Professor Caliguirli`s Slides on Research Ethics

Research Ethics Michael Caligiuri, Ph.D. Professor-in-Residence Dept of Psychiatry Director, HRPP

Part I: Ethical Considerations in Human Subjects Research

Human Research Abuses 

1940’s 

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1950’s 

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Thalidomide Tragedy

1960’s    

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Nazi war crimes and Nuremburg code (1948)

Human Radiation Experiments New York City’s Jewish Chronic Disease Hospital Willowbrook Studies Milgram Study

1970’s  

Tuskegee Syphilis Stanford Prison Experiment

IRBs: Historical Background  

Declaration of Helsinki (1964-2007) Response to Research Abuse 

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Beecher, 1966  Call for Journal editors to require ethical review  Call for national policy on IRB review The National Research Act (1974)  Set-up formal IRBs Belmont Report (1979)

The Belmont Report 

Established Responsibilities 

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IRB must ensure that the researcher and the participant distinguish clinical practice from research. IRB must minimize the potential for therapeutic misconception.

Ethical Principles 

Respect, Beneficence, Justice

Guiding Principles: Belmont Report 

Respect for Persons 

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Individuals should be treated as autonomous agents Persons with diminished autonomy are entitled to protection (‘special populations’) 

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Children Mental disabilities Prisoners

The Common Rule “An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.” 45 CFR 46.116

Guiding Principles: Belmont Report 

Beneficence  

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Do no harm Maximize possible benefits and minimize risks Applied at both an individual level for research participants and a societal level for the effect of the knowledge gained from the research

Guiding Principles: Belmont Report 

Justice 

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fair distribution of the burdens and benefits of research selection of research participants should involve those groups who will benefit from research, not ‘convenience’ populations that are more likely to be disadvantaged

Part II: Threats to the Ethical Conduct of Human Subjects Research

Threats to the Principle of Respect

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Coercion Undue Inducements Exploitation

Coercion 

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Coercion occurs when an overt threat of harm is intentionally presented by one person to obtain compliance from another. Coercion does not mean:  

involuntary or under strong influence doing something because there are no good options.

Coercion 

Exactly what is Coercion? 

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Perceived coercion in research can occur with  

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To be coercive, a subject who refuses must be made worse off than if he/she were never asked Requires the presence of a threat Prisoners Students and staff

Payment for research is not coercive: 

Payment is an offer not a threat

Inducement 

Definition: 

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Inducements are offers that get people to do things they would not otherwise do:

Acceptable Inducements: Higher salary for greater responsibility  Free car wash with fill-up 

Inducement 

Inducements in Research:   

Anything that encourages participation Usually monetary Medical/diagnostic services   

Results from MRI scan Knowledge of genetic testing Neuropsychological work-up for child enrolled as a “control”

Inducement 

Undue Inducements 

Excessively attractive offers that lead people to do something to which they normally would object based on risk or other fundamental value (Dickert, 2004)

Undue Inducement 

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Monetary inducement that alters individual’s decision-making process such that they underestimate risks; Payments that undermine a person’s capacity to exercise a free choice invalidates the consent process* *Council for International Organizations of Medical Sciences, 2002; guideline 7

Undue Inducement 

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Undue inducements may prompt subjects to lie or conceal information that, if known, would disqualify them from participation. Under 45 CFR 46.111 failure of the participant to appropriately judge risks is considered improper informed consent.

Undue Inducement 

Ambiguities  

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What is excessive? Reasonability of risks varies among study participants Impact of risk can change throughout the study, should the inducement also change? In the absence of a standard metric, IRBs vary in their assessment of risk and appropriateness of payments.

Undue Inducement 

Little empirical support that the amount of payment affects subject’s perception of risks 

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No relationship between amount of money offered and risk (Bentley and Thacker, 2004) Public thinks other people are more likely to have impaired judgment as a result of payment than they are themselves (Casarett et al., 2002)

Undue Inducement Risk is likely more important than money when considering enrollment

Halpern, S. D. et al. Arch Intern Med. 2004

payment

-5% -9%

Exploitation 

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An exploitative transaction is one in which person A takes unfair advantage of person B (Wertheimer, 1999). IRB’s are always concerned when vulnerable individuals are paid to enroll in medical research

Exploitation 

There is always an ethical concern when recruiting from vulnerable populations: 

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Poor; homeless Mentally Ill Terminally Ill Prisoners Students Staff

For each group, there is a different solution

Exploitation 

Solutions to avoid exploitation: 

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Pay vulnerable patients more? Engage patient advocates? Exclude vulnerable populations? IRBs need to define what is “fair” Appropriate IRB member expertise

Scientific Impact 

Undue inducements or exploitative subject payment can impact science    

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Unqualified subjects enrolling in FDA monitored studies Conceal information important to outcome Less likely to report adverse events Skewing population

Not disclosing participation in multiple clinical trials can confound results.

Case Scenarios

Case 1: Alexis St. Martin 

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“The Intrepid Guinea Pig of the Great Lakes” In 1822, accidentally shot in the gut and left with a permanent gastric fistula. William Beaumont paid him room, board, and $150 a year for use of his stomach.

http://www.guineapigzero.com/AlexisStMartin.html

Case 2: Walter Reed’s Yellow Fever Study 

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Paid $100 in gold for participation. $100 bonus for successful infection with yellow fever. Payable to family in the event of death.

http://etext.lib.virginia.edu/healthsci/reed/commission.html#vol

Case 3: You

Threats to the Principle of Beneficence

Stanford Prison Experiment PI: Philip Zimbardo, Ph.D.; 1971

http://www.prisonexp.org/

Stanford Prison Experiment 

Purpose: 

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To test the idea that the inherent personality traits of prisoners and guards were summarily key to understanding abusive prison situations.

Experimental Questions: 

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What happens when you put good people in an evil place? Does humanity win over evil, or does evil triumph?

Stanford Prison Experiment 

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Subjects answered a local newspaper ad calling for volunteers in a study of the psychological effects of prison life. More than 70 applicants responded 

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given diagnostic interviews and personality tests to eliminate candidates with psychological problems 24 college students met criteria

Earned $15/day

Stanford Prison Experiment 

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Randomly assign subjects to two groups: guards or prisoners. The prisoners were then brought into our jail one at a time and greeted by the warden 

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Each was systematically searched, stripped naked, deloused.

The guards were given no specific training on how to be guards. 

Free, within limits, to do whatever they thought was necessary to maintain law and order in the prison.

Stanford Prison Experiment 

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Less than 36 hours into the experiment, one prisoner began suffering from acute emotional disturbance, disorganized thinking, crying, and rage. On the 5th night, visiting parents asked the PI to contact a lawyer in order to get their son out of prison. Most prisoners were withdrawing and behaving in pathological ways Some of the guards were behaving sadistically Study was then stopped after 6 days.

Stanford Prison Experiment: Conclusions 

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PI argued that the results demonstrate the impressionability and obedience of people when provided with a legitimizing ideology and social and institutional support. Results supported a situational attribution of behavior; that is, the situation caused the participants' behavior, rather than anything inherent in their individual personalities.

Stanford Prison Experiment: Scientific Challenges 

Critics challenged the generalizability of the study.  

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Small sample size (n=12 in each group) The experiment would be difficult for other researchers to reproduce. Screening procedures could not exclude tendencies for sadism; so contrary to the PI’s conclusions, the “experiment” itself may not have produced these behaviors.

It was impossible to keep traditional scientific controls. Examiner Bias: The PI was not merely a neutral observer, but influenced the direction of the experiment as its "superintendent".

Stanford Prison Experiment: Scientific Challenges 

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Questionable ecological validity: blindfolding incoming "prisoners", not allowing them to wear underwear, not allowing them to look out of windows or use their names

Selection Bias: Western Kentucky U. (in a similar study later) found that students volunteering for a prison life study possessed dispositions toward abusive behavior. The study was never published in a peer-reviewed journal

Stanford Prison Experiment: Ethical Challenges 

Questions regarding beneficence : 

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What are the risks of participating in this research? Were they disclosed? Were they minimized? What were the benefits – to society?

The Milgram Study 1961

The Milgram Study 

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Experiment on obedience to authority figures The experiments began in July 1961, three months after the start of the trial of German Nazi war criminal Adolf Eichmann. Milgram devised this study to answer the question: "Was it that Eichmann and his accomplices in the Holocaust had mutual intent, with regard to the goals of the Holocaust or were the accomplices merely following orders?"

The experimenter (E) orders the teacher (T), the subject of the experiment, to give what the subject believes are painful electric shocks to a learner (L), who is actually an actor and confederate. The subjects (T) believed that for each wrong answer, the learner was receiving actual shocks, but in reality there were no shocks. The confederate (L) set up a tape recorder integrated with the electro-shock generator, which played pre-recorded sounds for each shock level.

The Milgram Study 

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Only the "teacher" is an actual participant, i.e. unaware about the actual setup. The participant and the learner were told by the experimenter that they would be participating in an experiment helping his study of memory and learning in different situations. Deception was a necessary component.

The Milgram Study:Results 

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Before conducting the experiment, respondents believed that only a few (average 1.2%) would be prepared to inflict the maximum voltage. In the first set of experiments, 65 percent of the participants administered the experiment's final massive 450-volt shock   

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though many were very uncomfortable doing so; every participant paused and questioned the experiment; some said they would refund the money they were paid for participating in the experiment.

Only one participant steadfastly refused to administer shocks below the 300-volt level.

Ethical Issues 

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Respect for Persons: Stanley Milgram deceived his study's subjects (failure to disclose important aspects of study to allow a voluntary decision to participate) Beneficence: Subjects (T) were placed under more pressure than many believe was necessary to test the study hypothesis. Respect for Persons: Subjects were coerced into remaining in study against their will.