Ethical Issues for Human Subjects Research

1
Ethical Issues for Human Subjects Research

• Role of IRBs

2
I. Purpose of Human Subjects Research

• Understand Disease
• Validate New Therapies
• Understand Physiological Processes
• Study Human Behavior
• Evaluate Curricular Changes
• Evaluate New Teaching Methods

3
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.

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Ethical Issues in Research

• World War IIThe Nuremburg Trial
• Joseph Mengele and unethical experiments
  performed by Nazi doctors

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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

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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

7
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

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Ethical Issues in Research

• Unfortunately, codes were not always followed
• Tuskegee Syphilis Study-USPHS-1930s
• Not treated even after penicillin discovered
• Jewish Chronic Disease Hospital
• Patients injected with cancer cells
• Midgeville State Hospital
• Investigational drugs used without consent

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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

10
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

11
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 IRBs to review human subject studies
• Provided standards for appointment of IRBs,
  record-keeping and oversight in research

12
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

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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

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II. Institutional Review Boards

• IRBS 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

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III. IRB Review of Research

• Three categories of Review
• Exempt
• Expedited
• Full Review

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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.

17
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

18
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

19
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

20
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

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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

22
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

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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

24
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

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IRB Review of Research

• Full Review-Full Committee
• Investigational drugs, devices, invasive
  techniques (PET scan), implants, etc.
• Higher risk research
• NOTE-research not approved by IRB cannot be
  approved by higher authorities, however approved
  research may be disapproved by higher authorities

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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

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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

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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

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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

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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

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Basic Elements of Consent

• Explanation of purpose and duration
• Description of risks
• Description of benefits
• Disclosure of alternatives to participation

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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

33
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

34
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

35
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

36
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

37
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

38
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

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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

40
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

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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

42
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

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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

44
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

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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/gres
  earch.htm

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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

47
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

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Laboratory Research Animals
49
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

50
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

51
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

52
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

53
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

54
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

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Case Number 1

• Social scientist
• Observing 1st grade play activities
• What level of review?
• Exempt
• Expedited
• Full Review

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Case Number 2

• Psychologist
• Interviewing 1st graders
• Benign questions no names or identifiers
• What level of review
• Exempt
• Expedited
• Full Review

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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

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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.

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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.

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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.