0A4F4F9BD490A749D5437F821CF06DF1
Manual for Submission of Modifications, Amendments, Suspensions and Cancellations on DDCM (2018)
http://portal.anvisa.gov.br/documents/33836/2492465/Manual+Para+Submiss%C3%A3o+de+Modifica%C3%A7%C3%B5es%2C+Emendas%2C+Suspens%C3%B5es+e+Cancelamentos+-+4%C2%AA+edi%C3%A7%C3%A3o/85672ffa-db76-4869-b286-ff59bc3fcf60
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| 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
Health / Drug Usage
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p.000002: Carlos Augusto Martins Netto Carolina Pingret Cintra Christiane Santiago Maia Claudio Nishizawa
p.000002: Claudiosvam Martins Alves de Souza Fanny Nascimento Moura Viana Fernando Casseb Flosi
p.000002: Flávia Regina Souza Sobral Gláucia Pacheco Buffon Kellen from Rocio Malaman Leandro Garcia Bueno Silva Leonardo Fabio
p.000002: Costa Filho Miriam Motizuki Onishi Ricardo Eccard da Silva Sônia Costa e Silva
p.000002: Layout and Review
p.000002: Anvisa Publisher
p.000002: Graphic project
p.000002: Anvisa Publisher
p.000002: Catalog Card:
p.000002: Manual for Submitting Modifications, Amendments, Suspensions and Cancellations / Brasília. Anvisa 2018
p.000002: 28 p.
p.000002: Amendments; Modifications; Clinical Trials.
p.000003: 3
p.000003: Manual for Submitting Modifications,
p.000003: Amendments, Suspensions and Cancellations
p.000003: SUMMARY
p.000003: 1. SIGLARY
p.000005: 5
p.000005: 2. INTRODUCTION
p.000005: 5
p.000005: 3. LEGAL BASIS
p.000005: 5
p.000005: 4. OBJECTIVE
p.000005: 5
p.000005: 5. MODIFICATIONS TO THE DDCM
p.000006: 6
p.000006: 6. PROTOCOL AMENDMENTS
p.000010: 10
p.000010: 7. SUSPENSIONS AND CANCELLATIONS
p.000014: 14
p.000014: 8. GLOSSARY
p.000016: 16
p.000016: 9. BIBLIOGRAPHIC REFERENCES
p.000017: 17
p.000017: 10. ANNEXES
p.000018: 18
p.000018: 11. HISTORY OF CHANGES
p.000021: 21
p.000004: 4
p.000004: Manual for Submitting Modifications,
p.000004: Amendments, Suspensions and Cancellations
p.000004: 1. SIGLARY
p.000004: DDCM - IFA Medicines Development Dossier - Active Pharmaceutical Ingredient
p.000004: ORPC - Representative Organization of Clinical Research RDC - Resolution of the Collegiate Board
p.000004: 2. INTRODUCTION
p.000004: The publication of regulations on Clinical Trials with medicines in Brazil provides for modifications,
p.000004: amendments, suspensions and cancellations as part of clinical drug development. This one
p.000004: manual is intended to provide guidance for the sponsor, investigator-sponsor or ORPC to make these
p.000004: submissions properly.
p.000004: This is a non-binding regulatory measure adopted as a complement to legislation
p.000004: health, with the educational purpose of providing guidance on routines and procedures for compliance with
p.000004: legislation, not intended to expand or restrict established technical or administrative requirements.
p.000004: 3. LEGAL BASIS
p.000004: Anvisa Resolution - RDC nº 9, of February 20, 2015, which provides for the regulation for the
p.000004: conducting clinical trials with medicines in Brazil.
p.000004: 4. OBJECTIVE
p.000004: Without prejudice to the existing provisions in the legal provisions, this manual aims to guide submissions
p.000004: of changes to the Clinical Drug Development Dossier (DDCM), amendments to the protocols
p.000004: clinical, suspensions and cancellations, as described in chapters IV, V and VI of RDC nº 09/2015.
p.000004: The document is broken down into specific sections for each type of change. The changes are described in
p.000004: details, with examples and the respective specific petition matters.
p.000004: We emphasize that the situations and examples contained in this manual are illustrative, but in no way restrictive or
p.000004: exhaustive. Each situation must be assessed on a case-by-case basis, and contexts that differ from those described here
p.000004: accompanied by justifications.
p.000005: 5
p.000005: Manual for Submitting Modifications,
p.000005: Amendments, Suspensions and Cancellations
p.000005: 5. MODIFICATIONS TO THE DDCM
p.000005: Modifications to the DDCM, in the context of RDC No. 09/2015, are defined as any changes made to the
p.000005: DDCM global context - especially those related to the quality of the product under investigation - or
p.000005: administrative changes, such as form updates.
p.000005: All changes must be submitted to Anvisa. Substantial changes must be filed when
p.000005: its realization and its implementation must await manifestation, while the non-substantial ones must be
p.000005: presented as part of the security update report for the development of the
p.000005: experimental medicine. Details on the application procedures will be described below.
p.000005: Substantial changes can be filed at any time after the initial submission of the DDCM,
p.000005: even before Anvisa's final manifestation.
p.000005: For the purposes of the Resolution, substantial changes consist of:
p.000005: I - Inclusion of protocol (s) of clinical trial (s) not foreseen or different (s) from that (s) previously
p.000005: established in the initial development plan;
p.000005: II - Exclusion of clinical trial protocol (s);
p.000005: III - Changes that potentially impact the quality or safety of the experimental drug,
p.000005: active comparator or placebo.
p.000005: It is the sponsor's responsibility to assess whether a modification is considered substantial or not and
p.000005: its impact on clinical development. This assessment should always be done on a case-by-case basis, based on the criteria
p.000005: above and in the examples below.
p.000005: The following are examples of substantial modifications related to the quality or safety of the product under investigation.
p.000005: We emphasize that the lists below are illustrative only, not exhausting all possibilities.
p.000005: 1. Substantial changes:
p.000005: The. Changes related to the active pharmaceutical ingredient;
p.000005: B. Changes related to quality control and stability of the active pharmaceutical ingredient and medication
p.000005: experimental;
p.000005: ç. Changes related to excipient quality control;
p.000005: d. Changes in the description and composition of the experimental drug;
p.000006: 6
p.000006: Manual for Submitting Modifications,
p.000006: Amendments, Suspensions and Cancellations
p.000006: and. Changes related to the place of manufacture of the experimental medicine;
p.000006: f. Changes related to the production process of the experimental drug;
p.000006: g. Changes related to the production equipment of the experimental medicine;
p.000006: H. Changes related to the batch size of the experimental drug;
p.000006: i. Changes related to the packaging of the experimental drug;
p.000006: j. Inclusion of new presentation;
p.000006: k. Changes related to the validity period since there has been a change in the evaluation criteria of
p.000006: previously established stability, that the values are not within the permitted ranges or
p.000006: the validity period is defined based on reduced models of stability study plan (grouping
p.000006: and Matrix);
p.000006: l. Inclusion of new concentration;
p.000006: m. Inclusion of a new pharmaceutical form;
p.000006: n. Changes related to dosage;
p.000006: O. Expansion of use;
p.000006: P. Inclusion of a new route of administration;
p.000006: q. Inclusion of a new therapeutic indication;
p.000006: r. Inclusion of placebo not previously provided for in the DDCM.
p.000006: 2. Non-substantial changes:
p.000006: The. Update of the DDCM Petition Form;
p.000006: B. Change in labeling of the product under investigation;
p.000006: ç. Any changes to placebos previously provided for in the DDCM;
p.000006: d. Update on the Development Plan for the Experimental Medication, the change of which does not impact the trials
p.000006: clinics to be conducted in Brazil;
p.000006: and. Spell check in documents;
p.000006: f. Small clarifications;
p.000006: g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of modifications
p.000006: substantial.
p.000006: To modify any information contained in the Form, simply submit a new form with the information
p.000006: updated information and document describing the justifications for each change. Clinical trial amendment
p.000006: does not constitute modification, as explained in the next section. It is recommended that substantial modifications
p.000006: accompanied by a comparative table, if applicable.
p.000007: 7
p.000007: Manual for Submitting Modifications,
p.000007: Amendments, Suspensions and Cancellations
p.000007: The applicant must update the forms whenever there is a change in the data contained therein (and not only at the time
p.000007: submission of annual reports, for example), as these data reflect the advertising of clinical trials on the website
p.000007: of Anvisa and will be used to guide inspections in Good Clinical Practices. Updating this
p.000007: form does not depend on a prior opinion by the Agency.
p.000007: Substantial modifications must constitute a petition secondary to the primary petition for submission of the DDCM for the drug
p.000007: experimental, with the exception of modification by inclusion of a clinical trial protocol not provided for in the initial
p.000007: development, which is a primary petition. The inclusion and exclusion of clinical trials has its own issues, the
p.000007: to know:
p.000007: • 10818 - CLINICAL TRIALS - Modification of DDCM - Inclusion of a clinical trial protocol not provided for in the plan
p.000007: initial development
p.000007: o The inclusion of clinical trial protocols that were already provided for in the initial development plan should
p.000007: be made using a specific subject, according to the Manual for Submission of Dossier of
p.000007: Clinical Drug Development (DDCM) and Specific Clinical Trial Dossier.
p.000007: • 10819 - CLINICAL TRIALS - Modification of DDCM - Exclusion of clinical trial protocol
p.000007: Changes that potentially impact the quality or safety of the experimental drug,
p.000007: active comparator or placebo, as examples above, should use the subject of petition 10820 - CLINICAL TRIALS -
p.000007: DDCM modification
p.000007: - Change that potentially impacts the quality or safety of the product under investigation. Must be presented
p.000007: (comparative) documentation of the initial situation and the proposal accompanied by technical justification and any
p.000007: additional documents required to prove that the change will not impact the clinical development of the
p.000007: product.
p.000007: It is worth mentioning that it is the sponsor's responsibility to evaluate and classify the changes
p.000007: prior submission to the Agency, so that a risk / benefit analysis
p.000007: need for supporting documentation. As a suggestion for greater agility and ease in submitting
p.000007: changes to the analysis, can be completed and submitted together with the other documents, optionally, the
p.000007: Annex I of this manual, available in DOC version on the Anvisa website.
p.000008: 8
p.000008: Manual for Submitting Modifications,
p.000008: Amendments, Suspensions and Cancellations
p.000008: The change in validity period must use the subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
p.000008: Expiry Date. As a suggestion for greater agility and ease in analyzing this type of petition, it can be
p.000008: completed and submitted together with the other documents, optionally, Annex III of this manual,
p.000008: available in DOC version on Anvisa's website. In addition, it is recommended for this petition subject:
p.000008: • Submit justifications for any changes in analytical method that have occurred since the last
p.000008: submission, including a brief summary of its characteristics and status of validation of the new method;
p.000008: • Investigate and justify any deviation from specifications that has been found, even
p.000008: that occurred only under the accelerated study conditions;
p.000008: • Present stability study after dilution or reconstitution, for applicable products;
p.000008: • Present a photo-stability study or justification for its absence;
p.000008: • For files that have been updated since the previous submission, send a version with highlighted changes; and
p.000008: • In cases where there are multiple manufacturing plants for IFA and for finished product, the files
p.000008: sent should easily allow the identification of the manufacturing plants to which they refer.
p.000008: Non-substantial changes do not have a specific petition issue and should be integrated into the
p.000008: petition 10825 - CLINICAL TRIALS - Drug Development Safety Update Report
p.000008: Experimental.
p.000009: 9
p.000009: Manual for Submitting Modifications,
p.000009: Amendments, Suspensions and Cancellations
p.000009: 6. PROTOCOL AMENDMENTS
p.000009: Amendments, in the context of RDC No. 09/2015, are defined as any changes made to the clinical protocol,
p.000009: whether they are substantial or not.
p.000009: All amendments must be submitted to Anvisa. Substantial amendments must be filed when they are made.
p.000009: implementation and its implementation must await manifestation, while non-substantial ones must be
p.000009: presented as part of the annual clinical trial report. Details on procedures for filing
p.000009: will be described below.
p.000009: Substantial amendments can be filed at any time after the inclusion of the first clinical protocol to the
p.000009: DDCM, even before Anvisa's final manifestation.
p.000009: Substantial changes are those where one or more of the following criteria are met:
p.000009: • Change in clinical trial protocol that interferes with safety or physical or mental integrity
p.000009: of individuals;
p.000009: • Change in the scientific value of the clinical trial protocol;
p.000009: Conceptually, a clinical trial has scientific value if:
p.000009: The. Evaluate a therapeutic or diagnostic intervention that can lead to improvements in health or quality of life; or
p.000009: B. It is a preliminary etiological, pathophysiological or epidemiological study to develop such an intervention;
p.000009: or
p.000009: ç. Test a hypothesis that can generate important knowledge about the structure or the
p.000009: functioning of human biological systems, even if that knowledge has no immediate practical ramifications.
p.000009: It is the sponsor's responsibility to assess whether an amendment is considered substantial or not and its impact on the
...
p.000013: definitive, with no possibility of further reactivation.
p.000014: 14
p.000014: Manual for Submitting Modifications,
p.000014: Amendments, Suspensions and Cancellations
p.000014: It is important to remember that cancellation only applies to clinical trial protocols that have already been
p.000014: started by the sponsor. If the protocol is provided for in the DDCM, but has not yet started,
p.000014: the exclusion from the protocol must be made, as provided in the previous section.
p.000014: If the cancellation occurs at the company's request, including cases of cancellation for security reasons, it must be
p.000014: used the subject of petition 10767 - CLINICAL TRIALS - Cancellation of Clinical Trial Protocol on request;
p.000014: if the cancellation is due to a global transfer of responsibility, the subject of the petition is 10053 - TESTS
p.000014: CLINICS - Global Transfer of Responsibility on Clinical Trial Protocol. In the specific case
p.000014: cancellation on request, the requirements that must be submitted for the monitoring plan and
p.000014: for the risk minimization / mitigation measures of clinical trial participants are detailed in the Manual
p.000014: for Adverse Event Notification and Safety Monitoring in Clinical Trials.
p.000014: For suspensions, the subject to be used is 10830 - CLINICAL TRIALS - Temporary suspension of
p.000014: Clinical Trial. By definition, these have a temporary character and can be reversed with the subject of
p.000014: petition 10831 - CLINICAL TRIALS - Reactivation of suspended clinical trial protocol. Reactivation depends on
p.000014: prior approval by Anvisa.
p.000015: 15
p.000015: Manual for Submitting Modifications,
p.000015: Amendments, Suspensions and Cancellations
p.000015: 8. GLOSSARY
p.000015: I - Clinical Drug Development Dossier (DDCM) - compiled from documents to be submitted to the
p.000015: Anvisa in order to evaluate the steps inherent to the development of an experimental drug
p.000015: aiming to obtain information to subsidize the registration or post-registration changes of said product;
p.000015: II - Specific Dossier for each Clinical Trial - compiled from documents to be submitted to Anvisa with the
p.000015: purpose of obtaining information regarding clinical trials, to be conducted in Brazil, which are part of the
p.000015: Experimental Drug Development Plan;
p.000015: III - Amendment to the clinical trial protocol - any proposed modification to a clinical trial protocol
p.000015: original, always presented with the justification that motivated it, and this amendment may be substantial or not;
p.000015: IV - Clinical trial - research conducted in humans with the aim of discovering or confirming the effects
p.000015: clinical and / or pharmacological and / or any other pharmacodynamic effects of the experimental medicine and / or
p.000015: identify any adverse reaction to the experimental drug and / or study absorption,
p.000015: distribution, metabolism and excretion of the experimental drug to verify its safety and / or effectiveness;
p.000015: V - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, with the
p.000015: purpose of obtaining information for your registration or post-registration;
p.000015: VI - Representative Organization for Clinical Research (ORPC) - every company regularly installed
p.000015: in national territory hired by the sponsor or by the sponsoring investigator, who assumes partial or
p.000015: with Anvisa, the sponsor's duties;
p.000015: VII - Placebo - formulation without pharmacological effect, administered to the participant of the clinical trial for the purpose of
p.000015: masking or comparator;
p.000015: VIII - Product under investigation - experimental drug, placebo, active comparator or any other product to be
p.000015: used in the clinical trial;
p.000015: IX - Clinical Trial Protocol - document that describes the objectives, design, methodology,
p.000015: statistical considerations and trial organization. It also provides the context and rationale for the essay
p.000015: clinical;
p.000016: 16
p.000016: Manual for Submitting Modifications,
p.000016: Amendments, Suspensions and Cancellations
p.000016: 9. BIBLIOGRAPHIC REFERENCES
p.000016: 1. BRAZIL. ANVISA. National Health Surveillance Agency. RDC Resolution No. 09, of February 20, 2015, published
p.000016: in the D.O.U. March 3, 2015. Deals with the regulation for conducting clinical trials with drugs in the
p.000016: Brazil. Official Diary of the Union; Executive Branch, of March 3, 2015.
p.000016: 2. EUROPEAN COMMISSION. Communication from the Commission - Detailed guidance on the request to the competent
p.000016: authorities for authorization of a clinical trial on a medicinal product for human use, the notification of
p.000016: substantial amendments and the declaration of the end of the trial (CT-1).
p.000016: Available at: http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf. Accessed in 20
p.000016: November 2014.
p.000016: 3. FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments.
p.000016: Available in:
p.000016: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
p.000016: Approved / ApprovalApplications / InvestigationalNewDrugINDApplication / ucm362503.h tm. Accessed on November 19, 2014.
p.000016: 4. HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Available
p.000016: at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic- demande / guide-ld / clini / ctdcta_ctddec-eng.php. Accessed on 21
p.000016: November 2014.
p.000017: 17
p.000017: Manual for Submitting Modifications,
p.000017: Amendments, Suspensions and Cancellations
p.000017: 10. ANNEXES
p.000017: The attachments to this manual are also available in DOC format at Anvisa's Electronic Portal>
p.000017: Medicines> Clinical Research> Forms.
p.000017: ANNEX I
p.000017: PETITION FORM FOR SUBSTANTIAL MODIFICATION OF THE MEDICAL DRUG CLINICAL DEVELOPMENT DOSSIER (DDCM)
p.000017: Document Identification
p.000017: National Health Surveillance Agency Clinical Research
p.000017: Petition Form for Substantial Modification of the Clinical Drug Development Dossier (DDCM)
p.000017: (For use by the receiving agency)
p.000017: DDCM File Number Expedient (Day / Month
p.000017: / Year)
p.000017: / /
p.000017: Company Data
p.000017: Requestor Number
p.000017: Authorization / Registration
p.000017: 3 4
p.000017: 5 Manufacturer 6
p.000017: Authorization / Registration Number
p.000017: DDCM data
p.000017: Modification Type:
p.000017: a) Inclusion of clinical trial protocol (s) not foreseen or different (s) from that (s) previously
p.000017: established in the initial development plan?
p.000017: b) Exclusion of clinical trial protocol (s)?
p.000017: c) Changes that potentially impact quality or safety
p.000017: 7 of the product under investigation?
p.000017: The. If yes, see item 9.
p.000017: d) Modification resulting from recommendations or alerts issued by health authorities?
p.000017: a) () Yes () No
p.000017: b) () Yes () No
p.000017: c) () Yes () No
p.000017: d) () Yes () No
p.000017: Reasons for Substantial Modification:
p.000017: a) Changes related to the active pharmaceutical ingredient?
p.000017: b) Changes related to the quality control and stability of the
p.000017: 8 active pharmaceutical ingredient and experimental medicine?
p.000017: c) Changes related to excipient quality control?
p.000017: d) Changes in the description and composition of the experimental drug?
p.000017: a) () Yes () No
p.000017: b) () Yes () No
p.000017: c) () Yes () No
p.000017: d) () Yes () No
p.000017: e) () Yes () No
p.000018: 18
p.000018: Manual for Submitting Modifications,
p.000018: Amendments, Suspensions and Cancellations
p.000018: e) Changes related to the place of manufacture of the experimental medicine?
p.000018: f) Changes related to the production process of the experimental drug?
p.000018: g) Changes related to the production equipment of the experimental medicine?
p.000018: h) Changes related to the batch size of the medication? experimental
p.000018: i) Changes related to the packaging of the experimental drug?
p.000018: j) Inclusion of a new presentation?
p.000018: k) Changes related to the period of validity provided there has been a change in the criteria for
p.000018: stability assessment previously established, that the values are not within the ranges
p.000018: permitted or that the validity period is defined based on reduced models of a study plan.
p.000018: stability (grouping and matrix)?
p.000018: l) Inclusion of a new concentration?
p.000018: m) Inclusion of a new pharmaceutical form?
p.000018: n) Changes related to dosage?
p.000018: o) Expansion of use?
p.000018: p) Inclusion of a new route of administration?
p.000018: q) Inclusion of a new therapeutic indication?
p.000018: r) Inclusion of placebo not previously provided for in the DDCM
p.000018: f) () Yes () No
p.000018: g) () Yes () No
p.000018: h) () Yes () No
p.000018: i) () Yes () No
p.000018: j) () Yes () No
p.000018: k) () Yes () No
p.000018: l) () Yes () No
p.000018: m) () Yes () No
p.000018: n) () Yes () No
p.000018: o) () Yes () No
p.000018: p) () Yes () No
p.000018: q) () Yes () No
p.000018: r) () Yes () No
p.000019: 19
p.000019: Manual for Submitting Modifications,
p.000019: Amendments, Suspensions and Cancellations
p.000019: ANNEX II
p.000019: SUBSTANTIAL AMENDMENT PETITION FORM TO CLINICAL TEST PROTOCOL
p.000019: Document Identification
p.000019: National Health Surveillance Agency Clinical Research
p.000019: Petition Form for Substantial Amendment to Clinical Trial Protocol
p.000019: (For use by the receiving agency)
p.000019: File Number of the Dossier Specific to the Clinical Trial File (Day / Month / Year)
p.000019: / /
p.000019: Company Data
p.000019: Requestor Number
p.000019: Authorization / Registration
p.000019: 3 4
p.000019: 5 Manufacturer 6
p.000019: Authorization / Registration Number
p.000019: Clinical Protocol Data
...
p.000036: • Considering the new examples from the list of substantial modifications, the removal of this paragraph was necessary
p.000036: to align the text with the list of examples.
p.000036: • Inclusion is to identify from which date the manual is in force
p.000036: • The change was made to comply with the terms of RDC 09/2015.
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: • Item 5, subitem 1: Substantial Modifications
p.000036: k. Changes related to the validity period since there has been a change in the criteria for
p.000036: stability assessment previously established, that the values are not within the limits of the
p.000036: permitted ranges or that the validity period is defined based on reduced study plan models
p.000036: changes (grouping and matrix) Changes related to the expiration date or
p.000036: care of the product under investigation
p.000036: • Item 5, sub-item 2: Non-substantial changes
p.000036: d. Update on the Development Plan for Experimental Medicines, whose
p.000036: change does not impact the clinical trials to be conducted in Brazil
p.000036: • Item 5, sub-item 2: Non-substantial changes
p.000036: and. Comparator package insert update
p.000036: The remaining items were renumbered from "f" and "g" to "e" and "f".
p.000036: • Item 5, sub-item 2: Non-substantial changes
p.000036: g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of substantial modifications
p.000036: • Item 5 - Modifications to the DDCM
p.000036: Substantial modifications must constitute a secondary petition to the primary petition of
p.000036: submission of the DDCM for the experimental drug, with the exception of modification by inclusion of a
p.000036: clinical trial not provided for in the initial development plan, which is a primary petition.
p.000036: • The text was changed to reduce the situations in which the change in the validity period must
p.000036: considered as a substantial modification.
p.000036: • Phrase included to make it clear that in cases of substantial modification by inclusion
p.000036: protocol not provided for in the plan, an updated development plan must be provided. To the
p.000036: in other cases, the update is considered to be non-substantial.
p.000036: • The example was taken to avoid confusion in understanding, as per question 3.2.8 of
p.000036: Questions and Answers version 2 document.
p.000036: • The inclusion was made to reflect the reduction of cases in which the change in the validity period
p.000036: should be considered as substantial modification.
p.000036: • The inclusion of the sentence was made to indicate that the substantial modification by
p.000036: inclusion of a protocol not provided for in the initial development plan is a primary petition, as it
p.000036: sets up the Specific Clinical Trial Dossier (DEEC), which is a primary petition.
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: • Item 5, subitem 2, Non-substantial amendments c. Change in documentation used by the study team to
p.000036: data capture and recording;
p.000036: Subsequent letters were renumbered from "d" to "l" to "c" to "k".
p.000036: • Annex I, item 8
p.000036: k. Changes related to the validity period since there has been a change in the criteria for
p.000036: stability assessment previously established, that the values are not within the limits of the
p.000036: permitted ranges or that the validity period is defined based on reduced study plan models
p.000036: changes (grouping and matrix) Changes related to the expiration date or
p.000036: care of the product under investigation
p.000036: • Annex I, item 8:
p.000036: • r.Exclusion of drug manufacturing site or primary packaging site or secondary packaging site or
p.000036: product manufacturing site?
p.000036: • Annex I, item 8:
p.000036: • t.Other changes?
p.000036: o If yes, specify:
p.000036: • Annex II, item 12: exclusion of the item
p.000036: The subsequent item was renumbered "13" to "12".
p.000036: • Annex II, item 13:
p.000036: f) Other changes?
p.000036: o If yes, specify:
p.000036: • The example was taken to avoid confusion in understanding, as per question 3.2.12 of
p.000036: Questions and Answers version 2 document.
p.000036: • Change made to reflect changes to the manual
p.000036: • Exclusion of the item to reflect the criteria established in the manual
p.000036: • Exclusion of the item to reflect the criteria established in the manual as a substantial modification
p.000036: • Exclusion of the item, as the criteria established to be considered a substantial amendment is already in
p.000036: subsequent question.
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000015: distribution, metabolism and excretion of the experimental drug to verify its safety and / or effectiveness;
p.000015: V - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, with the
p.000015: purpose of obtaining information for your registration or post-registration;
p.000015: VI - Representative Organization for Clinical Research (ORPC) - every company regularly installed
p.000015: in national territory hired by the sponsor or by the sponsoring investigator, who assumes partial or
p.000015: with Anvisa, the sponsor's duties;
p.000015: VII - Placebo - formulation without pharmacological effect, administered to the participant of the clinical trial for the purpose of
p.000015: masking or comparator;
p.000015: VIII - Product under investigation - experimental drug, placebo, active comparator or any other product to be
p.000015: used in the clinical trial;
p.000015: IX - Clinical Trial Protocol - document that describes the objectives, design, methodology,
p.000015: statistical considerations and trial organization. It also provides the context and rationale for the essay
p.000015: clinical;
p.000016: 16
p.000016: Manual for Submitting Modifications,
p.000016: Amendments, Suspensions and Cancellations
p.000016: 9. BIBLIOGRAPHIC REFERENCES
p.000016: 1. BRAZIL. ANVISA. National Health Surveillance Agency. RDC Resolution No. 09, of February 20, 2015, published
p.000016: in the D.O.U. March 3, 2015. Deals with the regulation for conducting clinical trials with drugs in the
p.000016: Brazil. Official Diary of the Union; Executive Branch, of March 3, 2015.
p.000016: 2. EUROPEAN COMMISSION. Communication from the Commission - Detailed guidance on the request to the competent
p.000016: authorities for authorization of a clinical trial on a medicinal product for human use, the notification of
p.000016: substantial amendments and the declaration of the end of the trial (CT-1).
p.000016: Available at: http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf. Accessed in 20
p.000016: November 2014.
p.000016: 3. FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments.
p.000016: Available in:
p.000016: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
p.000016: Approved / ApprovalApplications / InvestigationalNewDrugINDApplication / ucm362503.h tm. Accessed on November 19, 2014.
p.000016: 4. HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Available
p.000016: at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic- demande / guide-ld / clini / ctdcta_ctddec-eng.php. Accessed on 21
p.000016: November 2014.
p.000017: 17
p.000017: Manual for Submitting Modifications,
p.000017: Amendments, Suspensions and Cancellations
p.000017: 10. ANNEXES
p.000017: The attachments to this manual are also available in DOC format at Anvisa's Electronic Portal>
p.000017: Medicines> Clinical Research> Forms.
p.000017: ANNEX I
p.000017: PETITION FORM FOR SUBSTANTIAL MODIFICATION OF THE MEDICAL DRUG CLINICAL DEVELOPMENT DOSSIER (DDCM)
p.000017: Document Identification
p.000017: National Health Surveillance Agency Clinical Research
p.000017: Petition Form for Substantial Modification of the Clinical Drug Development Dossier (DDCM)
p.000017: (For use by the receiving agency)
...
Social / education
Searching for indicator educational:
(return to top)
p.000002: Layout and Review
p.000002: Anvisa Publisher
p.000002: Graphic project
p.000002: Anvisa Publisher
p.000002: Catalog Card:
p.000002: Manual for Submitting Modifications, Amendments, Suspensions and Cancellations / Brasília. Anvisa 2018
p.000002: 28 p.
p.000002: Amendments; Modifications; Clinical Trials.
p.000003: 3
p.000003: Manual for Submitting Modifications,
p.000003: Amendments, Suspensions and Cancellations
p.000003: SUMMARY
p.000003: 1. SIGLARY
p.000005: 5
p.000005: 2. INTRODUCTION
p.000005: 5
p.000005: 3. LEGAL BASIS
p.000005: 5
p.000005: 4. OBJECTIVE
p.000005: 5
p.000005: 5. MODIFICATIONS TO THE DDCM
p.000006: 6
p.000006: 6. PROTOCOL AMENDMENTS
p.000010: 10
p.000010: 7. SUSPENSIONS AND CANCELLATIONS
p.000014: 14
p.000014: 8. GLOSSARY
p.000016: 16
p.000016: 9. BIBLIOGRAPHIC REFERENCES
p.000017: 17
p.000017: 10. ANNEXES
p.000018: 18
p.000018: 11. HISTORY OF CHANGES
p.000021: 21
p.000004: 4
p.000004: Manual for Submitting Modifications,
p.000004: Amendments, Suspensions and Cancellations
p.000004: 1. SIGLARY
p.000004: DDCM - IFA Medicines Development Dossier - Active Pharmaceutical Ingredient
p.000004: ORPC - Representative Organization of Clinical Research RDC - Resolution of the Collegiate Board
p.000004: 2. INTRODUCTION
p.000004: The publication of regulations on Clinical Trials with medicines in Brazil provides for modifications,
p.000004: amendments, suspensions and cancellations as part of clinical drug development. This one
p.000004: manual is intended to provide guidance for the sponsor, investigator-sponsor or ORPC to make these
p.000004: submissions properly.
p.000004: This is a non-binding regulatory measure adopted as a complement to legislation
p.000004: health, with the educational purpose of providing guidance on routines and procedures for compliance with
p.000004: legislation, not intended to expand or restrict established technical or administrative requirements.
p.000004: 3. LEGAL BASIS
p.000004: Anvisa Resolution - RDC nº 9, of February 20, 2015, which provides for the regulation for the
p.000004: conducting clinical trials with medicines in Brazil.
p.000004: 4. OBJECTIVE
p.000004: Without prejudice to the existing provisions in the legal provisions, this manual aims to guide submissions
p.000004: of changes to the Clinical Drug Development Dossier (DDCM), amendments to the protocols
p.000004: clinical, suspensions and cancellations, as described in chapters IV, V and VI of RDC nº 09/2015.
p.000004: The document is broken down into specific sections for each type of change. The changes are described in
p.000004: details, with examples and the respective specific petition matters.
p.000004: We emphasize that the situations and examples contained in this manual are illustrative, but in no way restrictive or
p.000004: exhaustive. Each situation must be assessed on a case-by-case basis, and contexts that differ from those described here
p.000004: accompanied by justifications.
p.000005: 5
p.000005: Manual for Submitting Modifications,
p.000005: Amendments, Suspensions and Cancellations
p.000005: 5. MODIFICATIONS TO THE DDCM
p.000005: Modifications to the DDCM, in the context of RDC No. 09/2015, are defined as any changes made to the
p.000005: DDCM global context - especially those related to the quality of the product under investigation - or
p.000005: administrative changes, such as form updates.
p.000005: All changes must be submitted to Anvisa. Substantial changes must be filed when
p.000005: its realization and its implementation must await manifestation, while the non-substantial ones must be
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000006: n. Changes related to dosage;
p.000006: O. Expansion of use;
p.000006: P. Inclusion of a new route of administration;
p.000006: q. Inclusion of a new therapeutic indication;
p.000006: r. Inclusion of placebo not previously provided for in the DDCM.
p.000006: 2. Non-substantial changes:
p.000006: The. Update of the DDCM Petition Form;
p.000006: B. Change in labeling of the product under investigation;
p.000006: ç. Any changes to placebos previously provided for in the DDCM;
p.000006: d. Update on the Development Plan for the Experimental Medication, the change of which does not impact the trials
p.000006: clinics to be conducted in Brazil;
p.000006: and. Spell check in documents;
p.000006: f. Small clarifications;
p.000006: g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of modifications
p.000006: substantial.
p.000006: To modify any information contained in the Form, simply submit a new form with the information
p.000006: updated information and document describing the justifications for each change. Clinical trial amendment
p.000006: does not constitute modification, as explained in the next section. It is recommended that substantial modifications
p.000006: accompanied by a comparative table, if applicable.
p.000007: 7
p.000007: Manual for Submitting Modifications,
p.000007: Amendments, Suspensions and Cancellations
p.000007: The applicant must update the forms whenever there is a change in the data contained therein (and not only at the time
p.000007: submission of annual reports, for example), as these data reflect the advertising of clinical trials on the website
p.000007: of Anvisa and will be used to guide inspections in Good Clinical Practices. Updating this
p.000007: form does not depend on a prior opinion by the Agency.
p.000007: Substantial modifications must constitute a petition secondary to the primary petition for submission of the DDCM for the drug
p.000007: experimental, with the exception of modification by inclusion of a clinical trial protocol not provided for in the initial
p.000007: development, which is a primary petition. The inclusion and exclusion of clinical trials has its own issues, the
p.000007: to know:
p.000007: • 10818 - CLINICAL TRIALS - Modification of DDCM - Inclusion of a clinical trial protocol not provided for in the plan
p.000007: initial development
p.000007: o The inclusion of clinical trial protocols that were already provided for in the initial development plan should
p.000007: be made using a specific subject, according to the Manual for Submission of Dossier of
p.000007: Clinical Drug Development (DDCM) and Specific Clinical Trial Dossier.
p.000007: • 10819 - CLINICAL TRIALS - Modification of DDCM - Exclusion of clinical trial protocol
p.000007: Changes that potentially impact the quality or safety of the experimental drug,
p.000007: active comparator or placebo, as examples above, should use the subject of petition 10820 - CLINICAL TRIALS -
p.000007: DDCM modification
p.000007: - Change that potentially impacts the quality or safety of the product under investigation. Must be presented
p.000007: (comparative) documentation of the initial situation and the proposal accompanied by technical justification and any
p.000007: additional documents required to prove that the change will not impact the clinical development of the
p.000007: product.
p.000007: It is worth mentioning that it is the sponsor's responsibility to evaluate and classify the changes
...
p.000010: 1. Substantial Amendments:
p.000010: The. Changing the primary objective of the clinical protocol;
p.000010: B. Change in primary outcomes;
p.000010: ç. Use of a new parameter to measure the primary outcome;
p.000010: d. Removal of the Independent Data Monitoring Committee initially planned for the study;
p.000010: and. Change in the calculation of the sample size planned for the study.
p.000010: 2. Non-substantial amendments:
p.000010: The. Alteration, addition or removal of exploratory outcomes;
p.000010: B. Proposal to extend or continue the research with the same recruited participants,
p.000010: without changing the design, methods and objectives of the original project. If any of these
p.000010: modifications, another research protocol must be submitted, not an amendment;
p.000010: ç. Addition of preventive security monitoring, unrelated to any security announcements issued.
p.000010: d. New data or interpretation of pharmacological or toxicological data;
p.000010: and. Change in the criteria established for the termination of the protocol, even though it has already ended;
p.000010: f. Change in the inclusion and exclusion criteria;
p.000010: g. Reduction in the number of scheduled visits;
p.000010: H. Change in diagnostic procedures or medical monitoring;
p.000010: i. Change in secondary or exploratory outcomes
p.000010: j. Small clarifications to the protocol;
p.000010: k. Spell check.
p.000010: The applicant must update the Clinical Trial Submission Form whenever there is a change in the data there
p.000010: contained (and not only at the time of submission of annual reports, for example), as these data reflect the
p.000010: advertising of clinical trials on Anvisa's website and will be used to guide inspections in Good
p.000010: Clinical Practices. The updating of this form does not depend on a prior opinion by the Agency, except when there are:
p.000010: • Change in the title or code of the clinical trial protocol;
p.000010: • Inclusion or exclusion of products under investigation to be imported
p.000010: • Change in storage conditions and shelf life of the products under investigation.
p.000011: 11
p.000011: Manual for Submitting Modifications,
p.000011: Amendments, Suspensions and Cancellations
p.000011: For these cases, a new version of the CE will be issued.
p.000011: 3. Examples that do not constitute amendments to the protocol:
p.000011: The. Researcher's Brochure Update. This must be requested as 10821
p.000011: - CLINICAL TRIALS - Update of the Researcher's Brochure, unless it also substantiates changes in the
p.000011: clinical protocol. In this case, the change must be evaluated by the Sponsor and classified as substantial
p.000011: or not, and the respective procedures must be followed.
p.000011: B. Changes to the DDCM submission form or attached documents. These must be requested as 10822 -
p.000011: CLINICAL TRIALS - Alteration of the DDCM Petition Form.
p.000011: ç. Changes to the clinical protocol submission form. These must be requested as 10823 -
p.000011: CLINICAL TRIALS - Change of Clinical Trial Presentation Form.
p.000011: 1. The applicant must update the Clinical Trial Presentation Form whenever there is a change in the
p.000011: data contained therein, as these data reflect the advertising of clinical trials on Anvisa's website and
p.000011: will be used to guide inspections in Good Clinical Practice. Updating this form will not
p.000011: depends on prior approval by the Agency, except when:
p.000011: i. Change in the title or code of the clinical trial protocol;
p.000011: ii. Inclusion or exclusion of products under investigation to be imported;
p.000011: iii. Change in storage conditions and shelf life of the products under investigation.
...
p.000036: of updates made.
p.000036: • Exclusion of example "a", once
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: o 2. Non-substantial changes.
p.000036: ▪ a. Update of the DDCM Petition Form. (Page 4)
p.000036: • Modifications to DDCM
p.000036: o 2. Non-substantial changes.
p.000036: ▪ b. Update of the Experimental Medication Development Plan. (Page 4)
p.000036: • Modifications to DDCM
p.000036: o 2. Non-substantial changes.
p.000036: ▪ c. Update of the comparator medicine package insert. (Page 4)
p.000036: • Modifications to DDCM
p.000036: that the form update is a secondary petition with its own subject, and should not be integrated into the report
p.000036: annual situation of non-substantial change.
p.000036: • Inclusion of the "Update on the Development Plan for Experimental Medicines" as an example of modification
p.000036: non-substantial. Updating the plan is only required when petitioning for substantial changes, but
p.000036: it must be possible to update it at the sponsor's discretion.
p.000036: • Exclusion, for clarity, of example "c" after receipt of contribution, considering that the update of
p.000036: comparator medication leaflet is not an item covered by RDC No. 09/2015.
p.000036: • In line with the first amendment, the section that
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 2nd Edition
p.000036: o The applicant must update the forms whenever there is a change in the data contained therein (and not only in the
p.000036: when submitting annual reports, for example), as these data reflect
p.000036: advertising of clinical trials on Anvisa's website and will be used to guide inspections in Good
p.000036: Clinical Practices. The updating of this form does not depend on a prior opinion by the Agency. (Page 5)
p.000036: • Amendments to the Protocol
p.000036: o 2. Non-substantial amendments.
p.000036: ▪ c. Change in the documentation used by the study team to capture and record the data. (Page 9)
p.000036: mentioned the possibility of sending an updated form in the case of non-substantial modification, since the
p.000036: Form update is a secondary petition with its own subject.
p.000036: • Exclusion of example "c" after receiving contributions reporting that the type of change highlighted is not included in the
p.000036: clinical protocol. For all purposes, any changes to the documentation or media used during the protocol may
p.000036: checked at the time of a BPC inspection.
p.000036: 2nd Edition
p.000036: • Amendments to the Protocol
p.000036: o 2. Non-substantial amendments.
p.000036: ▪ g. Update of Clinical Trial Presentation Form. (Page 9)
p.000036: • Exclusion of example "g", since updating the form is a secondary petition with its own subject,
p.000036: and should not be included in the annual report in the case of a non-substantial amendment.
p.000036: 2nd Edition
p.000036: • Amendments to the Protocol
p.000036: o The applicant must update the Clinical Trial Presentation Form whenever
p.000036: • Excluded the section that mentioned the possibility of sending an updated form in the situation of modification
p.000036: not-
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: change in the data contained therein (and not only when submitting the annual reports, for example), as these
p.000036: data reflect the advertising of clinical trials on Anvisa's website and will be used to guide
p.000036: inspections in Good Clinical Practice. Updating this form does not depend on a prior opinion by the Agency,
p.000036: substantial, as the form update is a secondary petition with its own subject. The paragraph in its
p.000036: integrity has been moved to constitute subitem of example "c" of item "3. Examples that do not constitute amendments to
p.000036: protocol "for better fit and clarity.
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: except when there are:
p.000036: The. Change in the title or code of the clinical trial protocol;
p.000036: B. Inclusion or exclusion of products under investigation to be imported
p.000036: ç. Change in storage conditions and shelf life of the products under investigation.
p.000036: For these cases, a new version of the CE will be issued. (Page 10)
p.000036: • Changed the name of the petition subject to: 10827 - CLINICAL TRIALS - Global Transfer of Responsibility
p.000036: about DDCM (page 14).
p.000036: • Changed the name of the petition subject to: 10053 - CLINICAL TRIALS - Global Transfer of Responsibility
p.000036: Clinical Trial Protocol (page 15).
p.000036: • Title of item 1 of the Form contained in annexes I and II
p.000036: • Exclusion of item 7 of the Form contained in annexes I and II
p.000036: • Changing the name of the petition subject.
p.000036: • Changing the name of the petition subject.
p.000036: • As the request for the process number is already made in the header, field 7 has been removed to avoid
p.000036: redundancies and the title of the
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 2nd Edition
p.000036: 3rd Edition
p.000036: 3rd Edition
p.000036: • Added Annex III, "Template for sending updated stability information"
p.000036: • Modifications to the DDCM:
p.000036: o "Changing the expiration date must use subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000004: details, with examples and the respective specific petition matters.
p.000004: We emphasize that the situations and examples contained in this manual are illustrative, but in no way restrictive or
p.000004: exhaustive. Each situation must be assessed on a case-by-case basis, and contexts that differ from those described here
p.000004: accompanied by justifications.
p.000005: 5
p.000005: Manual for Submitting Modifications,
p.000005: Amendments, Suspensions and Cancellations
p.000005: 5. MODIFICATIONS TO THE DDCM
p.000005: Modifications to the DDCM, in the context of RDC No. 09/2015, are defined as any changes made to the
p.000005: DDCM global context - especially those related to the quality of the product under investigation - or
p.000005: administrative changes, such as form updates.
p.000005: All changes must be submitted to Anvisa. Substantial changes must be filed when
p.000005: its realization and its implementation must await manifestation, while the non-substantial ones must be
p.000005: presented as part of the security update report for the development of the
p.000005: experimental medicine. Details on the application procedures will be described below.
p.000005: Substantial changes can be filed at any time after the initial submission of the DDCM,
p.000005: even before Anvisa's final manifestation.
p.000005: For the purposes of the Resolution, substantial changes consist of:
p.000005: I - Inclusion of protocol (s) of clinical trial (s) not foreseen or different (s) from that (s) previously
p.000005: established in the initial development plan;
p.000005: II - Exclusion of clinical trial protocol (s);
p.000005: III - Changes that potentially impact the quality or safety of the experimental drug,
p.000005: active comparator or placebo.
p.000005: It is the sponsor's responsibility to assess whether a modification is considered substantial or not and
p.000005: its impact on clinical development. This assessment should always be done on a case-by-case basis, based on the criteria
p.000005: above and in the examples below.
p.000005: The following are examples of substantial modifications related to the quality or safety of the product under investigation.
p.000005: We emphasize that the lists below are illustrative only, not exhausting all possibilities.
p.000005: 1. Substantial changes:
p.000005: The. Changes related to the active pharmaceutical ingredient;
p.000005: B. Changes related to quality control and stability of the active pharmaceutical ingredient and medication
p.000005: experimental;
p.000005: ç. Changes related to excipient quality control;
p.000005: d. Changes in the description and composition of the experimental drug;
p.000006: 6
p.000006: Manual for Submitting Modifications,
p.000006: Amendments, Suspensions and Cancellations
p.000006: and. Changes related to the place of manufacture of the experimental medicine;
p.000006: f. Changes related to the production process of the experimental drug;
p.000006: g. Changes related to the production equipment of the experimental medicine;
p.000006: H. Changes related to the batch size of the experimental drug;
p.000006: i. Changes related to the packaging of the experimental drug;
p.000006: j. Inclusion of new presentation;
p.000006: k. Changes related to the validity period since there has been a change in the evaluation criteria of
p.000006: previously established stability, that the values are not within the permitted ranges or
p.000006: the validity period is defined based on reduced models of stability study plan (grouping
p.000006: and Matrix);
p.000006: l. Inclusion of new concentration;
p.000006: m. Inclusion of a new pharmaceutical form;
p.000006: n. Changes related to dosage;
p.000006: O. Expansion of use;
p.000006: P. Inclusion of a new route of administration;
p.000006: q. Inclusion of a new therapeutic indication;
p.000006: r. Inclusion of placebo not previously provided for in the DDCM.
p.000006: 2. Non-substantial changes:
p.000006: The. Update of the DDCM Petition Form;
p.000006: B. Change in labeling of the product under investigation;
p.000006: ç. Any changes to placebos previously provided for in the DDCM;
p.000006: d. Update on the Development Plan for the Experimental Medication, the change of which does not impact the trials
p.000006: clinics to be conducted in Brazil;
p.000006: and. Spell check in documents;
p.000006: f. Small clarifications;
p.000006: g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of modifications
p.000006: substantial.
p.000006: To modify any information contained in the Form, simply submit a new form with the information
p.000006: updated information and document describing the justifications for each change. Clinical trial amendment
p.000006: does not constitute modification, as explained in the next section. It is recommended that substantial modifications
p.000006: accompanied by a comparative table, if applicable.
p.000007: 7
p.000007: Manual for Submitting Modifications,
p.000007: Amendments, Suspensions and Cancellations
p.000007: The applicant must update the forms whenever there is a change in the data contained therein (and not only at the time
p.000007: submission of annual reports, for example), as these data reflect the advertising of clinical trials on the website
p.000007: of Anvisa and will be used to guide inspections in Good Clinical Practices. Updating this
p.000007: form does not depend on a prior opinion by the Agency.
p.000007: Substantial modifications must constitute a petition secondary to the primary petition for submission of the DDCM for the drug
p.000007: experimental, with the exception of modification by inclusion of a clinical trial protocol not provided for in the initial
p.000007: development, which is a primary petition. The inclusion and exclusion of clinical trials has its own issues, the
p.000007: to know:
p.000007: • 10818 - CLINICAL TRIALS - Modification of DDCM - Inclusion of a clinical trial protocol not provided for in the plan
p.000007: initial development
p.000007: o The inclusion of clinical trial protocols that were already provided for in the initial development plan should
p.000007: be made using a specific subject, according to the Manual for Submission of Dossier of
p.000007: Clinical Drug Development (DDCM) and Specific Clinical Trial Dossier.
p.000007: • 10819 - CLINICAL TRIALS - Modification of DDCM - Exclusion of clinical trial protocol
p.000007: Changes that potentially impact the quality or safety of the experimental drug,
p.000007: active comparator or placebo, as examples above, should use the subject of petition 10820 - CLINICAL TRIALS -
p.000007: DDCM modification
p.000007: - Change that potentially impacts the quality or safety of the product under investigation. Must be presented
p.000007: (comparative) documentation of the initial situation and the proposal accompanied by technical justification and any
p.000007: additional documents required to prove that the change will not impact the clinical development of the
p.000007: product.
p.000007: It is worth mentioning that it is the sponsor's responsibility to evaluate and classify the changes
p.000007: prior submission to the Agency, so that a risk / benefit analysis
p.000007: need for supporting documentation. As a suggestion for greater agility and ease in submitting
p.000007: changes to the analysis, can be completed and submitted together with the other documents, optionally, the
p.000007: Annex I of this manual, available in DOC version on the Anvisa website.
p.000008: 8
p.000008: Manual for Submitting Modifications,
p.000008: Amendments, Suspensions and Cancellations
p.000008: The change in validity period must use the subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
p.000008: Expiry Date. As a suggestion for greater agility and ease in analyzing this type of petition, it can be
p.000008: completed and submitted together with the other documents, optionally, Annex III of this manual,
p.000008: available in DOC version on Anvisa's website. In addition, it is recommended for this petition subject:
p.000008: • Submit justifications for any changes in analytical method that have occurred since the last
p.000008: submission, including a brief summary of its characteristics and status of validation of the new method;
p.000008: • Investigate and justify any deviation from specifications that has been found, even
...
p.000015: aiming to obtain information to subsidize the registration or post-registration changes of said product;
p.000015: II - Specific Dossier for each Clinical Trial - compiled from documents to be submitted to Anvisa with the
p.000015: purpose of obtaining information regarding clinical trials, to be conducted in Brazil, which are part of the
p.000015: Experimental Drug Development Plan;
p.000015: III - Amendment to the clinical trial protocol - any proposed modification to a clinical trial protocol
p.000015: original, always presented with the justification that motivated it, and this amendment may be substantial or not;
p.000015: IV - Clinical trial - research conducted in humans with the aim of discovering or confirming the effects
p.000015: clinical and / or pharmacological and / or any other pharmacodynamic effects of the experimental medicine and / or
p.000015: identify any adverse reaction to the experimental drug and / or study absorption,
p.000015: distribution, metabolism and excretion of the experimental drug to verify its safety and / or effectiveness;
p.000015: V - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, with the
p.000015: purpose of obtaining information for your registration or post-registration;
p.000015: VI - Representative Organization for Clinical Research (ORPC) - every company regularly installed
p.000015: in national territory hired by the sponsor or by the sponsoring investigator, who assumes partial or
p.000015: with Anvisa, the sponsor's duties;
p.000015: VII - Placebo - formulation without pharmacological effect, administered to the participant of the clinical trial for the purpose of
p.000015: masking or comparator;
p.000015: VIII - Product under investigation - experimental drug, placebo, active comparator or any other product to be
p.000015: used in the clinical trial;
p.000015: IX - Clinical Trial Protocol - document that describes the objectives, design, methodology,
p.000015: statistical considerations and trial organization. It also provides the context and rationale for the essay
p.000015: clinical;
p.000016: 16
p.000016: Manual for Submitting Modifications,
p.000016: Amendments, Suspensions and Cancellations
p.000016: 9. BIBLIOGRAPHIC REFERENCES
p.000016: 1. BRAZIL. ANVISA. National Health Surveillance Agency. RDC Resolution No. 09, of February 20, 2015, published
p.000016: in the D.O.U. March 3, 2015. Deals with the regulation for conducting clinical trials with drugs in the
p.000016: Brazil. Official Diary of the Union; Executive Branch, of March 3, 2015.
p.000016: 2. EUROPEAN COMMISSION. Communication from the Commission - Detailed guidance on the request to the competent
p.000016: authorities for authorization of a clinical trial on a medicinal product for human use, the notification of
p.000016: substantial amendments and the declaration of the end of the trial (CT-1).
p.000016: Available at: http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf. Accessed in 20
p.000016: November 2014.
p.000016: 3. FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments.
p.000016: Available in:
p.000016: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
p.000016: Approved / ApprovalApplications / InvestigationalNewDrugINDApplication / ucm362503.h tm. Accessed on November 19, 2014.
p.000016: 4. HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Available
...
p.000017: a) Changes related to the active pharmaceutical ingredient?
p.000017: b) Changes related to the quality control and stability of the
p.000017: 8 active pharmaceutical ingredient and experimental medicine?
p.000017: c) Changes related to excipient quality control?
p.000017: d) Changes in the description and composition of the experimental drug?
p.000017: a) () Yes () No
p.000017: b) () Yes () No
p.000017: c) () Yes () No
p.000017: d) () Yes () No
p.000017: e) () Yes () No
p.000018: 18
p.000018: Manual for Submitting Modifications,
p.000018: Amendments, Suspensions and Cancellations
p.000018: e) Changes related to the place of manufacture of the experimental medicine?
p.000018: f) Changes related to the production process of the experimental drug?
p.000018: g) Changes related to the production equipment of the experimental medicine?
p.000018: h) Changes related to the batch size of the medication? experimental
p.000018: i) Changes related to the packaging of the experimental drug?
p.000018: j) Inclusion of a new presentation?
p.000018: k) Changes related to the period of validity provided there has been a change in the criteria for
p.000018: stability assessment previously established, that the values are not within the ranges
p.000018: permitted or that the validity period is defined based on reduced models of a study plan.
p.000018: stability (grouping and matrix)?
p.000018: l) Inclusion of a new concentration?
p.000018: m) Inclusion of a new pharmaceutical form?
p.000018: n) Changes related to dosage?
p.000018: o) Expansion of use?
p.000018: p) Inclusion of a new route of administration?
p.000018: q) Inclusion of a new therapeutic indication?
p.000018: r) Inclusion of placebo not previously provided for in the DDCM
p.000018: f) () Yes () No
p.000018: g) () Yes () No
p.000018: h) () Yes () No
p.000018: i) () Yes () No
p.000018: j) () Yes () No
p.000018: k) () Yes () No
p.000018: l) () Yes () No
p.000018: m) () Yes () No
p.000018: n) () Yes () No
p.000018: o) () Yes () No
p.000018: p) () Yes () No
p.000018: q) () Yes () No
p.000018: r) () Yes () No
p.000019: 19
p.000019: Manual for Submitting Modifications,
p.000019: Amendments, Suspensions and Cancellations
p.000019: ANNEX II
p.000019: SUBSTANTIAL AMENDMENT PETITION FORM TO CLINICAL TEST PROTOCOL
p.000019: Document Identification
p.000019: National Health Surveillance Agency Clinical Research
p.000019: Petition Form for Substantial Amendment to Clinical Trial Protocol
p.000019: (For use by the receiving agency)
p.000019: File Number of the Dossier Specific to the Clinical Trial File (Day / Month / Year)
p.000019: / /
p.000019: Company Data
p.000019: Requestor Number
p.000019: Authorization / Registration
p.000019: 3 4
p.000019: 5 Manufacturer 6
p.000019: Authorization / Registration Number
p.000019: Clinical Protocol Data
p.000019: 7 Petition Subject (codes and description) 8 Generating Fact (datavisa)
p.000019: 9 Title and Code of the Clinical Trial Protocol 10 Protocol No. (Version and
p.000019: date)
p.000019: Reasons for Substantial Amendment:
p.000019: 11 Trial Phase
p.000019: I () II () III () IV ()
p.000019: a) Changing the primary objective of the clinical protocol;
p.000019: b) Change in primary outcomes;
p.000019: c) Use of a new parameter to measure the primary outcome;
p.000019: 12 d) Removal of the Independent Data Monitoring Committee
p.000019: initially planned for the study;
p.000019: e) Change in the calculation of the sample size planned for the study
p.000019: a) () Yes () No
p.000019: b) () Yes () No
p.000019: c) () Yes () No
p.000019: d) () Yes () No
p.000019: e) () Yes () No
...
p.000036: 2nd Edition
p.000036: 2nd Edition
p.000036: except when there are:
p.000036: The. Change in the title or code of the clinical trial protocol;
p.000036: B. Inclusion or exclusion of products under investigation to be imported
p.000036: ç. Change in storage conditions and shelf life of the products under investigation.
p.000036: For these cases, a new version of the CE will be issued. (Page 10)
p.000036: • Changed the name of the petition subject to: 10827 - CLINICAL TRIALS - Global Transfer of Responsibility
p.000036: about DDCM (page 14).
p.000036: • Changed the name of the petition subject to: 10053 - CLINICAL TRIALS - Global Transfer of Responsibility
p.000036: Clinical Trial Protocol (page 15).
p.000036: • Title of item 1 of the Form contained in annexes I and II
p.000036: • Exclusion of item 7 of the Form contained in annexes I and II
p.000036: • Changing the name of the petition subject.
p.000036: • Changing the name of the petition subject.
p.000036: • As the request for the process number is already made in the header, field 7 has been removed to avoid
p.000036: redundancies and the title of the
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 2nd Edition
p.000036: 3rd Edition
p.000036: 3rd Edition
p.000036: • Added Annex III, "Template for sending updated stability information"
p.000036: • Modifications to the DDCM:
p.000036: o "Changing the expiration date must use subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
p.000036: Expiry Date. As a suggestion for greater agility and ease in analyzing this type of petition, it can be
p.000036: completed and submitted together with the other documents, optionally, Annex III of this manual "
p.000036: • Modifications to DDCM
p.000036: o 1. Substantial Modifications
p.000036: ▪ New item “q”: Inclusion of placebo not previously provided for in the DDCM;
p.000036: • Modifications to DDCM
p.000036: 2. Non-substantial changes
p.000036: ▪ New item “c”: Any changes in placebos previously foreseen in the DDCM;
p.000036: field 1 has been clarified for each form
p.000036: • A model was created to send stability information, in an attempt to harmonize the information
p.000036: received and optimize the analysis by technicians
p.000036: • A new item referring exclusively to the placebo was inserted to be a counterpoint to the new sub-item “c”, item
p.000036: 2.
p.000036: Non-substantial changes. The annexes to the Manual have been updated to reflect this change.
p.000036: • Based on a risk analysis carried out by COPEC, it was decided to explicitly exemplify what changes
p.000036: referring to placebos already foreseen previously are no longer considered substantial. A counterpoint was added
p.000036: to item 1 of the same section to exclude from this situation the inclusion of placebos that were not included in the analysis
p.000036: initial. Annexes to the Manual
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 3rd Edition
p.000036: 3rd Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: • Amendments to the Protocol
p.000036: o Substantial Amendments - transposition of the following examples to now appear as an example of
p.000036: NON-substantial amendments:
p.000036: d. New data or interpretation of pharmacological or toxicological data, which may have an impact on the analysis of
p.000036: risk;
p.000036: and. Change in the criteria established for the termination of the protocol, even though it has already ended;
p.000036: f. Addition of experimental arms or placebo group;
p.000036: g. Change in the inclusion and exclusion criteria;
p.000036: H. Reduction in the number of scheduled visits;
p.000036: i. Change in diagnostic procedures or medical monitoring;
p.000036: j. Change in the product under investigation;
p.000036: k. Change in the dosage of the product under investigation;
p.000036: l. Change in the administration of the product under investigation;
p.000036: m. Change in the design of the clinical protocol;
p.000036: n. Change in secondary or exploratory outcomes
p.000036: Update of Clinical Trial Presentation Form.
p.000036: • Amendments to the Protocol
p.000036: Thus, examples of changes in scientific value are the change from a placebo comparator to a comparator
p.000036: active, the insertion of additional experimental arms or changes in the statistical analysis plan.
p.000036: • Cover: inclusion of the effective date
p.000036: • Item 5, subitem 1. Substantial Modifications:
p.000036: The letters "b," d "to" i "had the term" product under investigation "changed to" experimental medicine "
p.000036: have been updated to reflect this change.
p.000036: • Based on a risk analysis carried out by COPEC, it was decided to list these items as examples of
p.000036: NON-substantial amendments as of the 3rd edition. The annexes to the Manual have been updated to reflect this change.
p.000036: • Considering the new examples from the list of substantial modifications, the removal of this paragraph was necessary
p.000036: to align the text with the list of examples.
p.000036: • Inclusion is to identify from which date the manual is in force
p.000036: • The change was made to comply with the terms of RDC 09/2015.
p.000036: Manual for Submitting Modifications,
p.000036: Amendments, Suspensions and Cancellations
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: 4th Edition
p.000036: • Item 5, subitem 1: Substantial Modifications
p.000036: k. Changes related to the validity period since there has been a change in the criteria for
p.000036: stability assessment previously established, that the values are not within the limits of the
p.000036: permitted ranges or that the validity period is defined based on reduced study plan models
p.000036: changes (grouping and matrix) Changes related to the expiration date or
p.000036: care of the product under investigation
p.000036: • Item 5, sub-item 2: Non-substantial changes
p.000036: d. Update on the Development Plan for Experimental Medicines, whose
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| drug | Drug Usage |
| educational | education |
| opinion | philosophical differences/differences of opinion |
| placebo | participants in a control group |
| union | Trade Union Membership |
Indicator Peers (Indicators in Same Vulnerability)
Trigger Words
risk
Applicable Type / Vulnerability / Indicator Overlay for this Input