Nuremberg Code (1947)
A research ethics code that arose in response to the Nazis' inhumane experimentation (nuremberg trials) - holocaust, racial hygiene
... [Show More] / eugenics / master race.
The Nuremberg Code - 10 points
1. voluntary
2. necessary for results
3. logical design and results
4. avoid unnecessary harm
5. cannot result in death or disablement
6. risk assessment
7. protect subjects against harm
8. qualified investigators
9. right to withdrawal
10. right to end trial if needed
Belmont Report (1979)
Three core principles are identified: respect for persons, beneficence, and justice.
Arose in response to Tuskegee Syphilis Study - studying untreated syphilis on African-American men unaware of their true condition and tx plan.
Belmont Report - definitions of core
1. Respect for persons: informed consent + no deception
2. Beneficence: maximize benefits and minimize risk
3: Justice: fair procedures considering risk analysis.
Belmont Report - current role
Serves as a historical document and provides the moral framework for understanding regulations in the United States on the use of humans in experimental methods.
Belmont Report - review of 7 items for research trials
1. IRB approved
2. Obtain informed consent
3. Ensure understanding
4. No coercion
5. Monitor adverse events
6. Maintain privacy
7. Ensure patients receive minimal care for their condition
Declaration of Helsinki (1964, 1975)
Set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA)
Good Clinical Practice (GCP)
ICH-GCP and ISO-GCP (medical device) enforces guidelines on ethical aspects of a clinical trial.
Covers human rights, standards on trial conduct, roles and responsibilities (IRB, PI, sponsor, monitors).
GCP v Declaration of Helinski
GCP lacks moral principles and guidance surrounding COI, study design, benefits, result reporting.
Also restricts placebo in control group v effective alternative tx
Common Rule
US federal policy that specifies ethics regulations for human subjects research
1. ICF in reasonable language, reasons why they would not want to participate in research
2. Disclosure of use of de-identified data / specimens for future studies, commercial profit, clinically relevant results disclosed, genome sequencing
3. Consent waiver only if research could not be carried out without accessing / using information / specimens in an identifiable format. Pre-screening for trial permitted if able to obtain oral or written communication OR access records / stored biospecimens.
4. Exempt / Limited IRB if
- record review both retrospectively AND propectively
- benign behavioral interactions
- collect identifiable sensitive data via adults in surveys/interviews
5. Continuing review - not required if expedited level
6. Multi-instituitional research studies required to use 1 IRB (effective 01-19-2020)
Title 21 US Code of Federal Regulations (11, 50, 56, 312, 812)
Title 21 is part of the code of federal regulations governing good and drugs for the FDA, DEA, and ONDCP (office of national drug control policy)
11 - e-records + e-signatures
50 - protection human subjects
56 - IRB that oversee trials
312 - drug trial requirements
812 - controlled substances
Title 21 CFR Part 11
1. Controls - audits, validators, audit trails, e-sigs, documentation for software + systems processing e-data.
2. E-records cannot be illegible, inaccessible, or corrupted
3. "Hard copies" are authoritative documents for regulatory purposes
Title 21 CFR Part 50
...
The National Research Act of 1974
Established the National Commission.
Issued in 1974, 45 CFR 46 raised to regulatory status:
US Public Health Service Policy
Henry K. Beecher Article (1966)
Detailed 22 published medical studies presenting risk to subjects without their knowledge or approval.
Beecher's article clearly demonstrated that unethical research was not confined to Nazi atrocities.
U.S. Public Health Service (PHS) Study of Untreated Syphilis / Tuskegee Syphilis Study (1932-1972)
Examined the natural course of untreated syphilis in Black American men.
All were impoverished sharecroppers from Macon County, Alabama, were unknowing subjects in the study; they were not told that they had syphilis, nor were they offered effective treatment when it became available in the late 1940s with the availability of penicillin.
Willowbrook studies (1956-1970)
Children with intellectual disabilities were deliberately infected with the hepatitis virus
Jewish Chronic Disease Hospital study (1963)
Live cancer cells were injected into 22 cognitively impaired patients.
National Research Act (1974)
Congress passed this act in response to the concern on prior studies (PHS Syphilis, prisoner research, willowbrook etc)
- est. National Commission to identify basic ethical principles + guidelines
- required IRBs at organizations receiving funding
The National Commission (1975-1978)
Created recommendations for regulating human subject research - vulnerable populations, psychosurgery, IRBs, etc.
Final report published 1979 - Ethical Principles and Guidelines for the Protection of Human Subjects of Research
-> Belmont Report
The Belmont Report
Based on National Commission deliberations.
1. Respect for Persons
2. Beneficence
3. Justice
Analytical framework guiding the resolution of problems arising from human subject research.
Belmont: Respect for Persons
Subjects are autonomous agents - informed consent
If diminished autonomy, need additional protection.
- Condition (age, health, cognition)
- Circumstances (poverty, lack of education, social status)
Also respect person's right to privacy (not directly addressed in Belmont).
Belmont: Beneficence
Strive to do no harm while maximizing benefits + minimizing harm.
Systematic Assessment - account for probability and magnitude of potential harm
Benefit - to individual or advancement of scientific knowledge
Minimize risk - risks in research should be the minimum to achieve the research objective. Researchers + IRBs should carefully consider alternative, less risky procedures / modifications to reduced magnitude or probability of harm.
Belmont: Justice
Injustice is when benefit is denied from a person without good reason, and some the burden is imposed unduly.
Example: research on prisoners or institutionalized children - both will not see the benefit and must bear the burden.
Subject selection - are some selected due to availability, compromised position, or manipulatability? Must be based on scientific need, not convenience.
Do not exclude so they do not derive benefit (i.e. not speaking english). Undue influences from real or perceived pressures - financial, power, implied benefits.
45 CFR 46
PHS policy raised to regulatory status for "Regulations for the Protection of Human Subjects of Biomedical and Behavior Research) in anticipation of the National Research Act.
First set of federal regulations detailing requirement of organizational assurances, IRB review, ICF, and ethical conduct.
Revised in 1981
21 CFR 50 + 21 CFR 56
Adopted by FDA on ICF in 1980, IRBs in 1981 respectively
21 CFR 812 + 21 CFR 312
Adopted by FDA in 1980 and 1981 for investigational medical devices + drugs & biologics respectively.
45 CFR 46, Subpart A
1991 - 17 federal agencies that conduct, support, or otherwise regulate human subjects research issued uniform regulations - "The Federal Policy for the Protection of Human Subjects." = Common Rule
Updated -> 2018 Requirements: strengthen human subject protections, reduce administrative burdens, add flexibility. Major changes to IRB operations, ICF, definitions, and exemptions.
Declaration of Helsinki
International codes + standard in response to Nuremberg Trials
1964 - World Medical Assembly meeting in Helsinki Finland adopted "Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects."
Has been revised multiple times (1975, 1983, 1989, 1996, 2000, 2008, and 2013).
CIOMS guidelines
International codes + standard in response to Nuremberg Trials
1982 - Council for International Organizations of Medical Sciences adopted "International Ethical Guidelines for Biomedical Research Involving Human Subjects".
Revised in 1993, 2002, and 2016.
WHO guidelines
International codes + standard in response to Nuremberg Trials
2001 - World Health Organization (WHO) adopted "Standards and Operational Guidance for Ethics Review of Health-Related Research with Human Participants."
Designed to serve as international guidelines for the review + conduct of human subject research.
ICH guidelines
International codes + standard in response to Nuremberg Trials
1996 - International Conference on Harmonisation (ICH) brings together drug regulatory authorities and pharmaceutical industry of Europe, Japan, and the U.S.
They adopted standards on Good Clinical Practice (ICH E6).
ICH E6 details the responsibilities and expectations of all individuals - including researchers, monitors, sponsors, and IRBs.
ICH E6 standards, while not part of any country's regulations, provide international standards for transnational pharmaceutical research.
ICH renamed itself "International Council for Harmonisation" in 2015, added members, and in 2016 released a revised E6(R2) guideline. The FDA adopted the revised E6(R2) guideline as guidance.
Presidential Commission report
1983 - Response on to further concerns regarding human subject research despite new regulations.
Report raised concerns on adequacy of IRB review process.
Office for the Protection from Research Risks (OPRR) (the predecessor to OHRP) at the National Institutes of Health (NIH) conducted multiple investigations of allegations of non-compliance with the regulations.
Independent Reviews - General Accounting Office (GAO) & HHS Inspector General
March 1996 and June 1998 respectfully
GAO - IRBs overworks, competing demands, limited funds for inspections, complex research + large volumes
HHS - reviewed too much too quickly with little expertise, minimal CR of approved research, little training.
Are IRBs effective?
Response to IRB concerns
increased vigilance. OPRR began for cause and not for cause investigations.
Did enact change, however then human subject Jesse Gelsinger died -> public outcry. [Show Less]