Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
v. 1
Brasilia, 2015
portal.anvisa.gov.br
Copyright © 2015. National Health Surveillance Agency.
Partial or total reproduction of this work is permitted, provided the source is mentioned. Legal Deposit at the National Library,
according to Decree No. 1.825, of December 20, 1907.
CEO
Jaime César de Moura Oliveira
Deputy Chief Executive Officer
Diogo Penha Soares
Directors
José Carlos Magalhães da Silva Moutinho Renato Alencar Porto
Ivo Bucaresky
Chief of Staff
Luciana Shimizu Takara
Superintendence of Correlates and Food
João Tavares Neto
Coordination of Clinical Research in Correlates and Food
Alessandro Ferreira do Nascimento
Responsible for the manual:
Alessandro Ferreira do Nascimento
Collaboration:
Adriane Alves de Oliveira
André Luís Carvalho Santos Souza Bruno de Paula Coutinho
Bruno Zago Franca Diniz Candida Luci Pessoa and Silva Carla Abrahao Brichesi Carlos Augusto Martins Netto Claudio
Nishizawa
Fanny Nascimento Moura Fernando Casseb Flosi Flávia Regina Souza Sobral
Janaina Lopes Domingos Kellen from Rocio Malaman Miriam Motizuki Onishi Patrícia Ferrari Andreotti Ricardo Eccard da
Silva Sônia Costa e Silva
summary
1. Introduction
2
2. Modifications to the DICD
3
3. Amendments to the Protocol
6
4. Suspensions and Cancellations 10
5. References
12
Attachments
13
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
1. Introduction
Without prejudice to the existing provisions in the legal provisions, this manual aims to guide
submissions of modifications to the Medical Device Clinical Investigation Dossier (DICD), amendments to
clinical protocols, suspensions and cancellations, as described in chapters III, IV and V of RDC 10/2015.
The document is broken down into specific sections for each type of change. The changes are described in detail,
with examples and the respective specific petition matters.
This manual 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, and is not intended to expand or restrict technical requirements or
established administrative procedures.
The guidelines contained in this manual are subject to receiving suggestions from society in the form and for a period to be
established by Anvisa. Thus, this manual is open to contributions, with a process of
recurring review. The suggestions received will be evaluated to support the revision of the manual and consequent
publication of a new version with each update.
We emphasize that the situations and examples contained in this manual are illustrative, but in a
restrictive or exhaustive. Each situation must be assessed “on a case-by-case” basis, and contexts that
just described must always be accompanied by justifications.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
2. Modifications to the DICD
Modifications to the DICD, in the context of RDC 10/2015, are defined as any changes made in the global context
DICD - especially those related to the quality of the product under investigation - or modifications
administrative tasks, such as form updates.
All modifications must be submitted to Anvisa: the substantial modifications must be
when it is carried out, and its implementation must await a manifestation from this agency, while
non-substantial ones should be presented as part of the development security update report
medical device under investigation. Details on the application procedures will be
described below.
Substantial changes can be filed at any time after the initial submission of the DICD, including
before the final manifestation of Anvisa.
For the purposes of the Resolution, substantial changes consist of:
I - Inclusion of clinical trial protocol (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 Medical Device under Investigation,
active comparator, placebo or simulated device.
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 product quality or safety under
investigation. We emphasize that the lists below are illustrative only, not exhausting all possibilities:
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
1. Substantial changes:
The. Changes related to the design of the medical device;
B. Changes related to the design of the medical device;
ç. Inclusion of new presentation;
d. Changes related to the expiration date or care of conservation of the product under investigation;
and. Expansion of use;
f. Inclusion of a new therapeutic indication;
2. Non-substantial changes:
The. Update of the DICD Petition Form that does not foresee the changes mentioned above;
B. Change in labeling of the product under investigation;
ç. Update of instructions for use of the comparator medical device;
d. Spell check in documents;
and. Small clarifications.
To modify any information contained in the Form, simply submit a new form with
the updated information and document describing the justifications for each change. Amendment to non-clinical trial
constitutes modification, as explained in the next section. It is recommended that substantial modifications be
accompanied by a comparative table, if applicable.
The applicant must update the forms whenever there is a change in the data contained therein (and not only
time of submission of annual reports, for example), as these data reflect the publicity of the trials
on the Anvisa website and will be used to guide inspections in Good Practices
Clinics. The updating of this form does not depend on a prior opinion by the Agency.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
Substantial modifications must constitute a secondary petition to the primary petition for submission of the
Investigative Medical Device DICD. The inclusion and exclusion of clinical trials has important
own, namely:
• 80107 - CLINICAL TRIALS - Modification of DICD - Inclusion of 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 carried out using specific subject, according to the Manual for Submission of Development Dossier
Medical Device Clinician (DICD) and Specific Clinical Trial Dossier.
• 80108 - CLINICAL TRIALS - Modification of DICD - Exclusion of clinical trial protocol
Changes that potentially impact the quality or safety of the Medical Device in
Research, simulated device, active comparator or placebo, according to the examples above, should use the
petition subject 80109 - CLINICAL TRIALS - DICD modification - Alteration that potentially generates
impact on the quality or safety of the product under investigation. Must be presented
(comparative) documentation of the initial situation and the proposal accompanied by technical and
any additional documents required to prove that the change will not impact development
product.
It is worth mentioning that it is the sponsor's responsibility to evaluate and classify the changes prior to
submission to the agency, so that a risk / benefit analysis and need for
supporting documentation. For greater agility and ease in submitting changes to analysis, you can
Attachment I of this manual must be completed and submitted together with the other documents.
Non-substantial modifications do not have a specific petition subject and should be integrated into the petition
80121 - CLINICAL TRIALS - Medical Device Clinical Development Report.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
3. Amendments to the Protocol
Amendments, in the context of RDC 10/2015, are defined as any changes made to the clinical protocol (s),
whether they are substantial or not.
All amendments must be submitted to Anvisa, as follows:
• Substantial ones must be filed when they are carried out and their implementation must wait
manifestation of this agency.
• Nonsubstantials must be presented as part of the clinical trial annual report.
Substantial amendments can be filed at any time after the inclusion of the first protocol
to the DICD, even before the final manifestation of Anvisa.
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 will have scientific value if:
a) 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
c) Test a hypothesis that can generate important knowledge about the structure or the
functioning of human biological systems, even if that knowledge has no practical ramifications
immediate.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
Thus, examples of changes in scientific value are the change in the comparability profile (active comparator
for historical series, for example), the insertion of additional experimental arms or changes in the
statistical analysis.
It is the sponsor's responsibility to assess whether an amendment is considered substantial or not and its impact
in 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 constitute an amendment.
We emphasize that the list below is only illustrative, not exhausting all possibilities.
1. Substantial Amendments:
The. Changing the primary objective of the clinical protocol;
B. Change in primary and / or secondary outcomes;
ç. Use of a new parameter to measure the primary outcome;
d. New data or interpretation of non-clinical data, which may have an impact on risk analysis;
and. Change in the criteria established for the termination of the protocol, even though it has already ended;
f. Addition of experimental 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 diagnostic procedures or medical monitoring;
k. Removal of the Independent Data Monitoring Committee initially planned for the study;
l. Change in the product under investigation;
m. Change in the procedure adopted to subject the research subject to that of the product under investigation;
n. Change in the design of the clinical protocol;
O. Change in the initial statistical analysis plan.
2. Non-substantial amendments:
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
The. Alteration, addition or removal of exploratory outcomes;
B. Proposal for the extension or continuation of the research with the same recruited participants, without
changes in the design, methods and objectives of the original project; occurring such changes, should be
another research protocol was submitted, not an amendment;
ç. Change in the documentation used by the study team to capture and record the data;
d. Addition of preventive security monitoring, unrelated to any security announcements
issued.
and. Small clarifications to the protocol;
f. Spell check;
g. Update of Clinical Trial Presentation Form.
The applicant must update the Clinical Trial Submission Form whenever there is a change in the
data contained therein (and not just when submitting annual reports, for example), as these data
reflect the advertising of clinical trials on Anvisa's website and will be used for
guide inspections in Good Clinical Practices. Updating this form does not depend on a manifestation
prior notice from the Agency, except when:
• 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.
For these cases, a new version of the Special Communiqué (CE) will be issued.
3. Examples that do not constitute amendments to the protocol:
The. Researcher's Brochure Update. This must be requested using subject 80110
- CLINICAL TRIALS - Researcher Brochure Update - Medical Devices, unless also configured
change in 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.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
B. Changes to the DICD submission form or attached documents. These must be requested using
subject 80111 - CLINICAL TRIALS - Alteration of the DICD Petition Form.
ç. Changes to the clinical protocol submission form. These must be requested using subject 80112
- CLINICAL TRIALS - Change of Clinical Trial Presentation Form - Medical Devices
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 DICD, with no amendment to
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 process that inserted the clinical protocol in
Investigative Medical Device DICD. As a suggestion for greater agility and ease in submitting
amendments to the analysis, Appendix II of this manual can be completed and submitted with the other documents. The subject
specific request is 80113 - CLINICAL TRIALS - Substantial Amendment to Clinical Protocol - Medical Devices
Non-substantial amendments do not have a specific petition subject, and must be integrated into the petition
80120 - CLINICAL TRIALS - Annual Clinical Trial Protocol Monitoring Report - Devices
Doctors, with the same documents required for substantial amendments.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
4. Suspensions and Cancellations
• For DICD:
A DICD can be canceled or suspended. These situations have their own petition issues and should not
constitute none of the aforementioned modification requests. After decision of
suspension 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 80114 - CLINICAL TRIALS - Cancellation of DICD on request; if the
cancellation occurs by global transfer of responsibility, the subject of petition is 80115 -
CLINICAL TRIALS - Cancellation of DICD due to global transfer of responsibility
by the Responsible Sponsor. It is important to remember that cancellations, under the terms of RDC 10/2015, are
definitive, with no possibility of further reactivation, and that once a DICD has been canceled, no clinical trial
related to it may be continued in the country.
In the specific case of cancellation of DICD on request, the requirements that must be submitted for the
monitoring plan and risk minimization / mitigation measures for trial participants
ongoing clinical trials.
It is important to remember that, for a DICD, cancellation can occur at any time, even if it has not yet
been evaluated.
For suspensions, the subject to be used is 80116 - CLINICAL TRIALS - Temporary suspension of DICD. Per
definition, these have a temporary character and can be reversed with the subject of petition 80117 -
CLINICAL TRIALS - Reactivation of suspended DICD. The reactivation depends on prior approval by Anvisa.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
• For a Clinical Trial:
Like the DICD, 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 calendar days from
from the date of suspension. In addition, cancellations under RDC 10/2015 are final,
with no possibility of further reactivation.
It is important to remember that the cancellation only applies to clinical trial protocols that have already been initiated by the
sponsor. If the protocol is provided for in the DICD, but has not yet been started, the
exclusion from the protocol, as provided in the previous section.
If the cancellation is at the company's request, including cases of cancellation for security reasons, you must
the subject of petition 80123 - Cancellation of Clinical Trial Protocol on request -
Medical Devices; if the cancellation occurs by global transfer of responsibility, the matter of
petition is 80124 - CLINICAL TRIALS - Cancellation of Clinical Trial Protocol due to transfer
global responsibility - Medical Devices. In the specific case of cancellation on request,
requirements that must be presented for the monitoring plan and for the
risk minimization / mitigation measures for clinical trial participants.
For suspensions, the subject to be used is 80118 - CLINICAL TRIALS - Temporary suspension of
Clinical Trial - Medical Devices. By definition, these are temporary in nature and can be reversed
with the subject of petition 80119 - CLINICAL TRIALS - Reactivation of Suspended Clinical Trials Protocol -
Medical Devices. The reactivation depends on prior approval by Anvisa.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
5. References
BRAZIL. ANVISA. National Health Surveillance Agency. RDC Resolution No. 10, of February 20, 2015,
published in the D.O.U. March 3, 2015. Provides for the regulation for conducting tests
medical devices in Brazil. Official Diary of the Union; Executive Branch, of March 3, 2015.
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 in:
http://ec.europa.eu/health/files/eudralex/vol- 10 / 2010_c82_01 / 2010_c82_01_en.pdf. Accessed on November 20, 2014.
FOOD AND DRUG ADMINISTRATION. IND Application Reporting: Protocol Amendments. Available
in:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAppr
oved / ApprovalApplications / InvestigationalNewDrugINDApplication / ucm362503.htm.
Accessed on November 19, 2014.
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 November 21, 2014.
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
Attachments
ANNEX I
PETITION FORM FOR SUBSTANTIAL MODIFICATION OF THE MEDICAL DEVICE CLINICAL DEVELOPMENT DOSSIER (DICD)
Document Identification
National Health Surveillance Agency
Coordination of Clinical Research in Correlates and Food Petition Form for Substantial Modification of Dossier
Medical Device Development (DICD)
(For use by the receiving agency)
Process number
1
Hours (Day / Month / Year) 2 / /
Company Data
Requestor Number
Authorization / Registration
3 4
5 Manufacturer 6
Authorization / Registration Number
DICD data
7 Process number of the Medical Device Clinical Development (DICD) dossier:
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 have an impact on quality or
8 product safety 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
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
Reasons for Substantial Modification:
a) Changes related to the design of the medical device;
b) Changes related to the design of the medical device;
c) Inclusion of a new presentation;
d) Changes related to the expiration date or care of conservation of the product under investigation;
e) Expansion of use;
f) Inclusion of a new therapeutic indication;
9 g) Changes related to the packaging of the Medical Device under Investigation?
h) Inclusion of a new presentation?
i) Changes related to the expiration date or care of the Medical Device in
Investigation?
j) Other changes?
The. If yes, specify:
a) () Yes () No
b) () Yes () No
c) () Yes () No
d) () Yes () No
e) () Yes () No
f) () Yes () No
g) () Yes () No
h) () Yes () No
i) () Yes () No
j) () Yes () No
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
ANNEX II
PETITION FORM FOR SUBSTANTIAL AMENDMENT TO CLINICAL TEST PROTOCOL
Document Identification
National Health Surveillance Agency
Coordination of Clinical Research in Correlates and Food Petition Form for Substantial Amendment to Protocol of
Clinical Trial
(For use by the receiving agency)
Process number
1
Hours (Day / Month / Year) 2 / /
Company Data
Requestor Number
Authorization / Registration
3 4
5 Manufacturer 6
Authorization / Registration Number
Clinical Protocol Data
7 Process number of the clinical trial protocol and its linked DICD:
8 Subject of the Petition (codes and description) 9 Factual Generator (datavisa)
10 Title and Code of the Clinical Trial Protocol 11 Protocol No. (Version and date)
12 Trial Phase
I () II () III () IV ()
() Feasibility () Pivotal
() others, specify
Substantial Splice Type
a) Change in the clinical trial protocol that interferes with the safety or physical or mental integrity of the
participants?
B) Change in the scientific value of the clinical trial protocol?
a) () Yes () No
b) () Yes () No
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Manual for Submitting Modifications, Amendments, Suspensions and Cancellations
Reasons for Substantial Amendment:
a) Changing the primary objective of the clinical protocol;
b) Change in primary and / or secondary outcomes;
c) Use of a new parameter to measure the primary outcome;
d) New data or interpretation on non-clinical data, which may have an impact on the analysis of
risk;
e) Change in the criteria established for the termination of the protocol, even if it has already ended;
f) Addition of experimental 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 diagnostic or monitoring procedures
14 doctors;
k) Removal of the Independent Data Monitoring Committee initially planned for the study;
l) Change in the product under investigation;
m) Change in the procedure adopted to subject the research subject to that of the product under investigation;
n) Change in the design of the clinical protocol;
o) Change in the initial statistical analysis plan.
p) Other changes?
The. If yes, specify:
a) () Yes () No
b) () Yes () No
c) () Yes () No
d) () Yes () No
e) () Yes () No
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