Human Research Protections

1
Human Research Protections

• Suzanne E. Bentler, MS
• IRB Administrator
• Office of the Vice President for Research
• The University of Iowa
• http//www.research.uiowa.edu/hso/

2
Historical Perspective

• 1947 - The Nuremberg Code
• Developed by International Military Tribunal
• Nazi physician experiments on concentration camp
  inmates
• First internationally recognized code of research
  ethics

3
The Nuremberg Code

• Voluntary consent is absolutely essential
• Study should yield fruitful results for good of
  society
• Anticipated results should justify conducting the
  study
• Study should be conducted to avoid unnecessary
  physical/mental injury
• No a priori reason to suspect death/injury

4
The Nuremberg Code

• Risk should not exceed importance of question
  being answered
• Subjects protected from even remote possibility
  of injury
• Study conducted by qualified persons
• Subject free to end participation in study
• Scientist must stop subjects participation if
  continuing likely to result in injury

5
Historical Perspective

• 1964 Declaration of Helsinki
• 18th World Medical Assembly
• Recommendations to physicians
• Revised 5 times, most recently in 2002
• 1966 Henry Beecher, NEJM article
• 22 examples of unethical or questionably
  ethical studies
• Injecting live cancer cells into nursing home
  patients
• Transplanting melanoma from daughter to mother
• 1966-74 Policies for the Protection of Human
  Subjects from Office for Protection from
  Research Risks (OPRR), NIH

6
Historical Perspective

• 1972 - Syphilis Victims in US Study Went
  Untreated for 40 Years - NY Times headline
• Tuskeegee Study of Untreated Syphilis in the
  Negro Male
• Initiated in 1932, planned for 6-8 months
• Public Health Service investigators
• Penicillin available 1950s, subjects not told

7
Historical Perspective

• 1974 - Congress passes National Research Act
• DHHS Policies for become Regulations for
• National Commission for the Protection of Human
  Subjects of Biomedical and Behavioral Research
  created
• Identify basic ethical principles underlying
  research involving human subjects

8
Historical Perspective

• 1979 - Belmont Report Ethical Principles and
  Guidelines for the Protection of Human Subjects
  of Research
• 1981 - Title 45 Code of Federal Regulations Part
  46 (45 CFR 46)
• 1983 - 45 CFR 46 revised for special classes of
  subjects

9
Historical Perspective

• 1991 - 45 CFR 46 incorporated into the Common
  Rule
• Common Federal policy for protection of human
  subjects
• Adopted by 15 Federal agencies, including
• Education
• Transportation
• VA
• NSF
• NASA
• EPA

10
The Belmont Report

• Respect for Persons
• Recognition of personal dignity and autonomy
• Special protection of those with diminished
  autonomy
• Informed Consent
• Information
• Comprehension
• Voluntariness

11
The Belmont Report

• Beneficence
• Obligation to protect persons from harm
• Maximize anticipated benefit, minimize possible
  harm
• Risk/benefit ratio
• Risk probability, magnitude
• Benefit subject, society

12
The Belmont Report

• Justice
• Fair distribution of research benefits and
  burdens
• Inclusion/exclusion on scientific basis rather
  than convenience, availability
• Two levels of justice
• Social
• Individual
• More information about the Belmont Report can
  be found in the UI Investigators Guide Chapter 2.

13
Regulations

• DHHS
• Title 45 CFR Part 46
• FDA
• Title 21 CFR Part 50, Protection of Human
  Subjects
• Title 21 CFR Part 56, Institutional Review Boards

14
21 CFR 50 and 56

• Research involving products regulated by FDA
• Nearly identical to DHHS regulations
• Both sets of regulations may be applicable

15
45 CFR 46 Major Components

• Definitions
• Assurance of compliance
• IRB duties and review criteria
• Informed consent
• Types of IRB review
• PI responsibilities after approval

16
45 CFR 46 - Definitions

• Research
• Systematic investigation designed to develop or
  contribute to generalizable knowledge
• UI Investigators Guide, Chapter 3, Section B1
• Human Subject
• Living individual about whom an investigator
  conducting research obtains (a) data through
  intervention or interaction with the individual
  or (b) identifiable private information
• UI Investigators Guide, Chapter 3, Section B2

17
45 CFR 46 - Definitions

• Minimal Risk
• Probability and magnitude of harm or discomfort
  anticipated in the research are not greater in
  and of themselves than those ordinarily
  encountered in daily life or during the
  performance of routine physical or psychological
  examinations or tests
• Does not apply to IND/IDE studies
  (investigational new drugs and devices)
• UI Investigators Guide, Chapter 4

18
45 CFR 46 - Assurances

• Federalwide Assurance (FWA)
• Binding, written document with Office of Human
  Research Protections (OHRP) in DHHS
• Assures compliance with regulations,
• principles of Belmont Report
• Designates IRBs, assures institutional support
• UI applies regulations to all research,
• regardless of funding
• FWA00003007, renewed every 3 years
• UI Investigators Guide, Chapter 3, Section A

19
Institutional Review Boards

• Composition
• Duties
• Review Criteria

20
45 CFR 46 IRB Composition

• At least 5 members
• Quorum more than half
• Varying backgrounds
• One member nonscientific (required for quorum)
• One member not affiliated
• No individual conflict of interest

21
IRBs at the University of Iowa

• IRB-01 (Biomedical)
• Chairs Andy Bertolatus, Herbert Berger, Martha
  Jones
• 15 primary members, 53 alternates
• Colleges of Medicine, Pharmacy, Dentistry, Public
  Health, Dept of Speech Pathology/Audiology or UI
  patients
• Meets weekly for new project review
• Meets every other week for continuing review of
  ongoing research
• UI Investigators Guide, Chapter 3, Section C1

22
IRBs at the University of Iowa

• IRB-02 (Behavioral/Social Science)
• Chairs Jerry Suls, Kristine Fitch, Martha Jones
• 9 primary members, 7 alternates
• Colleges of Liberal Arts, Law, Education,
  Engineering, Business Administration, Nursing
• Meets twice monthly
• UI Investigators Guide, Chapter 3, Section C2

23
45 CFR 46 IRB Duties

• Review and approve, require modifications (for
  approval), or disapprove research
• Require informed consent and documentation as
  required by regulations
• Notify investigator in writing
• Continuing review at intervals appropriate to
  degree of risk (at least annually)

24
45 CFR 46 IRB Approval Criteria

• Risks to subjects minimized
• Risks to subjects reasonable in relation to
• anticipated direct benefit
• knowledge to be gained
• Selection of subjects equitable
• Informed consent sought and documented
• Appropriate provisions for monitoring safety
• Provisions to protect privacy confidentiality
• Additional safeguards for vulnerable populations
• UI Investigators Guide Chapter 6, Section F

25
45 CFR 46 Vulnerable Populations

• Subpart B Pregnant Women, Human Fetuses, and
  Neonates
• Risk to fetus caused solely by procedure that has
  prospect of direct benefit to mother
• If no direct benefit to mother, risk to fetus
  minimal and purpose of research to develop
  knowledge that cannot be obtained otherwise
• If direct benefit solely to fetus, both parents
  must consent, unless minimal risk to fetus
• UI Investigators Guide, Chapter 8, Section A

26
45 CFR 46 Vulnerable Populations

• Subpart C Prisoners
• Causes, effects, processes of incarceration
• Prisons as institutional structures or prisoners
  as incarcerated persons
• Conditions particularly affecting prisoners
  (hepatitis, sexual assault)
• Practices that have intent, probability of
  improving health, well-being
• UI Investigators Guide, Chapter 8, Section B

27
45 CFR 46 Vulnerable Populations

• Subpart D Children
• No greater than minimal risk one signature may
  be sufficient
• Greater than minimal risk, prospect of direct
  benefit one signature may be sufficient
• Greater than minimal risk, no prospect of direct
  benefit, likely to yield knowledge about
  condition/disorder two signatures
• None of above, but opportunity to understand,
  prevent, alleviate serious problem affecting
  health/welfare of children two signatures
• UI Investigators Guide, Chapter 8, Section C

28
QUIZ TIME!

• Part I

29
Informed Consent - Purpose

• Informed consent primary ethical principle
  governing human subjects research
• Empowers subjects to make their own determination
  about whether to participate
• Ensures subjects understand nature of research
  and knowledgeably and voluntarily make a decision
• UI Investigators Guide, Chapter 5, Section A

30
Informed Consent A Process

• Not an isolated event or a single document
  process includes recruitment
• An educational interaction between investigator
  and prospective participant
• In studies involving multiple visits
• confirm willingness to continue
• opportunity for additional interaction and
  questions about the research

31
Elements of Consent 45 CFR 46

• Statement that study involves research
• Purposes
• Duration of subjects participation
• Procedures, are any experimental
• Risks
• Reasonably foreseeable
• May include social, legal, emotional, financial
• Benefits
• To subject or others
• Reasonably expected from the research
• Alternative procedures/treatments, if any

32
Elements of Consent 45 CFR 46

• Extent of confidentiality of records
• For research involving more than minimal risk
• Is compensation available for research related
  injury
• Where treatment is available, who to contact if
  injury occurs
• If questions, who to call
• About research itself
• About subject rights
• Voluntary participation
• Okay to refuse - no penalty or loss of benefits
• May discontinue at any time

33
Additional Elements 45 CFR 46

• Unforseeable risks of treatment/procedure
• Circumstances where investigator may terminate
  subjects participation
• Additional costs to subject
• Consequences of subjects decision to withdraw
• New findings affecting willingness to participate
  will be provided to subject
• Number of subjects in study

34
Comprehension of Consent

• Investigator enhance subjects comprehension
• Consider nature of subject population, type of
  information, circumstances of consent.
• Valid consent Subjects must understand what is
  being explained.

35
Obtaining Consent

• Subject must have opportunity to consider
  participation
• Minimize possibility of coercion or undue
  influence
• Subject should be capable (legally mentally) of
  consent

36
Consent A Legal Concept

• Only legally competent adults can give consent
• Incompetent adults cannot give legal consent
• Cognitively impaired, unconscious,
  developmentally disabled
• Evaluation of competence on case by case basis
• Children cannot give legal consent

37
Assent

• Children, incompetent adults should be asked to
  assent knowledgeable agreement
• Objection of child, incompetent adult is a veto
  of the consent of legally authorized
  representative unless IRB stipulates otherwise
• Documentation of Assent/Consent
• Assent Document Informed Consent Document for
  younger children and parent/guardian
• Informed Consent Document alone if at appropriate
  reading level for teenager

38
Writing a Consent

• Start with our template!
• Avoid technical terms, complex sentences, passive
  voice
• Pictures, diagrams, flow charts, tables
• Short paragraphs
• Lots of white space
• Clear chronology of ALL procedures

39
Documentation of Consent

• Consent process must be documented
• Using consent document approved by IRB
• With signature of subject or legally authorized
  representative
• Copy of consent document must be given to person
  signing the form
• Consent and its documentation may be waived in
  certain circumstances

40
Waiver of Elements of Consent

• IRB may waive some or all consent requirements if
  it finds and documents that
• research involves no more than minimal risk
• waiver will not adversely affect rights/welfare
  of subjects
• research could not practicably be carried out
  without the waiver AND
• subjects will be provided with pertinent
  information afterwards, when appropriate.
• UI Investigators Guide, Chapter 5, Section C5

41
Waiver of Documentation of Consent

• IRB may waive requirement for signed consent if
  it finds and documents that
• the only record linking subject and research is
  consent document, and the main risk is potential
  harm resulting from breach of confidentiality or
• the study is minimal risk and involves procedures
  that do not require written consent outside of a
  research context
• Written document still may be required
• UI Investigators Guide, Chapter 5, Section C5

42
Types of Review

• ExemptUI Investigators Guide, Chapter 4,
  Section A
• ExpeditedUI Investigators Guide, Chapter 4,
  Section B
• Full BoardUI Investigators Guide, Chapter 4,
  Section C

43
Exempt Research

• Determination by IRB chair
• Exempt from 45 CFR 46
• Continuing review not required
• Informed consent not required,
• but may be used
• Minimal risk
• Specific categories

44
Exempt Categories

• Surveys, interviews
• -- anonymous, or if not anonymous,
• -- no risk of damage to reputation,
  employability, criminal or civil liability
• Existing (at time of application) data,
  documents, records, specimens
• -- if publicly available or anonymous
• Educational settings involving normal educational
  practices
• -- comparison of techniques, curricula

45
Expedited Research

• Determination by IRB chair
• Minimal risk
• No overlap with exempt
• Requires continuing review
• Informed consent
• Specific categories

46
Expedited Research Categories

• Non-invasive specimen collection
• Non-invasive procedures, excluding x-ray
• Small amounts of blood
• Existing data, specimens OR specimens
  prospectively collected for non-research purposes
• Surveys, interviews

47
Full Board Review

• Greater than minimal risk
• Requires continuing review
• Chair assigns primary reviewer (IRB member) to
  present study at full board meeting
• Protocol and/or grant
• Investigators (Drug) Brochure
• All members at meeting review/discuss
• Application
• Informed Consent
• Other materials

48
After IRB Approval

• Continuing ReviewUI Investigators Guide,
  Chapter 7, Section B
• ModificationsUI Investigators Guide, Chapter 7,
  Section A
• Unanticipated ProblemsUI Investigators Guide,
  Chapter 7, Section C

49
Continuing Review

• Intervals appropriate to degree of risk, but at
  least once per year
• Expiration date on Informed Consent Document and
  notice of approval
• Full board review if initially full board
• On-site monitoring program (Monitoring UI
  Investigators Guide, Chapter 7, Section D)

50
Modifications

• Reasons
• Change in protocol
• Change in investigators
• Increase in number of subjects
• Change in sponsor
• Change in Informed Consent
• Submit receive approval prior to initiation
• Minor changes may be expedited
• May be combined with continuing review

51
Unanticipated Problems

• Prompt reporting of unanticipated problems
  involving risk to subjects or others required
• Considerations
• Modify Informed Consent Document?
• Notify subjects?
• Reportable Events Form

52
Suggestions for what you can do

• Practice good science
• Acknowledge conflicts of interest
• Become educated in research subject protections
• Take personal responsibility for implementation
  of ethical principles through your research
  practices

53
Human Subjects Office

• Administrative support for both IRBs
• Serves as resource for investigators
  Investigators Guide, website
• HawkIRB Electronic application submission
  Database of applications Automatic
  notification reminders approvals
• Website www.research.uiowa.edu/hso
• Contact 340 CMAB, 335-6564