Human Research Vaughn Chapter 6 For historical perspective, click image, watch two minutes of life at The Knickerbocker Hospital in NYC…

Human Research Only a Utilitarian Could Love? Nazi experimentation on prisoners and civilians US Public Health Service study of syphilis using poor black men from Macon County, AL US government Cold War studies of radiation effects on thousands of human subjects from 1944-74 Willowbrook State Hospital in NY study of hepatitis, infecting mentally retarded children Negative public reaction to the above events, and others, produced: The Nuremburg Code (guidelines for ethical research), 1947 Declaration of Helsinki, embraced by the World Medical Association (WMA) in 1964 Belmont Report, 1979, of the National Commission for the protection of Human Subjects of Biomedical and Behavioral Research 1993 guidelines from World Health Organization (WHO), and Council for International Organizations of Medical Sciences (CIOMS) Prompted President Bill Clinton’s public apology, 1997

Clinical Trials Clinical Trial = “[a] scientific study designed to test a medical intervention in humans ...” –Vaughn, 194 Clinical trials … exist to determine whether a given drug or procedure is safe and effective are the best available method to determine that Vaughn mentions 3 virtues of clinical trials: maximize objectivity minimize bias avoid errors What kinds of value to 1 - 3 have? Intrinsic? Instrumental? Combination?

Clinical Trials Composition: Experimental group the group getting the new treatment Control group the group(s) not getting the new treatment Placebo control = group gets a sugar pill or equivalent Active control = group gets a standard treatment already known to work (to some degree) 2 kinds

Clinical Trials Blinding = keeping experimental and control group membership secret single-blind study = test subjects are kept in the dark regarding group membership double-blind study = both test subjects and researchers are kept in the dark as to who is in which group Randomization = assigning experimental and control group membership randomly to ensure the variety of test subjects are evenly distributed between groups eliminate researcher bias

Clinical Trials Phases I small group adverse reactions safe doses non-therapeutic / no testing for efficacy Phase II medium group safety preliminary effectiveness study Phases III large group (thousands) therapeutic (hopefully, to those in experimental group) success here qualifies the drug or procedure for widespread use Phase IV not universally used done after procedure or drug is marketed long-term effects

Beneficence, Science, and Placebos Beneficence = doing good for others in the context of medical science (treatment of patients and test subjects), beneficence = the duty to help others non-malfeasance = the duty not to harm others Science = in Vaughn, science is presented as in occasional conflict with the duties of beneficence and non- malfeasance Question: why present the conflict this way, rather than between duties to present and future patients?

Beneficence, Science, and Placebos Beneficence vs. ‘Science’ “… conflict with the aim of doing science.” - para2, p197 “… treated merely as a means to the end of scientific knowledge.” –para3, p197 “ … beneficence and science collide.” –last paragraph, p198 Is this a trumped up conflict? Is it really some abstract love of science researchers are motivated by when researching drugs and procedures? (See previous slide for another possible motive … can you think of still others?) Watch this melodrama between Dr. Crusher (seated) & Utilitarian researcher … When Dr. Crusher says ‘you take shortcuts’ … can’t the shamed researcher respond, ‘Yeah, because slow research kills people’?

Beneficence, Science, and Placebos The main question of this section (Beneficence, Science, and Placebos), is … How can a physician recommend a patient for clinical trials over prescribing the best known treatment? Problem: “As a physician, she has an obligation to act in the best interests of her patients, which requires that she offer to them only those treatments she judges to be the best. But in clinical trials, patients are randomized into experimental and control groups where they may not receive the treatment that the physician believes is best.” – para1, p198

Beneficence, Science, and Placebos Reply to problem: Physicians can recommend participation in clinical trials because they don’t know which treatment is better; they are in a state of equipoise (“rationally balanced between the alternatives” –para2, p198), and so cannot be recommending a treatment they know to be inferior Defense of problem: Physicians owe their patients their best judgment, and if there is just a hunch that a standard treatment is better than a new one, physicians cannot recommend, they are not in a state of equipoise

Beneficence, Science, and Placebos Reply to Defense: Equipoise is not subjective … it is the state of scientific knowledge where the relative merits of 2 or more treatments are unknown. When those are unknown, including patients in randomized trials is permissible So, is there any conflict between 1, physicians revealing their honest treatment preferences and 2, offering patients a chance to participate in clinical trials? –para2, p198 Vaughn suggests that as long as full disclosure is met and informed consent is gained, the answer is ‘no’.

Beneficence, Science, and Placebos Placebos raise another problem: “Can the deliberate nontreatment of patients be justified?” –para1, p199 The book says ‘Yes’, although: No, if there is an effective treatment already available, a placebo controlled human study is “unethical”… Also, when lack of treatment is life-threatening, the above rule is at its strongest 3 Questions: Did the AZT placebo-controlled trial violate proviso #1? –see quotation on p199 If the lack of treatment results in minor harm, is a placebo-controlled trial permissible under any conditions, according to Vaughn? Is equipoise possible in a placebo-controlled trial?

Science and Informed Consent Vaughn provides a checklist (from CIOMS and WHO) of what research scientists owe clinical trial participants (see p200-201) Main worries about the possibility of getting meaningful informed consent: subjects are not able to comprehend enough science to give informed consent subjects may, in some cases, consent out of desperation, fear, or wishful thinking, … all of which threaten informed consent subjects may be coerced or exploited by payments for helping in the research You should know Vaughn’s responses to these objections (1 & 3 … he gives no reply to 2)

Research on the Vulnerable Problematic special cases are clinical trials that involve those who cannot give informed consent and are at the mercy of others: children mentally disabled prisoners minorities people in developing countries Vaughn tells us many effective therapies that help children, for example, could only be developed by studies on children, as their physiology and pathologies differ substantially from adults …

Research on the Vulnerable According to Vaughn, “most official policies” follow these guidelines: “… research in children is morally acceptable if it is conducted for their sake, if it is done to generate the therapies they need.” (individually, or as a group?) consent is required (age of consent is controversial) a proper balance of risk and reward for the research subjects “[t]he child’s refusal to participate in research must always be respected unless according to the research protocol the child would receive therapy for which there is no medically acceptable alternative.” –p203, (Vaughn cites CIOMS and WHO)

Research on the Vulnerable The previous slide is about the justification of therapeutic research on children. What about non-therapeutic research using children? Is that ever morally permissible? See Vaughn’s discussion on p203 … as risk to the research subject goes up, so do requirements for … meaningful consent, better balance of reward vs. risk, and therapeutic benefit for the child undergoing the tests

Research on the Vulnerable The guidelines for treatment of the mentally disabled are similar to those for children, but with special concern for susceptibility to exploitation: conditioned to defer to authority figures fear punishment from caretakers for refusing to participate desperation for change of routine or special attention might amount to coercion

Research on the Vulnerable Vulnerable subjects in Third World countries … Vaughn provides this scenario: AZT is a drug that reduces HIV transmission from women to their fetuses The dose of the drug was too high to be affordable in these countries (Thailand and some African countries) Placebo-controlled trials were conducted to determine if a lower, cheaper dose would work Because placebo-controlled trials guarantee some women will not get the experimental dose, those women’s children are virtually guaranteed to get HIV The results of the trials were positive; the lower dose worked in reducing HIV transmission Compare Marcia Angell’s condemnation of these trials to Baruch Brody’s defense of them (p204-205); who is right?