Research Ethics

Michael Caligiuri, Ph.D.Professor-in-Residence

Dept of PsychiatryDirector, HRPP

Part I: Ethical Considerations in

Human Subjects Research

Human Research Abuses

1940’s Nazi war crimes and Nuremburg code (1948)

1950’s Thalidomide Tragedy

1960’s Human Radiation Experiments New York City’s Jewish Chronic Disease Hospital Willowbrook Studies Milgram Study

1970’s Tuskegee Syphilis Stanford Prison Experiment

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

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)

IRBs: Historical Background

The Belmont Report

Established Responsibilities 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

Respect for Persons Individuals should be treated as

autonomous agents Persons with diminished autonomy

are entitled to protection (‘special populations’)

Children Mental disabilities Prisoners

Guiding Principles: Belmont Report

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

Beneficence 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 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

Guiding Principles: Belmont Report

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

Threats to the Principle of Respect

Coercion Undue Inducements Exploitation

Coercion

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?

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 Perceived coercion in research can

occur with Prisoners Students and staff

Payment for research is not coercive: Payment is an offer not a threat

Inducement

Definition: 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

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

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

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 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

-5%

-9%

payment

Exploitation

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:

Poor; homeless Mentally Ill Terminally Ill Prisoners Students Staff

For each group, there is a different solution

Exploitation

Solutions to avoid exploitation: 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

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

“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

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/

Purpose: To test the idea that the inherent

personality traits of prisoners and guards were summarily key to understanding abusive prison situations.

Experimental Questions: What happens when you put good

people in an evil place? Does humanity win over evil, or does

evil triumph?

Stanford Prison Experiment

Subjects answered a local newspaper ad calling for volunteers in a study of the psychological effects of prison life.

More than 70 applicants responded given diagnostic interviews and personality

tests to eliminate candidates with psychological problems

24 college students met criteria Earned $15/day

Stanford Prison Experiment

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 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

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

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:Conclusions

Critics challenged the generalizability of the study. 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

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:Scientific Challenges

Questions regarding beneficence : What are the risks of participating in

this research? Were they disclosed? Were they

minimized? What were the benefits – to society?

Stanford Prison Experiment:Ethical Challenges

The Milgram Study1961

The Milgram Study 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

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

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

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 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.