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
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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Serves as a historical document and provides the moral framework for understanding regulations in the United States on the use of humans in experimental methods.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.
Human Research Protections Program (HRPP)
Response to issues with IRBs to further protect human subjects.
Objective to assist in meeting ethical principles and regulatory requirements.
Resulted in
- Higher IRB standrads
- Inc responsibility for researches
- Inc requirements for COI
- Accreditation requirements of HRPPs
NBAC
National Bioethics Advisory Committee (NBAC, 2001)
Defines vulnerable subjects
Deciding to use vulnerable populations requires:
1. To include vulnerable population?
2. Is it possible to do research without using the vulnerable population?
Vulnerable population
Populations at higher risk for:
- Physical control, coercion, undue influence, manipulation.
Federally, Due to:
- children, prisoners, impaired decision-making, economically / educationally disadvantaged (45 CFR 46.111(b))
NBAC wishes to not categorize, but look at individual circumstances that may not allow them to give voluntary informed consent:
- Cognitive / communicative, institutional, deferential, medical, economic, social
IRB role and responsibilities
- IRB's role, authority, and composition requirements are defined by federal regulations
- review committee to help protect human subjects
- approve, modify, disapprove, continuing review, material changes, observe, suspend / terminate approval
-5+ members, varied background, 1 non-scientist, 1 scientist, 1 unaffiliated
-Members must be qualified, knowledgeable and diverse
HHS
U.S. Department of Health and Human Services
OHRP
Office for Human Research Protections
IRB Requirements
- Risk / Benefit Analysis
- ICF / Assent procedures + documentation
- Subject Selection, include safeguards if research involved vulnerable populations
- Privacy during recruitment and confidentiality during research
- Plan for data collections, storage, and analysis (DSMB)
- Design / Methods are scientifically sound
- Additional - recruitment + safeguards
Will also review:
- PI qualifications + scientific collaborators
- compliance w/ laws + regulations
-IB + protocols (for FDA-regulated research)
Type of IRB Review
1. Convened Committee Review - standard approach, for all new and greater than minimal risk research
2. Expedited Review - minimal changes to an approved study, no more than minimal risk &
- IND / IDE not required
- only collecting blood by sticks or venipuncture
- noninvasive specimen collection
- noninvasive procedures commonly done in clinical practice (no anesthesia or sedation, only FDA approved medical devices being used as marketed)
- data collection / voice-video etc
- individual group characteristic/behavior research
-CR where enrollment is permanently closed with all subjected completed and is only in long-term follow-up
-CR where no subjects enrolled with no additional risks
-CR where study is only doing data analysis
3. Limited IRB Review of Select Exempt Categories
- research education instructional strategies, techniques, curricula, or classroom management methods, which is not likely to adversely impact the student.
- interactions for educational tests, surveys, interviews, or observations of public behavior & (1 or more) + privacy is kept with no identifiers
+ no liability to the subjects
+ identity can be ascertained by the investigator if needed.
- Benign behavior interventions w/ data collection & (1 or more)
+ see above. Examples: board games, puzzles with various noises, etc.
- Secondary research using private info / identifiable biospecimens & (1 or more)
+knowledge is publicly available
- Internal federal employee studies, contract/consulting arrangements, cooperative agreements, grants to better the public programs.
- Consumer taste / food quality study
- Broad consent to store / maintain identifiable private info / biospecimens for potential secondary research
- Broad consent to use data/specimens for secondary research
NOT Exempt: subjects prisoners, children, or observation of children with research participating in activities being observed.
PI Recordkeeping
PIs must keep signed consent documents, IRB correspondence, and research records for at least 3 years post trial. - sponsor/IRB may require longer.
HHS Regulations
45 CFR 46 (Protection of Human Subjects 2018) applies to all human research submitted to or funded by HHS.
Subpart A: Basic HHS Policy for the Protection of Human Subjects
Subpart B: Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research
Subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects
Subpart D: Additional Protections for Children Involved as Subjects in Research
Subpart E: Registration of Institutional Review Boards
NIH Regulations
sIRBs be used for multi-site trials. All Phase III randomized clinical trials are to have DSMB/DSMCs
Site FWA
Federalwide Assurance (FWA) = compliance assurance is a written document submitted by an organization (not an IRB) that is engaged in non-exempt human subjects research conducted or supported by HHS.
Site in non-exempt research + Subject to Common Rule
Each IRB that is designated by an organization under an assurance of compliance approved for federal wide use by OHRP under 45 CFR 46.103(a) and that reviews research involving human subjects conducted or supported by the HHS must be registered with HHS.
sIRB
Single IRBs for multi-site trials.
HHS regulations further require a reliance agreement between organizations that are relying and serving as sIRBs to include the responsibilities that each will undertake.
Broad Consent
Broad consent may be used as an alternative to informed consent for studies involving the storage, maintenance, and secondary research uses of identifiable private information and biospecimens.
ICF Parts
1. This a research study aimed to X, expected to last Y years for X visits. Every 6 months you will come in for follow-up and an injection.
2. Risks
3. Benefits
4. Alt options
5. Confidentiality, if applicable FDA inspections
6. If greater than minimal risk - explain compensation / medical tx available in the event of injury.
7. Who to contact
8. Voluntary participation statement
9. Collecting identifiable information / identifiable biospecimens must include statement about use of future studies or will not be used for future studies.
Legally effective elements as applicable include:
1. Possibility of unforeseeable risks
2. Subject participation terminated by the researcher
3. Costs to the subject
4. Consequences of withdrawing consent
5. Significant new findings will be communicated if it may relate to subject's willingness to continue
6. Approximate total number of subjects
7. Biospecimens (if de-identified) may be used for commercial profit and if subject will share in that profit.
8. If results will be disclosed and under what conditions.
9. Biospecimens if it will include whole genome sequencing
42 USC 282(j)(1)(A)
A description of this clinical trial will be available http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
Qualifies as a clinical trial under the HHS definition and is subject to the Common Rule, there is an additional requirement to post the consent for to a publicly available federal website from 46.116(h). Until a special website is developed, or further guidance is provided, an option is posting the consent form for the trial to ClinicalTrials.gov or a docket folder on Regulations.gov (OHRP 2019).
HHS Regulations for Waivers and Alterations
1. Government projects (public service like initiatives)
2. General waivers and alterations
- no more than minimal risk
- cannot be carried out w/o waiver
- cannot be carried out w/o private info (if applicable)
- will not adversely affect rights + welfare
- subjects provided with pertinent info after participation (whenever appropriate)
3. Screening, recruiting, or determining eligibility
ICF Exceptions
- emergency research requirements are met
- life-threatening with requirements for an exception met + documentation of
(a). researcher + physician agree the situation calls for test article
(b). subject/LAR unable to communicate
(c). insufficient time to obtain consent
(d). no alternative exists providing equal or better chance of survival
Waiver of Signed Consent / Oral Consent
FDA - minimal risk, no procedures
HHS -
+ only identifiable link of subject to research would be the consent and principal risk would be breach of confidentiality. Subjects will be asked if they want consent to be documented.
+ minimal risk, no procedures
+ subject part of group/community where signing forms is not the norm, minimal risk, appropriate alternative mechanism to documents ICF obtained.
LAR verbal telephone consent
FDA - Fax ICF to LAR, review on phone, LAR returns faxed ICF to researcher
HHS - does allow the exchange of consent information to take place face-to-face or by mail, telephone, fax, or video. An electronic format for the consent signature is also allowed.
Electronic informed consent (eIC)
video to demonstrate a study procedure, use of a tablet instead of a paper-based consent form, and use of electronic signatures
HHS regulations also require that a written copy be given to the person signing the informed consent form. The copy could be in paper or an electronic format (Protection of Human Subjects 2018).
SBR
Social and Behavioral Research (SBR)
Refers broadly to research that deals with human attitudes, beliefs, and behaviors. Biomedical and clinical researchers sometimes incorporate SBR questions and methodologies into their physiological research.
SBR Methods
Questionnaires
Opinion data and other oral data
Direct observation
Data already collected for other purposes (such as records from education, healthcare, social service programs, employment, and insurance coverage)
Non-invasive physiological measurement (such as skin impedance and pupil dilation as reflection of emotional arousal or attention).
SBR Risks + Benefits
Psychosocial stress + discomfort
Physiological harms that are less predictable, more subjective, variable, and less remediable.
Socio-cultural factors (i.e. collecting demographics of undocumented immigrants v citizens)
Main risk tends to be breaches of confidentiality involving sensitive data
SBR Data Management
Code data, secure master list, secure environment, de-linking data from identifiers
SBR Debriefing
Distress or deception experiment design includes debriefing about information withheld at the end of their participation.
Ex: debrief subject with a description of what really happened, explain why the research could not be conducted otherwise, issue an apology.
*IF deceoption is used for benign behavioral intervention, research must inform the subject that they will be deceived before participating in research.
Records-Based Research
Hypotheses can be posed and answered by analyzing documented information in various types of paper or electronic records (such as medical, motor vehicle, criminal justice, or school records).
Must:
1. Understand risks
2. Plan to minimize those risks
3. Obtain required approvals before conducting research
Privacy
defined in terms of having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) or information about oneself with others.
*Low when patient gave IC, however much higher if records review without consent.
Confidentiality
pertains to the actual handling of the personal information once it is obtained.
Risk Minimization
Ethical and regulatory responsibility to minimize research risks to human subjects
Common rule - research exclusions
The Common Rule specifically excludes certain activities from the definition of research:
- Scholarly or journalistic activities
- Public health surveillance activities
- Criminal justice activities (collection and analysis of information, biospecimens, or records) conducted for criminal justice purposes
- Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions
Is the research eligible for exemption from the federal regulations?
Records-based research may be exempt if any of the following apply:
1. identifiable private info is publicly available
2. Info recorded in a manner that the subject cannot be identified (no contact, will se identifiers but will not record)
3. Research information for purpose of "health care operation" or "research" 45 CFR 164.501 - or "public health activities and purposes" - 45 CFR 164.512[b]
4. Federal dept/agency using gov't information for non-research activities
5. Identifiable private information used for secondary research in which broad consent was obtained + documented; waiver of consent obtained; IRB does limited IRB review to determine secondary research is within scope of broad consent + does not include returning individual research results to subjects unless legally required
Expedited review?
If the records review activity constitutes human subjects research, and does not qualify for exemption, it will then be subject to federal regulations.
- no more than minimal risk
- in expedited review category 5 (prospective / retrospective research using materials)
limited data set
If most, but not all, mandated identifiers are removed
Family Educational Rights and Privacy Act (FERPA)
Includes public kindergarten through twelfth grade (K-12) schools and postsecondary institutions
Genomics v Genetics
Genomics - DNA sequence in cell to biological function
Genetics - inherited differences in DNA sequence between individuals + the effect of the difference in biological function if any
Genetic & Genomic Research Risks
- reveal predispositions to future disease, making information psychologically powerful + raising concerns of stigma/discrimination
- Gene sequences shared by relatives, one person's genetic info provides information on their relatives who did not necessarily consent
- Reveal ancestry conflicting with family / social / religious histories & beliefs
- Genetic concepts + info have historically been misused to affect social/political ends
Genetic Determinism
controlling influence on human health, behavior, and disease.
GWAS studies with WGS or WES
GWAS = genome-wide association studies
WGS = whole genome sequencing
WES = only parts of genome coding for proteins (1% of entire DNA sequence)
Large genomic studies by NIH requirements
de-identify
upload to central databases
Maximizes use of information generated since studies are complex, difficult, and expensive
Clinical v Research Information
Many organizations do not segregate clinical and research information in electronic medical records.
Is DNA truly able to anonymized?
Yes
In order to re-identify DNA sequence information, those attempting the re-identification must have a reference sequence that includes individual identifiers. That is, the DNA sequence is not intrinsically identifiable.
While the risk of re-identification currently is low, it may increase with time due to technological developments. Therefore, research subjects should be told that there is a small risk of future re-identification of de-identified information or biospecimens. As with all research involving informational risks, researchers cannot guarantee complete confidentiality.
To date, there are no instances of re-identification of data or specimens for illicit motives.
Researchers who obtain access to some de-identified datasets, like the NIH database of Genotypes and Phenotypes (dbGaP) resource, are required to guarantee that they will not attempt to re-identify data. Any attempt to re-identify data or specimens would be a serious breach of research ethics unless explicitly authorized by an IRB for a critical purpose.
Group privacy
More broadly, some genetic research can produce discoveries about entire subpopulations, some of which correspond to racial or ethnic groups.
Genetic Research ICF
- lay language.
- specimen storage & access information
- if can be contacted about individual results
- if a code can be used to re-link identity to samples
- plan to develop commercial products or assays, and info about financial rights
- future testing of samples.
- future research studies, including those that may have a different focus.
- if result (general, personal results, or incidental) will be returned to subjects.
- yes/no to whole genome sequencing
- commercial profit - sharing y/n
- disclosure if clinically relevant results
Managing incidental findings
If the genetic analysis is likely to yield incidental findings, the study should describe plans for management of such findings. Management plans should include a description of the responsible individual that makes the determination of what results to return and who will inform the research subjects.
Genetic Information Nondiscrimination Act (GINA) in 2008
GINA prohibits discrimination in healthcare insurance and employment based on genetic information.
NIH Genomic Data Sharing Policy (2014)
- Genomic data without associated phenotypic characteristics are available in an unrestricted fashion to the general public
- Genomic data without associated phenotypic characteristics are available in an unrestricted fashion to the general public [Show Less]