Research Involving Human Subjects: Ethics, Law and Regulation

1. Research Involving Human Subjects: Ethics, Law and Regulation December 2002

2. William Beaumont & Alexis St. Martin • Beaumont carried out a series of experiments on Alexis St. Martin over a period of many years • Was Beaumont a pioneer in ethical research or someone who abused his research subject? • Be careful of applying present-day standards to historical figures • The prime value of this case lies in what it tells us about how to do things today, not whether Beaumont was a good or bad man

3. Beaumont (1785-1853) • Had a 2 year apprenticeship with a country doctor • Enlisted as a surgeon’s mate in 1812. Briefly left the army after the War of 1812, but rejoined as a surgeon in 1820 • 1822 – Encounters St. Martin • 1833 – Experiments and Observations on the Gastric Juices and the Physiology of Digestion • “produced a picture of the living stomach that has required only a little updating in the century and a half since he made his observations.”

4. St. Martin (1803?-1880) • June 6, 1822 – St. Martin, a French-Canadian working for the American Fur Company, was accidentally shot in Northern Michigan • The result was a fistula exposing part of St. Martin’s lung and stomach • St. Martin survived, but the fistula never closed fully • After 8-10 months of attempts to close it, Beaumont concluded that the only means of doing so was to suture the sides together, “an operation to which the patient would not submit.”

5. The Experiments • First experiment in May, 1823? • Administering a cathartic by pouring it in • Literally hundreds between 1825 and 1833, most involving inserting or removing material through the ‘valve’ in St. Martin’s stomach

6. The Relationship • 1825 – Beaumont carried out experiments from May-August then St. Martin “returned to Canada … without obtaining my consent.” (18) • In correspondence, Beaumont described this as a “faithless absconding”. • 1829 – St. Martin enters Beaumont’s “service” in August • St. Martin “performed all the duties of a common servant” when experiments were not being carried out. (19) • This continues until March, 1831, when Beaumont allows St. Martin to return home.

7. The Relationship • 1832 – In October, St. Martin returns. • The two sign a contract binding St. Martin to “obey, suffer & comply with all reasonable & proper orders or experiments.” • In exchange, St. Martin was to receive $150 plus room and board. • In 1832, St. Martin was persuaded to join the U.S. Army for a period of 5 years. He was eventually assigned to Beaumont as an assistant

8. The Relationship • 1833 – A new contract is signed, for 2 years at $200 a year • Shortly afterward, Beaumont advances St. Martin some of the $200 in order for St. Martin to return his family to Canada. • St. Martin never returned, although Beaumont made increasingly lucrative offers ($500/year in 1850, shortly before Beaumont’s death)

9. Beaumont as Medical Ethics Pioneer? • Beecher (1970) credits Beaumont with producing the “oldest American code” concerning human experimentation: • “5. The voluntary consent of the subject is necessary… • “6. The experiment is to be discontinued when it causes distress to the subject… • 7. The project must be abandoned when the subject becomes dissatisfied.” • There is, however, some dispute about whether this code actually existed. (Numbers, 1979)

10. Some Issues • When did Beaumont take St. Martin into his home? • Beaumont tells us it was before he began using St. Martin as a research subject. Others (Numbers, 1979) say it was after. • Returning to Canada “without my permission”? • Some experiments clearly caused St. Martin discomfort • Payment for participation in research

11. Outline A. what is research? B. rationale for research ethics review C. ethical/legal/regulatory framework for human subject research in Canada D. some major ethical/legal issues in biomedical research

12. What is Research? • sometimes difficult to distinguish research from therapy: • often carried out simultaneously • investigators often physicians • terminology - “therapeutic research”, “clinical research”, “experimental interventions” • research vs. “innovative care”

13. Research and/or Therapy? • Why is the distinction important? • determines whether particular set of regulations or research ethics guidelines must be followed • determines whether prior approval by a Research Ethics Board (REB) is required • affects the legal standard for disclosure of information • may affect ability of substitute decision-maker to give consent

14. What is Human Subject Research? • “the generation of data about persons, through intervention or otherwise, that goes beyond that necessary for the person’s immediate well-being” • 1987 MRC Guidelines • an activity that involves “a systematic investigation to establish facts, principles or generalizable knowledge” • 1998 Tri-Council Policy Statement: Ethical Conduct of Research Involving Humans

15. Rationale For Research Ethics Review • part of crucial system of checks and balances • safeguard rights and well-being of research subjects • address actual, perceived, potential conflicts of interest • reinforce and rehabilitate public trust in medical research

16. Rationale For Research Ethics Review • inherent tension between primary aims of research and treatment • when patients participate in clinical research, physician-investigator may experience this tension • notion of “clinical equipoise”: - RCT’s ethically acceptable where expert community in state of honest professional disagreement as to relative merits of two alternatives

17. Research Codes and Guidelines • primary purpose - to protect the physical well-being, dignity and integrity of individuals who serve as participants • interests of investigators in pursuing their professions • interests of society in increasing knowledge re public and individual health

18. Historical Context • will be covered in future session • several instances of research controversies and atrocities in many different countries • a number of international instruments have been developed to try to address ethical standards and regulation of human subject research

19. Governance of Human Subject Research in Canada • in Canada, no comprehensive legislation to regulate all research involving humans - biomedical research governed by law that is primarily directed to other purposes - some legislation applies almost inadvertently to research - other legislation re health care deliberately excludes research from its ambit - role of the common law- consent, negligence, etc. - Quebec - Civil Code

20. Newfoundland Legislation • some statutes in NF containing provisions applicable to research: - Advance Health Care Directives Act - Access to Information and Protection of Privacy Act - Hospitals Act - Human Tissue Act

21. Codes, Guidelines and Policies • these “extra-legal instruments” play important role in regulation of research in Canada • promulgated by governmental bodies, funding agencies, professional organizations and local institutions • ethics codes, guidelines and policy statements usually lack means of direct legal enforcement • however may be relied on by courts to indicate applicable standards of conduct

22. Tri-Council Policy Statement on the Ethical Conduct of Research Involving Human Subjects (1998) • MRC, NSERC, SSHRC • context - the need for research, guiding ethical principles, “subject-centered perspective” • research requiring ethics review, REB’s • consent, confidentiality, conflict of interest • inclusion in research - women, incompetent individuals, aboriginal people • clinical trials • human genetic research, research on embryos/fetuses and human tissues

23. CMA Code of Ethics • duty of physicians to obtain from research ethics committee review and approval of research involving humans • duty of physicians to obtain informed consent from potential research subjects • duty to report unethical research behaviour

24. Some Major Ethical/Legal Issues in Medical Research 1. conflicts of interest 2. consent - informed, voluntary 3. confidentiality, access to information 4. scope of acceptable research 5. children, mentally incompetent individuals 6. justice in recruitment of subjects

25. Conflicts of Interest • investigator’s interests - fame, publishable results, medical breakthroughs to benefit society • financial conflicts of interest - pharmaceutical companies - partnerships between academic institutions and corporations - commercial value of research results

26. Conflicts of Interest and REB’s • one role of REB’s is conflict of interest oversight: - financial conflicts - impact of conflicts on informed consent • conflicts of interest involving the REB: - membership, operation within institution - collegiality, concerns about promotion, bringing valuable research funding into institution, etc.

27. Consent - General Principles • capacity - must be given by person legally capable of making decision • voluntary - no coercion/undue influence • specific - to procedure(s), physician(s) involved • informed - disclosure/discussion required

28. Consent to Research in the Courts • two categories of research dealt with differently by the courts: 1. consent to research with no intended benefit for participants 2. consent to research with intended benefit with participants

29. Research with no Intended Benefit for Participants Halushka v. U. of Saskatchewan (Sask. C.A. 1965) - healthy university student paid $50 to participate in anesthetic drug trial, requiring cardiac catheterization - told test was “nothing to worry about” - suffered cardiac arrest, residual injuries Court held: duty of disclosure of investigators at least as great as, if not greater than, duty of ordinary physician/surgeon to patient - full and frank disclosure - no “therapeutic privilege”, no waiver

30. Research with no Intended Benefit for Participants Weiss v. Solomon (Que. Sup. Ct. 1989) - trial of ophthalmic drops in reducing post-op retinal edema - fluorescein angiography used to verify effects of drops - told risks: discomfort, nausea and minor allergic reactions - patient died from severe allergic reaction Court held: investigator and REB at fault for failure to warn of all the risks involved in the research - all risks must be disclosed, even if rare/remote, particularly if serious consequences - court based decision in part on Helsinki Declaration

31. Research with Intended Benefit for Participants • no Canadian cases involving research pursuant to protocol reviewed for ethical/scientific merit • cases involving individual MDs testing therapeutic innovations of their own design in course of Dr.-pt. relationship • courts have applied standard of disclosure generally applied to Dr.-pt. relationship - “What would reasonable pt. want to know? • fact that procedure “unique” or “experimental” something most people would want to know

32. Confidentiality • general obligation of confidentiality owed by physicians to patients extends to researchers • embodied in research codes, guidelines • REB’s typically require policies re storage and destruction of data and samples, anonymization of data • should also be addressed in consent forms

33. Confidentiality • tension between need to share data and privacy of subjects • beware of over-promising confidentiality: - access to data for safety and ethics monitoring -Health Protection Branch, Health Canada - periodic review by REB’s - genetic research - right to know/right not to know? - duty/right to inform relatives of their risks?