Ethical Issues for Human Subjects Research

Role of IRBs

I. Purpose of Human Subjects Research Understand Disease Validate New Therapies Understand Physiological Processes Study Human Behavior Evaluate Curricular Changes Evaluate New Teaching Methods

Ethical Issues in Research When using humans or animals for

research, important ethical issues must be addressed Historically, these issues were addressed by the

professional code of ethics Codes of conduct have evolved and now have

been codified into law.

Ethical Issues in Research World War II—The Nuremburg Trial

Joseph Mengele and unethical experiments performed by Nazi doctors

Ethical Issues in Research World War II-The Nuremburg Trial

20 doctors were charged with War Crimes and Crimes against humanity

Joseph Mengele fled and was not tried Lead to Nuremburg Code of 10 Principles

Nuremburg Code

Requires voluntary consent Experiments must be rational Experiments must be based on animal studies and

knowledge of the disease Experiments should avoid suffering No experiment should involve excessive risks,

except in those studies where physical experimental physicians also serve as subjects

Nuremburg Code Degree of risks should be determined by importance of the

problem Precautions should be taken to avoid against even remote

possibilities of injury, disability, or death Experiment should be conducted only by scientifically

qualified persons Subjects should be able to end experiment at any time The scientist in charge must be prepared to terminate the

experiment at any stage, if they believe the experiment is likely to result in injury, disability, or death to the subject

Ethical Issues in Research Unfortunately, codes were not always

followed: Tuskegee Syphilis Study-USPHS-1930’s

Not treated even after penicillin discovered

Jewish Chronic Disease Hospital Patients injected with cancer cells

Midgeville State Hospital Investigational drugs used without consent

Ethical Issues in Research Willowbrook State Hospital-1970

Retarded injected with viral hepatitis US Department of Energy-1950s-60s

Studies on radioactive fallout University of Iowa-1940s

Research on stuttering in orphans home Johns Hopkins-2001

Asthma study with hexamethonium

National Research Act

Increased Public concern led to congressional action and National Research Act of 1974 President Nixon then established National Commission for the

Protection of Human Subjects of Biomedical and Behavioral research

Commission charged to consider: Boundaries between practice and research Assessment of role of risk vs. benefit in research Guidelines for selection of subjects Informed Consent

Belmont Report National Commission submitted the Belmont

Report to President in 1979 Led to 1981 revision of 1974 guidance (45 CFR 46) for

human research committees 45 CFR 46-has become the bible for reviewing research

funded by DHHS Required appointment of Institutional Review Boards or IRB’s

to review human subject studies Provided standards for appointment of IRBs, record-keeping

and oversight in research

45 CFR 46 Revised in 1983 and 1991

In 1991 revisions referred to as Common Rule Adopted by 15 federal agencies, not just DHHS

Institutions with NIH funding must submit assurance of compliance to OHRP, DHHS

After February 28, 2001-assurances must cover all research at institution, not just NIH

II. Institutional Review Boards Makeup of IRB

At least 5 members Male/Female Professionals/laypersons External “non-affiliated” member Must represent community Lay person must be at meeting for reviews

II. Institutional Review Boards IRB’S must be guided by principles

outlined in Belmont Report: Respect for persons: respect for patient

autonomy Beneficence: maximize benefits and minimize

harm Justice: Equitable distribution of research

burdens and benefits

III. IRB Review of Research Three categories of Review:

Exempt Expedited Full Review

IRB Review of Research Exempt-by Chair or Administrator

Research in educational settings involving normal educational practices

Instructional strategies Effectiveness of instructional techniques Comparison of techniques or curricula, etc.

IRB Review of Research Exempt-by Chair or Administrator

Research involving educational tests (cognitive, diagnostic, aptitude)

Unless– Names or identifiers are recorded and

– Disclosure could put subject at risk of criminal liability or affect employability

IRB Review of Research Exempt-by Chair or Administrator

Survey research without identifiers; interviews, observation of public behavior

Unless– Names or identifiers are recorded and

– Disclosure could put subject at risk of criminal liability or affect employability

IRB Review of Research Exempt-by Chair or Administrator

Collection or study of existing data, documents, records, pathological or diagnostic specimens

If the sources are publicly available, or If information is recorded so that the subject cannot

be identified, directly or indirectly

IRB Review of Research Exempt-by Chair or Administrator

Research and demonstration projects conducted by or subject to approval by DHHS to study, evaluate or examine:

Public benefit or service programs Procedures for obtaining benefits or services from

these programs Other changes in these programs

– Taste and food quality evaluation and consumer acceptance studies

IRB Review of Research Expedited Review

Research activities reviewed by Chair or designee Two cautions however:

Only for activities involving minimal risk-i.e., no more risks than those in everyday life

Cannot be used if subject responses might pose civil or criminal risk to subject, unless

– Reasonable protections can be implemented so that risks related to invasion of privacy and breach of confidentiality are minimal

IRB Review of Research Expedited Review-Categories eligible

Some studies of approved drugs or devices Collection of blood from adults

Not to exceed 550mL in 8 weeks Not more often than 2 times per week

Collection of specimens by non-invasive means: sweat, excreta, amniotic fluid, hair, teeth, plaque

IRB Review of Research Expedited Review-Categories eligible

Collection of data through non-invasive means, excluding X-ray and microwave

EKG, ECG, MRI, weighing, thermography, ultrasound, doppler blood flow, exercise, flexibility testing, etc.

Research involving data, records, specimens collected, or that will be collected solely for non-research purposes

Collection of voice, video, digital, or images made for research purposes

IRB Review of Research Expedited Review-Categories eligible Research on individual or group characteristics or behavior

including: Perception, cognition, motivation, identity, language,

communication, beliefs or practices, etc.

Research involving surveys, interview focus groups, program evaluations, or quality assurance methods

Continuing reviews for previously approved projects Minor changes in previously approved research

IRB Review of Research Full Review-Full Committee

Investigational drugs, devices, invasive techniques (PET scan), implants, etc.

Higher risk researchNOTE-research not approved by IRB cannot be

approved by higher authorities, however approved research may be disapproved by higher authorities

IV. IRB Approval To be approved:

Risks must be minimized by sound research design

Risks must be reasonable in relation to benefits Selection of subjects must be equitable Informed consent will be sought from each

subject

IRB Approval To be approved-continued:

Informed consent will be appropriately documented

When appropriate, research plan must ensure continued safety of subjects

Where appropriate, provisions made to protect privacy of subjects and data

When working with subjects vulnerable to coercion, must consider added safeguards

Continuing Review For research continuing more than one year,

an annual review is required New standards under review:

Will probably require IRB monitoring of some clinical trials

Constant assessment of conflict of interest of the investigators

Informed Consent Not needed for exempt studies Required for Expedited Review-but may be

simplified for low risk studies Rigorous consent for Full Review projects May be waived by IRB for emergency

Medicine research-controversial issue

Informed Consent Consent must address critical elements or

points outlined by Federal Law Consent signed by subject or legal

representative and investigator Subject must be given copy of consent No exculpatory language may be used in

the written consent

Basic Elements of Consent Explanation of purpose and duration Description of risks Description of benefits Disclosure of alternatives to participation

Basic Elements of Consent Explanation of Confidentiality of Records Who to contact regarding patient rights

For research with more than minimal risks, comment on compensation and care for injury

Right to withdraw without prejudice Statement regarding unforeseen risks,

especially to unborn child

Additional Elements for Consent Statement that investigator may terminate

patient participation Information regarding any costs Statement regarding consequences of

withdrawing-especially for drug studies Number of subjects in study

Special Populations-Children Special Considerations

Children are persons who have not attained the legal age for consent to treatments or procedures involved in research

Research not involving greater than minimal risk may be approved: With assent of the child and permission of

parents

Special Populations-Children Special Considerations

Research involving greater than minimal risk and the prospect of direct benefit to the child may be approved:

If the risk is justified by the anticipated benefit The relation of the benefit to risk is at least as

favorable to subjects as the alternative approaches With assent of the child and permission of parents

Special Populations-Children Special Considerations

Research involving greater than minimal risk and no prospect of direct benefit to the child may be approved:

If the risk represents a minor risk over minimal risk If the intervention presents experiences that are reasonably

similar to those in actual medical, dental, social, psychological, or educational situations

If the intervention is likely to yield generalizeable knowledge about the disorder or condition

With assent of the child and permission of parents

Special Populations-Children Special Considerations Assent of the child

Usually verbal-confirmed by parents “Assent” cam usually be provided by children

over six years of age-but varies based on maturity and psychological state

Failure to object should not, absent affirmative agreement, be construed as assent

Special Populations-Prisoners Special Considerations IRB membership

Majority of members must have no association with the prison

Must include a prisoner, or prisoner representative with experience to serve in this capacity

Special Populations-Prisoners Special Considerations

The research may be approved if: The advantages of participation are not “enticing” or

prohibit good judgment Risks are similar to those for non-prisoner research Consent is understandable to prison population Decision to participate will not affect parole

Special Populations-Prisoners Special Considerations

Permitted Research: Study of causes, effects, or processes involving

incarceration Study of prisons as institutional structures or of

prisoners as incarcerated persons Study of conditions affecting prisoners as a class

– Vaccine trials for diseases prevalent in prisons

– Study of social behavior of prison population

VI. Federal Oversight FDA spot checks IRBs to monitor

compliance with drug and device studies Recent problems at Rush, Duke, UIC, U of

Colorado, U of Oklahoma, and Hopkins have prompted calls for greater scrutiny of IRBs

VI. Federal Oversight New 2000/2001 DHHS guidelines require:

Training of investigators and “key” personnel in human research protection

Certification by investigators that they have received training (NIH offers on web)

Certification that investigator has no conflict of interest

Monitoring of clinical trials by IRB

VI. Federal Oversight Education on “Responsible Conduct of

Research” Nine Areas:

Data acquisition, management, sharing, ownership Mentor, trainee practices and responsibilities Publication practices and responsible ownership Peer review

VI. Federal Oversight Education on “Responsible Conduct of

Research” Nine Areas:

Collaborative science Human subjects Research involving animals Research misconduct Conflict of interest and commitment

VII. New HIPAA regulations Health Insurance Portability and

Accountability Act of 1996 Privacy Rules effective April 14th, 2001

Health insurers must safeguard personal health information

May not disclose to employers for employment-related decisions

However, information can be used for research approved by a properly convened IRB

– http://www.hipadvisory.com/regs/finaladvisory/gresearch.htm

HIPAA allows research with conditions If material has been or can be de-identified,

no conflict with HIPAA regulations Appropriate if records custodian uses data Often not practical to disclose since records

custodian may simply state this is too difficult

HIPAA allows research with conditions To use or disclose data without patient authorization:

Discloser (records custodian) must document that waiver (of consent) has been obtained from an IRB

or Researcher must represent in writing or orally, that

disclosure is preparatory to research, and no records will be removed

or Researcher must represent in writing or orally that the

disclosure is for research on decedents Document of death may be required by disclosure

Laboratory Research Animals

Laboratory Research Animals All NIH funded research with animals

requires IACUC approval IACUC or Institutional Animal Care and Use

Committee must meet NIH standards Scientist Non-scientist Non-affiliated member Veterinarian

Laboratory Research Animals Functions of the IACUC

Review animal care and use program every six months Inspect facilities for housing animals every six months Prepare reports o reviews for Institutional Official Review concerns involving animals at institution Make recommendations regarding program to Official

Laboratory Research Animals Functions of the IACUC

Review, approve, require modifications in applications for animal use

Review, approve, require modifications of proposed changes in approved animal projects

Suspend activities not adhering to approved uses

Laboratory Research Animals To approve animal use:

Procedures must avoid pain or discomfort and have sound research design

Procedures involving minor discomfort or pain must include sedation, analgesia, or anesthesia

Animals that would experience chronic pain must be euthanized at the end of the procedure

Laboratory Research Animals To approve animal use:

Living conditions must be appropriate for species Medical care must be available from veterinarian Personnel conducting procedures must be qualified Methods of euthanasia must abide by AVMA rules Studies approved by IACUC may be disapproved by

Institutional offices, however, unapproved studies may not be approved by higher officials

Laboratory Research Animals USDA and NIH have oversight

NIH does not have inspection arm USDA makes periodic, unannounced visits to

assess compliance for “covered” species

Case Number 1 Social scientist

Observing 1st grade play activities What level of review?

Exempt Expedited Full Review

Case Number 2 Psychologist

Interviewing 1st graders Benign questions: no names or identifiers

What level of review Exempt Expedited Full Review

Case Number 3 Behavioral Scientist

Interviewing 3rd graders Questions regarding sexual behavior, parental

handling of bad behavior, etc.

What level of review? Exempt Expedited Full Review

Nuremburg Code The voluntary consent of the human subject is absolutely essential The experiment should be such as to yield fruitful results for the

good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment.

The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

Nuremburg Code No experiment should be conducted, where there is an a priori

reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

Nuremburg Code The experiment should be conducted only by scientifically qualified

persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible.

During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.