Research Ethics

1. Research Ethics PHL281Y Bioethics Summer 2005 University of Toronto www.chass.utoronto.ca/~kirstin

2. Reminder • No class Monday (University closed) • Classes and tutorials resume next Wednesday

3. Overview • Recent History of Human Experimentation • Nuremberg Code • Declaration of Helsinki • Medical Research • Definitions/distinctions • Contemporary Issues and Cases: • Global Research (Angell) • Randomized Controlled Trials (RCTs) (Hellman & Hellman) • Nancy Olivieri Case and Academic Freedom • Children and Animals in Research

4. Recent History • Late 1800’s STD trials (France, Russia, Ireland, USA) • Nazi experimentation • Radiation Experiments (USA) • Tuskegee trials (USA) • …

5. Tuskegee Study of Untreated Syphilis • U.S. Public Health Service • 1932-1972 • 412 poor African-American men with untreated syphilis followed • Possible effects: tumors, heart disease, paralysis, blindness, insanity, and death • In spite of known efficacy of penicillin (1945), and trial continued (best treatment denied) with AMA approval • Deliberate deception • No informed consent

6. Justifications • The men probably would not have been treated anyway • Investigators were just observing • “Never-to-be-repeated opportunity” • Results would be especially valuable to that same population • Analysis?

7. Nuremberg Code • As a result of the medical experimentation conducted by Nazis during World War II, the U.S. Military Tribunal in Nuremberg in 1947 set forth a code of medical ethics for researchers conducting clinical trials • Justice • Autonomy • Informed Consent

8. Declaration of Helsinki • A series of guidelines adopted by the 18th World Medical Assembly in Helsinki, Finland (1964) • “Concern for the interests of the subject must always prevail over the interests of science and society” (236) • Revised several times – textbook version (1996), more recently (2000) • Recommendations include the procedures required to ensure subject safety in clinical trials, including informed consent and Ethics Committee reviews • Allows proxy consent for the legally incompetent

9. Ethical Standards for Medical Research • Independent review and approval by ethics committee (REBs in Canada, IRBs in the USA) • Informed consent • Favorable risk-benefit ratio • Fair selection of study population • Scientific validity • Social value • Respect for participants and study communities • Collaborative partnership between researchers, policy makers, and community …

10. Why allow any research? Utilitarian calculus (future benefits): • Development and evaluation of new treatments • Example: cardiovascular surgery, renal transplantation, chemotherapy • Evaluating current treatments / prevention of iatrogenic diseases (caused by medical interventions) necessary for good medical practice • History of bad medical practices • Examples: blood-letting, freezing the stomachs of patients with ulcers… • Fairness • We have benefited from the sacrifices of those individuals who participated in medical research in the past (sacrifices for humanity) • Obligation to reciprocate • Reply: moral goal, not moral duty?

11. Definitions and Distinctions • Therapeutic research – concerned with the acquisition of knowledge and the prospect of direct benefit to subjects • Acceptable degree of risk is thought to be higher than for nontherapeutic research • Example: first patients on kidney dialysis machines • Nontherapeutic research – concerned solely with acquisition of knowledge • Example: historical examples just discussed, phase I clinical trials

12. Medical Research • Phase I – small group of healthy people (20-80), evaluating safety, determining a safe dosage range, and identifying side effects (determining a treatment’s toxicity, absorption, distribution and metabolism) • Phase II – larger group of people with the disease for which the treatment is designed (100-300), evaluating efficacy and further evaluating safety • Phase III – large groups of people (1,000-3,000+) to confirm efficacy, monitor side effects, compare to commonly used treatments, and collect information that will allow the treatment to be used safely (information to be used on label) • Phase IV – after approval, the treatment may be compared to a competitor, additional patient populations might be explored, and any adverse events may be studied

13. Medical Research • Therapy vs. research/experimentation • The experimental nature of medicine • Medical research is methodologically and systematically planned investigation • Aim: greater knowledge • Reducing (not eliminating) uncertainty in medicine • Complexity of the human body and its diseases • Individuality and variability of each patient – susceptibility to disease, response to treatment

14. Medical Research • Descriptive research (uncontrolled) • Case studies, qualitative studies • Ex/ Disease distribution in a population • Comparative research (controlled) • Cause-effect research • Observational • Case-control studies, cohort studies • Experimental • Randomized Controlled Trials

15. Medical Research Terminology • Placebo - an inactive substance designed to resemble the drug being tested. It is used as a control to rule out any psychological effects testing may present • Blinding - the process through which one or more parties to a clinical trial are made unaware of the treatment assignments. Blinded studies are conducted to prevent the unintentional biases that can affect subject data when treatment assignments are known • In a single-blinded study the subjects are unaware of the treatment assignments • In a double-blinded study, both the subjects and the investigators are unaware of the treatment assignments. In addition, sometimes the data analysts and monitors are unaware

16. Medical Research Terminology • Randomization – study participants are assigned to groups in such a way that each participant has an equal chance of being assigned to each treatment (or control) group. Since randomization ensures that no specific criteria are used to assign any patients to a particular group, all the groups should be approximately equally comparable

17. Medical Research Terminology • Equipoise – genuine uncertainty on the comparative merits of the treatments under study • Individual vs. Clinical Equipoise • “A condition of perfect balance or equilibrium” (OED) • “[T]here [is] no good reason for thinking one [treatment] is better than the other” (265)

18. Research in Developing Countries • Vast increase • Focus: phase III trials • “Race to the bottom”? Finally paying attention to the needs of the poor? • 90/10 gap • Subjects tend to be more compliant, less educated, and live in poverty

19. AIDS

20. AZT Controversy • AZT (azidothymidine) and maternal-fetal transmission of AIDS in developing countries (Southeast Asia and Africa) • Cheaper/shorter protocols of AZT (‘CDC protocols’) studied with placebo controls in developing countries despite accepted efficacy of the longer protocol of AZT in USA • Parallels in justification? • Women in developing countries would not receive antiretroviral treatment anyway • Investigators are simply observing what would happen to their infants without treatment • Information would have great value… • Especially to that same population in developing countries

21. Further Justification • To be of use to local governments (context of poverty) it would be better to investigate the safety of short course AZT against placebo • Maternal-fetal transmission is variable and determinants of this variation are not yet understood; A placebo-controlled study would provide a baseline against which to measure efficacy of treatments • Reply: Life-threatening vs. non-life-threatening?

22. Standard of Care • Are placebo-controlled trials justified in the developing world when a proven treatment already exists in developed countries? • Universal (best established) standard of care vs. local standard of care • Some ethical guidelines (International Ethical Guidelines, CIOMS) explicitly mandate that researchers have “an ethical responsibility to provide treatment that conforms to the standard of care in the sponsoring country, when possible” • The American standard of care was the 076 protocol of AZT • Declaration of Helsinki (II.3) “In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method” (236) • Best proven method was the 076 protocol of AZT

23. Justice & Exploitation • Exploitation • When one party takes advantage of another’s economic need to secure something for considerably less than its value • A exploits B when B receives an unfair level of benefits or unfair burden of risks as a result of interacting with A • Individuals in developing countries assume the risks of research, but most of the benefits may accrue to people in developed countries • Are placebo-controlled trials unjust because they exploit developing world subjects largely for the benefit of the more affluent populations of sponsoring countries? • Intentional Exploitation? • Unintentional Exploitation? • Are the research questions of relevance to the local population? • Are the benefits of the research made ‘reasonably available’ to research subjects (and local populations)?

24. ‘Reasonable availability’ • Research designed in response to local health needs • Responsibilities to the research subject • Provide treatment after the trial • Responsibilities to the local population • Reduced pricing? • Local infrastructure?

25. Hellman & Hellman • Randomized Controlled Trial (RCT) • From agriculture • Goal = to answer a scientific question of treatment efficacy: “Will this treatment prevent or remedy a particular disease?” • Isolate cause-effect relationship between treatment and results • Control group (often placebo) • Randomized • Double or single blind • Equipoise at the outset

26. Incompatible Roles of the Physician-Scientist (Hellman and Hellman) • Physician – act in patient’s best interests (central moral obligation) • Scientist – assess efficacy of treatments (gain knowledge, evaluate hypotheses) for the benefit of humanity generally • “Researchers participating in [RCTs] are required to modify their ethical commitments to individual patients and do serious damage to the concept of the physician as practicing, empathetic professional who is primarily concerned with each patient as an individual.” (254) • “If this commitment to the patient is attenuated, even for so good a cause as benefits to future patients, the implicit assumptions of the doctor-patient relationship are violated” (Angell, In Hellman & Hellman, 258)

27. Informed Consent • Can the patient waive rights implicit in the doctor-patient relationship? (The right to be treated as an individual deserving the physician’s best judgment – dignity/autonomy) • Altruism and opportunities for abuse (subtle coercion) • Asymmetry in knowledge and authority between researchers and their subjects

28. Opposition to RCTs • Not just an AIDS issue – extended to trials on advanced cancer and other serious and terminal illnesses • Equipoise • Clinical equipoise as solution? • Use other studies • For example: prospective matched-pair analysis

29. Interim findings of RCTs • Case: Dr. Nancy Olivieri • Mid 1990’s • Hospital for Sick Children (Toronto) • Apotex • Thalassemia • Hydroxypyridin-4-1 (deferiprone) • Academic freedom in clinical research

30. Children in Research • Don’t have decision-making capacity for informed consent • Proxy decision-makers (parents) • Non-therapeutic research?

31. Animal Research • Don’t have decision-making capacity for informed consent • Speciesism – a prejudice in favour of the interests of members of one’s own species and against members of other species (analogous to racism and sexism) • Being a research subject is rarely in the animal’s best interests • Justifiable?

32. Summary • Recent History • Ethical Guidelines • Medical Research • Contemporary Issues and Cases: • Global research (Angell) • Randomized Controlled Trials (RCTs) (Hellman & Hellman) • Nancy Olivieri Case • Children and Animals in Research

33. Contact Prof. Kirstin Borgerson Room 359S Munk Centre Office Hours: Tuesday 3-5pm and by appointment Course Website: www.chass.utoronto.ca/~kirstin Email: kirstin@chass.utoronto.ca