Manual for Submission of Changes, Amendments

Transcrição

[Brazilian Health Surveillance Agency]
Manual for Submission of
Changes, Amendments,
Suspensions, and Cancellations
v.1
Brasília, 2015
Science Translations
Av. Paulista, 2.073, 17º Andar – Cj. 1.702 – Horsa 02 – Cerqueira Cesar – São Paulo – SP
CEP: 01311-300
Fone: +55 11 4564-0800 │Fax: +55 11 4564-0900 │E-mail: [email protected]
Copyright © 2015: Brazilian Health Surveillance Agency.
The partial or total reproduction of this manual is allowed only when its source is
referred.
Legal Deposit at National Library, as Decree # 1,825 of December 20, 1907.
Director-President
Jaime César de Moura Oliveira
Associate Director-President
Diogo Penha Soares
Directors
José Carlos Magalhães da Silva Moutinho
Renato Alencar Porto
Ivo Bucaresky
Head of Office
Luciana Shimizu Takara
Superintendent of Drugs and Biological Products
Meiruze Sousa Freitas
Clinical Research Coordination on Drugs and Biological Products
Patrícia Ferrari Andreotti
Direct Participation:
André Luis Carvalho Santos Souza
Bruno Zago França Diniz
Candida Luci Pessoa e Silva
Sônia Costa e Silva
Cooperation:
Adriane Alves de Oliveira
Bruno de Paula Coutinho
Carla Abrahao Brichesi
Carlos Augusto Martins Netto
Claudio Nishizawa
Fanny Nascimento Moura
Fernando Casseb Flosi
Flávia Regina Souza Sobral
Janaina Lopes Domingos
Kellen do Rocio Malaman
Miriam Motizuki Onishi
Patrícia Ferrari Andreotti
Ricardo Eccard da Silva
CEP: 01311-300
Manual for Submission of Changes, Amendments, Suspensions, and Cancellations
1
Table of Contents
1. Introduction ................................................................................................................... 2
2. Changes to DDCM ....................................................................................................... 3
3. Amendments to the Protocol ........................................................................................ 7
4. Suspensions and Cancellations ................................................................................. 11
5. References ................................................................................................................. 13
Annexes .......................................................................................................................... 14
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1. Introduction
Without prejudice to the existing regulations in legal provisions, this manual
aims to guide the submissions of modifications to the Drugs Clinical Development
Dossier (DDCM), amendments to the clinical protocols, suspensions, and cancellations
according to chapters IV, V, and VI of the Collegial Board of Governor’s Resolution
(RDC 09/2015).
The document breaks down into specific sections for each type of change. The
changes are described in details, with examples and their specific petition application
issues.
This manual is non-binding regulatory provision adopted as a complement to
the health legislation with the educational purpose to guide on routines and procedures
for compliance with the legislation and is not intended to expand or restrict technical or
administrative requirements.
The guidelines contained in this manual are subject to the receipt of society
suggestions in the manner and for a period to be established by ANVISA. Thus, this
manual is open to contributions to recurrent review process. The suggestions received
will be evaluated to support the manual revision and consequent new version of
publication, at every update.
We emphasize that the situations and examples mentioned in this manual are
illustrative, but by no means, exhaustive or restrictive. Each situation must be assessed
on a case-by-case basis, and contexts lying outside the ones herein described shall be
always followed by rationales.
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2. Changes to DDCM
Changes to DDCM, in the context of RDC 09/2015, are defined as any changes
made to the overall context of DDCM - specifically those related to the quality of the
investigational product - or administrative changes, such as form updates.
All changes must be submitted to ANVISA: substantial changes shall be filed,
when their performing and implementation must await manifestation, while the nonsubstantial changes shall be submitted as part of the safety update report regarding the
experimental drug development. Details on the procedures for petitioning are described
below.
Substantial Changes can be filed at any time after the initial submission of
DDCM, even before the final manifestation by ANVISA.
For the purposes of Resolution, substantial changes are:
I – Inclusion of clinical trial protocol(s) not foreseen or different from that (those)
previously established in the initial development plan;
II – Exclusion of clinical trial protocol(s);
III – Amendments that may potentially generate impact to the quality or safety of
the investigational drug, active comparator, or placebo.
It is the responsibility of the sponsor to assess whether a change is considered
substantial or not and its impact on the clinical development. This assessment should
always be made on a case-by-case basis, based on the aforementioned criteria and on
the examples below.
The following are examples of substantial changes related to the quality or
safety of the investigational product. We emphasize that the lists below are illustrative
only, not exhausting all the possibilities:
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1. Substantial Changes:
a.
Changes related to the active pharmaceutical ingredient;
b.
Changes related to the quality control and stability of the active
pharmaceutical ingredient and investigational product;
c.
Changes related to the excipient quality control;
d.
Changes of description and composition the investigational product;
e.
Changes related to the manufacturing place of the investigational product;
f.
Changes related to the manufacturing process of the investigational product;
g.
Changes related to the manufacturing equipment of the investigational
product;
h.
Changes related to the batch size of the investigational product;
i.
Changes related to the packaging of the investigational product;
j.
Inclusion of new dosage form;
k.
Changes related to the shelf life or the conservation care of the
investigational product;
l.
Inclusion of new concentration;
m. Inclusion of new dosage form;
n.
Changes related to the dosage;
o.
Use magnification;
p.
Addition of a new route of administration;
q.
Addition of a new therapeutic indication;
2. Non-substantial changes:
a.
Update of DDCM Application Form;
b.
Labeling change of the investigational product;
c.
Update of the comparator drug package insert;
d.
Spell check in documents;
e.
Minor clarifications.
For changes of any information contained in the Form, the submission of new
form with updated information and document describing the reasons for each change is
enough. The clinical trial amendment is not a change, as explained in the next section.
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It is recommended that substantial changes are accompanied by a comparative table, if
applicable.
The applicant must update the forms whenever there is a change in the data
therein contained (and not just at the time of submission of annual reports, for
example), because this data reflect the advertising of clinical trials at ANVISA website
and will be used to guide inspections in Good Clinical Practices. The update for this
form does not depend on the Agency’s prior approval.
Substantial changes should be secondary to the primary petition of DDCM
submission for the experimental drug. The inclusion and exclusion of clinical trials have
their own issues, namely:

10818 - CLINICAL TRIALS – Changes of DDCM – Inclusion of clinical trial
protocol not foreseen in the initial development plan
o The inclusion of the clinical trial protocols that were already foreseen in
the initial development plan should be done using specific subject as
Manual for Submission of Drug Clinical Development Dossier (DDCM)
and Specific Clinical Trial Dossier.

10819 - CLINICAL TRIALS - Changes of DDCM – Exclusion of clinical trial
protocol
The changes that potentially generate impact on the quality or safety of the
investigational drug, active comparator or placebo as examples above, should use the
petitions subject 10820 - CLINICAL TRIALS – Changes of DDCM – Changes that may
potentially generate impact on the quality or safety of the investigational product.
(Comparative) documentation of the initial situation and of the proposal must be
submitted accompanied by technical rationale and any additional documents required
to prove that the change will not impact on the clinical development of the product.
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It is noteworthy to highlight that it is the responsibility of the sponsor to evaluate
and classify the changes prior to submission to the Agency, so that a risk/benefit
analysis and the need for supporting documentation is performed. As a suggestion for
greater flexibility and ease of submitting the changes to the analysis, the Annex I of this
manual can be, optionally, completed and submitted along with other documents.
Non-substantial changes do not have a specific petition subject and should be
integrated to the petition 10825 - CLINICAL TRIALS – Update Safety Report of the
Investigational Drug Development.
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3. Amendments to the Protocol
Amendments, in the context of RDC 09/2015, are defined as any changes
made to the clinical protocol, whether they are substantial or not.
All amendments must be submitted to ANVISA: substantial amendments shall
be filed, when their performing and implementation must await manifestation, while
non-substantial changes must be submitted as part of the annual report of the clinical
trial. Details on the procedures for filing will be described below.
Substantial amendments may be filed at any time after the inclusion of the first
clinical protocol to DDCM, even before the final manifestation by ANVISA.
Substantial changes are those where one or more of the following criteria are
met:

Changes in the clinical trial protocol affecting the safety or physical or mental
integrity of individuals;

Change in the scientific value of the clinical trial protocol;
Conceptually, a clinical trial has scientific value if:
a) Assess a therapeutic or diagnostic intervention that can lead to
improvements in health and quality of life; or
b) For an etiologic, physiopathological, or preliminary epidemiological study to
develop such intervention; or
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c) Test a hypothesis that can generate important knowledge about the structure
or the functioning of human biological systems, even if this knowledge has
no immediate practical ramifications.
Thus, scientific value change examples are switching from a placebo comparator to
an active comparator, the inclusion of additional experimental arms or changes in the
statistical analysis plan.
It is the responsibility of the sponsor to assess whether an amendment is
considered significant or not and its impact on clinical development. This assessment
should always be made on a case-by-case basis, based on the aforementioned criteria.
Here are some examples for each category of amendments, including examples of
situations that do not constitute an amendment. Note that the list below is illustrative
only, not exhausting all possibilities.
1. Substantial Amendments:
a.
Change of the primary objective of the clinical protocol;
b.
Change of the primary or secondary endpoints;
c.
Using new parameter to measure the primary endpoint;
d.
New information or interpretation of pharmacological or toxicological data,
which may impact on the risk analysis;
e.
Change in the criteria established for protocol completion, even though it
has already done;
f.
Addition of experimental arm or placebo arm;
g.
Change in the number of participants expected for the study;
h.
Change in the inclusion and exclusion criteria;
i.
Reduction in the number of scheduled visits;
j.
Change in medical monitoring or diagnostic procedures;
k.
Removing the Data Monitoring Independent Committee originally planned
for the study;
l.
Change in the investigational product;
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m. Change of dosage of the investigational product;
n.
Change in route of administration of the investigational product;
o.
Change in the clinical protocol design;
p.
Change to the original statistical analysis plan.
2. Non-substantial amendments:
a.
Change, addition, or removal of exploratory endpoints;
b.
Proposals for extending or continuing research with the same recruited
participants, without change in the design, methods and objectives of the
original project. In the case any of these changes takes place, another
research protocol must be submitted, not an amendment;
c.
Change in the documentation used by the study team to capture and record
the data;
d.
Addition of preventive security monitoring addition, not related to any
issued security advisories.
e.
Minor clarifications to the protocol;
f.
Spell check;
g.
Update of the Clinical Trial Presentation Form.
The applicant must update the Clinical Trial Presentation Form whenever there
is a change in the data contained therein (and not just at the time of submission of
annual reports, for example), because this data reflects the advertising of clinical trials
at the website of ANVISA and will be used to guide inspections for Good Clinical
Practices. The update for this form does not depend on prior approval of the Agency,
except where:

Change in the title or in the code of the clinical trial protocol;

Inclusion or exclusion of the investigational product to be imported

Change in storage and conditions and shelf life of the investigational products.
For these cases, a new version of the CE will be issued.
3. Examples that do not constitute amendments to the protocol:
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a. Investigator's Brochure update. This should be petitioned as 10821 - CLINICAL
TRIALS – Investigator’s Brochure Update, unless it also substantiates changes to the
clinical protocol. In this case, the change must be evaluated by the Sponsor and rated
as substantial or not, and respective procedures must be followed.
b.
Changes in the DDCM submission form or in accompanying documents.
These should be petitioned as 10822 - CLINICAL TRIALS - Change of
DDCM Application Form.
c.
Changes in the submission form of the clinical protocol. These should be
petitioned as 10823 - CLINICAL TRIALS - Change of Clinical Trial
Presentation Form.
d.
Proposal to extend the clinical protocol in which is provided for design
change, methods, or objectives. For this type of change, a new clinical
protocol should be added to DDCM, not fitting amendment to the protocol
already submitted, as explained in the examples of non-substantial
amendments.
e.
Exclusion, cancellation, suspension, or reactivation of clinical trial protocol.
Substantial amendments should be secondary to the primary petition that
entered the clinical protocol in DDCM for the investigational product. As a suggestion
for greater flexibility and ease of submitting amendments to the analysis, the Annex II
of this manual can be completed and submitted along with other documents, optionally.
The specific subject of petition is 10824 - CLINICAL TRIALS - Substantial Amendment
to Clinical Protocol.
Non-substantial amendments do not have a specific application subject and
should be integrated into the application in 1391 - CLINICAL TRIALS - Annual Clinical
Trial Follow-up Protocol with the same documents required for substantial
amendments.
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4. Suspensions and Cancellations

For DDCM:
A DDCM may be canceled or suspended. These situations have their own petition
subjects and should not constitute any of the petitions of the aforementioned changes.
After suspension or cancellation decision, the sponsor must notify ANVISA within 15
calendar days.
If the cancellation occurs through the request of the company, including cases of
cancellation for safety reasons, the petitions subject 10826 - CLINICAL TRIALS DDCM cancellation request should be used; if cancellation happens for global transfer
of responsibility, the petition subject is 10827 - CLINICAL TRIALS - DDCM cancellation
due to global transfer of responsibility for Responsible Sponsor. Please note that
cancellations under RDC 09/2015, are definitive, with no possibility of subsequent
reactivation, and that once a DDCM is cancelled, no clinical trials related thereto may
be continued in the country. In the specific case of DDCM cancellation request,
applications to be submitted to the following-up plan and for measures to
minimize/mitigate the risk of participants in clinical trials already ongoing are detailed in
the Manual for Adverse Event and Safety Clinical Trials Monitoring.
It is important to remember that for a DDCM, cancellation can occur at any time,
even though it has not yet been assessed.
For suspensions, the subject to be used is 10828 - CLINICAL TRIALS - Temporary
suspension of DDCM. By definition, these have a temporary character and can be
reversed with the petition subject 10829 - CLINICAL TRIALS - Reactivation of
suspended DDCM. Reactivation is subject to prior approval by ANVISA.
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
12
For a Clinical Trial:
As well as the DDCM, an individual clinical trial can be canceled or suspended.
These situations have their own petition subject and should not constitute any of the
petitions of the aforementioned amendments. After suspension or cancellation
decision, the sponsor must notify ANVISA within 15 calendar days, except in cases of
temporary suspension as an immediate safety measure, when the deadline is 7
calendar days from the date of suspension. In addition, cancellations under RDC
09/2015, are definitive, with no possibility of subsequent reactivation.
It is important to remember that the cancellation only applies to clinical trial
protocols that have been initiated by the sponsor. If the protocol is provided in DDCM,
but has not been started yet, the exclusion of the protocol should be made, as provided
in the previous section.
If the cancellation happens as a request of the company, including cases of
cancellation for security reasons, the petition subject 10767 - CLINICAL TRIALS –
request of Clinical Trial Protocol cancellation should be used; if cancellation happens
for global transfer of responsibility, the petition subject 10053 - CLINICAL TRIALS Clinical Trial Protocol Cancellation due to global transfer of responsibility. In the
specific case of the cancellation request, the requirements to be submitted to the
monitoring plan and for measures to minimize/mitigate the risk of trial participants are
detailed in the Manual for Adverse Event and Safety Monitoring in Clinical Trials.
For suspensions, the subject to be used is 10830 - CLINICAL TRIALS - Temporary
suspension of Clinical Trial Protocol. By definition, these have a temporary character
and can be reversed with the petition subject 10831 - CLINICAL TRIALS – suspended
Clinical Trial Protocol Reactivation. Reactivation is subject to prior approval by
ANVISA.
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5. References
BRASIL. ANVISA. Agência Nacional de Vigilância Sanitária. Resolução RDC n° 09,
de 20 de Fevereiro de 2015, publicada no D.O.U. de 03 de Março de 2015. Dispõe
sobre o regulamento para a realização de ensaios clínicos com medicamentos no
Brasil. Diário Oficial da União; Poder Executivo, de 03 de Março de 2015.
EUROPEAN COMISSION. Communication from the Commission — Detailed
guidance on the request to the competent authorities for authorisation of a clinical
trial on a medicinal product for human use, the notification of substantial
amendments and the declaration of the end of the trial (CT-1). Available at:
http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf.
Access on 20 Nov 2014.
FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol
Amendments.
Available
at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopeda
ndApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm3625
03.htm. Access on 19 Nov 2014.
HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial
Applications. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applicdemande/guide-ld/clini/ctdcta_ctddec-eng.php. Access on 21 Nov 2014.
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Annexes
ANNEX I
PETITION FORM FOR SUBSTANTIAL CHANGE OF THE DRUG CLINICAL
DEVELOPMENT DOSSIER (DDCM)
Brazilian Health Surveillance Agency
Clinical Research
Petition Form for Substantial Change of the Drug Clinical
Development Dossier (DDMC)
1. Process Number
2.
Document Identification
(For use of the receiver body)
Expedient (Day/ Month/ Year)
Company Data
3. Applicant
5. Manufacturer
Number of
Authorization/Registration
Number of
5.
Authorization/Registration
4.
DDMC Data
7. Number of the dossier process for drug clinical development (DDMC):
8
Change Type:
a) Inclusion of clinical trial protocol(s) not
foreseen or different from those previously
established in the initial development plan?
b) Exclusion of clinical trial protocol(s)?
c) Changes that may potentially generate impact to
the quality or safety of the investigational
product?
a. If so, see item 9.
d) Change from recommendations or warning
issued by health authorities?
a) ( ) Yes
( ) No
b) ( ) Yes
( ) No
c) ( ) Yes
( ) No
d) ( ) Yes
( ) No
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Reasons for Substantial Changes:
a) Changes related to the active pharmaceutical
ingredient?
b) Changes related to the quality control and stability of
the active pharmaceutical ingredient and
investigational product?
c) Changes related to the excipient quality control?
d) Description and composition changes of the
e) Changes related to the manufacturing site of the
f) Changes related to the manufacturing process of the
g) Changes related to the manufacturing equipment of
the investigational product?
h) Changes related to the batch size of the investigational
product?
i) Changes related to the packaging of the
j) Inclusion of new dosage form?
k) Changes related to the shelf life or the conservation
care of the investigational product?
l) Inclusion of new concentration?
m) Inclusion of new dosage form?
n) Changes related to the dosage?
o) Use magnification?
p) Addition of a new route of administration?
q) Addition of a new therapeutic indication;
r) Exclusion of the manufacturing place of the drug or
change of primary or secondary packaging place of
the product?
s) Other changes?
a. If so, specify:
15
a) ( ) Yes
( ) No
b) ( ) Yes
( ) No
c) ( ) Yes
d) ( ) Yes
( ) No
( ) No
e) ( ) Yes
( ) No
f) ( ) Yes
( ) No
g) ( ) Yes
( ) No
h) ( ) Yes
( ) No
i) ( ) Yes
( ) No
j) ( ) Yes
k) ( ) Yes
( ) No
( ) No
l)
m)
n)
o)
p)
q)
r)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
) Yes
) Yes
) Yes
) Yes
) Yes
) Yes
) Yes
s) ( ) Yes
) No
) No
) No
) No
) No
) No
) No
( ) No
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ANNEX II
PETITION FORM FOR SUBSTANTIAL CHANGE OF THE DRUG CLINICAL
DEVELOPMENT PROTOCOL
Brazilian Health Surveillance Agency
Clinical Research
Form for Substantial Change of the Drug Clinical
Development Dossier (DDMC)
1.
Process Number
Company Data
3. Applicant
5. Manufacturer
7.
8.
(For use of the receiver body)
2.
Expedient (Day/ Month/ Year)
4.
5.
Number of Authorization/Registration
Number of Authorization/Registration
Clinical Protocol Data
Number of the protocol process of the clinical trial and of its linked DDCM:
Petition Subject (codes and
description)
10. Title and Code of the Clinical Trial
Protocol
13
Document Identification
9.
Generator Factor (datavisa)
11.
Protocol number (version and date)
12.
Trial Phase
I ( ) II ( )
Type of Substantial Amendment
a) Changes in the clinical trial protocol affecting
the safety or physical or mental integrity of
individuals?
b) Change in the scientific value of the clinical
trial protocol?
III ( ) IV ( )
a) ( ) Yes
( ) No
b) ( ) Yes
( ) No
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Reasons for Substantial Amendment:
a) Change of the primary objective of the
clinical protocol?
b) Change of the primary or secondary
endpoints?
c) Using new parameter to measure the primary
endpoint?
d) New information or interpretation of
pharmacological or toxicological data, which
may have impact on the risk analysis?
e) Change in the criteria established for protocol
completion, even though it has already done?
f) Addition of experimental or placebo arms?
g) Change in the number of participants
expected for the study?
h) Change in the inclusion and exclusion
criteria?
i) Reduction in the number of scheduled visits?
j) Change in medical monitoring or diagnostic
procedures?
k) Removing the Data Monitoring Independent
Committee originally planned for the study?
l) Change in the investigational product?
m) Change of dosage of the investigational
product?
n) Change in the route of administration of the
o) Change in the clinical protocol design?
p) Changes in the initial statistical analysis?
q) Other changes?
a. If so, specify:
17
a) ( ) Yes
( ) No
b) ( ) Yes
( ) No
c) ( ) Yes
( ) No
d) ( ) Yes
( ) No
e) ( ) Yes
( ) No
f) ( ) Yes
g) ( ) Yes
( ) No
( ) No
h) ( ) Yes
( ) No
i)
j)
( ) Yes
( ) Yes
( ) No
( ) No
k) ( ) Yes
( ) No
l) ( ) Yes
m) ( ) Yes
( ) No
( ) No
n) ( ) Yes
( ) No
o) ( ) Yes
p) ( ) Yes
q) ( ) Yes
( ) No
( ) No
( ) No
CEP: 01311-300

Manual for Submission of Changes, Amendments

Transcrição

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