National Health Surveillance Agency MANUAL FOR SUBMISSION OF CLINICAL MEDICINE DEVELOPMENT DOSSIER (DDCM) AND SPECIFIC CLINICAL TRIAL DOSSIER General Management of Medicines - GGMED Coordination of Clinical Research on Medicines and Biological Products - COPEC 2017 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING MANUAL FOR SUBMISSION OF DOSSIER OF CLINICAL MEDICINE DEVELOPMENT (DDCM) AND SPECIFIC CLINICAL TRIAL DOSSIER This Manual aims to guide professionals in the area with information on how to apply Resolution RDC / Anvisa nº 09 February 20, 2015, contributing to the development of safe actions, in addition to providing relevant and updated information that can be better clarified through the Manual instrument. The Manual does not create new obligations and should be used by public and private agents as reference for compliance with existing legislation. 2 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING Copyright © 2017 Anvisa Copyright © 2017 Contributor Total or partial reproduction of this work is allowed, provided the source is mentioned. Edition: 3rd edition Organization - Anvisa General Management of Medicines Technical Review - Anvisa Adriane Alves de Oliveira André Luís Carvalho Santos Souza Bruno de Paula Coutinho Bruno Zago Franca Diniz Candida Luci Pessoa and Silva Carla Abrahao Brichesi Carlos Augusto Martins Netto Carolina Pingret Cintra Claudio Nishizawa Fanny Nascimento Moura Viana Fernando Casseb Flosi Flávia Regina Souza Sobral Janaina Lopes Domingos Kellen from Rocio Malaman Leonardo Fabio Costa Filho Miriam Motizuki Onishi Patrícia Ferrari Andreotti Ricardo Eccard da Silva Sônia Costa e Silva Layout and Review Anvisa Publisher Graphic project Anvisa Publisher Catalog Card: Manual for Clinical Drug Development Dossier (DDCM) and Specific Clinical Trial Dossier / Brasília. Anvisa 2017 27 p. DDCM; Specific Dossier; Clinical Trials. 3 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING SUMMARY 1. SIGLARY 5 2. INTRODUCTION 5 3. LEGAL BASIS 5 4. OBJECTIVE 5 5. SUBMISSION OF DDCM AND SPECIFIC DOSSIERS FOR EACH CLINICAL TRIAL 6 5.1 DDCM SUBMISSION 6 5.2 SUBMISSION OF SPECIFIC DOSSIERS FOR EACH CLINICAL TRIAL 8 6. DDCM DOCUMENTS 10 6.1 MEDICINE DEVELOPMENT PLAN 10 6.2 RESEARCHER BROCHURE 11 6.2 DOSAGE FOR EXPERIMENTAL MEDICINE 12 7. ISSUE OF THE SPECIAL COMMUNICATE (EC) AND DOCUMENT FOR IMPORTING PRODUCT (S) UNDER INVESTIGATION OF THE DOSSIER OF CLINICAL MEDICINE DEVELOPMENT (DDCM) 14 8. SECONDARY PETITIONS 15 9. GLOSSARY 16 10. BIBLIOGRAPHIC REFERENCES 19 11. HISTORY OF CHANGES 20 ANNEX I: Model of development plan 22 4 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 1. SIGLARY ATCC - Anatomical Therapeutic Chemical Code BI - Researcher's Brochure CE - Special Announcement DDCM - IFA Medicines Development Dossier - Active Pharmaceutical Ingredient ORPC - Representative Organization of Clinical Research RDC - Resolution of the Collegiate Board 2. INTRODUCTION The publication of the regulation on Clinical Trials with medicines in Brazil starts to evaluate Health Plans Development and not just isolated protocols. This manual is intended to provide guidelines for the sponsor, researcher-sponsor or ORPC to submit Development Dossiers Medicines Clinician (DDCM) and Specific Clinical Trial Dossiers in an appropriate manner. This is a non-binding regulatory measure adopted as a complement to legislation health, with the educational purpose of providing guidance on routines and procedures for compliance with legislation, not intended to expand or restrict established technical or administrative requirements. 3. LEGAL BASIS Anvisa Resolution - RDC nº 9, of February 20, 2015, which provides for the regulation for the conducting clinical trials with medicines in Brazil. 4. OBJECTIVE Without prejudice to the existing provisions in the legal provisions, this manual aims to guide and explain in a complementary way the submissions of Clinical Drug Development Dossiers (DDCM) and Specific Clinical Trial Dossiers, as described in chapter III of RDC No. 09/2015. We recommend that the format be standardized in terms of order and content to facilitate evaluation. 5 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 5. SUBMISSION OF DDCM AND SPECIFIC DOSSIERS FOR EACH CLINICAL TRIAL 5.1 DDCM SUBMISSION According to RDC No. 09/2015, the Clinical Drug Development Dossier (DDCM) is the compiled from documents to be submitted to Anvisa in order to evaluate the steps inherent to the development of an experimental drug in order to obtain information to support the registration or post-registration changes to that product. For the electronic petition of a DDCM at Anvisa, the regulated sector must inform one of the following primary petition matters: • 10750 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier Medicines (DDCM) - Synthetics • 10754 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier de Medicament (DDCM) - Biological Products • 10752 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier Medicines (DDCM) - Phytotherapics • 10748 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier of Medicines (DDCM) - Radiopharmaceuticals • 10751 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier of Medicines (DDCM) of ORPC`s - Synthetics • 10755 - CLINICAL TRIALS - Consent in Process of the Development Dossier ORPC`s Medication Clinic (DDCM) - Biological Products • 10753 - CLINICAL TRIALS - Consent in Process of the Clinical Development Dossier of Medicines (DDCM) of ORPC`s - Phytotherapics • 10749 - CLINICAL TRIALS - Consent in process of the Clinical Development Dossier of Medicines (DDCM) of ORPC`s - Radiopharmaceuticals The specific check-list for the subjects mentioned above can be consulted on Anvisa's website and these strictly follow the description of the items contained in the standard. The applicant must submit a DDCM to Anvisa only in the case where it intends to conduct clinical trials with medicines in national territory. DDCM applies 6 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING only to the development of an experimental medicine. For DDCM analysis purposes, it must be filed by the least one specific clinical trial dossier to be carried out in Brazil. At the time of electronic petition of one of the DDCM matters, the applicant must answer the following question: “Are there consent procedures filed with Anvisa to be linked to DDCM? ”. If so, the person responsible for petitioning must inform the case numbers of consent issues related to the DDCM experimental drug, already requested at Anvisa (these may have already been analyzed, approved, rejected, canceled, are in demand or awaiting technical analysis), which are part of the Development Plan product. Therefore, the consent processes already submitted to Anvisa must be linked to a single DDCM per experimental drug. The following subjects previously requested by Anvisa may be linked to a DDCM: • 10482 - CLINICAL TRIALS - Clinical Research Process Consent - Synthetic Drugs • 10479 - CLINICAL TRIALS - Consent to Clinical Research Process - Biological Products • 10476 - CLINICAL TRIALS - Consent in Clinical Research Process - Phytotherapics • 10483 - CLINICAL TRIALS - Consent in ORPC’s Clinical Research Process - Synthetic Drugs • 10478 - CLINICAL TRIALS - Consent to ORPC’s Clinical Research Process - Biological Products • 10477 - CLINICAL TRIALS - Consent in ORPC’s Clinical Research Process - Phytotherapics • 102 - CLINICAL TRIALS - Clinical Research Process Consent - Medicines • 1650 - CLINICAL TRIALS - Consent to the ORPC's Clinical Research Process - Medicines • 550- CLINICAL TRIALS - Notification in Clinical Research - Phase IV / Observational linked to DDCM The documents of a DDCM must be filed manually, at Anvisa, according to a specific check-list for the matter in question, except the Dossier (s) 7 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING Specific (s) for each Clinical Trial that will be a new process, petitioned and filed electronics. 5.2 SUBMISSION OF SPECIFIC DOSSIERS FOR EACH CLINICAL TRIAL Specific Dossiers for each Clinical Trial must be submitted as primary petitions and, therefore, will have process number, with specific subjects for each clinical trial that is to be carried out in Brazil and that still have not been submitted to Anvisa. Specific Dossiers for Clinical Trials can be submitted to Anvisa as one of the following subjects: • 10482 - CLINICAL TRIALS - Clinical Research Process Consent - Synthetic Drugs • 10479 - CLINICAL TRIALS - Consent to Clinical Research Process - Biological Products • 10476 - CLINICAL TRIALS - Consent in Clinical Research Process - Phytotherapics • 10773 - CLINICAL TRIALS - Consent in Clinical Research Process - Radiopharmaceuticals • 10483 - CLINICAL TRIALS - Consent in ORPC’s Clinical Research Process - Synthetic Drugs • 10478 - CLINICAL TRIALS - Consent to ORPC’s Clinical Research Process - Biological Products • 10477 - CLINICAL TRIALS - Consent in ORPC’s Clinical Research Process - Phytotherapics • 10774 - CLINICAL TRIALS - Consent in ORPC’s Clinical Research Process - Radiopharmaceuticals • 550- CLINICAL TRIALS - Notification in Clinical Research - Phase IV / Observational linked to DDCM Specific Dossiers for each Clinical Trial can be requested by institutions with CNPJ different from that informed in the DDCM. To petition the matters above, it must be informed the DDCM case number to which the Clinical Research Process Consent petition must be linked, as the system does not allow these matters to be petitioned without belonging to any DDCM. 8 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING The specific check-list for each subject mentioned above can be consulted on Anvisa's website and these strictly follow the description of the items required by the current regulation. Petitioning and filing must be done electronically. For each item contained in the checklist of these requests, it will be necessary for the applicant to attach at least one PDF file, which allows textual search. It will be possible to attach up to 5 files in the size of 750 Kb. For clarity, we recommend that the annex referring to the protocol is identified as "Protocol". For the application process to continue, each attached file must be viewed. After Upon completion of the petition, a transaction number is generated. In cases of fee collection, it is not It is not possible to make any changes to the dossier submitted after the payment of the fee has been made. Any subsequent changes can be made using a specific subject code. It should be noted that only dossiers for clinical trials to be carried out in Brazil should be requested. Only dossiers that already have a clinical and non-clinical basis must be filed to be initiated, therefore, the CE issued for DDCM, will only contain clinical trials that Anvisa considers subject to initiated. If a Development Plan is presented in a complete form containing tests phase 1, 2 and 3 clinical trials, but studies are still being carried out in the early stages, which able to subsidize later phase clinical trials, the phase 3 clinical trial, for example example, should not be initially requested at Anvisa. This clinical trial may be requested at the moment when there are already sufficient clinical and non-clinical bases for its beginning. It can be later included as a petition on the subjects of Specific Dossiers for Clinical Trial, if not is different from what has already been presented in the Development Plan or with a petition for Substantial Modification of DDCM (10818– CLINICAL TRIALS - Modification of DDCM - Inclusion of a clinical trial protocol not provided for in the plan initial development) for those cases in which there is a change in the Development Plan. The foregoing does not apply to the Drug Development Plan (described in detail in section 6), where all trials planned for that experimental drug, whether they be conducted in Brazil or not, they must be described. 9 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 6. DDCM DOCUMENTS For the submission of DDCM, Section II of Chapter III of RDC nº 09/2015 must be followed. We recommend that all documentation be submitted in Portuguese, especially the clinical protocol and the researcher's brochure, as, as established in RDC 50/2013, the evaluator of the technical area may Exarar requirement requesting free translation of the documentation presented. Follows the description of some documents to facilitate DDCM submission. 6.1 MEDICINE DEVELOPMENT PLAN The development of a Development Plan by the study sponsor allows the definition of objectives and methodologies, which make it possible to identify critical stages and challenges of the process and plan monitoring actions, based on established indicators. The information available on the experimental medicinal product should support the proposed clinical indication, target population and types of designs proposed for clinical trials. The Drug Development Plan should explain the steps required for clinical investigation of the experimental medicine. In short, this plan must demonstrate the rationale for the development of the drug, predicting all the steps already executed, in progress and those intended for the clinical investigation of the drug. The Development Plan must also indicate the clinical trials that have been, are being or will be carried out outside Brazil. It is recommended to send a table or a schematic drawing containing all clinical trials planned for clinical development over a given period of time, as well as the progress of these trials (finalized, in progress or planned). The Development Plan should start with a brief description of the drug experimental, informing the IFA or active substance, drug category, therapeutic class, of according to the ATCC classification - Anatomical Therapeutic Chemical Code and route of administration. At) indication (s) must be technically justified by the mechanism of action of the medication experimental, demonstrating that it is directly or indirectly involved in the therapeutic effect or diagnosis. Inform, even, if the mechanism of action is innovative. In that topic should be presented (s) only the indication (s) proposed in the Development Plan. 10 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING The sponsor must also inform the general objectives, listing all the intended indications for the experimental drug, even those that are not yet being investigated in the Development presented. A technical justification for clinical development should also be described. In addition, the expected duration of the proposed clinical development must be informed. In addition, the sponsor must provide a brief description for all clinical trials contained in the Development Plan, containing information about the phase, the design, the outcomes, the comparators, the objectives, the population to be studied, the hypothesis (s) to be tested, estimated number of participants and statistical planning. It is recommended to use the development plan template available in Annex I of this Manual. Anvisa recognizes that the Development Plan is not static and that it can be changed over the experimental drug development. In the Development Plan, it is not necessary to present the results of clinical trials already performed. The results of clinical trials should be presented in the Investigator's Brochure. In the case of the experimental drug already registered in Brazil, only the information that subsidize the proposed post-registration changes must be submitted to the Development Plan. 6.2 RESEARCHER BROCHURE The Researcher Brochure (BI) is a document that contains the compilation of non-clinical and clinical data from a experimental medicine that are relevant to the study in humans. Its objective is to provide researchers and others involved in conducting the clinical trial dose information, dose regimen, administration methods and security monitoring procedures. BI also provides support for monitoring clinical trial participants while conducting. In the meantime, information must be presented in a concise, clear, simple and objective language to better guide researchers in conducting the clinical trial. This item of the manual aims to explain the minimum information that must be included in a BI. According to the stage of development of the experimental drug and its category, the degree of details of available information may vary. If a drug already on the market is being investigated for 11 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING new indication or a new population, the BI must contain information that justifies and supports this new condition. The BI must contain a brief description of the experimental drug; of the characterization chemistry; biological activity; formulation; characterization of the pharmacological and toxicological effects of experimental medicine in animals and humans, when applicable; safety and effectiveness information in obtained from clinical trials already carried out; as well as any critical information to regarding the experimental medicine. BI must present the data already known, the results available non-clinical and clinical studies, as well as ongoing studies and their preliminary data, when available. BI should explain the description of possible risks and adverse events related to the experimental drug, based on past experience, as well as precautions, safety alerts or special accompaniments, including other regulatory authorities, to be followed during development, to better guide the researchers who will conduct the study. 6.3 DOSAGE FOR EXPERIMENTAL MEDICINE The documents referring to items a, b, c, d, and f of the dossier of the experimental medicine described in RDC nº 09/2015 will be addressed in a specific guide for technical evaluation of the products under investigation. Thus, in this item only items g and h of Section II, of Chapter III - Content and Format will be addressed of Request - RDC nº 09/2015. The critical analysis of non-clinical studies should include the following aspects: I - Justify the choice of the types of tests and animal models chosen, and discuss the possible limitations methodologies of the tests already carried out. The tests should support the clinical indication to be studied, via of administration and equivalent dose in humans. II - Discuss the findings in animal models, with identification of the target organs and possible implications of these findings in humans. It must also demonstrate that the safety profile of the experimental drug, from the results of pharmacological and toxicological studies, is acceptable for clinical investigation. III - Assess the possible benefits and risks involved to support the realization of clinical development of the experimental medicine. 12 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING IV - Present information on the locations where the studies are conducted, as well as where their records are available for consultation, including a statement that each study was conducted in accordance with Good Laboratory practices or absence justification. The critical analysis of clinical trials already carried out should provide for the following aspects: I - Discuss the scientific quality of clinical trial data based on the level of evidence and degree of recommendation of the available evidence. In addition, to discuss the possible methodological limitations of clinical trials already carried out and the procedures used to control systematic errors. II - Based on data from non-clinical tests, present a discussion on the monitoring of safety in clinical development. III - To substantiate the choice of safety and efficacy outcomes used in previous studies. These outcomes should be in line with objectives and assumptions. IV - In case of post-registration changes, such as, for example, increased use, new therapeutic indication, new pharmaceutical form or others, to base the choice of the type of design, study population, schemes doses and other relevant aspects related to the change. V - Risk management must be guided by the results of previous studies such as death or other events serious adverse events, type of sequelae resulting from these events, evaluations and recommendations of the Independent Monitoring of Safety, tolerability, toxicological findings, pharmacological safety (system cardiovascular, respiratory and nervous), among others. And yet, the recommendations of other agencies for the proposed study or experimental drug should be taken into account. VI - Present the assessment of the balance between the possible benefits and the risks involved for support the further clinical development of the experimental drug. 13 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 7. ISSUE OF THE SPECIAL COMMUNICATE (EC) AND DOCUMENT FOR IMPORTING PRODUCT (S) UNDER INVESTIGATION OF THE DOSSIER OF CLINICAL MEDICINE DEVELOPMENT (DDCM) According to RDC No. 09/2015, Special Communication (CE) is the authorizing document, issued by Anvisa, after analysis and approval of the DDCM, which can be used in import or export requests to a clinical trial. The EC describes all clinical trials authorized to be conducted in Brazil. Therefore, only the clinical trials listed in the EC can be started in the country, respecting the other ethical approvals. The EC also contains the list of products to be imported, referring to each clinical trial, as well as conditions storage and shelf life. This information is provided by the requester by by completing the "Clinical Trial Submission Form". If included or new clinical trials are excluded, products are included or excluded to be imported, or conditions are changed storage and expiration date, an EC update should be issued. Information regarding the inclusion of a Clinical Trial not provided for in the Development Plan must be provided to Anvisa through the subjects: 10818- CLINICAL TRIALS - DDCM Modification - Inclusion of clinical trial protocol not provided for in the initial development plan. In cases of inclusion protocol (s) already foreseen in the initial Development Plan, only submission through the subject (s) listed in item 5.2 of this Manual. Regarding the exclusion of protocols, the information will be provided through subject 10819 - CLINICAL TRIALS - DDCM modification - Exclusion of clinical trial protocol. For changes in information regarding the products under investigation, such as storage conditions and term, subject 10823 - CLINICAL TRIALS - Change of Form Clinical Trial Presentation. We emphasize that changes in expiration date are considered substantial changes and should be forwarded as explained in the Submission Manual Modifications, Amendments, Suspensions and Cancellations. For cases in which there is no manifestation by Anvisa in accordance with RDC No. 09/2015, an "Document for import of Product (s) under investigation of the Clinical Drug Development Dossier (DDCM) ”so that it is possible to import products necessary to conduct Clinical Trials. This document contains the same information as the CE regarding Clinical Trials and products to be imported. Therefore, in the case of changes to these 14 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING information, the same criteria and subjects presented for EC amendments must be followed. After sending documentation relevant to the changes by the requester, a "Document for import will be issued of Product (s) under investigation by the Clinical Drug Development Dossier (DDCM) " updated. 8. SECONDARY PETITIONS Secondary petitions must be linked to the respective specific processes, that is, secondary petitions related to a DDCM should be filed with the consent process in the Dossier of Clinical Drug Development (DDCM). Some examples of DDCM petitions are: DDCM Modification, DDCM Petition Form Change, Security Update Report Development of Experimental Medicines, Cancellation of DDCM on Request, Global Transfer of DDCM Liability, Temporary DDCM Suspension, Suspended DDCM Reactivation. Likewise, petitions related to Clinical Trial Dossiers must be linked to the respective processes clinical trial. Some examples of petitions for Clinical Trial Dossiers are: Change of Form Presentation of Clinical Trial, Substantial Amendment to Clinical Protocol, Annual Monitoring Report Clinical Trial Protocol, Cancellation of Clinical Trial Protocol on Request, Global Transfer of Liability for Clinical Trial Protocol, Temporary Trial Trial Suspension Clinical, Reactivation of Suspended Clinical Trials Protocol. The linking of secondary petitions to the corresponding processes is fundamental for the analysis and traceability of these in Anvisa's electronic systems. Secondary petitions must be filed electronically. For each item contained in the checklist of these petitions it will be necessary for the applicant to attach at least one PDF file, which allows textual search. It will be possible to attach up to 5 files in the size of 750 Kb. For the application process to continue, each attached file must be viewed. After Upon completion of the petition, a transaction number will be generated. In cases of fee collection, it will not be possible make no changes to the dossier submitted after payment of the fee. Any change can be carried out using a specific subject code. 15 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 9. GLOSSARY I - Good Laboratory Practices (GLP) - quality system that encompasses the organizational process and conditions in which non-clinical studies related to health and safety to the environment are planned, developed, monitored, recorded, filed and reported; II - Researcher's Brochure - compiled of clinical and non-clinical data on the drug (s) experimental (s), which are relevant for their study in humans; III - Independent Security Monitoring Committee - independent committee, constituted for the monitoring specific safety data collected from one or more clinical trials at defined intervals. Recommends to the sponsor if a study should be continued, modified or interrupted; IV - Special Communication (CE) - an authorizing document, issued by Anvisa, after analysis and DDCM approval, which can be used in import or export requests for a clinical trial; V - Clinical Drug Development Dossier (DDCM) - compiled from documents to be submitted to the Anvisa in order to evaluate the steps inherent to the development of an experimental drug with a view to obtaining information to support the registration or post-registration changes of said product; VI - Specific Dossier for each Clinical Trial - compiled from documents to be submitted to Anvisa with the purpose of obtaining information regarding clinical trials, to be conducted in Brazil, which are part of the Experimental Drug Development Plan; VI - Document for the Importation of Product (s) under investigation by the Clinical Development Dossier of Medication (DDCM): Document issued by Anvisa, necessary for the import or export request for a clinical trial, in cases of non-manifestation about DDCM; VII - Amendment to the clinical trial protocol - any proposed modification to a clinical trial protocol original, always presented with the justification that motivated it, and this amendment may be substantial or not; VIII - Clinical trial - research conducted on human beings with the objective of discovering or confirming the clinical and / or pharmacological effects and / or any other pharmacodynamic effect of the medicinal product experimental and / or identify any adverse reaction to the experimental drug and / or study absorption, distribution, metabolism and excretion of the experimental drug to verify its safety and / or effectiveness; 16 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING IX - Active Pharmaceutical Ingredient (IFA) - any substance introduced in the formulation of a pharmaceutical form that, when administered to a patient, it acts as an active ingredient. Such substances can exert activity pharmacological or other direct effect in the diagnosis, cure, treatment or prevention of a disease, affect the structure and functioning of the human organism; X - Investigator - person responsible for conducting a clinical trial at the site where the trial is conducted. If the study is conducted by a group of people, the researcher is the leader of the group and will be called principal investigator; XI - Investigator-Sponsor - individual responsible for conducting and coordinating clinical trials, alone or in a group, carried out under its immediate direction independently, developed with financial and material resources of the researcher, from national or international international research, private and non-profit entities; XII - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, for the purpose of obtaining information for your registration or post-registration; XIII - Representative Organization for Clinical Research (ORPC) - every company regularly installed in national territory hired by the sponsor or by the researcher-sponsor, who assumes partial or totally, with Anvisa, the sponsor's duties; XIV - Sponsor - person, company, institution or organization responsible for initiating, managing, control and / or finance a clinical study; XV - Placebo - formulation without pharmacological effect, administered to the participant of the clinical trial for the purpose of masking or comparator; XVI - Product under investigation - experimental drug, placebo, active comparator or any other product to be used in the clinical trial; XVII - Clinical Trial Protocol - document that describes the objectives, design, methodology, statistical considerations and trial organization. It also provides the context and rationale for the essay clinical; XVIII - Annual Monitoring Report - annual document containing specific information on the conduct of a specific clinical trial in centers in Brazil, according to the clinical protocol and the BPC; XIX - Safety update report for experimental drug development - report harmonized periodical containing safety information and development of an experimental drug; 17 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING XX - Active substance - is the substance with pharmacological effect for the intended therapeutic activity, used in the production of a given biological product. 18 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 10. BIBLIOGRAPHIC REFERENCES 1. BRAZIL. ANVISA. National Health Surveillance Agency. RDC Resolution No. 09, of February 20, 2015, published in the D.O.U. March 3, 2015. Deals with the regulation for conducting clinical trials with drugs in the Brazil. Official Diary of the Union; Executive Branch, of March 3, 2015. 2. GUIDELINE FOR GOOD CLINICAL PRACTICE. ICH E6 (R1). Available in: Accessed on: 02 sep. 2016. 19 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 11. HISTORY OF CHANGES Version Changes made Explanation and Justification 1st edition --- 2nd Edition 2nd Edition • Replacement in the entire document of "Resolution that provides for the Sanitary Regulation for carrying out clinical trials with medicines in Brazil "by" RDC nº 09/2015 " • Changed the name of the petition subject to: Global Transfer of Responsibility on DDCM (page 15). • Since the first edition of the Submission Manual had been finalized before the publication of the new standard, there was also the definition of the number of the new DRC. This was corrected in this first review. • Changing the name of the petition subject. 2nd Edition • Changed the name of the petition subject to: Global Transfer of Responsibility on Test Protocol Clinical (page 15). • Changing the name of the petition subject. 2nd Edition 3rd Edition 3rd Edition • Removed section "Transitional Provisions" • Inclusion of the following sentence in the 4th paragraph in item 6.1: “Inform, even, if the mechanism of action is innovative.” • Inclusion of the following sentence in the 5th paragraph in item 6.1: “A • With more than a year of implementation of RDC No. 09/2015, these transitional provisions have lost their objects and most apply. • Information on the innovation of the action mechanism is important to assess the rationale for development clinical. • For a better understanding of what is the technical justification for the 20 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING 3rd Edition 3rd Edition 3rd Edition technical justification for clinical development should also be described. ” • Inclusion of the following paragraph in item 6.1: “It is recommended to use the development plan model available in Annex I of this Manual. ” • Alteration of item “6.2. Experimental Medication Dossier ”for item 6.3 • Inclusion of Annex I clinical development. • Due to several problems identified in development plans evaluated so far, COPEC developed a model plan to facilitate analysis of the document by Anvisa. • Numbering correction • Provision of a development plan model to facilitate the analysis of the document by Anvisa 21 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING ANNEX I: Model of development plan MODELOv1 - Development Plan - Medicament XXX - Version XX of xx / xx / xxxx Sponsor: XXXXX 1) IFA or active substance Give a brief description of the IFA or active substance. For example: IFA name, physicochemical characteristics and biological. 2) Category of medication Inform whether the medicine is synthetic, biological, herbal or radiopharmaceutical 3) Therapeutic class Inform the therapeutic class of the medication 4) Route of administration Inform the studied and intended routes of administration In this item, one can also inform the pharmaceutical forms and dosages of the experimental drug. For example: 10 mg coated tablet for oral administration and granules for oral suspension of 5 mg. 5) Mechanism of action Briefly inform the mechanism of action and explain whether the mechanism is innovative. Submit a technical justification for this clinical development of this medicine. 6) Indications to be studied Inform the therapeutic indications of the experimental drug that have been studied and those that are intended to be evaluated in this clinical development. 7) General objectives and the planned duration for clinical development Inform the general objectives of clinical development and send a technical justification for this development clinical characteristics of this Inform the expected duration of development. For example: The estimated duration of clinical development is expected in 2025. In this section, you can also be informed if the medication has already been sent to the registration area Anvisa and for which indications / pharmaceutical forms / populations. 22 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING In this section, it can also be informed if the experimental drug has already been submitted for registration in other countries and awaits a response from other agencies. In this case, inform for which indications / pharmaceutical forms / populations the registration was submitted. 8) Clinical trials 8.1. List of completed, ongoing, and planned clinical trials Protocol THE Status Finished Start 01/01/2010 End 12/20/2010 Phase 1 Number of participants 30 Participation of Brazil Not Fill: • Protocol: inform the protocol code • Status: inform if the study has been completed, is in progress or is planned • Start: inform the date the study was started. If it is a planned study, place the forecast for the start of the clinical trial • End: inform the date that the study was completed. If it is a planned study, put the closure forecast clinical trial • Phase: inform if it is phase 1, 2, 3, etc. • Participation by Brazil: inform if the study was / is being / will be conducted in Brazil 8.2. Description of clinical trials 8.2.1. Clinical trials completed or in progress Planned clinical trial Participation of Centers in Brazil Estimated number of participants Status Phase Drawing Objectives Outcomes Protocol code: Yes No ( ) Finished () In progress () 23 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING Comparators Posology of the experimental drug Comparator dosage Pharmaceutical form of the experimental drug Population Note: If there is a clinical trial that is in progress outside of Brazil, but that is planned to be conducted in Brazil, include the study in “planned clinical trials”. 8.2.2. Planned clinical trials 8.2.2.1. Clinical trial A Planned clinical trial Participation of Centers in Brazil Estimated number of participants Status Design Phase Objectives Outcomes Comparators Posology of the experimental drug Comparator dosage Pharmaceutical form of the experimental drug Population Hypothesis Statistical planning Protocol code: Yes () No () Global Start Forecast: Brazil Start Forecast: End Forecast: 8.2.2.2 Clinical Trial B Planned clinical trial Participation of Centers in Brazil Estimated amount of Protocol code: Yes () No () 24 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING Status participants Design Phase Objectives Outcomes Comparators Posology of the experimental drug Comparator dosage Pharmaceutical form of the experimental drug Population Hypothesis Statistical planning Global Start Forecast: Brazil Start Forecast: End Forecast: 8.2.2.3 Clinical Trial C Planned clinical trial Participation of Centers in Brazil Estimated number of participants Status Design Phase Objectives Outcomes Comparators Posology of the experimental drug Comparator dosage Pharmaceutical form of the experimental drug Population Hypothesis Statistical planning Protocol code: Yes () No () Global Start Forecast: Brazil Start Forecast: End Forecast: 25 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING Fill: • Planned clinical trial: inform the protocol code • Participation of centers in Brazil: answer whether or not the participation of Brazil is foreseen in this clinical trial • Estimated number of participants: inform the number of participants expected in the study • Status: inform the expected date for the study to start in Brazil and in the world (if applicable) and the end forecast • Phase: inform if it is phase 1, 2, 3, etc. • Design: the title of the study can be informed • Objective: include at least the primary and secondary objectives • Outcome: include at least the outcomes for primary and secondary objectives • Comparator: inform the name of the active comparator or indicate whether it is placebo (or placebo + basic therapy) and justify the rationale for choosing the comparator. In the case of open studies, justify the rationale. • Posology of the experimental drug: inform the dose and treatment schedule • Posology of comparators: inform the dose and treatment schedule • Pharmaceutical form of the experimental drug: inform the pharmaceutical form used in this clinical trial • Population: inform the profile of the population (age group, gender, disease, etc.) • Hypothesis: inform if there is a hypothesis for the clinical trial. If yes, inform the hypothesis to be tested • Number of participants: inform the number of participants expected or recruited in the study • Statistical planning: inform at least the determination of the sample size, description of the analysis of effectiveness and safety. 9) Timeline with all clinical trials of drug development. Example: 26 MANUAL FOR SUBMISSION OF CLINICAL DEVELOPMENT DOSSIER MEDICINE (DDCM) AND SPECIFIC DOSAGE FOR CLINICAL TESTING GENERAL OBSERVATIONS: ✓ The plan should be written preferably in Portuguese. ✓ For each new plan update, change the document version, highlight the changes made and send a change tracking history. ✓ There is no need to include the results of clinical trials in this document. The results should be presented in the Investigator's Brochure. ✓ The development plan is the first technical document to be analyzed, as it provides an overview of the DDCM. In this way, the more complete and clear the document is, the faster the DDCM analysis will be as a whole. Other documents can be referenced in this document, however, the brief description of each item facilitates the analysis, as it allows to quickly verify the clinical development of the drug. ✓ It is clarified that Anvisa understands that the Development Plan is a dynamic document, which can be changed throughout clinical development. However, even so, such information is fundamental for a first moment of analysis of DDCM and understanding of the general idea of ​​drug development experimental. 27