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Guidelines for Submission of Drug Clinical Development Dossier (DCDD) and Clinical Trial Specific Dossier in ANVISA - Brasil
| 작성자 | 관리자 | 카테고리 | 전문가 인사이트 |
|---|---|---|---|
| 작성일 | 2018-08-29 | 조회수 | 2,810 |
| 원문 | 한국보건산업진흥원 | ||
| 출처 | |||
Title: Guidelines for Submission of Drug Clinical Development Dossier (DCDD) and Clinical Trial Specific Dossier in ANVISA - Brasil
- Name: Priscilla, Lima Viana Palhano
- Company Name& Position : Founder of Argo Consulting
□ Abstract
This paper has as main objective guide and explain submissions of Drug Clinical Development Dossiers (DCDD) and Specific Clinical Trial Dossiers. The main focus is the foreign companies that wish to export their products to Brazil.
□ Table of Contents
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1- Introduction ----------------------------------------------------------------------------------------------------------------- |
2 |
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2- Main Subject --------------------------------------------------------------------------------------------------------------- |
2 |
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2.1) LEGAL BASE ---------------------------------------------------------------------------------------------- |
2 |
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2.2) Submission of the DDCM and specific dossiers for each clinical trial code----------------- |
2 |
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2.2.1) DDCM submission code ------------------------------------------------------------------------------ |
2 |
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2.3) Submission of specific dossiers for each clinical trial---------------------------------------------- |
4 |
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2.4) DDCM documents----------------------------------------------------------------------------------------- |
5 |
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2.4.1) Drug Development Plan ------------------------------------------------------------------------------- |
5 |
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2.4.2 ) Investigator's Brochure ------------------------------------------------------------------------------- |
6 |
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2.4.3) Experimental Drug Dossier -------------------------------------------------------------------------- |
7 |
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2.4.4) Issuance Of Special Communication (CE) And Document For Importation Of Product(S) Under Investigation Of The Drug Clinical Development Dossier (DDCM) |
8 |
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2.4.5) Secondary Petitions ------------------------------------------------------------------------------------ |
9 |
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3 – Conclusion ---------------------------------------------------------------------------------------------------------------- |
10 |
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4- References ----------------------------------------------------------------------------------------------------------------- |
11 |
Acronyms
ATCC – Anatomical Therapeutic Chemical Code
IB – Investigator's Brochure
CE - Special Communication
DDCM - Drug Clinical Development Dossier
API - Active Pharmaceutical Ingredient
CRO - Contract Research Organization
RDC - Board of Directors Resolution
1. Introduction
The publication on the regulation about Clinical Trials with drugs in Brazil starts evaluating Development Plans and not only single protocols. This paper aims at providing guidance for the sponsor, investigator-sponsor or CRO to appropriately submit the Drugs Clinical Development Dossiers (DDCM) and Specific Dossiers for Clinical Trials. It is a non-binding regulatory measure adopted as a complement to the health legislation, with the educational purpose of orientation regarding routines and procedures for compliance with the legislation, not aimed at the extension or restriction of the established technical or administrative requirements
2. Main Subject
2.1 Legal base
Anvisa Resolution RDC no. 9, dated February 20th, 2015, that provided for the regulation for performing clinical trials with drugs in Brazil.
2.2 Submission of the DDCM and specific dossiers for each clinical trial code
2.2.1 DDCM submission code
According to RDC no. 09/2015 the Drug Clinical Development Dossier (DDCM) is a collection of documents to be submitted to Anvisa in order to assess the steps inherent to the development of an experimental drug with the aim to obtain information to support either the registration or post-registration changes of the referred product. For a DDCM electronic petition at Anvisa, the regulated sector must inform one of the following subjects for primary petition:
• 10750 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) - Synthetic Products
• 10754 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) - Biological Products
• 10752 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) - Herbal Products
• 10748 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) - Radiopharmaceutical products
• 10751 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) of CROs - Synthetic Products
• 10755 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) of CROs - Biological Products
• 10753 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) of CROs - Herbal Products
• 10749 - CLINICAL TRIALS - Process for Approval of Drug Clinical Development Dossier (DDCM) of CROs - Radiopharmaceutical Products
The specific checklist for the above-mentioned subjects can be checked at Anvisa's website and they strictly follow the description of the items included in the regulations. The applicant must submit a DDCM to Anvisa only if he/she intends to conduct clinical trials with drugs in Brazil. DDCM is only applicable for the development of experimental drugs. For DDCM analysis purposes, at least one specific dossier for the clinical trial to be conducted in Brazil must be filed.
Upon electronic petition for one of the DDCM's subjects, the applicant must answer the following question: “Are there approval processes filed at Anvisa to be linked to the DDCM?”. If positive, the one responsible for the petition must inform the process numbers of the approval subjects related to the experimental drug in the DDCM, already petitioned at Anvisa (and they may have already been analyzed, accepted, refused, canceled, pending or waiting for technical analysis), which are part of the product clinical Development Plan. Thus, the approval processes already submitted to Anvisa must be linked to a single DDCM per experimental drug.
The following subjects previously petitioned at Anvisa can be linked to a DDCM:
• 10482 - CLINICAL TRIALS - Clinical Research Approval Process - Synthetic Drugs
• 10479 - CLINICAL TRIALS - Clinical Research Approval Process - Biological Products
• 10476 - CLINICAL TRIALS - Clinical Research Approval Process - Herbal Products
• 10483 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Synthetic Drugs
• 10478 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Biological Products
• 10477 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Herbal Products
• 102 – CLINICAL TRIALS - Clinical Research Approval Process – Drugs
• 1650 – CLINICAL TRIALS – CRO's Clinical Research Approval Process – Drugs
• 550 – CLINICAL TRIALS - Clinical Research Notification – Phase IV/Observational linkable to the DDCM
The documents of a DDCM must be manually filed at Anvisa, according to the specific checklist for the subject in question, except Specific Dossier(s) for each Clinical Trial, which will be a new process, electronically petitioned and filed.
2.3 Submission of specific dossiers for each clinical trial
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The Specific Dossiers for each Clinical Trial must be submitted as primary petitions and, therefore, they will have process number, with specific subjects for each clinical trial intended to be conducted in Brazil and that have not been submitted to Anvisa yet. The Specific Dossiers for Clinical Trial can be submitted to Anvisa as one of the following subjects:
• 10482 - CLINICAL TRIALS - Clinical Research Approval Process - Synthetic Drugs
• 10479 - CLINICAL TRIALS - Clinical Research Approval Process - Biological Products
• 10476 - CLINICAL TRIALS - Clinical Research Approval Process - Herbal Products
• 10773 - CLINICAL TRIALS - Clinical Research Approval Process - Radiopharmaceutical Products
• 10483 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Synthetic Drugs
• 10478 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Biological Products
• 10477 - CLINICAL TRIALS - CRO´s Clinical Research Approval Process - Herbal Products
• 10774 - CLINICAL TRIALS – CRO's Clinical Research Approval Process - Radiopharmaceutical Products
• 550 – CLINICAL TRIALS - Clinical Research Notification – Phase IV/Observational linkable to the DDCM
The Specific Dossiers for each Clinical Trial can be petitioned by Institutions with CNPJ (Corporate Taxpayer’s Registry) different from that informed in the DDCM. For petitioning the above subjects, the DDCM process number to which the Clinical Research Approval Process petition shall be bound, must mandatorily be informed, because the system does not allow these subjects to be petitioned if not inserted in any DDCM.
The specific checklist for each of the above-mentioned subjects can be checked at Anvisa's website and they strictly follow the description of the items required by the regulation in force.
The petitioning and filing processes must be done electronically. For each item in these petitions' checklist, the applicant is required to attach at least one PDF file that allows text search. It is possible to attach up to 5 750 kb size files. For greater clarity, we recommend that the attachment related to the protocol is identified as "Protocol".
To continue the petition process, each attached file must be viewed. After the petitioning is completed, a transaction number is generated. For tax collection cases, no changes in the submitted dossier are possible after the tax is paid. Any later change can be done through a specific subject code.
It is important to note that only dossiers for clinical trials to be conducted in Brazil shall be petitioned. Only dossiers already containing clinical and non-clinical justification to be initiated must be filed, since the CE issued for the DDCM will only contain clinical trials that Anvisa considers feasible to be initiated. If the Development Plan is fully presented containing phase 1, 2 and 3 clinical trials, but early-stages clinical trials are still ongoing, and are not able to support clinical trials in later stages, the phase 3 clinical trial, for instance, must not be petitioned in Anvisa initially. This clinical trial may be petitioned when there is enough clinical and non-clinical justification for its initiation. It can be included later as a petition of the Specific Dossiers for Clinical Trial subjects, if not different from that presented in the Development Plan or as a petition for Substantial DDCM Modification (10818 - CLINICAL TRIALS - DDCM Modification - Inclusion of clinical trial protocol not foreseen in the initial development plan) for cases that have changes in the Development Plan.
The provision above is not applicable to the Drug Development Plan (described in detail in section 6), where all planned trials for that experimental drug, to be carried in Brazil or not, must be described.
2.4 DDCM documents
For DDCM submission, Section II of Chapter III from RDC no. 09/2015 must be followed. We recommend that all documentation be submitted in Portuguese, especially the clinical protocol and the investigator's brochure, because as established in RDC 50/2013, the technical evaluator may issue a query requesting the free translation of the presented documentation. Here follows the description of some documents to facilitate DDCM submission.
2.4.1 Drug Development Plan
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The preparation of a Development Plan by the study sponsor allows the definition of objectives and methodologies, which enable the identification of critical stages and process challenges and planning of monitoring actions, from the established indicators. The available information on the experimental drug must support the proposed clinical indication, the target population and the proposed designs types for the clinical trials.
The drug Development Plan must explain the necessary steps for the experimental drug clinical investigation. In short, this plan shall present all the drug development rationale, anticipating all steps already completed, in progress and those intended for the drug clinical investigation. The Development Plan must present, also, the clinical trials that have been, are being or will be conducted outside Brazil.
It is recommended to send a table or a chart containing all planned clinical trials for the clinical development during a specific period, as well as the progress of such trials (completed, in progress or planned).
The Development Plan must start with a brief description of the experimental drug, informing its API or active substance, drug category, therapeutic class, according to the ATCC – Anatomical Therapeutic Chemical Code and route of administration. The indication(s) must be technically justified by the experimental drug mechanism of action, showing that it is directly or indirectly involved in the therapeutic effect or diagnosis. Also inform if the mechanism of action is innovative. Only the indication(s) proposed in the Development Plan must be presented in this topic.
The Sponsor must also inform the general objectives listing all indications intended for the experimental drug, even those that are not yet under investigation in the presented Development Plan. A technical justification for the clinical development must also be described. Moreover, the expected duration of the proposed clinical development must be informed.
Additionally, the sponsor must present a brief description for all clinical trials comprised in the Development Plan, containing information on the phase, design, endpoints, comparators, objectives, population to be studied, hypothesis(es) to be tested, estimated number of participants and statistics planning.
It is recommended to use the development plan template available in the Attachment I of this Manual.
Anvisa is aware that the Development Plan is not statistic and it can be changed during the experimental drug development.
In the Development Plan, it is not necessary to present the results of already completed clinical trials. The clinical trial results must be presented in the Investigator's Brochure. If the experimental drug is already registered in Brazil, only the information supporting the proposed post-registration changes must be submitted in the Development Plan.
2.4.2 Investigator's Brochure
The Investigator's Brochure (IB) is a document containing the collection of non-clinical and clinical data of an experimental drug, which are relevant for the study in human beings. Its objective is to provide Investigators and other personnel conducting the clinical trial with information related to dose, posology, administration methods and safety monitoring procedures. The IB also provides support for the assessment of clinical trial participants during its progress. In the meantime, the information must be presented in a clear, concise, simple and objective language to better guide the investigators conducting the clinical trial.
This guidance item aims to explain the minimal information that must be included in an IB. Depending on the experimental drug development phase and its category, the level of details of the information available may vary. If an already marketed drug is 12 being investigated for a new indication or in a new population, the IB must contain information justifying and supporting this new condition
The IB must contain a brief description of the experimental drug; chemical characterization; biological activity; formulation; characterization of the experimental drug toxicological and pharmaceutical effects in animals and human beings, where applicable; safety and efficacy information on human beings obtained from already conduced clinical trials; as well as any critical information regarding the experimental drug. The IB must present already known data, results available from non-clinical and clinical studies, as well as the studies in progress and their preliminary data, if any.
The IB must explain the possible risks and adverse events related to the experimental drug, based on previous experiences, as well as precautions, safety warnings or special monitoring, including from other regulatory authorities, to be followed during the development to better guide the investigators who will conduct the study.
2.4.3 Experimental Drug Dossier
The documents related to items a, b, c, d and f of the experimental drug dossier described in RDC no. 09/2015 will be addressed in a specific guide for technical assessment of the products under investigation. Thus, in this item, only the subheads g and h of Section II, of Chapter III - Application Content and Format – of RDC no. 09/2015, will be addressed.
The critical analysis of non-clinical studies must describe the following aspects:
I - Justify the choice of test types and chosen animal models, and discuss the possible methodological limitations of already performed tests. The test must support the clinical indication to be studied, route of administration and equivalent dosage in human beings.
II - Discuss the findings in animal models, with identification of target organs and possible implications of such findings in human beings. It must also show that the experimental drug safety profile, from pharmacological and toxicological studies results, is acceptable for clinical investigation.
III - Assess possible benefits and risks involved in order to support the conduction of the experimental drug clinical development
IV - Present information on the study conduction sites, as well as where their records are available for consultation, including a statement that each study was conducted in compliance with the Good Laboratory Practices or justify the lack of it.
The critical analysis of already conducted clinical trials must describe the following aspects:
I - Discuss the scientific quality of clinical trials data based on the level of evidence and recommendation rate of available evidences. Additionally, discuss possible methodological limitations of already conducted clinical trials and procedures used to control systematic errors.
II - From non-clinical tests data, present an argument on safety monitoring in the clinical development.
III - Justify the choice of safety and efficacy endpoints used in previous studies. These endpoints must be consistent with the objectives and hypotheses.
IV - For post-registration changes, for instance, usage expansion, new therapeutic indication, new pharmaceutical form or others, justify the choice of the type of design, study population, dosage regimen and other relevant aspects related to the change.
V - Risk management must be guided by previous results such as death or serious adverse events, type of sequels due to such events, assessments and recommendations from the Independent Safety Monitoring Committee, tolerability, toxicological findings, pharmacological safety (cardiovascular, respiratory and nervous systems) among others. And also, recommendations from other agencies for the proposed study or for the experimental drug must be taken into consideration.
VI - Present assessment of the balance between possible benefits and risks involved in order to support the experimental drug clinical development continuation.
2.4.4 Issuance Of Special Communication (CE) And Document For Importation Of Product(S) Under Investigation Of The Drug Clinical Development Dossier (DDCM)
According to RDC 09/2015, Special Communication (CE) is an authorization document, issued by Anvisa, after DDCM analysis and approval, and it can be used in importing and exporting requests for a clinical trial. In the CE, all clinical trials authorized to be conducted in Brazil are described. Hence, only the clinical trials listed in the CE can be initiated in the country, respecting other ethical approvals.
The CE also contains a list of products to be imported, related to each clinical trial, as well as storage conditions and shelf life. This information is provided by the applicant by filling out the "Clinical trial presentation form". If new clinical trials are included or excluded, products to be imported are included or excluded or storage conditions and shelf life are changed, a CE update must be issued.
Information related to Clinical Trial inclusion not foreseen in the Development Plan must be provided to Anvisa through the following subjects: 10818 - CLINICAL TRIALS - DDCM Modification - Inclusion of clinical trial protocol not foreseen in the initial development plan. For the inclusion of protocol(s) already foreseen in the initial Development Plan, only the submission through the subjects(s) listed in item 5.2 of this Manual will be required. Regarding exclusion of protocols, the information will be provided through subject 10819 - CLINICAL TRIALS - DDCM Modification - Exclusion of clinical trial Protocol. For changes in information related to study products, such as storage conditions and shelf life, subject 10823 - CLINICAL TRIALS - Clinical Trial Presentation Form Change must be petitioned. We emphasize that shelf life changes are considered substantial changes and they must be submitted as explained in the Manual for Submission of Changes, Amendments, Suspension and Cancelations.
For cases with no manifestation from Anvisa according to new RDC no. 09/2015, a "Document for importation of the Study Product(s) from the Drug Clinical Development Dossier (DDCM)" is submitted, allowing the importation of products required for to conduct of Clinical Trials. This document contains the same CE information related to Clinical Trials and products to be imported.
Thus, for cases in which such information is changed, the same criteria and subjects presented for CE changes must be followed. Upon submission of documents pertaining to the changes by the applicant, an updated "Document for Importation of the Study Product(s) from the Drug Clinical Development Dossier (DDCM)" will be issued.
2.4.5 Secondary Petitions
Secondary petitions must be linked to their respective specific processes, i.e. secondary petitions related to a DCDD shall be filed to the application process of the Drug Clinical Development Dossier (DCDD). Some examples of DCDD petitions are: Subjects of DCDD Modification, Change to the DCDD Petition Form, Safety Update Report for development of the experimental drug, DCDD Cancellation Request, DCDD Cancellation due to Global Transfer of Responsibility by the Sponsor in charge, Temporary Suspension of DCDD, Reactivation of Suspended DCDD.
Similarly, petitions related to Clinical Trial Dossiers should be linked to their respective clinical trial processes. Examples of Clinical Trial Dossiers petitions are: Change to Form for clinical trial presentation, Substantial Amendment to Clinical Protocol, Annual Report for Clinical Trial Protocol Monitoring, Clinical Trial Protocol Cancellation Request, Clinical Trial Protocol Cancellation due to Global Transfer of Responsibility, Temporary Suspension of Clinical Trial Protocol, Reactivation of Suspended Clinical Trial Protocol.
The linking of secondary petitions to their corresponding processes is critical to their analysis and traceability within ANVISA’s electronic systems.
Secondary petitions shall be filed electronically. For each item contained in the check-list of these petitions, the applicant will need to attach at least one PDF file, with textual search enabled. It is possible to attach up to five 750-Kb files.
For the continuity of the petitioning process, each attached file will need to be viewed. After completion of the petitioning process, a transaction number will be generated. In cases of taxes collection, no changes can be made to the submitted dossier after payment of the referred tax. Any subsequent changes can be performed through the subject-specific codes.
3. Conclusion
This article tried to address the main points to be considered by international companies for the correct understanding of submission of of sanitary registration dossier for medicines at ANVISA.
It is important to note that in order for all of these processes to be successfully completed, it must be performed by a company registered in Brazil. One of the biggest misconceptions of foreign companies is the understanding that this process can be done directly by the foreign company without registration in Brasill, which is incorrect.
Some alternatives can be considered for this process to be executed, which are:
- The foreign company can open a branch registered in Brazil;
- The foreign company can establish a commercial partnership with an importer registered in Brazil;
- The foreign company may license and transfer the production technology of the product to a company registered in Brazil;
- Among other options that include a company registered in Brazil
Once the foreign company has the defined registration strategy, it is important that the company registered in Brazil schedules meetings with ANVISA through the system of parlatory, where the meetings are recorded and the audios may be requested by the Brazilian company. The meetings are held in Portuguese and are important for discussing the strategy of non-clinical and clinical development of the drug, so that ANVISA gives a prior consent for submission of the dossier, or if it is the case, suggest changes in the studies presented so that the company can present a satisfactory documentary result and that can be approved and registered in Brazil.
At present, at the beginning of this article, the different dossier submission codes in ANVISA, it is important to remember that the required documentation can vary from one case to another and therefore it is essential to check the exact cheklist of relevant documentation on the ANVISA website . This article presents an overview of the organization of the dossier for submission, and does not establish the exact list of documents to be submitted.
And to conclude it is always important that the companies talk to ANVISA before submitting their dossiers so that all the documents are aligned, thus avoiding requirements in the process that lead to long periods of evaluation of the application for registration.
4. Reference
1. 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. [Resolution RDC No. 09, of February 20, 2015, published in D.O.U. of 03 March 2015. Provides for the regulation for conducting clinical trials with drugs in Brazil. Official Diary of the Union; Executive Power, March 03, 2015].
2. GUIDELINE FOR GOOD CLINICAL PRACTICE. ICH E6(R1). Available at: Accessed on: 02 sep. 2016.
□ Profile
Priscilla Viana Palhano Lima was Manager of Regulatory Affairs and Special Projects of the Brazilian public laboratory. He was directly in charge of the legal compliance of technology transfers with foreign companies from France, Poland, the United States and South Korea. He has experience in dossier analysis and elaboration of Partnership for Productive Development projects for the Ministry of Health. She is currently a consultant Regulatory Affairs and organizations of Partnership Projects for Productive Development for the Ministry of Health. Priscilla is the founder of the Argo Consulting company that promotes consulting in the areas of regulatory affairs, business development, international partnerships and technology transfers in partnership with MM Assessoria Industrial company.
