manual for submission of drug clinical development dossier...

Science Translations

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Manual for Submission of Drug Clinical Development Dossier (DCDD)

and Clinical Trial Specific Dossier

v.1

Brasília, 2015



Copyright © 2015. Brazilian Health Surveillance Agency.

Partial or complete reproduction of this document is permitted, as long as the source is referenced. Legal

deposit at the National Library, in accordance with Decree n° 1.825, of December 20th, 1907.

Acting Director-President

Jaime Cesar de Moura Oliveira

Associate of Director-President

Diogo Penha Soares

Directors

Ivo Bucaresky

José Carlos Magalhães da Silva Moutinho

Renato Alencar Porto

Head of Office

Luciana Shimizu Takara

Superintendent of Drugs and Biological Products

Meiruze Sousa Freitas

Clinical Research Coordination for Drugs and Biological Products

Patrícia Ferrari Andreotti

Team Responsible for the Manual:

Adriane Alves de Oliveira

Flávia Regina Souza Sobral

Kellen do Rocio Malaman

Patrícia Ferrari Andreotti

Ricardo Eccard da Silva

Cooperation:

André Luís Carvalho Santos Souza Claudio Nishizawa

Bruno de Paula Coutinho Fanny Nascimento Moura

Bruno Zago Franca Diniz Fernando Casseb Flosi

Candida Luci Pessoa e Silva Janaina Lopes Domingos

Carla Abrahao Brichesi Miriam Motizuki Onishi

Carlos Augusto Martins Netto Sônia Costa e Silva

Manual for Submission of Drug Clinical Development Dossier (DCDD) and Clinical Trials Specific Dossiers 3



Table of Contents

1. Introduction ...................................................................................................................................... 4

2. DCDD Submission and Specific Clinical Trial Dossiers ..................................................................... 5

2.1 DCDD Submission ................................................................................................................... 5

2.2 Submission of Specific Clinical Trial Dossiers ........................................................................... 7

3. DCDD documents .......................................................................................................................... 10

3.1 Drug Development Plan ......................................................................................................... 10

3.2 Investigator’s Brochure........................................................................................................... 12

3.3 Experimental Drug Dossier..................................................................................................... 12

4. Issuance of Special Bulletin (SB) and Document for Importation of Investigational Product(s) Related

to the Drug Clinical Development Dossier (DCDD) .................................................................................. 15

5. Secondary Petitions ........................................................................................................................ 17

6. Transitional Provisions.................................................................................................................... 17

7. References ..................................................................................................................................... 19




1. Introduction

Without prejudice to existing regulations in legal provisions, this manual is intended to additionally

guide and explain submissions of Drug Clinical Development Dossiers (DCDD) and Specific Clinical Trial

Dossiers.




2. DCDD Submission and Specific Clinical Trial Dossiers

2.1 DCDD Submission

In accordance with Resolution which outlines Health Regulation regarding the conduct of clinical

trials with drugs in Brazil, the Drug Clinical Development Dossier (DCDD) is the compilation of documents

to be submitted to ANVISA with purposes of evaluating the stages related to the development of an

experimental drug, in order to obtain information to support the registration or post-registration changes

regarding the referred product.

For the electronic application of a DCDD at ANVISA, the regulated department must inform one of

the following primary petition subjects:

• 10750 - CLINICAL TRIALS - Approval in Process of Drug Clinical Development Dossier (DCDD)

– Synthetic Drugs

• 10754 - CLINICAL TRIALS - Approval in Process of Drug Clinical Development Dossier (DCDD) -

Biological Products


Herbal Products


Radiopharmaceuticals

• 10751 - CLINICAL TRIALS – CRO Approval in Process of Drug Clinical Development Dossier

(DCDD) – Synthetic Drugs


(DCDD) - Biological Products


(DCDD) - Herbal Products


(DCDD) - Radiopharmaceuticals

The specific checklist for the abovementioned subjects can be searched at ANVISA website and

they strictly follow the description of the items contained in the regulation.

The applicant must submit a DCDD to ANVISA only if intended to conduct clinical trials with drugs

in the country. DCDD applies only to the development of an experimental drug. For analysis purposes,

DCDD must be submitted with at least one specific clinical trial dossier to be performed in Brazil, and it

may be a clinical trial previously approved by ANVISA.

Upon electronic petition of one of DCDD subjects, the applicant must answer the following question:

“Are there application processes filed with ANVISA to be linked to this DCDD?”. If positive, the person

responsible for petitioning must inform the process numbers of subjects for approval related to DCDD

experimental drug, which were already submitted to ANVISA and that are part of the product clinical

Development Plan. They may have already been analyzed, approved, rejected, canceled, or being




awaiting resolution of pending issues or expecting technical analysis. Therefore, approval processes

already submitted to ANVISA must be linked to a single DCDD for each experimental drug.

The following subjects previously petitioned at ANVISA may be linked to a DCDD:

• 10477 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Herbal Products

• 10483 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Synthetic Drugs

• 10478 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Biological Products

• 0476 - CLINICAL TRIALS - Approval in Clinical Research Process - Herbal Products

• 10482 - CLINICAL TRIALS - Approval in Clinical Research Process - Synthetic Drugs

• 10479 - CLINICAL TRIALS - Approval in Clinical Research Process- Biological Products

• 102 - CLINICAL TRIALS - Approval in Clinical Research Process – Drug Products

• 1650 - CLINICAL TRIALS – CRO Approval in Clinical Research Process -




Drug Products

• 550 - CLINICAL TRIALS - Notification in Clinical Research - Phase IV/Observational linkable to the

DCDD

The documents of a DCDD must be manually filed with ANVISA, in accordance with a specific

checklist for the concerned subject, except for Specific Dossier(s) for each Clinical Trial which will be a

new process, electronically petitioned and filed.

2.2 Submission of Specific Clinical Trial Dossiers

The Specific Dossiers for each clinical trial must be submitted as primary petitions and, therefore,

will have a process number, with specific subjects for each clinical trial to be conducted in Brazil and that

have not yet been submitted to ANVISA.

The Clinical Trial Specific Dossiers may be submitted to ANVISA as one of the following subjects:

• 10482 - CLINICAL TRIALS - Approval in Clinical Research Process - Synthetic Drugs

• 10479 - CLINICAL TRIALS - Approval in Clinical Research Process- Biological Products

• 10476 - CLINICAL TRIALS - Approval in Clinical Research Process - Herbal Products

• 10773 - CLINICAL TRIALS - Approval in Clinical Research Process - Radiopharmaceuticals

• 10483 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Synthetic Drugs

• 10478 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Biological Products

• 10477 - CLINICAL TRIALS – CRO Approval in Clinical Research Process - Herbal Products

• 10774 - CLINICAL TRIALS – CRO Approval in Clinical Research Process -

Radiopharmaceuticals




• 550- CLINICAL TRIALS - Notification in Clinical Research - Phase IV/Observational linkable to

DCDD

The specific dossiers for each clinical trial can be petitioned by institutions with CNPJ (tax ID

number) different from the one informed in the DCDD. For submission of the above subjects, the following

must be informed: DCDD process number to which the petition for Application in Clinical Research

Process shall be linked to, because the system does not allow petitioning of these subjects without relating

to a DCDD.

Specific Dossiers for each Clinical Trial can be petitioned by institutions with Corporate

Taxpayers’ Registry (CNPJ) different from the one informed in DCDD. For petition of the above

subjects, the following must be informed: DCDD process number to which the petition for

Approval in Clinical Research Process shall be linked to, because the system does not allow

petitioning of these subjects without being related to a DCDD.

The specific checklist for each of the abovementioned subjects may be referenced at

ANVISA website and those strictly follow the description of items required by current regulation.

Petitioning and filing must be electronically performed. For each item contained in the

checklist of such petitions, the applicant will need to attach at least one PDF file, with textual

search allowed. It will be possible to attach up to five 750-Kb files. For greater clarity, we

recommend that the appendix concerning the protocol is identified as “Protocol”.

For the continuity of the petitioning process, each attached file needs to be viewed.

After the petitioning completion, a transaction number is 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.

It is emphasized that petitions should only be submitted for dossiers of clinical trials to

be conducted in Brazil. Only dossiers which have already clinical and non-clinical support to be

started should be filed, because the Special Bulletin (SB) issued to DCDD will contain only

clinical trials that ANVISA considers that can be started. If a Development Plan is

comprehensively presented, containing Phases 1, 2, and 3 clinical trials, but with early stage

studies ongoing, which are not able to support late stage clinical trials, the phase 3 trial, for

example, should not be initially petitioned at ANVISA. This clinical trial may be petitioned after

there are already sufficient clinical and non-clinical data to support its initiation. It may later be

included as a petition of subjects of the Clinical Trial Specific Dossiers, if it is not different from

what was already presented in the Development Plan; or it may be petitioned as a Substantial

DCDD Change (10818- CLINICAL TRIALS - DCDD Change - Inclusion of clinical trial protocol

not foreseen in the initial development plan) for cases where there is a change in the

Development Plan.




The foregoing provisions do not apply to the Drug Development Plan (described in detail

in Section 6), where all trials planned for that experimental drug should be described, regardless

those are to be conducted in Brazil or not.




3. DCDD documents

For the DCDD submission, Section II, Chapter III of the new Health Regulations for Clinical Trials

with Drugs should be followed. We recommend that all documentation be submitted in Portuguese,

especially the clinical protocol and the investigator's brochure, since it is established in RDC 50/2013 that

the evaluator of the technical area might issue pending requiring translation of the presented

documentation. Below is a description of some documents to facilitate the submission of the DCDD.

3.1 Drug Development Plan

The preparation of a Development Plan by the study sponsor enables the establishment of goals

and methodologies, making possible the identification of critical steps and challenges of the process as

well as planning the monitoring actions, based on established indicators. Information available on the

experimental drug shall support the proposed clinical indication, the target population and the types of

proposed clinical trials designs.

The Drug Development Plan should explain the required steps for clinical research of the

experimental drug. In short, the plan must show all rationale for drug development, forecasting all the steps

which have already been performed, that are in progress and are intended for the clinical research of the

drug. The Development Plan shall also indicate clinical trials that have been, are being or will be held

outside Brazil.

The agency recommends that a table or a schematic drawing is included, containing all clinical

trials planned for clinical development during a certain period of time as well as the progress of these trials

(completed, in progress or planned).




The Development Plan should be initiated with a brief description of the experimental drug, informing the

AFI (Active Pharmaceutical Ingredient), category of the drug, therapeutic class (according to the ATCC -

Anatomical Therapeutic Chemical Code) and route of administration. The indication(s) must be technically

justified through the experimental drug mechanism of action, demonstrating that it is directly or indirectly

involved in the diagnostic or therapeutic effect. This topic should only include the indication(s) proposed in

the Development Plan.

The sponsor should also inform the general objectives listing all indications intended for the

experimental drug, even those which are not yet being investigated in the presented Development Plan. In

addition, the planned duration of the proposed clinical development must be informed.

Additionally, the sponsor should provide a brief description for all clinical trials included in the

Development Plan, providing information on the phase, design, outcomes, comparators, objectives, the

population to be studied, the hypothesis(es) to be tested, estimated number of participants and statistical

plan.

ANVISA recognizes that the Development Plan is not static and that it can be changed throughout

an experimental drug’s development.

In the Development Plan, results of clinical trials that have already been done do not need to be

presented. The results of clinical trials should be presented in the Investigator's Brochure.

If the experimental drug is already recorded in Brazil, only information pertaining to proposed post-

registration amendments must be submitted in the Development Plan.




3.2 Investigator’s Brochure

The Investigator's Brochure (IB) is a document containing the compilation of the non-clinical and

clinical data of an experimental drug that are relevant to its study in humans. Its goal is to provide

researchers and others involved in the conduct of the clinical trial with information on the dose, dosing

regimen, methods of administration and safety monitoring procedures. The IB also provides support for the

monitoring of clinical trial participants during its conduction. In the meantime, information should be

presented in a concise, clear, simple and objective language to better guide researchers while conducting

the clinical trial.

This item in the manual aims to clarify the minimum information that should be included in an IB.

According to the development phase of the experimental drug and its category, the degree of detail of

information available may vary. If a drug already marketed is being investigated for a new indication or 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, its chemical characterization,

biological activity, and formulation, the characterization of pharmacological and toxicological effects of the

experimental drug in animals and humans, when applicable, safety and efficacy information in humans

obtained from clinical trials already carried out, as well as any critical information about the experimental

drug. The IB must present data that are already known, available results of non-clinical and clinical studies,

as well as ongoing studies and their preliminary data, if any.

The IB must specify the description of possible risks and adverse events related to the experimental

drug based on past experience, as well as precautions, safety warnings or special monitoring

requirements, including from other regulatory authorities, to be followed during development, to better

guide researchers who will lead the study.

3.3 Experimental Drug Dossier

Documents relating to items a, b, c, d, and f of the experimental drug dossier described in the

regulation will be addressed in a specific guide of technical evaluation of investigational products. Thus,

this item will only address subparagraphs g and h of




Section II, Chapter III - Application Content and Format - of the new regulation.

The critical analysis of non-clinical studies must provide for the following aspects:

i. Support for the choice of the types of tests and animal models chosen, and discuss possible

methodological limitations of tests already carried out. Tests should support the clinical indication being

studied, route of administration and equivalent dose in humans.

ii. Discuss the findings in animal models with identification of target organs and possible

implications of these findings in humans. Demonstrate that the safety profile of the experimental drug,

based on the results of pharmacological and toxicological studies, is acceptable for clinical research.

iii. Evaluate the possible benefits and risks involved to support the conduct of the experimental

drug’s clinical development.

iv. Present information on sites where the studies were conducted, as well as where their records

are available for inspection, including a statement that each study was conducted in accordance with Good

Laboratory Practice or a justification for the absence of such statement.

The critical analysis of clinical studies already performed must provide for the following aspects:

i. Discuss the scientific quality of clinical trial data based on the level of evidence and grade of

recommendation of available evidence. Also, discuss the possible methodological limitations of clinical

trials already conducted and the procedures used for controlling systematic errors.

ii. Based on non-clinical testing data, present a discussion on the safety monitoring in clinical

development.

iii. Support the choice of safety and efficacy outcomes used in previous studies. These outcomes

should be aligned with the objectives and hypotheses.

iv. In case of post-registration changes, such as expansion of use, new therapeutic indication, new

pharmaceutical form, among others, explain the choice of the type of design, study population, dose

regimens and other relevant aspects related to the changes.

v. Risk management should be guided by results of previous studies as death or other serious

adverse events, type of sequelae due to these events, assessments and recommendations of the

Independent Safety Monitoring Committee,




tolerability, toxicological findings, pharmacological safety (cardiovascular, respiratory, and nervous

systems), among others. In addition, recommendations from other agencies for the proposed study or the

experimental drug should be taken into consideration.

vi. Present the assessment of the balance between possible benefits and risks involved to support

the continued clinical development of the experimental drug.




4. Issuance of Special Bulletin (SB) and Document for Importation of Investigational Product(s) Related to the Drug Clinical Development Dossier (DCDD)

According to the resolution, Special Bulletin (SB) is the authorizing document issued by ANVISA,

after DCDD analysis and approval, and can be used in import or export requests for a clinical trial. All

clinical trials authorized to be conducted in Brazil are described in the SB. Therefore, only clinical trials

listed in the SB can be initiated in Brazil, respecting all other ethical approvals.

The SB also contains the list of products to be imported for each clinical trial, as well as storage

conditions and shelf life. This information is provided by the applicant when completing the “Form for

clinical trial presentation”. If new clinical trials are included or excluded, if products to import are included

or excluded, or if storage conditions and shelf life are changed, an updated SB shall be issued.

Information relating to the inclusion of Clinical Trials not foreseen in the Development Plan must be

provided to ANVISA through the subjects: 10818- CLINICAL TRIALS - DCDD Modification - Clinical trial

protocol inclusion not foreseen in the initial development plan. In cases of inclusion of protocol(s) already

foreseen in the initial development plan, only the submission through the subject(s) listed in Section 2.2 of

this Manual will be required. As for exclusion of protocols, the information will be provided through the

subject: 10819 - CLINICAL TRIALS - DCDD Modification - Clinical Trial Protocol Exclusion. For changes in

the information about the products under investigation, such as storage conditions and shelf life, the

following subject should be petitioned - 10823 - CLINICAL TRIALS – Modification to Form for clinical trial

presentation.

For cases when there is no manifestation from ANVISA, according to the new Health Resolution for

Clinical Trials with drugs, a “document for importation of




product(s) under investigation by the Drug Clinical Development Dossier (DCDD)” is sent, to allow import

of products needed to conduct the Clinical Trials. This document contains the same information of the SB

regarding Clinical Trials and products to be imported. Therefore, in cases of changes to this information,

the same criteria and subjects presented for amendments to the SB must be followed. After sending the

relevant documentation to allow changes by the applicant, an updated “document for importation of

product(s) under investigation by the Drug Clinical Development Dossier (DCDD)” will be issued.




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.

6. Transitional Provisions

The application processes in clinical trials filed within ANVISA which predate the publication of the

new resolution and that are still awaiting technical analysis will be evaluated according to the resolutions in

effect at the time of their submission.




In cases of petitions that are within the 90 (ninety) days scope described in the Transitional

Provisions of the Health Regulations for the conduct of clinical trials with drugs in Brazil, a SSB will be

issued for import purposes, according to the resolution in effect at the time of their submission.

This SSB will be needed to import requests as established in RDC 39/2008, that is, for these cases

a pre-shipment approval from the technical area (COPEC) and a post-shipment approval (location of

unloading) will be needed.

For processes falling outside the scope of 90 (ninety) days, it will be necessary to hold for approval

of the clinical trial by ANVISA, as provided in the Resolution current at the time of filing and the import

process will also occur as foreseen in RDC 39/2008.

The applicability for the processes assessment in accordance with current resolutions at the time of

filing also includes the analysis of other secondary petitions linked to them, such as: sites inclusion or

exclusion, change of principal investigator, change in the amount of products to be imported, among

others.




7. References

Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance