NIS Considerations - Brazil - CHCUK · 2018. 8. 28. · Brazil* Brazilian Research-based...

NIS Considerations - BrazilAn overview of the considerations when conducting Non-interventional Studies in Brazil

Stuart McCully • Compliance Healthcheck Consulting UK Ltd • NIS-C-BR-2012

©"Dr"Stuart"McCully"2012NIS3C3BR32012

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Table of Contents

Disclaimer! 6

Regulatory Requirements ! 7

COUNTRY-SPECIFIC REGULATORY REQUIREMENTS 7

REGULATORY BODIES 7

DEFINITION 8

Non-interventional Studies 8

Phase IV Research 8

REGULATORY FRAMEWORK 10

Applicable Legislation & Guidance 10

SUMMARY OF THE NIS REQUIREMENTS IN BRAZIL 12

APPROVAL & NOTIFICATION REQUIREMENTS 13

WHO IS RESPONSIBLE FOR WHAT? 14

THE CEP/CONEP SYSTEM 15

CEP/CONEP System Roles and Responsibilities 15

REGULATORY SUBMISSIONS ROADMAP 18

Approval of Research Projects in CONEP 19

REGULATORY SUBMISSIONS DOCUMENTS 22

Platform Brazil 22

REGULATORY SUBMISSION REQUIREMENTS 25

Cover Sheet for Research Involving Humans 25

SUBJECT OF RESEARCH 25

RESPONSIBLE RESEARCHER 26


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APPLICANT INSTITUTION 26

SPONSOR NA () 27

RESEARCH ETHICS COMMITTEE - CEP 27

NATIONAL COMMISSION FOR RESEARCH ETHICS - CONEP 28

Instructions for Filling Out the CONEP Cover Sheet for Research Involving Humans 28

Flowchart for Research Involving Humans 32

REGULATORY REQUIREMENTS - USEFUL LINKS 34

Study Conduct Considerations! 36

DEFINITIONS 36

Freely Given and Informed Consent 36

Non-interventional Studies 36

Phase IV Research 36

RESEARCH INVOLVING HUMAN SUBJECTS 37

Ethical Aspects of Research Involving Human Subjects 37

RESEARCH INVOLVING INDIGENOUS COMMUNITIES 41

Research Involving Indigenous Communities and Individuals 41

Ethical Aspects of Research Involving Indigenous Peoples 41

The Research Protocol (Research with Indigenous Communities) 42

Protection of Research Subjects (Research with Indigenous Communities) 43

INFORMED CONSENT 43

Documentary Requirements 43


NON-INTERVENTIONAL STUDIES 46

Considerations for Conducting Non-Interventional Studies 46

Purpose 46

Responsibilities of the Researcher 46

Intellectual Property, Technology, Data and Biological Material Transfer 47


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Competent Authority Approval 48

Favourable Ethics Opinion 48

Platform Brazil 49

Research Coordinated from Abroad and/or Involving Human Genetics 49

Reporting and Notifications to the Ethics Committee(s) 50

Contract 50

Protocol 52

Financial Compensation/ Remuneration 55

Adverse Event Reporting 56

Notification of SAEs to ANVISA 56

Notification of SAEs to CONEP 58

Study Registration 60

STUDY CONDUCT CONSIDERATIONS - USEFUL LINKS 61

Human Tissue Research! 63

DEFINITIONS 63

Biobank 63

Biorepository 63

THE REGULATORY FRAMEWORK 63

Registration of Biobanks 64

INFORMED CONSENT 64

OPERATIONAL ISSUES 66

Main Ethical and Operational Differences between Biobanks and Biorepositories 66

Collection Strategies 66

Custodianship 67

Access to Samples 68

Research Results 68

Disposal of Samples 69

HUMAN GENETIC RESEARCH 70


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General Principles 70

Ethical Aspects 71

Research Protocol 73

Informed Consent 74

Operational Aspects 75

HUMAN TISSUE RESEARCH CONSIDERATIONS - USEFUL LINKS 77

Best Practice Considerations! 79

DEFINITIONS 79


NON-INTERVENTIONAL STUDIES 79

Phase IV Research 79

CONSIDERATIONS FOR CONDUCTING NON-INTERVENTIONAL STUDIES 80

Purpose 80

Responsibilities of the Researcher 80

Prohibition of Promotion 81

Transparency in Professional Relationships 82

Limited Involvement of Medical Reps 82

Contract 82

Giveaways and Gifts 84

Gifts 84

Prohibited Items 84

Donations and Contributions 85

Attendance at Scientific Events, Hospitality and Travel 86

Company-Sponsored Events 86

Company’s Own Events 86

Venue 86

Reimbursement of Costs 86

Lunches and Snacks 87


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Entertainment 87

Prohibition of Promotion 88

Prohibited to Offer First Class Tickets 88

Hospitality and Related Payments - Further Considerations 88

Is it possible to pay for a doctor in connection with attending a scientific meeting? If so, what may be paid for? Is it possible to pay for his expenses (travel, accommodation, enrolment fees)? Is it possible to pay him for his time? 88

To what extent will a pharmaceutical company be held responsible by the regulatory authorities for the contents of and the hospitality arrangements for scientific meetings, either meetings directly sponsored or organised by the company or independent meetings in respect of which a pharmaceutical company may provide sponsorship to individual doctors to attend? 89

Is it possible to pay doctors to provide expert services (e.g. participating in focus groups)? If so, what restrictions apply? 89

Is it possible to pay doctors to take part in post marketing surveillance studies? What rules govern such studies? 89

Is it possible to pay doctors to take part in market research involving promotional materials? 90

BEST PRACTICE CONSIDERATIONS - USEFUL LINKS 91

NIS Definitions! 92

EUROPEAN NIS DEFINITIONS 92

NIS DEFINITIONS 92

Non-interventional Study (NIS) 92

Post-authorisation Safety Study (PASS) 93

Post-authorisation Efficacy Studies (PAES) 93

Common NIS Terminology! 94

COMMONLY USED NIS TERMS 94

COMMON NIS TERMINOLOGY 94


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DisclaimerAlthough this Compilation contains information of a legal nature, it has been developed for

informational purposes only and does not constitute legal advice or opinions as to the current

operative laws, regulations, or guidelines of any jurisdiction. In addition, because new

standards are issued on a continuing basis, this Compilation is not an exhaustive source of all

current applicable laws, regulations, and guidelines relating to non-interventional studies.

While reasonable efforts have been made to assure the accuracy and completeness of the

information provided, researchers and other individuals should check with local authorities

and/or research ethics committees before starting research activities.


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Regulatory Requirements COUNTRY-SPECIFIC REGULATORY REQUIREMENTS

REGULATORY BODIES

Competent Authority

Research Ethics Committees

Data Protection Agency

Pharmaceutical Self-Regulation Body

Pharmaceutical Code of Practice

The National Health Surveillance Agency

(ANVISA)

National Research Ethics Commission

(CONEP)

(Coordination and accreditation centre for the

institutional/ regional ethics committees)

Comitê de Ética em Pesquisa (CEP)

(Regional/ institutional ethics committees, of which

there are approximately 600 through Brazil to which

most research protocols will be sent for review. Special

projects are reviewed by CONEP)

There is no national regulatory authority in

Brazil*

Brazilian Research-based Pharmaceutical

Manufacturers Association (Interfarma)

Interfarma Code of Conduct - 2012 Revision

* refer to ‘Linklaters - Brazil’ for a summary of the data protection considerations


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http://www.anvisa.gov.br/eng/index.htm

http://www.anvisa.gov.br/eng/index.htm

http://www.conselho.saude.gov.br/Web_comissoes/conep/index.html

http://www.conselho.saude.gov.br/Web_comissoes/conep/index.html

http://www.conselho.saude.gov.br/Web_comissoes/conep/aquivos/cep/documentos/CEPs_credenciados_novembro_2010.pdf

http://www.conselho.saude.gov.br/Web_comissoes/conep/aquivos/cep/documentos/CEPs_credenciados_novembro_2010.pdf

http://www.interfarma.org.br/site2/index.php

http://www.interfarma.org.br/site2/index.php

http://livepage.apple.com/

http://livepage.apple.com/

https://clientsites.linklaters.com/Clients/dataprotected/Pages/Brazil.aspx

https://clientsites.linklaters.com/Clients/dataprotected/Pages/Brazil.aspx

DEFINITION

Non-interventional Studies

There is no specific mention of “non-interventional studies” in the legislation or guidelines.

However, these types of study are captured under the scope of “Phase IV Research” which is

defined on the ANVISA Website and in Resolution 251/97.

Phase IV Research

This is research performed when the product and/or therapeutic specialty is commercially

available (as per Section II.2.d of Resolution 251/97).

This research is based on the characteristics under which the medicine and/or therapeutic

specialty was authorized. These are usually post-commercialization surveillance studies that

aim at establishing the therapeutic value, [verifying] the emergence of new adverse reactions

and/or confirming the frequency of known adverse reactions, as well as the treatment

strategies (as per Section II.2.d of Resolution 251/97).

The same ethical and scientific norms applied in the research in the previous phases should be

used in Phase IV research (as per Section II.2.d of Resolution 251/97).

Once a medicine and/or therapeutic specialty is already commercially available, the clinical

research performed to explore new indications, new methods of administration, or new

combinations (associations), etc. shall be considered research of a new medicine and/or

therapeutic specialty (as per Section II.2.d of Resolution 251/97).

The post-marketing studies (Phase IV) are not primary object of this rule and are subject to

the "Notification on clinical research – Class 1". It is established that the initiation of these

studies should occur only after obtaining approval from the ethics in accordance with the law

(as per Article 5 of Resolution 39/08).

Except from the above provisions, the search for phase IV involving vaccines and research that

aimed to evaluate effectiveness and safety for drugs which have authorization for marketing or

revalidation of it, being regarded as the phase III (as per Article 5 of Resolution 39/08).


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http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Inicio/Medicamentos/Assunto+de+Interesse/Pesquisa+clinica/Consideracoes+e+definicoes+para+Pesquisa+Clinica


http://www.conselho.saude.gov.br/resolucoes/1997/Reso251.doc










http://www.anvisa.gov.br/medicamentos/pesquisa/legis/rdc39_08.pdf




ANVISA approval (in the form of a “Comunicado Especial”) is not required for non-

interventional studies:

Epidemiological studies, observational studies, in which there is no intervention at the

moment do not need the special bulletin issued by ANVISA (as per the ANVISA

Guidance).

If a drug and / or medical specialty has been sold, but need to demonstrate their safety

and effectiveness, or explore new indications, new methods of administration or new

combinations (associations), etc.; these trials must be controlled phase III studies (as

per the ANVISA Guidance).


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THE CEP/CONEP SYSTEM

In order to guarantee the respect to the ethical aspects related to research in human beings,

the Brazilian National Health Council created in 1996 the CEP/CONEP System. The CEP/

CONEP System represents the organized form of social control over the practices of science.

This System is responsible for the review and monitoring of the ethical aspects of scientific

research involving human beings throughout the national territory, keeping the databases

updated (Lopes, 2011).

CEP/CONEP System Roles and Responsibilities

The CEP/CONEP System ensures and safeguards the integrity of rights and freedom of the

volunteers participating in research, protecting them from potential abuse. On the other

hand, it assures society that the research is being ethically developed, i.e. that the interests

and the welfare of the human being prevail over the interests of researchers, society and

science. The economic and social conditions shown before make vulnerable part of our

population, limiting its autonomy. For this reason special attention is given to the recruitment

of human beings as subjects of research (Lopes, 2011).

It is also responsible for informing and advising the Ministry of Health, the Health National

Council and other instances of the Unified Health System, as well as the government and

society, on ethical issues regarding research with human beings (Lopes, 2011).

The System is formed by The National Commission for Ethics in Research (CONEP) directly

linked to the National Health Council. The Ministry of Health is responsible for the

functioning of the Commission and its Executive Secretariat; and The Committees for Ethics

in Research (CEPs) directly linked to the scientific research institutions. The scientific

research institutions are responsible for the functioning of the Committees and its Executive

Secretariat. Members of the CEP/CONEP System have complete independence to make

autonomous decisions in the exercise of their functions, keeping the confidentiality of all

information received (Lopes, 2011).

CEP is an independent and interdisciplinary committee, formed by members of both sexes,

with advisory, deliberative and educational character, designed to protect the interests of

research subjects in their integrity and dignity and to contribute to the development of

research within ethical standards. Institutions that conduct research involving human beings

may have one or more CEPs, as needed. CEPs maintain regular communication with CONEP.


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http://ec.europa.eu/bepa/european-group-ethics/docs/activities/brazil_anibal_gil_lopes.pdf








Their quarterly reports include the analyzed protocols, completed or in process (Lopes,

2011).

CONEP is an independent and interdisciplinary commission of the National Health Council,

formed by 30 members and 5 substitutes of both sexes, with consultative, deliberative,

legislative and educational duties. Each CEP indicates 2 candidates for the Health National

Council which is responsible to elect the members of CONEP for a 4 years term, with a

renewal of 1⁄2 of them every 2 years (Lopes, 2011).

CONEP coordinates the action of 598 CEPs established throughout the country. Over 9,000

members meet regularly in order to analyze and review the research protocols on human

beings submitted by scientists from different areas of knowledge. During the last 3 years, over

30,000 protocols were analyzed by the CEP/CONEP System (Lopes, 2011).

The CEP/CONEP System aims to:

Provide transparency in the scientific research process to bring under social control

potential conflicts of interests while preserving the confidentiality necessary to ensure

the intellectual property of researchers.

Potentiate and broaden the autonomy of subjects of research, strengthening the

participation of representatives and users of SUS (Public Health System) in the

Committees for Ethics in Research.

Establish the importance of the process for obtaining free and informed consent,

checking all aspects of the vulnerability conditions (physical, psychological and socio-

economical).

Ensure that the language used in the free and informed consent is clear and simple in

order to guarantee an easy understanding of all risks and benefits involved in the

experimental protocol.

Ensurethatancillarymedicaltreatmentisprovidedduringtheclinicaltrial.

Ensure that proper treatment and compensation are provided for subjects of research

injured during trials.

Ensure access to medicines in test, after the completion of the clinical study,

independently of the registration or commercialization of the drug in Brazil.


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In accordance with Brazilian regulations, the use of placebo control is ethically

acceptable when there is no effective treatment and its use will not cause any harm to

the participant.


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REGULATORY SUBMISSIONS DOCUMENTS

Note - Submission made through ‘Platform Brazil’

Platform Brazil

In order to further the social control on the ethics in research and give public transparency to

the research conducted in human beings, recently d the “Plataforma

Brasil” (www.saude.gov.br/plataformabrasil) was launched as an on line Brazilian data base

designed to facilitate the management of all the Research Protocols involving human subjects

analyzed by the CEP/CONEP System. This Platform allows following up scientific protocols

from the submission to the CEP/CONEP System up to its final approval and execution,

including the monitoring of its development via partial and final reports (Lopes, 2011).

The system provides transparency of the ethical analysis by offering access of public data of all

approved research protocols and of the operational flux of the analyses. This methodology

significantly reduces the time spent in the ethical analysis (Lopes, 2011).

Documents* Comments

Cover sheet for research involving humans

• All fields must be filled.

• Watch for date fields and signatures, which must be properly identified (full name and title, preferably by stamp), compatible with protocol information.

• The title should be in Portuguese and identical to that presented in the research project. (Res. CNS 196/96 VI.1 and Operational Manual for CEP, 9.1)


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REGULATORY REQUIREMENTS - USEFUL LINKS

Useful Links Accessed From

CONEP Circular No. 039/2011 - Use of

Data from Medical Records for the

Purposes of Research

http://www.conselho.saude.gov.br/

Web_comissoes/conep/carta_circular/

Uso_de_dados_de_prontuarios_para_fins

_de_Pesquisa.pdf

CONEP Standard Operating Procedures -

NP 002/007 - Approval of Research

Projects in CONEP

http://www.conselho.saude.gov.br/

Web_comissoes/conep/aquivos/

documentos/normaseprocedimento.doc

Constitution of Brazil http://www.v-brazil.com/government/

laws/titleII.html

Lopes - 2011: Aníbal Gil Lopes. Brazilian

R&D status and Brazilian System for ethical

analysis of scientific protocols involving

human subjects. 2011

http://ec.europa.eu/bepa/european-

group-ethics/docs/activities/

brazil_anibal_gil_lopes.pdf

Ministry of Health Ordinance No. 2201 -

National Guidelines for Biorepositories and

Biobanks (Ordinance No. 2201, dated 14

September 2011)

http://www.poderesaude.com.br/portal/

images/stories/1_-_Publicao_-_SIM_-

_15.09.2011.pdf

Ministry of Health Resolution No. 39/08 -

on the Rules for the Conduct of Clinical

Research Among Other Provisions

http://www.anvisa.gov.br/medicamentos/

pesquisa/legis/rdc39_08.pdf

Platform Brazil http://aplicacao.saude.gov.br/

plataformabrasil/login.jsf

Resolution CNS No. 196/96 -Approves the

guidelines and rules for research involving

humans

http://conselho.saude.gov.br/resolucoes/

1996/Reso196.doc


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Study Conduct ConsiderationsCONSIDERATIONS WHEN CONDUCTING NIS IN BRAZIL

DEFINITIONS

Freely Given and Informed Consent

Freely given and informed consent: agreement of the research subject and/or his/her legal

guardian, without flaws (simulation, fraud, or error), dependency, subordination, or

intimidation, after a complete and detailed explanation about the nature of the research, its

objectives, methods, foreseen benefits, potential risks, and discomfort that such research may

cause, set forth in a term of consent, authorizing the subject's voluntary participation in the

research (as per Section II.11 of Resolution 196/96).

Non-interventional Studies

There is no specific mention of “non-interventional studies” is the legislation or guidelines.



Phase IV Research









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RESEARCH INVOLVING HUMAN SUBJECTS

Ethical Aspects of Research Involving Human Subjects

All research involving human subjects must meet the fundamental scientific and ethical

requirements set down in Resolution 196/96. This Resolution is based on the main

international documents that gave rise to declarations and guidelines on research involving

human subjects which includes the International Guidelines for Ethical Review of

Epidemiological Studies (CIOMS, 1991).

Ethics in research signifies:

freely given and informed consent of target-individuals and the protection of vulnerable

groups and the legally disabled (autonomy). To that end, research involving human

subjects must always preserve their dignity, respect their autonomy and defend them in

their vulnerability;

weighing risks and benefits, both actual and potential, individual and collective

(beneficence), making a commitment to maximize benefits and minimize distress and

risks;


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Human Tissue ResearchCONSIDERATIONS WHEN CONDUCTING STUDIES WITH HUMAN SAMPLES AND

DATA IN BRAZIL

DEFINITIONS

Biobank

“biobank” refers to an institutional facility dedicated to the systematic collection of human

biological material to support multiple, future studies (as per Article 1 of Resolution CNS

441/11).

Biorepository

“biorepository” refers to a collection of samples amassed by researchers executing a single,

specific research project (as per Article 1 of Resolution CNS 441/11).

THE REGULATORY FRAMEWORK

In 2005, the National Health Council (CNS) of Brazil approved a resolution to regulate the

use of human biological materials in research projects (Resolution CNS 347/05). Prior to this

enactment, collection of human biospecimens for research purposes had been governed only

by certain chapters of prior resolutions (Marodin et al., 2012).

In addition to providing ethical oversight, Resolution CNS 347/05 consolidated some issues

and addressed others that had been raised by prior resolutions; still, it had limitations. Then,

in 2011, the Ministry of Health published the National Guidelines for Biorepositories and

Biobanks (Ordinance No. 2201, dated 14 September 2011) and the CNS also approved

Resolution CNS 441/11, an amendment to Resolution CNS 347/05 (Marodin et al., 2012).

Brazil now has two mutually supporting documents on biobanking activities related to human

health research. Resolution CNS 441/11 sets the guidelines for ethical analysis of research


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projects involving human samples or utilization of samples stored by prior studies. The

Ministry of Health Ordinance No. 2201 establishes a regulatory framework for biobanks and

biorepositories (Marodin et al., 2012).

Donors providing samples for biobanks now have the option of providing a general consent,

in lieu of consent for each new research project. Also, donors can indicate whether or not they

wish to be re-contacted should any relevant personal health information be derived from use

of their biological samples. This approach moves beyond the previous restriction requiring

donor consent for each new project, but still respects the individual’s rights and preferences

(Marodin et al., 2012).

On the other hand, some aspects of the new legislation still need improvement (for example,

the issues surrounding the return of research results and the distinction between relevant

results and incidental findings). As acknowledged by other countries and international

guidelines, these regulations may need to be adapted to meet future scientific advances and

changing public perception; however, they reflect the current stage of biobanking activity in

Brazil (Marodin et al., 2012).

Registration of Biobanks

Article 3 of Resolution CNS 441/11 requires all research biobanks to be approved by, and

registered with CONEP.

Re-registration/re-approval is required every 5 years (as per Article 11 of Resolution CNS

441/11).

INFORMED CONSENT

In Brazil, patient consent is required prior to collection and storage of human samples for

research . Although Resolution 347/05 mandated that consent forms include the possibility

of specimens being used for future research, it also required that the donor’s re-consent be

obtained. For biorepositories, this approach was, and still is, feasible; however for biobanks,

which aim to collect samples for future analysis, it became clear that this approach was

inefficient. Therefore, a general consent permitting future use was needed. Such a form, apart


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Best Practice ConsiderationsBEST PRACTICE CONSIDERATIONS WHEN CONDUCTING NIS IN BRAZIL

DEFINITIONS

Freely Given and Informed Consent

Freely given and informed consent: agreement of the research subject and/or his/her legal

guardian, without flaws (simulation, fraud, or error), dependency, subordination, or

intimidation, after a complete and detailed explanation about the nature of the research, its

objectives, methods, foreseen benefits, potential risks, and discomfort that such research may

cause, set forth in a term of consent, authorizing the subject's voluntary participation in the

research (as per Section II.11 of Resolution 196/96).

NON-INTERVENTIONAL STUDIES

There is no specific mention of “non-interventional studies” in the legislation or guidelines.



Phase IV Research









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CONSIDERATIONS FOR CONDUCTING NON-INTERVENTIONAL STUDIES

Purpose

Research involving human subjects, regardless of the field of knowledge, must be in

accordance with the scientific principles that justify it and the concrete possibility of

answering uncertainties (as per Section III.3.a of Resolution 196/96).

Responsibilities of the Researcher

Each and every research project involving human subjects must comply with the

recommendations set forth in this Resolution and the documents endorsed in its preamble.

The responsibility of the researcher cannot be transferred or refused, and includes all ethical

and legal aspects (as per Section IX.1 of Resolution 196/96).

The researcher must (as per Section IX.2 of Resolution 196/96):

submit a duly documented protocol of research to the CER and await the decision of

said body before beginning the research;


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