National Health Surveillance Agency
MANUAL FOR SUBMISSION OF MODIFICATIONS, AMENDMENTS, SUSPENSIONS AND CANCELLATIONS
General Management of Medicines - GGMED Coordination of Clinical Research on Medicines
and Biological Products - COPEC
Brasilia, 08/16/2018
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
MANUAL FOR SUBMISSION OF MODIFICATIONS, AMENDMENTS, SUSPENSIONS AND CANCELLATIONS
This Manual aims to guide professionals in the area with information on how to apply Resolution RDC / Anvisa nº 09 of 20
February 2015, contributing to the development of safe actions, in addition to providing information
relevant and up-to-date information that can best be clarified using the Manual instrument.
The Manual does not create new obligations, and should be used by public and private agents as a reference for
compliance with existing legislation.
2
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
Copyright © 2018 Anvisa Copyright © 2018 Contributor
Total or partial reproduction of this work is allowed, provided the source is mentioned.
Edition: 4th edition Organization - Anvisa
General Management of Medicines
Technical Review - Anvisa
Adriane Alves de Oliveira
André Luís Carvalho Santos Souza Bruno de Paula Coutinho Candida Luci Pessoa e Silva
Carla Abrahao Brichesi
Carlos Augusto Martins Netto Carolina Pingret Cintra Christiane Santiago Maia Claudio Nishizawa
Claudiosvam Martins Alves de Souza Fanny Nascimento Moura Viana Fernando Casseb Flosi
Flávia Regina Souza Sobral Gláucia Pacheco Buffon Kellen from Rocio Malaman Leandro Garcia Bueno Silva Leonardo Fabio
Costa Filho Miriam Motizuki Onishi Ricardo Eccard da Silva Sônia Costa e Silva
Layout and Review
Anvisa Publisher
Graphic project
Anvisa Publisher
Catalog Card:
Manual for Submitting Modifications, Amendments, Suspensions and Cancellations / Brasília. Anvisa 2018
28 p.
Amendments; Modifications; Clinical Trials.
3
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
SUMMARY
1. SIGLARY
5
2. INTRODUCTION
5
3. LEGAL BASIS
5
4. OBJECTIVE
5
5. MODIFICATIONS TO THE DDCM
6
6. PROTOCOL AMENDMENTS
10
7. SUSPENSIONS AND CANCELLATIONS
14
8. GLOSSARY
16
9. BIBLIOGRAPHIC REFERENCES
17
10. ANNEXES
18
11. HISTORY OF CHANGES
21
4
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
1. SIGLARY
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 regulations on Clinical Trials with medicines in Brazil provides for modifications,
amendments, suspensions and cancellations as part of clinical drug development. This one
manual is intended to provide guidance for the sponsor, investigator-sponsor or ORPC to make these
submissions properly.
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 submissions
of changes to the Clinical Drug Development Dossier (DDCM), amendments to the protocols
clinical, suspensions and cancellations, as described in chapters IV, V and VI of RDC nº 09/2015.
The document is broken down into specific sections for each type of change. The changes are described in
details, with examples and the respective specific petition matters.
We emphasize that the situations and examples contained in this manual are illustrative, but in no way restrictive or
exhaustive. Each situation must be assessed on a case-by-case basis, and contexts that differ from those described here
accompanied by justifications.
5
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
5. MODIFICATIONS TO THE DDCM
Modifications to the DDCM, in the context of RDC No. 09/2015, are defined as any changes made to the
DDCM global context - especially those related to the quality of the product under investigation - or
administrative changes, such as form updates.
All changes must be submitted to Anvisa. Substantial changes must be filed when
its realization and its implementation must await manifestation, while the non-substantial ones must be
presented as part of the security update report for the development of the
experimental medicine. Details on the application procedures will be described below.
Substantial changes can be filed at any time after the initial submission of the DDCM,
even before Anvisa's final manifestation.
For the purposes of the Resolution, substantial changes consist of:
I - Inclusion of protocol (s) of clinical trial (s) not foreseen or different (s) from that (s) previously
established in the initial development plan;
II - Exclusion of clinical trial protocol (s);
III - Changes that potentially impact the quality or safety of the experimental drug,
active comparator or placebo.
It is the sponsor's responsibility to assess whether a modification is considered substantial or not and
its impact on clinical development. This assessment should always be done on a case-by-case basis, based on the criteria
above and in the examples below.
The following are examples of substantial modifications related to the quality or safety of the product under investigation.
We emphasize that the lists below are illustrative only, not exhausting all possibilities.
1. Substantial changes:
The. Changes related to the active pharmaceutical ingredient;
B. Changes related to quality control and stability of the active pharmaceutical ingredient and medication
experimental;
ç. Changes related to excipient quality control;
d. Changes in the description and composition of the experimental drug;
6
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
and. Changes related to the place of manufacture of the experimental medicine;
f. Changes related to the production process of the experimental drug;
g. Changes related to the production equipment of the experimental medicine;
H. Changes related to the batch size of the experimental drug;
i. Changes related to the packaging of the experimental drug;
j. Inclusion of new presentation;
k. Changes related to the validity period since there has been a change in the evaluation criteria of
previously established stability, that the values ​​are not within the permitted ranges or
the validity period is defined based on reduced models of stability study plan (grouping
and Matrix);
l. Inclusion of new concentration;
m. Inclusion of a new pharmaceutical form;
n. Changes related to dosage;
O. Expansion of use;
P. Inclusion of a new route of administration;
q. Inclusion of a new therapeutic indication;
r. Inclusion of placebo not previously provided for in the DDCM.
2. Non-substantial changes:
The. Update of the DDCM Petition Form;
B. Change in labeling of the product under investigation;
ç. Any changes to placebos previously provided for in the DDCM;
d. Update on the Development Plan for the Experimental Medication, the change of which does not impact the trials
clinics to be conducted in Brazil;
and. Spell check in documents;
f. Small clarifications;
g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of modifications
substantial.
To modify any information contained in the Form, simply submit a new form with the information
updated information and document describing the justifications for each change. Clinical trial amendment
does not constitute modification, as explained in the next section. It is recommended that substantial modifications
accompanied by a comparative table, if applicable.
7
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
The applicant must update the forms whenever there is a change in the data contained therein (and not only at the time
submission of annual reports, for example), as these data reflect the advertising of clinical trials on the website
of Anvisa and will be used to guide inspections in Good Clinical Practices. Updating this
form does not depend on a prior opinion by the Agency.
Substantial modifications must constitute a petition secondary to the primary petition for submission of the DDCM for the drug
experimental, with the exception of modification by inclusion of a clinical trial protocol not provided for in the initial
development, which is a primary petition. The inclusion and exclusion of clinical trials has its own issues, the
to know:
• 10818 - CLINICAL TRIALS - Modification of DDCM - Inclusion of a clinical trial protocol not provided for in the plan
initial development
o The inclusion of clinical trial protocols that were already provided for in the initial development plan should
be made using a specific subject, according to the Manual for Submission of Dossier of
Clinical Drug Development (DDCM) and Specific Clinical Trial Dossier.
• 10819 - CLINICAL TRIALS - Modification of DDCM - Exclusion of clinical trial protocol
Changes that potentially impact the quality or safety of the experimental drug,
active comparator or placebo, as examples above, should use the subject of petition 10820 - CLINICAL TRIALS -
DDCM modification
- Change that potentially impacts the quality or safety of the product under investigation. Must be presented
(comparative) documentation of the initial situation and the proposal accompanied by technical justification and any
additional documents required to prove that the change will not impact the clinical development of the
product.
It is worth mentioning that it is the sponsor's responsibility to evaluate and classify the changes
prior submission to the Agency, so that a risk / benefit analysis
need for supporting documentation. As a suggestion for greater agility and ease in submitting
changes to the analysis, can be completed and submitted together with the other documents, optionally, the
Annex I of this manual, available in DOC version on the Anvisa website.
8
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
The change in validity period must use the subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
Expiry Date. As a suggestion for greater agility and ease in analyzing this type of petition, it can be
completed and submitted together with the other documents, optionally, Annex III of this manual,
available in DOC version on Anvisa's website. In addition, it is recommended for this petition subject:
• Submit justifications for any changes in analytical method that have occurred since the last
submission, including a brief summary of its characteristics and status of validation of the new method;
• Investigate and justify any deviation from specifications that has been found, even
that occurred only under the accelerated study conditions;
• Present stability study after dilution or reconstitution, for applicable products;
• Present a photo-stability study or justification for its absence;
• For files that have been updated since the previous submission, send a version with highlighted changes; and
• In cases where there are multiple manufacturing plants for IFA and for finished product, the files
sent should easily allow the identification of the manufacturing plants to which they refer.
Non-substantial changes do not have a specific petition issue and should be integrated into the
petition 10825 - CLINICAL TRIALS - Drug Development Safety Update Report
Experimental.
9
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
6. PROTOCOL AMENDMENTS
Amendments, in the context of RDC No. 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 must be filed when they are made.
implementation and its implementation must await manifestation, while non-substantial ones must be
presented as part of the annual clinical trial report. Details on procedures for filing
will be described below.
Substantial amendments can be filed at any time after the inclusion of the first clinical protocol to the
DDCM, even before Anvisa's final manifestation.
Substantial changes are those where one or more of the following criteria are met:
• Change in clinical trial protocol that interferes with 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:
The. Evaluate a therapeutic or diagnostic intervention that can lead to improvements in health or quality of life; or
B. It is a preliminary etiological, pathophysiological or epidemiological study to develop such an intervention;
or
ç. Test a hypothesis that can generate important knowledge about the structure or the
functioning of human biological systems, even if that knowledge has no immediate practical ramifications.
It is the sponsor's responsibility to assess whether an amendment is considered substantial or not and its impact on the
clinical development. This assessment should always be done on a case-by-case basis, based on the above criteria.
Here are some examples for each category of amendments, including examples of situations that do not
amendment. We emphasize that the list below is only illustrative, not exhausting all possibilities.
10
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
1. Substantial Amendments:
The. Changing the primary objective of the clinical protocol;
B. Change in primary outcomes;
ç. Use of a new parameter to measure the primary outcome;
d. Removal of the Independent Data Monitoring Committee initially planned for the study;
and. Change in the calculation of the sample size planned for the study.
2. Non-substantial amendments:
The. Alteration, addition or removal of exploratory outcomes;
B. Proposal to extend or continue the research with the same recruited participants,
without changing the design, methods and objectives of the original project. If any of these
modifications, another research protocol must be submitted, not an amendment;
ç. Addition of preventive security monitoring, unrelated to any security announcements issued.
d. New data or interpretation of pharmacological or toxicological data;
and. Change in the criteria established for the termination of the protocol, even though it has already ended;
f. Change in the inclusion and exclusion criteria;
g. Reduction in the number of scheduled visits;
H. Change in diagnostic procedures or medical monitoring;
i. Change in secondary or exploratory outcomes
j. Small clarifications to the protocol;
k. Spell check.
The applicant must update the Clinical Trial Submission Form whenever there is a change in the data there
contained (and not only at the time of submission of annual reports, for example), as these data reflect the
advertising of clinical trials on Anvisa's website and will be used to guide inspections in Good
Clinical Practices. The updating of this form does not depend on a prior opinion by the Agency, except when there are:
• Change in the title or code of the clinical trial protocol;
• Inclusion or exclusion of products under investigation to be imported
• Change in storage conditions and shelf life of the products under investigation.
11
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
For these cases, a new version of the CE will be issued.
3. Examples that do not constitute amendments to the protocol:
The. Researcher's Brochure Update. This must be requested as 10821
- CLINICAL TRIALS - Update of the Researcher's Brochure, unless it also substantiates changes in the
clinical protocol. In this case, the change must be evaluated by the Sponsor and classified as substantial
or not, and the respective procedures must be followed.
B. Changes to the DDCM submission form or attached documents. These must be requested as 10822 -
CLINICAL TRIALS - Alteration of the DDCM Petition Form.
ç. Changes to the clinical protocol submission form. These must be requested as 10823 -
CLINICAL TRIALS - Change of Clinical Trial Presentation Form.
1. The applicant must update the Clinical Trial Presentation Form whenever there is a change in the
data contained therein, as these data reflect the advertising of clinical trials on Anvisa's website and
will be used to guide inspections in Good Clinical Practice. Updating this form will not
depends on prior approval by the Agency, except when:
i. Change in the title or code of the clinical trial protocol;
ii. Inclusion or exclusion of products under investigation to be imported;
iii. Change in storage conditions and shelf life of the products under investigation.
For these cases, a new version of the CE will be issued.
d. Proposal for the extension of the clinical protocol in which changes in design, methods or objectives are foreseen. For
this type of change, a new clinical protocol must be added to the DDCM, and there is no need to amend the protocol
already submitted, as explained in the examples of non-substantial amendments.
and. Exclusion, cancellation, suspension or reactivation of clinical trial protocol.
Substantial amendments must constitute a petition secondary to the primary petition that inserted the clinical protocol in the DDCM
of the experimental medicine. As a suggestion for greater agility and ease in submitting amendments to
analysis, can be completed and submitted together with the other documents, optionally, Annex II of this manual,
available in DOC version on Anvisa's website. The subject
12
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
specific petition is 10824 - CLINICAL TRIALS - Substantial Amendment to Clinical Protocol.
Non-substantial amendments do not have a specific petition subject, and should be integrated with petition 1391 - TESTS
CLINICS - Annual Clinical Trial Protocol Monitoring Report with the same documents required for
substantial amendments.
13
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
7. SUSPENSIONS AND CANCELLATIONS
• For DDCM:
A DDCM can be canceled or suspended. These situations have their own petition issues and should not
constitute none of the aforementioned modification requests. After suspension decision
or cancellation, the sponsor must notify Anvisa within a maximum period of 15 calendar days.
If the cancellation occurs at the company's request, including cases of cancellation for security reasons, it must be
used the subject of petition 10826 - CLINICAL TRIALS - Cancellation of DDCM on request; if the
cancellation occurs by global transfer of responsibility, the subject of petition is 10827 -
CLINICAL TRIALS - Global Transfer of Responsibility on DDCM. It is important to remember that
Cancellations, under the terms of RDC No. 09/2015, are definitive, with no possibility of reactivation
later, and that once a DDCM is canceled, no clinical trial related to it can be
continued in the country. In the specific case of cancellation of DDCM on request, the requirements that must be
submitted for the monitoring plan and for the minimization / mitigation measures of
risks of clinical trial participants already underway are detailed in the Manual for Notification of Events
Adverse and Safety Monitoring in Clinical Trials.
It is important to remember that, for a DDCM, cancellation can occur at any time, even if it has not yet been
been evaluated.
For suspensions, the subject to be used is 10828 - CLINICAL TRIALS - Temporary suspension of DDCM. Per
definition, these have a temporary character and can be reversed with the subject of petition 10829 - TESTS
CLINICS - Reactivation of suspended DDCM. The reactivation depends on prior approval by Anvisa.
• For a Clinical Trial:
Like DDCM, an individual clinical trial can also be canceled or suspended. These situations have issues
own petitions and should not constitute any of the petitions for amendments mentioned above. After decision of
suspension or cancellation, the sponsor must notify Anvisa within a maximum period of 15 calendar days, except
in cases of temporary suspension as an immediate security measure, when the period is 7 days
from the date of suspension. In addition, cancellations, pursuant to RDC No. 09/2015, are
definitive, with no possibility of further reactivation.
14
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
It is important to remember that cancellation only applies to clinical trial protocols that have already been
started by the sponsor. If the protocol is provided for in the DDCM, but has not yet started,
the exclusion from the protocol must be made, as provided in the previous section.
If the cancellation occurs at the company's request, including cases of cancellation for security reasons, it must be
used the subject of petition 10767 - CLINICAL TRIALS - Cancellation of Clinical Trial Protocol on request;
if the cancellation is due to a global transfer of responsibility, the subject of the petition is 10053 - TESTS
CLINICS - Global Transfer of Responsibility on Clinical Trial Protocol. In the specific case
cancellation on request, the requirements that must be submitted for the monitoring plan and
for the risk minimization / mitigation measures of clinical trial participants are detailed in the Manual
for Adverse Event Notification and Safety Monitoring in Clinical Trials.
For suspensions, the subject to be used is 10830 - CLINICAL TRIALS - Temporary suspension of
Clinical Trial. By definition, these have a temporary character and can be reversed with the subject of
petition 10831 - CLINICAL TRIALS - Reactivation of suspended clinical trial protocol. Reactivation depends on
prior approval by Anvisa.
15
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
8. GLOSSARY
I - 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
aiming to obtain information to subsidize the registration or post-registration changes of said product;
II - 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;
III - 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;
IV - Clinical trial - research conducted in humans with the aim of discovering or confirming the effects
clinical and / or pharmacological and / or any other pharmacodynamic effects of the experimental medicine 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;
V - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, with the
purpose of obtaining information for your registration or post-registration;
VI - Representative Organization for Clinical Research (ORPC) - every company regularly installed
in national territory hired by the sponsor or by the sponsoring investigator, who assumes partial or
with Anvisa, the sponsor's duties;
VII - Placebo - formulation without pharmacological effect, administered to the participant of the clinical trial for the purpose of
masking or comparator;
VIII - Product under investigation - experimental drug, placebo, active comparator or any other product to be
used in the clinical trial;
IX - 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;
16
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
9. 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. EUROPEAN COMMISSION. Communication from the Commission - Detailed guidance on the request to the competent
authorities for authorization 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. Accessed in 20
November 2014.
3. FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments.
Available in:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
Approved / ApprovalApplications / InvestigationalNewDrugINDApplication / ucm362503.h tm. Accessed on November 19, 2014.
4. HEALTH CANADA. Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Available
at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic- demande / guide-ld / clini / ctdcta_ctddec-eng.php. Accessed on 21
November 2014.
17
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
10. ANNEXES
The attachments to this manual are also available in DOC format at Anvisa's Electronic Portal>
Medicines> Clinical Research> Forms.
ANNEX I
PETITION FORM FOR SUBSTANTIAL MODIFICATION OF THE MEDICAL DRUG CLINICAL DEVELOPMENT DOSSIER (DDCM)
Document Identification
National Health Surveillance Agency Clinical Research
Petition Form for Substantial Modification of the Clinical Drug Development Dossier (DDCM)
(For use by the receiving agency)
DDCM File Number Expedient (Day / Month
/ Year)
/ /
Company Data
Requestor Number
Authorization / Registration
3 4
5 Manufacturer 6
Authorization / Registration Number
DDCM data
Modification Type:
a) Inclusion of clinical trial protocol (s) not foreseen or different (s) from that (s) previously
established in the initial development plan?
b) Exclusion of clinical trial protocol (s)?
c) Changes that potentially impact quality or safety
7 of the product under investigation?
The. If yes, see item 9.
d) Modification resulting from recommendations or alerts issued by health authorities?
a) () Yes () No
b) () Yes () No
c) () Yes () No
d) () Yes () No
Reasons for Substantial Modification:
a) Changes related to the active pharmaceutical ingredient?
b) Changes related to the quality control and stability of the
8 active pharmaceutical ingredient and experimental medicine?
c) Changes related to excipient quality control?
d) Changes in the description and composition of the experimental drug?
a) () Yes () No
b) () Yes () No
c) () Yes () No
d) () Yes () No
e) () Yes () No
18
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
e) Changes related to the place of manufacture of the experimental medicine?
f) Changes related to the production process of the experimental drug?
g) Changes related to the production equipment of the experimental medicine?
h) Changes related to the batch size of the medication? experimental
i) Changes related to the packaging of the experimental drug?
j) Inclusion of a new presentation?
k) Changes related to the period of validity provided there has been a change in the criteria for
stability assessment previously established, that the values ​​are not within the ranges
permitted or that the validity period is defined based on reduced models of a study plan.
stability (grouping and matrix)?
l) Inclusion of a new concentration?
m) Inclusion of a new pharmaceutical form?
n) Changes related to dosage?
o) Expansion of use?
p) Inclusion of a new route of administration?
q) Inclusion of a new therapeutic indication?
r) Inclusion of placebo not previously provided for in the DDCM
f) () Yes () No
g) () Yes () No
h) () Yes () No
i) () Yes () No
j) () Yes () No
k) () Yes () No
l) () Yes () No
m) () Yes () No
n) () Yes () No
o) () Yes () No
p) () Yes () No
q) () Yes () No
r) () Yes () No
19
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
ANNEX II
SUBSTANTIAL AMENDMENT PETITION FORM TO CLINICAL TEST PROTOCOL
Document Identification
National Health Surveillance Agency Clinical Research
Petition Form for Substantial Amendment to Clinical Trial Protocol
(For use by the receiving agency)
File Number of the Dossier Specific to the Clinical Trial File (Day / Month / Year)
/ /
Company Data
Requestor Number
Authorization / Registration
3 4
5 Manufacturer 6
Authorization / Registration Number
Clinical Protocol Data
7 Petition Subject (codes and description) 8 Generating Fact (datavisa)
9 Title and Code of the Clinical Trial Protocol 10 Protocol No. (Version and
date)
Reasons for Substantial Amendment:
11 Trial Phase
I () II () III () IV ()
a) Changing the primary objective of the clinical protocol;
b) Change in primary outcomes;
c) Use of a new parameter to measure the primary outcome;
12 d) Removal of the Independent Data Monitoring Committee
initially planned for the study;
e) Change in the calculation of the sample size planned for the study
a) () Yes () No
b) () Yes () No
c) () Yes () No
d) () Yes () No
e) () Yes () No
20
ANNEX III
MODEL FOR SENDING UP-TO-DATE STABILITY INFORMATION
LONG TERM STABILITY STUDY (30 ° C ± 2 ° C / 75 UR ± 5% RH)
Product:
Active principle:
IFA Manufacturer Name and Address:
Name and Address of the Finished Product Manufacturer: Primary packaging:
Pharmaceutical form:
Manufacturing date:
Number of samples analyzed per period:
Study Start Date:
Study End Date:
Lot:
IFA Lot:
Lot size (IFA and Finished Product): Dosage:
Batch destination: Packaging position:
test
Specification
Method
*
Initial (t0)
**
3
months
**
6
months
**
9
months
**
12
months
**
18
months
**
24
months
**
36
months
* Also inform if it is pharmacopeial or not
** Justifications must be provided for any methods that will not or have not been implemented in all cases.
analysis times.
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
11. HISTORY OF CHANGES
1st Edition Version
2nd Edition
Changes made
• Inclusion of title 6. Change history (Page 15)
• Modifications to DDCM
---
Explanation and Justification
• Insertion of a comparative table of essays between versions for a more accurate monitoring
of updates made.
• Exclusion of example "a", once
2nd Edition
2nd Edition
2nd Edition
2nd Edition
o 2. Non-substantial changes.
▪ a. Update of the DDCM Petition Form. (Page 4)
• Modifications to DDCM
o 2. Non-substantial changes.
▪ b. Update of the Experimental Medication Development Plan. (Page 4)
• Modifications to DDCM
o 2. Non-substantial changes.
▪ c. Update of the comparator medicine package insert. (Page 4)
• Modifications to DDCM
that the form update is a secondary petition with its own subject, and should not be integrated into the report
annual situation of non-substantial change.
• Inclusion of the "Update on the Development Plan for Experimental Medicines" as an example of modification
non-substantial. Updating the plan is only required when petitioning for substantial changes, but
it must be possible to update it at the sponsor's discretion.
• Exclusion, for clarity, of example "c" after receipt of contribution, considering that the update of
comparator medication leaflet is not an item covered by RDC No. 09/2015.
• In line with the first amendment, the section that
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
2nd Edition
o The applicant must update the forms whenever there is a change in the data contained therein (and not only in the
when submitting annual reports, for example), as these data reflect
advertising of clinical trials on Anvisa's website and will be used to guide inspections in Good
Clinical Practices. The updating of this form does not depend on a prior opinion by the Agency. (Page 5)
• Amendments to the Protocol
o 2. Non-substantial amendments.
▪ c. Change in the documentation used by the study team to capture and record the data. (Page 9)
mentioned the possibility of sending an updated form in the case of non-substantial modification, since the
Form update is a secondary petition with its own subject.
• Exclusion of example "c" after receiving contributions reporting that the type of change highlighted is not included in the
clinical protocol. For all purposes, any changes to the documentation or media used during the protocol may
checked at the time of a BPC inspection.
2nd Edition
• Amendments to the Protocol
o 2. Non-substantial amendments.
▪ g. Update of Clinical Trial Presentation Form. (Page 9)
• Exclusion of example "g", since updating the form is a secondary petition with its own subject,
and should not be included in the annual report in the case of a non-substantial amendment.
2nd Edition
• Amendments to the Protocol
o The applicant must update the Clinical Trial Presentation Form whenever
• Excluded the section that mentioned the possibility of sending an updated form in the situation of modification
not-
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
change in the data contained therein (and not only when submitting the annual reports, for example), as these
data reflect the advertising of clinical trials on Anvisa's website and will be used to guide
inspections in Good Clinical Practice. Updating this form does not depend on a prior opinion by the Agency,
substantial, as the form update is a secondary petition with its own subject. The paragraph in its
integrity has been moved to constitute subitem of example "c" of item "3. Examples that do not constitute amendments to
protocol "for better fit and clarity.
2nd Edition
2nd Edition
2nd Edition
except when there are:
The. Change in the title or code of the clinical trial protocol;
B. Inclusion or exclusion of products under investigation to be imported
ç. Change in storage conditions and shelf life of the products under investigation.
For these cases, a new version of the CE will be issued. (Page 10)
• Changed the name of the petition subject to: 10827 - CLINICAL TRIALS - Global Transfer of Responsibility
about DDCM (page 14).
• Changed the name of the petition subject to: 10053 - CLINICAL TRIALS - Global Transfer of Responsibility
Clinical Trial Protocol (page 15).
• Title of item 1 of the Form contained in annexes I and II
• Exclusion of item 7 of the Form contained in annexes I and II
• Changing the name of the petition subject.
• Changing the name of the petition subject.
• As the request for the process number is already made in the header, field 7 has been removed to avoid
redundancies and the title of the
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
2nd Edition
3rd Edition
3rd Edition
• Added Annex III, "Template for sending updated stability information"
• Modifications to the DDCM:
o "Changing the expiration date must use subject 10849 - CLINICAL TRIALS - DDCM modification - Alteration
Expiry Date. As a suggestion for greater agility and ease in analyzing this type of petition, it can be
completed and submitted together with the other documents, optionally, Annex III of this manual "
• Modifications to DDCM
o 1. Substantial Modifications
▪ New item “q”: Inclusion of placebo not previously provided for in the DDCM;
• Modifications to DDCM
2. Non-substantial changes
▪ New item “c”: Any changes in placebos previously foreseen in the DDCM;
field 1 has been clarified for each form
• A model was created to send stability information, in an attempt to harmonize the information
received and optimize the analysis by technicians
• A new item referring exclusively to the placebo was inserted to be a counterpoint to the new sub-item “c”, item
2.
Non-substantial changes. The annexes to the Manual have been updated to reflect this change.
• Based on a risk analysis carried out by COPEC, it was decided to explicitly exemplify what changes
referring to placebos already foreseen previously are no longer considered substantial. A counterpoint was added
to item 1 of the same section to exclude from this situation the inclusion of placebos that were not included in the analysis
initial. Annexes to the Manual
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
3rd Edition
3rd Edition
4th Edition
4th Edition
• Amendments to the Protocol
o Substantial Amendments - transposition of the following examples to now appear as an example of
NON-substantial amendments:
d. New data or interpretation of pharmacological or toxicological data, which may have an impact on the analysis of
risk;
and. Change in the criteria established for the termination of the protocol, even though it has already ended;
f. Addition of experimental arms or placebo group;
g. Change in the inclusion and exclusion criteria;
H. Reduction in the number of scheduled visits;
i. Change in diagnostic procedures or medical monitoring;
j. Change in the product under investigation;
k. Change in the dosage of the product under investigation;
l. Change in the administration of the product under investigation;
m. Change in the design of the clinical protocol;
n. Change in secondary or exploratory outcomes
Update of Clinical Trial Presentation Form.
• Amendments to the Protocol
Thus, examples of changes in scientific value are the change from a placebo comparator to a comparator
active, the insertion of additional experimental arms or changes in the statistical analysis plan.
• Cover: inclusion of the effective date
• Item 5, subitem 1. Substantial Modifications:
The letters "b," d "to" i "had the term" product under investigation "changed to" experimental medicine "
have been updated to reflect this change.
• Based on a risk analysis carried out by COPEC, it was decided to list these items as examples of
NON-substantial amendments as of the 3rd edition. The annexes to the Manual have been updated to reflect this change.
• Considering the new examples from the list of substantial modifications, the removal of this paragraph was necessary
to align the text with the list of examples.
• Inclusion is to identify from which date the manual is in force
• The change was made to comply with the terms of RDC 09/2015.
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
4th Edition
4th Edition
4th Edition
4th Edition
4th Edition
• Item 5, subitem 1: Substantial Modifications
k. Changes related to the validity period since there has been a change in the criteria for
stability assessment previously established, that the values ​​are not within the limits of the
permitted ranges or that the validity period is defined based on reduced study plan models
changes (grouping and matrix) Changes related to the expiration date or
care of the product under investigation
• Item 5, sub-item 2: Non-substantial changes
d. Update on the Development Plan for Experimental Medicines, whose
change does not impact the clinical trials to be conducted in Brazil
• Item 5, sub-item 2: Non-substantial changes
and. Comparator package insert update
The remaining items were renumbered from "f" and "g" to "e" and "f".
• Item 5, sub-item 2: Non-substantial changes
g. Changes in validity periods not provided for in letter k of item 5, subitem 1 of substantial modifications
• Item 5 - Modifications to the DDCM
Substantial modifications must constitute a secondary petition to the primary petition of
submission of the DDCM for the experimental drug, with the exception of modification by inclusion of a
clinical trial not provided for in the initial development plan, which is a primary petition.
• The text was changed to reduce the situations in which the change in the validity period must
considered as a substantial modification.
• Phrase included to make it clear that in cases of substantial modification by inclusion
protocol not provided for in the plan, an updated development plan must be provided. To the
in other cases, the update is considered to be non-substantial.
• The example was taken to avoid confusion in understanding, as per question 3.2.8 of
Questions and Answers version 2 document.
• The inclusion was made to reflect the reduction of cases in which the change in the validity period
should be considered as substantial modification.
• The inclusion of the sentence was made to indicate that the substantial modification by
inclusion of a protocol not provided for in the initial development plan is a primary petition, as it
sets up the Specific Clinical Trial Dossier (DEEC), which is a primary petition.
Manual for Submitting Modifications,
Amendments, Suspensions and Cancellations
4th Edition
4th Edition
4th Edition
4th Edition
4th Edition
4th Edition
• Item 5, subitem 2, Non-substantial amendments c. Change in documentation used by the study team to
data capture and recording;
Subsequent letters were renumbered from "d" to "l" to "c" to "k".
• Annex I, item 8
k. Changes related to the validity period since there has been a change in the criteria for
stability assessment previously established, that the values ​​are not within the limits of the
permitted ranges or that the validity period is defined based on reduced study plan models
changes (grouping and matrix) Changes related to the expiration date or
care of the product under investigation
• Annex I, item 8:
• r.Exclusion of drug manufacturing site or primary packaging site or secondary packaging site or
product manufacturing site?
• Annex I, item 8:
• t.Other changes?
o If yes, specify:
• Annex II, item 12: exclusion of the item
The subsequent item was renumbered "13" to "12".
• Annex II, item 13:
f) Other changes?
o If yes, specify:
• The example was taken to avoid confusion in understanding, as per question 3.2.12 of
Questions and Answers version 2 document.
• Change made to reflect changes to the manual
• Exclusion of the item to reflect the criteria established in the manual
• Exclusion of the item to reflect the criteria established in the manual as a substantial modification
• Exclusion of the item, as the criteria established to be considered a substantial amendment is already in
subsequent question.
• Exclusion of the item to reflect the criteria established in the manual as a substantial amendment