Ethics of Human Subjects Research

1942-1945: 32 known "experiments"

experimental surgery (Ravenbrook) osteology (Auschwitz) sterilization research (Auschwitz) typhus experiments (Buchenwald) poison experiments (Buchenwald) freezing experiments (Dachau)

use of prisoners for research is a universally accepted practice -malaria studies at Stateville Penitentiary

Nuremberg Code -also 7 defendants sentenced to death -9 received prison terms

"The voluntary consent of the human subject is absolutely essential..."

Consent is a process ??Respect, Beneficience, Justice???

...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.

"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

2 categories: -Non-therapeutic clinical research -clinical research combined with professional care

"clinical research on a human being cannot be undertaken without his free consent, after he has been fully informed."

physicians required to obtain consent from patient-subjects only when "consistent with patient psychology"

"a truly responsible investigator"

(1932) research to study natural history of syphilis -400 black men with syphilis from rural south -"this was turning event"

CDC reviewed data & concluded that study should continue -"would be of immense benefit to future patients"

syphilis patients died untreated

-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

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

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

3 basic ethical principles: -respect for persons -beneficence -justice

informed consent additional protections for vulnerable subjects

maximize benefits for subject & society while minimizing risks

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

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

*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"

scientifically unsound research on human subjects

-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

-groups or individuals shouldn't be excluded from participation with good scientific or clinical reason -exclusion disenfranchises them from benefits of knowledge gained

groups & individuals who bear the risks & burdens of research should be in a position to enjoy its benefits

risks to individuals subjects must be minimized

potential benefits to individual subjects must be enhanced

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"

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

a state of general uncertainty on the part of the investigator regarding the therapeutic merits of each arm in a trial

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 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

-ensure respect for individuals' values & preferences -what constitutes respect varies from culture to culture so be aware -consent makes research ethical

-information -full disclosure -reasonable person v reasonable volunteer -comprehension -voluntary choice ??what reasonable person would want to know??

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

IRB is a body constituted to assure compliance with 45 CFR 46 (Federal Policy for the Protection of Human Subjects) [Federal regulation]

responsible for reviewing all research involving human subjects -at UNMC/UNO, TNMC, Children's hospital -conducted anywhere by UNMC/UNO, TNMC, Children's

Basic Policy for Protection of Human Research Subjects -final regulations issued in 1981

Informed Consent

IRBs

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

-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

protects: -human subjects -institution -investigator