Manual for Submission of Changes, Amendments, Suspensions, and Cancellations v.1

[Brazilian Health Surveillance Agency] Manual for Submission of Changes, Amendments, Suspensions, and Cancellations v.1 Brasília, 2015

Copyright 2015: Brazilian Health Surveillance Agency. The partial or total reproduction of this manual is allowed only when its source is referred. Legal Deposit at National Library, as Decree # 1,825 of December 20, 1907. Director-President Jaime César de Moura Oliveira Associate Director-President Diogo Penha Soares Directors José Carlos Magalhães da Silva Moutinho Renato Alencar Porto Ivo Bucaresky Head of Office Luciana Shimizu Takara Superintendent of Drugs and Biological Products Meiruze Sousa Freitas Clinical Research Coordination on Drugs and Biological Products Patrícia Ferrari Andreotti Direct Participation: André Luis Carvalho Santos Souza Bruno Zago França Diniz Candida Luci Pessoa e Silva Sônia Costa e Silva Cooperation: Adriane Alves de Oliveira Bruno de Paula Coutinho Carla Abrahao Brichesi Carlos Augusto Martins Netto Claudio Nishizawa Fanny Nascimento Moura Fernando Casseb Flosi Flávia Regina Souza Sobral Janaina Lopes Domingos Kellen do Rocio Malaman Miriam Motizuki Onishi Patrícia Ferrari Andreotti Ricardo Eccard da Silva

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 1 Table of Contents 1. Introduction... 2 2. Changes to DDCM... 3 3. Amendments to the Protocol... 7 4. Suspensions and Cancellations... 11 5. References... 13 Annexes... 14

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 2 1. Introduction Without prejudice to the existing regulations in legal provisions, this manual aims to guide the submissions of modifications to the Drugs Clinical Development Dossier (DDCM), amendments to the clinical protocols, suspensions, and cancellations according to chapters IV, V, and VI of the Collegial Board of Governor s Resolution (RDC 09/2015). The document breaks down into specific sections for each type of change. The changes are described in details, with examples and their specific petition application issues. This manual is non-binding regulatory provision adopted as a complement to the health legislation with the educational purpose to guide on routines and procedures for compliance with the legislation and is not intended to expand or restrict technical or administrative requirements. The guidelines contained in this manual are subject to the receipt of society suggestions in the manner and for a period to be established by ANVISA. Thus, this manual is open to contributions to recurrent review process. The suggestions received will be evaluated to support the manual revision and consequent new version of publication, at every update. We emphasize that the situations and examples mentioned in this manual are illustrative, but by no means, exhaustive or restrictive. Each situation must be assessed on a case-by-case basis, and contexts lying outside the ones herein described shall be always followed by rationales.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 3 2. Changes to DDCM Changes to DDCM, in the context of RDC 09/2015, are defined as any changes made to the overall context of DDCM - specifically those related to the quality of the investigational product - or administrative changes, such as form updates. All changes must be submitted to ANVISA: substantial changes shall be filed, when their performing and implementation must await manifestation, while the nonsubstantial changes shall be submitted as part of the safety update report regarding the experimental drug development. Details on the procedures for petitioning are described below. Substantial Changes can be filed at any time after the initial submission of DDCM, even before the final manifestation by ANVISA. For the purposes of Resolution, substantial changes are: I Inclusion of clinical trial protocol(s) not foreseen or different from that (those) previously established in the initial development plan; II Exclusion of clinical trial protocol(s); III Amendments that may potentially generate impact to the quality or safety of the investigational drug, active comparator, or placebo. It is the responsibility of the sponsor to assess whether a change is considered substantial or not and its impact on the clinical development. This assessment should always be made on a case-by-case basis, based on the aforementioned criteria and on the examples below. The following are examples of substantial changes related to the quality or safety of the investigational product. We emphasize that the lists below are illustrative only, not exhausting all the possibilities:

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 4 1. Substantial Changes: a. Changes related to the active pharmaceutical ingredient; b. Changes related to the quality control and stability of the active pharmaceutical ingredient and investigational product; c. Changes related to the excipient quality control; d. Changes of description and composition the investigational product; e. Changes related to the manufacturing place of the investigational product; f. Changes related to the manufacturing process of the investigational product; g. Changes related to the manufacturing equipment of the investigational product; h. Changes related to the batch size of the investigational product; i. Changes related to the packaging of the investigational product; j. Inclusion of new dosage form; k. Changes related to the shelf life or the conservation care of the investigational product; l. Inclusion of new concentration; m. Inclusion of new dosage form; n. Changes related to the dosage; o. Use magnification; p. Addition of a new route of administration; q. Addition of a new therapeutic indication; 2. Non-substantial changes: a. Update of DDCM Application Form; b. Labeling change of the investigational product; c. Update of the comparator drug package insert; d. Spell check in documents; e. Minor clarifications. For changes of any information contained in the Form, the submission of new form with updated information and document describing the reasons for each change is enough. The clinical trial amendment is not a change, as explained in the next section.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 5 It is recommended that substantial changes are accompanied by a comparative table, if applicable. The applicant must update the forms whenever there is a change in the data therein contained (and not just at the time of submission of annual reports, for example), because this data reflect the advertising of clinical trials at ANVISA website and will be used to guide inspections in Good Clinical Practices. The update for this form does not depend on the Agency s prior approval. Substantial changes should be secondary to the primary petition of DDCM submission for the experimental drug. The inclusion and exclusion of clinical trials have their own issues, namely: 10818 - CLINICAL TRIALS Changes of DDCM Inclusion of clinical trial protocol not foreseen in the initial development plan o The inclusion of the clinical trial protocols that were already foreseen in the initial development plan should be done using specific subject as Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Clinical Trial Dossier. 10819 - CLINICAL TRIALS - Changes of DDCM Exclusion of clinical trial protocol The changes that potentially generate impact on the quality or safety of the investigational drug, active comparator or placebo as examples above, should use the petitions subject 10820 - CLINICAL TRIALS Changes of DDCM Changes that may potentially generate impact on the quality or safety of the investigational product. (Comparative) documentation of the initial situation and of the proposal must be submitted accompanied by technical rationale and any additional documents required to prove that the change will not impact on the clinical development of the product.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 6 It is noteworthy to highlight that it is the responsibility of the sponsor to evaluate and classify the changes prior to submission to the Agency, so that a risk/benefit analysis and the need for supporting documentation is performed. As a suggestion for greater flexibility and ease of submitting the changes to the analysis, the Annex I of this manual can be, optionally, completed and submitted along with other documents. Non-substantial changes do not have a specific petition subject and should be integrated to the petition 10825 - CLINICAL TRIALS Update Safety Report of the Investigational Drug Development.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 7 3. Amendments to the Protocol Amendments, in the context of RDC 09/2015, are defined as any changes made to the clinical protocol, whether they are substantial or not. All amendments must be submitted to ANVISA: substantial amendments shall be filed, when their performing and implementation must await manifestation, while non-substantial changes must be submitted as part of the annual report of the clinical trial. Details on the procedures for filing will be described below. Substantial amendments may be filed at any time after the inclusion of the first clinical protocol to DDCM, even before the final manifestation by ANVISA. met: Substantial changes are those where one or more of the following criteria are Changes in the clinical trial protocol affecting the safety or physical or mental integrity of individuals; Change in the scientific value of the clinical trial protocol; Conceptually, a clinical trial has scientific value if: a) Assess a therapeutic or diagnostic intervention that can lead to improvements in health and quality of life; or b) For an etiologic, physiopathological, or preliminary epidemiological study to develop such intervention; or

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 8 c) Test a hypothesis that can generate important knowledge about the structure or the functioning of human biological systems, even if this knowledge has no immediate practical ramifications. Thus, scientific value change examples are switching from a placebo comparator to an active comparator, the inclusion of additional experimental arms or changes in the statistical analysis plan. It is the responsibility of the sponsor to assess whether an amendment is considered significant or not and its impact on clinical development. This assessment should always be made on a case-by-case basis, based on the aforementioned criteria. Here are some examples for each category of amendments, including examples of situations that do not constitute an amendment. Note that the list below is illustrative only, not exhausting all possibilities. 1. Substantial Amendments: a. Change of the primary objective of the clinical protocol; b. Change of the primary or secondary endpoints; c. Using new parameter to measure the primary endpoint; d. New information or interpretation of pharmacological or toxicological data, which may impact on the risk analysis; e. Change in the criteria established for protocol completion, even though it has already done; f. Addition of experimental arm or placebo arm; g. Change in the number of participants expected for the study; h. Change in the inclusion and exclusion criteria; i. Reduction in the number of scheduled visits; j. Change in medical monitoring or diagnostic procedures; k. Removing the Data Monitoring Independent Committee originally planned for the study; l. Change in the investigational product;

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 9 m. Change of dosage of the investigational product; n. Change in route of administration of the investigational product; o. Change in the clinical protocol design; p. Change to the original statistical analysis plan. 2. Non-substantial amendments: a. Change, addition, or removal of exploratory endpoints; b. Proposals for extending or continuing research with the same recruited participants, without change in the design, methods and objectives of the original project. In the case any of these changes takes place, another research protocol must be submitted, not an amendment; c. Change in the documentation used by the study team to capture and record the data; d. Addition of preventive security monitoring addition, not related to any issued security advisories. e. Minor clarifications to the protocol; f. Spell check; g. Update of the Clinical Trial Presentation Form. The applicant must update the Clinical Trial Presentation Form whenever there is a change in the data contained therein (and not just at the time of submission of annual reports, for example), because this data reflects the advertising of clinical trials at the website of ANVISA and will be used to guide inspections for Good Clinical Practices. The update for this form does not depend on prior approval of the Agency, except where: Change in the title or in the code of the clinical trial protocol; Inclusion or exclusion of the investigational product to be imported Change in storage and conditions and shelf life of the investigational products. For these cases, a new version of the CE will be issued. 3. Examples that do not constitute amendments to the protocol:

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 10 a. Investigator's Brochure update. This should be petitioned as 10821 - CLINICAL TRIALS Investigator s Brochure Update, unless it also substantiates changes to the clinical protocol. In this case, the change must be evaluated by the Sponsor and rated as substantial or not, and respective procedures must be followed. b. Changes in the DDCM submission form or in accompanying documents. These should be petitioned as 10822 - CLINICAL TRIALS - Change of DDCM Application Form. c. Changes in the submission form of the clinical protocol. These should be petitioned as 10823 - CLINICAL TRIALS - Change of Clinical Trial Presentation Form. d. Proposal to extend the clinical protocol in which is provided for design change, methods, or objectives. For this type of change, a new clinical protocol should be added to DDCM, not fitting amendment to the protocol already submitted, as explained in the examples of non-substantial amendments. e. Exclusion, cancellation, suspension, or reactivation of clinical trial protocol. Substantial amendments should be secondary to the primary petition that entered the clinical protocol in DDCM for the investigational product. As a suggestion for greater flexibility and ease of submitting amendments to the analysis, the Annex II of this manual can be completed and submitted along with other documents, optionally. The specific subject of petition is 10824 - CLINICAL TRIALS - Substantial Amendment to Clinical Protocol. Non-substantial amendments do not have a specific application subject and should be integrated into the application in 1391 - CLINICAL TRIALS - Annual Clinical Trial Follow-up Protocol with the same documents required for substantial amendments.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 11 4. Suspensions and Cancellations For DDCM: A DDCM may be canceled or suspended. These situations have their own petition subjects and should not constitute any of the petitions of the aforementioned changes. After suspension or cancellation decision, the sponsor must notify ANVISA within 15 calendar days. If the cancellation occurs through the request of the company, including cases of cancellation for safety reasons, the petitions subject 10826 - CLINICAL TRIALS - DDCM cancellation request should be used; if cancellation happens for global transfer of responsibility, the petition subject is 10827 - CLINICAL TRIALS - DDCM cancellation due to global transfer of responsibility for Responsible Sponsor. Please note that cancellations under RDC 09/2015, are definitive, with no possibility of subsequent reactivation, and that once a DDCM is cancelled, no clinical trials related thereto may be continued in the country. In the specific case of DDCM cancellation request, applications to be submitted to the following-up plan and for measures to minimize/mitigate the risk of participants in clinical trials already ongoing are detailed in the Manual for Adverse Event and Safety Clinical Trials Monitoring. It is important to remember that for a DDCM, cancellation can occur at any time, even though it has not yet been assessed. For suspensions, the subject to be used is 10828 - CLINICAL TRIALS - Temporary suspension of DDCM. By definition, these have a temporary character and can be reversed with the petition subject 10829 - CLINICAL TRIALS - Reactivation of suspended DDCM. Reactivation is subject to prior approval by ANVISA.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 12 For a Clinical Trial: As well as the DDCM, an individual clinical trial can be canceled or suspended. These situations have their own petition subject and should not constitute any of the petitions of the aforementioned amendments. After suspension or cancellation decision, the sponsor must notify ANVISA within 15 calendar days, except in cases of temporary suspension as an immediate safety measure, when the deadline is 7 calendar days from the date of suspension. In addition, cancellations under RDC 09/2015, are definitive, with no possibility of subsequent reactivation. It is important to remember that the cancellation only applies to clinical trial protocols that have been initiated by the sponsor. If the protocol is provided in DDCM, but has not been started yet, the exclusion of the protocol should be made, as provided in the previous section. If the cancellation happens as a request of the company, including cases of cancellation for security reasons, the petition subject 10767 - CLINICAL TRIALS request of Clinical Trial Protocol cancellation should be used; if cancellation happens for global transfer of responsibility, the petition subject 10053 - CLINICAL TRIALS - Clinical Trial Protocol Cancellation due to global transfer of responsibility. In the specific case of the cancellation request, the requirements to be submitted to the monitoring plan and for measures to minimize/mitigate the risk of trial participants are detailed in the Manual for Adverse Event and Safety Monitoring in Clinical Trials. For suspensions, the subject to be used is 10830 - CLINICAL TRIALS - Temporary suspension of Clinical Trial Protocol. By definition, these have a temporary character and can be reversed with the petition subject 10831 - CLINICAL TRIALS suspended Clinical Trial Protocol Reactivation. Reactivation is subject to prior approval by ANVISA.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 13 5. References BRASIL. ANVISA. Agência Nacional de Vigilância Sanitária. Resolução RDC n 09, de 20 de Fevereiro de 2015, publicada no D.O.U. de 03 de Março de 2015. Dispõe sobre o regulamento para a realização de ensaios clínicos com medicamentos no Brasil. Diário Oficial da União; Poder Executivo, de 03 de Março de 2015. EUROPEAN COMISSION. Communication from the Commission Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1). Available at: http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf. Access on 20 Nov 2014. FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopeda ndapproved/approvalapplications/investigationalnewdrugindapplication/ucm3625 03.htm. Access on 19 Nov 2014. HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applicdemande/guide-ld/clini/ctdcta_ctddec-eng.php. Access on 21 Nov 2014.

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 14 Annexes ANNEX I PETITION FORM FOR SUBSTANTIAL CHANGE OF THE DRUG CLINICAL DEVELOPMENT DOSSIER (DDCM) Brazilian Health Surveillance Agency Clinical Research Petition Form for Substantial Change of the Drug Clinical Development Dossier (DDMC) Document Identification (For use of the receiver body) 1. Process Number 2. Expedient (Day/ Month/ Year) Company Data 3. Applicant 4. 5. Manufacturer 5. Number of Authorization/Registration Number of Authorization/Registration DDMC Data 7. Number of the dossier process for drug clinical development (DDMC): 8 Change Type: a) Inclusion of clinical trial protocol(s) not foreseen or different from those previously established in the initial development plan? b) Exclusion of clinical trial protocol(s)? c) Changes that may potentially generate impact to the quality or safety of the investigational product? a. If so, see item 9. d) Change from recommendations or warning issued by health authorities? a) ( ) Yes ( ) No b) ( ) Yes ( ) No c) ( ) Yes ( ) No d) ( ) Yes ( ) No

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 15 Reasons for Substantial Changes: a) Changes related to the active pharmaceutical ingredient? b) Changes related to the quality control and stability of the active pharmaceutical ingredient and investigational product? c) Changes related to the excipient quality control? d) Description and composition changes of the investigational product? e) Changes related to the manufacturing site of the investigational product? f) Changes related to the manufacturing process of the investigational product? g) Changes related to the manufacturing equipment of the investigational product? h) Changes related to the batch size of the investigational product? i) Changes related to the packaging of the investigational product? j) Inclusion of new dosage form? k) Changes related to the shelf life or the conservation care of the investigational product? l) Inclusion of new concentration? m) Inclusion of new dosage form? n) Changes related to the dosage? o) Use magnification? p) Addition of a new route of administration? q) Addition of a new therapeutic indication; r) Exclusion of the manufacturing place of the drug or change of primary or secondary packaging place of the product? s) Other changes? a. If so, specify: a) ( ) Yes ( ) No b) ( ) Yes ( ) No c) ( ) Yes ( ) No d) ( ) Yes ( ) No e) ( ) Yes ( ) No f) ( ) Yes ( ) No g) ( ) Yes ( ) No h) ( ) Yes ( ) No i) ( ) Yes ( ) No j) ( ) Yes ( ) No k) ( ) Yes ( ) No l) ( ) Yes ( ) No m) ( ) Yes ( ) No n) ( ) Yes ( ) No o) ( ) Yes ( ) No p) ( ) Yes ( ) No q) ( ) Yes ( ) No r) ( ) Yes ( ) No s) ( ) Yes ( ) No

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 16 ANNEX II PETITION FORM FOR SUBSTANTIAL CHANGE OF THE DRUG CLINICAL DEVELOPMENT PROTOCOL Brazilian Health Surveillance Agency Clinical Research Form for Substantial Change of the Drug Clinical Development Dossier (DDMC) Document Identification (For use of the receiver body) 1. Process Number 2. Expedient (Day/ Month/ Year) Company Data 3. Applicant 4. Number of Authorization/Registration 5. Manufacturer 5. Number of Authorization/Registration Clinical Protocol Data 7. Number of the protocol process of the clinical trial and of its linked DDCM: 8. Petition Subject (codes and description) 9. Generator Factor (datavisa) 10. Title and Code of the Clinical Trial Protocol 13 Type of Substantial Amendment a) Changes in the clinical trial protocol affecting the safety or physical or mental integrity of individuals? b) Change in the scientific value of the clinical trial protocol? 11. Protocol number (version and date) 12. Trial Phase I ( ) II ( ) III ( ) IV ( ) a) ( ) Yes ( ) No b) ( ) Yes ( ) No

Manual for Submission of Changes, Amendments, Suspensions, and Cancellations 17 14 Reasons for Substantial Amendment: a) Change of the primary objective of the clinical protocol? b) Change of the primary or secondary endpoints? c) Using new parameter to measure the primary endpoint? d) New information or interpretation of pharmacological or toxicological data, which may have impact on the risk analysis? e) Change in the criteria established for protocol completion, even though it has already done? f) Addition of experimental or placebo arms? g) Change in the number of participants expected for the study? h) Change in the inclusion and exclusion criteria? i) Reduction in the number of scheduled visits? j) Change in medical monitoring or diagnostic procedures? k) Removing the Data Monitoring Independent Committee originally planned for the study? l) Change in the investigational product? m) Change of dosage of the investigational product? n) Change in the route of administration of the investigational product? o) Change in the clinical protocol design? p) Changes in the initial statistical analysis? q) Other changes? a. If so, specify: a) ( ) Yes ( ) No b) ( ) Yes ( ) No c) ( ) Yes ( ) No d) ( ) Yes ( ) No e) ( ) Yes ( ) No f) ( ) Yes ( ) No g) ( ) Yes ( ) No h) ( ) Yes ( ) No i) ( ) Yes ( ) No j) ( ) Yes ( ) No k) ( ) Yes ( ) No l) ( ) Yes ( ) No m) ( ) Yes ( ) No n) ( ) Yes ( ) No o) ( ) Yes ( ) No p) ( ) Yes ( ) No q) ( ) Yes ( ) No