Ethics of Human Subjects Research

Ethics of Human Subjects Research

when were Nazi medical experiments?
1942-1945: 32 known “experiments”
examples of Nazi medical experiments
experimental surgery (Ravenbrook)
osteology (Auschwitz)
sterilization research (Auschwitz)
typhus experiments (Buchenwald)
poison experiments (Buchenwald)
freezing experiments (Dachau)
use of human subjects prior to nuremberg
use of prisoners for research is a universally accepted practice
-malaria studies at Stateville Penitentiary
what was result of nuremberg trial?
Nuremberg Code
-also 7 defendants sentenced to death
-9 received prison terms
Essence of Nuremberg Code
“The voluntary consent of the human subject is absolutely essential…”
Why no consent prior to Nuremberg?
Consent is a process
??Respect, Beneficience, Justice???
Why was Nuremberg Code conceived?
…in reference to Nazi atrocities and was written for specific purpose of preventing brutal excesses from being committed or excused in the name of science.
opinion of Code in US
“The code…is in our opinion not necessarily pertinent to or adequate for the conduct of medical research in the US.”
Dean, Harvard Medical School
Declaration of Helsinki (1964)
2 categories:
-Non-therapeutic clinical research
-clinical research combined with professional care
non-therapeutic clinical research
“clinical research on a human being cannot be undertaken without his free consent, after he has been fully informed.”
clinical research combined with professional care
physicians required to obtain consent from patient-subjects only when “consistent with patient psychology”
What is a more “dependable safeguard” than consent?
“a truly responsible investigator”
What was PHS Syphilis Study?
(1932) research to study natural history of syphilis
-400 black men with syphilis from rural south
-“this was turning event”
PHS syphilis study (1969)
CDC reviewed data & concluded that study should continue
-“would be of immense benefit to future patients”
Why was PHS syphilis study so unethical?
syphilis patients died untreated
Ad Hoc Panel conclusion: PHS syphilis study
-PHS study was “ethically unjustified” and should be stopped immediately & remaining subjects be given necessary medical care
-neither DHEW nor any other agency in the govt had adequate policies for oversight of human subjects research
National Research Act (1974)
established National Commission for the Protection of Human Subjects of Biomedical & Behavioral Research
-recommend regulations to protect the rights & welfare of human subjects of research
-develop principles to govern the ethical conduct of research
National Commission decided…
investigators should NOT have the sole responsibility for determining whether research involving human subjects fulfills ethical standards. others who are independent of the research must share in this responsibility
belmont report (1979)
3 basic ethical principles:
-respect for persons
-beneficence
-justice
“respect for persons”
informed consent
additional protections for vulnerable subjects
“beneficence”
maximize benefits for subject & society while minimizing risks
What makes research ethical? (7)
1. social value
2. scientific validity
3. fair subject selection
4. reasonable balance of risks & benefits
5. independent review
6. informed consent
7. respect for enrolled subjects
social value
study must ask an important question
-valuable for improving health and/or for basic scientific knowledge
-may be difficult to justify research if the question is trivial, or has already be answered (“me-too” studies)
-ex. what’s social value of new drug if old drug
with a different name
scientific validity
*the research must be able to answer the scientific question that has been posed
-“for clinical research to be ethical the methods must be valid & feasible; the research must have a clear scientific objective; be designed using accepted principles, methods & practices; have sufficient power & offer a plausible data analysis plan”
ipso facto unethical
scientifically unsound research on human subjects
fair subject selection (FSS)
-in past, risk or non-beneficial research has enrolled mostly vulnerable populations (ex. minorities, mentally incapacitated)
-scientific goals of the study should main basis for deciding groups & individuals enrolled
rules of exclusion (FSS)
-groups or individuals shouldn’t be excluded from participation with good scientific or clinical reason
-exclusion disenfranchises them from benefits of knowledge gained
who should enjoy benefits? (FSS)
groups & individuals who bear the risks & burdens of research should be in a position to enjoy its benefits
nonmaleficence
risks to individuals subjects must be minimized
beneficence
potential benefits to individual subjects must be enhanced
risk/benefit balance
potential benefits to individual subjects & society outweigh the risks
-“risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, & the importance of the knowledge that may reasonably be expected to result”
example of risk/benefit balance
phase III placebo-controlled trial of an investigational drug in patients with progressive GI tumor
-drug is expected to produce significant improvement in a proportion of subjects
-subjects on placebo arm can’t receive “standard therapy” for the duration of the trial
is there equipoise?
a state of general uncertainty on the part of the investigator regarding the therapeutic merits of each arm in a trial
is there (at least) clinical equipoise?
there exists an honest, professional disagreement among expert clinicians about the preferred treatment
a clinical trial is instituted with the aim of resolving this dispute
independent review
independent review minimize the potential impact of such conflicts of interests
since investigators inherently have multiple interests these diverse interests can generate conflicts that may put research at risk
informed consent
-ensure respect for individuals’ values & preferences
-what constitutes respect varies from culture to culture so be aware
-consent makes research ethical
things needed for informed consent
-information
-full disclosure
-reasonable person v reasonable volunteer
-comprehension
-voluntary choice
??what reasonable person would want to know??
respect for subjects
maintain confidentiality, respect privacy
share new information during the trial
-changes in risk/benefit profile
-incidental findings
monitor subjects, provide necessary care for adverse events and/or injuries
inform subjects of results of the research after the trial is completed
what is an IRB?
IRB is a body constituted to assure compliance with 45 CFR 46 (Federal Policy for the Protection of Human Subjects) [Federal regulation]
UNMC IRB
responsible for reviewing all research involving human subjects
-at UNMC/UNO, TNMC, Children’s hospital
-conducted anywhere by UNMC/UNO, TNMC, Children’s
45 CFR 46 Subpart A
Basic Policy for Protection of Human Research Subjects
-final regulations issued in 1981
21 CFR 50
Informed Consent
21 CFR 56
IRBs
Federalwide Assurance
agreement btwn federal govt & the institution that:
-all research activities will be guided by ethical principles (ex. Belmont Report)
-research will comply with Common Rule
-All research will require written informed consent*
-All research will be reviewed by an IRB*
**any research done under organization not covered is governed by Federalwide Assurance
IRB Responsibilities (45 CFR 46.111)
-risks to subjects are minimized -> beneficence
-risks to subjects are reasonable in relation to anticipated benefits to subjects, & the importance of the knowledge that may be expect -> beneficence
-selection of subjects is equitable -> justice
-informed consent obtained & documented -> respect
-adequate provision for monitoring data & to protect privacy of subjects -> beneficence
What does IRB do?
protects:
-human subjects
-institution
-investigator