4)
p.000121: Notification/Submission to Regulatory Authority(ies) (ICH E6, Sec- tion 5.10)
p.000121: Safety Information (ICH E6, Section 5.16)
p.000121: For regulatory authorities, refer to:
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p.000121: What is the objective of obtaining IEC/IRB review of the protocol?
p.000121: It is the IEC/IRB “… whose responsibility it is to ensure the protection of the rights, safety, and well-being of human
p.000121: subjects involved in a trial and to provide public assurance of that protection, by, among other things,
p.000121: reviewing and approving/providing favourable opinion on the trial protocol …“ (ICH E6, 1.27)
p.000121: The principal focus of the IEC/IRB is ethical review of the protocol. However, “… [s]cientific review
p.000121: and ethical review cannot be sepa- rated: scientifically unsound research involving humans as subjects is
p.000121: ipso facto unethical in that it may expose them to risk or incon- venience to no purpose; even if there is
p.000121: no risk of injury, wasting of
p.000121:
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p.000121: 48 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: subjects’ and researchers’ time in unproductive activities represents loss of a valuable resource. Normally,
p.000121: therefore, an ethical review committee considers both the scientific and the ethical aspects of proposed
p.000121: research. It must either carry out or arrange for a proper scientific review or verify that a competent
p.000121: expert body has deter- mined that the research is scientifically sound …” (CIOMS, Interna- tional Ethical
p.000121: Guidelines, Commentary to Guideline 2)
p.000121: Review by the IEC/IRB also helps ensure that the research is evaluat- ed by a party that is independent of the trial.
p.000121: “The review committees must be independent of the research team, and any direct financial or other material benefit
p.000121: they may derive from the research should not be contingent on the outcome of their review.” (CIOMS, Interna-
p.000121: tional Ethical Guidelines, Guideline 2)
p.000121:
p.000121:
p.000121: How does the composition and operation of the IEC/IRB within GCP promote its independence?
p.000121: Within GCP, “the IRB/IEC should consist of a reasonable number of members, who collectively have the
p.000121: qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial.
p.000121: It is recommended that the IRB/IEC should include:
p.000121: (a) [a]t least five members, (b) [a]t least one member whose primary area of interest is in a nonscientific
p.000121: area, (c) [a]t least one member who is independent of the institution/trial site.” (ICH E6, Section 3.2)
p.000121: In its operations, “[o]nly those IRB/IEC members who are independ- ent of the investigator and the sponsor of
p.000121: the trial should vote/ provide opinion on a trial-related matter.” (ICH E6, Section 3.2).
p.000121: “To maintain the review committee’s independence from the inves- tigators and sponsors and to avoid conflict of
p.000121: interest, any member with a special or particular, direct or indirect, interest in a proposal should not
p.000121: take part in its assessment if that interest could subvert the member’s objective judgment. Members of ethical
p.000121: review com- mittees should be held to the same standard of disclosure as sci- entific and medical
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p.000121: IEC/IRB, monitor or regulatory authorities. “The investigator/ institution should take measures to prevent
p.000121: accidental or premature destruction of these records.” (ICH E6, Section 4.9)
p.000121:
p.000121:
p.000121: Why is it necessary for IECs/IRBs, investigators, sponsors, and monitors to maintain clinical trial information?
p.000121: Clinical trial information should be maintained to allow accurate re- construction and evaluation of the
p.000121: trial’s conduct and verification of the trial’s results.
p.000121:
p.000121:
p.000121: How do investigators know which records should be maintained and the methods for maintaining them?
p.000121: The study protocol generally specifies the information to be captured and the methods to be used (e.g. by
p.000121: providing “[s]amples of the standardized case-report forms to be used … ,” describing “… the methods of
p.000121: recording therapeutic response (description and evalua- tion of methods and frequency of measurement), the follow-up
p.000121: pro- cedures, and, if applicable, the measures proposed to determine the extent of compliance of subjects with
p.000121: the treatment … , [m]ethods of recording and reporting adverse events or reactions …” (CIOMS, International
p.000121: Ethical Guidelines, Appendix 1).
p.000121: Record-keeping and retention requirements may also be specified by national or local law and regulations.
p.000121:
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p.000121: 96 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
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p.000121: What is meant by “reporting”? How are essential documents and data combined to report the outcome of the trial?
p.000121: Reporting is the act of providing information or data to another party. National laws and regulations may require
p.000121: certain information to be reported within specific time frames, for example, reports of serious unanticipated adverse
p.000121: events.
p.000121: Responsibility for reporting clinical trial information and results is shared by:
p.000121: • the study sponsor, who reports adverse events to regulators, and prepares summary reports about clinical
p.000121: studies for inclusion in applications to obtain research permits or to market an investiga- tional product;
p.000121: • the monitor, who prepares and submits written reports of moni- toring visits and trial-related
p.000121: communications to the sponsor;
p.000121: • the clinical investigator who submits, for example, case report forms (CRFs) to the sponsor; progress
p.000121: reports or written sum- maries of the trial’s status to the institution, the IEC/IRB, and the sponsor;
p.000121: safety reports (e.g. adverse event reports, laboratory anomalies) to the sponsor and IEC/IRB; final reports upon
p.000121: comple- tion of the trial to the sponsor, IEC/IRB, and regulatory authorities;
p.000121: • the IEC/IRB, which notifies the investigator and institution, and sometimes the regulatory
p.000121: authority(ies) about trial-related de- cisions and opinions (e.g. decisions to suspend or terminate a
p.000121: study), the reasons for such decisions/opinions, and procedures for appealing them.
p.000121: “The investigator should ensure the accuracy, completeness, legibili- ty, and timeliness of the data reported to the
p.000121: sponsor in the CRFs and in all required reports. Data reported on the CRF, which are derived from source documents
p.000121: should be consistent with the source docu- ments or the discrepancies should be explained.” (ICH E6, Section
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p.000121:
p.000121: Implementation
p.000121: All of the parties who conduct and oversee clinical trials (sponsors, investigators, IECs/IRBs, and
p.000121: regulatory authorities) should adopt and implement quality systems for the processes and activities for which they are
p.000121: responsible.
p.000121: Sponsors secure the services of monitors to ensure compliance of the clinical investigators and verify
p.000121: that the study was carried out according to the approved study protocol. Sponsors also audit the
p.000121: monitors’ performance and other quality control activities and sys- tems to ensure each system’s performance.
p.000121: Monitors review study records at the sites, report their findings to the sponsor, and prepare written
p.000121: reports that document each site visit or trial-related communication.
p.000121: Investigators supervise to ensure that study staff follow estab- lished procedures for the conduct of the
p.000121: study, e.g. obtaining IEC/IRB approval of the study, obtaining informed consent from subjects, es- tablishing and
p.000121: maintaining subjects’ case histories, transcribing data from subjects’ medical files to the CRFs, reporting
p.000121: adverse events and other unanticipated problems, etc.
p.000121: IECs/IRBs develop and adopt SOPs for reviewing studies and inform- ing the clinical investigator of any required
p.000121: modifications to the study protocol, and for assuring that such modifications are in place before
p.000121:
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p.000121: 118 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
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p.000121: the study proceeds. In accordance with national/local laws and regu- lations, IECs/IRBs may develop SOPs to allow
p.000121: IEC/IRB members or a third party to observe the consent process to verify that subjects are being provided
p.000121: the opportunity to ask questions about the study and that subjects receive a copy of the informed consent document.
p.000121: IECs/IRBs implement systems to assure that continuing review of the study takes place at intervals appropriate to the
p.000121: degree of risk, and that investigators are notified so that they may provide the necessary documentation to the IEC/IRB
p.000121: in advance of the deadline.
p.000121: In accordance with applicable laws/regulations, regulators may inspect all parties that conduct or
p.000121: oversee research and verify the information submitted to the regulatory authority. Regulators may ask for
p.000121: sponsors’ monitoring plans as a condition of allowing a study to proceed. Regulatory authorities also optimally
p.000121: develop SOPs and quality systems for internal regulatory activities, including policies and procedures for
p.000121: reviewing product applications and for the con- duct of GCP inspections.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For sponsors, refer to:
p.000121: Quality Assurance and Quality Control (ICH E6, Section 5.1)
p.000121: Trial Management, Data Handing, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Monitoring (ICH E6, Section 5.18) Audit (ICH E6, Section 5.19) Noncompliance (ICH E6, Section 5.20)
p.000121: Monitoring Arrangements (Clinical investigation of medical devices for human subjects, Part 2: Clinical investigation
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Searching for indicator political:
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p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 1995
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 57
p.000121:
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: Definitions for:
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Monitoring (ICH E6, 1.38)
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p.000121: 58 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
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p.000121: PRINCIPLE 7: INFORMED CONSENT
p.000121: Freely given informed consent should be obtained from every subject prior to research participation in
p.000121: accordance with na- tional culture(s) and requirements. When a subject is not ca- pable of giving
p.000121: informed consent, the permission of a legally authorized representative should be obtained in accordance
p.000121: with applicable law.
p.000121: “In particular, no one shall be subjected without his free consent to medical or scientific experimentation.” (United
p.000121: Nations International Covenant on Civil and Political Rights)
p.000121: “The subjects must be volunteers and informed participants in the research project.” (Declaration of Helsinki)
p.000121: “… [T]here is widespread agreement that the consent process can be analysed as containing three elements:
p.000121: information, comprehen- sion, and voluntariness.” (The Belmont Report)
p.000121: “For all biomedical research involving humans, the investigator must obtain the voluntary informed consent of the
p.000121: prospective subject or, in the case of an individual who is not capable of giving informed consent, the
p.000121: permission of a legally authorized representative in ac- cordance with applicable law. Waiver of informed
p.000121: consent is to be regarded as uncommon and exceptional, and must in all cases be ap- proved by an ethical review
p.000121: committee.” (CIOMS, International Ethi- cal Guidelines, Guideline 4)
p.000121: “Obtaining informed consent is a process that is begun when initial contact is made with a prospective
p.000121: subject and continues through- out the course of the study. By informing the prospective subjects, by
p.000121: repetition and explanation, by answering their questions as they arise, and by ensuring that each individual
p.000121: understands each proce- dure, investigators elicit their informed consent and in so doing mani- fest respect for
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p.000121: European Network of GCP Auditors and other GCP Experts. (in process of revision).
p.000121: 7. ICH E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 1994.
p.000121: http://www.ich.org/
p.000121: 8. ICH E2B(R): Revision of the E2B(M) ICH Guideline on Clinical Safety Data Management. Data Elements for
p.000121: Transmission of Individual Case Safety Reports. Step 3 undergoing consultation. May. 2005. http://www.ich.org/
p.000121: 9. ICH E3: Structure and Content of Clinical Study Reports. 1995. http://www. ich.org/
p.000121: 10. ICH E9: Statistical Principles for Clinical Trials. 1998. http://www.ich.org/
p.000121: 11. ICH E10: Choice of Control Group and Related Issues in Clinical Trials. 2000. http://www.ich.org/
p.000121: 12. ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Popula- tion. 2000. http://www.ich.org/
p.000121: 13. ICH M3: Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials
p.000121: for Pharmaceuticals. 1997. http://www.ich.org/
p.000121: 14. ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceu- ticals. 1997. http://www.ich.org/
p.000121:
p.000121:
p.000121: 122 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 15. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10,
p.000121: Vol. 2, pp. 181–182. Washing- ton, D.C.: U.S. Government Printing Office, 1949.
p.000121: http://www.med.umich.edu/irbmed/ethics/Nuremberg/NurembergCode. html
p.000121: 16. United Nations International Covenant on Civil and Political Rights. 1966.
p.000121: http://www.hrweb.org/legal/cpr.html
p.000121:
p.000121:
p.000121: Related documents
p.000121: 1. ETH. Global list of national bioethics committees with contact details. http://www.who.int/ethics/en
p.000121: 2. IVB. Ethical considerations arising from vaccine trials.
p.000121: http://www.who.int/entity/vaccine_research/documents/en/manu774. pdf
p.000121: 3. RHR. Implementation of Good Clinical Practice (GCP) guidelines in RHR re- search activities.
p.000121: http://www.who.int/reproductive-health/publications/RHR_02_05/ Section_11.PDF
p.000121: 4. RHR Guidelines for research. http://www.who.int/reproductivehealth/hrp/ ethical_issues.en.html
p.000121: http://www.who.int/reproductive health/hrp/SERG_guidelines.en.html
p.000121: 5. RHR. Guideline for obtaining informed consent for the procurement and use of human tissues, cells and fluids in
p.000121: research. http://www.who.int/reproductive-health/ hrp/SERG_guidelines.en.html
p.000121: 6. TDR Standard operating procedures for clinical investigators. TDR/TDP/ SOP/99.1
p.000121: www.who.int/tdr/publications/publications/sop.htm
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
p.000121: 8. TDR Guidelines for Ethical Clearance & TDR Ethical Clearance Checklist
p.000121: http://www.who.int/tdr/publications/
p.000121: 9. Indigenous peoples & participatory health research. http://www.who.int/ethics/indigenous_peoples/en/
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Political / vulnerable
Searching for indicator vulnerable:
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p.000121:
p.000121:
p.000121: Application
p.000121: Principle 1 is applied through:
p.000121: • design and approval of the protocol;
p.000121: • informed consent;
p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
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p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
p.000121: continue participation in the trial. (See WHO GCP Principle 7: Informed Consent)
p.000121:
p.000121:
p.000121:
p.000121: 22 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is meant by “beneficence” and how is it most directly implemented within GCP?
p.000121: “Beneficence refers to the ethical obligation to maximize benefit and to minimize harm. This principle
p.000121: gives rise to norms requiring that the risks of research be reasonable in the light of the expected benefits, that
p.000121: the research design be sound, and that the investiga- tors be competent both to conduct the research and to safeguard
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p.000121: Belmont Report)
p.000121: Within GCP, the principle of “beneficence” is most directly imple- mented through risk/benefit assessment
p.000121: during design and review (initial review as well as continuing review) of the study protocol. (See also WHO GCP
p.000121: Principles 3: Risk Identification; 4: Benefit-Risk Assess- ment; 8: Continuing Review/Ongoing Benefit-Risk Assessment)
p.000121:
p.000121:
p.000121: What is meant by “justice” and how is it most directly implemented within GCP?
p.000121: “… the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the
p.000121: selection of research sub- jects.” (The Belmont Report)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
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p.000121: 2000, Section 6.2)
p.000121: Follow-Up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, 2000, Section 9)
p.000121: Ethical review of externally sponsored research (CIOMS, Interna- tional Ethical Guidelines, Guideline 3)
p.000121: For clinical investigators, refer to:
p.000121: Communications with the IRB/IEC (ICH E6, Section 4.4) Informed Consent of Trial Subjects (ICH E6, Section 4.8) Safety
p.000121: Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
p.000121: Trial Design (ICH E6, Section 5.4)
p.000121: Notification/Submission to Regulatory Authority(ies) (ICH E6, Sec- tion 5.10)
p.000121: Safety Information (ICH E6, Section 5.16)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 3: Risk Identification
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 7: Informed Consent
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assess- ment
p.000121: Definitions for:
p.000121: Impartial Witness (ICH E6, 1.26) Informed Consent (ICH E6, 1.28)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 25
p.000121:
p.000121: Legally Acceptable Representative (ICH E6, 1.37) Vulnerable Subjects (ICH E6, 1.61)
p.000121: Well-being [of the Trial Subjects] (ICH E6, 1.62)
p.000121: Clinical Trial Protocol and Protocol Amendment(s):
p.000121: Selection and Withdrawal of Subjects (ICH E6, Section 6.5) Ethics (ICH E6, Section 6.12)
p.000121:
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p.000121: 26 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 2: RESEARCH DESCRIBED IN A PROTOCOL
p.000121: Research involving humans should be scientifically justified and described in a clear, detailed protocol.
p.000121: “The experiment should be such as to yield fruitful results ... unpro- curable by other methods or means of
p.000121: study, and not random and unnecessary in nature.” (The Nuremburg Code)
p.000121: “The design and performance of each experimental procedure involv- ing human subjects should be clearly formulated in
p.000121: an experimental protocol.” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 2 is applied through development of a clear, detailed, scien- tifically justified and ethically sound
p.000121: protocol that (1) complies with requirements established by national and local laws and regulations, and (2)
p.000121: undergoes scientific and ethical review prior to implementa- tion.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “scientifically justified”?
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p.000121: new findings on risks and/or benefits that become available as the protocol proceeds.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by spon- sors, investigators, IECs/IRBs, and regulators:
p.000121: The sponsor generally conducts the literature review to ensure that there is sufficient information available to
p.000121: support the proposed clinical trial in the population to be studied and that there is sufficient safety and efficacy
p.000121: data to support human exposure to the product. The sponsor may need to conduct pre-clinical studies to ensure
p.000121:
p.000121:
p.000121: 38 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: there is sufficient safety and efficacy data to support human expo- sure. The sponsor should summarize
p.000121: available information about the procedure/product in the investigator’s brochure, and accord- ingly set forth
p.000121: the design of the study in the protocol. In general, it is important that the sponsor develop a comprehensive, accurate
p.000121: and complete investigator’s brochure, as this is a principal means of com- municating vital safety and scientific
p.000121: information to the investigator and, in turn, to the IEC/IRB.
p.000121: Review of the protocol, investigator’s brochure, and other relevant information enables the IECs/IRBs to
p.000121: (1) determine whether the benefits outweigh the risks, (2) understand the study procedures or other steps that will
p.000121: be taken to minimize risks, and (3) ensure that the informed consent document accurately states the potential risks and
p.000121: benefits in a way that will facilitate comprehension by all study subjects, with particular attention to vulnerable
p.000121: groups.
p.000121: Investigators must be knowledgeable of the protocol, investigator’s brochure and other relevant information regarding
p.000121: potential risks and benefits, and must be able to adequately, accurately and objectively identify the potential risks
p.000121: and benefits to subjects. Investigators may need to do some additional literature search beyond that provided by the
p.000121: sponsor. Investigators should also be thoroughly familiar with the appropriate use of the trial
p.000121: product(s)/procedures and should take the necessary steps to remain aware of all relevant new data on the
p.000121: investigational product, procedure, or method that becomes avail- able during the course of the clinical trial.
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with existing national laws/regulations
p.000121: or internationally accepted standards. This may include prospective review of the pro- tocol, the investigator’s
p.000121: brochure and other relevant information to ensure that risk(s) and benefit(s) are accurately identified and
p.000121: justify allowing the protocol to proceed. As appropriate, adopted national standards should address
p.000121: additional national or regional racial, cul- tural, or religious standards/issues not otherwise covered by
p.000121: the international standards. In accordance with national/local laws and regulations, regulators may establish
p.000121: standards for the conduct of
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 39
p.000121:
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p.000121: “The manner and context in which information is conveyed is as im- portant as the information itself. For example,
p.000121: presenting information in a disorganized and rapid fashion, allowing too little time for consid- eration or curtailing
p.000121: opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.” (The Belmont
p.000121: Report)
p.000121: “Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather,
p.000121: the investigator must convey the information, whether orally or in writing, in language that
p.000121:
p.000121:
p.000121: 64 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: suits the individual’s level of understanding. The investigator must bear in mind that the prospective
p.000121: subject’s ability to understand the information necessary to give informed consent depends on that individual’s
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
...
p.000121: Section 6.2)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: For clinical investigators, refer to: Communication with IRB/IEC (ICH E6, Section 4.4)
p.000121: Informed Consent of Trial Subjects (ICH E6, Section 4.8)
p.000121: For sponsors, refer to:
p.000121: Confirmation of Review by IRB/IEC (ICH E6, Section 5.11) Monitoring (ICH E6, Section 5.18)
p.000121:
p.000121:
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p.000121:
p.000121: 70 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For regulatory authorities, refer to
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 1: Ethical Conduct
p.000121: GCP Principle 4: Benefit-Risk Assessment
p.000121: Definitions for:
p.000121: Informed Consent (ICH E6, 1.28)
p.000121: Legally Acceptable Representative (ICH E6, 1.37) Vulnerable Subjects (ICH E6, 1.61)
p.000121: Well-being (of the trial subjects) (ICH E6, 1.62)
p.000121:
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p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 71
p.000121:
p.000121: PRINCIPLE 8: CONTINUING REVIEW/ONGOING BENEFIT-RISK ASSESSMENT
p.000121: Research involving humans should be continued only if the ben- efit-risk profile remains favourable.
p.000121: “During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any
p.000121: stage, if he has prob- able cause to believe, in the exercise of the good faith, superior skill, and careful
p.000121: judgment required of him that a continuation of the ex- periment is likely to result in injury, disability, or
p.000121: death to the experi- mental subject.” (The Nuremberg Code)
p.000121: “… The ethical review committee should conduct further reviews as necessary in the course of the research,
p.000121: including monitoring of its progress.” (CIOMS, International Ethical Guidelines, Guideline 2)
p.000121: “… The committee has the right to monitor ongoing trials …“ (Decla- ration of Helsinki)
p.000121: “… Clinical trial sponsors should develop a process to assess, evalu- ate and act on safety information during drug
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p.000121: generally recommended for any controlled trial of any size that will compare rates of mortality or major
p.000121: morbidity, but a DSMB is not required or recommended for most clinical stud-
p.000121:
p.000121: 78 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ies. DSMBs are generally not needed, for example, for trials at early stages of product development. They are also
p.000121: generally not needed for trials addressing lesser outcomes, such as relief of symptoms, un- less the trial population
p.000121: is at elevated risk of more severe outcomes.
p.000121: “In most cases of research involving human subjects, it is unneces- sary to appoint a DSMB. To ensure
p.000121: that research is carefully moni- tored for the early detection of adverse events, the sponsor or the
p.000121: principal investigator appoints an individual to be responsible for ad- vising on the need to consider changing the
p.000121: system of monitoring for adverse events or the process of informed consent, or even to con- sider terminating the
p.000121: study.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 11)
p.000121: “… DSMBs are of value in the following situations:
p.000121: • large randomized, multi-center high morbidity/mortality trials;
p.000121: • studies where data could justify early study termination or where the design or executed data accrual is complex;
p.000121: • early studies of a high-risk intervention;
p.000121: • studies carried out in emergency situations in which informed con- sent is waived;
p.000121: • studies involving vulnerable populations; or,
p.000121: • studies in the early phases of a novel intervention with very limited information on clinical safety or where prior
p.000121: information may have raised safety concerns.”
p.000121: (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Appendix 5,
p.000121: Data and Safety Monitoring Boards)
p.000121:
p.000121: Implementation
p.000121: Sponsors, IECs/IRBs, DSMBs (if applicable), and regulators share responsibility for ongoing safety
p.000121: evaluations of the investigational product(s).
p.000121: The investigator reports unanticipated problems involving risks to subjects and provides periodic
p.000121: progress reports at intervals ap-
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 79
p.000121:
p.000121: propriate to the degree of risk to sponsors and IECs/IRBs in accord- ance with the national/local laws and
p.000121: regulations. The investigator provides adequate, accurate, and objective information on risks and benefits during
p.000121: informed consent of study subjects, and renews the consent of the subject to continue in the study, as appropriate.
p.000121: The sponsor monitors the study and performs safety evaluations of the investigational product(s) by
p.000121: analysing data received from the investigator(s) and the DSMB (if one has been appointed). The sponsor
p.000121: also assures reporting (including expedited reporting to investigator(s), IEC(s)/IRB(s), and the regulatory
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Health / Cognitive Impairment
Searching for indicator impairment:
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p.000121: and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the
p.000121: participation of healthy volunteers in medical research.” (Declaration of Helsinki)
p.000121: “For all biomedical research involving human subjects, the inves- tigator must ensure that potential
p.000121: benefits and risks are reason- ably balanced and risks are minimized.” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 8)
p.000121: “It is commonly said that benefits and risks must be ‘balanced’ and shown to be ‘in a favourable ratio.’ … Thus,
p.000121: there should first be a determination of the validity of the presuppositions of the research; then the nature,
p.000121: probability and magnitude of risk should be distin- guished with as much clarity as possible. The method
p.000121: of ascertain- ing risks should be explicit … It should also be determined whether
p.000121: … estimates of the probability of harm or benefits are reasonable, as judged by known facts or other
p.000121: available studies.” (The Belmont Report)
p.000121: “… Risks should be reduced to those necessary to achieve the research objective. It should be
p.000121: determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be
p.000121: entirely eliminated, but it can often be reduced by careful attention to alternative procedures … When research
p.000121: involves significant risk of serious impairment, review committees should be extraordinarily
p.000121:
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p.000121: 42 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: insistent on the justification of the risk (looking usually to the likeli- hood of benefit to the subject –
p.000121: or in some rare cases, to the manifest voluntariness of the participation) … ” (The Belmont Report)
p.000121: “… Scientific review must consider inter alia, the study design, in- cluding the provisions for avoiding or
p.000121: minimizing risk and for monitor- ing safety.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 2)
p.000121: “Risks and benefits of research may affect the individual subjects, the families of the individual subjects,
p.000121: and society at large (or special groups of subjects in society). … In balancing these different ele- ments,
p.000121: the risks and benefits affecting the immediate research sub- ject will normally carry special weight.” (The Belmont
p.000121: Report)
p.000121: “In medical research on human subjects, considerations related to the well-being of the human subject
p.000121: should take precedence over the interests of science and society.” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 4 is applied through appropriate study design and through ethical, scientific, and, where
p.000121: applicable, regulatory review of the study protocol prior to study initiation.
p.000121:
p.000121: Questions and Answers
p.000121: Who is responsible for determining that the risk/benefit profile of a study is acceptable or unacceptable?
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Health / Comatose
Searching for indicator comatose:
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p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
p.000121: How is informed consent documented? Is getting the subject (or the subject’s representative) to sign a consent document
p.000121: all that is necessary? How should the process be documented throughout the study?
...
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p.000121: Before medical products can be introduced onto the market or into public health programmes, they must undergo a series
p.000121: of investiga- tions designed to evaluate safety and efficacy within the parameters of toxicity, potency, dose
p.000121: finding, and field conditions. Full informa- tion must be documented on therapeutic indications, method of
p.000121: administration and dosage, contraindications, warnings, safety measures, precautions, interactions,
p.000121: effects in target populations and safety information.
p.000121: During the clinical research and development process, most medical products will only have been tested for
p.000121: short-term safety and effi- cacy on a limited number of carefully selected individuals. In some cases, as
p.000121: few as 100, and rarely more than 5000 subjects will have received the product prior to its approval for
p.000121: marketing. Given these circumstances and because the decision to allow a new product on the market has such broad
p.000121: public health significance, the clinical trial process and data must conform to rigorous standards to ensure that
p.000121: decisions are based on data of the highest quality and integrity.
p.000121: In the early 1960s, widespread concern about the safety and control of investigational drugs and the clinical research
p.000121: process developed among members of the medical profession, the scientific commu- nity, regulatory
p.000121: authorities, and the general public. In 1968, WHO convened a Scientific Group on Principles for Clinical
p.000121: Evaluation of Drugs. The Scientific Group was charged with reviewing and formu- lating principles for clinical
p.000121: evaluation of drug products, whether new or already marketed, including considerations for new indications or dosage
p.000121: forms for marketed products and new combination products. In 1975, another WHO Scientific Group was convened to
p.000121: specifically consider all aspects of the evaluation and testing of drugs and to for- mulate proposals and guidelines
p.000121: for research in the field of drug de- velopment. These reports formed the basis for WHO’s “Guidelines for good
p.000121: clinical practice (GCP) for trials on pharmaceutical products”, published in 1995, as well as many national and
p.000121: international guide- lines that have subsequently been developed, including:
p.000121:
p.000121:
p.000121: 4 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • International Conference on Harmonization (ICH) E6, “Good Clinical Practice: Consolidated Guideline” (1996)
p.000121: • International Standards Organization (ISO), “Clinical investigation of medical devices for human
p.000121: subjects, Part I (General require- ments) and Part 2 (Clinical investigation plans) (2001)
p.000121: • Pan American Health Organization (PAHO). Pan American Network on Drug Regulatory Harmonization (PANDRH). “Good
p.000121: Clinical Prac- tices: Document of the Americas” (2005)
p.000121: The conduct of clinical research in accordance with the principles of GCP helps to ensure that clinical
p.000121: research participants are not exposed to undue risk, and that data generated from the research are valid
p.000121: and accurate. By providing a basis both for the scientific and ethical integrity of research involving human subjects
p.000121: and for gener- ating valid observations and sound documentation of the findings, GCP not only serves the
p.000121: interests of the parties actively involved in the research process, but also protects the rights, safety
p.000121: and well- being of subjects and ensures that investigations are scientifically sound and advance public health
p.000121: goals.
p.000121:
p.000121: Objectives of this handbook
p.000121: The objectives of this current WHO Handbook for GCP include the fol- lowing:
p.000121: • to support and promote the achievement of a globally applicable unified standard for the conduct of all
p.000121: clinical research studies on human subjects;
p.000121: • to provide an overview and practical advice on the application and implementation of internationally accepted
p.000121: principles for GCP and clinical research in human subjects;
p.000121: • to provide an educational and reference tool for anyone interested in, or intending to become or already actively
p.000121: engaged in, clinical research by providing the necessary background and insight into the reasons for the
p.000121: requirements of GCP and their efficient appli- cation;
p.000121:
p.000121:
p.000121: INTRODUCTION | 5
p.000121:
p.000121: • to assist editors in evaluating the acceptability of reported research for publication, and regulators in
p.000121: evaluating the acceptability of any study that could affect the use or the terms of registration of a medical
p.000121: product.
p.000121: This handbook can be adopted or referenced by WHO Member States. Where national regulations or
p.000121: requirements do not exist or require supplementation, relevant regulatory authorities may desig- nate or
p.000121: adopt these GCP principles and standards. Where national or adopted international standards are more demanding than WHO
p.000121: GCP, the former should take precedence.
p.000121: Guidance on various aspects of clinical research is also available from several other national and international bodies
p.000121: such as, the Interna- tional Conference on Harmonization (ICH), the International Stand- ards Organization
p.000121: (ISO), the Council for International Organizations of Medical Sciences (CIOMS), the European Agency for the
p.000121: Evaluation of Medicinal Products (EMEA), and the United States Food and Drug Administration (FDA). (See References)
p.000121:
p.000121: Scope of this handbook
p.000121: This handbook defines fourteen principles of GCP, and provides guid- ance and assistance in the application and
p.000121: implementation of these principles by all parties involved in the clinical research process. In describing
p.000121: each principle, the handbook articulates the research processes and systems that need to be in place,
p.000121: and within these, the roles and responsibilities of various stakeholders (notably spon- sors, investigators, ethics
p.000121: committees, and regulatory authorities) involved in the conduct of health and clinical research studies.
p.000121: To the extent possible, the principles of GCP should generally apply to all clinical research involving human subjects,
p.000121: and not just research involving pharmaceutical or other medical products. Included here are:
p.000121: • studies of a physiological, biochemical, or pathological process, or of the response to a specific
p.000121: intervention – whether physical, chemical, or psychological – in healthy subjects or in patients;
p.000121:
p.000121:
p.000121: 6 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • controlled studies of diagnostic, preventive or therapeutic meas- ures, designed to demonstrate a
p.000121: specific generalizable response to these measures against a background of individual biological variation;
p.000121: • studies designed to determine the consequences for individuals and communities of specific preventive or
p.000121: therapeutic measures;
p.000121: • studies concerning human health-related behaviour in a variety of circumstances and environments;
...
p.000121: addressed in the protocol. These may include but are not limited to: communicating with the IEC/IRB;
p.000121: obtaining and updating informed consent; reporting adverse events; preparing and maintaining adequate records;
p.000121: administering the investigational product; and accounting for and disposing of the investigational product.
p.000121: IECs/IRBs should develop and follow written procedures for their operations, including but not limited to:
p.000121: membership requirements; initial and continuing review; communicating with the investigator(s) and institution; and
p.000121: minimizing or eliminating conflicts of interest.
p.000121:
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 9
p.000121:
p.000121: Regulators should consider developing written procedures for ac- tivities pertaining to the regulation of
p.000121: clinical research. These may include but are not limited to: reviewing applications and safety reports;
p.000121: conducting GCP inspections (where applicable) and com- municating findings to the inspected parties; and
p.000121: establishing an in- frastructure for due process and imposing sanctions on parties who violate national/local law or
p.000121: regulations.
p.000121:
p.000121: 3. Development of support systems and tools
p.000121: Appropriate support systems and tools facilitate the conduct of the study and collection of data required
p.000121: by the protocol. Support systems and tools include, but are not limited to, trial-related infor- mation
p.000121: documents (e.g. investigator’s brochure, case report forms [CRFs], checklists, study flow sheets, drug
p.000121: accountability logs; see Overview Process 4: Generation and approval of trial-related infor- mation documents),
p.000121: computer hardware and software, electronic patient diaries, and other specialized equipment.
p.000121: See WHO GCP Principles 2: Protocol; 11: Records; 14: Quality Systems.
p.000121: The sponsor is generally responsible for developing, maintaining, modifying, and ensuring the availability of
p.000121: support systems and tools for conducting the trial and collecting and reporting required data.
p.000121: For example, the sponsor may consider developing/designing/providing/ designating:
p.000121: • diagnostic or laboratory equipment required by the study protocol, and procedures/schedules for servicing the
p.000121: equipment according to the manufacturer’s specifications;
p.000121: • computer systems (hardware and software) to be used in the clinical trial (e.g. statistical or other
p.000121: software, electronic patient diaries, coding of personal data), and software validation systems, as needed;
p.000121: • facsimile or other communications equipment to facilitate report- ing of serious adverse events;
p.000121: • information and training tools for clinical investigators and site per- sonnel.
p.000121:
p.000121:
p.000121: 10 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 4. Generation and approval of trial-related documents
p.000121: Development of trial-related documents may facilitate the conduct of the study, collection and reporting
p.000121: of study-related data, and analysis of study results.
p.000121: The sponsor generally develops, designs, and provides various stand- ardized forms and checklists to assist the
...
p.000121: • description of the trial design;
p.000121: • criteria for inclusion, exclusion, and withdrawal of study subjects;
p.000121: • treatment information;
p.000121: • methods and timing for assessing, recording and analysing data gathered on the investigational product;
p.000121: • methods for obtaining safety information, including plans for safe- ty monitoring;
p.000121: • description of the statistical methods to be employed;
p.000121: • description of ethical considerations relating to the trial;
p.000121: • a statement related to permitting trial-related monitoring, audits, and inspection by the sponsor,
p.000121: IEC/IRB, and regulators, including direct access to source data/documents;
p.000121:
p.000121:
p.000121:
p.000121: 28 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • means for obtaining informed consent and communication of in- formation to prospective subjects.
p.000121:
p.000121:
p.000121: What is a “protocol amendment”?
p.000121: “A protocol amendment is a written description of a change(s) to or formal clarification of a protocol.” (ICH E6,
p.000121: Section 1.45)
p.000121:
p.000121:
p.000121: What types of changes may require formal amendment of the protocol?
p.000121: Regional,1 national, or local laws and regulations may require spon- sors to prepare formal protocol
p.000121: amendments to describe any change that significantly affects the safety of subjects, the scope of the in-
p.000121: vestigation, or the scientific quality of the study.
p.000121: Examples of changes that generally require formal amendment in- clude, but are not limited to:
p.000121: • changes in drug dosage or duration of exposure of individual sub- jects to an investigational product beyond
p.000121: that described in the current protocol;
p.000121: • significant increase in the number of subjects under study or in the duration of the study;
p.000121: • significant change in the study design, such as adding or dropping a study arm; and
p.000121: • addition of a new test or procedure that is intended to improve monitoring for or reduce the risk of a
p.000121: side effect or adverse event, or the dropping of a test intended to monitor safety.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 1 In this document, “regional” refers to supranational laws, regulations, or require- ments, such as those
p.000121: adopted by the European Union.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 29
p.000121:
p.000121: What is the “investigator’s brochure” and how does it relate to the protocol?
p.000121: The investigator’s brochure is a “compilation of the clinical and non- clinical data on the investigational
p.000121: product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6, 1.36)
p.000121: In general, the investigator’s brochure provides more complete back- ground information on the investigational
p.000121: product than is provided in the protocol. The investigator’s brochure assists the investigator in
p.000121: interpreting and implementing the study protocol, and may be of particular importance in helping the
p.000121: investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such
p.000121: events should be reported to the sponsor, IEC/IRB, and regulators.
p.000121:
...
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 31
p.000121:
p.000121: What is meant by “randomization”?
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
p.000121: another method, such as historical or literature controls, can be justified scientifically and ethi- cally. Assignment
p.000121: to treatment arms by randomization, in addition to its usual scientific superiority, offers the advantage
p.000121: of tending to render equivalent to all subjects the foreseeable benefits and risks of participation in a
p.000121: trial.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121: “The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken
p.000121: only in accordance with the protocol.” (ICH E6, Section 4.7)
p.000121:
p.000121:
p.000121: How should the protocol address reporting of adverse events?
p.000121: The protocol should specify procedures for eliciting reports of, and for recording and reporting, adverse
p.000121: event and inter-current illness- es; the type and duration of the follow-up of subjects after adverse events; and the
p.000121: methods to be used in, and timing for, assessing, recording, and analysing safety parameters.
p.000121: The protocol and investigator’s brochure will assist the investigator and sponsor in determining whether an
p.000121: adverse event is “unexpect- ed” and how it should be reported. Unexpected serious adverse drug reactions should be
p.000121: reported to the regulatory authority(ies) and to other investigators involved in the trial in accordance with
p.000121: applicable regulatory requirement(s).
p.000121:
p.000121: Implementation
p.000121: Sponsors are primarily responsible for (1) designing the clinical investigation, (2) developing the
p.000121: study protocol, investigator’s bro- chure, and related materials to describe the procedures that will be followed,
p.000121: study endpoints, data collection, and other study require-
p.000121:
p.000121: 32 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ments; and (3) ensuring that the protocol complies with applicable national and local laws and regulations.
p.000121: Investigators may be consulted by the sponsor during protocol de- sign or, in some cases, may personally contribute to
p.000121: the design of the protocol. Investigators are responsible for familiarizing themselves with the study protocol,
p.000121: investigator’s brochure, and related materi- als to ensure that they are able to carry out the study in compliance with
p.000121: the specifications of the protocol.
p.000121: IECs/IRBs are responsible for conducting ethical review of the study protocol. This also includes arranging for a
p.000121: scientific review or verify- ing that a competent body has determined that the research is scien- tifically sound. (See
p.000121: WHO GCP Principle 5: Review by IEC/IRB)
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with applicable laws and
p.000121: regulations. This may include prospective review of the protocol, the investigator’s brochure and other
...
p.000121: Well-being (of the trial subjects) (ICH E6, 1.62)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 71
p.000121:
p.000121: PRINCIPLE 8: CONTINUING REVIEW/ONGOING BENEFIT-RISK ASSESSMENT
p.000121: Research involving humans should be continued only if the ben- efit-risk profile remains favourable.
p.000121: “During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any
p.000121: stage, if he has prob- able cause to believe, in the exercise of the good faith, superior skill, and careful
p.000121: judgment required of him that a continuation of the ex- periment is likely to result in injury, disability, or
p.000121: death to the experi- mental subject.” (The Nuremberg Code)
p.000121: “… The ethical review committee should conduct further reviews as necessary in the course of the research,
p.000121: including monitoring of its progress.” (CIOMS, International Ethical Guidelines, Guideline 2)
p.000121: “… The committee has the right to monitor ongoing trials …“ (Decla- ration of Helsinki)
p.000121: “… Clinical trial sponsors should develop a process to assess, evalu- ate and act on safety information during drug
p.000121: development on a con- tinuous basis in order to ensure the earliest possible identification of safety concerns and to
p.000121: take appropriate risk minimization steps. Such steps can include modification of study protocols, to
p.000121: incorporate strategies to ensure that clinical trial participants are not exposed to undue risk.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Identification and Evaluation of Risk from
p.000121: Clinical Trial Data)
p.000121:
p.000121: Application
p.000121: Principle 8 is applied through development and implementation of processes for evaluating risks and
p.000121: benefits of the research as ad- ditional information becomes available during the course of the
p.000121: study. Principle 8 encompasses (1) safety monitoring of the study by investigator(s) and sponsor
p.000121: (including use of a data and safety monitoring board [DSMB], where appropriate); (2) reporting serious
p.000121: unexpected adverse events or other unanticipated risks to the spon- sor, IEC/IRB, and regulators; (3) review by
p.000121: the IEC/IRB of any unan-
p.000121:
p.000121:
p.000121: 72 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ticipated risks as they occur, or at scheduled intervals appropriate to the degree of risk; (4) revising the
p.000121: protocol, investigator’s brochure, and/or informed consent document as needed, and suspending or terminating
...
p.000121: Sponsors may also identify unanticipated risks to subjects in the course of study monitoring or from planned
p.000121: interim data analy- ses.
p.000121: “The frequent review of serious and special interest adverse events, as well as overall assessment of all AEs,
p.000121: regardless of seriousness, causality, or expectedness, should be performed periodically: (1) ad hoc, for serious and
p.000121: special interest AEs, (2) routine, periodic general review of all data, whose frequency will vary from trial
p.000121: to trial and from development program to development program and depend on many factors, and (3) reviews triggered by
p.000121: specific milestones estab- lished for a trial or a program (e.g. numbers of completed patients,
p.000121: end-of-trial, end-of program, preparation of integrated summary of safety, and a marketing application.”
p.000121: (Management of Safety Informa- tion from Clinical Trials, Report of CIOMS Working Group VI. Frequen- cy of Review of
p.000121: Safety Information)
p.000121:
p.000121:
p.000121: How should serious unexpected adverse events (SAEs) be reported and to whom?
p.000121: “All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the
p.000121: protocol or other docu- ment (e.g. investigator’s brochure) identifies as not needing immedi- ate reporting. The
p.000121: immediate reports should be followed promptly
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 73
p.000121:
p.000121: by detailed written reports. … The investigator should also comply with the applicable regulatory
p.000121: requirement(s) related to the report- ing of unexpected serious adverse drug reactions to the regulatory
p.000121: authority(ies) and the IRB/IEC.” (ICH E6, Section 4.11)
p.000121: “In addition to the usual criteria for an expedited report, adverse events that are not deemed to be
p.000121: drug-related but are considered to be protocol related should also be reported in an expedited fashion if they are
p.000121: serious.” (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory
p.000121: Reporting and other Communication of Safety Information from Clinical rials)
p.000121:
p.000121:
p.000121: Who is responsible for reviewing the benefit-risk profile of the investigational product(s) while the study is
p.000121: proceeding?
p.000121: Within GCP, the sponsor has primary responsibility for the ongo- ing safety evaluation of the
p.000121: investigational product(s) and should promptly notify all concerned investigator(s), institution(s), and the
p.000121: regulatory authority(ies) of information that could adversely affect the safety of subjects, the conduct
p.000121: of the trial, or alter the IEC/IRB approval/favourable opinion to continue the trial. Such reviews may be
p.000121: performed by the sponsor’s staff (e.g. physicians, statisticians) or by an independent data and safety monitoring board
p.000121: (DSMB), if one is established (see below).
p.000121: The IEC/IRB is also responsible for “… following the progress of all studies for which a positive decision
p.000121: has been reached, from the time the decision was taken until the termination of the research.” (See
p.000121: “Follow-up”, Section 9, WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research)
p.000121:
p.000121:
p.000121: How are follow-up reviews carried out?
p.000121: Sponsors generally monitor trials to ensure that (1) the study is being conducted according to the approved
...
p.000121: outweigh the risks.
p.000121: The regulatory authority reviews data submitted in research or marketing permits and may require
p.000121: modification to a protocol as a condition to its proceeding and/or may suspend or terminate a proto- col based on
p.000121: an unacceptable benefit-risk profile in accordance with applicable laws and regulations.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: For clinical investigators, refer to: Progress Reports (ICH E6, Section 4.10) Safety Reporting (ICH E6, Section 4.11)
p.000121: Premature Termination or Suspension of a Trial (ICH E6, Section 4.12) Clinical Trial Protocol and Protocol
p.000121: Amendment(s), General Infor-
p.000121: mation (ICH E6, Section 6)
p.000121:
p.000121: 80 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Investigator’s Brochure (ICH E6, Section 7)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Notification/Submission to Regulatory Authorities (ICH E6, Section 5.10)
p.000121: Adverse Drug Reaction Reporting (ICH E6, Section 5.17) Monitoring (ICH E6, Section 5.18)
p.000121: Premature Termination or Suspension of a Trial (ICH E6, Section 5.21)
p.000121: Clinical Trial Protocol, General Information (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: For regulators, refer to:
p.000121: Surveying and Evaluating Ethical Review Practices, a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees that Review Biomedical Research, WHO, 2002
p.000121: See also:
p.000121: The Council for International Organizations of Medical Sciences (CIOMS) Management of Safety Information from
p.000121: Clinical Trials: Report of CIOMS Working Group VI, Geneva, 2005
p.000121: Discussion of the WHO Principles of GCP GCP Principle 4: Benefit-Risk Assessment GCP Principle 5: Review by IEC/IRB
p.000121: Definitions for:
p.000121: Adverse Drug Reaction (ADR) (ICH E6, 1.1) Adverse Event (AE) (ICH E6, 1.2)
p.000121: Approval (in relation to Institutional Review Boards) (ICH E6, 1.5) Independent Data Monitoring Committee (IDMC) (Data
p.000121: and Safety
p.000121: Monitoring Board, Monitoring Committee, Data Monitoring Committee) (ICH E6, 1.25)
p.000121: Independent Ethics Committee (IEC) (ICH E6, 1.27) Informed Consent (ICH E6, 1.28)
p.000121: Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Se- rious ADR) (ICH E6, 1.50)
p.000121: Unexpected Adverse Drug Reaction (ICH E6, 1.60)
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 81
p.000121:
p.000121: PRINCIPLE 9: INVESTIGATOR QUALIFICATIONS
p.000121: Qualified and duly licensed medical personnel (i.e. physician or, when appropriate, dentist) should be responsible for
p.000121: the medi- cal care of research subjects, and for any medical decision(s) made on their behalf.
p.000121: ”The experiment should be conducted only by scientifically quali- fied persons. The highest degree of skill and
p.000121: care should be required through all stages of the experiment of those who conduct or engage in the experiment.” (The
p.000121: Nuremberg Code)
p.000121: “Medical research involving human subjects should be conducted only by scientifically qualified persons and
p.000121: under the supervision of a clinically competent medical person …” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 9 is applied through the responsibilities of the clinical inves- tigator to the study subject and
p.000121: through the sponsor’s selection of qualified investigator(s). (See also WHO GCP Principle 10: Staff Quali-
p.000121: fications)
p.000121:
p.000121: Questions and Answers
p.000121: Where may information about a clinical investigator’s qualifications be obtained?
p.000121: The investigator’s curriculum vitae or other statement of education, training and experience may provide initial
p.000121: information about the investigator’s qualifications to provide medical care and to conduct clinical
p.000121: research. Other sources of information about an investiga- tor’s qualifications may include medical
...
p.000121: The sponsor
p.000121: • “… should utilize appropriately qualified individuals” [e.g. biostat- isticians, clinical pharmacologists
p.000121: and physicians, as appropriate] “to supervise the overall conduct of the trial, to handle the data, to verify the
p.000121: data, to conduct the statistical analyses, and to prepare the trial reports.” (ICH E6, Section 5.5)
p.000121: • should include in the study protocol a “… description of the sta- tistical methods to be employed,
p.000121: including timing of any planned interim analysis(ses), … the level of significance to be used, …
p.000121: procedure for accounting for missing, unused, and spurious data, procedures for reporting any deviations from the
p.000121: original statistical plan… selection of subjects to be included in the analyses … ” (ICH E6, Section 6.9)
p.000121:
p.000121:
p.000121: How should clinical trial results be publicly reported?
p.000121: “Both authors and publishers have ethical obligations. In publication of the results of research, the
p.000121: investigators are obliged to preserve the accuracy of the results. Negative as well as positive results
p.000121: should be published or otherwise publicly available. … Reports of experimentation not in accordance with
p.000121: the principles laid down in this Declaration should not be accepted for publication.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121: 98 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: The study protocol may include:
p.000121: • “[i]n the case of a negative outcome, an assurance that the results will be made available, as appropriate,
p.000121: through publication or by reporting to the drug registration authority.” (CIOMS, International Ethical Guidelines,
p.000121: Appendix 1)
p.000121: • “[c]ircumstances in which it might be considered inappropriate to publish findings, such as when the findings of an
p.000121: epidemiological, sociological or genetics study may present risks to the interests of a community or
p.000121: population or of a racially or ethnically defined group of people.” (CIOMS, International Ethical Guidelines, Appen-
p.000121: dix 1)
p.000121:
p.000121:
p.000121: Who should have access to clinical trial records?
p.000121: Sponsors, monitors, IECs/IRBs, and regulators generally require direct access to all information
p.000121: pertaining to the conduct and over- sight of the clinical trial. Direct access means that these parties have
p.000121: “[p]ermission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation
p.000121: of a clinical trial.” (ICH E6, 1.21)
p.000121: “Any or all of the documents addressed in this guidance may be sub- ject to, and should be available for, audit by the
p.000121: sponsor’s auditor and inspection by the regulatory authority(ies).” (ICH E6, Section 8)
p.000121: Note that consent forms should inform study subjects “[t]hat the monitor(s), the auditor(s), the
p.000121: IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s
...
p.000121: access.” (ICH E6, 4.8) (See also WHO GCP Principle 7: Informed Consent)
p.000121: In addition, sponsors, monitors, investigators and regulators should be aware of the need to handle clinical
p.000121: trial information in a manner
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 99
p.000121:
p.000121: that protects the privacy and confidentiality of research subjects. These parties should also be fully informed
p.000121: about national/local laws/ regulations related to privacy and confidentiality. (See also WHO GCP Principle 12:
p.000121: Confidentiality/Privacy)
p.000121:
p.000121: Implementation
p.000121: IECs/IRBs, investigators, sponsors, and regulators all bear respon- sibility for documenting their
p.000121: activities within GCP, and maintaining records pertaining to duties related to the conduct or oversight
p.000121: of the clinical trial for the time required under national or local law and regulations. All parties are
p.000121: responsible for ensuring the accuracy, completeness, legibility and availability (as necessary) of such docu-
p.000121: ments.
p.000121: IECs/IRBs document their reviews of study protocols and informed consent/recruitment/advertising materials
p.000121: through minutes that capture the IECs’/IRBs’ deliberations and through copies of corre- spondence with the
p.000121: clinical investigator.
p.000121: Investigators prepare and maintain case histories that record all ob- servations and other data pertinent to the
p.000121: investigation on each indi- vidual administered the investigational drug or employed as a control in the investigation.
p.000121: Sponsors ensure that study protocols address appropriate data handling and record-keeping requirements and
p.000121: design CRFs appro- priately to facilitate the capture of all significant trial-related data and observations.
p.000121: Sponsors also secure the services of monitors to en- sure compliance of the clinical investigators, and verify
p.000121: that the study was carried out according to the approved study protocol.
p.000121: Regulators rely on clinical trial information to support regulatory decision-making and may inspect all of
p.000121: the parties involved in con- ducting or overseeing research. Critical to regulatory inspection is direct
p.000121: access to and review of existing clinical trial records. As part of an inspection, regulators compare records at the
p.000121: clinical investigator site and sponsor site with data and reports submitted to the regula- tory authority to verify
p.000121: the information submitted. Regulators also prepare and maintain records of their inspections and findings.
p.000121:
p.000121: 100 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3) Records (ICH E6,
p.000121: Section 3.4)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: Documentation and Archiving (WHO Operational Guidelines for Ethics Committees that Review Biomedical
p.000121: Research, Section 10)
p.000121: For investigators, refer to:
p.000121: Communication with IRB/IEC (ICH E6, Section 4.4) Compliance with Protocol (ICH E6, Section 4.5) Records and Reports
p.000121: (ICH E6, Section 4.9) Progress Reports (ICH E6, Section 4.10)
p.000121: Safety Reporting (ICH E6, Section 4.11)
p.000121: Final Report(s) by Investigator/Institution (ICH E6, Section 4.13) Clinical Trial Protocol, General Information (ICH
p.000121: E6, Section 6) Essential Documents for the Conduct of a Clinical Trial (ICH E6,
p.000121: Section 8)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Record Access (ICH E6, Section 5.15)
p.000121: Adverse Drug Reaction Reporting (ICH E6, Section 5.17) Monitoring (ICH E6, Section 5.18)
p.000121: Audit (ICH E6, Section 5.19)
p.000121: Clinical Trial/Study Reports (ICH E6, Section 5.22) Clinical Trial Protocol (ICH E6, Section 6)
p.000121: Essential Documents for the Conduct of a Clinical Trial (ICH E6, Section 8)
p.000121: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2A)
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 101
p.000121:
p.000121: Guidance on Data Elements for Transmission of Individual Case Safety Reports (ICH E2B)
p.000121: Statistical Principles for Clinical Trials (ICH E9)
p.000121: For regulatory authorities, refer to:
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: GCP Compliance Monitoring Programs by Regulatory Authorities (Chapter 7, Good Clinical Practices: Document of the
p.000121: Americas, PAHO)
p.000121: Surveying and Evaluating Ethical Review Practices (WHO Opera- tional Guidelines)
p.000121: Statistical Principles for Clinical Trials (ICH E9)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 6: Protocol Compliance GCP Principle 7: Informed Consent
p.000121: GCP Principle 12: Confidentiality/Privacy GCP Principle 14: Quality Systems
p.000121: Definitions for:
p.000121: Case Report Form (ICH E6, 1.11) Clinical Trial/Study Report (ICH E6, 1.13)
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Direct Access (ICH E6, 1.21)
p.000121: Documentation (ICH E6, 1.22) Essential Documents (ICH E6, 1.23)
p.000121: Interim Clinical Trial/Study Report (ICH E6, 1.32) Monitoring (ICH E6, 1.38)
...
p.000121: • coding or encryption of data;
p.000121: • restricting access to study records and subjects’ medical files (e.g. passwords on electronic files, files
p.000121: secured in locked cabinets or secured storage areas);
p.000121: • maintaining subjects’ names and identifying information separate- ly from case report forms;
p.000121: • establishing and following procedures to ensure subjects’ private information and trial data are protected.
p.000121:
p.000121:
p.000121: Why should potential risks related to release of private information be disclosed to study subjects?
p.000121: Each subject needs to consider whether risks related to release of private information are sufficiently
p.000121: controlled, such that he/she is still willing to participate in the investigation.
p.000121: “Research relating to individuals and groups may involve the col- lection and storage of information
p.000121: that, if disclosed to third parties, could cause harm or distress.” (CIOMS, International Ethical Guide-
p.000121: lines, Commentary to Guideline 18)
p.000121: “Prospective subjects should be informed of limits to the ability of investigators to ensure strict
p.000121: confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality. Some
p.000121: jurisdictions require the reporting to appropriate agencies of, for instance, certain communicable diseases or
p.000121: evidence of child abuse or neglect. Drug regulatory authorities have the right to inspect clini-
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 105
p.000121:
p.000121: cal-trial records, and a sponsor’s clinical-compliance audit staff may require and obtain access to confidential
p.000121: data. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
p.000121: the precautions that will be taken to protect confidentiality.” (CIOMS, International Ethical Guidelines, Commentary
p.000121: to Guideline 18)
...
p.000121: Monitoring (ICH E6, 1.38) Monitoring Report (ICH E6, 1.39)
p.000121: Quality Assurance (QA) (ICH E6, 1.46) Quality Control (QC) (ICH E6, 1.47)
p.000121: Standard Operating Procedures (SOPs) (ICH E6, 1.55)
p.000121:
p.000121:
p.000121:
p.000121: 120 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: References
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: Documents on the CD
p.000121: 1. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Annex 3 of The Use of Essential
p.000121: Drugs Sixth report of the WHO Expert Committee. Geneva. World Health Organization, 1995: 97–137.
p.000121: http://www.who.int/medicines/en/
p.000121: 2. ICH E6: Good Clinical Practice: Consolidated Guideline 1996. http://www. ich.org/
p.000121: 3. Operational guidelines for ethics committees that review biomedical re- search. TDR/PRD/ETHICS/2000.1 (2000).
p.000121: http://www.who.int/tdr/
p.000121: 4. Surveying and evaluating ethical review practices: A complementary guideline to the Operational guidelines
p.000121: for ethics committees that review biomedical research. TDR/PRD/ETHICS/2002.1 (2002). http://www.who.int/tdr/
p.000121: 5. Operational Guidelines for the Establishment and Functioning of Data & Safety Monitoring Boards. UNICEF/UNDP/WHO
p.000121: Special Programme on Re- search and Training in Tropical Diseases (TDR) 2005. In press.
p.000121: 6. Good Clinical Practices: Document of the Americas. Working Group on good clinical practices (GCP) Chapter 7 and
p.000121: Annex 4. Pan American Health Organization. Pan American Network on Drug Regulatory Harmonization (PANDRH).
p.000121: 7. International Ethical Guidelines for Biomedical Research Involving Human Subjects. CIOMS, Geneva, 2002.
p.000121: http://www.cioms.ch/
p.000121: 8. World Medical Association. Declaration of Helsinki. 2004 http://www.wma. net/e/policy/pdf/17c.pdf
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: | 121
p.000121:
p.000121: Other documents cited in the Handbook
p.000121: 1. WHO Expert Committee on Specifications for Pharmaceutical Preparations
p.000121: – WHO Technical Report Series, No. 902 – Thirty-sixth Report (WHO; 2002; 219 pages): 5. Quality assurance – good
p.000121: manufacturing practices. http://www.who.int/medicines/en/
p.000121: 2. Handbook: Good laboratory practice: Quality practices for regulated non- clinical research and development.
p.000121: TDR/PRD/GLP/01.2 (2001). http://www.who.int/tdr/
p.000121: 3. CIOMS Working Group Report. Pharmacogenetics: Towards improving treatment with medicines. Geneva 2005.
p.000121: http://www.cioms.ch/
p.000121: 4. CIOMS Working Group Report. Management of Safety Information from Clinical Trials. Geneva 2005.
p.000121: http://www.cioms.ch/
p.000121: 5. The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The
p.000121: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. April 18, 1979.
p.000121: http://www.nihtraining.com/ohsrsite/guidelines/belmont.html
p.000121: 6. The ENGAGE Guideline for Good Clinical Practice Compliance and Quality Systems Auditing. 21.08.1997. ENGAGE
p.000121: European Network of GCP Auditors and other GCP Experts. (in process of revision).
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p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
p.000121: continue participation in the trial. (See WHO GCP Principle 7: Informed Consent)
p.000121:
p.000121:
p.000121:
p.000121: 22 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is meant by “beneficence” and how is it most directly implemented within GCP?
...
p.000121: study (see also WHO GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment).
p.000121:
p.000121:
p.000121: What if the risk-benefit profile of a study appears favourable from a national, societal, institutional, or scientific
p.000121: standpoint but unfavourable to the participating research subjects?
p.000121: The most important considerations in a study are those related to the rights, safety, and well-being of the
p.000121: research subjects. “In medical research on human subjects, considerations related to the well-being of the human
p.000121: subject should take precedence over the interests of science and society.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121: What about financial reimbursements to research subjects?
p.000121: Financial reimbursements to subjects are distinct from any benefits contributing to the risk-benefit analysis.
p.000121: Where applicable laws and regulations allow, financial reimburse- ments may be provided to subjects for
p.000121: participation in a study. Where no requirements exist, fair compensation should be provided in an appropriate
p.000121: manner after consultation with the relevant institutions/ organizations. Such reimbursements are generally viewed as
p.000121: part of the recruitment process rather than as benefits of the study. How- ever, at the time of initial
p.000121: review, the IEC(s)/IRB(s) should review both the amount of the financial reimbursement(s) and the proposed method
p.000121: and timing of disbursement to assure that neither are co- ercive or present undue influence. The
p.000121: reimbursements provided should not be so large as to unduly induce subjects to enroll in the
p.000121:
p.000121:
p.000121: 44 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: study or to stay in the study when they would otherwise withdraw. Any credit for payment should accrue as the
p.000121: study progresses and not be contingent upon the subject completing the entire study. The reimbursements should not
p.000121: replace adequate insurance to be pro- vided by the sponsor against claims for any trial-related injuries.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by spon- sors, investigators, IECs/IRBs, and regulators.
p.000121: The sponsor should design research studies to ensure that risks to subjects are minimized.
p.000121: The investigator(s) should review the investigator’s brochure and other relevant risk and benefit
p.000121: information in making a decision to conduct the study. The investigator is also responsible for providing
p.000121: adequate, accurate, and objective information on risks and benefits during informed consent of study subjects.
p.000121: Prior to study initiation, the IECs/IRBs should review the protocol, investigator’s brochure, and other
p.000121: relevant information to (1) un- derstand the study procedures or other steps that will be taken to
p.000121: minimize risks, (2) understand the potential benefits (if any) and de- termine whether those benefits outweigh the
p.000121: anticipated risks, and
p.000121: (3) ensure that the informed consent document accurately states the potential risks and benefits in a way that will
...
p.000121: GCP Principle 3: Risk Identification GCP Principle 7: Informed Consent
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assess- ment
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 46 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Definitions for:
p.000121: Applicable Regulatory Requirement(s) (ICH E6, 1.4)
p.000121: Approval (in relation to institutional review boards [IRBs]) (ICH E6, 1.5)
p.000121: Informed Consent (ICH E6, 1.28) Investigator’s Brochure (ICH E6, 1.36)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 47
p.000121:
p.000121: PRINCIPLE 5: REVIEW BY IEC/IRB
p.000121: Research involving humans should receive independent eth- ics committee/institutional review board
p.000121: (IEC/IRB) approval/ favourable opinion prior to initiation.
p.000121: The “… protocol should be submitted for consideration, comment, guidance, and where appropriate, approval
p.000121: to a specially appointed ethical review committee, which must be independent of the in- vestigator, the
p.000121: sponsor, or any other kind of undue influence. This independent committee should be in conformity with
p.000121: the laws and regulations of the country in which the research experiment is per- formed …” (Declaration of
p.000121: Helsinki)
p.000121: “Failure to submit a protocol to the committee should be considered a clear and serious violation of ethical
p.000121: standards.” (CIOMS, Interna- tional Ethical Guidelines, Commentary to Guideline 2)
p.000121:
p.000121: Application
p.000121: Principle 5 is applied through protocol review by an IEC/IRB that is constituted and operating in
p.000121: accordance with GCP and applicable national/local laws and regulations.
p.000121:
p.000121: Questions and Answers
p.000121: What is the objective of obtaining IEC/IRB review of the protocol?
p.000121: It is the IEC/IRB “… whose responsibility it is to ensure the protection of the rights, safety, and well-being of human
p.000121: subjects involved in a trial and to provide public assurance of that protection, by, among other things,
p.000121: reviewing and approving/providing favourable opinion on the trial protocol …“ (ICH E6, 1.27)
p.000121: The principal focus of the IEC/IRB is ethical review of the protocol. However, “… [s]cientific review
p.000121: and ethical review cannot be sepa- rated: scientifically unsound research involving humans as subjects is
p.000121: ipso facto unethical in that it may expose them to risk or incon- venience to no purpose; even if there is
p.000121: no risk of injury, wasting of
p.000121:
p.000121:
p.000121: 48 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
...
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 59
p.000121:
p.000121: Application
p.000121: Principle 7 is applied through a process of informing and ensuring comprehension by study subjects
p.000121: (and/or their legally authorized representatives) about the research and obtaining their consent, in- cluding
p.000121: appropriate written informed consent.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “freely given” consent or “voluntary” participation in an investigation? How is this implemented
p.000121: within GCP?
p.000121: “Informed consent is based on the principle that competent individu- als are entitled to choose freely whether
p.000121: to participate in research. Informed consent protects the individual’s freedom of choice and respects the
p.000121: individual’s autonomy.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: “An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of
p.000121: informed consent requires conditions free of coercion and undue influence.” (The Belmont Re- port)
p.000121: “Unjustifiable pressures usually occur when persons in positions of authority or commanding influence –
p.000121: especially where possible sanctions are involved – urge a course of action for a subject. … [U]ndue
p.000121: influence would include actions such as manipulating a per- son’s choice through the controlling influence of a close
p.000121: relative and threatening to withdraw health services to which an individual would otherwise be entitled.” (The Belmont
p.000121: Report)
p.000121: “The quality of the consent of prospective subjects who are junior or subordinate members of a hierarchical group
p.000121: requires careful consid- eration, as their agreement to volunteer may be unduly influenced, whether justified
p.000121: or not, by the expectation of preferential treatment if they agree or by fear of disapproval or retaliation
p.000121: if they refuse.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 13)
p.000121:
p.000121:
p.000121:
p.000121: 60 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: “… The researcher should give no unjustifiable assurances about the benefits, risks or inconveniences of
p.000121: the research, for example, or induce a close relative or a community leader to influence a pro- spective subject’s
p.000121: decision.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 6)
p.000121:
p.000121:
p.000121: What is meant by “in accordance with national culture(s) and requirements”?
p.000121: “In some cultures, an investigator may enter a community to con- duct research or approach prospective
p.000121: subjects for their individual consent only after obtaining permission from a community leader, a council
p.000121: of elders, or another designated authority. Such customs must be respected. In no case, however, may the
p.000121: permission of a community leader or other authority substitute for individual in- formed consent.” (CIOMS,
p.000121: International Ethical Guidelines, Commen- tary on Guideline 4)
p.000121:
p.000121:
p.000121: What is meant by “informed” consent?
p.000121: “Informed consent is a decision to participate in research, taken by a competent individual who has received
p.000121: the necessary information; who has adequately understood the information; and who, after considering the
p.000121: information, has arrived at a decision without hav- ing been subjected to coercion, undue influence or
p.000121: inducement, or intimidation.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121:
p.000121: Who may administer informed consent?
p.000121: The person who conducts the consent interview should be knowl- edgeable about the study and able to answer
p.000121: questions. Some spon- sors and some IECs/IRBs require the clinical investigator to personally conduct the consent
p.000121: interview. If someone other than the clinical investigator conducts the interview and obtains consent, the
p.000121: clinical investigator should ensure that this responsibility is formally delegat-
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 61
p.000121:
p.000121: ed to that individual, and that the person so delegated is qualified and receives appropriate training to perform this
p.000121: activity.
p.000121:
p.000121:
p.000121: What “information” should be given to study subjects in accordance with GCP?
p.000121: GCP recognizes that certain essential elements of informed consent should be included in the informed consent
p.000121: discussion, the written informed consent form, and any other information to be provided to subjects who participate
p.000121: in the study. All information must be com- municated in a comprehensive and understandable manner to the
p.000121: research subject. This includes, but is not limited to:
p.000121: • title of the protocol;
...
Health / HIV/AIDS
Searching for indicator HIV:
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p.000121: http://www.hrweb.org/legal/cpr.html
p.000121:
p.000121:
p.000121: Related documents
p.000121: 1. ETH. Global list of national bioethics committees with contact details. http://www.who.int/ethics/en
p.000121: 2. IVB. Ethical considerations arising from vaccine trials.
p.000121: http://www.who.int/entity/vaccine_research/documents/en/manu774. pdf
p.000121: 3. RHR. Implementation of Good Clinical Practice (GCP) guidelines in RHR re- search activities.
p.000121: http://www.who.int/reproductive-health/publications/RHR_02_05/ Section_11.PDF
p.000121: 4. RHR Guidelines for research. http://www.who.int/reproductivehealth/hrp/ ethical_issues.en.html
p.000121: http://www.who.int/reproductive health/hrp/SERG_guidelines.en.html
p.000121: 5. RHR. Guideline for obtaining informed consent for the procurement and use of human tissues, cells and fluids in
p.000121: research. http://www.who.int/reproductive-health/ hrp/SERG_guidelines.en.html
p.000121: 6. TDR Standard operating procedures for clinical investigators. TDR/TDP/ SOP/99.1
p.000121: www.who.int/tdr/publications/publications/sop.htm
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
p.000121: 8. TDR Guidelines for Ethical Clearance & TDR Ethical Clearance Checklist
p.000121: http://www.who.int/tdr/publications/
p.000121: 9. Indigenous peoples & participatory health research. http://www.who.int/ethics/indigenous_peoples/en/
p.000121: 10. UNAIDS (Joint United Nations Programme on HIV/AIDS): Ethical considera- tions in HIV preventive vaccine research.
p.000121: http://www.unaids.org/publications/documents/vaccines/index.html
p.000121:
p.000121: REFERENCES | 123
p.000121:
p.000121: 11. International guidelines for ethical review of epidemiological studies. CIOMS, Geneva, 1991 (revision
p.000121: pending). http://www.cioms.ch/
p.000121: 12. Additional Protocol to the Convention of Human Rights and Biomedicine concerning biomedical research. Council of
p.000121: Europe. European Treaty Se- ries – 195. http://www.coe.int/T/E/Legal_Affairs/
p.000121: 13. Steering Committee on Bioethics (CDBI) Restricted CDBI/INF (2002) 5. Council of Europe.
p.000121: http://www.coe.int/T/E/Legal_Affairs/
p.000121:
p.000121:
p.000121: National good clinical practice and other guidelines
p.000121: Australia
p.000121: Regulation of clinical trials in Australia: http://www.tga.gov.au
p.000121:
p.000121: Canada
p.000121: Good clinical practices.
p.000121: http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/hp_gcp_e.html
p.000121:
p.000121: European Union
p.000121: European Agency for Evaluation of Medicines (EMEA). ICH topic E6. Note for guidance on good clinical practice
p.000121: (CPMP/ICH/135/95) http://www.emea.eu.int/pdfs/human/ich/013595en.pdf
p.000121: European Clinical Trials Directive for GCP, 2001/20/EC, 04.2001
p.000121:
p.000121: India
p.000121: Ethical guidelines for biomedical research on human subjects. http://icmr.nic.in/ethical.pdf
p.000121: Japan
p.000121: Ministry of Health, Labour and Welfare. “Standards on the Implementation of Clinical Trials on Drugs (New GCO)”.
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Health / Healthy People
Searching for indicator healthy volunteers:
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p.000121: for Biomedical Research Involving Human Subjects;
p.000121: 3) Other guidelines (see References).
p.000121:
p.000121:
p.000121: Application
p.000121: Principle 1 is applied through:
p.000121: • design and approval of the protocol;
p.000121: • informed consent;
p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
...
p.000121: GCP Principle 2: Protocol
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 7: Informed Consent
p.000121: Definitions for:
p.000121: Investigator’s Brochure (ICH E6, 1.36) Nonclinical Study (ICH E6, 1.41) Protocol (ICH E6, 1.44)
p.000121: Protocol Amendment (ICH E6, 1.45)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 41
p.000121:
p.000121: PRINCIPLE 4: BENEFIT-RISK ASSESSMENT
p.000121: Research involving humans should be initiated only if the antici- pated benefit(s) for the individual research subject
p.000121: and society clearly outweigh the risks. Although the benefit of the results of the trial to science and
p.000121: society should be taken into account, the most important considerations are those related to the rights,
p.000121: safety, and well being of the research subjects.
p.000121: “The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be
p.000121: solved by the experiment.” (The Nuremberg Code)
p.000121: “Every medical research project involving human subjects should be preceded by careful assessment of predictable risks
p.000121: and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the
p.000121: participation of healthy volunteers in medical research.” (Declaration of Helsinki)
p.000121: “For all biomedical research involving human subjects, the inves- tigator must ensure that potential
p.000121: benefits and risks are reason- ably balanced and risks are minimized.” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 8)
p.000121: “It is commonly said that benefits and risks must be ‘balanced’ and shown to be ‘in a favourable ratio.’ … Thus,
p.000121: there should first be a determination of the validity of the presuppositions of the research; then the nature,
p.000121: probability and magnitude of risk should be distin- guished with as much clarity as possible. The method
p.000121: of ascertain- ing risks should be explicit … It should also be determined whether
p.000121: … estimates of the probability of harm or benefits are reasonable, as judged by known facts or other
p.000121: available studies.” (The Belmont Report)
p.000121: “… Risks should be reduced to those necessary to achieve the research objective. It should be
p.000121: determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be
p.000121: entirely eliminated, but it can often be reduced by careful attention to alternative procedures … When research
p.000121: involves significant risk of serious impairment, review committees should be extraordinarily
p.000121:
p.000121:
p.000121: 42 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
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p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 57
p.000121:
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: Definitions for:
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Monitoring (ICH E6, 1.38)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 58 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT
p.000121: Freely given informed consent should be obtained from every subject prior to research participation in
p.000121: accordance with na- tional culture(s) and requirements. When a subject is not ca- pable of giving
p.000121: informed consent, the permission of a legally authorized representative should be obtained in accordance
p.000121: with applicable law.
p.000121: “In particular, no one shall be subjected without his free consent to medical or scientific experimentation.” (United
p.000121: Nations International Covenant on Civil and Political Rights)
p.000121: “The subjects must be volunteers and informed participants in the research project.” (Declaration of Helsinki)
p.000121: “… [T]here is widespread agreement that the consent process can be analysed as containing three elements:
p.000121: information, comprehen- sion, and voluntariness.” (The Belmont Report)
p.000121: “For all biomedical research involving humans, the investigator must obtain the voluntary informed consent of the
p.000121: prospective subject or, in the case of an individual who is not capable of giving informed consent, the
p.000121: permission of a legally authorized representative in ac- cordance with applicable law. Waiver of informed
p.000121: consent is to be regarded as uncommon and exceptional, and must in all cases be ap- proved by an ethical review
p.000121: committee.” (CIOMS, International Ethi- cal Guidelines, Guideline 4)
p.000121: “Obtaining informed consent is a process that is begun when initial contact is made with a prospective
p.000121: subject and continues through- out the course of the study. By informing the prospective subjects, by
p.000121: repetition and explanation, by answering their questions as they arise, and by ensuring that each individual
p.000121: understands each proce- dure, investigators elicit their informed consent and in so doing mani- fest respect for
p.000121: their dignity and autonomy.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
...
p.000121: presenting information in a disorganized and rapid fashion, allowing too little time for consid- eration or curtailing
p.000121: opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.” (The Belmont
p.000121: Report)
p.000121: “Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather,
p.000121: the investigator must convey the information, whether orally or in writing, in language that
p.000121:
p.000121:
p.000121: 64 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: suits the individual’s level of understanding. The investigator must bear in mind that the prospective
p.000121: subject’s ability to understand the information necessary to give informed consent depends on that individual’s
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
...
Health / Mentally Disabled
Searching for indicator disabled:
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p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
p.000121: continue participation in the trial. (See WHO GCP Principle 7: Informed Consent)
p.000121:
p.000121:
p.000121:
...
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
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Searching for indicator mentally:
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p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
...
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
...
Searching for indicator disability:
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p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
...
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 1: Ethical Conduct
p.000121: GCP Principle 4: Benefit-Risk Assessment
p.000121: Definitions for:
p.000121: Informed Consent (ICH E6, 1.28)
p.000121: Legally Acceptable Representative (ICH E6, 1.37) Vulnerable Subjects (ICH E6, 1.61)
p.000121: Well-being (of the trial subjects) (ICH E6, 1.62)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 71
p.000121:
p.000121: PRINCIPLE 8: CONTINUING REVIEW/ONGOING BENEFIT-RISK ASSESSMENT
p.000121: Research involving humans should be continued only if the ben- efit-risk profile remains favourable.
p.000121: “During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any
p.000121: stage, if he has prob- able cause to believe, in the exercise of the good faith, superior skill, and careful
p.000121: judgment required of him that a continuation of the ex- periment is likely to result in injury, disability, or
p.000121: death to the experi- mental subject.” (The Nuremberg Code)
p.000121: “… The ethical review committee should conduct further reviews as necessary in the course of the research,
p.000121: including monitoring of its progress.” (CIOMS, International Ethical Guidelines, Guideline 2)
p.000121: “… The committee has the right to monitor ongoing trials …“ (Decla- ration of Helsinki)
p.000121: “… Clinical trial sponsors should develop a process to assess, evalu- ate and act on safety information during drug
p.000121: development on a con- tinuous basis in order to ensure the earliest possible identification of safety concerns and to
p.000121: take appropriate risk minimization steps. Such steps can include modification of study protocols, to
p.000121: incorporate strategies to ensure that clinical trial participants are not exposed to undue risk.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Identification and Evaluation of Risk from
p.000121: Clinical Trial Data)
p.000121:
p.000121: Application
p.000121: Principle 8 is applied through development and implementation of processes for evaluating risks and
p.000121: benefits of the research as ad- ditional information becomes available during the course of the
p.000121: study. Principle 8 encompasses (1) safety monitoring of the study by investigator(s) and sponsor
p.000121: (including use of a data and safety monitoring board [DSMB], where appropriate); (2) reporting serious
p.000121: unexpected adverse events or other unanticipated risks to the spon- sor, IEC/IRB, and regulators; (3) review by
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
...
p.000121:
p.000121: form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so … When
p.000121: consent has been obtained orally, investigators are responsible for providing documen- tation or proof of consent.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: When material changes occur in the conditions or the procedures of a study, and also periodically in
p.000121: long-term studies, the investiga- tor should once again seek informed consent from the subjects …“ (CIOMS,
p.000121: International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: Is it ethical to include subjects who are unable to consent?
p.000121: “Research on individuals from whom it is not possible to obtain con- sent, including proxy or advance consent, should
p.000121: be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of
p.000121: the research population. The specific reasons for involving research subjects with a condition that renders them unable
p.000121: to give informed consent should be stated in the experi- mental protocol for consideration and approval of the
p.000121: review com- mittee …” (Declaration of Helsinki)
p.000121: “When there is ethical and scientific justification to conduct research with individuals incapable of giving
p.000121: informed consent, the risk from research interventions that do not hold out the prospect of direct
p.000121: benefit for the individual subject should be no more likely and not greater than the risk attached to
p.000121: routine medical or psychological ex- amination of such persons. Slight or minor increases above such risk may be
p.000121: permitted when there is an overriding scientific or medical rationale for such increases and when an ethical
p.000121: review committee has approved them.” (CIOMS, International Ethical Guidelines, Guide- line 9)
p.000121:
p.000121: When should informed consent be obtained? What is meant by “prior to trial participation”?
p.000121: Informed consent should be obtained from each subject or the sub- ject’s legally authorized representative prior to
p.000121: involving the subject
p.000121:
p.000121:
p.000121: 68 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: in any study-specific activities. This includes diagnostic or other tests that are administered solely for determining
p.000121: the subject’s eligibility to participate in the research.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing and overseeing the informed consent process is shared by sponsors,
p.000121: clinical investigators, IECs/ IRBs, and regulatory authorities.
p.000121: IECs/IRBs are responsible for:
...
Health / Motherhood/Family
Searching for indicator family:
(return to top)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
p.000121: How is informed consent documented? Is getting the subject (or the subject’s representative) to sign a consent document
p.000121: all that is necessary? How should the process be documented throughout the study?
p.000121: “Obtaining informed consent is a process that is begun when initial contact is made with a prospective
p.000121: subject, and continues through- out the course of the study. By informing the prospective subjects, by
p.000121: repetition and explanation, by answering their questions as they arise, and by ensuring that each
p.000121: individual understands each pro- cedure, investigators elicit their informed consent and in so doing
p.000121: manifest respect for their dignity and autonomy. Each individual must be given as much time as is needed to
p.000121: reach a decision, including time for consultation with family members or others. Adequate time and resources should
p.000121: be set aside for informed-consent procedures.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: “Consent may be indicated in a number of ways. The subject may imply consent by voluntary actions,
p.000121: express consent orally, or sign a consent form. As a general rule, the subject should sign a consent
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 67
p.000121:
p.000121: form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so … When
p.000121: consent has been obtained orally, investigators are responsible for providing documen- tation or proof of consent.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: When material changes occur in the conditions or the procedures of a study, and also periodically in
p.000121: long-term studies, the investiga- tor should once again seek informed consent from the subjects …“ (CIOMS,
p.000121: International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: Is it ethical to include subjects who are unable to consent?
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000121: “The investigator … should ensure that the code is broken only in accordance with the protocol. If the trial
p.000121: is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g.,
p.000121: accidental unblinding, unblinding due to a serious ad- verse event) of the investigational product(s).” (ICH E6,
p.000121: Section 4.7)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 31
p.000121:
p.000121: What is meant by “randomization”?
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
p.000121: another method, such as historical or literature controls, can be justified scientifically and ethi- cally. Assignment
p.000121: to treatment arms by randomization, in addition to its usual scientific superiority, offers the advantage
p.000121: of tending to render equivalent to all subjects the foreseeable benefits and risks of participation in a
p.000121: trial.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121: “The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken
p.000121: only in accordance with the protocol.” (ICH E6, Section 4.7)
p.000121:
p.000121:
p.000121: How should the protocol address reporting of adverse events?
p.000121: The protocol should specify procedures for eliciting reports of, and for recording and reporting, adverse
p.000121: event and inter-current illness- es; the type and duration of the follow-up of subjects after adverse events; and the
p.000121: methods to be used in, and timing for, assessing, recording, and analysing safety parameters.
p.000121: The protocol and investigator’s brochure will assist the investigator and sponsor in determining whether an
p.000121: adverse event is “unexpect- ed” and how it should be reported. Unexpected serious adverse drug reactions should be
p.000121: reported to the regulatory authority(ies) and to other investigators involved in the trial in accordance with
p.000121: applicable regulatory requirement(s).
p.000121:
p.000121: Implementation
p.000121: Sponsors are primarily responsible for (1) designing the clinical investigation, (2) developing the
p.000121: study protocol, investigator’s bro- chure, and related materials to describe the procedures that will be followed,
p.000121: study endpoints, data collection, and other study require-
p.000121:
p.000121: 32 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ments; and (3) ensuring that the protocol complies with applicable national and local laws and regulations.
p.000121: Investigators may be consulted by the sponsor during protocol de- sign or, in some cases, may personally contribute to
p.000121: the design of the protocol. Investigators are responsible for familiarizing themselves with the study protocol,
p.000121: investigator’s brochure, and related materi- als to ensure that they are able to carry out the study in compliance with
p.000121: the specifications of the protocol.
p.000121: IECs/IRBs are responsible for conducting ethical review of the study protocol. This also includes arranging for a
...
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
...
Searching for indicator physically:
(return to top)
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
...
Health / Physically Ill
Searching for indicator sick:
(return to top)
p.000121: during design and review (initial review as well as continuing review) of the study protocol. (See also WHO GCP
p.000121: Principles 3: Risk Identification; 4: Benefit-Risk Assess- ment; 8: Continuing Review/Ongoing Benefit-Risk Assessment)
p.000121:
p.000121:
p.000121: What is meant by “justice” and how is it most directly implemented within GCP?
p.000121: “… the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the
p.000121: selection of research sub- jects.” (The Belmont Report)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
...
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
...
Health / Pregnant
Searching for indicator pregnant:
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p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
...
Health / Terminally Ill
Searching for indicator terminally:
(return to top)
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
p.000121: How is informed consent documented? Is getting the subject (or the subject’s representative) to sign a consent document
...
Health / ill
Searching for indicator ill:
(return to top)
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
p.000121: How is informed consent documented? Is getting the subject (or the subject’s representative) to sign a consent document
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000121: requirements for the review and ap- proval of trial sites and/or investigators.]
p.000121: The sponsor is generally responsible for ensuring that the applicable regulatory authority(ies) review and provide
p.000121: any required authori- zations for the study before the study may proceed. The sponsor should also list
p.000121: the trial in applicable and/or required clinical trial registry(ies).
p.000121: See WHO GCP Principles 2: Protocol; 4: Benefit-Risk Assessment.
p.000121:
p.000121:
p.000121: 8. Enrollment of subjects into the study: recruitment, eligibility, and informed consent
p.000121: The clinical investigator has primary responsibility for recruiting subjects, ensuring that only
p.000121: eligible subjects are enrolled in the study, and obtaining and documenting the informed consent of each subject.
p.000121: Within GCP, informed consent must be obtained from each study subject prior to enrollment in the study or
p.000121: performing any spe- cific study procedures.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 7: In- formed Consent; 11: Records.
p.000121:
p.000121:
p.000121: 9. The investigational product(s): quality, handling and accounting
p.000121: Quality of the investigational product is assured by compliance with Good Manufacturing Practice (GMP) and by handling
p.000121: and storing the product according to the manufacturing specifications and the study protocol. GCP requires that
p.000121: sponsors control access to the inves-
p.000121:
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 13
p.000121:
p.000121: tigational product and also document the quantity(ies) produced, to whom the product is shipped, and
p.000121: disposition (e.g. return or de- struction) of any unused supplies. GCP also requires investigators to control
p.000121: receipt, administration, and disposition of the investigational product.
p.000121: See WHO GCP Principles 2: Protocol; 11: Records; 13: Good Manufac- turing Practice; 14: Quality Systems
p.000121:
p.000121:
p.000121: 10. Trial data acquisition: conducting the trial
p.000121: Research should be conducted according to the approved protocol and applicable regulatory requirements. Study
p.000121: records documenting each trial-related activity provide critical verification that the study has been carried
p.000121: out in compliance with the protocol.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 11: Records.
p.000121:
p.000121:
p.000121: 11. Safety management and reporting
p.000121: All clinical trials must be managed for safety. Although all parties who oversee or conduct clinical research have
p.000121: a role/responsibility for the safety of the study subjects, the clinical investigator has primary responsibility
p.000121: for alerting the sponsor and the IEC/IRB to adverse events, particularly serious/life-threatening
p.000121: unanticipated events, observed during the course of the research. The sponsor, in turn, has primary
p.000121: responsibility for reporting of study safety to regulatory authorities and other investigators and for the ongoing
p.000121: global safety assessment of the investigational product. A data and safety moni- toring board (DSMB) may be
p.000121: constituted by the sponsor to assist in overall safety management.
...
p.000121: A protocol “provides the background, rationale, and objective(s) of a biomedical research project and describes its
p.000121: design, methodology, and organization, including ethical and statistical considerations. Some of these
p.000121: considerations may be provided in other documents referred to in the protocol.” (WHO Operational
p.000121: Guidelines for Ethics Committees that Review Biomedical Research, Glossary)
p.000121:
p.000121:
p.000121: What information should be included in a study protocol?
p.000121: The study protocol is the core document communicating trial require- ments to all parties who have responsibility
p.000121: for approval, conduct, oversight, and analysis of the research.
p.000121: GCP recognizes that certain essential elements should be included in the study protocol. These include but are not
p.000121: limited to:
p.000121: • general information;
p.000121: • background information;
p.000121: • description of the trial objectives and purpose;
p.000121: • description of the trial design;
p.000121: • criteria for inclusion, exclusion, and withdrawal of study subjects;
p.000121: • treatment information;
p.000121: • methods and timing for assessing, recording and analysing data gathered on the investigational product;
p.000121: • methods for obtaining safety information, including plans for safe- ty monitoring;
p.000121: • description of the statistical methods to be employed;
p.000121: • description of ethical considerations relating to the trial;
p.000121: • a statement related to permitting trial-related monitoring, audits, and inspection by the sponsor,
p.000121: IEC/IRB, and regulators, including direct access to source data/documents;
p.000121:
p.000121:
p.000121:
p.000121: 28 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • means for obtaining informed consent and communication of in- formation to prospective subjects.
p.000121:
p.000121:
p.000121: What is a “protocol amendment”?
p.000121: “A protocol amendment is a written description of a change(s) to or formal clarification of a protocol.” (ICH E6,
p.000121: Section 1.45)
p.000121:
p.000121:
p.000121: What types of changes may require formal amendment of the protocol?
p.000121: Regional,1 national, or local laws and regulations may require spon- sors to prepare formal protocol
p.000121: amendments to describe any change that significantly affects the safety of subjects, the scope of the in-
p.000121: vestigation, or the scientific quality of the study.
p.000121: Examples of changes that generally require formal amendment in- clude, but are not limited to:
p.000121: • changes in drug dosage or duration of exposure of individual sub- jects to an investigational product beyond
p.000121: that described in the current protocol;
p.000121: • significant increase in the number of subjects under study or in the duration of the study;
p.000121: • significant change in the study design, such as adding or dropping a study arm; and
p.000121: • addition of a new test or procedure that is intended to improve monitoring for or reduce the risk of a
p.000121: side effect or adverse event, or the dropping of a test intended to monitor safety.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
...
p.000121: compliance with the protocol. Investigators should not implement any deviation from, or changes of the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB(s)/IEC(s) of an
p.000121: amendment, except where necessary to eliminate an immediate hazard(s) to research subjects.
p.000121: The sponsor monitors the study to ensure investigator compliance with the protocol and takes action to
p.000121: secure compliance or termi- nate the trial in the case of noncompliance. If the monitoring and/or auditing
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should
p.000121: terminate the investigator’s/institution’s participation in the trial. All parties, includ- ing the IEC/IRB, should be
p.000121: notified in such cases.
p.000121: In accordance with applicable laws/regulations, regulators may in- spect the investigator(s) or sponsor to
p.000121: ensure compliance with proto- col adherence requirements. Regulators should be promptly notified when a sponsor
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution leading to
p.000121: termination of the investigator’s/institution’s participation in a study.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to:
p.000121: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: For clinical investigators, refer to:
p.000121: Compliance with Protocol (ICH E6, Section 4.5)
p.000121: For sponsors, refer to:
p.000121: Record Access (ICH E6, Section 5.15) Monitoring (ICH E6, Section 5.18) Noncompliance (ICH E6, Section 5.20)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 1995
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 57
p.000121:
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: Definitions for:
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Monitoring (ICH E6, 1.38)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 58 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT
p.000121: Freely given informed consent should be obtained from every subject prior to research participation in
p.000121: accordance with na- tional culture(s) and requirements. When a subject is not ca- pable of giving
p.000121: informed consent, the permission of a legally authorized representative should be obtained in accordance
p.000121: with applicable law.
p.000121: “In particular, no one shall be subjected without his free consent to medical or scientific experimentation.” (United
...
p.000121: entitled;
p.000121: • the purpose of the trial;
p.000121: • the trial treatment(s) and the probability for random assignment to each treatment;
p.000121: • the trial procedures to be followed, including all invasive proce- dures;
p.000121: • the subject’s responsibilities;
p.000121: • those aspects of the trial that are experimental;
p.000121: • the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus or
p.000121: nursing infant;
p.000121:
p.000121:
p.000121:
p.000121: 62 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject
p.000121: should be made aware of this;
p.000121: • the alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
p.000121: • that records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regulations, will not be made publicly available. If the results of the trial are
p.000121: published, the subject’s identity will remain confidential;
p.000121: • the potential risks should confidentiality measures be compro- mised (e.g. stigma, loss of reputation,
p.000121: potential loss of insurabil- ity);
p.000121: • that the subject or the subject’s legally authorized representative will be informed in a timely manner if
p.000121: information becomes avail- able that may be relevant to the subject’s willingness to continue participation in the
p.000121: trial;
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 63
p.000121:
p.000121: • the person(s) to contact for further information regarding the trial and the rights of research subjects, and
p.000121: whom to contact in the event of trial-related injury;
p.000121: • the foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be
p.000121: terminated;
p.000121: • the expected duration of the subject’s participation in the trial;
p.000121: • the approximate number of subjects involved in the trial.
p.000121: “… Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and
p.000121: truthful answers should always be given to direct questions about the research. Care should be taken to distinguish
p.000121: cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply
p.000121: inconvenience the investigator.” (The Belmont Report)
...
p.000121:
p.000121: 82 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: May a non-medical person serve as a principal investigator?
p.000121: “Investigator” is defined as the “person responsible for the conduct of the clinical trial at a trial site. If
p.000121: a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the
p.000121: team and may be called the principal investigator.” (ICH E6, Sec- tion 1.34)
p.000121: In most clinical research, the investigator will be a physician, dentist, or (in accordance with national/local laws,
p.000121: regulations, and licensure provisions) equivalent medical professional.
p.000121: Where permitted under national/local laws and regulations, a non- physician may serve as a principal
p.000121: investigator. However, implicit in this designation are: (1) that the non-physician be qualified to person- ally
p.000121: conduct or supervise the investigation; and (2) the non-physician would need to secure the services of a physician as a
p.000121: subinvestigator to perform those study functions requiring medical expertise. (For example, a Ph.D.
p.000121: pharmacologist may be listed as a principal inves- tigator on a pharmacokinetic study with a physician
p.000121: subinvestigator. Another example might be a clinical psychologist principal investiga- tor with a physician
p.000121: subinvestigator.)
p.000121:
p.000121:
p.000121: Within GCP, what is the investigator’s responsibility for the medical care of research subjects?
p.000121: The investigator is responsible for protecting the rights, safety, and welfare of subjects under his/her care
p.000121: during a clinical trial. This im- plies that (1) the investigator is able to ensure access to a reasonable standard of
p.000121: medical care for study subjects for medical problems arising during participation in the trial that are,
p.000121: or could be related, to the study intervention, and (2) the investigator or other medically qualified individuals
p.000121: are readily available to provide such care during the study.
p.000121: “Although sponsors are, in general, not obliged to provide health- care services beyond that which is
p.000121: necessary for the conduct of the research, it is morally praiseworthy to do so. Such services typically include
p.000121: treatment for diseases contracted in the course of the study.
p.000121:
p.000121:
p.000121: PRINCIPLE 9 : INVESTIGATOR QUALIFICATIONS | 83
p.000121:
p.000121: It might, for example, be agreed to treat cases of an infectious dis- ease contracted during a trial of a
p.000121: vaccine designed to provide immu- nity to that disease, or to provide treatment of incidental conditions unrelated to
p.000121: the study. … When prospective or actual subjects are found to have diseases unrelated to the research
p.000121: or cannot be en- rolled in a study because they do not meet the health criteria, inves- tigators should, as
p.000121: appropriate, advise them to obtain, or refer them for, medical care.” (CIOMS, International Ethical Guidelines, Commen-
p.000121: tary on Guideline 21)
p.000121:
p.000121: Implementation
p.000121: The investigator is responsible for providing, or ensuring that sub- jects have access to, medical care for
p.000121: medical problems arising dur- ing their participation in the trial that are, or could be related to the study
p.000121: intervention, and for following the subjects’ status until the problem is resolved.
p.000121: “It is recommended that the investigator inform the subject’s primary physician about the subject’s participation
p.000121: in the trial if the subject has a primary physician and if the subject agrees to the primary phy- sician being
p.000121: informed.” (ICH E6, Section 4.3)
p.000121: Primary responsibility for selecting qualified clinical investigators to conduct a study resides with the
p.000121: sponsor.
p.000121: The IECs/IRBs is responsible for ensuring that the rights and welfare of study subjects are protected. Consideration of
p.000121: investigator quali- fications and experience and the adequacy of the site (including the supporting staff, available
p.000121: facilities, and emergency procedures) by the IEC/IRB will ensure that subjects have access to appropriate care for
p.000121: medical problems arising during participation in the trial.
p.000121: National and/or local regulatory authorities have indirect respon- sibility related to clinical investigator
p.000121: qualifications. Regulators (1) establish licensing and practice standards for physicians and other medical
p.000121: personnel, (2) enforce compliance with such standards, and
p.000121: (3) impose disciplinary actions, as appropriate, on physicians and
p.000121:
p.000121:
p.000121:
p.000121: 84 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: other medical personnel who fail to meet such standards. Differ- ent regulatory agencies and authorities
p.000121: may be responsible for the oversight of clinical research versus the licensure and oversight of medical
p.000121: professionals; exchange of information among regulatory agencies is encouraged in such circumstances.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Documentation (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 5.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1) Medical Care of Trial Subjects (ICH E6, Section 4.3)
p.000121: Safety Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
p.000121: Medical Expertise (ICH E6, Section 5.3) Investigator Selection (ICH E6, Section 5.6)
...
p.000121: obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic
p.000121: changes and corrections. … Sponsors should have written procedures to assure that changes or corrections in
p.000121: CRFs made by sponsor’s designated representatives are documented, are neces- sary, and are endorsed by the
p.000121: investigator. The investigator should retain records of the changes and corrections.” (ICH E6, Section 4.9)
p.000121:
p.000121:
p.000121: Who must keep clinical trial information and for how long? What is meant by the term “storage”?
p.000121: All of the parties who conduct or oversee research involving human subjects are expected to keep records and materials
p.000121: related to their specific trial responsibilities and activities for the period of time re- quired by
p.000121: national/local laws and regulations, or if such laws do not exist, in accordance with GCP standards.
p.000121: Within GCP, generally, “[e]ssential documents should be retained until at least 2 years after the last
p.000121: approval of a marketing applica-
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 95
p.000121:
p.000121: tion … and until there are no pending or contemplated marketing applications … or at least 2 years have
p.000121: elapsed since the formal dis- continuation of clinical development of the investigational product. These
p.000121: documents should be retained for a longer period, however, if required by the applicable regulatory
p.000121: requirements or by an agree- ment with the sponsor.” (ICH E6, Section 4.9)
p.000121: “Storage” (or “archiving”) implies that records are appropriately stored for future use, for example, to
p.000121: ensure their preservation and to enable direct access to the records when required by the spon- sor,
p.000121: IEC/IRB, monitor or regulatory authorities. “The investigator/ institution should take measures to prevent
p.000121: accidental or premature destruction of these records.” (ICH E6, Section 4.9)
p.000121:
p.000121:
p.000121: Why is it necessary for IECs/IRBs, investigators, sponsors, and monitors to maintain clinical trial information?
p.000121: Clinical trial information should be maintained to allow accurate re- construction and evaluation of the
p.000121: trial’s conduct and verification of the trial’s results.
p.000121:
p.000121:
p.000121: How do investigators know which records should be maintained and the methods for maintaining them?
p.000121: The study protocol generally specifies the information to be captured and the methods to be used (e.g. by
p.000121: providing “[s]amples of the standardized case-report forms to be used … ,” describing “… the methods of
p.000121: recording therapeutic response (description and evalua- tion of methods and frequency of measurement), the follow-up
p.000121: pro- cedures, and, if applicable, the measures proposed to determine the extent of compliance of subjects with
p.000121: the treatment … , [m]ethods of recording and reporting adverse events or reactions …” (CIOMS, International
p.000121: Ethical Guidelines, Appendix 1).
p.000121: Record-keeping and retention requirements may also be specified by national or local law and regulations.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 96 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is meant by “reporting”? How are essential documents and data combined to report the outcome of the trial?
p.000121: Reporting is the act of providing information or data to another party. National laws and regulations may require
...
p.000121: procedure for accounting for missing, unused, and spurious data, procedures for reporting any deviations from the
p.000121: original statistical plan… selection of subjects to be included in the analyses … ” (ICH E6, Section 6.9)
p.000121:
p.000121:
p.000121: How should clinical trial results be publicly reported?
p.000121: “Both authors and publishers have ethical obligations. In publication of the results of research, the
p.000121: investigators are obliged to preserve the accuracy of the results. Negative as well as positive results
p.000121: should be published or otherwise publicly available. … Reports of experimentation not in accordance with
p.000121: the principles laid down in this Declaration should not be accepted for publication.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121: 98 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: The study protocol may include:
p.000121: • “[i]n the case of a negative outcome, an assurance that the results will be made available, as appropriate,
p.000121: through publication or by reporting to the drug registration authority.” (CIOMS, International Ethical Guidelines,
p.000121: Appendix 1)
p.000121: • “[c]ircumstances in which it might be considered inappropriate to publish findings, such as when the findings of an
p.000121: epidemiological, sociological or genetics study may present risks to the interests of a community or
p.000121: population or of a racially or ethnically defined group of people.” (CIOMS, International Ethical Guidelines, Appen-
p.000121: dix 1)
p.000121:
p.000121:
p.000121: Who should have access to clinical trial records?
p.000121: Sponsors, monitors, IECs/IRBs, and regulators generally require direct access to all information
p.000121: pertaining to the conduct and over- sight of the clinical trial. Direct access means that these parties have
p.000121: “[p]ermission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation
p.000121: of a clinical trial.” (ICH E6, 1.21)
p.000121: “Any or all of the documents addressed in this guidance may be sub- ject to, and should be available for, audit by the
p.000121: sponsor’s auditor and inspection by the regulatory authority(ies).” (ICH E6, Section 8)
p.000121: Note that consent forms should inform study subjects “[t]hat the monitor(s), the auditor(s), the
p.000121: IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s
p.000121: original medical records for verification of clinical trial procedures and/or data, without violating the
p.000121: confidentiality of the subject, to the extent permitted by the applicable laws and regulations, and that by signing a
p.000121: written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such
p.000121: access.” (ICH E6, 4.8) (See also WHO GCP Principle 7: Informed Consent)
p.000121: In addition, sponsors, monitors, investigators and regulators should be aware of the need to handle clinical
p.000121: trial information in a manner
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 99
p.000121:
p.000121: that protects the privacy and confidentiality of research subjects. These parties should also be fully informed
p.000121: about national/local laws/ regulations related to privacy and confidentiality. (See also WHO GCP Principle 12:
p.000121: Confidentiality/Privacy)
p.000121:
p.000121: Implementation
p.000121: IECs/IRBs, investigators, sponsors, and regulators all bear respon- sibility for documenting their
p.000121: activities within GCP, and maintaining records pertaining to duties related to the conduct or oversight
p.000121: of the clinical trial for the time required under national or local law and regulations. All parties are
p.000121: responsible for ensuring the accuracy, completeness, legibility and availability (as necessary) of such docu-
p.000121: ments.
p.000121: IECs/IRBs document their reviews of study protocols and informed consent/recruitment/advertising materials
p.000121: through minutes that capture the IECs’/IRBs’ deliberations and through copies of corre- spondence with the
p.000121: clinical investigator.
p.000121: Investigators prepare and maintain case histories that record all ob- servations and other data pertinent to the
p.000121: investigation on each indi- vidual administered the investigational drug or employed as a control in the investigation.
p.000121: Sponsors ensure that study protocols address appropriate data handling and record-keeping requirements and
p.000121: design CRFs appro- priately to facilitate the capture of all significant trial-related data and observations.
p.000121: Sponsors also secure the services of monitors to en- sure compliance of the clinical investigators, and verify
p.000121: that the study was carried out according to the approved study protocol.
p.000121: Regulators rely on clinical trial information to support regulatory decision-making and may inspect all of
p.000121: the parties involved in con- ducting or overseeing research. Critical to regulatory inspection is direct
p.000121: access to and review of existing clinical trial records. As part of an inspection, regulators compare records at the
p.000121: clinical investigator site and sponsor site with data and reports submitted to the regula- tory authority to verify
p.000121: the information submitted. Regulators also prepare and maintain records of their inspections and findings.
p.000121:
p.000121: 100 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3) Records (ICH E6,
p.000121: Section 3.4)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: Documentation and Archiving (WHO Operational Guidelines for Ethics Committees that Review Biomedical
p.000121: Research, Section 10)
p.000121: For investigators, refer to:
p.000121: Communication with IRB/IEC (ICH E6, Section 4.4) Compliance with Protocol (ICH E6, Section 4.5) Records and Reports
p.000121: (ICH E6, Section 4.9) Progress Reports (ICH E6, Section 4.10)
p.000121: Safety Reporting (ICH E6, Section 4.11)
p.000121: Final Report(s) by Investigator/Institution (ICH E6, Section 4.13) Clinical Trial Protocol, General Information (ICH
p.000121: E6, Section 6) Essential Documents for the Conduct of a Clinical Trial (ICH E6,
p.000121: Section 8)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Record Access (ICH E6, Section 5.15)
p.000121: Adverse Drug Reaction Reporting (ICH E6, Section 5.17) Monitoring (ICH E6, Section 5.18)
p.000121: Audit (ICH E6, Section 5.19)
p.000121: Clinical Trial/Study Reports (ICH E6, Section 5.22) Clinical Trial Protocol (ICH E6, Section 6)
p.000121: Essential Documents for the Conduct of a Clinical Trial (ICH E6, Section 8)
p.000121: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2A)
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 101
p.000121:
p.000121: Guidance on Data Elements for Transmission of Individual Case Safety Reports (ICH E2B)
p.000121: Statistical Principles for Clinical Trials (ICH E9)
p.000121: For regulatory authorities, refer to:
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: GCP Compliance Monitoring Programs by Regulatory Authorities (Chapter 7, Good Clinical Practices: Document of the
p.000121: Americas, PAHO)
p.000121: Surveying and Evaluating Ethical Review Practices (WHO Opera- tional Guidelines)
p.000121: Statistical Principles for Clinical Trials (ICH E9)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 6: Protocol Compliance GCP Principle 7: Informed Consent
p.000121: GCP Principle 12: Confidentiality/Privacy GCP Principle 14: Quality Systems
p.000121: Definitions for:
p.000121: Case Report Form (ICH E6, 1.11) Clinical Trial/Study Report (ICH E6, 1.13)
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Direct Access (ICH E6, 1.21)
p.000121: Documentation (ICH E6, 1.22) Essential Documents (ICH E6, 1.23)
p.000121: Interim Clinical Trial/Study Report (ICH E6, 1.32) Monitoring (ICH E6, 1.38)
p.000121: Monitoring Report (ICH E6, 1.39) Original Medical Record (ICH E6, 1.43) Protocol (ICH E6, 1.44)
p.000121: Source Data (ICH E6, 1.51) Source Documents (ICH E6, 1.52)
p.000121: Standard Operating Procedures (SOPs) (ICH E6, 1.55)
p.000121:
p.000121:
p.000121:
p.000121: 102 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 12: CONFIDENTIALITY/PRIVACY
p.000121: The confidentiality of records that could identify subjects should be protected, respecting the privacy and
p.000121: confidentiality rules in accord- ance with the applicable regulatory requirement(s).
p.000121: “The right of research subjects to safeguard their integrity must al- ways be respected. Every precaution
p.000121: should be taken to respect the privacy of the subject, the confidentiality of the patient’s information and to minimize
p.000121: the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.”
p.000121: (Declaration of Helsinki)
p.000121: “The investigator must establish secure safeguards of the confiden- tiality of subjects’ research data. Subjects
p.000121: should be told the limits, legal or other, to the investigators’ ability to safeguard confidential- ity
p.000121: and the possible consequences of breaches of confidentiality.” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 18)
p.000121:
p.000121: Application
p.000121: Principle 12 is applied (1) through appropriate procedures to protect the privacy of the subject, and (2) by document
p.000121: and data control to protect the confidentiality of the subject’s information.
p.000121: Principle 12 is also applied through the informed consent process which requires as an essential element
p.000121: that certain explanations be provided to the subject about the confidentiality of the subject’s records and about
p.000121: access to those records by monitor(s), auditor(s), the IEC/IRB, and the regulatory authority(-ies).
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “privacy”? What is meant by “confidentiality”?
p.000121: Privacy embraces the concept that each individual should have the right to control personal and sensitive
p.000121: information about him/her. Privacy implies that such information, which may be contained in
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 103
p.000121:
p.000121: medical records, personal diaries, or elsewhere, will be protected and not disclosed without the
p.000121: knowledge/permission of the indi- vidual to whom it pertains.
p.000121: Privacy may not be absolute, however. For example, some informa- tion, such as exposure to a communicable
p.000121: disease, may be subject to limited disclosure under public health laws; access to information contained in clinical
p.000121: study records may be required by regulators to verify data submitted in a marketing application. Thus,
p.000121: individuals who participate in clinical trials should be told the extent to which their information will
p.000121: be protected and the circumstances under which the information will be disclosed, to whom, and the purpose(s) for
p.000121: doing so.
p.000121: Confidentiality embraces the concept that parties who obtain private information from patients and
p.000121: subjects will (1) protect the information itself and any records that contain such information from deliberate or
p.000121: accidental disclosure; and (2) develop and follow proce- dures for release of the information only to
p.000121: authorized parties who have a legitimate need for it, including notification of the patient/ subject prior
p.000121: to any disclosure.
p.000121:
p.000121:
p.000121: Who is responsible for protecting the confidentiality of the subjects’ private information?
p.000121: At all times throughout the investigation, all parties (sponsor, moni- tor, IECs/IRBs, investigator,
p.000121: investigator’s staff, and regulators) should protect subjects’ private information and ensure that all data are se-
p.000121: cured against unauthorized access. This applies but is not limited to subjects’ case report forms (CRFs), source data,
p.000121: source documents, and safety reports.
p.000121: “It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the
p.000121: human subject.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 104 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: How is confidentiality implemented within GCP?
p.000121: “… Investigators should arrange to protect the confidentiality of such information by, for example, omitting
p.000121: information that might lead to the identification of individual subjects, limiting access to the infor-
p.000121: mation, anonymizing data, or other means.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121: Other mechanisms to protect information include, but are not limited to:
p.000121: • coding or encryption of data;
p.000121: • restricting access to study records and subjects’ medical files (e.g. passwords on electronic files, files
p.000121: secured in locked cabinets or secured storage areas);
p.000121: • maintaining subjects’ names and identifying information separate- ly from case report forms;
p.000121: • establishing and following procedures to ensure subjects’ private information and trial data are protected.
p.000121:
p.000121:
p.000121: Why should potential risks related to release of private information be disclosed to study subjects?
p.000121: Each subject needs to consider whether risks related to release of private information are sufficiently
p.000121: controlled, such that he/she is still willing to participate in the investigation.
p.000121: “Research relating to individuals and groups may involve the col- lection and storage of information
p.000121: that, if disclosed to third parties, could cause harm or distress.” (CIOMS, International Ethical Guide-
p.000121: lines, Commentary to Guideline 18)
p.000121: “Prospective subjects should be informed of limits to the ability of investigators to ensure strict
p.000121: confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality. Some
p.000121: jurisdictions require the reporting to appropriate agencies of, for instance, certain communicable diseases or
p.000121: evidence of child abuse or neglect. Drug regulatory authorities have the right to inspect clini-
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 105
p.000121:
p.000121: cal-trial records, and a sponsor’s clinical-compliance audit staff may require and obtain access to confidential
p.000121: data. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
p.000121: the precautions that will be taken to protect confidentiality.” (CIOMS, International Ethical Guidelines, Commentary
p.000121: to Guideline 18)
p.000121: “Both the informed consent discussion and the written informed consent form and any other written
p.000121: information to be provided to subjects should include explanations of the following:
p.000121: “(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regu- latory authority(ies) will be granted direct
p.000121: access to the subject’s original medical records for verification of clinical trial procedures and/or data, without
p.000121: violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations
p.000121: and that, by signing a written informed consent form, the subject or the subject’s legally acceptable
p.000121: representative is authorizing such access.”
p.000121: “(o) That records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regula-
p.000121:
p.000121:
p.000121: 106 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: tions, will not be made publicly available. If the results of the trial are published, the subject’s identity will
p.000121: remain confidential.” (ICH E6, Section 4.8)
p.000121: “The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000121: medical records for trial- related monitoring, audit, IRB/IEC review, and regulatory inspection.” (ICH E6, Section
p.000121: 5.15)
p.000121:
p.000121: Implementation
p.000121: IECs/IRBs review/approve the informed consent procedures and document to ensure, among other things, that
p.000121: there is adequate explanation regarding (1) the risks related to release of the subject’s private information,
p.000121: (2) how the confidentiality of the subject’s records will be maintained, and (3) persons who may have
p.000121: access to the subject’s records (e.g. monitor(s), auditor(s), the IEC/IRB, and the regulatory authority(-ies)).
p.000121: Investigators should (1) implement procedures to protect and restrict access to study records and
p.000121: private information (e.g., pass- word protection for files, keeping study records in secured areas),
p.000121: (2) follow national/local laws and regulations relating to privacy and confidentiality, (3) ensure that study
p.000121: staff are aware of and receive appropriate training related to their responsibility and procedures to be
p.000121: used for protecting subjects’ private information and records,
p.000121: (4) ensure that study staff follow the procedures established for this purpose, and (5) ensure that the consent
p.000121: form and process inform study subjects about the procedures to be used to protect their pri- vate information and
p.000121: the circumstances under which their medical and study records may be viewed by regulators, sponsors, monitors,
p.000121: and/or the IEC/IRB.
p.000121: Sponsors ensure that sites (1) allow regulators, IECs/IRBs, and moni- tors direct access to records necessary to
p.000121: verify compliance with national/local laws and regulations pertaining to the conduct of clini- cal trials, and (2)
p.000121: inform subjects about, and obtain their consent for, such access.
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 107
p.000121:
p.000121: Regulatory authorities need to (1) be alert to issues of subject con- fidentiality, and (2) review sponsors’, clinical
p.000121: investigators’, and IECs’/ IRBs’ compliance with applicable national/local laws and regulations for handling private
p.000121: information and informing subjects about these issues.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Elements of the Review, Protection of Research Participant Con- fidentiality (WHO Operational Guidelines for
p.000121: Ethics Committees that Review Biomedical Research, Section 6.2.4)
p.000121: For clinical investigators, refer to:
p.000121: Informed Consent of Trial Subjects (ICH E6, Section 4.8) Safety Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Monitoring Committee (ICH E6, Section 5.5)
p.000121: Record Access (ICH E6, Section 5.15) Monitoring (ICH E6, Section 5.18)
p.000121: Clinical Trial Protocol and Protocol Amendments, Direct Access to Source Data/Documents (ICH E6, Section 6.10)
p.000121: For regulatory authorities, refer to:
p.000121: Confidentiality in the Survey and Evaluation Processes (Survey- ing and Evaluating Ethical Review
p.000121: Practices, a complementary guideline to the Operational Guidelines for Ethics Committees the Review Biomedical
p.000121: Research, WHO, 2002), Section 8
p.000121: Safeguarding Confidentiality (Guideline 18, CIOMS International Ethical Guidelines for Biomedical
p.000121: Research Involving Human Subjects, Geneva 2002)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 108 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: See also:
p.000121: Discussion of WHO GCP Principles GCP Principle 2: Protocol
p.000121: GCP Principle 3: Risk Identification
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 7: Informed Consent
p.000121: GCP Principle 11: Records
p.000121: Definitions for: Audit (ICH E6, 1.6)
p.000121: Confidentiality (ICH E6, 1.16) Direct Access (ICH E6, 1.21) Inspection (ICH E6, 1.29)
p.000121: Original Medical Record (ICH E6, 1.43) Subject Identification Code (ICH E6, 1.58) Well-being (of the trial subjects)
p.000121: (ICH E6, 1.62)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 109
p.000121:
p.000121: PRINCIPLE 13: GOOD MANUFACTURING PRACTICE
p.000121: Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing
p.000121: Prac- tice (GMP) and should be used in accordance with the approved protocol.
p.000121: “The sponsor should ensure that the investigational product(s) … is characterized as appropriate to the
p.000121: stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and
p.000121: labeled in a manner that protects the blinding, if ap- plicable …“ (ICH E6, Section 5.13)
p.000121:
p.000121: Application
p.000121: Principle 13 is applied through (1) appropriately characterizing the investigational product (including any
p.000121: active comparator(s) and pla- cebo, if applicable), (2) adhering to applicable Good Manufacturing Practice
p.000121: (GMP) standards in the manufacturing, handling and storage of the investigational product, and (3) using the product
p.000121: according to the approved study protocol.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “applicable” Good Manufacturing Practice” (GMP)?
p.000121: “Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently produced
...
p.000121: Monitoring Arrangements (Clinical investigation of medical devices for human subjects, Part 2: Clinical investigation
p.000121: plans, Interna- tional Standards Organization (ISO), 14155-2, 4.34)
p.000121: For monitors, refer to:
p.000121: Monitoring (ICH E6, Section 5.18)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 14 : QUALIT Y SYSTEMS | 119
p.000121:
p.000121: For IECs/IRBs, refer to:
p.000121: Composition, Functions, and Operations (ICH E6, Section 3.2) Procedures (ICH E6, Section 3.3)
p.000121: WHO Surveying and Evaluating Ethical Review Practices: A comple- mentary guideline to the Operational Guidelines for
p.000121: Ethics Com- mittees that Review Biomedical Research
p.000121: For regulatory authorities, refer to: Noncompliance (ICH E6, Section 5.20)
p.000121: GCP Compliance Monitoring Programs by Regulatory Authorities (Chapter 7, Good Clinical Practices: Document of the
p.000121: Americas, PAHO)
p.000121: A Guide to Clinical Investigator Inspections (Annex 4, Good Clinical Practices: Document of the Americas, PAHO)
p.000121: Optional Guideline for Good Clinical Practice Compliance and Qual- ity Systems Auditing (European Network of GCP
p.000121: Auditors and other GCP Experts [ENGAGE], European Forum for Good Clinical Practice, August 1997)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 6: Protocol Compliance GCP Principle 11: Records
p.000121: Definitions for: Audit (ICH E6, 1.6)
p.000121: Audit certificate (ICH E6, 1.7) Audit report (ICH E6, 1.8) Audit trail (ICH E6, 1.9)
p.000121: Compliance (in relation to trials) (ICH E6, 1.15) Direct Access (ICH E6, 1.21)
p.000121: Monitoring (ICH E6, 1.38) Monitoring Report (ICH E6, 1.39)
p.000121: Quality Assurance (QA) (ICH E6, 1.46) Quality Control (QC) (ICH E6, 1.47)
p.000121: Standard Operating Procedures (SOPs) (ICH E6, 1.55)
p.000121:
p.000121:
p.000121:
p.000121: 120 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: References
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: Documents on the CD
p.000121: 1. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Annex 3 of The Use of Essential
p.000121: Drugs Sixth report of the WHO Expert Committee. Geneva. World Health Organization, 1995: 97–137.
p.000121: http://www.who.int/medicines/en/
p.000121: 2. ICH E6: Good Clinical Practice: Consolidated Guideline 1996. http://www. ich.org/
p.000121: 3. Operational guidelines for ethics committees that review biomedical re- search. TDR/PRD/ETHICS/2000.1 (2000).
p.000121: http://www.who.int/tdr/
p.000121: 4. Surveying and evaluating ethical review practices: A complementary guideline to the Operational guidelines
p.000121: for ethics committees that review biomedical research. TDR/PRD/ETHICS/2002.1 (2002). http://www.who.int/tdr/
p.000121: 5. Operational Guidelines for the Establishment and Functioning of Data & Safety Monitoring Boards. UNICEF/UNDP/WHO
p.000121: Special Programme on Re- search and Training in Tropical Diseases (TDR) 2005. In press.
p.000121: 6. Good Clinical Practices: Document of the Americas. Working Group on good clinical practices (GCP) Chapter 7 and
...
Searching for indicator access to information:
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p.000121: Guideline 18)
p.000121:
p.000121: Application
p.000121: Principle 12 is applied (1) through appropriate procedures to protect the privacy of the subject, and (2) by document
p.000121: and data control to protect the confidentiality of the subject’s information.
p.000121: Principle 12 is also applied through the informed consent process which requires as an essential element
p.000121: that certain explanations be provided to the subject about the confidentiality of the subject’s records and about
p.000121: access to those records by monitor(s), auditor(s), the IEC/IRB, and the regulatory authority(-ies).
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “privacy”? What is meant by “confidentiality”?
p.000121: Privacy embraces the concept that each individual should have the right to control personal and sensitive
p.000121: information about him/her. Privacy implies that such information, which may be contained in
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 103
p.000121:
p.000121: medical records, personal diaries, or elsewhere, will be protected and not disclosed without the
p.000121: knowledge/permission of the indi- vidual to whom it pertains.
p.000121: Privacy may not be absolute, however. For example, some informa- tion, such as exposure to a communicable
p.000121: disease, may be subject to limited disclosure under public health laws; access to information contained in clinical
p.000121: study records may be required by regulators to verify data submitted in a marketing application. Thus,
p.000121: individuals who participate in clinical trials should be told the extent to which their information will
p.000121: be protected and the circumstances under which the information will be disclosed, to whom, and the purpose(s) for
p.000121: doing so.
p.000121: Confidentiality embraces the concept that parties who obtain private information from patients and
p.000121: subjects will (1) protect the information itself and any records that contain such information from deliberate or
p.000121: accidental disclosure; and (2) develop and follow proce- dures for release of the information only to
p.000121: authorized parties who have a legitimate need for it, including notification of the patient/ subject prior
p.000121: to any disclosure.
p.000121:
p.000121:
p.000121: Who is responsible for protecting the confidentiality of the subjects’ private information?
p.000121: At all times throughout the investigation, all parties (sponsor, moni- tor, IECs/IRBs, investigator,
p.000121: investigator’s staff, and regulators) should protect subjects’ private information and ensure that all data are se-
p.000121: cured against unauthorized access. This applies but is not limited to subjects’ case report forms (CRFs), source data,
p.000121: source documents, and safety reports.
p.000121: “It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the
p.000121: human subject.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121:
...
Social / Child
Searching for indicator child:
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p.000121: Other mechanisms to protect information include, but are not limited to:
p.000121: • coding or encryption of data;
p.000121: • restricting access to study records and subjects’ medical files (e.g. passwords on electronic files, files
p.000121: secured in locked cabinets or secured storage areas);
p.000121: • maintaining subjects’ names and identifying information separate- ly from case report forms;
p.000121: • establishing and following procedures to ensure subjects’ private information and trial data are protected.
p.000121:
p.000121:
p.000121: Why should potential risks related to release of private information be disclosed to study subjects?
p.000121: Each subject needs to consider whether risks related to release of private information are sufficiently
p.000121: controlled, such that he/she is still willing to participate in the investigation.
p.000121: “Research relating to individuals and groups may involve the col- lection and storage of information
p.000121: that, if disclosed to third parties, could cause harm or distress.” (CIOMS, International Ethical Guide-
p.000121: lines, Commentary to Guideline 18)
p.000121: “Prospective subjects should be informed of limits to the ability of investigators to ensure strict
p.000121: confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality. Some
p.000121: jurisdictions require the reporting to appropriate agencies of, for instance, certain communicable diseases or
p.000121: evidence of child abuse or neglect. Drug regulatory authorities have the right to inspect clini-
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 105
p.000121:
p.000121: cal-trial records, and a sponsor’s clinical-compliance audit staff may require and obtain access to confidential
p.000121: data. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
...
Searching for indicator children:
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p.000121: • informed consent;
p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
...
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
p.000121: infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered
p.000121: on its own terms. Even for these persons, however, respect requires giving
p.000121:
p.000121:
p.000121:
p.000121: 66 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections
p.000121: of these subjects to involvement should be honored, unless the research entails provid- ing them a therapy
p.000121: unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to
p.000121: protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
...
Social / Elderly
Searching for indicator elderly:
(return to top)
p.000121: any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and
p.000121: documented approval/favourable opinion from the IEC/IRB of a protocol amendment (see ICH E6, Sec- tion 4.5).
p.000121: “Ethical review committees generally have no authority to impose sanctions on researchers who violate
p.000121: ethical standards in the con- duct of research involving humans. They may, however, withdraw ethical
p.000121: approval of a research project if judged necessary.” (CIOMS, International Ethical Guidelines, Commentary to
p.000121: Guideline 2)
p.000121:
p.000121:
p.000121: If the benefit-risk profile of the study changes and/or substantive protocol modifications are made, how should the
p.000121: information be communicated to study subjects?
p.000121: How is this documented?
p.000121: “Sponsors and investigators have a duty to … renew the informed consent of each subject if there are
p.000121: significant changes in the condi- tions or procedures of the research or if new information becomes available
p.000121: that could affect the willingness of subjects to continue to participate …” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 6)
p.000121: Periodically in long-term studies, the investigator should also con- sider renewing consent (e.g. in
p.000121: long-term studies involving elderly subjects).
p.000121: Communicating the new information to study subjects should follow customary procedures for obtaining and documenting
p.000121: informed con- sent.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 77
p.000121:
p.000121: What is an Independent Data and Safety Monitoring Board (DSMB, also known as an independent Data Monitoring Committee
p.000121: [DMC])?
p.000121: An independent data and safety monitoring board (DSMB) is a group of individuals with pertinent expertise that reviews
p.000121: on a regular basis accumulating data from one or more ongoing clinical trials. The DSMB advises the sponsor
p.000121: regarding the continuing safety of current trial participants and those yet to be recruited to the trial, as well
p.000121: as the continuing validity and scientific merit of the trial.
p.000121: “At intervals defined by the protocol, the DSMB reviews and evalu- ates the data on clinical efficacy
p.000121: and safety collected during the study, and assesses reports on cumulated serious adverse events (SAEs). The
p.000121: DSMB may also be requested by the sponsor to conduct emergency reviews of data to assess safety-related issues. … At
p.000121: the conclusion of the review, the DSMB provides a written recommenda- tion to the sponsor regarding whether a protocol
p.000121: should be amended and/or a study should proceed based on its review of the data and the progress report
p.000121: submitted by the sponsor.” (Operational Guide- lines for the Establishment and Functioning of Data and Safety
p.000121: Moni- toring Boards, WHO TDR).
...
Social / Ethnicity
Searching for indicator ethnicity:
(return to top)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
p.000121: standards. This in- cludes the investigator(s) and site staff, the sponsor and sponsor’s staff (including
p.000121: monitors and auditors), the ethics committee(s), the regulatory authority(-ies), and the individual research subjects.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 24 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities):
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
...
Social / Fetus/Neonate
Searching for indicator fetus:
(return to top)
p.000121: activity.
p.000121:
p.000121:
p.000121: What “information” should be given to study subjects in accordance with GCP?
p.000121: GCP recognizes that certain essential elements of informed consent should be included in the informed consent
p.000121: discussion, the written informed consent form, and any other information to be provided to subjects who participate
p.000121: in the study. All information must be com- municated in a comprehensive and understandable manner to the
p.000121: research subject. This includes, but is not limited to:
p.000121: • title of the protocol;
p.000121: • identity of the sponsor;
p.000121: • identity of the clinical investigator and institutional affiliation of the investigator;
p.000121: • source of research funding (e.g. public, private, or both);
p.000121: • that the trial involves research;
p.000121: • that the subject’s participation in the trial is voluntary and that the subject may refuse to participate or
p.000121: withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise
p.000121: entitled;
p.000121: • the purpose of the trial;
p.000121: • the trial treatment(s) and the probability for random assignment to each treatment;
p.000121: • the trial procedures to be followed, including all invasive proce- dures;
p.000121: • the subject’s responsibilities;
p.000121: • those aspects of the trial that are experimental;
p.000121: • the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus or
p.000121: nursing infant;
p.000121:
p.000121:
p.000121:
p.000121: 62 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject
p.000121: should be made aware of this;
p.000121: • the alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
...
Social / Homeless Persons
Searching for indicator homeless:
(return to top)
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
...
Social / Incarcerated
Searching for indicator restricted:
(return to top)
p.000121: http://www.who.int/reproductive health/hrp/SERG_guidelines.en.html
p.000121: 5. RHR. Guideline for obtaining informed consent for the procurement and use of human tissues, cells and fluids in
p.000121: research. http://www.who.int/reproductive-health/ hrp/SERG_guidelines.en.html
p.000121: 6. TDR Standard operating procedures for clinical investigators. TDR/TDP/ SOP/99.1
p.000121: www.who.int/tdr/publications/publications/sop.htm
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
p.000121: 8. TDR Guidelines for Ethical Clearance & TDR Ethical Clearance Checklist
p.000121: http://www.who.int/tdr/publications/
p.000121: 9. Indigenous peoples & participatory health research. http://www.who.int/ethics/indigenous_peoples/en/
p.000121: 10. UNAIDS (Joint United Nations Programme on HIV/AIDS): Ethical considera- tions in HIV preventive vaccine research.
p.000121: http://www.unaids.org/publications/documents/vaccines/index.html
p.000121:
p.000121: REFERENCES | 123
p.000121:
p.000121: 11. International guidelines for ethical review of epidemiological studies. CIOMS, Geneva, 1991 (revision
p.000121: pending). http://www.cioms.ch/
p.000121: 12. Additional Protocol to the Convention of Human Rights and Biomedicine concerning biomedical research. Council of
p.000121: Europe. European Treaty Se- ries – 195. http://www.coe.int/T/E/Legal_Affairs/
p.000121: 13. Steering Committee on Bioethics (CDBI) Restricted CDBI/INF (2002) 5. Council of Europe.
p.000121: http://www.coe.int/T/E/Legal_Affairs/
p.000121:
p.000121:
p.000121: National good clinical practice and other guidelines
p.000121: Australia
p.000121: Regulation of clinical trials in Australia: http://www.tga.gov.au
p.000121:
p.000121: Canada
p.000121: Good clinical practices.
p.000121: http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/hp_gcp_e.html
p.000121:
p.000121: European Union
p.000121: European Agency for Evaluation of Medicines (EMEA). ICH topic E6. Note for guidance on good clinical practice
p.000121: (CPMP/ICH/135/95) http://www.emea.eu.int/pdfs/human/ich/013595en.pdf
p.000121: European Clinical Trials Directive for GCP, 2001/20/EC, 04.2001
p.000121:
p.000121: India
p.000121: Ethical guidelines for biomedical research on human subjects. http://icmr.nic.in/ethical.pdf
p.000121: Japan
p.000121: Ministry of Health, Labour and Welfare. “Standards on the Implementation of Clinical Trials on Drugs (New GCO)”.
p.000121: Japan’s New GCP and Other Rules on Clinical Trials, Parts 1, 2, and 3 issued by the Ministry of Health and Welfare with
p.000121: a copyright of 1998
p.000121: South Africa
p.000121: Guidelines for good practice in the conduct of clinical trials in human partici- pants in South Africa.
p.000121: http://196.36.153.56/docs/policy/trials/trials-full.html
p.000121:
p.000121: United States of America
p.000121: Good clinical practice in FDA regulated clinical trials. http://www.fda.gov/oc/gcp/default.htm
p.000121:
p.000121:
p.000121:
p.000121: 124 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Acknowledgements
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
...
Social / Infant
Searching for indicator infant:
(return to top)
p.000121:
p.000121: What “information” should be given to study subjects in accordance with GCP?
p.000121: GCP recognizes that certain essential elements of informed consent should be included in the informed consent
p.000121: discussion, the written informed consent form, and any other information to be provided to subjects who participate
p.000121: in the study. All information must be com- municated in a comprehensive and understandable manner to the
p.000121: research subject. This includes, but is not limited to:
p.000121: • title of the protocol;
p.000121: • identity of the sponsor;
p.000121: • identity of the clinical investigator and institutional affiliation of the investigator;
p.000121: • source of research funding (e.g. public, private, or both);
p.000121: • that the trial involves research;
p.000121: • that the subject’s participation in the trial is voluntary and that the subject may refuse to participate or
p.000121: withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise
p.000121: entitled;
p.000121: • the purpose of the trial;
p.000121: • the trial treatment(s) and the probability for random assignment to each treatment;
p.000121: • the trial procedures to be followed, including all invasive proce- dures;
p.000121: • the subject’s responsibilities;
p.000121: • those aspects of the trial that are experimental;
p.000121: • the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus or
p.000121: nursing infant;
p.000121:
p.000121:
p.000121:
p.000121: 62 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject
p.000121: should be made aware of this;
p.000121: • the alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
p.000121: • that records identifying the subject will be kept confidential and, to the extent permitted by the
...
Social / Institutionalized
Searching for indicator institutionalized:
(return to top)
p.000121: Principles 3: Risk Identification; 4: Benefit-Risk Assess- ment; 8: Continuing Review/Ongoing Benefit-Risk Assessment)
p.000121:
p.000121:
p.000121: What is meant by “justice” and how is it most directly implemented within GCP?
p.000121: “… the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the
p.000121: selection of research sub- jects.” (The Belmont Report)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
...
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.000121: “… Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and
p.000121: truthful answers should always be given to direct questions about the research. Care should be taken to distinguish
p.000121: cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply
p.000121: inconvenience the investigator.” (The Belmont Report)
p.000121: Due consideration should be given to obtaining consent for the col- lection and/or use of biological specimens,
p.000121: including future purposes. Guidance is developing in this area (see CIOMS International Ethical Guidelines;
p.000121: CIOMS Report on Pharmacogenetics – Towards improving treatment with medicines, 2005; Council of Europe [CDBI]
p.000121: Additional Protocols to Oviedo Convention, 2005).
p.000121:
p.000121:
p.000121: What is meant by “comprehension”? That is, how do investigators ensure that subjects understand information about the
p.000121: study, and how is this implemented in accordance with GCP?
p.000121: “The manner and context in which information is conveyed is as im- portant as the information itself. For example,
p.000121: presenting information in a disorganized and rapid fashion, allowing too little time for consid- eration or curtailing
p.000121: opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.” (The Belmont
p.000121: Report)
p.000121: “Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather,
p.000121: the investigator must convey the information, whether orally or in writing, in language that
p.000121:
p.000121:
p.000121: 64 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: suits the individual’s level of understanding. The investigator must bear in mind that the prospective
p.000121: subject’s ability to understand the information necessary to give informed consent depends on that individual’s
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
...
p.000121: benefit for the individual subject should be no more likely and not greater than the risk attached to
p.000121: routine medical or psychological ex- amination of such persons. Slight or minor increases above such risk may be
p.000121: permitted when there is an overriding scientific or medical rationale for such increases and when an ethical
p.000121: review committee has approved them.” (CIOMS, International Ethical Guidelines, Guide- line 9)
p.000121:
p.000121: When should informed consent be obtained? What is meant by “prior to trial participation”?
p.000121: Informed consent should be obtained from each subject or the sub- ject’s legally authorized representative prior to
p.000121: involving the subject
p.000121:
p.000121:
p.000121: 68 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: in any study-specific activities. This includes diagnostic or other tests that are administered solely for determining
p.000121: the subject’s eligibility to participate in the research.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing and overseeing the informed consent process is shared by sponsors,
p.000121: clinical investigators, IECs/ IRBs, and regulatory authorities.
p.000121: IECs/IRBs are responsible for:
p.000121: • reviewing the informed consent document to ensure that it is ac- curate, complete, and written in language that
p.000121: will be understood by the potential study subjects and translated into other languag- es, as appropriate;
p.000121: • requesting modifications to the informed consent document, as appropriate; and
p.000121: • at their discretion, observing the consent process and the re- search.
p.000121: Investigators are responsible for ensuring that:
p.000121: • staff responsible for obtaining informed consent receive appropri- ate training, both in research ethics and in the
p.000121: requirements of the specific study protocol;
p.000121: • the IEC/IRB reviews and approves the informed consent form and other written information to be used in the study
p.000121: prior to its use; and
p.000121: • informed consent is obtained from each subject or the subject’s representative prior to involving the
p.000121: subject in any study related activities, including diagnostic or other tests that are administered solely for
p.000121: determining the subject’s eligibility to participate in the research.
p.000121: Sponsors are responsible for monitoring the research at study sites to ensure that sites are obtaining informed
p.000121: consent from all study subjects prior to subjects’ inclusion in the research study.
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 69
p.000121:
p.000121: In accordance with national and local laws and regulations, regula- tors may inspect the various parties
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000121: Group and Related Issues in Clinical Trials)
p.000121: “As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive
p.000121: intervention should receive an established effective intervention. In some circumstances it may be ethi- cally
p.000121: acceptable to use an alternative comparator, such as placebo or “no treatment”.” (CIOMS, International Ethical
p.000121: Guidelines, Guideline 11)
p.000121:
p.000121:
p.000121: 30 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What can be done to minimize bias in a clinical investigation?
p.000121: Bias implies subjective or unfair distortion of judgment in favour of or against a person or thing. The purpose
p.000121: of conducting a clinical trial of an investigational product is to distinguish the effect of the inves- tigational
p.000121: product from other factors, such as spontaneous changes in the course of the disease, placebo effects, or
p.000121: biased/subjective observation. Bias can be minimized in a clinical trial by designing well-controlled
p.000121: studies, by using procedures to randomize subjects to various study arms based on the generation of a random
p.000121: alloca- tion sequence, and by using concealment and blinding.
p.000121:
p.000121:
p.000121: What is meant by “blinding” or “masking”?
p.000121: Blinding or masking is “[a] procedure in which one or more parties to the trial are kept unaware of the
p.000121: treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double blinding
p.000121: usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being
p.000121: unaware of the treatment assignment(s).” (ICH E6, 1.10)
p.000121:
p.000121:
p.000121: When is unblinding of the trial by the investigator permissible? How should unblinding be accomplished (in those
p.000121: situations where it would be allowed)?
p.000121: Unblinding may be necessary in the event of a medical emergency for a research subject. Generally breaking the blind
p.000121: involves procedures specified in the study protocol that allow the investigator and/or sponsor to find out
p.000121: whether a particular subject received the inves- tigational product, or received a comparator product or
p.000121: placebo, where applicable, while on the study.
p.000121: “The investigator … should ensure that the code is broken only in accordance with the protocol. If the trial
p.000121: is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g.,
p.000121: accidental unblinding, unblinding due to a serious ad- verse event) of the investigational product(s).” (ICH E6,
p.000121: Section 4.7)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 31
p.000121:
p.000121: What is meant by “randomization”?
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
...
Social / Property Ownership
Searching for indicator property:
(return to top)
p.000121: of study-related data, and analysis of study results.
p.000121: The sponsor generally develops, designs, and provides various stand- ardized forms and checklists to assist the
p.000121: clinical investigator and his/ her staff in capturing and reporting data required by the protocol.
p.000121: See WHO GCP Principles 2: Protocol; 7: Informed Consent; 11: Records; 14: Quality Systems.
p.000121: Examples of trial information documents include, but are not limited to:
p.000121: • investigator’s brochure;
p.000121: • checklists to identify and document the required steps for each of the various clinical trial activities (e.g.
p.000121: investigator selection, ap- provals and clearances, monitoring, adverse event reporting and evaluation,
p.000121: analysis of interim data);
p.000121: • investigational supplies accountability forms to document the amount and source of investigational
p.000121: product shipped and re- ceived, the amount dispensed to subjects, and the return/destruc- tion, as appropriate, of
p.000121: any unused product;
p.000121: • signature logs and other forms to document by whom activities are completed, when, and the sequence in
p.000121: which they are carried out;
p.000121: • case report forms (CRFs) for each scheduled study visit to capture all of the necessary data collected from and
p.000121: reported for each sub- ject;
p.000121: • informed consent documents;
p.000121: • adverse event or safety reporting forms;
p.000121: • administrative forms to track research funds and expenses;
p.000121: • forms to disclose information about the investigator’s financial, property, or other interests in the
p.000121: product under study, in accord- ance with national/local law or regulations;
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 11
p.000121:
p.000121: • formats for reports of monitoring visits;
p.000121: • formats for progress reports, annual reports, and final study re- ports.
p.000121:
p.000121:
p.000121: 5. Selection of trial sites and the selection of properly qualified, trained, and experienced investigators and study
p.000121: personnel
p.000121: Clinical investigators must be qualified and have sufficient resources and appropriately trained staff to conduct
p.000121: the investigation and be knowledgeable of the national setting and circumstances of the site and study
p.000121: population(s). Sponsors should review the requirements of the study protocol to determine the type(s) of expertise
p.000121: required and identify clinical investigators who have the particular medical expertise necessary to conduct the
p.000121: study and who have knowledge, training and experience in the conduct of clinical trials and human subject
p.000121: protection.
p.000121: See WHO GCP Principles 2: Protocol; 9: Investigator Qualifications; 10: Staff Qualifications.
p.000121:
p.000121:
p.000121: 6. Ethics committee review and approval of the protocol
p.000121: Within GCP, studies must be reviewed and receive approval/ favourable opinion from an Independent
p.000121: Ethics Committee (IEC)/ Institutional Review Board (IRB) prior to enrollment of study subjects.
...
Social / Racial Minority
Searching for indicator race:
(return to top)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
p.000121: standards. This in- cludes the investigator(s) and site staff, the sponsor and sponsor’s staff (including
p.000121: monitors and auditors), the ethics committee(s), the regulatory authority(-ies), and the individual research subjects.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 24 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities):
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
...
Searching for indicator racial:
(return to top)
p.000121: during design and review (initial review as well as continuing review) of the study protocol. (See also WHO GCP
p.000121: Principles 3: Risk Identification; 4: Benefit-Risk Assess- ment; 8: Continuing Review/Ongoing Benefit-Risk Assessment)
p.000121:
p.000121:
p.000121: What is meant by “justice” and how is it most directly implemented within GCP?
p.000121: “… the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the
p.000121: selection of research sub- jects.” (The Belmont Report)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
...
p.000121: (1) determine whether the benefits outweigh the risks, (2) understand the study procedures or other steps that will
p.000121: be taken to minimize risks, and (3) ensure that the informed consent document accurately states the potential risks and
p.000121: benefits in a way that will facilitate comprehension by all study subjects, with particular attention to vulnerable
p.000121: groups.
p.000121: Investigators must be knowledgeable of the protocol, investigator’s brochure and other relevant information regarding
p.000121: potential risks and benefits, and must be able to adequately, accurately and objectively identify the potential risks
p.000121: and benefits to subjects. Investigators may need to do some additional literature search beyond that provided by the
p.000121: sponsor. Investigators should also be thoroughly familiar with the appropriate use of the trial
p.000121: product(s)/procedures and should take the necessary steps to remain aware of all relevant new data on the
p.000121: investigational product, procedure, or method that becomes avail- able during the course of the clinical trial.
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with existing national laws/regulations
p.000121: or internationally accepted standards. This may include prospective review of the pro- tocol, the investigator’s
p.000121: brochure and other relevant information to ensure that risk(s) and benefit(s) are accurately identified and
p.000121: justify allowing the protocol to proceed. As appropriate, adopted national standards should address
p.000121: additional national or regional racial, cul- tural, or religious standards/issues not otherwise covered by
p.000121: the international standards. In accordance with national/local laws and regulations, regulators may establish
p.000121: standards for the conduct of
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 39
p.000121:
p.000121: non-clinical studies, review non-clinical and clinical data submitted in support of research permits or
p.000121: marketing applications, and/or in- spect facilities that conduct non-clinical and clinical studies.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: For clinical investigators, refer to: Investigator’s Brochure (ICH E6, Section 7)
p.000121: Clinical Trial Protocol, General Information (ICH E6, Section 6)
p.000121: For sponsors, refer to:
p.000121: Investigator’s Brochure (ICH E6, Section 7) Clinical Trial Protocol (ICH E6, Section 6)
p.000121: UNDP/World Bank WHO Special Programme for Research and Training in Tropical Diseases (TDR) “Handbook on
p.000121: Good Labora- tory Practice (GLP): Quality Practices for Regulated Non-Clinical Research and Development” (September
p.000121: 2000)
p.000121: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (ICH M3)
...
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
...
Social / Religion
Searching for indicator faith:
(return to top)
p.000121: For regulatory authorities, refer to
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 1: Ethical Conduct
p.000121: GCP Principle 4: Benefit-Risk Assessment
p.000121: Definitions for:
p.000121: Informed Consent (ICH E6, 1.28)
p.000121: Legally Acceptable Representative (ICH E6, 1.37) Vulnerable Subjects (ICH E6, 1.61)
p.000121: Well-being (of the trial subjects) (ICH E6, 1.62)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 71
p.000121:
p.000121: PRINCIPLE 8: CONTINUING REVIEW/ONGOING BENEFIT-RISK ASSESSMENT
p.000121: Research involving humans should be continued only if the ben- efit-risk profile remains favourable.
p.000121: “During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any
p.000121: stage, if he has prob- able cause to believe, in the exercise of the good faith, superior skill, and careful
p.000121: judgment required of him that a continuation of the ex- periment is likely to result in injury, disability, or
p.000121: death to the experi- mental subject.” (The Nuremberg Code)
p.000121: “… The ethical review committee should conduct further reviews as necessary in the course of the research,
p.000121: including monitoring of its progress.” (CIOMS, International Ethical Guidelines, Guideline 2)
p.000121: “… The committee has the right to monitor ongoing trials …“ (Decla- ration of Helsinki)
p.000121: “… Clinical trial sponsors should develop a process to assess, evalu- ate and act on safety information during drug
p.000121: development on a con- tinuous basis in order to ensure the earliest possible identification of safety concerns and to
p.000121: take appropriate risk minimization steps. Such steps can include modification of study protocols, to
p.000121: incorporate strategies to ensure that clinical trial participants are not exposed to undue risk.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Identification and Evaluation of Risk from
p.000121: Clinical Trial Data)
p.000121:
p.000121: Application
p.000121: Principle 8 is applied through development and implementation of processes for evaluating risks and
p.000121: benefits of the research as ad- ditional information becomes available during the course of the
p.000121: study. Principle 8 encompasses (1) safety monitoring of the study by investigator(s) and sponsor
...
Searching for indicator belief:
(return to top)
p.000121: including future purposes. Guidance is developing in this area (see CIOMS International Ethical Guidelines;
p.000121: CIOMS Report on Pharmacogenetics – Towards improving treatment with medicines, 2005; Council of Europe [CDBI]
p.000121: Additional Protocols to Oviedo Convention, 2005).
p.000121:
p.000121:
p.000121: What is meant by “comprehension”? That is, how do investigators ensure that subjects understand information about the
p.000121: study, and how is this implemented in accordance with GCP?
p.000121: “The manner and context in which information is conveyed is as im- portant as the information itself. For example,
p.000121: presenting information in a disorganized and rapid fashion, allowing too little time for consid- eration or curtailing
p.000121: opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.” (The Belmont
p.000121: Report)
p.000121: “Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather,
p.000121: the investigator must convey the information, whether orally or in writing, in language that
p.000121:
p.000121:
p.000121: 64 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: suits the individual’s level of understanding. The investigator must bear in mind that the prospective
p.000121: subject’s ability to understand the information necessary to give informed consent depends on that individual’s
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
...
Searching for indicator religious:
(return to top)
p.000121: be taken to minimize risks, and (3) ensure that the informed consent document accurately states the potential risks and
p.000121: benefits in a way that will facilitate comprehension by all study subjects, with particular attention to vulnerable
p.000121: groups.
p.000121: Investigators must be knowledgeable of the protocol, investigator’s brochure and other relevant information regarding
p.000121: potential risks and benefits, and must be able to adequately, accurately and objectively identify the potential risks
p.000121: and benefits to subjects. Investigators may need to do some additional literature search beyond that provided by the
p.000121: sponsor. Investigators should also be thoroughly familiar with the appropriate use of the trial
p.000121: product(s)/procedures and should take the necessary steps to remain aware of all relevant new data on the
p.000121: investigational product, procedure, or method that becomes avail- able during the course of the clinical trial.
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with existing national laws/regulations
p.000121: or internationally accepted standards. This may include prospective review of the pro- tocol, the investigator’s
p.000121: brochure and other relevant information to ensure that risk(s) and benefit(s) are accurately identified and
p.000121: justify allowing the protocol to proceed. As appropriate, adopted national standards should address
p.000121: additional national or regional racial, cul- tural, or religious standards/issues not otherwise covered by
p.000121: the international standards. In accordance with national/local laws and regulations, regulators may establish
p.000121: standards for the conduct of
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 39
p.000121:
p.000121: non-clinical studies, review non-clinical and clinical data submitted in support of research permits or
p.000121: marketing applications, and/or in- spect facilities that conduct non-clinical and clinical studies.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: For clinical investigators, refer to: Investigator’s Brochure (ICH E6, Section 7)
p.000121: Clinical Trial Protocol, General Information (ICH E6, Section 6)
p.000121: For sponsors, refer to:
p.000121: Investigator’s Brochure (ICH E6, Section 7) Clinical Trial Protocol (ICH E6, Section 6)
p.000121: UNDP/World Bank WHO Special Programme for Research and Training in Tropical Diseases (TDR) “Handbook on
p.000121: Good Labora- tory Practice (GLP): Quality Practices for Regulated Non-Clinical Research and Development” (September
p.000121: 2000)
p.000121: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (ICH M3)
p.000121: Preclinical Testing of Biotechnology-Derived Pharmaceuticals (ICH S6)
...
Social / Soldier
Searching for indicator military:
(return to top)
p.000121: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. April 18, 1979.
p.000121: http://www.nihtraining.com/ohsrsite/guidelines/belmont.html
p.000121: 6. The ENGAGE Guideline for Good Clinical Practice Compliance and Quality Systems Auditing. 21.08.1997. ENGAGE
p.000121: European Network of GCP Auditors and other GCP Experts. (in process of revision).
p.000121: 7. ICH E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 1994.
p.000121: http://www.ich.org/
p.000121: 8. ICH E2B(R): Revision of the E2B(M) ICH Guideline on Clinical Safety Data Management. Data Elements for
p.000121: Transmission of Individual Case Safety Reports. Step 3 undergoing consultation. May. 2005. http://www.ich.org/
p.000121: 9. ICH E3: Structure and Content of Clinical Study Reports. 1995. http://www. ich.org/
p.000121: 10. ICH E9: Statistical Principles for Clinical Trials. 1998. http://www.ich.org/
p.000121: 11. ICH E10: Choice of Control Group and Related Issues in Clinical Trials. 2000. http://www.ich.org/
p.000121: 12. ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Popula- tion. 2000. http://www.ich.org/
p.000121: 13. ICH M3: Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials
p.000121: for Pharmaceuticals. 1997. http://www.ich.org/
p.000121: 14. ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceu- ticals. 1997. http://www.ich.org/
p.000121:
p.000121:
p.000121: 122 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 15. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10,
p.000121: Vol. 2, pp. 181–182. Washing- ton, D.C.: U.S. Government Printing Office, 1949.
p.000121: http://www.med.umich.edu/irbmed/ethics/Nuremberg/NurembergCode. html
p.000121: 16. United Nations International Covenant on Civil and Political Rights. 1966.
p.000121: http://www.hrweb.org/legal/cpr.html
p.000121:
p.000121:
p.000121: Related documents
p.000121: 1. ETH. Global list of national bioethics committees with contact details. http://www.who.int/ethics/en
p.000121: 2. IVB. Ethical considerations arising from vaccine trials.
p.000121: http://www.who.int/entity/vaccine_research/documents/en/manu774. pdf
p.000121: 3. RHR. Implementation of Good Clinical Practice (GCP) guidelines in RHR re- search activities.
p.000121: http://www.who.int/reproductive-health/publications/RHR_02_05/ Section_11.PDF
p.000121: 4. RHR Guidelines for research. http://www.who.int/reproductivehealth/hrp/ ethical_issues.en.html
p.000121: http://www.who.int/reproductive health/hrp/SERG_guidelines.en.html
p.000121: 5. RHR. Guideline for obtaining informed consent for the procurement and use of human tissues, cells and fluids in
p.000121: research. http://www.who.int/reproductive-health/ hrp/SERG_guidelines.en.html
p.000121: 6. TDR Standard operating procedures for clinical investigators. TDR/TDP/ SOP/99.1
p.000121: www.who.int/tdr/publications/publications/sop.htm
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
...
Social / Threat of Stigma
Searching for indicator stigma:
(return to top)
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
p.000121: • that records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regulations, will not be made publicly available. If the results of the trial are
p.000121: published, the subject’s identity will remain confidential;
p.000121: • the potential risks should confidentiality measures be compro- mised (e.g. stigma, loss of reputation,
p.000121: potential loss of insurabil- ity);
p.000121: • that the subject or the subject’s legally authorized representative will be informed in a timely manner if
p.000121: information becomes avail- able that may be relevant to the subject’s willingness to continue participation in the
p.000121: trial;
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 63
p.000121:
p.000121: • the person(s) to contact for further information regarding the trial and the rights of research subjects, and
p.000121: whom to contact in the event of trial-related injury;
p.000121: • the foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be
p.000121: terminated;
p.000121: • the expected duration of the subject’s participation in the trial;
p.000121: • the approximate number of subjects involved in the trial.
p.000121: “… Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and
p.000121: truthful answers should always be given to direct questions about the research. Care should be taken to distinguish
p.000121: cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply
p.000121: inconvenience the investigator.” (The Belmont Report)
p.000121: Due consideration should be given to obtaining consent for the col- lection and/or use of biological specimens,
p.000121: including future purposes. Guidance is developing in this area (see CIOMS International Ethical Guidelines;
p.000121: CIOMS Report on Pharmacogenetics – Towards improving treatment with medicines, 2005; Council of Europe [CDBI]
...
p.000121: confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality. Some
p.000121: jurisdictions require the reporting to appropriate agencies of, for instance, certain communicable diseases or
p.000121: evidence of child abuse or neglect. Drug regulatory authorities have the right to inspect clini-
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 105
p.000121:
p.000121: cal-trial records, and a sponsor’s clinical-compliance audit staff may require and obtain access to confidential
p.000121: data. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
p.000121: the precautions that will be taken to protect confidentiality.” (CIOMS, International Ethical Guidelines, Commentary
p.000121: to Guideline 18)
p.000121: “Both the informed consent discussion and the written informed consent form and any other written
p.000121: information to be provided to subjects should include explanations of the following:
p.000121: “(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regu- latory authority(ies) will be granted direct
p.000121: access to the subject’s original medical records for verification of clinical trial procedures and/or data, without
p.000121: violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations
p.000121: and that, by signing a written informed consent form, the subject or the subject’s legally acceptable
p.000121: representative is authorizing such access.”
p.000121: “(o) That records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regula-
p.000121:
p.000121:
p.000121: 106 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000121:
p.000121: • means for obtaining informed consent and communication of in- formation to prospective subjects.
p.000121:
p.000121:
p.000121: What is a “protocol amendment”?
p.000121: “A protocol amendment is a written description of a change(s) to or formal clarification of a protocol.” (ICH E6,
p.000121: Section 1.45)
p.000121:
p.000121:
p.000121: What types of changes may require formal amendment of the protocol?
p.000121: Regional,1 national, or local laws and regulations may require spon- sors to prepare formal protocol
p.000121: amendments to describe any change that significantly affects the safety of subjects, the scope of the in-
p.000121: vestigation, or the scientific quality of the study.
p.000121: Examples of changes that generally require formal amendment in- clude, but are not limited to:
p.000121: • changes in drug dosage or duration of exposure of individual sub- jects to an investigational product beyond
p.000121: that described in the current protocol;
p.000121: • significant increase in the number of subjects under study or in the duration of the study;
p.000121: • significant change in the study design, such as adding or dropping a study arm; and
p.000121: • addition of a new test or procedure that is intended to improve monitoring for or reduce the risk of a
p.000121: side effect or adverse event, or the dropping of a test intended to monitor safety.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 1 In this document, “regional” refers to supranational laws, regulations, or require- ments, such as those
p.000121: adopted by the European Union.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 29
p.000121:
p.000121: What is the “investigator’s brochure” and how does it relate to the protocol?
p.000121: The investigator’s brochure is a “compilation of the clinical and non- clinical data on the investigational
p.000121: product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6, 1.36)
p.000121: In general, the investigator’s brochure provides more complete back- ground information on the investigational
p.000121: product than is provided in the protocol. The investigator’s brochure assists the investigator in
p.000121: interpreting and implementing the study protocol, and may be of particular importance in helping the
p.000121: investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such
p.000121: events should be reported to the sponsor, IEC/IRB, and regulators.
p.000121:
p.000121: What is meant by a well-controlled study?
p.000121: A well-controlled study uses a design that permits a comparison of subjects treated with the
p.000121: investigational agent/intervention to a suitable control population, so that the effect of the
p.000121: investigational agent/intervention can be determined and distinguished from other influences, such as spontaneous
p.000121: change, “placebo” effects, concom- itant therapy(ies)/intervention(s), or observer expectations.
p.000121:
p.000121: What are some designs for controlled clinical studies?
p.000121: Commonly used designs for controlled clinical studies include: pla- cebo concurrent control; no-treatment
p.000121: concurrent control; dose- response concurrent control; active (positive) concurrent control; external control
...
p.000121: 7. TDR. Workbook for investigators. Section 2, 1999, 22 pages, TDR/TDP/SOP/
p.000121: 99.1 and 2002 TDR/PRD/GCP/02.1b 271 pages English. http://www.who.int/tdr/publications/publications/sop.htm
p.000121: 8. TDR Guidelines for Ethical Clearance & TDR Ethical Clearance Checklist
p.000121: http://www.who.int/tdr/publications/
p.000121: 9. Indigenous peoples & participatory health research. http://www.who.int/ethics/indigenous_peoples/en/
p.000121: 10. UNAIDS (Joint United Nations Programme on HIV/AIDS): Ethical considera- tions in HIV preventive vaccine research.
p.000121: http://www.unaids.org/publications/documents/vaccines/index.html
p.000121:
p.000121: REFERENCES | 123
p.000121:
p.000121: 11. International guidelines for ethical review of epidemiological studies. CIOMS, Geneva, 1991 (revision
p.000121: pending). http://www.cioms.ch/
p.000121: 12. Additional Protocol to the Convention of Human Rights and Biomedicine concerning biomedical research. Council of
p.000121: Europe. European Treaty Se- ries – 195. http://www.coe.int/T/E/Legal_Affairs/
p.000121: 13. Steering Committee on Bioethics (CDBI) Restricted CDBI/INF (2002) 5. Council of Europe.
p.000121: http://www.coe.int/T/E/Legal_Affairs/
p.000121:
p.000121:
p.000121: National good clinical practice and other guidelines
p.000121: Australia
p.000121: Regulation of clinical trials in Australia: http://www.tga.gov.au
p.000121:
p.000121: Canada
p.000121: Good clinical practices.
p.000121: http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/hp_gcp_e.html
p.000121:
p.000121: European Union
p.000121: European Agency for Evaluation of Medicines (EMEA). ICH topic E6. Note for guidance on good clinical practice
p.000121: (CPMP/ICH/135/95) http://www.emea.eu.int/pdfs/human/ich/013595en.pdf
p.000121: European Clinical Trials Directive for GCP, 2001/20/EC, 04.2001
p.000121:
p.000121: India
p.000121: Ethical guidelines for biomedical research on human subjects. http://icmr.nic.in/ethical.pdf
p.000121: Japan
p.000121: Ministry of Health, Labour and Welfare. “Standards on the Implementation of Clinical Trials on Drugs (New GCO)”.
p.000121: Japan’s New GCP and Other Rules on Clinical Trials, Parts 1, 2, and 3 issued by the Ministry of Health and Welfare with
p.000121: a copyright of 1998
p.000121: South Africa
p.000121: Guidelines for good practice in the conduct of clinical trials in human partici- pants in South Africa.
p.000121: http://196.36.153.56/docs/policy/trials/trials-full.html
p.000121:
p.000121: United States of America
p.000121: Good clinical practice in FDA regulated clinical trials. http://www.fda.gov/oc/gcp/default.htm
p.000121:
p.000121:
p.000121:
p.000121: 124 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Acknowledgements
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: This Handbook has been developed further to requests by Member States. The draft manuscript has been
p.000121: widely circulated and dis- cussed at several informal consultations with international experts involved in
p.000121: clinical trials. Sincere thanks for their contributions and critical review of the text are due to the following
p.000121: persons:
p.000121: Dr Kwabllah Adwazi, Ghana, Dr Francis Crawley, Belgium, Dr J.E. Idän- pään-Heikkilä , Secretary-General CIOMS,
...
Social / Victim of Abuse
Searching for indicator abuse:
(return to top)
p.000121: Other mechanisms to protect information include, but are not limited to:
p.000121: • coding or encryption of data;
p.000121: • restricting access to study records and subjects’ medical files (e.g. passwords on electronic files, files
p.000121: secured in locked cabinets or secured storage areas);
p.000121: • maintaining subjects’ names and identifying information separate- ly from case report forms;
p.000121: • establishing and following procedures to ensure subjects’ private information and trial data are protected.
p.000121:
p.000121:
p.000121: Why should potential risks related to release of private information be disclosed to study subjects?
p.000121: Each subject needs to consider whether risks related to release of private information are sufficiently
p.000121: controlled, such that he/she is still willing to participate in the investigation.
p.000121: “Research relating to individuals and groups may involve the col- lection and storage of information
p.000121: that, if disclosed to third parties, could cause harm or distress.” (CIOMS, International Ethical Guide-
p.000121: lines, Commentary to Guideline 18)
p.000121: “Prospective subjects should be informed of limits to the ability of investigators to ensure strict
p.000121: confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality. Some
p.000121: jurisdictions require the reporting to appropriate agencies of, for instance, certain communicable diseases or
p.000121: evidence of child abuse or neglect. Drug regulatory authorities have the right to inspect clini-
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 105
p.000121:
p.000121: cal-trial records, and a sponsor’s clinical-compliance audit staff may require and obtain access to confidential
p.000121: data. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
...
Social / Women
Searching for indicator women:
(return to top)
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
p.000121: that the research could not be carried out equally well with less vulnerable subjects; seeking permission of a legal
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000121: long-term studies, the investiga- tor should once again seek informed consent from the subjects …“ (CIOMS,
p.000121: International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: Is it ethical to include subjects who are unable to consent?
p.000121: “Research on individuals from whom it is not possible to obtain con- sent, including proxy or advance consent, should
p.000121: be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of
p.000121: the research population. The specific reasons for involving research subjects with a condition that renders them unable
p.000121: to give informed consent should be stated in the experi- mental protocol for consideration and approval of the
p.000121: review com- mittee …” (Declaration of Helsinki)
p.000121: “When there is ethical and scientific justification to conduct research with individuals incapable of giving
p.000121: informed consent, the risk from research interventions that do not hold out the prospect of direct
p.000121: benefit for the individual subject should be no more likely and not greater than the risk attached to
p.000121: routine medical or psychological ex- amination of such persons. Slight or minor increases above such risk may be
p.000121: permitted when there is an overriding scientific or medical rationale for such increases and when an ethical
p.000121: review committee has approved them.” (CIOMS, International Ethical Guidelines, Guide- line 9)
p.000121:
p.000121: When should informed consent be obtained? What is meant by “prior to trial participation”?
p.000121: Informed consent should be obtained from each subject or the sub- ject’s legally authorized representative prior to
p.000121: involving the subject
p.000121:
p.000121:
p.000121: 68 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: in any study-specific activities. This includes diagnostic or other tests that are administered solely for determining
p.000121: the subject’s eligibility to participate in the research.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing and overseeing the informed consent process is shared by sponsors,
p.000121: clinical investigators, IECs/ IRBs, and regulatory authorities.
p.000121: IECs/IRBs are responsible for:
p.000121: • reviewing the informed consent document to ensure that it is ac- curate, complete, and written in language that
p.000121: will be understood by the potential study subjects and translated into other languag- es, as appropriate;
p.000121: • requesting modifications to the informed consent document, as appropriate; and
...
Social / education
Searching for indicator education:
(return to top)
p.000121: research subject and society clearly outweigh the risks. Although the benefit of the results of the trial to science
p.000121: and society should be taken into account, the most important considerations are those related to the rights,
p.000121: safety, and well-being of the research subjects.
p.000121: Principle 5: Research involving humans should receive independ- ent ethics committee/institutional review
p.000121: board (IEC/IRB) approval/ favourable opinion prior to initiation.
p.000121: Principle 6: Research involving humans should be conducted in com- pliance with the approved protocol.
p.000121: Principle 7: Freely given informed consent should be obtained from every subject prior to research participation in
p.000121: accordance with na- tional culture(s) and requirements. When a subject is not capable of giving informed consent, the
p.000121: permission of a legally authorized repre- sentative should be obtained in accordance with applicable law.
p.000121:
p.000121:
p.000121: | 19
p.000121:
p.000121: Principle 8: Research involving humans should be continued only if the benefit-risk profile remains favourable.
p.000121: Principle 9: Qualified and duly licensed medical personnel (i.e. phy- sician or, when appropriate, dentist)
p.000121: should be responsible for the medical care of research subjects, and for any medical decision(s) made on
p.000121: their behalf.
p.000121: Principle 10: Each individual involved in conducting a trial should be qualified by education, training, and experience
p.000121: to perform his or her respective task(s) and currently licensed to do so, where required.
p.000121: Principle 11: All clinical trial information should be recorded, han- dled, and stored in a way that allows
p.000121: its accurate reporting, interpre- tation, and verification.
p.000121: Principle 12: The confidentiality of records that could identify sub- jects should be protected, respecting
p.000121: the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
p.000121: Principle 13: Investigational products should be manufactured, han- dled, and stored in accordance with applicable Good
p.000121: Manufacturing Practice (GMP) and should be used in accordance with the approved protocol.
p.000121: Principle 14: Systems with procedures that assure the quality of every aspect of the trial should be
p.000121: implemented.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 20 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT
p.000121: Research involving humans should be scientifically sound and conducted in accordance with basic ethical
p.000121: principles, which have their origin in the Declaration of Helsinki. Three basic ethi- cal principles of equal
p.000121: importance, namely respect for persons, beneficence, and justice, permeate all other GCP principles enu- merated below.
p.000121: Ethical principles have been established by many national and inter- national bodies, including:
p.000121: 1) The World Medical Association. Declaration of Helsinki;
...
p.000121: Due consideration should be given to obtaining consent for the col- lection and/or use of biological specimens,
p.000121: including future purposes. Guidance is developing in this area (see CIOMS International Ethical Guidelines;
p.000121: CIOMS Report on Pharmacogenetics – Towards improving treatment with medicines, 2005; Council of Europe [CDBI]
p.000121: Additional Protocols to Oviedo Convention, 2005).
p.000121:
p.000121:
p.000121: What is meant by “comprehension”? That is, how do investigators ensure that subjects understand information about the
p.000121: study, and how is this implemented in accordance with GCP?
p.000121: “The manner and context in which information is conveyed is as im- portant as the information itself. For example,
p.000121: presenting information in a disorganized and rapid fashion, allowing too little time for consid- eration or curtailing
p.000121: opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.” (The Belmont
p.000121: Report)
p.000121: “Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather,
p.000121: the investigator must convey the information, whether orally or in writing, in language that
p.000121:
p.000121:
p.000121: 64 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: suits the individual’s level of understanding. The investigator must bear in mind that the prospective
p.000121: subject’s ability to understand the information necessary to give informed consent depends on that individual’s
p.000121: maturity, intelligence, education and belief system … The investigator must then ensure that the
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
...
p.000121: Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Se- rious ADR) (ICH E6, 1.50)
p.000121: Unexpected Adverse Drug Reaction (ICH E6, 1.60)
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 81
p.000121:
p.000121: PRINCIPLE 9: INVESTIGATOR QUALIFICATIONS
p.000121: Qualified and duly licensed medical personnel (i.e. physician or, when appropriate, dentist) should be responsible for
p.000121: the medi- cal care of research subjects, and for any medical decision(s) made on their behalf.
p.000121: ”The experiment should be conducted only by scientifically quali- fied persons. The highest degree of skill and
p.000121: care should be required through all stages of the experiment of those who conduct or engage in the experiment.” (The
p.000121: Nuremberg Code)
p.000121: “Medical research involving human subjects should be conducted only by scientifically qualified persons and
p.000121: under the supervision of a clinically competent medical person …” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 9 is applied through the responsibilities of the clinical inves- tigator to the study subject and
p.000121: through the sponsor’s selection of qualified investigator(s). (See also WHO GCP Principle 10: Staff Quali-
p.000121: fications)
p.000121:
p.000121: Questions and Answers
p.000121: Where may information about a clinical investigator’s qualifications be obtained?
p.000121: The investigator’s curriculum vitae or other statement of education, training and experience may provide initial
p.000121: information about the investigator’s qualifications to provide medical care and to conduct clinical
p.000121: research. Other sources of information about an investiga- tor’s qualifications may include medical
p.000121: licensing boards, malprac- tice registries, and/or disciplinary bodies that may have information about the
p.000121: investigator’s history of medical practice. References from those familiar with the investigator’s clinical and/or
p.000121: research practice may provide useful adjunctive information.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 82 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: May a non-medical person serve as a principal investigator?
p.000121: “Investigator” is defined as the “person responsible for the conduct of the clinical trial at a trial site. If
p.000121: a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the
p.000121: team and may be called the principal investigator.” (ICH E6, Sec- tion 1.34)
p.000121: In most clinical research, the investigator will be a physician, dentist, or (in accordance with national/local laws,
p.000121: regulations, and licensure provisions) equivalent medical professional.
p.000121: Where permitted under national/local laws and regulations, a non- physician may serve as a principal
p.000121: investigator. However, implicit in this designation are: (1) that the non-physician be qualified to person- ally
p.000121: conduct or supervise the investigation; and (2) the non-physician would need to secure the services of a physician as a
p.000121: subinvestigator to perform those study functions requiring medical expertise. (For example, a Ph.D.
...
p.000121: Allocation of Duties and Functions (ICH E6, Section 5.7)
p.000121: Ethical Obligations of External Sponsors to Provide Health-Care Services (CIOMS, International Ethical
p.000121: Guidelines for Biomedical Research Involving Human Subjects, Guideline 21)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: GCP Compliance Monitoring Programs by Regulatory Authori- ties (Good Clinical Practice: Document of
p.000121: the Americas, PAHO, Chapter 7)
p.000121: Ethical Obligations of External Sponsors to Provide Health-Care Services (CIOMS, International Ethical
p.000121: Guidelines for Biomedical Research Involving Human Subjects, Guideline 21)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 9 : INVESTIGATOR QUALIFICATIONS | 85
p.000121:
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 10: Staff Qualifications
p.000121: Definitions for:
p.000121: Investigator (ICH E6, 1.34) Subinvestigator (ICH E6, 1.56)
p.000121: Well-being (of the trial subjects) (ICH E6, 1.62)
p.000121:
p.000121:
p.000121:
p.000121:
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p.000121:
p.000121:
p.000121: 86 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 10: STAFF QUALIFICATIONS
p.000121: Each individual involved in conducting a trial should be quali- fied by education, training, and
p.000121: experience to perform his or her respective task(s) and currently licensed to do so, where required.
p.000121: GCP requires that the clinical investigator is appropriately qualified by education, training, and
p.000121: experience to conduct the clinical trial. GCP also requires that each clinical investigator will have
p.000121: adequate resources available, including sufficient staff, who are also appropri- ately qualified by education,
p.000121: training, and experience, to assist him/ her with the trial and ensure the safety of study subjects.
p.000121:
p.000121: Application
p.000121: Principle 10 is chiefly applied through the clinical investigator’s selec- tion of appropriate staff to assist with the
p.000121: conduct of the study.
p.000121:
p.000121: Questions and Answers
p.000121: What does it mean to be “qualified” to conduct clinical research and how is this implemented within GCP?
p.000121: GCP requires generally that individuals who conduct research have appropriate education, training, and
p.000121: experience to assume respon- sibility for the conduct of the trial. The investigator should have knowledge
p.000121: of applicable laws and regulations and broad knowledge of internationally accepted principles and practices for
p.000121: the conduct of clinical research within GCP, including ethical requirements for the protection of human subjects
p.000121: involved in the research. The investiga- tor should also have training or expertise appropriate to carry out the
p.000121: requirements of the specific study protocol.
p.000121: The investigator should understand and be qualified to execute the responsibility to personally supervise any
p.000121: individual to whom a study task is delegated. The investigator should further ensure that any in- dividual to whom a
p.000121: study task is delegated is qualified by education, training, and experience to perform the delegated task, for example
p.000121:
p.000121:
p.000121: PRINCIPLE 10 : STAFF QUALIFICATIONS | 87
p.000121:
p.000121: that the assigned task falls within the scope of the individual’s profes- sional license(s). When delegating tasks, the
p.000121: investigator should con- sider, among other things, whether the tasks require formal medical training and whether
p.000121: national or local licensing requirements apply to such duties. (Duties that warrant such consideration, include,
p.000121: but are not necessarily limited to, the following: screening evaluations, including medical histories and
p.000121: assessment of inclusion/exclusion criteria; physical examinations; assessment of adverse events; as- sessments
p.000121: of primary study endpoints (e.g. tumor response, global assessment scales); control of investigational
p.000121: products.)
p.000121: The investigator should ensure that staff are (1) familiar with the study protocol and investigational
p.000121: product; (2) appropriately trained to carry out trial-related duties; (3) informed/aware of their obliga-
p.000121: tions to protect the rights, safety and welfare of the study subjects; and (4) informed of any requirements imposed by
p.000121: the national regula- tory authority for GCP and the conduct of clinical studies.
p.000121:
p.000121:
p.000121: What does it mean to be qualified by “education, training, and experience”; that is, what does each of these terms
p.000121: embrace?
p.000121: Education refers to degrees, certification, and/or licensing earned as a result of formal schooling or courses
p.000121: of study at an institution of higher learning (e.g. M.D., Ph.D., R.N., board certification in a speci-
p.000121: fied field, medical licenses). Training generally refers to short, fo- cused programs on specific topics (e.g.
p.000121: a two-week training program in research ethics, an online course on GCP, “investigator training” provided by
p.000121: the study sponsor related to a specific protocol) and/or mentoring by an appropriately educated, trained, and
p.000121: experienced professional. Experience includes direct participation in activities that provide additional expertise in a
p.000121: specific area (e.g. various positions a physician has held during his/her practice of medicine, previous work assisting
p.000121: another investigator in conducting clinical research, experi- ence as an investigator in a previous study).
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 88 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Where may information about the qualifications of an investigator or the investigator’s staff be obtained?
p.000121: A curriculum vitae or other statement of education, training, and ex- perience for each staff member may provide
p.000121: initial information about the staff member’s qualifications. Other sources of information may include medical
p.000121: licensing boards, malpractice registries, and/or dis- ciplinary bodies. References from those familiar with the
p.000121: individual’s past clinical and/or research experience may provide useful adjunc- tive information.
p.000121:
p.000121:
p.000121: How should an investigator inform a sponsor about the individuals to whom duties have been delegated?
p.000121: Maintaining a list of individuals to whom the investigator has as- signed each trial-related duty may assist
p.000121: the sponsor and regulators alike in determining which staff members were authorized to carry out specific
p.000121: duties during the course of the trial.
p.000121:
p.000121: Implementation
p.000121: The investigator bears primary responsibility for (1) selecting quali- fied staff to assist in the conduct of
p.000121: the investigation; (2) ensuring that study staff receive appropriate training, related to ethics and
p.000121: consent procedures as well as requirements of the specific protocol;
p.000121: (3) establishing clear procedures for activities related to the conduct of the study; (4) assigning tasks to staff,
p.000121: based on their qualifications, experience, and professional licenses; and (5) personally supervising staff to ensure
p.000121: that they satisfactorily fulfill their study-related duties. Although the investigator may delegate tasks to members of
p.000121: his/her staff, nevertheless, the investigator retains overall responsibility for the study and ensuring that
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p.000121: National Good Clinical Practice and Other Guidelines 124
p.000121: Acknowledgements 125
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: | iii
p.000121:
p.000121:
p.000121:
p.000121: Preamble
p.000121:
p.000121:
p.000121: Clinical research is necessary to establish the safety and effective- ness of specific health and medical
p.000121: products and practices. Much of what is known today about the safety and efficacy of specific prod- ucts and
p.000121: treatments has come from randomized controlled clinical trials1 that are designed to answer important
p.000121: scientific and health care questions. Randomized controlled trials form the foundation for “evidence-based
p.000121: medicine”, but such research can be relied upon only if it is conducted according to principles and
p.000121: standards collec- tively referred to as “Good Clinical Research Practice” (GCP).
p.000121: This handbook is issued as an adjunct to WHO’s “Guidelines for good clinical practice (GCP) for trials on
p.000121: pharmaceutical products” (1995), and is intended to assist national regulatory authorities, sponsors,
p.000121: investigators and ethics committees in implementing GCP for industry- sponsored, government-sponsored,
p.000121: institution-sponsored, or inves- tigator-initiated clinical research. The handbook is based on major
p.000121: international guidelines, including GCP guidelines issued subsequent to 1995, such as the International Conference on
p.000121: Harmonization (ICH) Good Clinical Practice: Consolidated Guideline, and is organized as a reference and educational
p.000121: tool to facilitate understanding and imple- mentation of GCP by:
p.000121: • describing the clinical research process as it relates to health and medical products, and identifying and
p.000121: explaining each of the activi- ties that are common to most trials and the parties who are ordi- narily responsible for
p.000121: carrying them out;
p.000121: • linking each of these processes to one or more Principle(s) of GCP within this Handbook;
p.000121:
p.000121: 1 These trials assign trial subjects to treatment or control groups using an element of chance to determine the
p.000121: assignments in order to reduce bias.
p.000121:
p.000121:
p.000121:
p.000121: | 1
p.000121:
p.000121: • explaining each GCP Principle and providing guidance on how each Principle is routinely applied and implemented;
p.000121: • directing the reader to specific international guidelines or other references that provide more
p.000121: detailed advice on how to comply with GCP.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
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p.000121:
p.000121:
p.000121: 2 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Introduction
p.000121:
p.000121:
p.000121: Good Clinical Research Practice (GCP) is a process that incorporates established ethical and scientific quality
p.000121: standards for the design, conduct, recording and reporting of clinical research involving the participation
...
p.000121: • International Standards Organization (ISO), “Clinical investigation of medical devices for human
p.000121: subjects, Part I (General require- ments) and Part 2 (Clinical investigation plans) (2001)
p.000121: • Pan American Health Organization (PAHO). Pan American Network on Drug Regulatory Harmonization (PANDRH). “Good
p.000121: Clinical Prac- tices: Document of the Americas” (2005)
p.000121: The conduct of clinical research in accordance with the principles of GCP helps to ensure that clinical
p.000121: research participants are not exposed to undue risk, and that data generated from the research are valid
p.000121: and accurate. By providing a basis both for the scientific and ethical integrity of research involving human subjects
p.000121: and for gener- ating valid observations and sound documentation of the findings, GCP not only serves the
p.000121: interests of the parties actively involved in the research process, but also protects the rights, safety
p.000121: and well- being of subjects and ensures that investigations are scientifically sound and advance public health
p.000121: goals.
p.000121:
p.000121: Objectives of this handbook
p.000121: The objectives of this current WHO Handbook for GCP include the fol- lowing:
p.000121: • to support and promote the achievement of a globally applicable unified standard for the conduct of all
p.000121: clinical research studies on human subjects;
p.000121: • to provide an overview and practical advice on the application and implementation of internationally accepted
p.000121: principles for GCP and clinical research in human subjects;
p.000121: • to provide an educational and reference tool for anyone interested in, or intending to become or already actively
p.000121: engaged in, clinical research by providing the necessary background and insight into the reasons for the
p.000121: requirements of GCP and their efficient appli- cation;
p.000121:
p.000121:
p.000121: INTRODUCTION | 5
p.000121:
p.000121: • to assist editors in evaluating the acceptability of reported research for publication, and regulators in
p.000121: evaluating the acceptability of any study that could affect the use or the terms of registration of a medical
p.000121: product.
p.000121: This handbook can be adopted or referenced by WHO Member States. Where national regulations or
p.000121: requirements do not exist or require supplementation, relevant regulatory authorities may desig- nate or
p.000121: adopt these GCP principles and standards. Where national or adopted international standards are more demanding than WHO
p.000121: GCP, the former should take precedence.
p.000121: Guidance on various aspects of clinical research is also available from several other national and international bodies
p.000121: such as, the Interna- tional Conference on Harmonization (ICH), the International Stand- ards Organization
p.000121: (ISO), the Council for International Organizations of Medical Sciences (CIOMS), the European Agency for the
p.000121: Evaluation of Medicinal Products (EMEA), and the United States Food and Drug Administration (FDA). (See References)
p.000121:
p.000121: Scope of this handbook
p.000121: This handbook defines fourteen principles of GCP, and provides guid- ance and assistance in the application and
p.000121: implementation of these principles by all parties involved in the clinical research process. In describing
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p.000121: investigator should con- sider, among other things, whether the tasks require formal medical training and whether
p.000121: national or local licensing requirements apply to such duties. (Duties that warrant such consideration, include,
p.000121: but are not necessarily limited to, the following: screening evaluations, including medical histories and
p.000121: assessment of inclusion/exclusion criteria; physical examinations; assessment of adverse events; as- sessments
p.000121: of primary study endpoints (e.g. tumor response, global assessment scales); control of investigational
p.000121: products.)
p.000121: The investigator should ensure that staff are (1) familiar with the study protocol and investigational
p.000121: product; (2) appropriately trained to carry out trial-related duties; (3) informed/aware of their obliga-
p.000121: tions to protect the rights, safety and welfare of the study subjects; and (4) informed of any requirements imposed by
p.000121: the national regula- tory authority for GCP and the conduct of clinical studies.
p.000121:
p.000121:
p.000121: What does it mean to be qualified by “education, training, and experience”; that is, what does each of these terms
p.000121: embrace?
p.000121: Education refers to degrees, certification, and/or licensing earned as a result of formal schooling or courses
p.000121: of study at an institution of higher learning (e.g. M.D., Ph.D., R.N., board certification in a speci-
p.000121: fied field, medical licenses). Training generally refers to short, fo- cused programs on specific topics (e.g.
p.000121: a two-week training program in research ethics, an online course on GCP, “investigator training” provided by
p.000121: the study sponsor related to a specific protocol) and/or mentoring by an appropriately educated, trained, and
p.000121: experienced professional. Experience includes direct participation in activities that provide additional expertise in a
p.000121: specific area (e.g. various positions a physician has held during his/her practice of medicine, previous work assisting
p.000121: another investigator in conducting clinical research, experi- ence as an investigator in a previous study).
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 88 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Where may information about the qualifications of an investigator or the investigator’s staff be obtained?
p.000121: A curriculum vitae or other statement of education, training, and ex- perience for each staff member may provide
p.000121: initial information about the staff member’s qualifications. Other sources of information may include medical
p.000121: licensing boards, malpractice registries, and/or dis- ciplinary bodies. References from those familiar with the
p.000121: individual’s past clinical and/or research experience may provide useful adjunc- tive information.
p.000121:
p.000121:
p.000121: How should an investigator inform a sponsor about the individuals to whom duties have been delegated?
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p.000121: activity.
p.000121:
p.000121:
p.000121: What “information” should be given to study subjects in accordance with GCP?
p.000121: GCP recognizes that certain essential elements of informed consent should be included in the informed consent
p.000121: discussion, the written informed consent form, and any other information to be provided to subjects who participate
p.000121: in the study. All information must be com- municated in a comprehensive and understandable manner to the
p.000121: research subject. This includes, but is not limited to:
p.000121: • title of the protocol;
p.000121: • identity of the sponsor;
p.000121: • identity of the clinical investigator and institutional affiliation of the investigator;
p.000121: • source of research funding (e.g. public, private, or both);
p.000121: • that the trial involves research;
p.000121: • that the subject’s participation in the trial is voluntary and that the subject may refuse to participate or
p.000121: withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise
p.000121: entitled;
p.000121: • the purpose of the trial;
p.000121: • the trial treatment(s) and the probability for random assignment to each treatment;
p.000121: • the trial procedures to be followed, including all invasive proce- dures;
p.000121: • the subject’s responsibilities;
p.000121: • those aspects of the trial that are experimental;
p.000121: • the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus or
p.000121: nursing infant;
p.000121:
p.000121:
p.000121:
p.000121: 62 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject
p.000121: should be made aware of this;
p.000121: • the alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
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Social / gender
Searching for indicator gender:
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p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
p.000121: offer potentially beneficial research to only some patients who are in favor or select only “unde- sirable” persons for
p.000121: risky research.” (The Belmont Report)
p.000121: Social justice relates to groups of subjects, including the involvement of vulnerable subjects or subject populations.
p.000121: “Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the
p.000121: institutionalized may continually be sought as research sub- jects, owing to their ready availability in
p.000121: settings where research is conducted.” (The Belmont Report) “Equity requires that no group or class of persons
p.000121: should bear more than its fair share of the burdens of participation in research. Similarly, no group should be
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
p.000121: standards. This in- cludes the investigator(s) and site staff, the sponsor and sponsor’s staff (including
p.000121: monitors and auditors), the ethics committee(s), the regulatory authority(-ies), and the individual research subjects.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 24 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities):
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
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p.000001:
p.000001: HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP)
p.000001: GUIDANCE FOR
p.000001: IMPLEMENTATION
p.000001:
p.000001:
p.000001:
p.000001:
p.000001: HANDBOOK FOR GOOD CLINICAL
p.000001: RESEARCH PRACTICE
p.000001: (GCP)
p.000001: GUIDANCE FOR
p.000001: IMPLEMENTATION
p.000001:
p.000001: WHO Library Cataloguing-in-Publication Data
p.000001: Handbook for good clinical research practice (GCP) : guidance for implementation.
p.000001: 1. Clinical trials – methods. 2. Biomedical research – methods.
p.000001: 3. Ethics, Research. 4. Manuals. I. World Health Organization. ISBN 92 4 159392 X (NLM
p.000001: classification: W 20.5)
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001: The World Health Organization welcomes requests for permission to reproduce or translate its publications, in
p.000001: part or in full. Applications and enquiries should be ad- dressed to the Office of Publications, World Health
p.000001: Organization, Geneva, Switzer- land, which will be glad to provide the latest information on any changes made to the
p.000001: text, plans for new editions, and reprints and translations already available.
p.000001: © World Health Organization 2005
p.000001: Publications of the World Health Organization enjoy copyright protection in accord- ance with the
p.000001: provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.
p.000001: The designations employed and the presentation of the material in this publication do not imply the
p.000001: expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning
p.000001: the legal status of any country, terri- tory, city or area or of its authorities, or concerning the delimitation
p.000001: of its frontiers or boundaries.
p.000001: The mention of specific companies or of certain manufacturers’ products does not imply that they are
p.000001: endorsed or recommended by the World Health Organization in preference to others of a similar nature that are
p.000001: not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial
p.000001: capital let- ters.
p.000001: Designed by minimum graphics Printed in France
p.000001:
p.000001: Contents
p.000001:
p.000001:
p.000001: Preamble
p.000001: 1
p.000001: Introduction
p.000003: 3
p.000003: Overview of the Clinical Research Process 8
p.000003: WHO Principles of GCP 19
p.000003: Principle 1: Ethical Conduct 21
p.000003: Principle 2: Research described in a protocol 27
p.000003: Principle 3: Risk Identification 35
p.000003: Principle 4: Benefit-Risk Assessment 42
p.000003: Principle 5: Review by Independent Ethics Committee/ Independent Review Board
p.000048: 48
p.000048: Principle 6: Protocol Compliance 54
...
p.000121: • adverse event or safety reporting forms;
p.000121: • administrative forms to track research funds and expenses;
p.000121: • forms to disclose information about the investigator’s financial, property, or other interests in the
p.000121: product under study, in accord- ance with national/local law or regulations;
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 11
p.000121:
p.000121: • formats for reports of monitoring visits;
p.000121: • formats for progress reports, annual reports, and final study re- ports.
p.000121:
p.000121:
p.000121: 5. Selection of trial sites and the selection of properly qualified, trained, and experienced investigators and study
p.000121: personnel
p.000121: Clinical investigators must be qualified and have sufficient resources and appropriately trained staff to conduct
p.000121: the investigation and be knowledgeable of the national setting and circumstances of the site and study
p.000121: population(s). Sponsors should review the requirements of the study protocol to determine the type(s) of expertise
p.000121: required and identify clinical investigators who have the particular medical expertise necessary to conduct the
p.000121: study and who have knowledge, training and experience in the conduct of clinical trials and human subject
p.000121: protection.
p.000121: See WHO GCP Principles 2: Protocol; 9: Investigator Qualifications; 10: Staff Qualifications.
p.000121:
p.000121:
p.000121: 6. Ethics committee review and approval of the protocol
p.000121: Within GCP, studies must be reviewed and receive approval/ favourable opinion from an Independent
p.000121: Ethics Committee (IEC)/ Institutional Review Board (IRB) prior to enrollment of study subjects.
p.000121: The investigator generally assumes responsibility for obtaining IEC/ IRB review of the study protocol. Copies of
p.000121: any approval/favourable opinion are then provided to the sponsor.
p.000121: See WHO GCP Principles 1: Ethical Conduct; 2: Protocol; 4: Benefit- Risk Assessment; 5: Review by IEC/IRC; 7: Informed
p.000121: Consent; 8: Con- tinuing Review/Ongoing Benefit-Risk Assessment; 11: Records; 12: Confidentiality/Privacy.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 12 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 7. Review by regulatory authorities
p.000121: Within GCP, studies must undergo review by regulatory authority(ies) for use of the investigational product or
p.000121: intervention in human sub- jects and to ensure that the study is appropriately designed to meet its stated
p.000121: objectives, according to national/regional/local law and regulations. [Note: Some countries may not have
p.000121: systems in place for reviewing research or may depend on external review. Also, some countries may have additional
p.000121: requirements for the review and ap- proval of trial sites and/or investigators.]
p.000121: The sponsor is generally responsible for ensuring that the applicable regulatory authority(ies) review and provide
p.000121: any required authori- zations for the study before the study may proceed. The sponsor should also list
p.000121: the trial in applicable and/or required clinical trial registry(ies).
p.000121: See WHO GCP Principles 2: Protocol; 4: Benefit-Risk Assessment.
p.000121:
p.000121:
...
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 18 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: WHO Principles of GCP
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: Principle 1: Research involving humans should be scientifically sound and conducted in accordance
p.000121: with basic ethical principles, which have their origin in the Declaration of Helsinki. Three basic ethical
p.000121: principles of equal importance, namely respect for persons, beneficence, and justice, permeate all other GCP
p.000121: principles.
p.000121: Principle 2: Research involving humans should be scientifically justi- fied and described in a clear, detailed
p.000121: protocol.
p.000121: Principle 3: Before research involving humans is initiated, foresee- able risks and discomforts and any
p.000121: anticipated benefit(s) for the in- dividual research subject and society should be identified. Research of
p.000121: investigational products or procedures should be supported by adequate non-clinical and, when applicable,
p.000121: clinical information.
p.000121: Principle 4: Research involving humans should be initiated only if the anticipated benefit(s) for the individual
p.000121: research subject and society clearly outweigh the risks. Although the benefit of the results of the trial to science
p.000121: and society should be taken into account, the most important considerations are those related to the rights,
p.000121: safety, and well-being of the research subjects.
p.000121: Principle 5: Research involving humans should receive independ- ent ethics committee/institutional review
p.000121: board (IEC/IRB) approval/ favourable opinion prior to initiation.
p.000121: Principle 6: Research involving humans should be conducted in com- pliance with the approved protocol.
p.000121: Principle 7: Freely given informed consent should be obtained from every subject prior to research participation in
p.000121: accordance with na- tional culture(s) and requirements. When a subject is not capable of giving informed consent, the
p.000121: permission of a legally authorized repre- sentative should be obtained in accordance with applicable law.
p.000121:
p.000121:
p.000121: | 19
p.000121:
p.000121: Principle 8: Research involving humans should be continued only if the benefit-risk profile remains favourable.
p.000121: Principle 9: Qualified and duly licensed medical personnel (i.e. phy- sician or, when appropriate, dentist)
p.000121: should be responsible for the medical care of research subjects, and for any medical decision(s) made on
p.000121: their behalf.
p.000121: Principle 10: Each individual involved in conducting a trial should be qualified by education, training, and experience
p.000121: to perform his or her respective task(s) and currently licensed to do so, where required.
p.000121: Principle 11: All clinical trial information should be recorded, han- dled, and stored in a way that allows
p.000121: its accurate reporting, interpre- tation, and verification.
p.000121: Principle 12: The confidentiality of records that could identify sub- jects should be protected, respecting
p.000121: the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
...
p.000121: and society at large (or special groups of subjects in society). … In balancing these different ele- ments,
p.000121: the risks and benefits affecting the immediate research sub- ject will normally carry special weight.” (The Belmont
p.000121: Report)
p.000121: “In medical research on human subjects, considerations related to the well-being of the human subject
p.000121: should take precedence over the interests of science and society.” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 4 is applied through appropriate study design and through ethical, scientific, and, where
p.000121: applicable, regulatory review of the study protocol prior to study initiation.
p.000121:
p.000121: Questions and Answers
p.000121: Who is responsible for determining that the risk/benefit profile of a study is acceptable or unacceptable?
p.000121: Within GCP, the sponsor of the study, the investigator(s), IECs/IRBs, and the regulatory authority(-ies) each
p.000121: have responsibilities for evalu- ating the risk/benefit profile of a study (see Implementation, below). In
p.000121: accordance with applicable laws and regulations, the regulatory authority may stop a study from proceeding or
p.000121: require modifications to the protocol based on an unacceptable risk/benefit profile. The IEC/IRB has authority to
p.000121: issue an approval/favourable opinion; require modi- fications prior to approval/favourable opinion; issue a
p.000121: disapproval/ negative opinion; or terminate/suspend a prior approval/favourable
p.000121:
p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 43
p.000121:
p.000121: opinion. An investigator may decide either to participate or not par- ticipate in a study based on
p.000121: his/her assessment of the risk/benefit profile. The sponsor may decide either not to initiate or to terminate/
p.000121: suspend a trial where the risk/benefit profile is unacceptable.
p.000121:
p.000121:
p.000121: When should a risk/benefit determination be performed?
p.000121: A risk/benefit determination should be performed prior to study initiation as well as periodically during the
p.000121: study (see also WHO GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment).
p.000121:
p.000121:
p.000121: What if the risk-benefit profile of a study appears favourable from a national, societal, institutional, or scientific
p.000121: standpoint but unfavourable to the participating research subjects?
p.000121: The most important considerations in a study are those related to the rights, safety, and well-being of the
p.000121: research subjects. “In medical research on human subjects, considerations related to the well-being of the human
p.000121: subject should take precedence over the interests of science and society.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121: What about financial reimbursements to research subjects?
p.000121: Financial reimbursements to subjects are distinct from any benefits contributing to the risk-benefit analysis.
p.000121: Where applicable laws and regulations allow, financial reimburse- ments may be provided to subjects for
...
p.000121: Clinical Trial Protocol, General Information (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 3: Risk Identification GCP Principle 7: Informed Consent
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assess- ment
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 46 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Definitions for:
p.000121: Applicable Regulatory Requirement(s) (ICH E6, 1.4)
p.000121: Approval (in relation to institutional review boards [IRBs]) (ICH E6, 1.5)
p.000121: Informed Consent (ICH E6, 1.28) Investigator’s Brochure (ICH E6, 1.36)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
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p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 47
p.000121:
p.000121: PRINCIPLE 5: REVIEW BY IEC/IRB
p.000121: Research involving humans should receive independent eth- ics committee/institutional review board
p.000121: (IEC/IRB) approval/ favourable opinion prior to initiation.
p.000121: The “… protocol should be submitted for consideration, comment, guidance, and where appropriate, approval
p.000121: to a specially appointed ethical review committee, which must be independent of the in- vestigator, the
p.000121: sponsor, or any other kind of undue influence. This independent committee should be in conformity with
p.000121: the laws and regulations of the country in which the research experiment is per- formed …” (Declaration of
p.000121: Helsinki)
p.000121: “Failure to submit a protocol to the committee should be considered a clear and serious violation of ethical
p.000121: standards.” (CIOMS, Interna- tional Ethical Guidelines, Commentary to Guideline 2)
p.000121:
p.000121: Application
p.000121: Principle 5 is applied through protocol review by an IEC/IRB that is constituted and operating in
p.000121: accordance with GCP and applicable national/local laws and regulations.
p.000121:
p.000121: Questions and Answers
p.000121: What is the objective of obtaining IEC/IRB review of the protocol?
p.000121: It is the IEC/IRB “… whose responsibility it is to ensure the protection of the rights, safety, and well-being of human
p.000121: subjects involved in a trial and to provide public assurance of that protection, by, among other things,
p.000121: reviewing and approving/providing favourable opinion on the trial protocol …“ (ICH E6, 1.27)
p.000121: The principal focus of the IEC/IRB is ethical review of the protocol. However, “… [s]cientific review
p.000121: and ethical review cannot be sepa- rated: scientifically unsound research involving humans as subjects is
p.000121: ipso facto unethical in that it may expose them to risk or incon- venience to no purpose; even if there is
p.000121: no risk of injury, wasting of
p.000121:
p.000121:
p.000121: 48 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: subjects’ and researchers’ time in unproductive activities represents loss of a valuable resource. Normally,
p.000121: therefore, an ethical review committee considers both the scientific and the ethical aspects of proposed
p.000121: research. It must either carry out or arrange for a proper scientific review or verify that a competent
p.000121: expert body has deter- mined that the research is scientifically sound …” (CIOMS, Interna- tional Ethical
p.000121: Guidelines, Commentary to Guideline 2)
p.000121: Review by the IEC/IRB also helps ensure that the research is evaluat- ed by a party that is independent of the trial.
p.000121: “The review committees must be independent of the research team, and any direct financial or other material benefit
p.000121: they may derive from the research should not be contingent on the outcome of their review.” (CIOMS, Interna-
p.000121: tional Ethical Guidelines, Guideline 2)
p.000121:
p.000121:
p.000121: How does the composition and operation of the IEC/IRB within GCP promote its independence?
p.000121: Within GCP, “the IRB/IEC should consist of a reasonable number of members, who collectively have the
p.000121: qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial.
p.000121: It is recommended that the IRB/IEC should include:
p.000121: (a) [a]t least five members, (b) [a]t least one member whose primary area of interest is in a nonscientific
p.000121: area, (c) [a]t least one member who is independent of the institution/trial site.” (ICH E6, Section 3.2)
p.000121: In its operations, “[o]nly those IRB/IEC members who are independ- ent of the investigator and the sponsor of
p.000121: the trial should vote/ provide opinion on a trial-related matter.” (ICH E6, Section 3.2).
p.000121: “To maintain the review committee’s independence from the inves- tigators and sponsors and to avoid conflict of
p.000121: interest, any member with a special or particular, direct or indirect, interest in a proposal should not
p.000121: take part in its assessment if that interest could subvert the member’s objective judgment. Members of ethical
p.000121: review com- mittees should be held to the same standard of disclosure as sci- entific and medical
p.000121: research staff with regard to financial or other interests that could be construed as conflicts of interest. A
p.000121: practical
p.000121:
p.000121:
p.000121: PRINCIPLE 5 : REVIEW BY IEC/ IRB | 49
p.000121:
p.000121: way of avoiding such conflict of interest is for the committee to insist on a declaration of possible conflict of
p.000121: interest by any of its members. A member who makes such a declaration should then withdraw, if to do so is
p.000121: clearly the appropriate action to take, either at the mem- ber’s own discretion or at the request of the other members.
p.000121: Before withdrawing, the member should be permitted to offer comments on the protocol or to respond to questions of
p.000121: other members.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 2)
p.000121: “The investigator may provide information on any aspect of the trial, but should not participate in the deliberations
p.000121: of the IRB/IEC or in the vote/opinion of the IRB/IEC.” (ICH E6, Section 3.2)
p.000121: “[T]here should be a predefined method for arriving at a decision (e.g. by consensus, by vote); it is recommended that
p.000121: decisions be arrived at through consensus, where possible; when a consensus appears unlikely, it is
p.000121: recommended that the EC vote.” (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 7, Decision Making)
p.000121:
p.000121:
p.000121: Within GCP, what is meant by “prior” opinion by the IEC/IRB?
p.000121: GCP requires that “[b]efore initiating a trial, the investigator/ institution should have written
p.000121: and dated approval/favourable opin- ion from the IRB/IEC for the trial protocol, written informed consent form,
p.000121: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to
p.000121: be provided to subjects.” (ICH E6, Section 4.4)
p.000121: “The IRB/IEC should establish, document in writing, and follow its procedures, which should include: …
p.000121: [s]pecifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000121: approval/favourable opinion of the trial.” (ICH E6, Section 3.3)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 50 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is the authority of the IEC/IRB with respect to rendering a decision/opinion on the protocol?
p.000121: The IEC/IRB may render a decision/opinion that can be positive, con- ditional, or negative. Regardless of the nature of
p.000121: the decision/opinion, it should be documented and communicated in writing to the appli- cant.
p.000121: Approval/favourable opinion. This positive decision/opinion is re- quired prior to initiating a new protocol and
p.000121: prior to making changes in a protocol that has previously received an approval/favourable opinion. In
p.000121: communicating this decision/opinion to the applicant, the IEC/IRB should include a statement of the
p.000121: responsibilities of the applicant.
p.000121: Modifications required prior to its approval/favourable opinion. This is a conditional decision/opinion that
p.000121: requires response from the applicant and consideration of the applicant’s response by the IEC/IRB.
p.000121: Implementation of the protocol/protocol change(s) may not occur until required modifications are made and the IEC/IRB
p.000121: has ren- dered an approval/favourable opinion based on these modifications. In the case of a conditional
p.000121: decision/opinion, any requirements of the IEC/IRB, including clear suggestions for revision and the procedure
p.000121: for having the application re-reviewed should be specified in writ- ten communication to the applicant.
p.000121: The written communication should emphasize that no study activities requiring IEC/IRB approval/ favourable opinion
p.000121: may take place under a conditional decision.
p.000121: Disapproval/negative opinion. This negative decision/opinion can apply to the disapproval/negative opinion of
p.000121: a new protocol or the disapproval/negative opinion of changes to an ongoing protocol. Communication of a
p.000121: disapproval/negative opinion should include clearly stated reason(s) for the negative decision/opinion.
p.000121: Termination/suspension of any prior approval/favourable opin- ion. This negative decision/opinion constitutes an
p.000121: action by the IEC/ IRB to terminate or suspend its prior approval/favourable opinion. Written communication by
p.000121: the IEC/IRB should include clearly stated reason(s) for this decision/opinion.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 5 : REVIEW BY IEC/ IRB | 51
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by IEC(s)/ IRB(s), investigators, sponsors, and
p.000121: regulators.
p.000121: A properly constituted and operational IEC/IRB reviews the proto- col (and/or any proposed changes to the
p.000121: protocol) and provides the investigator with a written decision/opinion. IEC/IRB written proce- dures should
p.000121: ensure that no subject be admitted to a trial and no deviations from, or changes to, the protocol be
p.000121: initiated before the IEC/IRB issues its approval/favourable opinion.
p.000121: Investigators submit the study protocol to their IEC(s)/IRB(s) and are responsible for securing an approval/favourable
p.000121: opinion prior to ad- mitting any subjects to the trial. Investigators should not implement any deviation from, or
p.000121: changes to, the protocol without agreement by the sponsor and prior review and documented approval/favourable
p.000121: opinion from the IEC(s)/IRB(s) of an amendment, except where nec- essary to eliminate an immediate hazard(s) to
p.000121: research subjects. (See WHO GCP Principle 6: Protocol Compliance)
p.000121: The sponsor develops the protocol, selects qualified investigators/ institutions, and confirms that each
p.000121: investigator has had the study protocol reviewed by an IEC/IRB and received IEC/IRB approval/fa- vourable
p.000121: opinion.
p.000121: In accordance with applicable laws/regulations, regulators may in- spect the investigator(s), sponsor(s),
p.000121: and/or IEC(s)/IRB(s) to ensure compliance with IEC/IRB review requirements. Regulators should also encourage
p.000121: IECs/IRBs to communicate with them directly on is- sues or concerns they may encounter in their review of human
p.000121: trials.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Composition, Functions, and Operations (ICH E6, Section 3.2) Procedures (ICH E6, Section 3.3)
p.000121: Records (ICH E6, Section 3.4)
p.000121:
p.000121:
p.000121:
p.000121: 52 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Constituting an EC (WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research, Section
p.000121: 4)
p.000121: Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 6)
p.000121: Decision-Making (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 7)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-Up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: Documentation and Archiving (WHO Operational Guidelines for Eth- ics Committees that Review Biomedical Research,
p.000121: Section 10) Ethical review committees (Guideline 2) and Ethical review of ex-
p.000121: ternally sponsored research (Guideline 3), (CIOMS International Ethical Guidelines, 2002)
p.000121: For clinical investigators, refer to: Communication with IRB/IEC (ICH E6, Section 4.4)
p.000121: For sponsors, refer to:
p.000121: Confirmation of Review by IRB/IEC (ICH E6, Section 5.11)
p.000121: For regulatory authorities, refer to:
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees that Review Biomedical Research), WHO, 2002
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 6: Protocol Compliance
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment
p.000121: Definitions for:
p.000121: Approval (in relation to institutional review boards (IRBs)) (ICH E6, 1.5) Independent Ethics Committee (IEC) (ICH E6,
p.000121: 1.27)
p.000121: Institutional Review Board (IRB) (ICH E6, 1.31)
p.000121: Opinion (in relation to Independent Ethics Committee) (ICH E6, 1.42)
p.000121:
p.000121:
p.000121: PRINCIPLE 5 : REVIEW BY IEC/ IRB | 53
p.000121:
p.000121: PRINCIPLE 6: PROTOCOL COMPLIANCE
p.000121: Research involving humans should be conducted in compliance with the approved protocol.
p.000121: Once the IEC/IRB gives its approval/favourable decision on the proto- col, it is essential that the trial be conducted
p.000121: in compliance with that protocol so that the decision on the ethical acceptability of the trial remains valid.
p.000121: “The investigator should not implement any deviation from, or changes of, the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of
p.000121: an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the
p.000121: change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), change
p.000121: of telephone number(s)).” (ICH E6, Section 4.5)
p.000121:
p.000121: Application
p.000121: Principle 6 is applied through: (1) verifiable investigator adherence to the protocol requirements; (2) submission
p.000121: of any protocol changes to the sponsor and to the IEC/IRB (with approval/favourable opinion) prior to their
p.000121: implementation; and (3) effective monitoring of the study by the sponsor.
p.000121:
p.000121: Questions and Answers
p.000121: What does conducting the trial in compliance with the protocol mean?
p.000121: Compliance with the protocol means performing all of the study ac- tivities covered by the protocol (i.e. identifying,
p.000121: informing, selecting, treating, observing, recording, withdrawing, terminating, reporting, analysing) in the
p.000121: precise manner specified in the approved protocol.
p.000121: It is especially important that those study activities most critical to ensuring the rights and well being of
p.000121: subjects and the quality and in- tegrity of safety and efficacy data are carried out strictly according to the approved
p.000121: protocol, including but not limited to:
p.000121:
p.000121:
p.000121: 54 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • informing subjects fully and obtaining their agreement and docu- mented consent before enrolling them in
p.000121: the study;
p.000121: • selecting subjects in accordance with the inclusion and exclusion criteria;
p.000121: • treating subjects with the investigational product as specified in the protocol;
p.000121: • observing and accurately recording key safety and efficacy end- point data;
p.000121: • reporting all serious adverse events (SAEs) to the sponsor imme- diately except for those SAEs that the protocol or
p.000121: other document (e.g. investigator’s brochure) identifies as not needing immediate reporting.
p.000121:
p.000121:
p.000121: How is compliance with the protocol ensured and documented within GCP?
p.000121: The first step in promoting protocol compliance is the development of a well-designed, clearly written protocol. (See
p.000121: WHO GCP Principle 2: Protocol)
p.000121: To ensure and document understanding of the protocol “[t]he spon- sor should obtain the
p.000121: investigator’s/institution’s agreement: (a) To conduct the trial in compliance with GCP, with the applicable regula-
p.000121: tory requirement(s), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the
p.000121: IRB/IEC …” (ICH E6, Section 5.6)
p.000121: “… The investigator/institution and the sponsor should sign the pro- tocol, or an alternative contract, to confirm
p.000121: their agreement” to con- duct the study in compliance with the protocol. (ICH E6, Section 4.5; see also Section 5.6)
p.000121: Once the study is underway, compliance with the protocol is princi- pally ensured through the investigator’s
p.000121: supervision and through the sponsor’s monitoring of the study. Within GCP, the purposes of trial monitoring
p.000121: explicitly include verifying that “… [t]he conduct of the trial is in compliance with the currently approved
p.000121: protocol/amendment(s),
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 55
p.000121:
p.000121: with GCP, and with applicable regulatory requirement(s).” (ICH E6, Section 5.18)
p.000121: “The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.”
p.000121: (ICH E6, Section 5.18)
p.000121: “Noncompliance with the protocol, SOPs, GCP, and/or applicable reg- ulatory requirement(s) by an
p.000121: investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure
p.000121: compliance.” (ICH E6, Section 5.20)
p.000121: “… If the monitoring and/or auditing identifies serious and/or per- sistent noncompliance on the part of an
p.000121: investigator/institution, the sponsor should terminate the investigator’s/institution’s participa- tion in the
p.000121: trial …” (ICH E6, Section 5.20)
p.000121: The IEC/IRB may also terminate or suspend any prior approval/ favourable opinion. Within GCP,
p.000121: this would include the authority to terminate or suspend an approval/favourable opinion when informa- tion is
p.000121: received that the study is not being conducted in compliance with the protocol or other requirements of the IEC/IRB.
p.000121:
p.000121:
p.000121: Who is responsible for compliance with the protocol?
p.000121: The investigator has direct contact with study subjects and bears pri- mary responsibility for complying with the
p.000121: provisions of the protocol. The investigator also bears responsibility to personally supervise all study staff
p.000121: and ensure their compliance with the protocol.
p.000121: The sponsor has responsibility to monitor the study and ensure the investigator and site staff comply with
p.000121: the protocol.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by IECs/ IRBs, investigators, sponsors, and
p.000121: regulators.
p.000121: IEC/IRB written procedures should ensure that no subject be admit- ted to a trial and no deviations from, or changes
p.000121: of, the protocol be initiated before the IEC/IRB issues its approval/favourable opinion.
p.000121:
p.000121:
p.000121: 56 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Investigators should be thoroughly familiar with the protocol and are responsible for conducting the trial in
p.000121: compliance with the protocol. Investigators should not implement any deviation from, or changes of the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB(s)/IEC(s) of an
p.000121: amendment, except where necessary to eliminate an immediate hazard(s) to research subjects.
p.000121: The sponsor monitors the study to ensure investigator compliance with the protocol and takes action to
p.000121: secure compliance or termi- nate the trial in the case of noncompliance. If the monitoring and/or auditing
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should
p.000121: terminate the investigator’s/institution’s participation in the trial. All parties, includ- ing the IEC/IRB, should be
p.000121: notified in such cases.
p.000121: In accordance with applicable laws/regulations, regulators may in- spect the investigator(s) or sponsor to
p.000121: ensure compliance with proto- col adherence requirements. Regulators should be promptly notified when a sponsor
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution leading to
p.000121: termination of the investigator’s/institution’s participation in a study.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to:
p.000121: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: For clinical investigators, refer to:
p.000121: Compliance with Protocol (ICH E6, Section 4.5)
p.000121: For sponsors, refer to:
p.000121: Record Access (ICH E6, Section 5.15) Monitoring (ICH E6, Section 5.18) Noncompliance (ICH E6, Section 5.20)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 1995
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 57
p.000121:
...
p.000121: immediate reports should be followed promptly
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 73
p.000121:
p.000121: by detailed written reports. … The investigator should also comply with the applicable regulatory
p.000121: requirement(s) related to the report- ing of unexpected serious adverse drug reactions to the regulatory
p.000121: authority(ies) and the IRB/IEC.” (ICH E6, Section 4.11)
p.000121: “In addition to the usual criteria for an expedited report, adverse events that are not deemed to be
p.000121: drug-related but are considered to be protocol related should also be reported in an expedited fashion if they are
p.000121: serious.” (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory
p.000121: Reporting and other Communication of Safety Information from Clinical rials)
p.000121:
p.000121:
p.000121: Who is responsible for reviewing the benefit-risk profile of the investigational product(s) while the study is
p.000121: proceeding?
p.000121: Within GCP, the sponsor has primary responsibility for the ongo- ing safety evaluation of the
p.000121: investigational product(s) and should promptly notify all concerned investigator(s), institution(s), and the
p.000121: regulatory authority(ies) of information that could adversely affect the safety of subjects, the conduct
p.000121: of the trial, or alter the IEC/IRB approval/favourable opinion to continue the trial. Such reviews may be
p.000121: performed by the sponsor’s staff (e.g. physicians, statisticians) or by an independent data and safety monitoring board
p.000121: (DSMB), if one is established (see below).
p.000121: The IEC/IRB is also responsible for “… following the progress of all studies for which a positive decision
p.000121: has been reached, from the time the decision was taken until the termination of the research.” (See
p.000121: “Follow-up”, Section 9, WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research)
p.000121:
p.000121:
p.000121: How are follow-up reviews carried out?
p.000121: Sponsors generally monitor trials to ensure that (1) the study is being conducted according to the approved
p.000121: protocol, GCP, and applicable regulatory requirements, and (2) all data, including adverse event reports
p.000121: are accurately and completely recorded and reported. The sponsor also employs qualified individuals (e.g.
p.000121: physicians, statisti-
p.000121:
p.000121:
p.000121: 74 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: cians) as appropriate, throughout all stages of the trial process, to analyse data and prepare interim
p.000121: reports about the progress of the trial and the benefits and risks of the investigational product. The
p.000121: sponsor may also establish an independent data and safety monitor- ing board (DSMB, see below) to review the
p.000121: accumulating data. The sponsor should ensure that significant new information that arises about a clinical
p.000121: trial is promptly shared with all investigators, regula- tory authorities and IECs/IRBs.
...
p.000121:
p.000121:
p.000121: What should be done if the benefit-risk profile of a study becomes unfavourable?
p.000121: The sponsor should notify investigator(s), the IEC(s)/IRB(s), and in accordance with national/local laws
p.000121: and regulations, the national regulatory authority if the benefit-risk profile of a study becomes un- favourable. In
p.000121: consultation with the IEC(s)/IRB(s), investigator(s), and regulatory authority(ies), the sponsor may need to amend the
p.000121: study protocol and/or revise the investigator’s brochure and informed con- sent document(s) to reflect the new
p.000121: information.
p.000121: “If a significant safety issue is identified, either from an individual case report or review of
p.000121: aggregate data, then the sponsor should issue a prompt notification to all parties, namely regulatory authori-
p.000121: ties, investigators and IECs/IRBs. A significant safety issue could be defined as one that has a significant
p.000121: impact on the course of the clini- cal trial or programme (including the potential for suspension of the trial
p.000121: programme or amendments to protocols), or warrants immedi- ate update of informed consent.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory Reporting and other
p.000121: Communication of Safety Information from Clini- cal Trials)
p.000121:
p.000121:
p.000121: What happens if the IEC/IRB determines that it must withdraw its approval/favourable opinion of the trial?
p.000121: The IEC/ IRB should notify the clinical investigator and study spon- sor of all decisions (favourable or
p.000121: unfavourable) in writing. Because a study may not proceed without approval/favourable opinion of an IEC/IRB, in
p.000121: some cases, it may be necessary to prematurely termi- nate or suspend the study (See ICH E6, Section 4.12).
p.000121: Should a study
p.000121:
p.000121:
p.000121:
p.000121: 76 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: be prematurely terminated, any subjects currently participating should be notified and procedures for
p.000121: withdrawal of enrolled sub- jects should consider the rights and welfare of the subjects.
p.000121: In other cases, the unanticipated risk(s) might be appropriately man- aged through a protocol change (e.g. eliminating
p.000121: a study arm, intro- ducing additional safety monitoring or testing, etc.) Note, however, that except where
p.000121: necessary to eliminate an immediate hazard(s) to research subjects, the investigator should not implement
p.000121: any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and
p.000121: documented approval/favourable opinion from the IEC/IRB of a protocol amendment (see ICH E6, Sec- tion 4.5).
p.000121: “Ethical review committees generally have no authority to impose sanctions on researchers who violate
p.000121: ethical standards in the con- duct of research involving humans. They may, however, withdraw ethical
p.000121: approval of a research project if judged necessary.” (CIOMS, International Ethical Guidelines, Commentary to
p.000121: Guideline 2)
p.000121:
p.000121:
p.000121: If the benefit-risk profile of the study changes and/or substantive protocol modifications are made, how should the
p.000121: information be communicated to study subjects?
p.000121: How is this documented?
p.000121: “Sponsors and investigators have a duty to … renew the informed consent of each subject if there are
p.000121: significant changes in the condi- tions or procedures of the research or if new information becomes available
p.000121: that could affect the willingness of subjects to continue to participate …” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 6)
p.000121: Periodically in long-term studies, the investigator should also con- sider renewing consent (e.g. in
p.000121: long-term studies involving elderly subjects).
p.000121: Communicating the new information to study subjects should follow customary procedures for obtaining and documenting
p.000121: informed con- sent.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 77
p.000121:
...
Economic / Economic/Poverty
Searching for indicator poor:
(return to top)
p.000121: according to the approved study protocol.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “applicable” Good Manufacturing Practice” (GMP)?
p.000121: “Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently produced
p.000121: and controlled according to quality standards. … GMP covers all aspects of production, from the starting
p.000121: materials, premises and equipment to the training and personal hygiene of staff. Detailed, written procedures
p.000121: are essential for each process that could affect the quality of the finished product. There must be systems to
p.000121: provide documented proof that correct procedures are consistently followed at each step in the manufac-
p.000121: turing process – every time the product is made. … WHO has estab- lished detailed guidelines for good
p.000121: manufacturing practice. Many countries have formulated their own requirements for GMP based on
p.000121:
p.000121:
p.000121:
p.000121: 110 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: WHO GMP.” (WHO, Good Manufacturing Practice in Pharmaceutical Production)
p.000121: Compliance with GMP standards is intended to:
p.000121: • assure consistency between and within batches of the investiga- tional product and thus assure the
p.000121: reliability of clinical trials;
p.000121: • assure consistency between the investigational product and the future commercial product and therefore the
p.000121: relevance of the clini- cal trial to the efficacy and safety of the marketed product;
p.000121: • protect subjects of clinical trials from poor-quality products result- ing from manufacturing errors (omission
p.000121: of critical steps such as sterilization, contamination and cross-contamination, mix-ups, in- correct labelling,
p.000121: etc.), or from starting materials and components of inadequate quality; and
p.000121: • document all changes in the manufacturing process.
p.000121: “… [T]he principles of GMP should be applied, as appropriate, to the preparation of [investigational] products.”
p.000121: (WHO, Good Manufactur- ing Practice in Pharmaceutical Production)
p.000121: In accordance with national/local laws and regulations, GMP compli- ance may be a requirement. Where not
p.000121: required by national/local laws and regulations, GMP standards provide important guidance to the manufacture of
p.000121: quality investigational products.
p.000121:
p.000121:
p.000121: What constitutes handling and storage of the investigational product(s)?
p.000121: In addition to packaging, labelling, quarantine and release associated with the manufacturing process at the
p.000121: production site, handling of the product by the sponsor also includes shipping, return, and final
p.000121: disposition of the investigational products.
p.000121: “Investigational products should be shipped in accordance with the orders given by the sponsor. A
p.000121: shipment is sent to an investigator only after the following two-step release procedure: (i) the release of the
p.000121: product after quality control (“technical green light”); and (ii) the
p.000121:
p.000121:
p.000121: PRINCIPLE 13 : GOOD MANUFACTURING PR ACTICE | 111
p.000121:
p.000121: authorization to use the product, given by the sponsor (“regulatory green light”). Both releases should be
p.000121: recorded. The sponsor should ensure that the shipment will be received and acknowledged by the correct addressee as
...
General/Other / Diminished Autonomy
Searching for indicator diminished:
(return to top)
p.000121: principles, which have their origin in the Declaration of Helsinki. Three basic ethi- cal principles of equal
p.000121: importance, namely respect for persons, beneficence, and justice, permeate all other GCP principles enu- merated below.
p.000121: Ethical principles have been established by many national and inter- national bodies, including:
p.000121: 1) The World Medical Association. Declaration of Helsinki;
p.000121: 2) The Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines
p.000121: for Biomedical Research Involving Human Subjects;
p.000121: 3) Other guidelines (see References).
p.000121:
p.000121:
p.000121: Application
p.000121: Principle 1 is applied through:
p.000121: • design and approval of the protocol;
p.000121: • informed consent;
p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
...
p.000121: prospective subject has adequately understood the information. The investigator should give each one full opportunity
p.000121: to ask questions and should answer them honestly, promptly and completely. In some instances the investiga- tor may
p.000121: administer an oral or a written test or otherwise determine whether the information has been adequately understood.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121: What is meant by “vulnerable persons”?
p.000121: In general, all individuals, including healthy volunteers, who partici- pate as research subjects should be
p.000121: viewed as intrinsically vulnerable because:
p.000121: 1) during the course of the study they are (or may be) exposed to an investigational product about which the safety and
p.000121: efficacy is un- known or incompletely understood; and
p.000121: 2) there may be other factors – social, cultural, economic, psycho- logical, medical – that may adversely
p.000121: affect the subjects’ ability to make rational, objective choices that protect their own interests, but which
p.000121: may not be readily apparent to the researcher.
p.000121: Some vulnerabilities may be readily identified because they are obvi- ous (e.g. institutionalized subjects, individuals
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
...
General/Other / Impaired Autonomy
Searching for indicator autonomy:
(return to top)
p.000121: principles, which have their origin in the Declaration of Helsinki. Three basic ethi- cal principles of equal
p.000121: importance, namely respect for persons, beneficence, and justice, permeate all other GCP principles enu- merated below.
p.000121: Ethical principles have been established by many national and inter- national bodies, including:
p.000121: 1) The World Medical Association. Declaration of Helsinki;
p.000121: 2) The Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines
p.000121: for Biomedical Research Involving Human Subjects;
p.000121: 3) Other guidelines (see References).
p.000121:
p.000121:
p.000121: Application
p.000121: Principle 1 is applied through:
p.000121: • design and approval of the protocol;
p.000121: • informed consent;
p.000121: • scientific and ethical review;
p.000121: • a favourable risk/benefit assessment;
p.000121: • fair and transparent procedures and outcomes in the selection of research subjects;
p.000121: • compliance with national and international laws, regulations, and standards.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 21
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “respect for persons” and how is it most directly implemented within GCP?
p.000121: “Respect for persons incorporates at least two ethical convictions: first, that individuals should be
p.000121: treated as autonomous agents, and second, that persons with diminished autonomy are entitled to pro- tection.”
p.000121: (The Belmont Report; CIOMS, International Ethical Guide- lines)
p.000121: “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to
p.000121: choose what shall or shall not happen to them. This opportunity is provided when adequate standards for
p.000121: informed consent are satisfied.” (The Belmont Report)
p.000121: In general, all individuals, including healthy volunteers, who participate as research subjects should be viewed as
p.000121: intrinsically vulnerable.
p.000121: When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled
p.000121: persons, or economically or educationally disadvantaged persons are likely to be more vulner- able to coercion or undue
p.000121: influence, additional safeguards should be included in the study to protect the rights and welfare of these sub- jects.
p.000121: These safeguards may include, but are not limited to: special justification to the ethical review committee
...
p.000121: “The subjects must be volunteers and informed participants in the research project.” (Declaration of Helsinki)
p.000121: “… [T]here is widespread agreement that the consent process can be analysed as containing three elements:
p.000121: information, comprehen- sion, and voluntariness.” (The Belmont Report)
p.000121: “For all biomedical research involving humans, the investigator must obtain the voluntary informed consent of the
p.000121: prospective subject or, in the case of an individual who is not capable of giving informed consent, the
p.000121: permission of a legally authorized representative in ac- cordance with applicable law. Waiver of informed
p.000121: consent is to be regarded as uncommon and exceptional, and must in all cases be ap- proved by an ethical review
p.000121: committee.” (CIOMS, International Ethi- cal Guidelines, Guideline 4)
p.000121: “Obtaining informed consent is a process that is begun when initial contact is made with a prospective
p.000121: subject and continues through- out the course of the study. By informing the prospective subjects, by
p.000121: repetition and explanation, by answering their questions as they arise, and by ensuring that each individual
p.000121: understands each proce- dure, investigators elicit their informed consent and in so doing mani- fest respect for
p.000121: their dignity and autonomy.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 59
p.000121:
p.000121: Application
p.000121: Principle 7 is applied through a process of informing and ensuring comprehension by study subjects
p.000121: (and/or their legally authorized representatives) about the research and obtaining their consent, in- cluding
p.000121: appropriate written informed consent.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “freely given” consent or “voluntary” participation in an investigation? How is this implemented
p.000121: within GCP?
p.000121: “Informed consent is based on the principle that competent individu- als are entitled to choose freely whether
p.000121: to participate in research. Informed consent protects the individual’s freedom of choice and respects the
p.000121: individual’s autonomy.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: “An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of
p.000121: informed consent requires conditions free of coercion and undue influence.” (The Belmont Re- port)
p.000121: “Unjustifiable pressures usually occur when persons in positions of authority or commanding influence –
p.000121: especially where possible sanctions are involved – urge a course of action for a subject. … [U]ndue
p.000121: influence would include actions such as manipulating a per- son’s choice through the controlling influence of a close
p.000121: relative and threatening to withdraw health services to which an individual would otherwise be entitled.” (The Belmont
p.000121: Report)
p.000121: “The quality of the consent of prospective subjects who are junior or subordinate members of a hierarchical group
p.000121: requires careful consid- eration, as their agreement to volunteer may be unduly influenced, whether justified
p.000121: or not, by the expectation of preferential treatment if they agree or by fear of disapproval or retaliation
p.000121: if they refuse.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 13)
p.000121:
p.000121:
p.000121:
...
p.000121: and by the use of third parties to protect them from harm.” (The Belmont Report)
p.000121: “The third parties chosen should be those who are most likely to understand the incompetent subject’s
p.000121: situation and to act in that person’s best interest. The person authorized to act on behalf of the
p.000121: subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the
p.000121: subject from the research, if such action appears in the subject’s best interest.” (The Belmont Report)
p.000121:
p.000121:
p.000121: How is informed consent documented? Is getting the subject (or the subject’s representative) to sign a consent document
p.000121: all that is necessary? How should the process be documented throughout the study?
p.000121: “Obtaining informed consent is a process that is begun when initial contact is made with a prospective
p.000121: subject, and continues through- out the course of the study. By informing the prospective subjects, by
p.000121: repetition and explanation, by answering their questions as they arise, and by ensuring that each
p.000121: individual understands each pro- cedure, investigators elicit their informed consent and in so doing
p.000121: manifest respect for their dignity and autonomy. Each individual must be given as much time as is needed to
p.000121: reach a decision, including time for consultation with family members or others. Adequate time and resources should
p.000121: be set aside for informed-consent procedures.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: “Consent may be indicated in a number of ways. The subject may imply consent by voluntary actions,
p.000121: express consent orally, or sign a consent form. As a general rule, the subject should sign a consent
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 67
p.000121:
p.000121: form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so … When
p.000121: consent has been obtained orally, investigators are responsible for providing documen- tation or proof of consent.”
p.000121: (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: When material changes occur in the conditions or the procedures of a study, and also periodically in
p.000121: long-term studies, the investiga- tor should once again seek informed consent from the subjects …“ (CIOMS,
p.000121: International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
...
General/Other / Manipulable
Searching for indicator manipulate:
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p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
p.000121: legally incompetent mi- nor, the investigator must obtain informed consent from the legally authorized
p.000121: representative in accordance with applicable law. These groups should not be included in research unless
p.000121: the research is necessary to promote the health of the population represented and this research cannot instead be
p.000121: performed on legally competent per- sons.” (Declaration of Helsinki)
p.000121: “Special provision may need to be made when comprehension is se- verely limited … for example, by conditions of
p.000121: immaturity or mental disability. Each class of subjects that one might consider as incom- petent (e.g.
...
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p.000121: standards for the design, conduct, recording and reporting of clinical research involving the participation
p.000121: of human subjects. Compliance with GCP provides public assurance that the rights, safety, and
p.000121: well-being of research subjects are protected and respected, consistent with the principles enunciated in the
p.000121: Declaration of Helsinki and other internationally recognized ethical guidelines, and ensures the integrity
p.000121: of clinical research data. The conduct of clinical research is complex and this complexity is compounded
p.000121: by the need to involve a number of dif- ferent individuals with a variety of expertise, all of who must perform
p.000121: their tasks skillfully and efficiently.
p.000121: The responsibility for GCP is shared by all of the parties involved, including sponsors, investigators
p.000121: and site staff, contract research organizations (CROs), ethics committees, regulatory authorities and research
p.000121: subjects.
p.000121:
p.000121: Background
p.000121: For the purposes of this handbook, a general definition of human research is:
p.000121: “Any proposal relating to human subjects including healthy vol- unteers that cannot be considered as an
p.000121: element of accepted clinical management or public health practice and that involves either (i) physical or
p.000121: psychological intervention or observation, or
p.000121: (ii) collection, storage and dissemination of information relating to individuals. This definition relates not only to
p.000121: planned trials involv- ing human subjects but to research in which environmental factors are manipulated in a way that
p.000121: could incidentally expose individuals
p.000121:
p.000121:
p.000121: | 3
p.000121:
p.000121: to undue risks.” (World Health Organization, Governance, rules and procedures, WHO Manual XVII).
p.000121: Before medical products can be introduced onto the market or into public health programmes, they must undergo a series
p.000121: of investiga- tions designed to evaluate safety and efficacy within the parameters of toxicity, potency, dose
p.000121: finding, and field conditions. Full informa- tion must be documented on therapeutic indications, method of
p.000121: administration and dosage, contraindications, warnings, safety measures, precautions, interactions,
p.000121: effects in target populations and safety information.
p.000121: During the clinical research and development process, most medical products will only have been tested for
p.000121: short-term safety and effi- cacy on a limited number of carefully selected individuals. In some cases, as
p.000121: few as 100, and rarely more than 5000 subjects will have received the product prior to its approval for
p.000121: marketing. Given these circumstances and because the decision to allow a new product on the market has such broad
p.000121: public health significance, the clinical trial process and data must conform to rigorous standards to ensure that
p.000121: decisions are based on data of the highest quality and integrity.
p.000121: In the early 1960s, widespread concern about the safety and control of investigational drugs and the clinical research
p.000121: process developed among members of the medical profession, the scientific commu- nity, regulatory
p.000121: authorities, and the general public. In 1968, WHO convened a Scientific Group on Principles for Clinical
...
General/Other / Natural Hazards
Searching for indicator hazard:
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p.000121: action by the IEC/ IRB to terminate or suspend its prior approval/favourable opinion. Written communication by
p.000121: the IEC/IRB should include clearly stated reason(s) for this decision/opinion.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 5 : REVIEW BY IEC/ IRB | 51
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by IEC(s)/ IRB(s), investigators, sponsors, and
p.000121: regulators.
p.000121: A properly constituted and operational IEC/IRB reviews the proto- col (and/or any proposed changes to the
p.000121: protocol) and provides the investigator with a written decision/opinion. IEC/IRB written proce- dures should
p.000121: ensure that no subject be admitted to a trial and no deviations from, or changes to, the protocol be
p.000121: initiated before the IEC/IRB issues its approval/favourable opinion.
p.000121: Investigators submit the study protocol to their IEC(s)/IRB(s) and are responsible for securing an approval/favourable
p.000121: opinion prior to ad- mitting any subjects to the trial. Investigators should not implement any deviation from, or
p.000121: changes to, the protocol without agreement by the sponsor and prior review and documented approval/favourable
p.000121: opinion from the IEC(s)/IRB(s) of an amendment, except where nec- essary to eliminate an immediate hazard(s) to
p.000121: research subjects. (See WHO GCP Principle 6: Protocol Compliance)
p.000121: The sponsor develops the protocol, selects qualified investigators/ institutions, and confirms that each
p.000121: investigator has had the study protocol reviewed by an IEC/IRB and received IEC/IRB approval/fa- vourable
p.000121: opinion.
p.000121: In accordance with applicable laws/regulations, regulators may in- spect the investigator(s), sponsor(s),
p.000121: and/or IEC(s)/IRB(s) to ensure compliance with IEC/IRB review requirements. Regulators should also encourage
p.000121: IECs/IRBs to communicate with them directly on is- sues or concerns they may encounter in their review of human
p.000121: trials.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Composition, Functions, and Operations (ICH E6, Section 3.2) Procedures (ICH E6, Section 3.3)
p.000121: Records (ICH E6, Section 3.4)
p.000121:
p.000121:
p.000121:
p.000121: 52 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Constituting an EC (WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research, Section
p.000121: 4)
p.000121: Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 6)
p.000121: Decision-Making (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 7)
...
p.000121: Commit- tees that Review Biomedical Research), WHO, 2002
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 6: Protocol Compliance
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment
p.000121: Definitions for:
p.000121: Approval (in relation to institutional review boards (IRBs)) (ICH E6, 1.5) Independent Ethics Committee (IEC) (ICH E6,
p.000121: 1.27)
p.000121: Institutional Review Board (IRB) (ICH E6, 1.31)
p.000121: Opinion (in relation to Independent Ethics Committee) (ICH E6, 1.42)
p.000121:
p.000121:
p.000121: PRINCIPLE 5 : REVIEW BY IEC/ IRB | 53
p.000121:
p.000121: PRINCIPLE 6: PROTOCOL COMPLIANCE
p.000121: Research involving humans should be conducted in compliance with the approved protocol.
p.000121: Once the IEC/IRB gives its approval/favourable decision on the proto- col, it is essential that the trial be conducted
p.000121: in compliance with that protocol so that the decision on the ethical acceptability of the trial remains valid.
p.000121: “The investigator should not implement any deviation from, or changes of, the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of
p.000121: an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the
p.000121: change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), change
p.000121: of telephone number(s)).” (ICH E6, Section 4.5)
p.000121:
p.000121: Application
p.000121: Principle 6 is applied through: (1) verifiable investigator adherence to the protocol requirements; (2) submission
p.000121: of any protocol changes to the sponsor and to the IEC/IRB (with approval/favourable opinion) prior to their
p.000121: implementation; and (3) effective monitoring of the study by the sponsor.
p.000121:
p.000121: Questions and Answers
p.000121: What does conducting the trial in compliance with the protocol mean?
p.000121: Compliance with the protocol means performing all of the study ac- tivities covered by the protocol (i.e. identifying,
p.000121: informing, selecting, treating, observing, recording, withdrawing, terminating, reporting, analysing) in the
p.000121: precise manner specified in the approved protocol.
p.000121: It is especially important that those study activities most critical to ensuring the rights and well being of
p.000121: subjects and the quality and in- tegrity of safety and efficacy data are carried out strictly according to the approved
p.000121: protocol, including but not limited to:
p.000121:
p.000121:
p.000121: 54 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • informing subjects fully and obtaining their agreement and docu- mented consent before enrolling them in
p.000121: the study;
p.000121: • selecting subjects in accordance with the inclusion and exclusion criteria;
p.000121: • treating subjects with the investigational product as specified in the protocol;
...
p.000121: received that the study is not being conducted in compliance with the protocol or other requirements of the IEC/IRB.
p.000121:
p.000121:
p.000121: Who is responsible for compliance with the protocol?
p.000121: The investigator has direct contact with study subjects and bears pri- mary responsibility for complying with the
p.000121: provisions of the protocol. The investigator also bears responsibility to personally supervise all study staff
p.000121: and ensure their compliance with the protocol.
p.000121: The sponsor has responsibility to monitor the study and ensure the investigator and site staff comply with
p.000121: the protocol.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by IECs/ IRBs, investigators, sponsors, and
p.000121: regulators.
p.000121: IEC/IRB written procedures should ensure that no subject be admit- ted to a trial and no deviations from, or changes
p.000121: of, the protocol be initiated before the IEC/IRB issues its approval/favourable opinion.
p.000121:
p.000121:
p.000121: 56 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Investigators should be thoroughly familiar with the protocol and are responsible for conducting the trial in
p.000121: compliance with the protocol. Investigators should not implement any deviation from, or changes of the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB(s)/IEC(s) of an
p.000121: amendment, except where necessary to eliminate an immediate hazard(s) to research subjects.
p.000121: The sponsor monitors the study to ensure investigator compliance with the protocol and takes action to
p.000121: secure compliance or termi- nate the trial in the case of noncompliance. If the monitoring and/or auditing
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should
p.000121: terminate the investigator’s/institution’s participation in the trial. All parties, includ- ing the IEC/IRB, should be
p.000121: notified in such cases.
p.000121: In accordance with applicable laws/regulations, regulators may in- spect the investigator(s) or sponsor to
p.000121: ensure compliance with proto- col adherence requirements. Regulators should be promptly notified when a sponsor
p.000121: identifies serious and/or persistent noncompliance on the part of an investigator/institution leading to
p.000121: termination of the investigator’s/institution’s participation in a study.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to:
p.000121: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: For clinical investigators, refer to:
p.000121: Compliance with Protocol (ICH E6, Section 4.5)
p.000121: For sponsors, refer to:
p.000121: Record Access (ICH E6, Section 5.15) Monitoring (ICH E6, Section 5.18) Noncompliance (ICH E6, Section 5.20)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 1995
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 57
p.000121:
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 2: Protocol
p.000121: Definitions for:
...
p.000121: programme or amendments to protocols), or warrants immedi- ate update of informed consent.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory Reporting and other
p.000121: Communication of Safety Information from Clini- cal Trials)
p.000121:
p.000121:
p.000121: What happens if the IEC/IRB determines that it must withdraw its approval/favourable opinion of the trial?
p.000121: The IEC/ IRB should notify the clinical investigator and study spon- sor of all decisions (favourable or
p.000121: unfavourable) in writing. Because a study may not proceed without approval/favourable opinion of an IEC/IRB, in
p.000121: some cases, it may be necessary to prematurely termi- nate or suspend the study (See ICH E6, Section 4.12).
p.000121: Should a study
p.000121:
p.000121:
p.000121:
p.000121: 76 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: be prematurely terminated, any subjects currently participating should be notified and procedures for
p.000121: withdrawal of enrolled sub- jects should consider the rights and welfare of the subjects.
p.000121: In other cases, the unanticipated risk(s) might be appropriately man- aged through a protocol change (e.g. eliminating
p.000121: a study arm, intro- ducing additional safety monitoring or testing, etc.) Note, however, that except where
p.000121: necessary to eliminate an immediate hazard(s) to research subjects, the investigator should not implement
p.000121: any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and
p.000121: documented approval/favourable opinion from the IEC/IRB of a protocol amendment (see ICH E6, Sec- tion 4.5).
p.000121: “Ethical review committees generally have no authority to impose sanctions on researchers who violate
p.000121: ethical standards in the con- duct of research involving humans. They may, however, withdraw ethical
p.000121: approval of a research project if judged necessary.” (CIOMS, International Ethical Guidelines, Commentary to
p.000121: Guideline 2)
p.000121:
p.000121:
p.000121: If the benefit-risk profile of the study changes and/or substantive protocol modifications are made, how should the
p.000121: information be communicated to study subjects?
p.000121: How is this documented?
p.000121: “Sponsors and investigators have a duty to … renew the informed consent of each subject if there are
p.000121: significant changes in the condi- tions or procedures of the research or if new information becomes available
p.000121: that could affect the willingness of subjects to continue to participate …” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 6)
p.000121: Periodically in long-term studies, the investigator should also con- sider renewing consent (e.g. in
p.000121: long-term studies involving elderly subjects).
...
General/Other / Public Emergency
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p.000121: Guidelines, Guideline 11)
p.000121:
p.000121:
p.000121: 30 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What can be done to minimize bias in a clinical investigation?
p.000121: Bias implies subjective or unfair distortion of judgment in favour of or against a person or thing. The purpose
p.000121: of conducting a clinical trial of an investigational product is to distinguish the effect of the inves- tigational
p.000121: product from other factors, such as spontaneous changes in the course of the disease, placebo effects, or
p.000121: biased/subjective observation. Bias can be minimized in a clinical trial by designing well-controlled
p.000121: studies, by using procedures to randomize subjects to various study arms based on the generation of a random
p.000121: alloca- tion sequence, and by using concealment and blinding.
p.000121:
p.000121:
p.000121: What is meant by “blinding” or “masking”?
p.000121: Blinding or masking is “[a] procedure in which one or more parties to the trial are kept unaware of the
p.000121: treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double blinding
p.000121: usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being
p.000121: unaware of the treatment assignment(s).” (ICH E6, 1.10)
p.000121:
p.000121:
p.000121: When is unblinding of the trial by the investigator permissible? How should unblinding be accomplished (in those
p.000121: situations where it would be allowed)?
p.000121: Unblinding may be necessary in the event of a medical emergency for a research subject. Generally breaking the blind
p.000121: involves procedures specified in the study protocol that allow the investigator and/or sponsor to find out
p.000121: whether a particular subject received the inves- tigational product, or received a comparator product or
p.000121: placebo, where applicable, while on the study.
p.000121: “The investigator … should ensure that the code is broken only in accordance with the protocol. If the trial
p.000121: is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g.,
p.000121: accidental unblinding, unblinding due to a serious ad- verse event) of the investigational product(s).” (ICH E6,
p.000121: Section 4.7)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 31
p.000121:
p.000121: What is meant by “randomization”?
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
p.000121: another method, such as historical or literature controls, can be justified scientifically and ethi- cally. Assignment
p.000121: to treatment arms by randomization, in addition to its usual scientific superiority, offers the advantage
p.000121: of tending to render equivalent to all subjects the foreseeable benefits and risks of participation in a
p.000121: trial.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121: “The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken
...
p.000121: with diminished men- tal capacities) or relevant to the research (e.g. children participating in a paediatric vaccine
p.000121: trial). Other vulnerabilities of subjects may not be so readily identified (e.g. subjects who are homeless or economi-
p.000121: cally disadvantaged). Subjects may also become more or less vulner- able throughout a study as circumstances
p.000121: about their health status and lives change.
p.000121: “Vulnerable persons are those who are relatively (or absolutely) in- capable of protecting their own
p.000121: interests. More formally, they may have insufficient power, intelligence, education, resources, strength,
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 65
p.000121:
p.000121: or other needed attributes to protect their own interests.” (CIOMS, International Ethical Guidelines,
p.000121: Commentary on Guideline 13)
p.000121: Examples of vulnerable persons include, but are not limited to: children, individuals with
p.000121: diminished mental capacity, prisoners, in- stitutionalized persons (including orphans), patients in emergency
p.000121: situations, the economically disadvantaged, individuals who cannot give consent.
p.000121: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups,
p.000121: such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000121: continually be sought as research subjects, owing to their ready availability in settings where research is
p.000121: conducted. Given their de- pendent status and their frequently compromised capacity for free consent, they
p.000121: should be protected against the danger of being in- volved in research solely for administrative convenience,
p.000121: or because they are easy to manipulate as a result of their illness or socioeco- nomic condition.” (The
p.000121: Belmont Report)
p.000121:
p.000121: What special protections are required to enable vulnerable populations to participate in research?
p.000121: “For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a
...
p.000121: significant changes in the condi- tions or procedures of the research or if new information becomes available
p.000121: that could affect the willingness of subjects to continue to participate …” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 6)
p.000121: Periodically in long-term studies, the investigator should also con- sider renewing consent (e.g. in
p.000121: long-term studies involving elderly subjects).
p.000121: Communicating the new information to study subjects should follow customary procedures for obtaining and documenting
p.000121: informed con- sent.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 77
p.000121:
p.000121: What is an Independent Data and Safety Monitoring Board (DSMB, also known as an independent Data Monitoring Committee
p.000121: [DMC])?
p.000121: An independent data and safety monitoring board (DSMB) is a group of individuals with pertinent expertise that reviews
p.000121: on a regular basis accumulating data from one or more ongoing clinical trials. The DSMB advises the sponsor
p.000121: regarding the continuing safety of current trial participants and those yet to be recruited to the trial, as well
p.000121: as the continuing validity and scientific merit of the trial.
p.000121: “At intervals defined by the protocol, the DSMB reviews and evalu- ates the data on clinical efficacy
p.000121: and safety collected during the study, and assesses reports on cumulated serious adverse events (SAEs). The
p.000121: DSMB may also be requested by the sponsor to conduct emergency reviews of data to assess safety-related issues. … At
p.000121: the conclusion of the review, the DSMB provides a written recommenda- tion to the sponsor regarding whether a protocol
p.000121: should be amended and/or a study should proceed based on its review of the data and the progress report
p.000121: submitted by the sponsor.” (Operational Guide- lines for the Establishment and Functioning of Data and Safety
p.000121: Moni- toring Boards, WHO TDR).
p.000121: An important function of a DSMB “… is to protect the research sub- jects from previously unknown adverse reactions;
p.000121: another is to avoid unnecessarily prolonged exposure to an inferior therapy.” (CIOMS, International Ethical
p.000121: Guidelines, Commentary on Guideline 11)
p.000121:
p.000121:
p.000121: Should DSMBs be established for every study?
p.000121: All clinical trials require safety monitoring but not all trials require monitoring by a formal committee
p.000121: that may be external to the trial organizers, sponsors and investigators. DSMBs have generally been
p.000121: established for large, randomized multi-site studies that evaluate treatments intended to prolong life or reduce
p.000121: risk of a major adverse health outcome such as a cardiovascular event or recurrence of cancer. DSMBs are
p.000121: generally recommended for any controlled trial of any size that will compare rates of mortality or major
p.000121: morbidity, but a DSMB is not required or recommended for most clinical stud-
p.000121:
p.000121: 78 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ies. DSMBs are generally not needed, for example, for trials at early stages of product development. They are also
p.000121: generally not needed for trials addressing lesser outcomes, such as relief of symptoms, un- less the trial population
p.000121: is at elevated risk of more severe outcomes.
p.000121: “In most cases of research involving human subjects, it is unneces- sary to appoint a DSMB. To ensure
p.000121: that research is carefully moni- tored for the early detection of adverse events, the sponsor or the
p.000121: principal investigator appoints an individual to be responsible for ad- vising on the need to consider changing the
p.000121: system of monitoring for adverse events or the process of informed consent, or even to con- sider terminating the
p.000121: study.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 11)
p.000121: “… DSMBs are of value in the following situations:
p.000121: • large randomized, multi-center high morbidity/mortality trials;
p.000121: • studies where data could justify early study termination or where the design or executed data accrual is complex;
p.000121: • early studies of a high-risk intervention;
p.000121: • studies carried out in emergency situations in which informed con- sent is waived;
p.000121: • studies involving vulnerable populations; or,
p.000121: • studies in the early phases of a novel intervention with very limited information on clinical safety or where prior
p.000121: information may have raised safety concerns.”
p.000121: (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Appendix 5,
p.000121: Data and Safety Monitoring Boards)
p.000121:
p.000121: Implementation
p.000121: Sponsors, IECs/IRBs, DSMBs (if applicable), and regulators share responsibility for ongoing safety
p.000121: evaluations of the investigational product(s).
p.000121: The investigator reports unanticipated problems involving risks to subjects and provides periodic
p.000121: progress reports at intervals ap-
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 79
p.000121:
p.000121: propriate to the degree of risk to sponsors and IECs/IRBs in accord- ance with the national/local laws and
p.000121: regulations. The investigator provides adequate, accurate, and objective information on risks and benefits during
p.000121: informed consent of study subjects, and renews the consent of the subject to continue in the study, as appropriate.
p.000121: The sponsor monitors the study and performs safety evaluations of the investigational product(s) by
p.000121: analysing data received from the investigator(s) and the DSMB (if one has been appointed). The sponsor
...
p.000121: It might, for example, be agreed to treat cases of an infectious dis- ease contracted during a trial of a
p.000121: vaccine designed to provide immu- nity to that disease, or to provide treatment of incidental conditions unrelated to
p.000121: the study. … When prospective or actual subjects are found to have diseases unrelated to the research
p.000121: or cannot be en- rolled in a study because they do not meet the health criteria, inves- tigators should, as
p.000121: appropriate, advise them to obtain, or refer them for, medical care.” (CIOMS, International Ethical Guidelines, Commen-
p.000121: tary on Guideline 21)
p.000121:
p.000121: Implementation
p.000121: The investigator is responsible for providing, or ensuring that sub- jects have access to, medical care for
p.000121: medical problems arising dur- ing their participation in the trial that are, or could be related to the study
p.000121: intervention, and for following the subjects’ status until the problem is resolved.
p.000121: “It is recommended that the investigator inform the subject’s primary physician about the subject’s participation
p.000121: in the trial if the subject has a primary physician and if the subject agrees to the primary phy- sician being
p.000121: informed.” (ICH E6, Section 4.3)
p.000121: Primary responsibility for selecting qualified clinical investigators to conduct a study resides with the
p.000121: sponsor.
p.000121: The IECs/IRBs is responsible for ensuring that the rights and welfare of study subjects are protected. Consideration of
p.000121: investigator quali- fications and experience and the adequacy of the site (including the supporting staff, available
p.000121: facilities, and emergency procedures) by the IEC/IRB will ensure that subjects have access to appropriate care for
p.000121: medical problems arising during participation in the trial.
p.000121: National and/or local regulatory authorities have indirect respon- sibility related to clinical investigator
p.000121: qualifications. Regulators (1) establish licensing and practice standards for physicians and other medical
p.000121: personnel, (2) enforce compliance with such standards, and
p.000121: (3) impose disciplinary actions, as appropriate, on physicians and
p.000121:
p.000121:
p.000121:
p.000121: 84 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: other medical personnel who fail to meet such standards. Differ- ent regulatory agencies and authorities
p.000121: may be responsible for the oversight of clinical research versus the licensure and oversight of medical
p.000121: professionals; exchange of information among regulatory agencies is encouraged in such circumstances.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Documentation (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 5.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1) Medical Care of Trial Subjects (ICH E6, Section 4.3)
p.000121: Safety Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
...
p.000121: the sponsor and regulators alike in determining which staff members were authorized to carry out specific
p.000121: duties during the course of the trial.
p.000121:
p.000121: Implementation
p.000121: The investigator bears primary responsibility for (1) selecting quali- fied staff to assist in the conduct of
p.000121: the investigation; (2) ensuring that study staff receive appropriate training, related to ethics and
p.000121: consent procedures as well as requirements of the specific protocol;
p.000121: (3) establishing clear procedures for activities related to the conduct of the study; (4) assigning tasks to staff,
p.000121: based on their qualifications, experience, and professional licenses; and (5) personally supervising staff to ensure
p.000121: that they satisfactorily fulfill their study-related duties. Although the investigator may delegate tasks to members of
p.000121: his/her staff, nevertheless, the investigator retains overall responsibility for the study and ensuring that
p.000121: his/her staff complies with applicable laws and regulations for human subject protection and the conduct of
p.000121: clinical research.
p.000121: The IEC/IRB is responsible for ensuring that the rights and welfare of study subjects are protected.
p.000121: Consideration of the site’s charac- teristics (e.g. number and qualifications of supporting staff, available
p.000121:
p.000121:
p.000121: PRINCIPLE 10 : STAFF QUALIFICATIONS | 89
p.000121:
p.000121: facilities and equipment, and emergency procedures) will allow the IEC/IRB to evaluate the adequacy of
p.000121: the site, and ensure that sub- jects’ welfare is not compromised during the trial.
p.000121: Sponsors have the responsibility for selecting appropriately quali- fied investigators to conduct the study;
p.000121: part of that consideration is ensuring that investigators have sufficient staff (also with appropriate qualifications)
p.000121: available, who are appropriately trained to conduct all study-related activities, and who understand how to
p.000121: capture and document required observations and data.
p.000121: In accordance with national and/or local laws and regulations, regu- latory authorities may inspect study sites to
p.000121: determine if the con- duct of the study is in compliance with local laws/regulations. Such inspections would include
p.000121: finding out who was assigned responsibil- ity for conducting various study-related activities (e.g. screening sub-
p.000121: jects to determine if they meet inclusion/exclusion criteria; obtaining informed consent; conducting physical
p.000121: examinations; collecting and analysing study data; recording, transcribing, or reporting data to the sponsor;
p.000121: administering the investigational product to subjects), and determining whether these activities were
p.000121: appropriately assigned and within the scope of the staff member’s professional license(s).
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to:
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics- Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: For investigators, refer to:
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000121: required and identify clinical investigators who have the particular medical expertise necessary to conduct the
p.000121: study and who have knowledge, training and experience in the conduct of clinical trials and human subject
p.000121: protection.
p.000121: See WHO GCP Principles 2: Protocol; 9: Investigator Qualifications; 10: Staff Qualifications.
p.000121:
p.000121:
p.000121: 6. Ethics committee review and approval of the protocol
p.000121: Within GCP, studies must be reviewed and receive approval/ favourable opinion from an Independent
p.000121: Ethics Committee (IEC)/ Institutional Review Board (IRB) prior to enrollment of study subjects.
p.000121: The investigator generally assumes responsibility for obtaining IEC/ IRB review of the study protocol. Copies of
p.000121: any approval/favourable opinion are then provided to the sponsor.
p.000121: See WHO GCP Principles 1: Ethical Conduct; 2: Protocol; 4: Benefit- Risk Assessment; 5: Review by IEC/IRC; 7: Informed
p.000121: Consent; 8: Con- tinuing Review/Ongoing Benefit-Risk Assessment; 11: Records; 12: Confidentiality/Privacy.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 12 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 7. Review by regulatory authorities
p.000121: Within GCP, studies must undergo review by regulatory authority(ies) for use of the investigational product or
p.000121: intervention in human sub- jects and to ensure that the study is appropriately designed to meet its stated
p.000121: objectives, according to national/regional/local law and regulations. [Note: Some countries may not have
p.000121: systems in place for reviewing research or may depend on external review. Also, some countries may have additional
p.000121: requirements for the review and ap- proval of trial sites and/or investigators.]
p.000121: The sponsor is generally responsible for ensuring that the applicable regulatory authority(ies) review and provide
p.000121: any required authori- zations for the study before the study may proceed. The sponsor should also list
p.000121: the trial in applicable and/or required clinical trial registry(ies).
p.000121: See WHO GCP Principles 2: Protocol; 4: Benefit-Risk Assessment.
p.000121:
p.000121:
p.000121: 8. Enrollment of subjects into the study: recruitment, eligibility, and informed consent
p.000121: The clinical investigator has primary responsibility for recruiting subjects, ensuring that only
p.000121: eligible subjects are enrolled in the study, and obtaining and documenting the informed consent of each subject.
p.000121: Within GCP, informed consent must be obtained from each study subject prior to enrollment in the study or
p.000121: performing any spe- cific study procedures.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 7: In- formed Consent; 11: Records.
p.000121:
p.000121:
p.000121: 9. The investigational product(s): quality, handling and accounting
p.000121: Quality of the investigational product is assured by compliance with Good Manufacturing Practice (GMP) and by handling
p.000121: and storing the product according to the manufacturing specifications and the study protocol. GCP requires that
p.000121: sponsors control access to the inves-
p.000121:
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 13
p.000121:
p.000121: tigational product and also document the quantity(ies) produced, to whom the product is shipped, and
...
p.000121: deprived of its fair share of the benefits of research, short-term or long-term
p.000121: … Subjects should be drawn from the qualifying population in the general geographic area of the trial without
p.000121: regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwise.”
p.000121: (CIOMS, International Ethical Guidelines, Commen- tary on Guideline 12)
p.000121: Within GCP, the principle of “justice” is most directly implemented by considering procedures and outcomes for
p.000121: subject selection during the design and review of the study protocol as well as during recruit- ment and enrollment
p.000121: of study subjects. (See also WHO GCP Principles 2: Protocol, and 7: Informed Consent)
p.000121:
p.000121: Implementation
p.000121: The basic ethical principles of biomedical research are reflected in all GCP principles and processes,
p.000121: impacting on the role and respon- sibilities of each party within GCP. Each party participating in clinical research
p.000121: has responsibility for ensuring that research is ethically and scientifically conducted according to the highest
p.000121: standards. This in- cludes the investigator(s) and site staff, the sponsor and sponsor’s staff (including
p.000121: monitors and auditors), the ethics committee(s), the regulatory authority(-ies), and the individual research subjects.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 24 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities):
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: 2000, Section 6.2)
p.000121: Follow-Up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, 2000, Section 9)
p.000121: Ethical review of externally sponsored research (CIOMS, Interna- tional Ethical Guidelines, Guideline 3)
p.000121: For clinical investigators, refer to:
p.000121: Communications with the IRB/IEC (ICH E6, Section 4.4) Informed Consent of Trial Subjects (ICH E6, Section 4.8) Safety
p.000121: Reporting (ICH E6, Section 4.11)
p.000121: For sponsors, refer to:
p.000121: Trial Design (ICH E6, Section 5.4)
p.000121: Notification/Submission to Regulatory Authority(ies) (ICH E6, Sec- tion 5.10)
p.000121: Safety Information (ICH E6, Section 5.16)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 3: Risk Identification
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 7: Informed Consent
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assess- ment
p.000121: Definitions for:
p.000121: Impartial Witness (ICH E6, 1.26) Informed Consent (ICH E6, 1.28)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 25
p.000121:
p.000121: Legally Acceptable Representative (ICH E6, 1.37) Vulnerable Subjects (ICH E6, 1.61)
p.000121: Well-being [of the Trial Subjects] (ICH E6, 1.62)
p.000121: Clinical Trial Protocol and Protocol Amendment(s):
p.000121: Selection and Withdrawal of Subjects (ICH E6, Section 6.5) Ethics (ICH E6, Section 6.12)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
...
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
p.000121: another method, such as historical or literature controls, can be justified scientifically and ethi- cally. Assignment
p.000121: to treatment arms by randomization, in addition to its usual scientific superiority, offers the advantage
p.000121: of tending to render equivalent to all subjects the foreseeable benefits and risks of participation in a
p.000121: trial.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121: “The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken
p.000121: only in accordance with the protocol.” (ICH E6, Section 4.7)
p.000121:
p.000121:
p.000121: How should the protocol address reporting of adverse events?
p.000121: The protocol should specify procedures for eliciting reports of, and for recording and reporting, adverse
p.000121: event and inter-current illness- es; the type and duration of the follow-up of subjects after adverse events; and the
p.000121: methods to be used in, and timing for, assessing, recording, and analysing safety parameters.
p.000121: The protocol and investigator’s brochure will assist the investigator and sponsor in determining whether an
p.000121: adverse event is “unexpect- ed” and how it should be reported. Unexpected serious adverse drug reactions should be
p.000121: reported to the regulatory authority(ies) and to other investigators involved in the trial in accordance with
p.000121: applicable regulatory requirement(s).
p.000121:
p.000121: Implementation
p.000121: Sponsors are primarily responsible for (1) designing the clinical investigation, (2) developing the
p.000121: study protocol, investigator’s bro- chure, and related materials to describe the procedures that will be followed,
p.000121: study endpoints, data collection, and other study require-
p.000121:
p.000121: 32 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ments; and (3) ensuring that the protocol complies with applicable national and local laws and regulations.
p.000121: Investigators may be consulted by the sponsor during protocol de- sign or, in some cases, may personally contribute to
p.000121: the design of the protocol. Investigators are responsible for familiarizing themselves with the study protocol,
p.000121: investigator’s brochure, and related materi- als to ensure that they are able to carry out the study in compliance with
p.000121: the specifications of the protocol.
p.000121: IECs/IRBs are responsible for conducting ethical review of the study protocol. This also includes arranging for a
p.000121: scientific review or verify- ing that a competent body has determined that the research is scien- tifically sound. (See
p.000121: WHO GCP Principle 5: Review by IEC/IRB)
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with applicable laws and
p.000121: regulations. This may include prospective review of the protocol, the investigator’s brochure and other
p.000121: relevant information. Where the protocol or investigator’s brochure is inaccurate or materially incomplete,
p.000121: where the protocol does not adequately provide for the protection of subject rights and safety, or where the protocol
p.000121: is deficient in design to meet its stated objectives, the regulatory authority may require protocol modifica-
p.000121: tion or take action to disallow the protocol to proceed in accordance with applicable laws and regulations.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to:
p.000121: Clinical Trial Protocol (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: Documentation (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 5.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1) Adequate Resources (ICH E6, Section 4.2)
p.000121: Compliance with Protocol (ICH E6, Section 4.5)
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 33
p.000121:
p.000121: Randomization Procedures and Unblinding (ICH E6, Section 4.7) Safety Reporting (ICH E6, Section 4.11)
p.000121: Clinical Trial Protocol (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: For sponsors, refer to:
p.000121: Trial Design (ICH E6, Section 5.4)
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Notification/Submission to Regulatory Authorities (ICH E6, Section 5.10)
p.000121: Clinical Trial Protocol (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: Items to be Included in a Protocol (or Associated Documents) for Biomedical Research Involving Human Subjects (CIOMS,
p.000121: Interna- tional Ethical Guidelines, Appendix 1)
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995 (Section 2)
...
p.000121:
p.000121: 42 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: insistent on the justification of the risk (looking usually to the likeli- hood of benefit to the subject –
p.000121: or in some rare cases, to the manifest voluntariness of the participation) … ” (The Belmont Report)
p.000121: “… Scientific review must consider inter alia, the study design, in- cluding the provisions for avoiding or
p.000121: minimizing risk and for monitor- ing safety.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 2)
p.000121: “Risks and benefits of research may affect the individual subjects, the families of the individual subjects,
p.000121: and society at large (or special groups of subjects in society). … In balancing these different ele- ments,
p.000121: the risks and benefits affecting the immediate research sub- ject will normally carry special weight.” (The Belmont
p.000121: Report)
p.000121: “In medical research on human subjects, considerations related to the well-being of the human subject
p.000121: should take precedence over the interests of science and society.” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 4 is applied through appropriate study design and through ethical, scientific, and, where
p.000121: applicable, regulatory review of the study protocol prior to study initiation.
p.000121:
p.000121: Questions and Answers
p.000121: Who is responsible for determining that the risk/benefit profile of a study is acceptable or unacceptable?
p.000121: Within GCP, the sponsor of the study, the investigator(s), IECs/IRBs, and the regulatory authority(-ies) each
p.000121: have responsibilities for evalu- ating the risk/benefit profile of a study (see Implementation, below). In
p.000121: accordance with applicable laws and regulations, the regulatory authority may stop a study from proceeding or
p.000121: require modifications to the protocol based on an unacceptable risk/benefit profile. The IEC/IRB has authority to
p.000121: issue an approval/favourable opinion; require modi- fications prior to approval/favourable opinion; issue a
p.000121: disapproval/ negative opinion; or terminate/suspend a prior approval/favourable
p.000121:
p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 43
p.000121:
p.000121: opinion. An investigator may decide either to participate or not par- ticipate in a study based on
p.000121: his/her assessment of the risk/benefit profile. The sponsor may decide either not to initiate or to terminate/
p.000121: suspend a trial where the risk/benefit profile is unacceptable.
p.000121:
p.000121:
p.000121: When should a risk/benefit determination be performed?
p.000121: A risk/benefit determination should be performed prior to study initiation as well as periodically during the
p.000121: study (see also WHO GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment).
p.000121:
p.000121:
p.000121: What if the risk-benefit profile of a study appears favourable from a national, societal, institutional, or scientific
p.000121: standpoint but unfavourable to the participating research subjects?
p.000121: The most important considerations in a study are those related to the rights, safety, and well-being of the
...
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by spon- sors, investigators, IECs/IRBs, and regulators.
p.000121: The sponsor should design research studies to ensure that risks to subjects are minimized.
p.000121: The investigator(s) should review the investigator’s brochure and other relevant risk and benefit
p.000121: information in making a decision to conduct the study. The investigator is also responsible for providing
p.000121: adequate, accurate, and objective information on risks and benefits during informed consent of study subjects.
p.000121: Prior to study initiation, the IECs/IRBs should review the protocol, investigator’s brochure, and other
p.000121: relevant information to (1) un- derstand the study procedures or other steps that will be taken to
p.000121: minimize risks, (2) understand the potential benefits (if any) and de- termine whether those benefits outweigh the
p.000121: anticipated risks, and
p.000121: (3) ensure that the informed consent document accurately states the potential risks and benefits in a way that will
p.000121: allow study subjects to understand what they are undertaking.
p.000121: Regulators bear responsibility for allowing a protocol to proceed in accordance with applicable laws and
p.000121: regulations. This may include prospective review of the protocol, the investigator’s brochure, and other
p.000121: relevant information to ensure that risk(s) and benefit(s) are accurately identified and justify allowing the
p.000121: protocol to proceed. The regulatory authority may require modification to a protocol as a con- dition to its proceeding
p.000121: and/or may suspend or terminate a protocol based on an unacceptable risk/benefit profile in accordance with ap-
p.000121: plicable laws and regulations.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 45
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: Inducement to participate in research (CIOMS International Ethical Guidelines, 2002, Guideline 7)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1) Clinical Trial Protocol, General Information (ICH
p.000121: E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: Inducement to participate in research (CIOMS International Ethical Guidelines, 2002, Guideline 7)
p.000121: For sponsors, refer to:
p.000121: Notification/Submission to Regulatory Authority(ies) (ICH E6, Sec- tion 5.10)
p.000121: Clinical Trial Protocol, General Information (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: For regulatory authorities, refer to:
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 2: Protocol
p.000121: GCP Principle 3: Risk Identification GCP Principle 7: Informed Consent
p.000121: GCP Principle 8: Continuing Review/Ongoing Benefit-Risk Assess- ment
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 46 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Definitions for:
p.000121: Applicable Regulatory Requirement(s) (ICH E6, 1.4)
p.000121: Approval (in relation to institutional review boards [IRBs]) (ICH E6, 1.5)
p.000121: Informed Consent (ICH E6, 1.28) Investigator’s Brochure (ICH E6, 1.36)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 4 : BENEFIT- RISK ASSESSMENT | 47
p.000121:
p.000121: PRINCIPLE 5: REVIEW BY IEC/IRB
p.000121: Research involving humans should receive independent eth- ics committee/institutional review board
...
p.000121: “[T]here should be a predefined method for arriving at a decision (e.g. by consensus, by vote); it is recommended that
p.000121: decisions be arrived at through consensus, where possible; when a consensus appears unlikely, it is
p.000121: recommended that the EC vote.” (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 7, Decision Making)
p.000121:
p.000121:
p.000121: Within GCP, what is meant by “prior” opinion by the IEC/IRB?
p.000121: GCP requires that “[b]efore initiating a trial, the investigator/ institution should have written
p.000121: and dated approval/favourable opin- ion from the IRB/IEC for the trial protocol, written informed consent form,
p.000121: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to
p.000121: be provided to subjects.” (ICH E6, Section 4.4)
p.000121: “The IRB/IEC should establish, document in writing, and follow its procedures, which should include: …
p.000121: [s]pecifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000121: approval/favourable opinion of the trial.” (ICH E6, Section 3.3)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 50 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is the authority of the IEC/IRB with respect to rendering a decision/opinion on the protocol?
p.000121: The IEC/IRB may render a decision/opinion that can be positive, con- ditional, or negative. Regardless of the nature of
p.000121: the decision/opinion, it should be documented and communicated in writing to the appli- cant.
p.000121: Approval/favourable opinion. This positive decision/opinion is re- quired prior to initiating a new protocol and
p.000121: prior to making changes in a protocol that has previously received an approval/favourable opinion. In
p.000121: communicating this decision/opinion to the applicant, the IEC/IRB should include a statement of the
p.000121: responsibilities of the applicant.
p.000121: Modifications required prior to its approval/favourable opinion. This is a conditional decision/opinion that
p.000121: requires response from the applicant and consideration of the applicant’s response by the IEC/IRB.
p.000121: Implementation of the protocol/protocol change(s) may not occur until required modifications are made and the IEC/IRB
p.000121: has ren- dered an approval/favourable opinion based on these modifications. In the case of a conditional
...
p.000121: IRB/IEC …” (ICH E6, Section 5.6)
p.000121: “… The investigator/institution and the sponsor should sign the pro- tocol, or an alternative contract, to confirm
p.000121: their agreement” to con- duct the study in compliance with the protocol. (ICH E6, Section 4.5; see also Section 5.6)
p.000121: Once the study is underway, compliance with the protocol is princi- pally ensured through the investigator’s
p.000121: supervision and through the sponsor’s monitoring of the study. Within GCP, the purposes of trial monitoring
p.000121: explicitly include verifying that “… [t]he conduct of the trial is in compliance with the currently approved
p.000121: protocol/amendment(s),
p.000121:
p.000121:
p.000121: PRINCIPLE 6 : PROTOCOL COMPLIANCE | 55
p.000121:
p.000121: with GCP, and with applicable regulatory requirement(s).” (ICH E6, Section 5.18)
p.000121: “The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.”
p.000121: (ICH E6, Section 5.18)
p.000121: “Noncompliance with the protocol, SOPs, GCP, and/or applicable reg- ulatory requirement(s) by an
p.000121: investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure
p.000121: compliance.” (ICH E6, Section 5.20)
p.000121: “… If the monitoring and/or auditing identifies serious and/or per- sistent noncompliance on the part of an
p.000121: investigator/institution, the sponsor should terminate the investigator’s/institution’s participa- tion in the
p.000121: trial …” (ICH E6, Section 5.20)
p.000121: The IEC/IRB may also terminate or suspend any prior approval/ favourable opinion. Within GCP,
p.000121: this would include the authority to terminate or suspend an approval/favourable opinion when informa- tion is
p.000121: received that the study is not being conducted in compliance with the protocol or other requirements of the IEC/IRB.
p.000121:
p.000121:
p.000121: Who is responsible for compliance with the protocol?
p.000121: The investigator has direct contact with study subjects and bears pri- mary responsibility for complying with the
p.000121: provisions of the protocol. The investigator also bears responsibility to personally supervise all study staff
p.000121: and ensure their compliance with the protocol.
p.000121: The sponsor has responsibility to monitor the study and ensure the investigator and site staff comply with
p.000121: the protocol.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by IECs/ IRBs, investigators, sponsors, and
p.000121: regulators.
p.000121: IEC/IRB written procedures should ensure that no subject be admit- ted to a trial and no deviations from, or changes
p.000121: of, the protocol be initiated before the IEC/IRB issues its approval/favourable opinion.
p.000121:
p.000121:
p.000121: 56 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Investigators should be thoroughly familiar with the protocol and are responsible for conducting the trial in
p.000121: compliance with the protocol. Investigators should not implement any deviation from, or changes of the protocol without
p.000121: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB(s)/IEC(s) of an
...
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 59
p.000121:
p.000121: Application
p.000121: Principle 7 is applied through a process of informing and ensuring comprehension by study subjects
p.000121: (and/or their legally authorized representatives) about the research and obtaining their consent, in- cluding
p.000121: appropriate written informed consent.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “freely given” consent or “voluntary” participation in an investigation? How is this implemented
p.000121: within GCP?
p.000121: “Informed consent is based on the principle that competent individu- als are entitled to choose freely whether
p.000121: to participate in research. Informed consent protects the individual’s freedom of choice and respects the
p.000121: individual’s autonomy.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121: “An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of
p.000121: informed consent requires conditions free of coercion and undue influence.” (The Belmont Re- port)
p.000121: “Unjustifiable pressures usually occur when persons in positions of authority or commanding influence –
p.000121: especially where possible sanctions are involved – urge a course of action for a subject. … [U]ndue
p.000121: influence would include actions such as manipulating a per- son’s choice through the controlling influence of a close
p.000121: relative and threatening to withdraw health services to which an individual would otherwise be entitled.” (The Belmont
p.000121: Report)
p.000121: “The quality of the consent of prospective subjects who are junior or subordinate members of a hierarchical group
p.000121: requires careful consid- eration, as their agreement to volunteer may be unduly influenced, whether justified
p.000121: or not, by the expectation of preferential treatment if they agree or by fear of disapproval or retaliation
p.000121: if they refuse.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 13)
p.000121:
p.000121:
p.000121:
p.000121: 60 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: “… The researcher should give no unjustifiable assurances about the benefits, risks or inconveniences of
p.000121: the research, for example, or induce a close relative or a community leader to influence a pro- spective subject’s
p.000121: decision.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 6)
p.000121:
p.000121:
p.000121: What is meant by “in accordance with national culture(s) and requirements”?
p.000121: “In some cultures, an investigator may enter a community to con- duct research or approach prospective
p.000121: subjects for their individual consent only after obtaining permission from a community leader, a council
p.000121: of elders, or another designated authority. Such customs must be respected. In no case, however, may the
p.000121: permission of a community leader or other authority substitute for individual in- formed consent.” (CIOMS,
p.000121: International Ethical Guidelines, Commen- tary on Guideline 4)
p.000121:
p.000121:
p.000121: What is meant by “informed” consent?
p.000121: “Informed consent is a decision to participate in research, taken by a competent individual who has received
p.000121: the necessary information; who has adequately understood the information; and who, after considering the
p.000121: information, has arrived at a decision without hav- ing been subjected to coercion, undue influence or
p.000121: inducement, or intimidation.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 4)
p.000121:
p.000121:
p.000121: Who may administer informed consent?
p.000121: The person who conducts the consent interview should be knowl- edgeable about the study and able to answer
p.000121: questions. Some spon- sors and some IECs/IRBs require the clinical investigator to personally conduct the consent
p.000121: interview. If someone other than the clinical investigator conducts the interview and obtains consent, the
p.000121: clinical investigator should ensure that this responsibility is formally delegat-
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 61
p.000121:
...
p.000121: entitled;
p.000121: • the purpose of the trial;
p.000121: • the trial treatment(s) and the probability for random assignment to each treatment;
p.000121: • the trial procedures to be followed, including all invasive proce- dures;
p.000121: • the subject’s responsibilities;
p.000121: • those aspects of the trial that are experimental;
p.000121: • the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus or
p.000121: nursing infant;
p.000121:
p.000121:
p.000121:
p.000121: 62 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: • the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject
p.000121: should be made aware of this;
p.000121: • the alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000121: potential benefits and risks;
p.000121: • the compensation and/or treatment available to the subject in the event of trial-related injury;
p.000121: • the anticipated prorated money or other forms of payment (e.g. material goods), if any, to the subject for
p.000121: participating in the trial;
p.000121: • the anticipated expenses, if any, to the subject for participating in the trial. This may include
p.000121: expenses to the subject for routine medical care for conditions that are not within the scope of the
p.000121: research;
p.000121: • that the monitor(s), the auditor(s), the IEC/IRB, and the regula- tory authority(-ies) will be granted
p.000121: direct access to the subject’s original medical records for verification of clinical trial procedures and/or data,
p.000121: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000121: regulations and that, by signing a written informed consent form, the subject or the subject’s legally
p.000121: authorized representative is authorizing such access;
p.000121: • that records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regulations, will not be made publicly available. If the results of the trial are
p.000121: published, the subject’s identity will remain confidential;
p.000121: • the potential risks should confidentiality measures be compro- mised (e.g. stigma, loss of reputation,
p.000121: potential loss of insurabil- ity);
p.000121: • that the subject or the subject’s legally authorized representative will be informed in a timely manner if
p.000121: information becomes avail- able that may be relevant to the subject’s willingness to continue participation in the
p.000121: trial;
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 63
p.000121:
p.000121: • the person(s) to contact for further information regarding the trial and the rights of research subjects, and
p.000121: whom to contact in the event of trial-related injury;
p.000121: • the foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be
p.000121: terminated;
...
p.000121: interim data analy- ses.
p.000121: “The frequent review of serious and special interest adverse events, as well as overall assessment of all AEs,
p.000121: regardless of seriousness, causality, or expectedness, should be performed periodically: (1) ad hoc, for serious and
p.000121: special interest AEs, (2) routine, periodic general review of all data, whose frequency will vary from trial
p.000121: to trial and from development program to development program and depend on many factors, and (3) reviews triggered by
p.000121: specific milestones estab- lished for a trial or a program (e.g. numbers of completed patients,
p.000121: end-of-trial, end-of program, preparation of integrated summary of safety, and a marketing application.”
p.000121: (Management of Safety Informa- tion from Clinical Trials, Report of CIOMS Working Group VI. Frequen- cy of Review of
p.000121: Safety Information)
p.000121:
p.000121:
p.000121: How should serious unexpected adverse events (SAEs) be reported and to whom?
p.000121: “All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the
p.000121: protocol or other docu- ment (e.g. investigator’s brochure) identifies as not needing immedi- ate reporting. The
p.000121: immediate reports should be followed promptly
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 73
p.000121:
p.000121: by detailed written reports. … The investigator should also comply with the applicable regulatory
p.000121: requirement(s) related to the report- ing of unexpected serious adverse drug reactions to the regulatory
p.000121: authority(ies) and the IRB/IEC.” (ICH E6, Section 4.11)
p.000121: “In addition to the usual criteria for an expedited report, adverse events that are not deemed to be
p.000121: drug-related but are considered to be protocol related should also be reported in an expedited fashion if they are
p.000121: serious.” (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory
p.000121: Reporting and other Communication of Safety Information from Clinical rials)
p.000121:
p.000121:
p.000121: Who is responsible for reviewing the benefit-risk profile of the investigational product(s) while the study is
p.000121: proceeding?
p.000121: Within GCP, the sponsor has primary responsibility for the ongo- ing safety evaluation of the
p.000121: investigational product(s) and should promptly notify all concerned investigator(s), institution(s), and the
p.000121: regulatory authority(ies) of information that could adversely affect the safety of subjects, the conduct
p.000121: of the trial, or alter the IEC/IRB approval/favourable opinion to continue the trial. Such reviews may be
p.000121: performed by the sponsor’s staff (e.g. physicians, statisticians) or by an independent data and safety monitoring board
p.000121: (DSMB), if one is established (see below).
p.000121: The IEC/IRB is also responsible for “… following the progress of all studies for which a positive decision
p.000121: has been reached, from the time the decision was taken until the termination of the research.” (See
p.000121: “Follow-up”, Section 9, WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research)
p.000121:
p.000121:
p.000121: How are follow-up reviews carried out?
p.000121: Sponsors generally monitor trials to ensure that (1) the study is being conducted according to the approved
p.000121: protocol, GCP, and applicable regulatory requirements, and (2) all data, including adverse event reports
p.000121: are accurately and completely recorded and reported. The sponsor also employs qualified individuals (e.g.
p.000121: physicians, statisti-
p.000121:
p.000121:
p.000121: 74 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: cians) as appropriate, throughout all stages of the trial process, to analyse data and prepare interim
p.000121: reports about the progress of the trial and the benefits and risks of the investigational product. The
p.000121: sponsor may also establish an independent data and safety monitor- ing board (DSMB, see below) to review the
...
p.000121: analysed in a compre- hensive fashion at the end of a trial or development program, they also must be
p.000121: evaluated in an ongoing fashion, so that important safety signals can be detected early and that trial
p.000121: participants are protected.” (Management of Safety Information from Clinical Trials, Report of CIOMS Working
p.000121: Group VI. Identification and Evaluation of Risk from Clinical Trial Data)
p.000121: A sponsor may establish a schedule of interim analyses. The study protocol will generally describe this
p.000121: schedule and will also typically describe the statistical approach to the interim analysis of trial data. To
p.000121: minimize the potential for bias, these descriptions should be com- pleted before the conduct of any interim analyses.
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 75
p.000121:
p.000121: The IEC/IRB should conduct follow-up reviews in accordance with es- tablished procedures. In general, the IEC/IRB
p.000121: should conduct follow- up review of each ongoing trial at scheduled intervals appropriate to the degree of risk, but,
p.000121: generally, at least once per year.
p.000121:
p.000121:
p.000121: What should be done if the benefit-risk profile of a study becomes unfavourable?
p.000121: The sponsor should notify investigator(s), the IEC(s)/IRB(s), and in accordance with national/local laws
p.000121: and regulations, the national regulatory authority if the benefit-risk profile of a study becomes un- favourable. In
p.000121: consultation with the IEC(s)/IRB(s), investigator(s), and regulatory authority(ies), the sponsor may need to amend the
p.000121: study protocol and/or revise the investigator’s brochure and informed con- sent document(s) to reflect the new
p.000121: information.
p.000121: “If a significant safety issue is identified, either from an individual case report or review of
p.000121: aggregate data, then the sponsor should issue a prompt notification to all parties, namely regulatory authori-
p.000121: ties, investigators and IECs/IRBs. A significant safety issue could be defined as one that has a significant
p.000121: impact on the course of the clini- cal trial or programme (including the potential for suspension of the trial
p.000121: programme or amendments to protocols), or warrants immedi- ate update of informed consent.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Regulatory Reporting and other
p.000121: Communication of Safety Information from Clini- cal Trials)
p.000121:
p.000121:
p.000121: What happens if the IEC/IRB determines that it must withdraw its approval/favourable opinion of the trial?
p.000121: The IEC/ IRB should notify the clinical investigator and study spon- sor of all decisions (favourable or
p.000121: unfavourable) in writing. Because a study may not proceed without approval/favourable opinion of an IEC/IRB, in
p.000121: some cases, it may be necessary to prematurely termi- nate or suspend the study (See ICH E6, Section 4.12).
p.000121: Should a study
p.000121:
p.000121:
p.000121:
p.000121: 76 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: be prematurely terminated, any subjects currently participating should be notified and procedures for
p.000121: withdrawal of enrolled sub- jects should consider the rights and welfare of the subjects.
p.000121: In other cases, the unanticipated risk(s) might be appropriately man- aged through a protocol change (e.g. eliminating
p.000121: a study arm, intro- ducing additional safety monitoring or testing, etc.) Note, however, that except where
p.000121: necessary to eliminate an immediate hazard(s) to research subjects, the investigator should not implement
p.000121: any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and
p.000121: documented approval/favourable opinion from the IEC/IRB of a protocol amendment (see ICH E6, Sec- tion 4.5).
p.000121: “Ethical review committees generally have no authority to impose sanctions on researchers who violate
p.000121: ethical standards in the con- duct of research involving humans. They may, however, withdraw ethical
p.000121: approval of a research project if judged necessary.” (CIOMS, International Ethical Guidelines, Commentary to
p.000121: Guideline 2)
p.000121:
p.000121:
p.000121: If the benefit-risk profile of the study changes and/or substantive protocol modifications are made, how should the
p.000121: information be communicated to study subjects?
p.000121: How is this documented?
p.000121: “Sponsors and investigators have a duty to … renew the informed consent of each subject if there are
p.000121: significant changes in the condi- tions or procedures of the research or if new information becomes available
p.000121: that could affect the willingness of subjects to continue to participate …” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 6)
p.000121: Periodically in long-term studies, the investigator should also con- sider renewing consent (e.g. in
p.000121: long-term studies involving elderly subjects).
p.000121: Communicating the new information to study subjects should follow customary procedures for obtaining and documenting
p.000121: informed con- sent.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 77
p.000121:
p.000121: What is an Independent Data and Safety Monitoring Board (DSMB, also known as an independent Data Monitoring Committee
p.000121: [DMC])?
...
p.000121: • studies in the early phases of a novel intervention with very limited information on clinical safety or where prior
p.000121: information may have raised safety concerns.”
p.000121: (Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI. Appendix 5,
p.000121: Data and Safety Monitoring Boards)
p.000121:
p.000121: Implementation
p.000121: Sponsors, IECs/IRBs, DSMBs (if applicable), and regulators share responsibility for ongoing safety
p.000121: evaluations of the investigational product(s).
p.000121: The investigator reports unanticipated problems involving risks to subjects and provides periodic
p.000121: progress reports at intervals ap-
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 79
p.000121:
p.000121: propriate to the degree of risk to sponsors and IECs/IRBs in accord- ance with the national/local laws and
p.000121: regulations. The investigator provides adequate, accurate, and objective information on risks and benefits during
p.000121: informed consent of study subjects, and renews the consent of the subject to continue in the study, as appropriate.
p.000121: The sponsor monitors the study and performs safety evaluations of the investigational product(s) by
p.000121: analysing data received from the investigator(s) and the DSMB (if one has been appointed). The sponsor
p.000121: also assures reporting (including expedited reporting to investigator(s), IEC(s)/IRB(s), and the regulatory
p.000121: authority(ies) of ad- verse reactions that are both serious and unexpected.
p.000121: As the study progresses, the IECs/IRBs conducts follow-up reviews appropriate to the degree of risk, but generally at
p.000121: least once per year, including review of the investigator’s progress reports to determine if the benefits still
p.000121: outweigh the risks.
p.000121: The regulatory authority reviews data submitted in research or marketing permits and may require
p.000121: modification to a protocol as a condition to its proceeding and/or may suspend or terminate a proto- col based on
p.000121: an unacceptable benefit-risk profile in accordance with applicable laws and regulations.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: For clinical investigators, refer to: Progress Reports (ICH E6, Section 4.10) Safety Reporting (ICH E6, Section 4.11)
p.000121: Premature Termination or Suspension of a Trial (ICH E6, Section 4.12) Clinical Trial Protocol and Protocol
p.000121: Amendment(s), General Infor-
p.000121: mation (ICH E6, Section 6)
p.000121:
p.000121: 80 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Investigator’s Brochure (ICH E6, Section 7)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Notification/Submission to Regulatory Authorities (ICH E6, Section 5.10)
p.000121: Adverse Drug Reaction Reporting (ICH E6, Section 5.17) Monitoring (ICH E6, Section 5.18)
p.000121: Premature Termination or Suspension of a Trial (ICH E6, Section 5.21)
...
p.000121: requirements of the specific study protocol.
p.000121: The investigator should understand and be qualified to execute the responsibility to personally supervise any
p.000121: individual to whom a study task is delegated. The investigator should further ensure that any in- dividual to whom a
p.000121: study task is delegated is qualified by education, training, and experience to perform the delegated task, for example
p.000121:
p.000121:
p.000121: PRINCIPLE 10 : STAFF QUALIFICATIONS | 87
p.000121:
p.000121: that the assigned task falls within the scope of the individual’s profes- sional license(s). When delegating tasks, the
p.000121: investigator should con- sider, among other things, whether the tasks require formal medical training and whether
p.000121: national or local licensing requirements apply to such duties. (Duties that warrant such consideration, include,
p.000121: but are not necessarily limited to, the following: screening evaluations, including medical histories and
p.000121: assessment of inclusion/exclusion criteria; physical examinations; assessment of adverse events; as- sessments
p.000121: of primary study endpoints (e.g. tumor response, global assessment scales); control of investigational
p.000121: products.)
p.000121: The investigator should ensure that staff are (1) familiar with the study protocol and investigational
p.000121: product; (2) appropriately trained to carry out trial-related duties; (3) informed/aware of their obliga-
p.000121: tions to protect the rights, safety and welfare of the study subjects; and (4) informed of any requirements imposed by
p.000121: the national regula- tory authority for GCP and the conduct of clinical studies.
p.000121:
p.000121:
p.000121: What does it mean to be qualified by “education, training, and experience”; that is, what does each of these terms
p.000121: embrace?
p.000121: Education refers to degrees, certification, and/or licensing earned as a result of formal schooling or courses
p.000121: of study at an institution of higher learning (e.g. M.D., Ph.D., R.N., board certification in a speci-
p.000121: fied field, medical licenses). Training generally refers to short, fo- cused programs on specific topics (e.g.
p.000121: a two-week training program in research ethics, an online course on GCP, “investigator training” provided by
p.000121: the study sponsor related to a specific protocol) and/or mentoring by an appropriately educated, trained, and
p.000121: experienced professional. Experience includes direct participation in activities that provide additional expertise in a
p.000121: specific area (e.g. various positions a physician has held during his/her practice of medicine, previous work assisting
p.000121: another investigator in conducting clinical research, experi- ence as an investigator in a previous study).
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 88 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: Where may information about the qualifications of an investigator or the investigator’s staff be obtained?
p.000121: A curriculum vitae or other statement of education, training, and ex- perience for each staff member may provide
...
p.000121: conduct of a trial and the quality of the data produced.
p.000121:
p.000121: Application
p.000121: Principle 11 is applied through: (1) the understanding and applica- tion of basic elements of data quality and
p.000121: integrity; (2) adherence to the study protocol as well as applicable written procedures for col- lecting,
p.000121: recording, reporting, maintaining and analysing clinical trial information; and (3) the preparation of essential
p.000121: documents (includ- ing source documents), at all stages throughout the conduct of the clinical trial.
p.000121:
p.000121: Questions and Answers
p.000121: What is “clinical trial information”? What is meant by “essential documents”?
p.000121: The term, “clinical trial information,” encompasses all study related data, materials, and documents. The term
p.000121: includes “[a]ll records, in any form (including, but not limited to, written, electronic, magnetic, and optical
p.000121: records; and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a
p.000121: trial, the factors affecting a trial, and the actions taken.” (ICH E6, 1.22)
p.000121: Essential documents are “… those documents that individually and collectively permit evaluation of the conduct
p.000121: of a study and the qual- ity of the data produced. These documents serve to demonstrate the compliance of the
p.000121: investigator, sponsor, and monitor with the stand-
p.000121:
p.000121:
p.000121: 92 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ards of GCP and with all applicable regulatory requirements. Essen- tial documents are “… usually audited by the
p.000121: sponsor’s independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm
p.000121: the validity of the trial conduct and the in- tegrity of the data collected.” (ICH E6, Section 8)
p.000121: Examples include:
p.000121: • Source data: “All information in original records and certified cop- ies of original records of clinical
p.000121: findings, observations, or other activities in a clinical trial necessary for the reconstruction and
p.000121: evaluation of the trial. Source data are contained in source docu- ments (original records or certified copies).” (ICH
p.000121: E6, 1.51)
p.000121: • Source documents: “Original documents, data, and records (e.g. hospital records, clinical and office
p.000121: charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing
p.000121: records, recorded data from automated instruments, copies or transcriptions certified after verification as
p.000121: being accu- rate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject
p.000121: files, and records kept at the pharmacy, at the laboratories, and at medico-technical depart- ments
p.000121: involved in the clinical trial).” (ICH E6, 1.52)
p.000121: • Case report forms: “… [P]rinted, optical, or electronic document[s] designed to record all of the
p.000121: protocol-required information to be reported to the sponsor on each trial subject.” (ICH E6, 1.11)
p.000121: • Correspondence between any of the parties who conduct or over- see the research (e.g. approval/favourable decision
p.000121: by the IEC/IRB; reports of adverse events submitted to the sponsors, IECs/IRBs, and regulators; monitor’s
p.000121: reports to the sponsor).
p.000121: • Other study related documents and materials (e.g. study protocol, protocol amendments, investigator’s brochure,
...
p.000121: Ethical Guidelines, Appendix 1).
p.000121: Record-keeping and retention requirements may also be specified by national or local law and regulations.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 96 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is meant by “reporting”? How are essential documents and data combined to report the outcome of the trial?
p.000121: Reporting is the act of providing information or data to another party. National laws and regulations may require
p.000121: certain information to be reported within specific time frames, for example, reports of serious unanticipated adverse
p.000121: events.
p.000121: Responsibility for reporting clinical trial information and results is shared by:
p.000121: • the study sponsor, who reports adverse events to regulators, and prepares summary reports about clinical
p.000121: studies for inclusion in applications to obtain research permits or to market an investiga- tional product;
p.000121: • the monitor, who prepares and submits written reports of moni- toring visits and trial-related
p.000121: communications to the sponsor;
p.000121: • the clinical investigator who submits, for example, case report forms (CRFs) to the sponsor; progress
p.000121: reports or written sum- maries of the trial’s status to the institution, the IEC/IRB, and the sponsor;
p.000121: safety reports (e.g. adverse event reports, laboratory anomalies) to the sponsor and IEC/IRB; final reports upon
p.000121: comple- tion of the trial to the sponsor, IEC/IRB, and regulatory authorities;
p.000121: • the IEC/IRB, which notifies the investigator and institution, and sometimes the regulatory
p.000121: authority(ies) about trial-related de- cisions and opinions (e.g. decisions to suspend or terminate a
p.000121: study), the reasons for such decisions/opinions, and procedures for appealing them.
p.000121: “The investigator should ensure the accuracy, completeness, legibili- ty, and timeliness of the data reported to the
p.000121: sponsor in the CRFs and in all required reports. Data reported on the CRF, which are derived from source documents
p.000121: should be consistent with the source docu- ments or the discrepancies should be explained.” (ICH E6, Section
p.000121: 4.9; see also, ICH E6, Section 4.10: Progress Reports; ICH E6, Section 4.11: Safety Reporting, and ICH E6,
p.000121: Section 4.13: Final Report(s) by Investigator/Institution.)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 97
p.000121:
p.000121: What is meant by “interpretation” of clinical trial information and how is this achieved within GCP?
p.000121: “Interpreting” clinical trial information refers to analysing the meaning and significance of data and other
p.000121: observations and information col- lected during the clinical trial. The study protocol generally describes the overall
p.000121: plan for interpreting clinical trial data. Sponsors, in close collaboration with the investigator(s), generally analyse
p.000121: and interpret clinical trial data and prepare summaries as part of an application for approval to market an
p.000121: investigational product. Such summaries and analyses enable regulators to make a determination about the safety and/or
p.000121: effectiveness of a product that is the subject of a research permit or marketing application.
p.000121: The sponsor
p.000121: • “… should utilize appropriately qualified individuals” [e.g. biostat- isticians, clinical pharmacologists
p.000121: and physicians, as appropriate] “to supervise the overall conduct of the trial, to handle the data, to verify the
p.000121: data, to conduct the statistical analyses, and to prepare the trial reports.” (ICH E6, Section 5.5)
p.000121: • should include in the study protocol a “… description of the sta- tistical methods to be employed,
p.000121: including timing of any planned interim analysis(ses), … the level of significance to be used, …
p.000121: procedure for accounting for missing, unused, and spurious data, procedures for reporting any deviations from the
p.000121: original statistical plan… selection of subjects to be included in the analyses … ” (ICH E6, Section 6.9)
p.000121:
p.000121:
p.000121: How should clinical trial results be publicly reported?
p.000121: “Both authors and publishers have ethical obligations. In publication of the results of research, the
p.000121: investigators are obliged to preserve the accuracy of the results. Negative as well as positive results
p.000121: should be published or otherwise publicly available. … Reports of experimentation not in accordance with
p.000121: the principles laid down in this Declaration should not be accepted for publication.” (Declaration of Helsinki)
p.000121:
p.000121:
p.000121: 98 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: The study protocol may include:
p.000121: • “[i]n the case of a negative outcome, an assurance that the results will be made available, as appropriate,
p.000121: through publication or by reporting to the drug registration authority.” (CIOMS, International Ethical Guidelines,
p.000121: Appendix 1)
p.000121: • “[c]ircumstances in which it might be considered inappropriate to publish findings, such as when the findings of an
p.000121: epidemiological, sociological or genetics study may present risks to the interests of a community or
p.000121: population or of a racially or ethnically defined group of people.” (CIOMS, International Ethical Guidelines, Appen-
p.000121: dix 1)
p.000121:
p.000121:
p.000121: Who should have access to clinical trial records?
p.000121: Sponsors, monitors, IECs/IRBs, and regulators generally require direct access to all information
p.000121: pertaining to the conduct and over- sight of the clinical trial. Direct access means that these parties have
p.000121: “[p]ermission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation
p.000121: of a clinical trial.” (ICH E6, 1.21)
p.000121: “Any or all of the documents addressed in this guidance may be sub- ject to, and should be available for, audit by the
p.000121: sponsor’s auditor and inspection by the regulatory authority(ies).” (ICH E6, Section 8)
p.000121: Note that consent forms should inform study subjects “[t]hat the monitor(s), the auditor(s), the
p.000121: IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s
p.000121: original medical records for verification of clinical trial procedures and/or data, without violating the
p.000121: confidentiality of the subject, to the extent permitted by the applicable laws and regulations, and that by signing a
p.000121: written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such
p.000121: access.” (ICH E6, 4.8) (See also WHO GCP Principle 7: Informed Consent)
p.000121: In addition, sponsors, monitors, investigators and regulators should be aware of the need to handle clinical
p.000121: trial information in a manner
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 99
p.000121:
p.000121: that protects the privacy and confidentiality of research subjects. These parties should also be fully informed
p.000121: about national/local laws/ regulations related to privacy and confidentiality. (See also WHO GCP Principle 12:
p.000121: Confidentiality/Privacy)
p.000121:
p.000121: Implementation
p.000121: IECs/IRBs, investigators, sponsors, and regulators all bear respon- sibility for documenting their
p.000121: activities within GCP, and maintaining records pertaining to duties related to the conduct or oversight
p.000121: of the clinical trial for the time required under national or local law and regulations. All parties are
p.000121: responsible for ensuring the accuracy, completeness, legibility and availability (as necessary) of such docu-
p.000121: ments.
p.000121: IECs/IRBs document their reviews of study protocols and informed consent/recruitment/advertising materials
p.000121: through minutes that capture the IECs’/IRBs’ deliberations and through copies of corre- spondence with the
p.000121: clinical investigator.
p.000121: Investigators prepare and maintain case histories that record all ob- servations and other data pertinent to the
p.000121: investigation on each indi- vidual administered the investigational drug or employed as a control in the investigation.
p.000121: Sponsors ensure that study protocols address appropriate data handling and record-keeping requirements and
p.000121: design CRFs appro- priately to facilitate the capture of all significant trial-related data and observations.
p.000121: Sponsors also secure the services of monitors to en- sure compliance of the clinical investigators, and verify
p.000121: that the study was carried out according to the approved study protocol.
p.000121: Regulators rely on clinical trial information to support regulatory decision-making and may inspect all of
p.000121: the parties involved in con- ducting or overseeing research. Critical to regulatory inspection is direct
p.000121: access to and review of existing clinical trial records. As part of an inspection, regulators compare records at the
p.000121: clinical investigator site and sponsor site with data and reports submitted to the regula- tory authority to verify
p.000121: the information submitted. Regulators also prepare and maintain records of their inspections and findings.
p.000121:
p.000121: 100 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1) Procedures (ICH E6, Section 3.3) Records (ICH E6,
p.000121: Section 3.4)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Follow-up (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 9)
p.000121: Documentation and Archiving (WHO Operational Guidelines for Ethics Committees that Review Biomedical
p.000121: Research, Section 10)
p.000121: For investigators, refer to:
p.000121: Communication with IRB/IEC (ICH E6, Section 4.4) Compliance with Protocol (ICH E6, Section 4.5) Records and Reports
p.000121: (ICH E6, Section 4.9) Progress Reports (ICH E6, Section 4.10)
p.000121: Safety Reporting (ICH E6, Section 4.11)
p.000121: Final Report(s) by Investigator/Institution (ICH E6, Section 4.13) Clinical Trial Protocol, General Information (ICH
p.000121: E6, Section 6) Essential Documents for the Conduct of a Clinical Trial (ICH E6,
p.000121: Section 8)
p.000121: For sponsors, refer to:
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Record Access (ICH E6, Section 5.15)
...
p.000121: The confidentiality of records that could identify subjects should be protected, respecting the privacy and
p.000121: confidentiality rules in accord- ance with the applicable regulatory requirement(s).
p.000121: “The right of research subjects to safeguard their integrity must al- ways be respected. Every precaution
p.000121: should be taken to respect the privacy of the subject, the confidentiality of the patient’s information and to minimize
p.000121: the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.”
p.000121: (Declaration of Helsinki)
p.000121: “The investigator must establish secure safeguards of the confiden- tiality of subjects’ research data. Subjects
p.000121: should be told the limits, legal or other, to the investigators’ ability to safeguard confidential- ity
p.000121: and the possible consequences of breaches of confidentiality.” (CIOMS, International Ethical Guidelines,
p.000121: Guideline 18)
p.000121:
p.000121: Application
p.000121: Principle 12 is applied (1) through appropriate procedures to protect the privacy of the subject, and (2) by document
p.000121: and data control to protect the confidentiality of the subject’s information.
p.000121: Principle 12 is also applied through the informed consent process which requires as an essential element
p.000121: that certain explanations be provided to the subject about the confidentiality of the subject’s records and about
p.000121: access to those records by monitor(s), auditor(s), the IEC/IRB, and the regulatory authority(-ies).
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “privacy”? What is meant by “confidentiality”?
p.000121: Privacy embraces the concept that each individual should have the right to control personal and sensitive
p.000121: information about him/her. Privacy implies that such information, which may be contained in
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 103
p.000121:
p.000121: medical records, personal diaries, or elsewhere, will be protected and not disclosed without the
p.000121: knowledge/permission of the indi- vidual to whom it pertains.
p.000121: Privacy may not be absolute, however. For example, some informa- tion, such as exposure to a communicable
p.000121: disease, may be subject to limited disclosure under public health laws; access to information contained in clinical
p.000121: study records may be required by regulators to verify data submitted in a marketing application. Thus,
p.000121: individuals who participate in clinical trials should be told the extent to which their information will
p.000121: be protected and the circumstances under which the information will be disclosed, to whom, and the purpose(s) for
p.000121: doing so.
p.000121: Confidentiality embraces the concept that parties who obtain private information from patients and
p.000121: subjects will (1) protect the information itself and any records that contain such information from deliberate or
p.000121: accidental disclosure; and (2) develop and follow proce- dures for release of the information only to
...
p.000121: prospective subjects.” (CIOMS, International Ethical Guidelines, Commentary to Guideline 18)
p.000121:
p.000121:
p.000121: How should subjects be informed of the measures that will be used to protect their private information? How should
p.000121: potential risks related to release of private information be disclosed to study subjects?
p.000121: The informed consent document should describe (1) who will have access to personal data of the research
p.000121: participants, including medi- cal records and biological samples; (2) the measures taken to ensure the confidentiality
p.000121: and security of research participants’ personal information; and (3) the potential risks to subjects if such
p.000121: measures are breached (e.g. stigma, loss of reputation, potential loss of insur- ability, etc.).
p.000121: “… During the process of obtaining informed consent the investigator should inform the prospective subjects about
p.000121: the precautions that will be taken to protect confidentiality.” (CIOMS, International Ethical Guidelines, Commentary
p.000121: to Guideline 18)
p.000121: “Both the informed consent discussion and the written informed consent form and any other written
p.000121: information to be provided to subjects should include explanations of the following:
p.000121: “(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regu- latory authority(ies) will be granted direct
p.000121: access to the subject’s original medical records for verification of clinical trial procedures and/or data, without
p.000121: violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations
p.000121: and that, by signing a written informed consent form, the subject or the subject’s legally acceptable
p.000121: representative is authorizing such access.”
p.000121: “(o) That records identifying the subject will be kept confidential and, to the extent permitted by the
p.000121: applicable laws and/or regula-
p.000121:
p.000121:
p.000121: 106 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: tions, will not be made publicly available. If the results of the trial are published, the subject’s identity will
p.000121: remain confidential.” (ICH E6, Section 4.8)
p.000121: “The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000121: medical records for trial- related monitoring, audit, IRB/IEC review, and regulatory inspection.” (ICH E6, Section
p.000121: 5.15)
p.000121:
p.000121: Implementation
p.000121: IECs/IRBs review/approve the informed consent procedures and document to ensure, among other things, that
p.000121: there is adequate explanation regarding (1) the risks related to release of the subject’s private information,
p.000121: (2) how the confidentiality of the subject’s records will be maintained, and (3) persons who may have
p.000121: access to the subject’s records (e.g. monitor(s), auditor(s), the IEC/IRB, and the regulatory authority(-ies)).
p.000121: Investigators should (1) implement procedures to protect and restrict access to study records and
p.000121: private information (e.g., pass- word protection for files, keeping study records in secured areas),
p.000121: (2) follow national/local laws and regulations relating to privacy and confidentiality, (3) ensure that study
p.000121: staff are aware of and receive appropriate training related to their responsibility and procedures to be
p.000121: used for protecting subjects’ private information and records,
p.000121: (4) ensure that study staff follow the procedures established for this purpose, and (5) ensure that the consent
p.000121: form and process inform study subjects about the procedures to be used to protect their pri- vate information and
p.000121: the circumstances under which their medical and study records may be viewed by regulators, sponsors, monitors,
p.000121: and/or the IEC/IRB.
p.000121: Sponsors ensure that sites (1) allow regulators, IECs/IRBs, and moni- tors direct access to records necessary to
p.000121: verify compliance with national/local laws and regulations pertaining to the conduct of clini- cal trials, and (2)
p.000121: inform subjects about, and obtain their consent for, such access.
p.000121:
p.000121:
p.000121: PRINCIPLE 12 : CONFIDENTIALIT Y/ PRIVACY | 107
p.000121:
...
p.000121: With respect to storage, “[t]he sponsor should determine, for the investigational product(s), acceptable
p.000121: storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and
p.000121: procedures, and devices for product infusion, if any. The sponsor should inform all involved parties
p.000121: (e.g. monitors, investiga- tors, pharmacists, storage managers) of these determinations.” (ICH E6, Section 5.13)
p.000121: “The sponsor should ensure that written procedures include instruc- tions that the investigator/institution should
p.000121: follow for the handling and storage of investigational product(s) for the trial and documenta- tion thereof …” (ICH
p.000121: E6, Section 5.14)
p.000121: At the site, the investigator is responsible for ensuring that the in- vestigational product(s) are “…
p.000121: stored as specified by the sponsor … and in accordance with applicable regulatory requirements” … [and] “are used
p.000121: only in accordance with the approved protocol.” (ICH E6, Section 4.6)
p.000121:
p.000121: Implementation
p.000121: Responsibility for implementing this principle is shared by sponsors (or contract manufacturers/ contract
p.000121: research organizations), inves- tigators, and regulators.
p.000121: Sponsors implement this principle directly or indirectly through con- tract, by developing and characterizing the
p.000121: investigational product.
p.000121:
p.000121:
p.000121:
p.000121: 112 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: They make the necessary notifications/submissions to the applicable regulatory authority(ies), identify GMP
p.000121: requirements, if any, that may apply to the manufacturing, handling and storage of the investiga- tional
p.000121: product, and ensure compliance with those requirements. Sponsors manufacture the investigational product directly
p.000121: or have it manufactured under contract at a manufacturing site in accordance with applicable GMP. They are
p.000121: responsible within GCP for the han- dling, storage, distribution and final disposition of the investigational
p.000121: product(s).
p.000121: The sponsor also develops the study protocol and investigator’s bro- chure, monitors protocol compliance, and ensures
p.000121: that written pro- cedures include instructions that the investigator/institution should follow for the handling
p.000121: and storage of investigational products for the trial and documentation thereof.
p.000121: Investigators are responsible for familiarity with the investigator’s brochure and for conducting the
p.000121: research in compliance with the protocol, including any instructions for storing and handling inves-
p.000121: tigational products. Investigators are responsible for explaining correct use (including handling and
p.000121: storage) of the investigational product to the study subjects. Investigators also ensure that any un- used
p.000121: investigational products are returned to the sponsor after the trial is completed.
p.000121: In accordance with national/local laws and regulations, regulators may establish GMP requirements for
p.000121: investigational products, review manufacturing data submitted in support of research permits or mar- keting
p.000121: applications, and/or inspect manufacturing facilities. Because investigational products may be imported,
...
p.000121: recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and the applicable
p.000121: regulatory requirement(s).” (ICH E6, 1.38; see also ICH E6 Section 5.18, generally, for detailed guidance on
p.000121: study monitoring.)
p.000121:
p.000121: What is the difference between monitoring, auditing, and inspecting?
p.000121: Monitoring is a quality control activity conducted by the sponsor or a representative of the sponsor to ensure that the
p.000121: research is conduct- ed in accordance with the study protocol, GCP, and applicable regu- latory requirements and that
p.000121: research data are accurate, complete, and verifiable from source documents. Monitors generally compare source
p.000121: documents with case report forms and seek to resolve any discrepancies. Monitors also try to verify that
p.000121: activities related to protecting the rights and welfare of study subjects (e.g. prior approv- al of the IEC/IRB,
p.000121: obtaining legally effective informed consent from all study subjects) were appropriately carried out.
p.000121: Auditing is an independent quality assurance activity used by the sponsor to evaluate the effectiveness of a
p.000121: monitoring program and/ or specific monitoring activities. Auditing is distinguished from moni- toring by the fact that
p.000121: monitoring is carried out while the study is in progress (see discussion of “Quality control” above) whereas
p.000121: audit- ing can occur anytime during or after the study.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 14 : QUALIT Y SYSTEMS | 117
p.000121:
p.000121: An inspection is “[t]he act by a regulatory authority(ies) of conduct- ing an official review of documents, facilities,
p.000121: records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that
p.000121: may be located at the site of the trial, at the sponsor’s and/or contract research organization’s
p.000121: (CRO’s) facilities or at other establishments deemed appropriate by the regulatory authority(ies).” (ICH E6,
p.000121: 1.29) The purpose of such inspection is to determine whether research was conducted in compliance
p.000121: with national/local laws and regulations for the conduct of research and the protection of human subjects.
p.000121:
p.000121: Implementation
p.000121: All of the parties who conduct and oversee clinical trials (sponsors, investigators, IECs/IRBs, and
p.000121: regulatory authorities) should adopt and implement quality systems for the processes and activities for which they are
p.000121: responsible.
p.000121: Sponsors secure the services of monitors to ensure compliance of the clinical investigators and verify
p.000121: that the study was carried out according to the approved study protocol. Sponsors also audit the
p.000121: monitors’ performance and other quality control activities and sys- tems to ensure each system’s performance.
p.000121: Monitors review study records at the sites, report their findings to the sponsor, and prepare written
p.000121: reports that document each site visit or trial-related communication.
p.000121: Investigators supervise to ensure that study staff follow estab- lished procedures for the conduct of the
p.000121: study, e.g. obtaining IEC/IRB approval of the study, obtaining informed consent from subjects, es- tablishing and
p.000121: maintaining subjects’ case histories, transcribing data from subjects’ medical files to the CRFs, reporting
p.000121: adverse events and other unanticipated problems, etc.
p.000121: IECs/IRBs develop and adopt SOPs for reviewing studies and inform- ing the clinical investigator of any required
p.000121: modifications to the study protocol, and for assuring that such modifications are in place before
p.000121:
p.000121:
p.000121:
p.000121: 118 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: the study proceeds. In accordance with national/local laws and regu- lations, IECs/IRBs may develop SOPs to allow
p.000121: IEC/IRB members or a third party to observe the consent process to verify that subjects are being provided
p.000121: the opportunity to ask questions about the study and that subjects receive a copy of the informed consent document.
p.000121: IECs/IRBs implement systems to assure that continuing review of the study takes place at intervals appropriate to the
p.000121: degree of risk, and that investigators are notified so that they may provide the necessary documentation to the IEC/IRB
p.000121: in advance of the deadline.
p.000121: In accordance with applicable laws/regulations, regulators may inspect all parties that conduct or
p.000121: oversee research and verify the information submitted to the regulatory authority. Regulators may ask for
p.000121: sponsors’ monitoring plans as a condition of allowing a study to proceed. Regulatory authorities also optimally
p.000121: develop SOPs and quality systems for internal regulatory activities, including policies and procedures for
p.000121: reviewing product applications and for the con- duct of GCP inspections.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For sponsors, refer to:
p.000121: Quality Assurance and Quality Control (ICH E6, Section 5.1)
p.000121: Trial Management, Data Handing, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Monitoring (ICH E6, Section 5.18) Audit (ICH E6, Section 5.19) Noncompliance (ICH E6, Section 5.20)
p.000121: Monitoring Arrangements (Clinical investigation of medical devices for human subjects, Part 2: Clinical investigation
p.000121: plans, Interna- tional Standards Organization (ISO), 14155-2, 4.34)
p.000121: For monitors, refer to:
p.000121: Monitoring (ICH E6, Section 5.18)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 14 : QUALIT Y SYSTEMS | 119
p.000121:
p.000121: For IECs/IRBs, refer to:
p.000121: Composition, Functions, and Operations (ICH E6, Section 3.2) Procedures (ICH E6, Section 3.3)
p.000121: WHO Surveying and Evaluating Ethical Review Practices: A comple- mentary guideline to the Operational Guidelines for
p.000121: Ethics Com- mittees that Review Biomedical Research
p.000121: For regulatory authorities, refer to: Noncompliance (ICH E6, Section 5.20)
p.000121: GCP Compliance Monitoring Programs by Regulatory Authorities (Chapter 7, Good Clinical Practices: Document of the
p.000121: Americas, PAHO)
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General/Other / Undue Influence
Searching for indicator undue influence:
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General/Other / participants in a control group
Searching for indicator control group:
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p.000121: The investigator’s brochure is a “compilation of the clinical and non- clinical data on the investigational
p.000121: product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6, 1.36)
p.000121: In general, the investigator’s brochure provides more complete back- ground information on the investigational
p.000121: product than is provided in the protocol. The investigator’s brochure assists the investigator in
p.000121: interpreting and implementing the study protocol, and may be of particular importance in helping the
p.000121: investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such
p.000121: events should be reported to the sponsor, IEC/IRB, and regulators.
p.000121:
p.000121: What is meant by a well-controlled study?
p.000121: A well-controlled study uses a design that permits a comparison of subjects treated with the
p.000121: investigational agent/intervention to a suitable control population, so that the effect of the
p.000121: investigational agent/intervention can be determined and distinguished from other influences, such as spontaneous
p.000121: change, “placebo” effects, concom- itant therapy(ies)/intervention(s), or observer expectations.
p.000121:
p.000121: What are some designs for controlled clinical studies?
p.000121: Commonly used designs for controlled clinical studies include: pla- cebo concurrent control; no-treatment
p.000121: concurrent control; dose- response concurrent control; active (positive) concurrent control; external control
p.000121: (including historical control); and combination (multi- ple control group) designs. (See ICH E10: Choice of Control
p.000121: Group and Related Issues in Clinical Trials)
p.000121: “As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive
p.000121: intervention should receive an established effective intervention. In some circumstances it may be ethi- cally
p.000121: acceptable to use an alternative comparator, such as placebo or “no treatment”.” (CIOMS, International Ethical
p.000121: Guidelines, Guideline 11)
p.000121:
p.000121:
p.000121: 30 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What can be done to minimize bias in a clinical investigation?
p.000121: Bias implies subjective or unfair distortion of judgment in favour of or against a person or thing. The purpose
p.000121: of conducting a clinical trial of an investigational product is to distinguish the effect of the inves- tigational
p.000121: product from other factors, such as spontaneous changes in the course of the disease, placebo effects, or
p.000121: biased/subjective observation. Bias can be minimized in a clinical trial by designing well-controlled
p.000121: studies, by using procedures to randomize subjects to various study arms based on the generation of a random
p.000121: alloca- tion sequence, and by using concealment and blinding.
p.000121:
p.000121:
p.000121: What is meant by “blinding” or “masking”?
p.000121: Blinding or masking is “[a] procedure in which one or more parties to the trial are kept unaware of the
p.000121: treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double blinding
p.000121: usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being
...
p.000121: manufacturing practices. http://www.who.int/medicines/en/
p.000121: 2. Handbook: Good laboratory practice: Quality practices for regulated non- clinical research and development.
p.000121: TDR/PRD/GLP/01.2 (2001). http://www.who.int/tdr/
p.000121: 3. CIOMS Working Group Report. Pharmacogenetics: Towards improving treatment with medicines. Geneva 2005.
p.000121: http://www.cioms.ch/
p.000121: 4. CIOMS Working Group Report. Management of Safety Information from Clinical Trials. Geneva 2005.
p.000121: http://www.cioms.ch/
p.000121: 5. The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The
p.000121: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. April 18, 1979.
p.000121: http://www.nihtraining.com/ohsrsite/guidelines/belmont.html
p.000121: 6. The ENGAGE Guideline for Good Clinical Practice Compliance and Quality Systems Auditing. 21.08.1997. ENGAGE
p.000121: European Network of GCP Auditors and other GCP Experts. (in process of revision).
p.000121: 7. ICH E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 1994.
p.000121: http://www.ich.org/
p.000121: 8. ICH E2B(R): Revision of the E2B(M) ICH Guideline on Clinical Safety Data Management. Data Elements for
p.000121: Transmission of Individual Case Safety Reports. Step 3 undergoing consultation. May. 2005. http://www.ich.org/
p.000121: 9. ICH E3: Structure and Content of Clinical Study Reports. 1995. http://www. ich.org/
p.000121: 10. ICH E9: Statistical Principles for Clinical Trials. 1998. http://www.ich.org/
p.000121: 11. ICH E10: Choice of Control Group and Related Issues in Clinical Trials. 2000. http://www.ich.org/
p.000121: 12. ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Popula- tion. 2000. http://www.ich.org/
p.000121: 13. ICH M3: Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials
p.000121: for Pharmaceuticals. 1997. http://www.ich.org/
p.000121: 14. ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceu- ticals. 1997. http://www.ich.org/
p.000121:
p.000121:
p.000121: 122 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 15. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10,
p.000121: Vol. 2, pp. 181–182. Washing- ton, D.C.: U.S. Government Printing Office, 1949.
p.000121: http://www.med.umich.edu/irbmed/ethics/Nuremberg/NurembergCode. html
p.000121: 16. United Nations International Covenant on Civil and Political Rights. 1966.
p.000121: http://www.hrweb.org/legal/cpr.html
p.000121:
p.000121:
p.000121: Related documents
p.000121: 1. ETH. Global list of national bioethics committees with contact details. http://www.who.int/ethics/en
p.000121: 2. IVB. Ethical considerations arising from vaccine trials.
p.000121: http://www.who.int/entity/vaccine_research/documents/en/manu774. pdf
p.000121: 3. RHR. Implementation of Good Clinical Practice (GCP) guidelines in RHR re- search activities.
p.000121: http://www.who.int/reproductive-health/publications/RHR_02_05/ Section_11.PDF
p.000121: 4. RHR Guidelines for research. http://www.who.int/reproductivehealth/hrp/ ethical_issues.en.html
...
Searching for indicator placebo:
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p.000121: side effect or adverse event, or the dropping of a test intended to monitor safety.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 1 In this document, “regional” refers to supranational laws, regulations, or require- ments, such as those
p.000121: adopted by the European Union.
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 29
p.000121:
p.000121: What is the “investigator’s brochure” and how does it relate to the protocol?
p.000121: The investigator’s brochure is a “compilation of the clinical and non- clinical data on the investigational
p.000121: product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6, 1.36)
p.000121: In general, the investigator’s brochure provides more complete back- ground information on the investigational
p.000121: product than is provided in the protocol. The investigator’s brochure assists the investigator in
p.000121: interpreting and implementing the study protocol, and may be of particular importance in helping the
p.000121: investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such
p.000121: events should be reported to the sponsor, IEC/IRB, and regulators.
p.000121:
p.000121: What is meant by a well-controlled study?
p.000121: A well-controlled study uses a design that permits a comparison of subjects treated with the
p.000121: investigational agent/intervention to a suitable control population, so that the effect of the
p.000121: investigational agent/intervention can be determined and distinguished from other influences, such as spontaneous
p.000121: change, “placebo” effects, concom- itant therapy(ies)/intervention(s), or observer expectations.
p.000121:
p.000121: What are some designs for controlled clinical studies?
p.000121: Commonly used designs for controlled clinical studies include: pla- cebo concurrent control; no-treatment
p.000121: concurrent control; dose- response concurrent control; active (positive) concurrent control; external control
p.000121: (including historical control); and combination (multi- ple control group) designs. (See ICH E10: Choice of Control
p.000121: Group and Related Issues in Clinical Trials)
p.000121: “As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive
p.000121: intervention should receive an established effective intervention. In some circumstances it may be ethi- cally
p.000121: acceptable to use an alternative comparator, such as placebo or “no treatment”.” (CIOMS, International Ethical
p.000121: Guidelines, Guideline 11)
p.000121:
p.000121:
p.000121: 30 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What can be done to minimize bias in a clinical investigation?
p.000121: Bias implies subjective or unfair distortion of judgment in favour of or against a person or thing. The purpose
p.000121: of conducting a clinical trial of an investigational product is to distinguish the effect of the inves- tigational
p.000121: product from other factors, such as spontaneous changes in the course of the disease, placebo effects, or
p.000121: biased/subjective observation. Bias can be minimized in a clinical trial by designing well-controlled
p.000121: studies, by using procedures to randomize subjects to various study arms based on the generation of a random
p.000121: alloca- tion sequence, and by using concealment and blinding.
p.000121:
p.000121:
p.000121: What is meant by “blinding” or “masking”?
p.000121: Blinding or masking is “[a] procedure in which one or more parties to the trial are kept unaware of the
p.000121: treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double blinding
p.000121: usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being
p.000121: unaware of the treatment assignment(s).” (ICH E6, 1.10)
p.000121:
p.000121:
p.000121: When is unblinding of the trial by the investigator permissible? How should unblinding be accomplished (in those
p.000121: situations where it would be allowed)?
p.000121: Unblinding may be necessary in the event of a medical emergency for a research subject. Generally breaking the blind
p.000121: involves procedures specified in the study protocol that allow the investigator and/or sponsor to find out
p.000121: whether a particular subject received the inves- tigational product, or received a comparator product or
p.000121: placebo, where applicable, while on the study.
p.000121: “The investigator … should ensure that the code is broken only in accordance with the protocol. If the trial
p.000121: is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g.,
p.000121: accidental unblinding, unblinding due to a serious ad- verse event) of the investigational product(s).” (ICH E6,
p.000121: Section 4.7)
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 31
p.000121:
p.000121: What is meant by “randomization”?
p.000121: Randomization is the “process of assigning trial subjects to treatment or control groups using an element of
p.000121: chance to determine the as- signments in order to reduce bias.” (ICH E6, 1.48)
p.000121: “Randomization is the preferred method for assigning subjects to the various arms of the clinical trial unless
p.000121: another method, such as historical or literature controls, can be justified scientifically and ethi- cally. Assignment
p.000121: to treatment arms by randomization, in addition to its usual scientific superiority, offers the advantage
p.000121: of tending to render equivalent to all subjects the foreseeable benefits and risks of participation in a
p.000121: trial.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121: “The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken
p.000121: only in accordance with the protocol.” (ICH E6, Section 4.7)
p.000121:
p.000121:
p.000121: How should the protocol address reporting of adverse events?
p.000121: The protocol should specify procedures for eliciting reports of, and for recording and reporting, adverse
...
Orphaned Trigger Words
p.000001: the legal status of any country, terri- tory, city or area or of its authorities, or concerning the delimitation
p.000001: of its frontiers or boundaries.
p.000001: The mention of specific companies or of certain manufacturers’ products does not imply that they are
p.000001: endorsed or recommended by the World Health Organization in preference to others of a similar nature that are
p.000001: not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial
p.000001: capital let- ters.
p.000001: Designed by minimum graphics Printed in France
p.000001:
p.000001: Contents
p.000001:
p.000001:
p.000001: Preamble
p.000001: 1
p.000001: Introduction
p.000003: 3
p.000003: Overview of the Clinical Research Process 8
p.000003: WHO Principles of GCP 19
p.000003: Principle 1: Ethical Conduct 21
p.000003: Principle 2: Research described in a protocol 27
p.000003: Principle 3: Risk Identification 35
p.000003: Principle 4: Benefit-Risk Assessment 42
p.000003: Principle 5: Review by Independent Ethics Committee/ Independent Review Board
p.000048: 48
p.000048: Principle 6: Protocol Compliance 54
p.000048: Principle 7: Informed Consent 59
p.000048: Principle 8: Continuing Review/Ongoing Benefit-Risk Assessment
p.000072: 72
p.000072: Principle 9: Investigator Qualifications 82
p.000072: Principle 10: Staff Qualifications 87
p.000072: Principle 11: Records 92
p.000072: Principle 12: Confidentiality/Privacy 103
p.000072: Principle 13: Good Manufacturing Practice 110
p.000072: Principle 14: Quality Systems 115
p.000072: References:
p.000121: 121
p.000121: Documents on CD 121
p.000121: Other documents cited in the Handbook 122
p.000121: Related documents 123
p.000121: National Good Clinical Practice and Other Guidelines 124
p.000121: Acknowledgements 125
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: | iii
p.000121:
p.000121:
p.000121:
p.000121: Preamble
p.000121:
p.000121:
p.000121: Clinical research is necessary to establish the safety and effective- ness of specific health and medical
p.000121: products and practices. Much of what is known today about the safety and efficacy of specific prod- ucts and
p.000121: treatments has come from randomized controlled clinical trials1 that are designed to answer important
p.000121: scientific and health care questions. Randomized controlled trials form the foundation for “evidence-based
...
p.000121: therapeutic measures;
p.000121: • studies concerning human health-related behaviour in a variety of circumstances and environments;
p.000121: • studies that employ either observation or physical, chemical, or psychological intervention. Such studies
p.000121: may generate records or make use of existing records containing biomedical or other infor- mation about individuals who
p.000121: may or may not be identifiable from the records or information. The use of such records and the pro- tection
p.000121: of the confidentiality of data obtained from those records are discussed in the “International Guidelines for Ethical
p.000121: Review of Epidemiological Studies” (CIOMS, 1991, currently being updated).
p.000121: Although some principles of GCP may not apply to all types of re- search on human subjects,
p.000121: consideration of these principles is strongly encouraged wherever applicable as a means of ensuring the
p.000121: ethical, methodologically sound and accurate conduct of human subjects’ research.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: INTRODUCTION | 7
p.000121:
p.000121: Overview of the clinical research process
p.000121:
p.000121: This section outlines key activities involved in the conduct of a clini- cal trial. This shows one possible sequence in
p.000121: which these activities may occur; other sequences (e.g. simultaneous completion of one or more activities) are also
p.000121: acceptable. Multiple parties are responsible for the success of these activities and procedures; the
p.000121: individual responsibilities of investigators, sponsors, ethics committees, and regulatory authorities will be the
p.000121: topic of subsequent sections of this Handbook.
p.000121:
p.000121: Key trial activities include:
p.000121: 1. Development of the trial protocol
p.000121: Within GCP, clinical trials should be described in a clear, detailed pro- tocol.
p.000121: The sponsor, often in consultation with one or more clinical investiga- tors, generally designs the study protocol;
p.000121: clinical investigators may also design and initiate clinical studies, as sponsor-investigators. In- tegral to protocol
p.000121: development are the concepts of risk identification, study design and control groups, and statistical
p.000121: methodology. The sponsor and clinical investigator(s) should be aware of any national/ local laws or regulations
p.000121: pertaining to designing, initiating, and con- ducting the study.
p.000121: See WHO GCP Principles 2: Protocol; 3: Risk Identification; 4: Benefit- Risk Assessment.
p.000121:
p.000121: 2. Development of standard operating procedures (SOPs)
p.000121: All parties who oversee, conduct or support clinical research (i.e. sponsors, clinical investigators,
p.000121: Independent Ethics Committees/
p.000121:
p.000121:
p.000121: 8 |
p.000121:
p.000121: Institutional Review Boards [IECs/IRBs] monitors, contract research organizations [CROs]) should develop and
p.000121: follow written standard op- erating procedures (SOPs) that define responsibilities, records, and methods to be
p.000121: used for study-related activities.
p.000121: See WHO GCP Principles 6: Protocol Compliance; 7: Informed Consent; 11: Records; 12: Confidentiality/Privacy; and 14:
p.000121: Quality Systems.
p.000121: Sponsors should consider preparing SOPs including those for:
p.000121: • developing and updating the protocol, investigator’s brochure, case report forms (CRFs), and other
p.000121: study-related documents;
p.000121: • supplies procurement, shipping, handling, and accounting for all supplies of the investigational product;
p.000121: • standardizing the activities of sponsors and study personnel (e.g. review of adverse event reports by medical
p.000121: experts; data analysis by statisticians);
p.000121: • standardizing the activities of clinical investigators to ensure that trial data is accurately captured;
p.000121: • monitoring, to ensure that processes are consistently followed and activities are consistently documented;
p.000121: • auditing, to determine whether monitoring is being appropriately carried out and the systems for quality
p.000121: control are operational and effective.
p.000121: Similarly, clinical investigators should consider developing SOPs for common trial-related procedures not
p.000121: addressed in the protocol. These may include but are not limited to: communicating with the IEC/IRB;
p.000121: obtaining and updating informed consent; reporting adverse events; preparing and maintaining adequate records;
p.000121: administering the investigational product; and accounting for and disposing of the investigational product.
p.000121: IECs/IRBs should develop and follow written procedures for their operations, including but not limited to:
p.000121: membership requirements; initial and continuing review; communicating with the investigator(s) and institution; and
p.000121: minimizing or eliminating conflicts of interest.
p.000121:
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 9
p.000121:
...
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 13
p.000121:
p.000121: tigational product and also document the quantity(ies) produced, to whom the product is shipped, and
p.000121: disposition (e.g. return or de- struction) of any unused supplies. GCP also requires investigators to control
p.000121: receipt, administration, and disposition of the investigational product.
p.000121: See WHO GCP Principles 2: Protocol; 11: Records; 13: Good Manufac- turing Practice; 14: Quality Systems
p.000121:
p.000121:
p.000121: 10. Trial data acquisition: conducting the trial
p.000121: Research should be conducted according to the approved protocol and applicable regulatory requirements. Study
p.000121: records documenting each trial-related activity provide critical verification that the study has been carried
p.000121: out in compliance with the protocol.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 11: Records.
p.000121:
p.000121:
p.000121: 11. Safety management and reporting
p.000121: All clinical trials must be managed for safety. Although all parties who oversee or conduct clinical research have
p.000121: a role/responsibility for the safety of the study subjects, the clinical investigator has primary responsibility
p.000121: for alerting the sponsor and the IEC/IRB to adverse events, particularly serious/life-threatening
p.000121: unanticipated events, observed during the course of the research. The sponsor, in turn, has primary
p.000121: responsibility for reporting of study safety to regulatory authorities and other investigators and for the ongoing
p.000121: global safety assessment of the investigational product. A data and safety moni- toring board (DSMB) may be
p.000121: constituted by the sponsor to assist in overall safety management.
p.000121: See WHO GCP Principles 2: Protocol; 3: Risk Identification; 6: Protocol Compliance; 8: Continuing Review/Ongoing
p.000121: Benefit-Risk Assessment; 11: Records; 14: Quality Systems
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 14 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: 12. Monitoring the trial
p.000121: Sponsors generally perform site monitoring of a clinical trial to assure high quality trial conduct. The sponsor may
p.000121: perform such monitoring directly, or may utilize the services of an outside individual or organi- zation (e.g. contract
p.000121: research organization [CRO]). The sponsor deter- mines the appropriate extent and nature of monitoring based on the
p.000121: objective, purpose, design, complexity, size, blinding, and endpoints of the trial, and the risks posed by the
p.000121: investigational product.
p.000121: The “on site” monitors review individual case histories in order to verify adherence to the protocol, ensure
p.000121: the ongoing implementation of appropriate data entry and quality control procedures, and verify adherence to GCP. In
p.000121: blinded studies, these monitors remain blinded to study arm assignment.
p.000121: For an investigator-initiated study, the sponsor-investigator should consider the merits of arranging
p.000121: independent, external monitoring of the study, particularly when the study involves novel products or potential
p.000121: significant risks to subjects.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 8: Con- tinuing Review; 11: Records; 14: Quality Systems.
p.000121:
p.000121:
p.000121: 13. Managing trial data
p.000121: Within GCP, managing clinical trial data appropriately assures that the data are complete, reliable and
p.000121: processed correctly, and that data integrity is preserved. Data management includes all processes and procedures for
p.000121: collecting, handling, manipulating, analysing, and storing/archiving of data from study start to completion.
p.000121: The sponsor bears primary responsibility for developing appropriate data management systems. The sponsor and the
p.000121: investigator share responsibility for implementing such systems to ensure that the in- tegrity of trial data
p.000121: is preserved.
p.000121: See WHO GCP Principles 2: Protocol; 6: Protocol Compliance; 11: Records; 14: Quality Systems.
p.000121:
p.000121:
p.000121:
p.000121: OVERVIEW OF THE CLINICAL RESEARCH PROCESS | 15
p.000121:
p.000121: See also Overview Processes 1: Protocol development; 2: Develop- ment of standard operating procedures; 3:
p.000121: Support systems and tools; 4: Trial information documents; 10: Trial data acquisition.
p.000121: Data management systems should address (as applicable):
p.000121: • data acquisition;
p.000121: • confidentiality of data/data privacy;
p.000121: • electronic data capture (if applicable);
p.000121: • data management training for investigators and staff;
p.000121: • completion of CRFs and other trial-related documents, and proce- dures for correcting errors in such documents;
p.000121: • coding/terminology for adverse events, medication, medical histo- ries;
p.000121: • safety data management and reporting;
p.000121: • data entry and data processing (including laboratory and external data);
p.000121: • database closure;
p.000121: • database validation;
p.000121: • secure, efficient, and accessible data storage;
p.000121: • data quality measurement (i.e. how reliable are the data) and qual- ity assurance;
p.000121: • management of vendors (e.g. CROs, pharmacies, laboratories, soft- ware suppliers, off-site storage) that
p.000121: participate directly or indi- rectly in managing trial data and materials.
p.000121:
p.000121: 14. Quality assurance of the trial performance and data
p.000121: Quality assurance (QA) verifies through systematic, independent audits that existing quality control
...
p.000121: guardian or other legally authorized representa- tive when the prospective subject is otherwise substantially
p.000121: unable to give informed consent; including an impartial witness to attend the informed consent process if
p.000121: the subject or the subject’s legally authorized representative cannot read; and/or additional monitoring of the
p.000121: conduct of the study.
p.000121: Within GCP, the principle of “respect for persons” is most directly im- plemented through the process of informed
p.000121: consent. Included here is the provision that the subject (or subject’s legally authorized repre- sentative) will be
p.000121: informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to
p.000121: continue participation in the trial. (See WHO GCP Principle 7: Informed Consent)
p.000121:
p.000121:
p.000121:
p.000121: 22 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: What is meant by “beneficence” and how is it most directly implemented within GCP?
p.000121: “Beneficence refers to the ethical obligation to maximize benefit and to minimize harm. This principle
p.000121: gives rise to norms requiring that the risks of research be reasonable in the light of the expected benefits, that
p.000121: the research design be sound, and that the investiga- tors be competent both to conduct the research and to safeguard
p.000121: the welfare of the research subjects. Beneficence further proscribes the deliberate infliction of harm on persons; this
p.000121: aspect of beneficence is sometimes expressed as a separate principle, nonmaleficence “do no harm”. (CIOMS,
p.000121: International Ethical Guidelines)
p.000121: The principle of “beneficence” bears a close relationship to the (GCP) “requirement that research be justified on
p.000121: the basis of a favourable risk/benefit assessment.” (The Belmont Report)
p.000121: “Risks and benefits of research may affect the individual subjects,
p.000121: … and society at large (or special groups of subjects in society).” “In balancing these different elements, the
p.000121: risks and benefits affecting the immediate research subject will normally carry special weight.” (The
p.000121: Belmont Report)
p.000121: Within GCP, the principle of “beneficence” is most directly imple- mented through risk/benefit assessment
p.000121: during design and review (initial review as well as continuing review) of the study protocol. (See also WHO GCP
p.000121: Principles 3: Risk Identification; 4: Benefit-Risk Assess- ment; 8: Continuing Review/Ongoing Benefit-Risk Assessment)
p.000121:
p.000121:
p.000121: What is meant by “justice” and how is it most directly implemented within GCP?
p.000121: “… the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the
p.000121: selection of research sub- jects.” (The Belmont Report)
p.000121: Justice in the selection of research subjects requires attention in two respects: the individual and the social.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 1: ETHICAL CONDUCT | 23
p.000121:
p.000121: ”Individual justice in the selection of subjects requires that research- ers exhibit fairness; thus, they should not
...
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 26 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 2: RESEARCH DESCRIBED IN A PROTOCOL
p.000121: Research involving humans should be scientifically justified and described in a clear, detailed protocol.
p.000121: “The experiment should be such as to yield fruitful results ... unpro- curable by other methods or means of
p.000121: study, and not random and unnecessary in nature.” (The Nuremburg Code)
p.000121: “The design and performance of each experimental procedure involv- ing human subjects should be clearly formulated in
p.000121: an experimental protocol.” (Declaration of Helsinki)
p.000121:
p.000121: Application
p.000121: Principle 2 is applied through development of a clear, detailed, scien- tifically justified and ethically sound
p.000121: protocol that (1) complies with requirements established by national and local laws and regulations, and (2)
p.000121: undergoes scientific and ethical review prior to implementa- tion.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “scientifically justified”?
p.000121: The protocol must be carefully designed to generate statistically and scientifically sound answers to the
p.000121: questions that are being asked and meet the objective(s) of the study. The objective(s) should also
p.000121: justify the risk; that is, the potential benefits (if any) of participation in the study should outweigh the risks.
p.000121: “A clinical trial cannot be justified ethically unless it is capable of producing scientifically reliable
p.000121: results.” (CIOMS, International Ethical Guidelines, Guideline 11)
p.000121:
p.000121: What is a clear detailed protocol?
p.000121: A protocol “describes the objective(s), design, methodology, statisti- cal considerations, and organization of a
p.000121: trial. The protocol usually also gives the background and rationale for the trial, but these could
p.000121:
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 27
p.000121:
p.000121: be provided in other protocol referenced documents.” (ICH E6, Sec- tion 1.44)
p.000121: A protocol “provides the background, rationale, and objective(s) of a biomedical research project and describes its
p.000121: design, methodology, and organization, including ethical and statistical considerations. Some of these
p.000121: considerations may be provided in other documents referred to in the protocol.” (WHO Operational
p.000121: Guidelines for Ethics Committees that Review Biomedical Research, Glossary)
p.000121:
p.000121:
p.000121: What information should be included in a study protocol?
p.000121: The study protocol is the core document communicating trial require- ments to all parties who have responsibility
p.000121: for approval, conduct, oversight, and analysis of the research.
p.000121: GCP recognizes that certain essential elements should be included in the study protocol. These include but are not
p.000121: limited to:
p.000121: • general information;
p.000121: • background information;
p.000121: • description of the trial objectives and purpose;
p.000121: • description of the trial design;
...
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: For clinical investigators, refer to:
p.000121: Investigator’s Qualifications and Agreements (ICH E6, Section 4.1) Adequate Resources (ICH E6, Section 4.2)
p.000121: Compliance with Protocol (ICH E6, Section 4.5)
p.000121:
p.000121: PRINCIPLE 2 : PROTOCOL | 33
p.000121:
p.000121: Randomization Procedures and Unblinding (ICH E6, Section 4.7) Safety Reporting (ICH E6, Section 4.11)
p.000121: Clinical Trial Protocol (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: For sponsors, refer to:
p.000121: Trial Design (ICH E6, Section 5.4)
p.000121: Trial Management, Data Handling, Recordkeeping, and Independ- ent Data Monitoring Committee (ICH E6, Section 5.5)
p.000121: Notification/Submission to Regulatory Authorities (ICH E6, Section 5.10)
p.000121: Clinical Trial Protocol (ICH E6, Section 6) Investigator’s Brochure (ICH E6, Section 7)
p.000121: Items to be Included in a Protocol (or Associated Documents) for Biomedical Research Involving Human Subjects (CIOMS,
p.000121: Interna- tional Ethical Guidelines, Appendix 1)
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995 (Section 2)
p.000121: For regulatory authorities, refer to:
p.000121: GCP Compliance Monitoring Programs by Regulatory Authorities (Good Clinical Practices: Document of the
p.000121: Americas, PAHO, Chapter 7)
p.000121: WHO Guidelines for good clinical practice (GCP) for trials on phar- maceutical products, 1995
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 3: Risk Identification
p.000121: GCP Principle 4: Benefit-Risk Assessment GCP Principle 5: Review by IEC/IRB
p.000121: GCP Principle 6: Protocol Compliance GCP Principle 11: Records
p.000121: Definitions for:
p.000121: Investigator’s Brochure (ICH E6, 1.36) Protocol (ICH E6, 1.44)
p.000121: Protocol Amendment (ICH E6, 1.45)
p.000121:
p.000121:
p.000121:
p.000121: 34 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 3: RISK IDENTIFICATION
p.000121: Before research involving humans is initiated, foreseeable risks and discomforts and any anticipated benefit(s) for the
p.000121: individual research subject and society should be identified. Research of investigational products or
p.000121: procedures should be supported by adequate non-clinical and, when applicable, clinical informa- tion.
p.000121: “The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural
p.000121: history of the disease or other problem under study that the anticipated results will justify the performance of the
p.000121: experiment.” (The Nuremberg Code)
p.000121: “Medical research involving human subjects must conform to gener- ally accepted scientific principles, be based on a
p.000121: thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and,
p.000121: where appropriate animal experimenta- tion.” (Declaration of Helsinki)
p.000121: “The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some
p.000121: cases, alternative ways of obtain- ing the benefits sought in the research [T]he assessment presents
p.000121: both an opportunity and a responsibility to gather systematic and comprehensive information about proposed
p.000121: research.” (The Belmont Report)
p.000121:
p.000121: Application
p.000121: Principle 3 is applied through:
p.000121: • conducting a thorough search of available scientific information about the investigational product or
p.000121: procedure(s) (including find- ings from tests in laboratory animals and any previous human ex- perience);
p.000121: • developing the investigator’s brochure, the study protocol, and the informed consent document to adequately,
p.000121: accurately, and objec- tively reflect the available scientific information on foreseeable risks and anticipated
p.000121: benefits.
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 35
p.000121:
p.000121: Questions and Answers:
p.000121: What is meant by “risk(s)” and “benefit(s)”?
p.000121: “The term “risk” refers to a possibility that harm may occur. However, when expressions such as “small risk” or
p.000121: “high risk” are used, they usually refer (often ambiguously) both to the chance (probability) of
p.000121: experiencing a harm and the severity (magnitude) of the envisioned harm. The term “benefit” is used in the
p.000121: research context to refer to something of positive value related to health or welfare.” (The Bel- mont
p.000121: Report)
p.000121: “Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of
p.000121: psychological harm, physi- cal harm, legal harm, social harm and economic harm and the cor- responding
p.000121: benefits. While the most likely types of harms to research subjects are those of psychological or physical pain
p.000121: or injury, other possible kinds should not be overlooked.” (The Belmont Report)
p.000121: “Risks and benefits of research may affect the individual subjects, the families of the individual subjects,
p.000121: and society at large (or special groups of subjects in society).” “… In balancing these different ele- ments,
p.000121: the risks and benefits affecting the immediate research sub- ject will normally carry special weight.” (The
p.000121: Belmont Report) (See WHO GCP Principle 1: Ethical Conduct)
p.000121:
p.000121:
p.000121: How is identification of risks and benefits implemented within GCP and where may information about risks and benefits
p.000121: be obtained?
p.000121: Within GCP, the identification of risks and benefits is undertaken as part of the scientific review that
p.000121: accompanies protocol develop- ment.
p.000121: “… [M]edical research involving humans must conform to generally accepted scientific principles, and be
p.000121: based on a thorough knowl- edge of the scientific literature, other relevant sources of information and adequate
p.000121: laboratory and, where indicated, animal experimen- tation. Scientific review must consider, inter alia, the
p.000121: study design,
p.000121:
p.000121:
p.000121:
p.000121: 36 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: including the provisions for avoiding or minimizing risk and for moni- toring safety.” (CIOMS, International Ethical
p.000121: Guidelines, Commentary on Guideline 2)
p.000121: Important to any scientific review is the critical selection and evalua- tion of literature accessed from available
p.000121: scientific publications. How- ever, it may also be important to review relevant unpublished data,
p.000121: particularly where such data raise concerns for subject safety.
p.000121:
p.000121:
p.000121: What is non-clinical information?
p.000121: Non-clinical information is information derived from non-clinical studies, defined as “Biomedical
p.000121: studies not performed on human subjects.” (ICH, E6, 1.41)
p.000121: The term includes in vivo (animal or plant studies) or in vitro (labora- tory) experiments in which investigational
p.000121: products are studied in test systems under laboratory conditions to determine their safety. Regulators and
p.000121: others may require non-clinical studies to comply with standards for Good Laboratory Practice (GLP); such
p.000121: studies may be called or referred to as “GLP studies”.
p.000121:
p.000121:
p.000121: What is GLP (Good Laboratory Practice) and what is the relationship between GLP and GCP Principle 3?
p.000121: The purpose of GLP is to assure the quality and integrity of non-clini- cal (notably animal) data submitted in support
p.000121: of research permits or marketing applications. In accordance with national/local laws and regulations,
p.000121: regulators may establish GLP standards for the conduct and reporting of non-clinical studies. GLP standards include
p.000121: require- ments for: organization and management of the testing facility, quali- fications of personnel and the study
p.000121: director, quality assurance units, characteristics of animal care facilities, laboratory operation areas, and
p.000121: specimen and data storage facilities, equipment maintenance, standard operating procedures, characterization
p.000121: of test and control articles, protocols, study conduct, reports, and record keeping.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 3 : RISK IDENTIFICATION | 37
p.000121:
p.000121: In accordance with national/local laws and regulations, compliance with GLP may be a requirement for the
p.000121: acceptance of animal toxi- cology studies in support of human testing. Where not required by
p.000121: national/local laws and regulations, GLP standards provide important guidance to the conduct of quality animal
p.000121: toxicology studies.
p.000121:
p.000121:
p.000121: What does the term “clinical information” include?
p.000121: Clinical information here refers to information derived from prior clinical study or experience. A
p.000121: clinical study is defined as “[a]ny in- vestigation in human subjects intended to discover or verify the clini-
p.000121: cal, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to
p.000121: identify any adverse reactions to an investigational product(s), and/or to study absorption, distribu- tion,
p.000121: metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.
p.000121: The terms clini- cal trial and clinical study are synonymous.” (ICH E6, 1.12)
p.000121:
p.000121:
p.000121: What is meant by “foreseeable” and “anticipated”?
p.000121: The terms “foreseeable” and “anticipated” connote knowledge that is available or predictable at the time
p.000121: of protocol review. Implicit in these terms is the obligation to conduct a thorough search of scien- tific
p.000121: literature contemporaneous to the time of initial protocol review and the obligation to keep apprised of significant
p.000121: new findings on risks and/or benefits that become available as the protocol proceeds.
p.000121:
p.000121: Implementation
p.000121: The responsibility for implementing this principle is shared by spon- sors, investigators, IECs/IRBs, and regulators:
...
p.000121: • at their discretion, observing the consent process and the re- search.
p.000121: Investigators are responsible for ensuring that:
p.000121: • staff responsible for obtaining informed consent receive appropri- ate training, both in research ethics and in the
p.000121: requirements of the specific study protocol;
p.000121: • the IEC/IRB reviews and approves the informed consent form and other written information to be used in the study
p.000121: prior to its use; and
p.000121: • informed consent is obtained from each subject or the subject’s representative prior to involving the
p.000121: subject in any study related activities, including diagnostic or other tests that are administered solely for
p.000121: determining the subject’s eligibility to participate in the research.
p.000121: Sponsors are responsible for monitoring the research at study sites to ensure that sites are obtaining informed
p.000121: consent from all study subjects prior to subjects’ inclusion in the research study.
p.000121:
p.000121:
p.000121: PRINCIPLE 7: INFORMED CONSENT | 69
p.000121:
p.000121: In accordance with national and local laws and regulations, regula- tors may inspect the various parties
p.000121: who conduct or oversee re- search to ensure that they are complying with applicable laws and regulations
p.000121: and enforcing non-compliance. For example, regulators may inspect IECs/IRBs to ensure that informed consent
p.000121: documents and procedures are appropriately reviewed; they may inspect clinical investigators to determine whether
p.000121: informed consent was obtained prior to subjects’ inclusion in the study; they may inspect sponsors to ascertain whether
p.000121: studies are being appropriately monitored.
p.000121:
p.000121: For more information (including Roles and Responsibilities)
p.000121: For all parties:
p.000121: CIOMS International Ethical Guidelines for Biomedical Research In- volving Human Subjects, Guidelines 4, 5, 6, 13, 14,
p.000121: 15, and 16 Clinical Investigation of Medicinal Products in the Pediatric Popula-
p.000121: tion (ICH E11)
p.000121: For IECs/IRBs, refer to: Responsibilities (ICH E6, Section 3.1)
p.000121: Documentation (WHO Operational Guidelines for Ethics Commit- tees that Review Biomedical Research, Section 5.3)
p.000121: Elements of the Review (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research,
p.000121: Section 6.2)
p.000121: Communicating a Decision (WHO Operational Guidelines for Ethics Committees that Review Biomedical Research, Section 8)
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: For clinical investigators, refer to: Communication with IRB/IEC (ICH E6, Section 4.4)
p.000121: Informed Consent of Trial Subjects (ICH E6, Section 4.8)
p.000121: For sponsors, refer to:
p.000121: Confirmation of Review by IRB/IEC (ICH E6, Section 5.11) Monitoring (ICH E6, Section 5.18)
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: 70 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: For regulatory authorities, refer to
p.000121: Surveying and Evaluating Ethical Review Practices (a complemen- tary guideline to the Operational Guidelines for Ethics
p.000121: Commit- tees That Review Biomedical Research), WHO, 2002
p.000121: A Guide to Clinical Investigator Inspections (Good Clinical Prac- tices: Document of the Americas, PAHO, Annex
p.000121: 4)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP GCP Principle 1: Ethical Conduct
p.000121: GCP Principle 4: Benefit-Risk Assessment
p.000121: Definitions for:
...
p.000121: take appropriate risk minimization steps. Such steps can include modification of study protocols, to
p.000121: incorporate strategies to ensure that clinical trial participants are not exposed to undue risk.” (Management of Safety
p.000121: Information from Clinical Trials, Report of CIOMS Working Group VI. Identification and Evaluation of Risk from
p.000121: Clinical Trial Data)
p.000121:
p.000121: Application
p.000121: Principle 8 is applied through development and implementation of processes for evaluating risks and
p.000121: benefits of the research as ad- ditional information becomes available during the course of the
p.000121: study. Principle 8 encompasses (1) safety monitoring of the study by investigator(s) and sponsor
p.000121: (including use of a data and safety monitoring board [DSMB], where appropriate); (2) reporting serious
p.000121: unexpected adverse events or other unanticipated risks to the spon- sor, IEC/IRB, and regulators; (3) review by
p.000121: the IEC/IRB of any unan-
p.000121:
p.000121:
p.000121: 72 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: ticipated risks as they occur, or at scheduled intervals appropriate to the degree of risk; (4) revising the
p.000121: protocol, investigator’s brochure, and/or informed consent document as needed, and suspending or terminating
p.000121: studies if necessary to protect the rights and welfare of study subjects.
p.000121:
p.000121: Questions and Answers:
p.000121: How are unanticipated risks identified during the course of a study?
p.000121: Investigators and site staff are often the first to discover or observe unanticipated risks to subjects (e.g.
p.000121: serious unexpected adverse events; significant breaches of confidentiality) during the course of a study.
p.000121: Sponsors may also identify unanticipated risks to subjects in the course of study monitoring or from planned
p.000121: interim data analy- ses.
p.000121: “The frequent review of serious and special interest adverse events, as well as overall assessment of all AEs,
p.000121: regardless of seriousness, causality, or expectedness, should be performed periodically: (1) ad hoc, for serious and
p.000121: special interest AEs, (2) routine, periodic general review of all data, whose frequency will vary from trial
p.000121: to trial and from development program to development program and depend on many factors, and (3) reviews triggered by
p.000121: specific milestones estab- lished for a trial or a program (e.g. numbers of completed patients,
p.000121: end-of-trial, end-of program, preparation of integrated summary of safety, and a marketing application.”
p.000121: (Management of Safety Informa- tion from Clinical Trials, Report of CIOMS Working Group VI. Frequen- cy of Review of
p.000121: Safety Information)
p.000121:
p.000121:
p.000121: How should serious unexpected adverse events (SAEs) be reported and to whom?
p.000121: “All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the
p.000121: protocol or other docu- ment (e.g. investigator’s brochure) identifies as not needing immedi- ate reporting. The
p.000121: immediate reports should be followed promptly
p.000121:
p.000121:
...
p.000121: “Follow-up”, Section 9, WHO Operational Guidelines for Ethics Com- mittees that Review Biomedical Research)
p.000121:
p.000121:
p.000121: How are follow-up reviews carried out?
p.000121: Sponsors generally monitor trials to ensure that (1) the study is being conducted according to the approved
p.000121: protocol, GCP, and applicable regulatory requirements, and (2) all data, including adverse event reports
p.000121: are accurately and completely recorded and reported. The sponsor also employs qualified individuals (e.g.
p.000121: physicians, statisti-
p.000121:
p.000121:
p.000121: 74 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: cians) as appropriate, throughout all stages of the trial process, to analyse data and prepare interim
p.000121: reports about the progress of the trial and the benefits and risks of the investigational product. The
p.000121: sponsor may also establish an independent data and safety monitor- ing board (DSMB, see below) to review the
p.000121: accumulating data. The sponsor should ensure that significant new information that arises about a clinical
p.000121: trial is promptly shared with all investigators, regula- tory authorities and IECs/IRBs.
p.000121: The IEC/IRB generally establishes procedures for (1) ensuring that new information that may adversely
p.000121: affect the safety of subjects or the conduct of the trial (e.g. serious/unexpected adverse events; unanticipated
p.000121: risks) are communicated to the IEC/IRB; (2) conducting the follow-up review; and (3) communicating
p.000121: decisions/opinions to the investigator.
p.000121:
p.000121: When or how often should a benefit-risk determination be performed?
p.000121: An evaluation should be carried out promptly following receipt of significant new information that may
p.000121: adversely affect the safety of subjects or the conduct of the trial. Generally, such new information is supplied by
p.000121: the clinical investigator(s), but it may also come from a DSMB or the study sponsor.
p.000121: “An important principle in the evaluation of safety data from clinical trials is that while the data are designed to be
p.000121: analysed in a compre- hensive fashion at the end of a trial or development program, they also must be
p.000121: evaluated in an ongoing fashion, so that important safety signals can be detected early and that trial
p.000121: participants are protected.” (Management of Safety Information from Clinical Trials, Report of CIOMS Working
p.000121: Group VI. Identification and Evaluation of Risk from Clinical Trial Data)
p.000121: A sponsor may establish a schedule of interim analyses. The study protocol will generally describe this
p.000121: schedule and will also typically describe the statistical approach to the interim analysis of trial data. To
p.000121: minimize the potential for bias, these descriptions should be com- pleted before the conduct of any interim analyses.
p.000121:
p.000121: PRINCIPLE 8 : CONTINUING REVIEW/ ONGOING BENEFIT- RISK ASSESSMENT | 75
p.000121:
p.000121: The IEC/IRB should conduct follow-up reviews in accordance with es- tablished procedures. In general, the IEC/IRB
p.000121: should conduct follow- up review of each ongoing trial at scheduled intervals appropriate to the degree of risk, but,
p.000121: generally, at least once per year.
p.000121:
p.000121:
...
p.000121: the validity of the trial conduct and the in- tegrity of the data collected.” (ICH E6, Section 8)
p.000121: Examples include:
p.000121: • Source data: “All information in original records and certified cop- ies of original records of clinical
p.000121: findings, observations, or other activities in a clinical trial necessary for the reconstruction and
p.000121: evaluation of the trial. Source data are contained in source docu- ments (original records or certified copies).” (ICH
p.000121: E6, 1.51)
p.000121: • Source documents: “Original documents, data, and records (e.g. hospital records, clinical and office
p.000121: charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing
p.000121: records, recorded data from automated instruments, copies or transcriptions certified after verification as
p.000121: being accu- rate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject
p.000121: files, and records kept at the pharmacy, at the laboratories, and at medico-technical depart- ments
p.000121: involved in the clinical trial).” (ICH E6, 1.52)
p.000121: • Case report forms: “… [P]rinted, optical, or electronic document[s] designed to record all of the
p.000121: protocol-required information to be reported to the sponsor on each trial subject.” (ICH E6, 1.11)
p.000121: • Correspondence between any of the parties who conduct or over- see the research (e.g. approval/favourable decision
p.000121: by the IEC/IRB; reports of adverse events submitted to the sponsors, IECs/IRBs, and regulators; monitor’s
p.000121: reports to the sponsor).
p.000121: • Other study related documents and materials (e.g. study protocol, protocol amendments, investigator’s brochure,
p.000121: clinical investiga- tor’s curriculum vitae, approved consent form, subjects’ signed consent forms, subject
p.000121: screening logs, documentation of investi- gational product destruction, advertisements used to recruit sub- jects,
p.000121: reports by independent data monitoring committees).
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 11: RECORDS | 93
p.000121:
p.000121: What is meant by “recording”?
p.000121: “Recording” is the act of writing down or otherwise committing to durable medium (e.g. paper, electronic
p.000121: medium, etc.) information or data to provide evidence of what has occurred or has been observed. All of the parties who
p.000121: conduct or oversee clinical trials are responsi- ble for preparing records (i.e. “essential documents”) that document
p.000121: their activities and data or observations related to the trial.
p.000121:
p.000121:
p.000121: What is meant by “data quality”? What is meant by “data integrity”? How are the terms related, and how are data quality
p.000121: and integrity achieved within GCP?
p.000121: “Data quality” refers to the essential characteristics of each piece of data; in particular, quality data
p.000121: should be:
p.000121: • accurate;
p.000121: • legible;
p.000121: • complete and contemporaneous (recorded at the time the activity occurs);
p.000121: • original;
p.000121: • attributable to the person who generated the data.
p.000121: “Data integrity” refers to the soundness of the body of data as a whole. In particular, the body of
p.000121: data should be credible, internally consistent, and verifiable.
p.000121: Quality and integrity are both essential for data to be relied upon for regulatory decision-making. Data quality
p.000121: and integrity are achieved when each piece of data is collected in accordance with the study protocol
p.000121: and procedures, giving attention to each of the quality characteristics above, and subsequently handled
...
p.000121: For regulatory authorities, refer to:
p.000121: WHO, A Compendium of Guidelines and Related Materials, Volume 2: Good Manufacturing Practices and Inspections
p.000121: (http://www.who.int/medicines/organization/qsm/activities/ qualityassurance/gmp/gmpthree_inves.html)
p.000121: Active Pharmaceutical Ingredients for Use in Clinical Trials (GMP for Active Pharmaceutical Ingredients, ICH
p.000121: Q7A, Section XIX)
p.000121: See also:
p.000121: Discussion of the WHO Principles of GCP: GCP Principle 6: Protocol Compliance
p.000121: Definitions for:
p.000121: Comparator (Product) (ICH E6, 1.14) Compliance (in relation to trials) (ICH E6, 1.15)
p.000121: Contract Research Organization (CRO) (ICH E6, 1.20) Investigational Product (ICH E6, 1.33)
p.000121: Monitoring (ICH E6, 1.38)
p.000121:
p.000121: 114 | HANDBOOK FOR GOOD CLINICAL RESEARCH PR ACTICE
p.000121:
p.000121: PRINCIPLE 14: QUALITY SYSTEMS
p.000121: Systems with procedures that assure the quality of every aspect of the trial should be implemented.
p.000121:
p.000121: Application
p.000121: Principle 14 is applied through development of procedures to control, assure, and improve the quality of data and
p.000121: records and the quality and effectiveness of processes and activities related to the conduct and oversight of clinical
p.000121: research.
p.000121:
p.000121: Questions and Answers
p.000121: What is meant by “quality” in the context of a clinical trial?
p.000121: “Quality” is a measure of the ability of a product, process, or serv- ice to satisfy stated or implied needs. A high
p.000121: quality product readily meets those needs.
p.000121: In the context of a clinical trial, quality may apply to data (e.g. data are accurate and reliable) or
p.000121: processes (e.g. compliance with the study protocol and GCP; ensuring informed consent; adequate data
p.000121: handling and record-keeping, etc.). (See WHO GCP Principles 6: Pro- tocol Compliance; 7: Informed Consent; 11: Records)
p.000121: A common way to assure data and process quality is through the development and application of
p.000121: standard operating procedures (SOPs) that define responsibilities, specify records to be established and
p.000121: maintained, and specify methods and procedures to be used in carrying out study-related activities. SOPs coupled
p.000121: with close per- sonal supervision of the trial’s conduct by the clinical investigator and careful monitoring by the
p.000121: sponsor help to ensure that processes are consistently followed and activities are consistently documented. As a
p.000121: result, data collected using such procedures and under such super- vision should ordinarily be reliable enough
p.000121: for regulatory decision- making.
p.000121:
p.000121:
p.000121:
p.000121:
p.000121: PRINCIPLE 14 : QUALIT Y SYSTEMS | 115
p.000121:
p.000121: What are “quality systems” with respect to clinical trials?
p.000121: “Quality systems” for clinical trials are formalized practices (e.g. mon- itoring programs, auditing programs,
p.000121: complaint handling systems) for periodically reviewing the adequacy of clinical trial activities and practices, and
p.000121: for revising such practices as needed so that data and process quality are maintained.
p.000121:
p.000121:
p.000121: How are quality systems implemented within GCP?
p.000121: Within GCP, quality systems are implemented through quality man- agement: that is, through coordination of
p.000121: activities by the sponsor, by the investigator(s) and site staff, by the IECs/IRBs and by regulators to direct and
p.000121: control their operations with respect to quality. Quality management embraces three major components: quality
p.000121: control; quality assurance; and quality improvement.
p.000121:
p.000121:
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| HIV | HIV/AIDS |
| abuse | Victim of Abuse |
| access | Access to Social Goods |
| access to information | Access to information |
| authority | Relationship to Authority |
| autonomy | Impaired Autonomy |
| belief | Religion |
| child | Child |
| children | Child |
| comatose | Comatose |
| control group | participants in a control group |
| diminished | Diminished Autonomy |
| disability | Mentally Disabled |
| disabled | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| educational | education |
| elderly | Elderly |
| embryo | embryo |
| emergency | Public Emergency |
| ethnicity | Ethnicity |
| faith | Religion |
| family | Motherhood/Family |
| fetus | Fetus/Neonate |
| gender | gender |
| hazard | Natural Hazards |
| healthy volunteers | Healthy People |
| hiv/aids | HIV/AIDS |
| homeless | Homeless Persons |
| ill | ill |
| illness | Physically Disabled |
| impairment | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| indigenous | Indigenous |
| infant | Infant |
| influence | Drug Usage |
| institutionalized | Institutionalized |
| language | Linguistic Proficiency |
| manipulate | Manipulable |
| manipulated | Manipulable |
| mentally | Mentally Disabled |
| military | Soldier |
| minor | Youth/Minors |
| opinion | philosophical differences/differences of opinion |
| party | political affiliation |
| physically | Physically Disabled |
| placebo | participants in a control group |
| political | political affiliation |
| poor | Economic/Poverty |
| pregnant | Pregnant |
| prisoners | Criminal Convictions |
| property | Property Ownership |
| race | Racial Minority |
| racial | Racial Minority |
| religious | Religion |
| restricted | Incarcerated |
| schooling | education |
| sick | Physically Ill |
| single | Marital Status |
| stigma | Threat of Stigma |
| terminally | Terminally Ill |
| undue influence | Undue Influence |
| union | Trade Union Membership |
| volunteers | Healthy People |
| vulnerable | vulnerable |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| HIV | ['hiv/aids'] |
| belief | ['faith', 'religious'] |
| child | ['children'] |
| children | ['child'] |
| control group | ['placebo'] |
| disability | ['disabled', 'mentally'] |
| disabled | ['mentally', 'disability'] |
| drug | ['influence'] |
| education | ['educational', 'schooling'] |
| educational | ['education', 'schooling'] |
| faith | ['belief', 'religious'] |
| healthy volunteers | ['volunteers'] |
| hiv/aids | ['HIV'] |
| illness | ['physically'] |
| influence | ['drug'] |
| manipulate | ['manipulated'] |
| manipulated | ['manipulate'] |
| mentally | ['disabled', 'disability'] |
| party | ['political'] |
| physically | ['illness'] |
| placebo | ['controlXgroup'] |
| political | ['party'] |
| race | ['racial'] |
| racial | ['race'] |
| religious | ['faith', 'belief'] |
| schooling | ['education', 'educational'] |
| volunteers | ['healthyXvolunteers'] |
Trigger Words
capacity
coercion
consent
cultural
developing
ethics
harm
justice
protect
protection
risk
sensitive
volunteer
welfare
Applicable Type / Vulnerability / Indicator Overlay for this Input