History & Ethics of Human Subjects Research

As a result of Nazi regime's atrocities during World War II. Performed medical experiments upon concentration camp inmates & human w/o consent.

Permissible Medical Experiment ruled by court - Little direct impact on human research as origin in concern abt nazi Atrocities - not adopted as law or as part of any professional ethical code

1. Voluntary consent of human subject is absolutely essential 2. Experiment should yield fruitful results for good of society; unprocurable by other methods; not random & unnecessary 3. Experiment designed & based on results of animal experimentation & knowledge of the natural history of the disease or other problem under study; anticipated results will justify the performance of the experiment 4. Experiment conducted to avoid all unnecessary physical & mental suffering / injury 5. If believed that death/ disabling injuring will occur, experiment should NOT be conducted 6. Degree of risk not exceed that determined by the humanitarian importance of the problem to be solved by the experiment 7. Proper preparations; adequate facilities; remote possibilities of injury, disability/ death 8. Experiment conducted only by scientifically qualified person. Highest degree of skill & care in all stages 9. Human subject have the liberty to bring experiment to end if reached physical/ mental state where continuation seemed impossible 10. Scientist in charge to terminate experiment if he believe that continuation of experiment will result in injury/ death / disability

-Legal capacity to give consent -Able to exercise free power of choice -Sufficient knowledge & comprehension of the elements -Made known to him the nature, duration, purpose of experiment; method and means by which it is conducted -Inconveniences & hazards; effects upon health / person

-Study of untreated Syphilis in Negro Males - Examined the natural course of untreated syphilis in Black American men -Were not told they had syphilis; not offered effective treatment (penicillin) -Subjects not free to decline (not informed they were in a research study) NO INFORMED CONSENT OBTAINED

Willowbrook studies (1926 - 1970) -Children w intellectual disabilites deliberately infected w hepatitis virus Jewish Chronic Disease Hospital Study (1963) -Live cancer cells injected into 22 cognitively imparired patients -Publicity about extensive medical research conducted on prisoners

-Response to ethics of PHS Syphilis Study, Prisoner research, willowbrook - Hearing on "Quality of Health Care - Human Experimentation" held before the before the Subcommittee on Health of the U.S. Senate Committee on Labor & Public welfare (1973) -Passed the 1974 National Research Act -Established National Commission & required the establishment of IRBs at institutions receiving PHS support for human subjects research

- Identify basic ethical principles underlying human subjects research - Develop guidelines for ensuing the conduct of human subjects research is conducted acc to guidelines -Issued series of reports on vulnerable populations (fetuses, children, prinsoner, mentally infirm), psychosugery, IRBs

-Based on deliberations of National Commission -Identified 3 basic principles: Respect for Persons, Beneficence, and Justice

-Individuals should be treated as autonomous agents -Individuals w diminished autonomy (age health cognitive ability) (poverty, lack of education, social status) need additional protections - Extent of protection depend upon risk of harm/ likelihood of benefit -Judgement that any individual lacks autonomy should be periodically reevaluated and will vary in diff situations - Application: Informed consent; Privacy

ROP requires subjects, to the degree that they are capable, be given opportunity to choose what shall or shall not happen to them. -Information: Information should be sufficient so that a reasonable volunteer can decide whether to participate -Comprehension: Info provided such a way that can be understood what is being conveyed.; Adapt presentation of info to subject's capacities; Investigators responsible for ascertaining subject fully comprehended the info -Voluntariness: Belmont Report - Agreement to participate in research constitutes a valid consent only if voluntarily give. (Undue influence; inequitable social pressure/ inappropriate rewards)

ROP involves respecting individual's right privacy - Right to control access to one's self & info - Protecting the confidentiality of private, identifiable info abt indiv -Ensure subject's right of privacy is not violated & confidentiality of info protected

-Obligation of researchers to strive to do no harm -Maximize benefits & minimize harm -Respecting decision; protect from harm; make efforts to secure well-being -benefits should be foregone because of risk - Applications: Systematic assessment of risks & benefits; minimization of risk

- Risk is not harm, it is possibility of harm. -Analysis of risks: take into account magnitude + possbility of harm -Anticipated benefits: to individual subjects or in the form of advancement of scientific knowledge - In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. On the other hand, interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects' rights have been protected

-Investigators & IRBs should carefully consider alternative, less risky procedures / modifications to the procedures that reduce the magnitude / probability of possible harm to subjects

-Requires selection of subjects is equitable -Injustice = some benefit to which person is entitled is denied w/o good reason or when some burden is imposed unduly -Application: Selection of Subjects

-Selection of research subjects needs to be scrutinized to determine if some classes are being systematically selected due to easy availability, compromised position, manipulability, rather than directly related to problem being studied - Selection must be based on scientific needs of research; not on convenience - Subjects no denied access to potential benefits of participating in research because of considerations such as whether they speak english -Avoid undue influence (financial incentives, inequitable power relationships, implid benefits) -Nazi experiment clearly not equitable. Limited freedom to refuse. Prisoner used to advance medical knowledge not benefit the prisoners. -Willowbrook studies: vulnerable instituionalized children used as research subjects although parents gave consent, not clear if it was truly informed consent.

-First imposed requirements on research involving human subjects: Kefauver-Harris Drug Amendments to the FDA (1962). FDA faced challenge controlling drug to prevent morning sickness in pregnant women that caused birth defects. -Amendment: Evidence of safety + Effectiveness of drugs from well-controlled studies + informed consent of study subjects -Independent determination: 1. of the rights and welfare or individual ; 2. of the appropriateness of the methods used to secure informed consent; 3. of the risks & potential medical benefits of the investigation -1974: In anticipation of National Research Act, PHS policy raised to regulatory status in 45 CFR 46. First set of federal regulations to detail specific requirements & procedures for institutional assurances, IRB review, informed consent & ethical conduct of research -Addtional protections for vulnerable populations added to 45 CFR 46. Recommended by national commission

1964: 18th world medical assembly meeting in Helsinki, Finland; adopted "recommendation guiding medical doctors in Biomedical research involving human subjects" / declaration of Helsinki 1982: CIOMS adopted "international ethical guidelines for biomedical research involving human subjects" 2001: WHO adopted "standards and operational guidance for ethics review of health related research w human participants" Designed to serve as international guidelines for review and conduct of research involving human subjects 1996: ICH -- organization that brings together the drug regulatory authorities and pharmaceutical industry of Europe jap and US; adopted standards on good clinical practice. ICH-GCP: -details responsibilities & expectations of all participants in conduct of clinical trial. - provide international standards for translation pharmaceutical research

1974 to mid 1990s: concerns regarding ethical research had been addressed by the federal regulations -most established IRBs and IRB review & approval required for federally funded research & research conducted under FDA regulations BUT -concerns on investigators/ IRBs not fully complying w federal regulations on human subjects.

-IRB not enough to protect human subjects in research -Address problems w IRB system arose concept of human research protections program (HRPP). -HRPP: comprehensive organized system of shared responsibility at an organization to ensure protection of human volunteers -Objective: Assist organization in meeting ethical principles & regulatory requirements for protection of human subjects -IRB is impt componnent of HRPP; but is the only 1 part of an overall organizational program to protect human subjects -In addition, resulted in higher standards for IRB review; increased reponsibility for investigators; increased requirements regarding conflict of interest; accreditation of HRPPs.