Research ethics

1. Research ethics Research Ethics: • The Tuskegee Study • The Common Rule • The Belmont Report • This is a PowerPoint Show • Open it as a show by going to “slide show”. • Click through it by pressing any key. • Focus & think about each point; do not just passively click. • Print it using the instructions on the home page. Dr. David J. McKirnan, University of Illinois at Chicago, Psychology; mckirnanuic@gmail.com

2. Research questions, hypotheses & designs • The Tuskegee Study: A case study of research ethics • The Common Rule: Core criteria for ethical research • The Belmont Report and the Informed Consent document 

3. Tuskegee & the Natural History of Syphilis • The Tuskegee study began as a potentially important treatment trial. • Became a “Natural history” of untreated syphilis • Natural History studies… • Monitor disease as it emerges & changes. • Crucial to understanding disease progression • Typically address: • Natural progression in morbidity & mortality • Individual differences in progression • Variables that confer vulnerability / resistance to disease progression. • Data on African-American syphilis progression were limited • However, there were systematic Northern European data

4. Tuskegee & the Natural History of Syphilis • Tuskegee addressed a serious public health problem: • Around 1930, when the study began, the prevalence of Syphilis in poor, rural Black men was extremely high; • 25% of African-American employees at a private Alabama company tested positive for syphilis • Prevalence in the 5 county rural area surrounding Macon, Alabama ranged from 35% to 40%. • For context, an infection rate of 5% or so is considered a “syphilis outbreak” by the CDC today. • At study outset treatments were only marginally effective • Mercury was one of the earliest treatments, used extensively in Europe from the Renaissance to the 1940s • "A night in the arms of Venus leads to a lifetime on Mercury”. • The arsenic-derived drug Salvarsan was the treatment of choice in 1930. • One “folk” treatment actually consisted of drinking kerosene (!).

5. Tuskegee & the Natural History of Syphilis • 1928 – 1930: Tuskegee is begun as a prevalence and treatment study • Funding: • The Public Health Service (PHS, predecessor to the CDC) • The Rosenwald Fund (An African-American development fund). • Participants: primarily poor, uneducated, African-Americans. • Stage 1: Prevalence study • 7,000 – 10,000 people tested; • Syphilis prevalence = 36% • Stage 2: Treatment trial • Salvarson & Mercury; Penicillin not yet used in general medicine. • 1,200 treated by 1930. • Thus, the eventual observational study was not even a true natural history: treatment was provided in the early stages.

6. Tuskegee & the Natural History of Syphilis • 1930 – 1932: The Depression slashes funding • The treatment arm of the study is defunded. • Rosenwald fund pulls out of the study • Neither the PHS nor the State of Alabama have funds to continue the study. • Men still followed by the Tuskegee Institute • European data showed most syphilis symptoms to be physical rather than neurological. • Tuskegee Investigators hypothesized that symptoms among African-Americans would be predominantly neurological. • Since no coherent theory would predict this, it is a classic example of “scientific racism”.

7. Tuskegee & the Natural History of Syphilis • 1934: PHS funds the continuation of the Natural History study. • Participants: 600 poor, African-American sharecroppers • 399 participants had syphilis at study outset. • Participants told they are simply receiving medical treatment, not that they are in a research study • Incentives for participation: medical care, meals, burial insurance. • Infected men not told they had syphilis. • Cohort is recruited and maintained by local African-American Nurse, “Miss Evers” • Nurse Evers cultivates personal relationships with participants, and drives them to their medical visits.

8. Tuskegee & the Natural History of Syphilis • 1943: Penicillin becomes generally available. • Alexander Fleming had first identified Penicillin in 1929. • The treatment potential of Penicillin was recognized in 1939. • Larger scale production begun by the U.S. War Production Board (WPB) in 1943, to treat “venereal disease”. • Tuskegee participants not informed that treatment is available • One rationalization was that penicillin may not be effective for longer-standing syphilis. • There was no clear theoretical rationale for this assumption • The assumption – later proved false – was not tested by giving the Tuskegee men treatment. • Treatment was given only when the study was stopped.

9. Tuskegee & the Natural History of Syphilis 1963 1956 1935 1950s - 1960s; Multiple papers published in Medical Journals describe the study. Few or no ethical questions posed to PHS or the journals

10. Tuskegee & the Natural History of Syphilis • 1965: Dr. Irwin Schatz sends a letter to PHS (Then CDC) • “I am utterly astounded by the fact that physicians allow patients with a potentially fatal disease to remain untreated when effective therapy is available.” • CDC files the letter, noting it was the first such letter received. • No reply was written. • 1966: Dr. Peter Buxtun writes CDC after reviewing published articles on Tuskegee • Buxtum invited to CDC to discuss the study. • CDC does not change its policy or stop the study. • 1968: Buxtun again writes CDC • Committee formed to investigate the study. • CDC again does not change policy or stop the study.

11. Tuskegee & the Natural History of Syphilis • 1972: Buxtun discusses the study with a reporter from the Associate Press. • AP is interested in the story, assigns it to Jean Heller • Heller writes an explosive columns for the Washington Star (now Washington Post) and New York Times. • 1972: Secretary of Health & Human Welfare (now Health &Human Services) convenes a panel • … in response to the Washington Star report, not from any communication from CDC. • Describes himself as “shocked” and “horrified”. • 1973: Sen. Ted Kennedy begins congressional hearings. • Congress hears about the study for the first time, despite 40 years of government funding for it. • The study ends and remaining participants given penicillin.

12. Tuskegee & the Natural History of Syphilis • 1975; Class action suit brought by surviving members of the cohort. • 1980s; HIV / AIDS re-invokes prospect of unethical research or treatment • Incidence of HIV infections skewed toward African-Americans & other minorities • Search for vaccines & treatmentsraises the prospects of racist or unequal treatment. • 1997; Presidential apology • Bill Clinton apologizes to the 8 remaining cohort members.

13. Core ethical issues in Tuskegee • No informed consent • Key issue: Research was presented as Clinical care • Refusal of treatment • …not informed when Penicillin became available • Coercive enrollment & retention • Deception: Patients unaware they were in a research study • Exploitation: • Primary incentive was burial $, which would require lifetime participation • Co-opted population members: • Local African-American Medical Personnel were key players on the research and study team. • personal relationships with Nurse Evers • vulnerability of uneducated, poor men with a disease

14. Ethical Principles stemming from Tuskegee aftermath: • Include participants of all races & both genders in study cohorts • Barring a compelling reason to exclude groups. • Members of the target population included on research team & design boards • Note: African-Americans were on the research and outreach teams in Tuskegee • Facilitate access to an intervention to the entire population • Cannot withhold “Standard of Care”. • Standard of Care shifted during the Tuskegee study – from Salvarsonto penicillin – but study procedures did not. • Research must contribute to population being studied • Communicate research results • Develop applied programs or interventions

15. Ethics procedures stemming from Tuskegee • Informed consent • Non-coercive enrollment & retention • Led to the 1979 Belmont Report • Indirectly to core elements of the “Common Rule”. • Ethical review & monitoring • Led to establishment of the Federal Office for Human Research Protections (OHRP) • Led to laws requiring Institutional Review Boards (IRBs) • All Federally funded research must be reviewed and monitored by a local IRB • Most institutions (e.g., UIC) require IRB approval of all research, federally funded or not.

16. Tuskegee Study: Overview • Tuskegee study begin as a potentially valuable trial of treatment outcomes • Begun – and should have remained – a natural history of participants’ response to treatment. • Had the virtue of being conducted by a local institution – Tuskegee Institute – with African-American Investigators & staff. • Became a wholly unethical no-treatment history. • Based on spurious – and racist – scientific reasoning about differences between Africans and Caucasians • Investigators took advantage of participants economic and social vulnerability to exploit and harm them. • Note: Tuskegee participants were not actually given syphilis; they were not given treatment. • Tuskegee led to many of our research norms and institutional controls. SUMMARY

17. Research questions, hypotheses & designs  • The Tuskegee Study • The Common Rule: Core criteria for ethical research • The Belmont Report and the Informed Consent document  Still from the Milgram Study on obedience Dr. David J McKirnan, McKirnanUIC@gmail.com

18. The “Common Rule” criteria for Human Subjects Protection • The Common Rule • Minimize risks • Risks must be reasonable • Recruit participants equitably • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality

19. Minimization of risks Core issue: • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Risks should not exceed those of everyday behavior. Potential harms from research: • Loss of time, money, change in self-perception… • Direct: Tuskegee-like • Indirect: Clinical trials, wait-list designs • Withholding care • Use of deception in experimental manipulation • Is the informed consent valid? • Possible embarrassment or negative shift in self-perception • Erosion of trust & confidence in social science

20. Potential harms, cont. • Physical harm • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Cold War radiation experiments, • Army psychoactive drug research • Drug trials in prison populations • Some forms of Animal research Direct: Indirect: • Behavior induced by the experiment: • Experimental conditions that encourage risk, alcohol & drug use, smoking… • Psychological harm • Experiments that induce anxiety or other negative moods • Discomfort or pain • The Zimbardo or Milgram studies led participants to believe they were capable of harming others • Changed self-perception • Embarrassment • Loss of confidentiality or privacy

21. Potential harms, cont. • Social or political harm • Portraying social groups in a negative light, e.g.: • IQ among lower socio-economic status or minority participants • “Pathologizing” GLBT or other populations • Ignoring or discounting some groups: e.g., women or minorities in clinical research… • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality Factors that make researchers vulnerable to research harm: • Financial pressure for study results • Publication & grant pressure • Simple bias or prejudice • Lackof institutional controls • Active Institutional Review Board • Study monitors

22. Harm to Participants, cont. • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Prevention of research harms: • Independent & rigorous Institutional Review Board [IRB] • Diversity among investigators, research centers • Study monitoring • Careful pilot testing & monitoring of study manipulations • Informed consentand debriefingto: • a) fully inform participants about the study; • b) eliminate any imposed state

23. Reasonableness of risks Core issue: • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Whether a risk to participants is reasonable rests on a Cost – benefit analysis • Does the study present risks greater than every-day life? • How much greater, for how long? • Are they justified by the likely knowledge to be gained? • Potentially harmful research may be justified if it provides invaluable data, e.g.: • Milgram obedience studies • Zimbardo prison experiment • Intrusive animal studies • Studies that pay people to take medical or behavioral risks

24. The Zimbardo Prison Study subjected college students to real stress… …but provided invaluable data about how social roles and the physical setting affects behavior. Reasonableness of risks • Research that presents little harm may be unjustified if it will not provide useful data: • Research always requires time, effort, potential embarrassment… • Research that is trivial or incompetent may be inherently unethical for those reasons. • Weighing risks against potential benefits is difficult and complex… • We lack a scientific metric for evaluating degrees of potential harm. • The benefits of research are rarely guaranteed. • Often research that has great scientific or applied benefit has no direct benefit for the study participants.

25. Reasonableness of risk • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Prevention: • Independent & rigorous Institutional Review Board [IRB]. • An advisory board of people from the target population (CAB or Community Advisory Board). • Pilot testing to assess the actual risks of the research. Causes of unreasonable research risk: The “Costs” of participation may not be fully understood by investigator Benefits may be overstated or not framed in terms of target population. Publication & grant pressure to recruit participants at any cost.

26. Participant Recruitment Equitable recruitment: • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • People potentially affected by research must: • Have the opportunity to join the study • Have the opportunity to withdraw once enrolled • Not be coerced or deceived into enrollment • How do we ensure that all social groups are represented? • Some groups are less likely to enlist than are others; • How much should Investigators try to overcome peoples’ reluctance to join a study? • At what point does that become coercive? • Some groups – drug abusers, those in poverty – will respond to even a small monetary incentive to join even high risk studies. • Is offering a monetary incentive to those individuals coercive? • Are they treated inequitably by not being offered money?

27. Participant Recruitment • Potential problems in recruitment: • Arbitrary bias in sampling • Excluding – or only including – groups for reasons unrelated to the research protocol (I,e, convenience, or ease of recruitment). • Using highly unrepresentative samples (e.g., reliance on college students in social / behavioral research). • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • Coercive payments or incentives; • Culturally or socio-economically coercive. • Potential loss of benefits, such as recruitment in a medical setting. • Deceptive descriptions of experiment • Ability to comprehend protocol & provide informed consent; • Children, elderly, developmentally delayed, mentally ill… • Highly complex or long-term research protocols • Prevention: • Local IRB & Funder’s requirements for equitable representation.

28. Informed consent • Key elements of the Informed Consent document: • Purpose & procedures of the study. • Why the participant was recruited. • Study requirements and duration. • Possible risks or harms, • The study is voluntary & the participant can withdraw at any time. • Any potential benefits or costs of participation. • Who to contact for information / concerns, including the IRB. • Written signature. • How do we know the participant understood? • Administer consent quiz, or personal interview. • How to document consent? • For studies where participants are anonymous the IRB can waive written consent. • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality

29. Informed consent • Deception in experiments: • How do we provide informed consent if the participant cannot know the hypothesis? • The study must present no risks of harm • The participant must be thoroughly debriefedafter the study. • Deception can erode trust & confidence in social science • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Data monitoring for safety • Protect vulnerable participants & maintain confidentiality • The consent document is one of the most closely examined issued in IRB ethical reviews.

30. Data and clinical trial monitoring • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • Two key elements of Research Monitoring: • Monitoring of clinical trials • Studies of a new drug or treatment • Behavioral intervention studies • Participants are followed over time with multiple study visits. • Data Safety Monitoring Boards • Independent bodies that oversee data collection and analyses

31. Data and clinical trial monitoring • Monitoring for safety: • Trial monitoring • Data Safety Monitoring Board • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • Investigators in clinical trials are required to monitor and report any health or safety “adverse events” • Trial related – due to a feature of the trial protocol • E.g., heart complications during trials of weight loss drugs • Can be deemphasized or ignored in trials testing products • Often ignored in behavioral intervention studies • Non-Trial related; • e.g., deaths during longitudinal study of injection drug users • Trial-related Serious Adverse Events may require a protocol change or may stop the study.

32. Fen-Phen; a case study of failed trial Monitoring • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • Large Pharmaceutical Companies can have substantial influence in FDA decisions • Wyeth spends $52 million promoting the drug, garnering $300 million in annual sales. • Time Magazine notes Fen-Phen as the hot new diet drug, but raises safety questions. • 1997; 30 year-old woman dies of cardiac event after taking Fen-Phen for a month. • 1998 ; Mayo clinic finds multiple cases of cardiac problems in women taking Fen-Phen • FDA receives 144 Adverse Event reports; 30% of patients taking Fen-Phen show cardiac abnormalities. Fen-Phen pulled from market. • 2003; Forbes Magazine reports 153,000 law suits against Wyeth, who pays out $13 billion in settlements. Click for a PBS Frontline documentary on Fen-Phen • 1992; Physicians begin prescribing a combination of Fenflouramine and Phentermine (Fen-Phen) for obesity, with no FDA approval. • 1996; After clinical trials by the manufacturer the FDA approves Redux, a Fen-Phen drug. • The manufacturer reported 4 cases of severe cardiac effects during trial monitoring, despite 41 having actually occurred. • The Food and Drug Administration bypassed staff who had concerns, and approved the drug without a “black box” warning.

33. Data and clinical trial monitoring • Monitoring for safety: • Trial monitoring • Data Safety Monitoring Board • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • The DSMB monitors: • Trial integrity; is the research protocol being followed correctly. • “Stopping rules” for research risks or positive findings • Data integrity: • Ensures that data are collected in a valid fashion • Guards the data against “unblinding” of participants or investigators; • The DSMB is entrusted with all the codes for experimental groups and “unblinds” participants and investigators only when the trial is over.

34. The Women’s Health Initiative; a case study of “stopping rules” for a clinical trial. • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • 2002: Part of the Women's Health Initiative is stopped after women in the study taking E+P show higher rates of heart attack, stroke and breast cancer. Millions of women abandon hormones overnight. • 2004: The study of estrogen only is stopped one year early: women taking estrogen show fewer breast cancers and only small increased risk of stroke. Both arms of the study were stopped early: • The first trial because the DSMB detected adverse effects of E+P therapy • The second because the estrogen-only arm showed positive enough results that the “control” women were all put on therapy. • 1980s-90s: Millions of women use Hormone Replacement Therapy of estrogen plus progestin (E+P) to relive menopausal symptoms. • 1991: NIH begins a study of hormones after observational data suggest that women using hormones have lower rates of heart disease.

35. Thought questions: Monitoring for safety How do we separate self-interest & political pressure from science? • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & maintain confidentiality • How much does military or corporate (pharmaceuticals, tobacco..) funding for research distort scientific findings? • How sensitive should scientists be to political or social pressures around their research, e.g., • sexual behavior • stem cells • gun risks • global warming • evolution v. creation debate • Are scientists responsible for the social impact of their findings? • E.g., negative portrayal of social “out-groups” • The use of empirically validated techniques for unethical practices

36. Case study of the unethical use of scientifically validated techniques. The APA endorsed Psychologists serving as interrogators at Guantánamo Bay until September 15, 2008. • American Psychiatric & Medical Associations refused to endorse interrogations • Interrogations linked to torture & unlawful detention • As “helping professions” they are prohibited from this • As a research organization APA declared itself exempt from ethical standards of “helpers” • If research-based techniques are used, does APA as a research organization have an ethical responsibility? • After years of boycotts and protests, APA finally altered its stance and accepted the “do no harm” ethical stance of helping professions. • Any time we use a scientific principle to achieve a personal end (persuasion, advertising, jury selection) we are “coercing” someone – where are the ethical lines?

37. Vulnerability to coercion in research • What is coercion in research? • Enrollment: • Joining a study that a reasonable person would see as harmful or exploitive • Continued participation: • Not recognizing harm or exploitation that emerges once the research begins • Recognizing harms but not having the psychological or physical capacity to withdraw. • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & confidentiality What makes someone vulnerable to coercion in research? Cognitive:The capacity to think about and provide informed consent for participation; • Children, older adults • Dementia or cognitive limitations, mentally ill, drug users.

38. Vulnerability to coercion in research What makes someone vulnerable to coercion in research? • The Common Rule • Minimize risks • Reasonable risks • Equitable recruitment • Informed consent • Document consent • Monitor for safety • Protect vulnerable participants & confidentiality • Authority: liable to authorities who have a vested • interest in your participation. • Prisoners • Medical patients, students via Dual Role • Patients may feel obligated to participate in a study conducted by their physician • Students  their Professor’s research • Deferential:participation due to deferential attitudes or cultural pressure rather than actual willingness. • Medical:selected due to serious health-related condition for which there are no satisfactory remedies. • Poor / disadvantaged:lacking important social goods – money or health care – provided via research participation.

39. Bonus section: Ethics and the research “industry” • Drug licensing, marketing diagnostic devices or behavioral interventions all require positive findings. • The varieties of research fraud • Simple faking of data; DeitrikStapelsuccessfully faked 20 years of data (click image & below for the story) • He was aided by trust and lack of strong oversight in the research industry. • “Cherry Picking” results; publishing only those that “work”. • Drug companies would selectively submit only successful trials to the FDA • FDA now requires submission and access to all drug trials • Selective choice of variables: • Large data sets contain multiple variables, • Investigators can “cheat” by analyzing those that show positive results. There is substantial pressure – and temptation – for data faking • Career advancement – and funding – requires finding positive results • Experiments must “work” to be published

40. Research questions, hypotheses & designs • The Tuskegee Study • The Common Rule: Core criteria for ethical research • The Belmont Report and the Informed Consent document 

41. Belmont Report (CITI training) 1. Respect For Persons • Right to exercise autonomy & make informed choices. 2. Beneficence • Minimization of risk + maximization of social/individual benefit How much information should participants get from a blinded, randomized trial? See ethics of clinical trials 3. Justice • Research should not unduly involve groups unlikely to benefit from subsequent applications. • Include participants of all races & both genders • Members of target population on design & research team • Research & researchers contribute to study population studied • Communicate research results & develop programs/ interventions

42. The informed consent document • procedures, • purposes, • potential risks & benefits, • potential outcomes. Brief descriptions.. Why am I being asked to participate in this research? • ..who is being recruited or selected? Why is this research being done? Overview Box: What is the purpose of this research? What procedures are involved? What are the potential risks and discomforts? Are there benefits to taking part in this research? What other options are there? ...What happens if I decline participation?

43. Informed consent elements, 2 Will I be told about new information that may affect my decision to participate? What about privacy and confidentiality? What if I am injured as a result of my participation? What are the costs for participating in this research? • ...e.g., for services, etc. Will I be reimbursed for any of my expenses for participation in this research? Can I withdraw or be removed from the study? Who should I contact if I have questions? Signature of participant or legally authorized representative