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Legal aspects of clinical trials (patients, investigators, sponsor) and Reporting requirements of local regulatory bodies. Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP-ICESP) Medical Oncology – Hospital Sírio Libanês. Introduction. LA is a diverse environment

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Legal aspects of clinical trials (patients, investigators, sponsor)andReporting requirements of local regulatory bodies

Max S. Mano

Assist. Prof. Medical Oncology – University of São Paulo (USP-ICESP)

Medical Oncology – Hospital Sírio Libanês



LA is a diverse environment

This talk – mainly Brazilian situation

Current clinical research ‘philosophy’ likely to be similar in LA countries

peculiarities in brazil

Peculiarities in Brazil

Directives 196/96, 251/87, 292/99 and Resolution 404

Institutional contracts – will roughly follow the national directives and resolutions

peculiarities in brazil1

Peculiarities in Brazil

Resolution and directives: do not have the power of federal law

brazil peculiarities

Brazil – peculiarities


I.4 – In any clinical trial and in particularly when potential conflicts of interest with novel compounds may apply, the dignity and well-being of the study subject must prevail over all other interests, whether financial, scientific of communitary.

brazil current regulations

Brazil – current regulations



V.5 – The investigator, the sponsor and the institution shall take the responsibility of providing full assistance to occasional complications and damage incurring from the forseen risks

V.6 – Study subjects that suffer any damage forseen or not in the informed consent form, in addition to full medical assistance, have the right to benefit from appropriate compensation

V.7 – It can never be required from the study subject, whatever the argument, to resign from his/her right to receive compensation for occasional damage (and especially - never require this in the ICF!!)

investigator responsibilities in brazil

Investigator responsibilities in Brazil

GCP, local research regulations


Medical laws/regulations will usually apply

investigator responsibilities in brazil1

Investigator responsibilities in Brazil

Investigator – liability

Medical laws/regulations will usually apply

Professional (medical ethics code)

Suspended, banned from medical register


In Brazil, = obligation to repair occasional damage


Usually, detention 1 -12 months

investigator liability

Investigator – liability



Speculative Clinical Research

Art. 106. Be involved in any medical research involving humans, that will make use of placebo, when there is a recognized treatment for the condition

investigator liability1

Investigator – liability



Informed consent

Art. 101. Misconduct – not take from the patient or his/her representative the Informed Consent Form for the research, after appropriate explanations about the nature and consequences of the research.

Underage – in addition to the legal representative, take the individudual’s authorization as appropriate according to his/her level of understanding

investigator liability2

Investigator – liability



(RESOLUTION CFM Nº 1.931, 17 SEPT 2009)

I – Current ethics code applies to physicians during activities such as teaching and research and in any other activities that will use the knowledge acquired from the study of medicine.

Clinical research – medical activity

investigator liability3

Investigator – liability


Obligation to repair any damage caused to somebody else, trying to repair the situation to its previous status (usually compensation)

Relation patient - physician

Legal Fundaments: Art. 951 Brazilian Civil Code

Art. 951. Compensation from those who, when practicing his/her professional activity, due to any malpractice - misconduct, cause the death of the patient, worsen his condition, cause physical damage or make him/her uncapable of working.

investigator liability4

Investigator – liability


Penal code – Crime of danger – Unnecessary to demonstrate Damage

Art. 132 - Expose the life or health of others to danger

Penalty - detention, 1 – 12 months, unless more severe crime applies

contract issues


Contract for Clinical Trials

Rights - Obligations


Post-trial access to the drug. (Resolution CNS nº 404/08) At the end of the study, all participants must be given access to the best prophilactic, therapeutic and diagnostic methods identified by the study)

Compensations – (from damage resulting from the administration of the study drug according to the study protocol)

Audits to the centre

Check site infra-structure

Financing the study

Occasional patents

contract issues1



Contract for Clinical Trials

Rights – Obligations

Study site

Infra structure for running the study;

Principal investigator

Run the study according to the study protocol and local/national legislation;

Reports to the sponsor and regulatory agencies;

Transparent relationship with patients;


Managing the resources

contract issues2


Remember: there are also significant language barriers leading to complex back and forth translations that may take a long time

In our institution contract negociation has occasionally overcome regulatory flow as the ‘time’ bottleneck…

contract negociation sponsored research

Contract Negociation – sponsored research

Basically, to ensure that all National directives/resolutions have been addressed


Full coverage of all research costs – no further damage to our already financially deprived health systems

Ensure that all ethical principles are fully respected

Institututional and investigator liability – comprehensive trial insurance

Define responsibilities from all parties

Reminder: long term sustainability of clinical research units relies on good contract negociation....

196 ethical aspects

196 – Ethical aspects

III.3.n) Benefits obtained with the research should someway return to the community or persons in which it has been performed

III.3.s) Research performed in other countries or in cooperation with other countries: guarantees that there will be potential benefits for the Brazilian subjects

Include documents attesting for the ethical aprovaI in the country of origin

III.3.t) Biologic specimens – only used for the purposes specified in the study protocol

196 ethical aspects1

196 – Ethical aspects

III.1d) “Social relevance” of the research with significant benefit for research subjects and minimal onus for vulnerable subjects, also taking into account its eventual socio-humanitarian goals (justice and equality)

  • Multinational clinical trials in oncology and post-trial benefits for host countries: where do we stand? Mano MS et al, EJC 2004 v. 42, p. 2675-2677, 2006
  • Building research capacity and clinical trials in developing countries. Arai R.J., Mano MS, et al. Lancet Oncol. 2010 Aug;11(8):712-3
196 study protocol

196 – Study protocol

VI.3.h) Forsee reimbursement of expenditures to the study subjects

In Brazil, meals and transport regardless of the study ‘arm’ or schedule

196 risks and benefits

196 – Risks and Benefits

IV.V2) Research with no direct benefit to the subjects should at least be well tolerated by the study subjects, also considering the individual’s physical, psychic, social and educational background

‘biopsy’ studies – eg for translational research studies

brazil peculiarities use of placebo post trial access to treatments

Brazil - peculiaritiesUse of placebo, post trial access to treatments

Resolution 404, August 2008

Reaction to the 2008 Declaration of Helsinki, especially against 2 “clarifications notes” (on the use of placebo and post trial access to treatments)

These clarifications are not acceptable and for the Brazilian regulatory process the content of the 2000 version of the Declaration of Helsinki is retained

In other words:

At the end of the study, all patients should be given acess to the treatments that have been proven effective (by the study sponsor)

No placebo except in situations where no effective therapy exists

*Confusion (difficult interpretation)


*Rejected studies

*Withdrawals (from sponsors)...

196 local ecs

196 – Local ECs

VII.4) Should be composed by no less than 7 members; should be multidisciplinary, with no more than 50% from one professional category, at least 1 member representing the society (‘institution clients’)

No payments – can only benefit though from reductions in his/her routine institutional activity (usually hypocrisy...)


Special circumstances=mandatory submission to CONEP (central EC)

  • Res.196/96:
  • Human Genetics (Res. 340/04)
  • Human Reproduction (Res. 303/00)
  • New drugs and diagnostic tests (Res. 251/97)
  • New (or not yet granted registration in Brazil) equipments, inputs and devices

Submission also




Special circumstances=mandatory submission to CONEP (central EC)

5. New procedures not consensually accepted by the literature

6. Indigenous populations (Res. 304/00)

7. Projects with issues of biosecurity

8.Research coordinated by other countries or with their participation and research involving shipment of biologic specimens abroad (Res. 292/99)

9. Projects for which institutional ECs judged suitable for evaluation by central EC (CONEP).

RESOLUTION Nº. 292, 08/07/1999Internationally coordinated research or involving international collaboration –definitions
  • a – collaboration of foreign person(s) or company(ies), either public or private;
  • b – flow of human biologic specimens across borders;
  • c – flow of data that will contribute to the results of the research;
  • d – international multicentric clinical trials
biologic specimens storage and use
Biologic specimens storage and use
  • RESOLUTION Nº 347, 13/01/2005
    • Justify the need for future use
    • Specific ICF
    • Declaration that any new research will be submitted to EC (local and central, as indicated)
    • Ensure confidentiality
    • 5 years, renewable
    • Abroad – Brazilian investigators and institutions have partial ‘ownership’ (very difficult to define)
    • Use of stored specimens: EC approval, re-consent or apply for exemption, justify, etc

RESOLUTION Nº. 292, 08/07/1999Internationally coordinated research or involving international collaborationStudy protocol – requirements

  • VII.1 Original approval document in the country of origin
  • VII.2 When not being simultaneously run in the country of origin, justification
  • VII.3 Resourse transparency, investigator income, spending with infra-stracture etc. Try to avoid as long as possible that the flow of resources generate potential discrimination among health professionals and hospital clients since they can occasionally lead to extraordinary benefits to the study subjects and participants
  • VII.5 Declaration that biologic specimens will be used exclusively to the goals deliniated in the study protocol
  • VII.6 Statement of the investigator on the appropriateness study protocol in case he/she has not had the change of participating in the study design
resolution n 251 07 08 1997 responsibilities of the pi
RESOLUTION Nº 251, 07/08/1997Responsibilities of the PI
  • a – Submit the research to the EC (196/96 and 251/97);
  • b – keep archives, respecting the subject confidentiality, for 5 years, after the end of the study;
  • c – Present reports when requested or established by local EC, by central EC (CONEP) or SVS/MS;
  • d – Communicate occurrence of adverse events and/or SUSARS to EC;
  • e – Communicate occasional project modifications or justify occasional interruptions and await EC feedback, except in urgent need for modifications, in this case communicate ASAP;
  • g – Continuous analyses of the results;
  • h – Minimum EC reports: 6-monthly and final report;
  • i – Provide details of results of tests/exams and treatment outcome to patients as requested;
academic institutional non sponsored research

Academic (Institutional, Non Sponsored) Research

No specific legislation for academic reserch

All CNS directives/resolutions apply

Very difficult to obtain trial insurance in Brazil (probably in L.A. in general)

Uninsured research is potentially dangerous for institutions and investigators

Many institutions are right in severely restricting the development of academic trials



Almost impossible to deal with local legal/regulatory issues without the support of a good CRO with a long track of experience in the country

Legal complexity in many LA countries should not be underestimated and have represented a barrier for further development of clinical research

Remember – after all, institutional loyers are your partners – in protecting you from liability…

Qualify your staff with highly specialized loyers

Consider having a reference person specialized in contract negociation – this will eventually pay off…