Research vs. Treatment

Two Positions:

• Similarity Position: The ethics of clinical trials rest on the same moral considerations as the ethics of therapeutic medicine

• Difference Position: The ethics of clinical trials begin with the realization that research and treatment are different

Research and Therapy

• There is always uncertainty in medical decision-making (of diagnosis, that a treatment will be effective, etc.)

• The difference in uncertainty between research and treatment is one of degree

– the boundary between them is not clear

• Miller and Brody say that the boundary actually is clear: We just need to distinguish between research and therapy on the basis of their goals

– therapy aims to provide individualized care to one patient

– research aims to provide generalizable knowledge that will improve the care of future patients

Clinical Medicine

• Aim is to provide a patient with the best care, based on their individual needs and values

• Ethical principles: therapeutic beneficence, therapeutic nonmaleficence

– the risks to the patient are justified by the benefits

Clinical Research

• Not therapeutic: aim is to answer a scientific question and so produce knowledge about general cases

• Deals with groups, not individuals

• Principles of beneficence and nonmaleficence lack the therapeutic meaning they carry in clinical medicine

Clinical Equipoise

• In order to enroll a patient in a clinical trial:

Theoretical equipoise

OR

Clinical equipoise (Freedman, 1987)?

• RCT - 3 arms:

– sertraline (Zoloft)

– hypericum (St. John’s Wort)

– placebo

• Neither sertraline nor hypericum was significantly more effective than placebo

The Ethics of Research

• M&B: RCTs should be governed by norms appropriate to clinical research

• They draw on a paper by Emanuel, Wendler and Grady, who give 7 ethical requirements for clinical research

• M&B: These norms do not require equipoise

1. Scientific or social value

2. Scientific validity**

3. Fair subject selection

5. Independent review (REB/IRB)

6. Informed consent**

7. Respect for enrolled participants

4. Favourable risk-benefit ratio

– “…ultimately comes down to a matter of judgment”

– Exclusion of patients at high risk, monitoring during the course of the study

– Risks were “not excessive and justified by the anticipated value of the knowledge to be gained by the research”

– Equivocation?

• Risk to individual vs risk to society

– The risk to the individual is justified by:

• Value to society

• Informed consent

• Monitoring to ensure risk to individual safety is minimized

Two questions:

• Can we justify asking people to forego treatment for their illness in order that society as a whole will benefit from new treatments?

• Will adopting the “difference position” and emphasizing the (ethical) difference between research and treatment make people less likely to volunteer for research?

• Eliminating placebo would undermine scientific validity of study and so make the risk-benefit ratio unfavourable

• Adopting the difference position will help to avoid the (real) therapeutic misconception

History of Research Ethics

• Nuremberg Code (l940s): developed in response to disclosure of Nazi’s use of prisoners of war, civilians in experiments

– emphasizes need for voluntary consent of subject

– little impact in scientific community because Code perceived to pertain to “anomaly” of Nazi experimentation

– still, some influence on policies set by government agencies

• World Medial Association’s Declaration of Helsinki (1964)

– “replaces” Nuremburg code

– revised in 1975, 1983, 1989, 1996 and 2000

– included provisions for those unable to consent to research - allows proxy consent

– made a distinction between therapeutic and non-therapeutic research

• 1960s, 1970s - series of scandals

– Beecher: “Ethics and Clinical Research” NEJM 1966

– Jewish Chronic Disease Hospital (Brooklyn): 1963

– Willowbrook study (1963-1966)

– Tuskegee Syphilis Study (1932-1972)

• National Commission also proposed guidelines for review of research by ethics boards

– Institutional Review Board (IRB) (U.S.)

– Research Ethics Board (REB) (Canada)

• http://www.uwo.ca/research/ethics/

• 1974: National Research Act

– creation of National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

History of Research Ethics

• Belmont Report: 1979

– 3 principles governing research:

1) respect for persons

2) beneficence

3) justice

– Appendix (by Robert Levine): distinction between research and treatment

Contemporary Research Ethics in Canada

• Guidelines contained in Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (1998; most recent revision 2005)

– MRC (CIHR)

– SSHRC

– NSERC

• Institutional REBs follow these policies

TCPS: Guiding Ethical Principles

• Respect for Human Dignity

• Respect for Free and Informed Consent

• Respect for Vulnerable Persons

• Respect for Privacy and Confidentiality

• Respect for Justice and Inclusiveness

• Balancing Harms and Benefits

• Minimizing Harm

• Maximizing Benefit

Research vs. Therapy

• Miller and Brody – follow Levine in saying that the difference is not solely one of degree

• We must be clear on the distinction between research and therapy in order to think clearly about research ethics

• Clinical trials are scientific investigations, not therapy

“Clinical equipoise has emerged as the bridge between medical care and scientific experimentation, allegedly making it possible to conduct RCTs without sacrificing the therapeutic obligation of physicians to provide treatment according to a scientifically-validated standard of care”

Mastroianni and Kahn: Shifting Views of Justice

Protection

• 1970s - policies tended to emphasize protection of research subjects

• Since early 1990s, shift in emphasis from protection to the need to ensure equal access to the potential benefits of research participation

Belmont Report

• Principle of justice involves fair distribution of burdens and benefits of research

– in practice, protection for vulnerable: prisoners, children, pregnant women & fetuses

• Also discusses informed consent: understanding nature and extent of risks

Parallels with Informed Consent

• Right to determine what happens to one’s own body

• Right to treatment

• Fear of coercion (e.g. prisoners)

• Fear of lack of capacity (e.g. children)

• But on the other hand:

- paternalism

pregnant women, women of childbearing age

- National Commission study on prisoners

Women and Clinical Research

• Often, in the past, research protocols have included only men

– protection of women of childbearing potential

– fear that women’s menstrual cycles would “confound” the results of the research

Children and Clinical Research

• Many drugs used in children have not been tested in children

– adult dosages often “scaled down” by adjusting for weight

• Differences in metabolism in children/adolescents and adults may --> different effects, side effects

• Depression in children

– different symptoms/diagnosis than adults

– different neurochemical/neuroanatomical correlates?

– differences in metabolism/effects of drugs

• Pfizer’s study on Zoloft, fewer than 400 children

• Possible increase in suicidal thoughts?

Freedman, revisited

• Right to give informed consent (and have it taken seriously)

• But, this is not the same as the right to treatment or to participation in research

– Is there such a right?

– We generally think that people have a right to treatment (at least to some extent)

Justice as Access

• Mastroianni and Kahn suggest that there is now a tendency to interpret justice in terms of a right to access to research participation

• But this right appears to presuppose that there are benefits to participation in research

• AIDS activism: clinical trial participation as best hope for treatment

• Women’s health advocates: drugs tested on men, but women treated with them

• Cancer trials: better medical care than standard care. Also financial benefits?

The Right to Access

• Possible benefits to individual

– Opportunity to try new drugs/treatments before they are on the market

– Research protocols may involve more monitoring than standard care

• Benefit to groups: how generalizable is research conducted in one group to others, e.g. women, children, ethnic/racial groups

“Exclusion denies access to the benefits of research at two levels - first to the individuals who may themselves receive the direct medical benefit of research participation, and more notably to the groups from which the subjects come.”

1994 NIH Guidelines

• Require inclusion of particular groups (women, various ethnic groups) in NIH-funded studies

– as part of their application for funding, researchers must give a demographic profile of the subjects they’re going to include

– must also now explain why they choose to exclude certain groups, where relevant

• These guidelines have “flipped the presumption about research participation from exclusion to inclusion”

Changing Policies

• Increased NIH budget (to allow access to trial participation for those who want it)

• United Healthcare (first to pay costs associated with clinical trial participation)

• Medicare: Clinton --> Health Care Financing Administration, Gore campaign speech

• Waiver of consent requirement for research in emergency situations

Balancing Access and Protection

• Problems with informed consent

• Therapeutic misconception

• Overemphasis on benefits of research may lead to too little emphasis on risks

Conclusions

• “Research is a privilege not to be presumed or exploited, but earned through building and maintaining the public trust”

• Emphasis on managing potential conflicts of interest, possible accreditation of REBs: both suggestions are more relevant at the level of policy implementation than at the level of actually protecting individual subjects.