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

Legal aspects of clinical trials (patients, investigators, sponsor)

andReporting requirements of local

regulatory bodies

Max S. ManoAssist. Prof. Medical Oncology – University of São Paulo (USP-ICESP)

Medical Oncology – Hospital Sírio Libanês

Introduction

• LA is a diverse environment

• This talk – mainly Brazilian situation

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

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 Brazil

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

Brazil – peculiarities

• RESOLUTION CNS Nº 251/97

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

RESOLUTION CNS nº 196/96

V - RISKS AND BENEFITS

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

GCP, local research regulations

Liability– Medical laws/regulations will usually apply

Investigator responsibilities in Brazil

Investigator – liability Medical laws/regulations will usually apply

• Professional (medical ethics code)– Suspended, banned from medical register

• Civil – In Brazil, = obligation to repair occasional damage

• Criminal – Usually, detention 1 -12 months

Investigator – liability

• PROFESSIONAL RESPONSIBILITIES – MEDICAL ETHICS CODE – Chapter XII

– 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


• PROFESSIONAL RESPONSIBILITIES MEDICAL ETHICS CODE – Chapter XII

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


• PROFESSIONAL RESPONSIBILITIES

MEDICAL ETHICS CODE (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


CIVIL RESPONSIBILITY – 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.


• CRIMINAL RESPONSIBILITY

– 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

Sponsor: 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 ISSUESCONTRACTUAL RESPONSABILITIES FROM PARTIES

• 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;

Colaborator Managing the resources

CONTRACT ISSUES

• 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

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

Includes:• 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

• 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 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

• 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

• 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 - 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)*Delays*Rejected studies*Withdrawals (from sponsors)...

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.196/96:1.Human Genetics (Res. 340/04)2.Human Reproduction (Res. 303/00)3.New drugs and diagnostic tests (Res.

251/97)4.New (or not yet granted registration in

Brazil) equipments, inputs and devices

Submission also

toANVISA

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).

ICTW Punta del Este, Uruguay

RESOLUTION Nº. 292, 08/07/1999 Internationally 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• 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, 08/07/1999 Internationally coordinated research or involving international collaboration

Study 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 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

• 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

Conclusions

• 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…

Documents

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