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p.000037: 5.14. Supplying and handling investigational product(s) 38
p.000037: Guideline for good clinical practice E6(R2)
p.000037: EMA/CHMP/ICH/135/1995
p.000037: Page 3/68
p.000037:
p.000037: 5.15. Record access
p.000039: 39
p.000040: 5.16. Safety information
p.000040: 39
p.000040: 5.17. Adverse drug reaction reporting 39
p.000040: 5.18. Monitoring
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p.000050: 49
p.000050: 6.8. Assessment of Safety
p.000050: 49
p.000050: 6.9. Statistics
p.000050: 50
p.000051: 6.10. Direct access to source data/documents 50
p.000051: 6.11. Quality control and quality assurance 50
p.000051: 6.12. Ethics
p.000051: 50
p.000051: 6.13. Data handling and record keeping 51
p.000051: 6.14. Financing and insurance 51
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p.000060: 1.20. Contract Research Organization (CRO)
p.000060:
p.000060: A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a
p.000060: sponsor's trial-related duties and functions.
p.000060:
p.000060: 1.21. Direct access
p.000060:
p.000060: Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a
p.000060: clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with
p.000060: direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s)
p.000060: to maintain the confidentiality of subjects' identities and
p.000060: sponsor’s proprietary information.
p.000060:
p.000060: 1.22. Documentation
p.000060:
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p.000060:
p.000060: l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000060:
p.000060: m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or
p.000060: withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
p.000060: n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access
p.000060: to the subject's original medical records for verification of clinical trial procedures and/or data, without violating
p.000060: the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing
p.000060: a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such
p.000060: access.
p.000060: o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
p.000060: and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s
p.000060: identity will remain confidential.
p.000060: p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if
p.000060: information becomes available that may be relevant to the subject's willingness to continue participation in the trial.
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p.000060: investigator/institution.
p.000060:
p.000060: 4.9.7.
p.000060:
p.000060: Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make
p.000060: available for direct access all requested trial-related records.
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
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p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 31/68
p.000060:
p.000060: 5.1.2.
p.000060:
p.000060: The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all
p.000060: trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and
p.000060: inspection by domestic and foreign regulatory authorities.
p.000060:
p.000060: 5.1.3.
p.000060:
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p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 33/68
p.000060:
p.000060: c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and
p.000060: that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail).
p.000060: d) Maintain a security system that prevents unauthorized access to the data.
p.000060:
p.000060: e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
p.000060:
p.000060: f) Maintain adequate backup of the data.
p.000060:
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p.000060: b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications,
p.000060: should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent
p.000060: stability permits, samples should be retained either until the analyses of the trial data are complete or as required
p.000060: by the applicable regulatory requirement(s), whichever represents the longer retention period.
p.000060:
p.000060: 5.15. Record access
p.000060:
p.000060: 5.15.1.
p.000060:
p.000060: The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000060: investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits,
p.000060: IRB/IEC review, and regulatory inspection.
p.000060:
p.000060: 5.15.2.
p.000060:
p.000060: The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical
p.000060: records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
p.000060:
p.000060: 5.16. Safety information
p.000060:
p.000060: 5.16.1.
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p.000060: submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the
p.000060: level of risks to the trial subjects, and any identified problem(s).
p.000060: c) The observations and findings of the auditor(s) should be documented.
p.000060:
p.000060: d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely
p.000060: request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when
p.000060: evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
p.000060: e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
p.000060:
p.000060: 5.20. Noncompliance
p.000060:
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p.000060: 6.9.7.
p.000060:
p.000060: The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all
p.000060: eligible subjects, evaluable subjects).
p.000060:
p.000060: 6.10. Direct access to source data/documents
p.000060:
p.000060: The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000060: investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000060: inspection(s), providing direct access to source data/documents.
p.000060:
p.000060: 6.11. Quality control and quality assurance
p.000060:
p.000060: 6.12. Ethics
p.000060:
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p.000060: EMA/CHMP/ICH/135/1995
p.000060:
p.000060: Page 59/68
p.000060:
p.000060:
p.000060: The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the
p.000060: sponsor. The sponsor should not have exclusive control of those data.
p.000060: When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the
p.000060: requirements for certified copies.
p.000060:
p.000060: The investigator/institution should have control of all essential documents and records generated by the
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p.000060: conduct, adverse event (AE) reporting
p.000060:
p.000060:
p.000060: To document that consent is obtained in accordance with X GCP and protocol and dated prior to
p.000060: participation of each
p.000060: subject in trial. Also to document direct access permission (see 8.2.3)
p.000060:
p.000060:
p.000060: 8.3.13
p.000060:
p.000060:
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p.000060: including the following, if available:
p.000060: • Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution,
p.000060: and elimination).
p.000060: • Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference
p.000060: dosage form.
p.000060: • Population subgroups (e.g., gender, age, and impaired organ function).
p.000060:
p.000060: • Interactions (e.g., product-product interactions and effects of food).
p.000060:
p.000060: • Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000060:
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p.000036: 5.7. Allocation of responsibilities
p.000036: 36
p.000037: 5.8. Compensation to subjects and investigators 36
p.000037: 5.9. Financing
p.000037: 36
p.000037: 5.10. Notification/submission to regulatory authority(ies) 36
p.000037: 5.11. Confirmation of review by IRB/IEC 36
p.000037: 5.12. Information on investigational product(s) 37
p.000037: 5.13. Manufacturing, packaging, labelling, and coding investigational product(s) 37
p.000037: 5.14. Supplying and handling investigational product(s) 38
p.000037: Guideline for good clinical practice E6(R2)
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p.000060: having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed
p.000060: consent is documented by means of a written, signed and dated informed consent form.
p.000060:
p.000060: 1.29. Inspection
p.000060:
p.000060: The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any
p.000060: other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at
p.000060: the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other
p.000060: establishments deemed appropriate by the regulatory authority(ies).
p.000060:
p.000060: 1.30. Institution (medical)
p.000060:
p.000060: Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
p.000060:
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p.000060:
p.000060: The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
p.000060:
p.000060: 3.3.1.
p.000060:
p.000060: Determining its composition (names and qualifications of the members) and the authority under which it is established.
p.000060:
p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 18/68
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p.000060:
p.000060: 3.4. Records
p.000060:
p.000060: The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of
p.000060: occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at
p.000060: least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies).
p.000060: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and
p.000060: membership lists.
p.000060:
p.000060: 4. Investigator
p.000060: 4.1. Investigator's Qualifications and Agreements
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p.000060: 4.1.1.
p.000060:
p.000060: The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper
p.000060: conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and
p.000060: should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation
p.000060: requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
p.000060:
p.000060: 4.1.2.
p.000060:
p.000060: The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described
p.000060: in the protocol, in the current Investigator's Brochure, in the product information and in other information sources
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p.000060: The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
p.000060:
p.000060: 4.1.4.
p.000060:
p.000060: The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate
p.000060: regulatory authority(ies).
p.000060:
p.000060: 4.1.5.
p.000060:
p.000060: The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated
p.000060: significant trial-related duties.
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p.000060: 4.5. Compliance with Protocol
p.000060:
p.000060: 4.5.1.
p.000060:
p.000060: The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if
p.000060: required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. The
p.000060: investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
p.000060:
p.000060: 4.5.2.
p.000060:
p.000060: The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor
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p.000060: change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
p.000060: a) to the IRB/IEC for review and approval/favourable opinion,
p.000060:
p.000060: b) to the sponsor for agreement and, if required,
p.000060:
p.000060: c) to the regulatory authority(ies).
p.000060:
p.000060: 4.6. Investigational Product(s)
p.000060:
p.000060: 4.6.1.
p.000060:
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p.000060:
p.000060: l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000060:
p.000060: m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or
p.000060: withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
p.000060: n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access
p.000060: to the subject's original medical records for verification of clinical trial procedures and/or data, without violating
p.000060: the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing
p.000060: a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such
p.000060: access.
p.000060: o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
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p.000060: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000060: investigator/institution.
p.000060:
p.000060: 4.9.7.
p.000060:
p.000060: Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make
p.000060: available for direct access all requested trial-related records.
p.000060:
p.000060:
p.000060:
p.000060:
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p.000060: All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol
p.000060: or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports
p.000060: should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects
p.000060: by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification
p.000060: numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to
p.000060: the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.
p.000060:
p.000060: 4.11.2.
p.000060:
p.000060: Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be
p.000060: reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in
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p.000060:
p.000060: 4.12. Premature Termination or Suspension of a Trial
p.000060:
p.000060: If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform
p.000060: the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the
p.000060: applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
p.000060:
p.000060: 4.12.1.
p.000060:
p.000060: If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should
p.000060: inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the
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p.000060:
p.000060: 4.13. Final Report(s) by Investigator
p.000060:
p.000060: Upon completion of the trial, the investigator, where applicable, should inform the institution; the
p.000060: investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory
p.000060: authority(ies) with any reports required.
p.000060:
p.000060: 5. Sponsor
p.000060:
p.000060: ADDENDUM
p.000060:
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p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 34/68
p.000060:
p.000060: 5.5.10.
p.000060:
p.000060: Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the
p.000060: applicable regulatory requirement(s).
p.000060:
p.000060: 5.5.11.
p.000060:
p.000060: The sponsor specific essential documents should be retained until at least 2 years after the last approval of a
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p.000060: 5.9. Financing
p.000060:
p.000060: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000060: investigator/institution.
p.000060:
p.000060: 5.10. Notification/submission to regulatory authority(ies)
p.000060:
p.000060: Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the
p.000060: applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for
p.000060: review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s).
p.000060: Any notification/submission should be dated and contain sufficient information to identify the protocol.
p.000060:
p.000060: 5.11. Confirmation of review by IRB/IEC
p.000060:
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p.000060: The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
p.000060:
p.000060: 5.14.2.
p.000060:
p.000060: The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains
p.000060: all required documentation (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)).
p.000060:
p.000060: 5.14.3.
p.000060:
p.000060: The sponsor should ensure that written procedures include instructions that the investigator/institution should follow
p.000060: for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures
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p.000060:
p.000060: The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
p.000060:
p.000060: 5.16.2.
p.000060:
p.000060: The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of
p.000060: findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's
p.000060: approval/favourable opinion to continue the trial.
p.000060:
p.000060: 5.17. Adverse drug reaction reporting
p.000060:
p.000060: 5.17.1.
p.000060:
p.000060: The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where
p.000060: required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and
p.000060: unexpected.
p.000060:
p.000060:
p.000060:
p.000060:
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p.000060: Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for
p.000060: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
p.000060:
p.000060: 5.17.3.
p.000060:
p.000060: The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by
p.000060: applicable regulatory requirement(s).
p.000060:
p.000060: 5.18. Monitoring
p.000060:
p.000060: 5.18.1. Purpose
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p.000060: b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to
p.000060: submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the
p.000060: level of risks to the trial subjects, and any identified problem(s).
p.000060: c) The observations and findings of the auditor(s) should be documented.
p.000060:
p.000060: d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely
p.000060: request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when
p.000060: evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
p.000060: e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
p.000060:
p.000060: 5.20. Noncompliance
p.000060:
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p.000060: 5.20.2.
p.000060:
p.000060: If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an
p.000060: investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial.
p.000060: When an investigator's/institution’s participation is terminated because of noncompliance, the sponsor
p.000060: should notify promptly the regulatory authority(ies).
p.000060:
p.000060: 5.21. Premature termination or suspension of a trial
p.000060:
p.000060: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions,
p.000060: and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension.
p.000060: The IRB/IEC should also be informed promptly and
p.000060:
p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
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p.000060: For multicentre trials, the sponsor should ensure that:
p.000060:
p.000060: 5.23.1.
p.000060:
p.000060: All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required,
p.000060: by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.
p.000060:
p.000060: 5.23.2.
p.000060:
p.000060: The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who are
p.000060: collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.
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p.000060: and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor
p.000060: and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.
p.000060: Essential Documents also serve a number of other important purposes. Filing essential documents at the
p.000060: investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a
p.000060: trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the
p.000060: sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm
p.000060: the validity of the trial conduct and the integrity of data collected.
p.000060: The minimum list of essential documents which has been developed follows. The various documents are grouped in three
p.000060: sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase
p.000060: of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the
p.000060: trial. A description is given of the purpose of each document, and whether it should be filed in either the
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p.000060: individual elements are readily identifiable.
p.000060: Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and
p.000060: at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both
p.000060: investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.
p.000060: Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the
p.000060: sponsor’s auditor and inspection by the regulatory authority(ies).
p.000060: ADDENDUM
p.000060:
p.000060: The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential
p.000060: documents including source documents. The storage system used during the trial and for archiving (irrespective of the
p.000060: type of media used) should provide for document identification, version history, search, and retrieval.
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p.000060: 8.2.7
p.000060: SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.:
p.000060: - investigator/institution and sponsor
p.000060: - investigator/institution and CRO
p.000060: - sponsor and CRO
p.000060: - investigator/institution and authority(ies) (where required)
p.000060: DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000060: /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
p.000060: - protocol and any amendments
p.000060: - CRF (if applicable)
p.000060: - informed consent form(s)
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p.000060:
p.000060:
p.000060:
p.000060:
p.000060: 8.2.10
p.000060: REGULATORY AUTHORITY(IES) AUTHORISATION/APPROVAL/ NOTIFICATION OF PROTOCOL
p.000060: (where required)
p.000060:
p.000060: CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)
p.000060: To document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to
p.000060: initiation of the trial in compliance with the applicable regulatory requirement(s)
p.000060: To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects
p.000060: X
p.000060: (where required)
p.000060:
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p.000060:
p.000060:
p.000060: 8.3.5
p.000060: Title of Document
p.000060:
p.000060: REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFICAT IONS WHERE REQUIRED FOR:
p.000060: - protocol amendment(s) and other documents CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB- INVESTIGATOR(S)
p.000060: Purpose
p.000060:
p.000060: To document compliance with applicable regulatory requirements
p.000060:
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p.000060: 8.3.24
p.000060:
p.000060: 8.3.25
p.000060: Title of Document
p.000060:
p.000060: NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF
p.000060: UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
p.000060: NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
p.000060:
p.000060: SUBJECT SCREENING LOG
p.000060:
p.000060:
p.000060: SUBJECT IDENTIFICATION CODE LIST
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...
p.000060: Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of
p.000060: unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in
p.000060: accordance with 5.16.2 and 4.11.2
p.000060:
p.000060: Notification by sponsor to investigators of safety information in accordance with 5.16.2
p.000060: Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3
p.000060: To document identification of subjects who entered pre- trial screening
p.000060:
p.000060: To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers
p.000060: on enrolling in the trial. Allows investigator/institution to reveal identity of any subject To document chronological
p.000060: enrolment of subjects by trial number
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p.000060:
p.000060: AUDIT CERTIFICATE (if available)
p.000060: FINAL TRIAL CLOSE-OUT MONITORING REPORT
p.000060:
p.000060: TREATMENT ALLOCATION AND DECODING DOCUMENTATION
p.000060: FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)
p.000060: CLINICAL STUDY REPORT
p.000060: Purpose
p.000060:
p.000060: To document that the investigational product(s) have been used according to the protocol. To documents the final
p.000060: accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and
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p.000060: informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to
p.000060: continue participation in the trial. The communication of this information should be documented.
p.000060:
p.000060: 4.8.3.
p.000060:
p.000060: Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to
p.000060: continue to participate in a trial.
p.000060:
p.000060: 4.8.4.
p.000060:
p.000060: None of the oral and written information concerning the trial, including the written informed consent form, should
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p.000060: (i.e. in emergency situations).
p.000060:
p.000060: 3.1.8.
p.000060:
p.000060: The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of
p.000060: coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent
p.000060: on completion of the trial by the subject.
p.000060:
p.000060: 3.1.9.
p.000060:
p.000060: The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule
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p.000037:
p.000037: 5.15. Record access
p.000039: 39
p.000040: 5.16. Safety information
p.000040: 39
p.000040: 5.17. Adverse drug reaction reporting 39
p.000040: 5.18. Monitoring
p.000040: 40
p.000041: 5.18.1. Purpose
p.000041: 40
p.000041: 5.18.2. Selection and qualifications of monitors 40
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p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 6/68
p.000060:
p.000060: 1. Glossary
p.000060: 1.1. Adverse Drug Reaction (ADR)
p.000060:
p.000060: In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic
p.000060: dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should
p.000060: be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship
p.000060: between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be
p.000060: ruled out.
p.000060: Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses
p.000060: normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function
p.000060: (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
p.000060:
p.000060: 1.2. Adverse Event (AE)
p.000060:
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p.000060:
p.000060: Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the
p.000060: authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are
p.000060: sometimes referred to as competent authorities.
p.000060:
p.000060: 1.50. Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
p.000060:
p.000060: Any untoward medical occurrence that at any dose:
p.000060:
p.000060: • results in death,
p.000060:
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p.000060:
p.000060: 1.59. Trial site
p.000060:
p.000060: The location(s) where trial-related activities are actually conducted.
p.000060:
p.000060: 1.60. Unexpected adverse drug reaction
p.000060:
p.000060: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000060: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000060: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000060: Expedited Reporting).
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p.000060: Specifying that the investigator should promptly report to the IRB/IEC:
p.000060:
p.000060: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000060: 4.5.2, 4.5.4).
p.000060: b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000060: c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000060:
p.000060: d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000060:
p.000060: 3.3.9.
p.000060:
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p.000060: All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol
p.000060: or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports
p.000060: should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects
p.000060: by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification
p.000060: numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to
p.000060: the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.
p.000060:
p.000060: 4.11.2.
p.000060:
p.000060: Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be
p.000060: reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in
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p.000060:
p.000060: The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of
p.000060: findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's
p.000060: approval/favourable opinion to continue the trial.
p.000060:
p.000060: 5.17. Adverse drug reaction reporting
p.000060:
p.000060: 5.17.1.
p.000060:
p.000060: The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where
p.000060: required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and
p.000060: unexpected.
p.000060:
p.000060:
p.000060:
p.000060:
...
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p.000060:
p.000060: A summary of information should be provided about the investigational product's/products' (including metabolites, where
p.000060: appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans
p.000060: (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number
p.000060: of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by
p.000060: indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for
p.000060: all the clinical trials (including those for all the studied indications) would be useful. Important differences in
p.000060: adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000060: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of
p.000060: prior experiences with the product under investigation and with related products. A description should also be provided
p.000060: of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000060: c) Marketing experience
p.000060:
p.000060:
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p.000060: This section should provide an overall discussion of the nonclinical and clinical data, and should summarise the
p.000060: information from various sources on different aspects of the investigational product(s), wherever possible. In this
p.000060: way, the investigator can be provided with the most informative interpretation of the available data and with an
p.000060: assessment of the implications of the information for future clinical trials.
p.000060: Where appropriate, the published reports on related products should be discussed. This could help the investigator to
p.000060: anticipate adverse drug reactions or other problems in clinical trials.
p.000060: The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and
p.000060: adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial.
p.000060: This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological,
p.000060: and clinical information on the investigational product(s). Guidance should also be provided to the clinical
p.000060: investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous
p.000060: human experience and on the pharmacology of the investigational product.
p.000060:
p.000060:
p.000060:
p.000060:
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p.000060:
p.000060: 8.3.25
p.000060: Title of Document
p.000060:
p.000060: NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF
p.000060: UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
p.000060: NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
p.000060:
p.000060: SUBJECT SCREENING LOG
p.000060:
p.000060:
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p.000060:
p.000060: RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)
p.000060: Purpose
p.000060:
p.000060: Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of
p.000060: unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in
p.000060: accordance with 5.16.2 and 4.11.2
p.000060:
p.000060: Notification by sponsor to investigators of safety information in accordance with 5.16.2
p.000060: Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3
p.000060: To document identification of subjects who entered pre- trial screening
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p.000060: The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a
p.000060: qualified physician or, when appropriate, of a qualified dentist.
p.000060:
p.000060: 2.8.
p.000060:
p.000060: Each individual involved in conducting a trial should be qualified by education, training, and experience to perform
p.000060: his or her respective task(s).
p.000060:
p.000060: 2.9.
p.000060:
p.000060: Freely given informed consent should be obtained from every subject prior to clinical trial participation.
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p.000060: 4. Investigator
p.000060: 4.1. Investigator's Qualifications and Agreements
p.000060:
p.000060: 4.1.1.
p.000060:
p.000060: The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper
p.000060: conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and
p.000060: should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation
p.000060: requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
p.000060:
p.000060: 4.1.2.
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p.000060: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
p.000060: The physical and mental integrity of the subjects participating in a clinical trial.
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p.000060: 3.1.7.
p.000060:
p.000060: Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative
p.000060: is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s)
p.000060: adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials
p.000060: (i.e. in emergency situations).
p.000060:
p.000060: 3.1.8.
p.000060:
p.000060: The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of
p.000060: coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent
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...
p.000060: the investigational product is intended. Subjects in these trials should be particularly closely monitored and should
p.000060: be withdrawn if they appear to be unduly distressed.
p.000060:
p.000060: 4.8.15.
p.000060:
p.000060: In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally
p.000060: acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the
p.000060: subject’s legally acceptable representative is not available, enrolment of the subject should require measures
p.000060: described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the
p.000060: rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The
p.000060: subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and
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p.000060: transport and storage.
p.000060:
p.000060: 5.13.4.
p.000060:
p.000060: In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid
p.000060: identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the
p.000060: blinding.
p.000060:
p.000060: 5.13.5.
p.000060:
p.000060: If significant formulation changes are made in the investigational or comparator product(s) during the course of
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p.000060:
p.000060:
p.000060: PRE-TRIAL MONITORING REPORT
p.000060:
p.000060: TRIAL INITIATION MONITORING REPORT
p.000060: To document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking
p.000060: the blind for the remaining subjects' treatment To document method for randomisation of trial population
p.000060:
p.000060:
p.000060: To document that the site is suitable for the trial (may be combined with 8.2.20)
p.000060: To document that trial procedures were reviewed with the investigator and the investigator’s trial staff ( may be
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p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
p.000060: The physical and mental integrity of the subjects participating in a clinical trial.
p.000060:
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p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 25/68
p.000060:
p.000060: g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or
p.000060: nursing infant.
p.000060: h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000060: made aware of this.
p.000060: i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000060: potential benefits and risks.
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p.000060: including the following, if available:
p.000060: • Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution,
p.000060: and elimination).
p.000060: • Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference
p.000060: dosage form.
p.000060: • Population subgroups (e.g., gender, age, and impaired organ function).
p.000060:
p.000060: • Interactions (e.g., product-product interactions and effects of food).
p.000060:
p.000060: • Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000060:
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p.000060: that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
p.000060: The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the
p.000060: United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these
p.000060: jurisdictions.
p.000060: The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and
p.000060: the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).
p.000060: This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory
p.000060: authorities.
p.000060: The principles established in this guideline may also be applied to other clinical investigations that may have an
p.000060: impact on the safety and well-being of human subjects.
p.000060: ADDENDUM
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p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
p.000060: The physical and mental integrity of the subjects participating in a clinical trial.
p.000060:
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p.000060: 4.3.2.
p.000060:
p.000060: During and following a subject's participation in a trial, the investigator/institution should ensure that
p.000060: adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory
p.000060: values, related to the trial. The investigator/institution should inform a subject when medical care is needed for
p.000060: intercurrent illness(es) of which the investigator becomes aware.
p.000060:
p.000060: 4.3.3.
p.000060:
p.000060: It is recommended that the investigator inform the subject's primary physician about the subject's participation in the
p.000060: trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
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p.000060: including the following, if available:
p.000060: • Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution,
p.000060: and elimination).
p.000060: • Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference
p.000060: dosage form.
p.000060: • Population subgroups (e.g., gender, age, and impaired organ function).
p.000060:
p.000060: • Interactions (e.g., product-product interactions and effects of food).
p.000060:
p.000060: • Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000060:
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p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 25/68
p.000060:
p.000060: g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or
p.000060: nursing infant.
p.000060: h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000060: made aware of this.
p.000060: i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important
p.000060: potential benefits and risks.
p.000060: j) The compensation and/or treatment available to the subject in the event of trial-related injury.
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p.000060: (i.e. in emergency situations).
p.000060:
p.000060: 3.1.8.
p.000060:
p.000060: The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of
p.000060: coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent
p.000060: on completion of the trial by the subject.
p.000060:
p.000060: 3.1.9.
p.000060:
p.000060: The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule
...
...
p.000060: informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to
p.000060: continue participation in the trial. The communication of this information should be documented.
p.000060:
p.000060: 4.8.3.
p.000060:
p.000060: Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to
p.000060: continue to participate in a trial.
p.000060:
p.000060: 4.8.4.
p.000060:
p.000060: None of the oral and written information concerning the trial, including the written informed consent form, should
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p.000060: continue to participate in a trial.
p.000060:
p.000060: 4.8.4.
p.000060:
p.000060: None of the oral and written information concerning the trial, including the written informed consent form, should
p.000060: contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear
p.000060: to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or
p.000060: their agents from liability for negligence.
p.000060:
p.000060: 4.8.5.
p.000060:
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p.000060:
p.000060: pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.
p.000060:
p.000060: 4.8.6.
p.000060:
p.000060: The language used in the oral and written information about the trial, including the written informed consent form,
p.000060: should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable
p.000060: representative and the impartial witness, where applicable.
p.000060:
p.000060: 4.8.7.
p.000060:
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p.000060: Determining the frequency of continuing review, as appropriate.
p.000060:
p.000060: 3.3.5.
p.000060:
p.000060: Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of
p.000060: minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.
p.000060:
p.000060: 3.3.6.
p.000060:
p.000060: Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable
p.000060: opinion of the trial.
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p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
p.000060: The physical and mental integrity of the subjects participating in a clinical trial.
p.000060:
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p.000060: copy of any amendments to the written information provided to subjects.
p.000060:
p.000060: 4.8.12.
p.000060:
p.000060: When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the
p.000060: consent of the subject’s legally acceptable representative (e.g., minors, or patients with
p.000060:
p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 26/68
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p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
p.000060: The physical and mental integrity of the subjects participating in a clinical trial.
p.000060:
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p.000060: The principles established in this guideline may also be applied to other clinical investigations that may have an
p.000060: impact on the safety and well-being of human subjects.
p.000060: ADDENDUM
p.000060:
p.000060: Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased.
p.000060: Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on
p.000060: relevant activities. When the original ICH E6(R1) text was prepared, clinical trials were performed in a largely
p.000060: paper-based process. Advances in use of electronic data recording and reporting facilitate implementation of other
p.000060: approaches. For example, centralized monitoring can now offer a greater advantage, to a broader range of trials than is
p.000060: suggested in the original text. Therefore, this guideline has been amended to encourage implementation of improved and
p.000060: more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to
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p.000060:
p.000060: 1.65. Validation of Computerized Systems
p.000060:
p.000060: A process of establishing and documenting that the specified requirements of a computerized system can be consistently
p.000060: fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation
p.000060: should be based on a risk assessment that takes into consideration
p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 14/68
p.000060:
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p.000060: The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current
p.000060: curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
p.000060:
p.000060: 3.1.4.
p.000060:
p.000060: The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to
p.000060: human subjects, but at least once per year.
p.000060:
p.000060: 3.1.5.
p.000060:
p.000060: The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the
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p.000060:
p.000060: Specifying that the investigator should promptly report to the IRB/IEC:
p.000060:
p.000060: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000060: 4.5.2, 4.5.4).
p.000060: b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000060: c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000060:
p.000060: d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000060:
p.000060: 3.3.9.
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p.000060: requested by the IRB/IEC.
p.000060:
p.000060: 4.10.2.
p.000060:
p.000060: The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable,
p.000060: the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to
p.000060: subjects.
p.000060:
p.000060: 4.11. Safety Reporting
p.000060:
p.000060: 4.11.1.
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p.000060: collection and processing, as well as the collection of information that is essential to decision making.
p.000060: The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the
p.000060: trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are
p.000060: operationally feasible and should avoid unnecessary complexity, procedures, and data collection. Protocols, case report
p.000060: forms, and other operational documents should be clear, concise, and consistent.
p.000060: The quality management system should use a risk-based approach as described below.
p.000060:
p.000060: 5.0.1. Critical process and data identification
p.000060:
p.000060: During protocol development, the sponsor should identify those processes and data that are critical to ensure human
p.000060: subject protection and the reliability of trial results.
p.000060:
p.000060: 5.0.2. Risk identification
p.000060:
p.000060: The sponsor should identify risks to critical trial processes and data. Risks should be considered at both the system
p.000060: level (e.g., standard operating procedures, computerized systems, personnel) and clinical trial level (e.g., trial
p.000060: design, data collection, informed consent process).
p.000060:
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p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
p.000060: Page 30/68
p.000060:
p.000060: 5.0.3. Risk evaluation
p.000060:
p.000060: The sponsor should evaluate the identified risks, against existing risk controls by considering:
p.000060:
p.000060: a) The likelihood of errors occurring.
p.000060:
p.000060: b) The extent to which such errors would be detectable.
p.000060:
p.000060: c) The impact of such errors on human subject protection and reliability of trial results.
p.000060:
p.000060: 5.0.4. Risk control
p.000060:
p.000060: The sponsor should decide which risks to reduce and/or which risks to accept. The approach used to reduce risk to an
p.000060: acceptable level should be proportionate to the significance of the risk. Risk reduction activities may be incorporated
p.000060: in protocol design and implementation, monitoring plans, agreements between parties defining roles and
p.000060: responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes
p.000060: and procedures.
p.000060: Predefined quality tolerance limits should be established, taking into consideration the medical and statistical
p.000060: characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can
p.000060: impact subject safety or reliability of trial results. Detection of deviations from the predefined quality tolerance
p.000060: limits should trigger an evaluation to determine if action is needed.
p.000060:
p.000060: 5.0.5. Risk communication
p.000060:
p.000060: The sponsor should document quality management activities. The sponsor should communicate quality management activities
p.000060: to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during
p.000060: clinical trial execution.
p.000060:
p.000060: 5.0.6. Risk review
p.000060:
p.000060: The sponsor should periodically review risk control measures to ascertain whether the implemented quality management
p.000060: activities remain effective and relevant, taking into account emerging knowledge and experience.
p.000060:
p.000060: 5.0.7. Risk reporting
p.000060:
p.000060: The sponsor should describe the quality management approach implemented in the trial and summarize important deviations
p.000060: from the predefined quality tolerance limits and remedial actions taken in the clinical study report (ICH E3, Section
p.000060: 9.6 Data Quality Assurance).
p.000060:
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p.000060: When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
p.000060: a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established
p.000060: requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
p.000060: ADDENDUM
p.000060:
p.000060: The sponsor should base their approach to validation of such systems on a risk assessment that takes into consideration
p.000060: the intended use of the system and the potential of the system to affect human subject protection and reliability of
p.000060: trial results.
p.000060: b) Maintains SOPs for using these systems.
p.000060:
p.000060: ADDENDUM
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p.000060: determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and
p.000060: extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled
p.000060: sampling may be an acceptable method for selecting the data to be verified.
p.000060: ADDENDUM
p.000060:
p.000060: The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The
p.000060: flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches
p.000060: that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site monitoring, a combination
p.000060: of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the
p.000060: rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
p.000060:
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p.000060: investigators and others involved in the trial with the information to facilitate their understanding of the rationale
p.000060: for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods
p.000060: of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of
p.000060: the study subjects during the course of the clinical trial. The information should be presented in a concise, simple,
p.000060: objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and
p.000060: make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a
p.000060: medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be
p.000060: approved by the disciplines that generated the described data.
p.000060: This guideline delineates the minimum information that should be included in an IB and provides suggestions for its
p.000060: layout. It is expected that the type and extent of information available will vary with the stage of development of the
p.000060: investigational product. If the investigational product is marketed and its pharmacology is widely understood by
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p.000060:
p.000060: • The information provided may include the following, as appropriate, if known/available:
p.000060:
p.000060: • Species tested
p.000060:
p.000060: • Number and sex of animals in each group
p.000060:
p.000060: • Unit dose (e.g., milligram/kilogram (mg/kg))
p.000060:
p.000060: • Dose interval
p.000060:
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p.000060: 3. Institutional Review Board / Independent Ethics Committee (IRB/IEC)
p.000060: 3.1. Responsibilities
p.000060:
p.000060: 3.1.1.
p.000060:
p.000060: An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid
p.000060: to trials that may include vulnerable subjects.
p.000060:
p.000060: 3.1.2.
p.000060:
p.000060: The IRB/IEC should obtain the following documents:
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p.000060: The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of
p.000060: the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000060:
p.000060: 3.2.6.
p.000060:
p.000060: An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000060:
p.000060: 3.3. Procedures
p.000060:
p.000060: The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
p.000060:
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p.000060: a) Nonclinical pharmacology
p.000060:
p.000060: A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant
p.000060: metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential
p.000060: therapeutic activity (e.g. efficacy models, receptor binding, and specificity) as well as those that assess safety
p.000060: (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).
p.000060: b) Pharmacokinetics and product metabolism in animals
p.000060:
p.000060: A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all
p.000060: species studied should be given. The discussion of the findings should address the absorption and the local and
p.000060: systemic bioavailability of the investigational product and its metabolites, and their relationship to the
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p.000060:
p.000060: • Repeated dose
p.000060:
p.000060: • Carcinogenicity
p.000060:
p.000060: • Special studies (e.g. irritancy and sensitisation)
p.000060:
p.000060: • Reproductive toxicity
p.000060:
p.000060: • Genotoxicity (mutagenicity)
p.000060:
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p.000060: indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for
p.000060: all the clinical trials (including those for all the studied indications) would be useful. Important differences in
p.000060: adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000060: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of
p.000060: prior experiences with the product under investigation and with related products. A description should also be provided
p.000060: of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000060: c) Marketing experience
p.000060:
p.000060:
p.000060: Guideline for good clinical practice E6(R2)
p.000060: EMA/CHMP/ICH/135/1995
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p.000060: investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the
p.000060: introductory statement should provide the general approach to be followed in evaluating the investigational product.
p.000060:
p.000060: 7.3.4. Physical, chemical, and pharmaceutical properties and formulation
p.000060:
p.000060: A description should be provided of the investigational product substance(s) (including the chemical and/or structural
p.000060: formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties.
p.000060: To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be
p.000060: used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and
p.000060: handling of the dosage form(s) should also be given.
p.000060: Any structural similarities to other known compounds should be mentioned.
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p.000060: (i.e. in emergency situations).
p.000060:
p.000060: 3.1.8.
p.000060:
p.000060: The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of
p.000060: coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent
p.000060: on completion of the trial by the subject.
p.000060:
p.000060: 3.1.9.
p.000060:
p.000060: The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule
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p.000060: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000060: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000060: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000060: Expedited Reporting).
p.000060:
p.000060: 1.61. Vulnerable subjects
p.000060:
p.000060: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000060: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000060: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as
p.000060: medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the
p.000060: pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include
p.000060: patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000060: situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
p.000060:
p.000060: 1.62. Well-being (of the trial subjects)
p.000060:
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p.000060: 3.1. Responsibilities
p.000060:
p.000060: 3.1.1.
p.000060:
p.000060: An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid
p.000060: to trials that may include vulnerable subjects.
p.000060:
p.000060: 3.1.2.
p.000060:
p.000060: The IRB/IEC should obtain the following documents:
p.000060:
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