Chapter 2 Research Ethics and Informed Consent

1. Chapter 2 Research Ethics and Informed Consent

2. Major Questions Chapter 2 examines several important issues related to medical research: (1) Medical research at some point requires tests on human subjects. • Who is it ethical to perform tests on? • To what extent does a test subject have to consent to or be informed about the nature of the research in which they are participating? (2) The goals of medical therapy and medical research are distinct and may conflict in cases where a physician is engaged in both and some of the physician’s patients are also actual or potential participants in research trials. • Under what conditions, if any, is it morally acceptable for a physician to enroll a patient of his in an research trial? • In particular, since some clinical trials involve the use of placebos (medically inactive substances), is it ethical for a physician to allow his patient to participate in the trial knowing that the patient might receive a placebo rather than what he, the physician believes, is the best treatment for his patient?

3. Major Questions (3) A common view is that an experimental drug should only become available to patients after they have been rigorously tested. But, suppose a drug shows substantial promise before clinical trials are complete. • Why shouldn’t terminally ill patients have a right to try such drugs if no other options exist? • Aren’t we wrongly depriving patients of the benefits of the drug by insisting that the trials be completed first? (4) Animals are used extensively in biomedical research. • Is animal experimentation ethically defensible? • Often experiments performed on animals would be found unacceptable if performed on human beings. What justifies treating humans and animals differently?

4. Clinical trials • The U.S. spends almost $100 billion per year on medical research, and a large proportion of the money goes to fund randomized clinical trials. • A randomized clinical trial (RCT) is a form of research in which the effectiveness and side effects of a treatment (for example, a drug, surgical procedure, medical device) are tested by administering it to human subjects. The discussion below uses drug testing as an illustrative example. • Trials have a preclinical and a clinical step. In the preclinical step, a chemical thought to be potentially beneficial to humans is tested on animals to determine its toxicity, more specifically, its therapeutic index (the ratio of a dose producing toxic effects to a dose producing desired effects).

5. Clinical trials • If a drug shows promise in animal testing and its side effects are acceptable, it is then moves on to the clinical step where it is tested on humans in four phases, as summarized to the right

6. Clinical trials • In the clinical part of testing, careful procedures are followed to attempt to exclude bias in the results by making use of a “double-blind” design of the experiment, which may also involve use of a placebo (from the Latin, placebo, meaning “I shall please”), a medically inactive substance (such as a sugar pill),. • In the classic version of the double-blind design, a number of patients are given the drug being tested and the remainder of the test group (the control group) is given a placebo, or the currently best available, approved treatment. • Patients are assigned to the treatment group or the control group in a random fashion (for example, by the flip of a coin). • Neither the investigators nor the patients are allowed to know who is receiving the drug and who is not—both are kept “blind.”

7. Clinical trials • An important part of an ideal RCT is that the participants are faithful representatives of the overall population for which the drug is intended. • Using a placebo, or currently best medical treatment, in the control group is important because of the potential bias resulting from the “placebo effect”. • The placebo effect refers to the fact that if a participant takes a substance (for example, a sugar pill or the best current treatment) with the possibility or expectation that it might help then, he may in fact show improvement. • This is possible because the participant’s hopes and expectations may affect how his body responds and how he feel. (In a pain-relief study, patients responded better to a placebo they were told cost $2.50 than to one said to cost ten cents.)

8. Section 1: Consent and Experimentation • An experiment on human subjects requires that a suitable number of subjects be available. • Nazi Germany and other tyrannical regimes, which have conducted medical experiments, have met this need by forcing people, viewed by the regimes as “undesirables” (for example, prisoners, certain ethnic minorities), to become test subjects, without their informed consent. • Today, participant consent and understanding are widely recognized as a fundamental to morally acceptable clinical trial, at least in most cases. • But, even with this general understanding, questions remain: • What exactly is meant by consent? What exactly is meant by understanding? • What kinds of individuals are ethically acceptable test subjects?

9. Section 1: Consent and Experimentation The “Informed” Part of Informed Consent • Consent to a research trial is more than simply saying yes to a request to participate. The decision to participate must be based on: (a) adequate information about the trial and (b) a clear understanding of that information. • The information must include a description of the nature of the trial as well as potential risks and benefits to the participants and alternatives the participants have to participating in the trial.

10. Section 1: Consent and Experimentation • Additionally, the information must be presented to potential participants in a clear and understandable way. • These two requirements are the source of some controversy. Medical research is highly technical. • Just how much does a subject need to be told? • How much can a patient reasonably be expected to understand? • Some researchers have argued that it is virtually useless to provide patients with relevant scientific information because patients lack the proper scientific background and therefore the patient’s interest is best served by allowing a physician to make the decision. • Others claim that it is entirely possible to tailor the explanation of the trial to the participants’ particular background. This may require an extra effort on the part of researchers to ensure that understanding has been achieved but researcher have an ethical obligation to make this effort.

11. Section 1: Consent and Experimentation The “Consent” Part of Informed Consent • Legitimate consent requires that the individual consenting did so voluntarily or out his “own free will”. This implies both that the person was competent to make the decision and that he was not coerced or pressured into making it. • But it is not always clear what competence means or whether the person is deciding under pressure which invalidates his consent. • For example, someone may volunteer to be a subject in a potentially hazardous experiment because she believes the experiment holds out the promise of helping countless others. In terms of self-interest alone, such an action would not be reasonable. Is the person deciding competently in this case? • A person, in financially difficult circumstances, may agree to participate in trial, because financial reward is offered for doing so. Was the decision freely made or did the person’s circumstances constitute “pressure” or “coercion”?

12. Reading: The Willowbrook Letters: Criticism and DefenseStephen Goldby, Saul Krugman, M. H Pappworth, and Geoffrey Edsall • This reading examines the moral legitimacy of a study of viral hepatitis that was conducted on mentally disturbed children at the Willowbrook School by Krugman and his associates from 1956 – 1970. As part of the experiment, children were deliberately infected with the hepatitis virus (See the Case Presentation on pages131-132 for more detail.). • Goldby charges that the study was “quite unjustifiable” because it was morally wrong to infect children when no benefit to them could result. • Krugman defends himself by claiming that his results demonstrated a “therapeutic effect” for the children involved, as well as for others. He presents several reasons for holding that the infecting of the children was justified. • Pappworthclaims that Krugman’s defense is presented only after the fact, whereas an experiment is ethical or not in its inception. Moreover; he asserts, consent was obtained through the use of coercion. • In the final letter, Edsall defends the Krugman study. The experiments, he asserts, involved no greater risk to the children involved than they would have run in any case. What is more, the results obtained were of general benefit.

13. Reading: Judgment on WillowbrookPaul Ramsey • Ramsey challenges the justifications offered for the Willowbrook experiments and argues that: • Children should not be subjects of risky experiments unless the experiments are intended, by the researcher, to directly protect the children’s health. • This ethical obligation should be made a matter of law. • The reason that such experiments should not be done (apart from the exception noted) is because children are incapable of giving informed consent. • Risky experiments are morally off-limits even if parental consent is given or even if the results of those experiments are likely to be highly beneficial to others.

14. Reading : Principles of the Nuremberg Code • These principles emerged from the trials of Nazi war criminals after the Second World War conducted in Nuremberg, Germany.. • The principles define conditions under which it is morally acceptable to perform medical experiments on people. Among other things, the principles emphasize the need for voluntary consent.

15. Reading: Belmont ReportNational Commission for the Protection of Human Subjects • The 1974 National Research Act mandated that every institution receiving federal funding and conducting research involving human subjects establish an institutional review board (IRB) to oversee such research. • The Act was prompted by public revelations about the United States Public Health Service—sponsored Tuskegee syphilis study(see Chapter 4) in which investigators enrolled patients without their consent and treated them in ways that were condemned at the 1947 Nuremberg trials of Nazi physicians and researchers. • The act also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and charged it with identifying the ethical principles basic to human research and formulating guidelines to guarantee that are followed in its conduct. This became the Belmont Report. • Among the principles it identified are those of respect for persons, beneficence, and justice.

16. Reading: Philosophical Reflectionson Experimenting with Human SubjectsHans Jonas • Jonas argues that experiments on individuals, which expose them to serious risks, can never be morally justified on the grounds that such experiments provide benefits to society. • Jonas asserts that an experiment on a human subject is only justified when: • The risk taken is voluntary • Subjects must be recruited from those who are most knowledgeable about the circumstances of research and who are intellectually most capable of grasping its purposes and procedures • The experiment must be undertaken for an adequate cause. Knowledge for knowledge sake is insufficient. Progress which may come from research is not necessarily worth our efforts or approval, and he reminds us that there are moral values which we ought not to lose in the pursuit of science.

17. Section 2: The Ethics of Randomized Clinical Trials (RCTs) • The goals of medical therapy and medical research are distinct and may conflict in cases where a physician is engaged in both and some of the physician’s patients are also actual or potential participants in research trials. • A physician, in his capacity as a physician is concerned to provide the best possible care for each of his patients. For example, if one of them has a heart condition, he will propose treatments he believes are best for improving that condition in this particular patient.

18. Section 2: The Ethics of Randomized Clinical Trials (RCTs) • But suppose the physician is also involved in a research trial of a drug intended to help people with the same condition as his patient, A. A could be a likely test subject in the trial. • Should he try to encourage A’s enrollment in the program or discourage it if the patient proposes participation on his own? Or, if A is already in the trial, could his obligation to give A the best treatment the physician thinks possible require him to breach trial protocol and recommend a possibly different treatment? • The question becomes even more acute if the trial in which patient A might participate involves the use of a placebo. Is it ethical for the physician to allow patient A to participate in the trial knowing that A might receive a placebo rather than what he, the physician believes, is the best treatment for him?

19. Reading: How to Resolve an Ethical Dilemma Concerning Randomized Clinical TrialsDon Marquis • Marquis addresses the dilemma a physician faces when she believes that one of the two treatments in a clinical trial is better for her patient. Should she advise the patient to choose the treatment she thinks best or let him enter the trial and have to accept the randomly assigned treatment? • If she keeps quiet she won’t be giving the patient the benefit of her judgment but if she doesn’t advise him, she will hinder the clinical trial. • Marquis rejects two attempts at resolving the dilemma. • The first holds that she doesn’t really know which treatment is better (“equipoise”), because, in the absence of the results of the RCT, she lacks the best evidence. This approach is in error because it wrongly assumes that only evidence from an RCT can support a view. • The second approach holds that because the professional community has not decided which treatment is best she need not express her view about the matter. But this is wrong because we expect the best advice from our physician. • Resolving the dilemma requires that the physician explains her views to the patient, informs the patient of the alternatives (explaining also that in the clinical trial the patient may not get the experimental treatment), then allows the patient to make the decision.

20. Reading: Clinical Trials: Are They Ethical?Eugene Passamani • The author argues that randomized clinical trials (RCTs) are the most reliable means of evaluating new therapies. Without RCTs, chance and bias may affect our conclusions. • Passamani rejects the argument that the physician–patient relationship demands that physicians recommend the “best” therapy for patients, no matter how poor the data on which the recommendation is based. • He acknowledges that RCTs pose ethical problems for physician–researchers but believes the difficulties can be overcome by: • Requiring that all participants give their informed consent. • Clinical equipoise must exist. [Equipoise exists when competent physicians are genuinely uncertain about which of the alternative therapies in the trial is superior and content to allow their patients to be treated with any of them] (c) The trial must be a critical test of the therapeutic alternatives.

21. Reading: How Necessary Are Randomized Controlled Trials?Robert Northcott • The author argues that although RCTs are usually considered the “gold standard” for testing a new treatment, they are not always the preferred way. • Historical studies, which assess the effectiveness of treatments on the basis of data drawn from experiences using them, are sometimes preferable to RCTs. • Northcott uses the case of extracorporeal membranous oxygenation (ECMO) to argue that when the treatment was introduced, it was so successful in saving the lives of newborns with underdeveloped lungs that no RCT was needed to prove its superiority to conventional treatment. • The belief that an RCT was required. Northcott claims, led to deaths that were not only tragic, but unnecessary

22. Section 3: Access to Experimental Drugs • A common view is that an experimental drug should only become available to patients after they have been rigorously tested. But, suppose a drug shows substantial promise before clinical trials are complete. • Why shouldn’t terminally ill patients have a right to try such drugs if no other options exist?

23. Section 3: Access to Experimental Drugs • Aren’t we wrongly depriving patients of the benefits of the drug by insisting that the trials be completed first? • The case of Abigail Burroughs illustrates some ethical and legal issues involved in trying to decide whether clinically unproven drugs should be available to people who are in medically desperate circumstances and where existing medical treatments have failed them.

24. Reading: Abigail Alliance V. FDA Majority Opinion:Patients Have a Right to Have Access to Experimental DrugsJudith W. Rogers • Circuit Judge Rogers argues that terminally ill adult patients should have access to investigational drugs if • they have no better treatment options (b) the drugs have completed Phase I trials and been found safe enough for additional human testing. • Her argument rests on two primary two claims: First, that for most of US history, “the government has not blocked access to new drugs”. Second, the right to access lifesaving drugs can be inferred from the Cruzan decision, in which the Supreme Court found a right to refuse lifesaving treatment. (For the Cruzan case, see pp. 591–593 of the text.)

25. Reading: Abigail Alliance V. FDA Dissenting Opinion:Patients Have No Right to Experimental DrugsThomas B. Griffith • Circuit Judge Griffith argues that Rogers’ opinion is based on a series of faulty inferences: (1) The fact that government has not always regulated drugs does not imply a recognition of a constitutional right to be free of such regulation; (2) The traditions of the necessity defense and the prohibition of forced medication do not imply a right of access to medication; (3) That a drug has completed Phase I testing does not imply that it has a medical benefit and a minimal risk. In fact, the government has regulated drugs for a long time through the executive and legislative bodies.

26. Reading: Abigail Alliance V. FDA Dissenting Opinion:Patients Have No Right to Experimental DrugsThomas B. Griffith • To ignore this and give the judicial branch the role of deciding which drugs are safe and beneficial enough for use would burden the courts with a task both practically and logically impossible to carry out. • Griffith concludes by agreeing with the lower court decision that even terminally ill patients have no right to get access to drugs that are still in the testing stage.

27. Section 4: Animal Experimentation Animals are used in virtually all basic biomedical research because of their physiological resemblance to human being in various respects. Experimentation on animals often involves: • Subjecting them to extreme pain or • Severely disabling them or • killing them. It is of course obvious that animal subjects do not consent to the experiments nor understand the possible harm to their welfare. All of the above circumstances were true of the inmates of Nazi concentration camps and are condemned in by the Nuremberg Code when applied to humans. So, why doesn’t the Nuremberg Code apply to animals as well? The usual answer is that humans are morally superior to non-human animals and because of this fact it is morally acceptable to use animals in experiments in a way that we would not condone if a human subject were involved. Is this a rationally defensible view? The two readings in this section explore this question.

28. Reading: Animal ExperimentationPeter Singer • Singer argues that most animal experiments cannot be justified because they cause great animal suffering, while producing little or no knowledge. • Singer provides multiple examples of painful, pointless experiments leading to the death of animal subjects. • He argues that our willingness to tolerate such experiments reflects an attitude of “speciesism”—the notion that the interests of nonhuman animals need not be considered.

29. Reading: Animal ExperimentationPeter Singer • Speciesism, Singer holds, is analogous to racism and is just as indefensible. • Singer argues that the fundamental issue in determining how we may treat animals is whether they suffer and that the pains of animals and humans deserve equal consideration. • Many animals are more intelligent than severely retarded or infant humans, so that if lack of intelligence would justify painful animal experiments, it would also justify the same experiments on retarded and infant humans. • Because it is immoral to subject humans to such experiments, we have good reason to believe it is also wrong to subject animals to them. • Singer holds that researchers should be required to demonstrate that the benefits of their research will outweigh the suffering of the animals involved. He recommends that ethics committees, with members representing the welfare of animals, be established to oversee experiments.

30. Reading: The Case for the Use of Animals in Biomedical ResearchCarl Cohen • The author argues that we have a strong duty to conduct experiments on animals for the benefit of human. • He rejects the claim that animals have rights, as humans do. • To have a right, a being must have the capacity to comprehend rules of duty (autonomy). Humans have this capacity, animals do not. • Because animals lack autonomy, Cohen rejects Peter Singer’s argument that the pleasures and pains of animals deserve consideration equal to those of humans in calculating the overall benefits of animal experiments. • Having autonomy makes the pleasures and pains of humans morally more important than those of animals (an attitude Singer stigmatizes as “specieism”). • Cohen believes that we should be specieists. Speciesism is “essential to right conduct,” because those who fail to make the relevant distinctions between humans and nonhumans will fail to recognize their moral duties. • Cohen concludes that a proper analysis of animal experimentation shows “that contrary to Singer; instead of having a duty to decrease the use of animal experimentation, we have a duty to increase it.