Research Ethics

PHL281Y BioethicsSummer 2005

University of Toronto

www.chass.utoronto.ca/~kirstin

Reminder

No class Monday (University closed) Classes and tutorials resume next

Wednesday

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

Recent History

Late 1800’s STD trials (France, Russia, Ireland, USA)

Nazi experimentation Radiation Experiments

(USA) Tuskegee trials (USA) …

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

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?

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

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

Ethical Standards for Medical Research

1. Independent review and approval by ethics committee (REBs in Canada, IRBs in the USA)

2. Informed consent3. Favorable risk-benefit ratio4. Fair selection of study population5. Scientific validity6. Social value7. Respect for participants and study communities8. Collaborative partnership between researchers, policy makers,

and community…

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?

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

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

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 medicine1. Complexity of the human body and its diseases

2. Individuality and variability of each patient – susceptibility to disease, response to treatment

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

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

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

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)

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

AIDS

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

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?

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

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)?

‘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?

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

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)

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

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

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

Children in Research

Don’t have decision-making capacity for informed consent

Proxy decision-makers (parents) Non-therapeutic research?

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?

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

Contact

Prof. Kirstin BorgersonRoom 359S Munk CentreOffice Hours: Tuesday 3-5pm and by appointmentCourse Website: www.chass.utoronto.ca/~kirstinEmail: kirstin@chass.utoronto.ca