David Wendler Department of Bioethics NIH Clinical Center

1. Research EthicsThe views expressed in this talk are my own. They do not represent the position or policy of NIH or DHHS David Wendler Department of Bioethics NIH Clinical Center

2. Outline • Background: primary ethical concern, example • Potential for exploitation: research versus charitable activities, passive subjects, 3 types of passivity, active researchers • Research using less than the best methods • Models, Scandals, Regulations • Learning Health Care • Industry Sponsorship

3. Background

4. Clinical Research Research: systematic collection of data Human subjects research: systematic collection of data from humans Clinical research: systematic collection of data from humans regarding clinical interventions The ultimate goal of clinical research is to improve health and well-being

5. Benefits and Risks Prospect of benefit research: Participation in clinical research frequently offers subjects the potential for medical benefit. ‘Non-beneficial’ research:Many clinical research procedures and studies expose subjects to risks in order to collect data to help future patients

6. Primary Ethical Concern • By exposing subjects to risks and burdens to benefit others, clinical research has the potential to exploit subjects (unfairly use or inappropriately take advantage of them). • Research ethics evaluates under what conditions it is possible to collect valuable data without exploiting subjects.

7. Marco • 10 year old with a serious illness. • Available treatments did not help Marco. • Marco is brought to a research clinic by his parents.

8. Phase I/II Study • The investigators propose to enroll Marco in a clinical trial that administers a drug once a week for 2 months. • The drug is approved for other conditions. • The study evaluates for the first time whether individuals with Marco’s condition tolerate the drug and whether there is any preliminary evidence that it benefits them.

9. Non-beneficial Procedure • In addition to taking the medication, subjects undergo 4 blood draws for research purposes. Quiz #1: Are these research blood draws ethically acceptable or ethically problematic (or both)?

10. Survey Data (N=100; RR=45%; N=89; RR=74%) • Pediatricians and researchers: 47% in UK, 59% in Canada believe pediatric research without potential clinical benefit is unethical. Sammons. Eur J Clin Pharmacol 2007;63:431-36 • Canadian medical students: 49% agree that children “should only participate in trials from which they receive a direct benefit.” Wang. J Pop Therapeutics Clin Pharm2007;18:e10-e16

11. The Potential for Exploitation in Clinical Research

12. Comparison • Many argue that ‘non-beneficial’ research is unethical. • Yet, individuals, including children, often face risks in the context of activities outside of research that are designed to benefit others.

13. Charitable Activities • Collecting money for Oxfam, participating in a charitable car wash, mowing the lawn of an infirm neighbor, donating blood. Quiz #2: Clinical research is MORE, EQUALLY, or LESS problematic than charitable activities?

14. Passivity • Many claim that clinical research is especially problematic because it treats subjects like passive objects. • Research subjects simply “allow things to be done to them.” (Carl Elliott, New Yorker Jan 7, 2008).

15. Hans Jonas “What is wrong with making a person an experimental subject is not so much that we make him thereby a means, as that we make him a thing—a passive thing merely to be acted on…The soldier’s case is instructive…he is still conscripted with his capacities to act.”

16. Implications • On this view, exposing Marco to the research blood draws is unethical because it exploits the fact that he is ill and turns him into a passive thing to further the investigators’ goals. • To assess this view, we need to distinguish at least 3 senses of passivity.

17. Physical Passivity • Not physically moving (e.g. Marco lies still during the blood draws). • Level of activity often is a proxy for how impressive a particular role or position is. • But not always: Rope-a-Dope (see: When we were Kings). • Lying still for research procedures that hurt?

18. Physical Passivity • Also, facing risks without moving to help others is not necessarily problematic. • Sitting and collecting money for Oxfam.

19. Consent or Will Passivity • Things being done without one’s consent (against one’s will). • Robbery victims display Will passivity, but often not physical passivity. • Clinical research typically requires consent, or parental permission and the child’s assent for pediatric research.

20. Ends or Interests Passivity • Facing risks in an activity that does not promote one’s own ends or interests. • To address this concern, subjects should be encouraged to (and frequently do) recognize and embrace the scientific goals of research. Motto: Highlight don’t hide the research

21. 177 Adolescent Subjects(RR= 95.2%) • 68.9% felt they were making an important contribution by participating in research. • 80.8% felt proud to be making the contribution. • Parents and adolescents equally willing to have the adolescent face risks to help others in a research study or in a charitable activity Pediatrics 2012; 130:692-699

22. Active Researchers • Consider possibility that references to passive subjects reflect concerns about active researchers. • Researchers actively do things to subjects that pose risks to them for the benefit of others. • The concern is not that Marco is lying still; it’s that the investigator is sticking a needle in him to collect data to benefit others.

23. Research versus Charity • Compare non-beneficial pediatric research to a charitable car wash. • The risks to the children may be similar. • But, investigators actively expose subjects to risks, often through bodily intrusions; Organizers of car washes do not drive cars over volunteers’ feet.

24. It’s Our Problem • This suggests much of the concern clinical research raises (and is thought to raise) traces to investigators’ active role. • And to the extent investigators act for our benefit and with our support, we are implicated.

25. Practical Relevance • Distinction between what we do to subjects and what happens to them valuable for assessing an important current debate.

26. Research involving Less than the Best Methods

27. Setting • Some communities and countries lack access to the best methods/interventions/treatments. • In these cases, investigators sometimes propose studies of less than the best methods. • These studies have been the subject of significant debate.

28. “Long Course” AZT studies • Long course AZT proven to significantly reduce vertical transmission of HIV from mother to child. • 1990s: Long course AZT not available in many developing countries due to cost and complexity.

29. “Short Course” AZT studies • Does a truncated AZT regimen that is feasible and affordable in developing countries reduce vertical transmission? • Placebo controlled trials compared short course AZT to placebo. • Critics argued that these studies were unethical.

30. Lead Paint Studies • Lead paint is bad for children • Many young children in Baltimore live in homes with lead paint; expensive to eliminate • Study in the 1990s randomizes families with small children to houses with no lead paint and houses with partial, but not complete lead paint abatement.

31. Beneficial or Risky? • Impact on subjects: being enrolled in the study is better for children than moving into a house will full lead paint. • Actions of investigators: intentionally placing children in houses known to contain lead paint in order to collect data. Quiz #3: Was placing children in these houses for research purposes ethical?

32. Declaration of Helsinki • Studies of interventions less effective than the best proven one are acceptable only when participants “will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.” • This requirement protects research participants, but at the cost of preventing studies that are important for them and their communities.

33. Lesson • It is important to protect subjects from harm and also to prevent investigators from exposing subjects to risks inappropriately. • Do current regulations achieve these goals, while still allowing valuable research?

34. Models of Research, Scandals, and Regulations

35. Clinical Trial • In 1747, James Lind, a British surgeon aboard the HMS Salisbury, assessed six existing treatments for scurvy. • He divided 12 of his patients into six groups of two, and gave each group one of the treatments.

36. The Integrated Model • Lind’s experiment represents the beginning of an essentially 200-year history of conducting clinical research in the context of providing clinical care. • This approach has significant advantages, including ease of recruitment and efficiency in conducting trials.

37. Concerns The integrated approach also raises concerns: • Is it acceptable for clinicians to experiment on their patients (Lind gave two patients sea water)? • Conflict of interest between promoting goals of care and research • Tendency to conflate research and care (increase chances of the therapeutic misconception)

38. Scandals • Conflicts of interest led to unethical research. • In 1966, Beecher describes 22 cases in the U.S. of (potentially) problematic research. • In 1972, a press report leads the U.S. government to stop the Tuskegee Syphilis Study. By then, approximately 100 subjects had died of untreated syphilis.

39. National Commission • In response to Tuskegee, the National Commission was formed to develop guidance to protect research subjects. • The Commission wrote a number of influential reports, including the Belmont Report, and the recommendations that form the basis for current US research regulations.

40. The Segregated Model • Response to the abuses involved drawing a “bright line between clinical research and clinical care.” Selby, Krumholz. Hastings Center Report 2013; 43: S34-S36 • On this model, clinical research is separated from clinical care, and subject to extensive regulation and oversight.

41. Regulations and Guidelines • Nuremberg Code • Declaration of Helsinki • CIOMS • Belmont Report • ICH/GCP • US DHHS and FDA regulations • Regulations in many countries

42. Comparison • Existing guidelines were developed for specific reasons, including past scandals, desire for consistent drug approval process. • As a result, while there is a good deal of overlap, there are also differences and outright conflicts between the guidelines.

43. Collaborative partnership Social Value Scientific Validity Fair subject selection Favorable risk-benefit ratio Independent review Informed consent Respect for human subjects JAMA 2000; 283:2701-2711 8 Ethical Requirements

44. Status • The 8 requirements are universal. They apply to clinical research everywhere. • The 8 requirements must be adapted to the local health, economic, cultural and technological circumstances.

45. Ethical Investigators • The need for judgment in applying and balancing the principles emphasizes the importance of knowledgeable and committed individuals. • Need more guidance on what it is acceptable for investigators to do to research subjects.

46. Return of the Integrated Model?

47. The Segregated Model • Treats research as distinct from care • Emphasizes differences between research and care. • The ‘therapeutic misconception’ is a primary concern.

48. Benefits • The segregated model has been fairly effective at protecting research subjects. • Comparatively few clear abuses or scandals in the past 30 years.

49. Concerns • Clinical care generates countless data points. • Segregation of research and care, along with strict research regulations, has discouraged systematic efforts to capture these data. • Also, clinical trials are slow and often fail to recruit sufficient number of subjects.

50. LHC Systems • Recently, there have been many calls for learning health care (LHC) systems to address the shortcomings of the segregated model. • In LHC systems, the collection of data is “embedded into the core of the practice of medicine”. Olson. The learning healthcare system: workshop summary 2007