1. Human Subjects Protection Regulation in the United States
How did we get here, and where are we going?
Ilene Wilets, PhD, CIP
IRB Chair, Program for the Protection of Human Subjects
Icahn School of Medicine at Mount Sinai at Mount Sinai
New York, NY

2. Human Subjects Protection Regulation in the U.S.
I. Historical Framework
Historical events leading to the inception of the IRB
The mission, structure and function of the IRB
II. Federal Regulation for Research Review
Federal regulation governing human subjects research
The structure and composition of an IRB
Review categories: exempt, expedited and full board review
Review Process: initial, continuing, amendments
IRB criteria for protocol review

3. Human Subjects Protection Regulation in the United states
III. Informed Consent
Form and process, consent form challenges
IV. Challenges, criticisms and institutional culture
IRB challenges: mission creep, inconsistency, lengthy time to study approval.
V. The Common Rule - soon to be revised!
Notification for Policy Rule-Making (NPRM)
What’s next for IRBs?
VI. Case-based class exercises

4. I. Historical Framework

5. Historical Events Shaping
Research Regulation

6. Genocide guised as research
National Archives. United States Holocaust Memorial Museum

7. Freezing Water Experiments
Dachau concentration camp, August 1942-May 1943

8. High Altitude Experiments
Dachau concentration camp, March-August 1942

9. Seawater Experiments
Dachau concentration camp, July September 1944

10. Nuremberg Trial
International Military Tribunal trial of war criminals at Nuremberg, December 10, Courtesy of National Archives and Records Administration.

11. Biological plausibility
Nuremberg Code
Biological plausibility
Favorable risk-benefit ratio
First in animals
Informed consent
Right to withdraw from research

12. The Natural History Study of Syphilis in the Negro Male (Tuskegee Study)
, United Health Service

13. Establishment of the IRB system
The National Research Act of established the modern IRB system for regulating research involving human subjects.
In 1981, the Department of Health and Human Services put forth the main IRB regulations in Title 45, Part 46 of the Code of Federal Regulations (45 CFR 46).

14. The Common Rule
Seventeen federal agencies have adopted the 45 CFR 46 regulation for the protection of human subjects.

15. Belmont Report Prepared in 1979
Basic ethical principles and guidelines:
Boundaries between practice and research
Basic ethical principles applications

16. Belmont Principles Respect for persons Beneficence Justice
BELMONT REPORT
Background: In 1974, Congress passed the National Research Act, which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979, the National Commission published the “Ethical Principles and Guidelines for the Protection of Human Subjects in Research,” which is more commonly known as the Belmont Report.
The Belmont Report was designed to present the broader ethical principles from which specific rules may be formulated, criticized and interpreted.
The broader ethical principles were introduced to cover more complex situations. They were finding that some of the specific codes and principles, mentioned earlier, at times would come into conflict and they were frequently difficult to interpret.
Thus came the basic principles of:
Respect for Persons
Individual Autonomy (informed consent, privacy & confidentiality)
Protection of individuals with reduced autonomy (special populations)
Beneficence
Maximize benefits and minimize harms (risk/benefit analysis; qualifications of PI)
Justice
Equitable distribution of research costs and benefits (subject selection, inclusion/exclusion, recruitment)

17. Application of Respect for Persons
Informed Consent Process
Information – all the information necessary to make a reasoned decision?
Comprehension –language understandable to potential participant?
Voluntariness – clearly indicate that participation is voluntary?
What additional protections for those with limited autonomy?
How to determine whether someone lacks the ability to make a reasoned decision?

18. Application of Beneficence
Assessment of Risks and Benefits
Risk
Probability of harm
Consider both probability and severity of harm
Benefit
promotes health
well-being, or welfare.
Risks of harm
Physical, psychological, social, and economic harms
Are the risks justified?
Can risks be minimized?
Can the design further minimize risk and maximize benefit?
What benefits to participant and society?

19. Application of Justice
Selection of subjects
Are these potential subjects appropriate for the research?
Are vulnerable populations being enrolled because it is appropriate? Or, are they seen as a population of convenience, or being manipulated as a result of their powerless situation?
Are recruitment procedures fair?
Are the inclusion and exclusion criteria fair and appropriate?

20. II. Federal Regulation for Research Review

21. NIH Policy on the Inclusion of Women and Minorities in Research
U.S. Federal Regulation and Guidance for the Protection of Human Subjects
DHHS 45 CFR 46 (Common Rule)
FDA 21 CFR Part 50
FDA 21 CFR Part 56
NIH Policy on the Inclusion of Women and Minorities in Research
NIH Policy on Inclusion of Children

22. DHHS Regulations: Title 45 CFR Part 46
Subpart A.
Basic HHS policy (the “Common Rule” federal policy)
includes IRB requirements
includes informed consent requirements
numerous other federal departments and agencies have adopted 45 CFR 46
FDA has it’s own policy

23. DHHS Regulations: Title 45 CFR Part 46
Subpart B. research involving pregnant women, human fetuses and neonates
Subpart C. research involving prisoners
Subpart D. research involving children

24. Definition: Research
“A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to the generalizable knowledge” 45 CFR (c)

25. Is Human Subjects Research Exempt from IRB Review?
45 CFR (b) refers to six categories of exempt research
(1) normal educational practices in established settings
(2) educational tests, surveys, interviews or observations of public behavior
(3) such procedures with public officials
(4) research using existing data, recorded without identifiers
(5) public programs
(6) taste and food quality evaluations

26. Expedited Review Procedures
Expedited review procedures per 45 CFR
Research involving:
- no greater than minimal risk, and for minor changes in previously approved research
- research must meet minimal risk definition, and be on list of categories for which expedited review is deemed acceptable (see next two slides).

27. Expedited Review Research deemed no greater than minimal risk and must be in one or more of the following categories
Studies of already approved drugs or devices (IND or IDE not required)
Studies that involve routine blood samples
Biological specimens obtained by non-invasive means
Data collection by non-invasive procedures
Materials collected for non-research purposes
Voice, video, digital, image recordings
Research on individual or group characteristics
Continuing review of previously approved (minimal risk) research

28. Definition: Minimal Risk
“The probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological testing”

29. Institutional Review Board (IRB)

30. IRB Mission
To assure the protection of the rights and welfare of human subjects in research is in compliance with federal and state regulations and institutional policies and procedures.
ROLE OF THE IRB
Outlined in our Federal Wide Assurance with OHRP

31. Who is on the IRB? At least 5 members
Professional competence necessary to review specific research activities, and know standards of professional conduct and practice
Ability to ascertain acceptability of proposed research in terms of institutional commitments and regulations
At least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas
At least one member who is not otherwise affiliated with the institution…

32. IRB Membership Composition
Scientific
Non-scientific
Affiliated
Not otherwise affiliated

33. IRB Member Training Requirements
Core knowledge required of IRB new member
In-depth knowledge required of experienced IRB member
Specialized knowledge required by specific members (e.g. legal experts, advocates for special populations)

34. IRB Primary Activities
Review new projects
Review modifications of approved studies
Annual review of approved studies
Focus on study risk vs. benefit
Informed consent

35. IRB Review Process
Except for expedited reviews, proposed research is reviewed at a convened (i.e., full board) IRB meeting.
At a full board meeting, the majority of IRB members must be present, and at least one member must be “nonscientific” and “unaffiliated” with the institution.

36. What does the IRB look for?
Minimize risks
Risks are reasonable in relation to anticipated burdens and the importance of the knowledge
Selection of subjects is equitable
Protection of participant rights
Adequate informed consent to participate
Procedures which assure maintenance of confidentiality of sensitive data
Right to refuse to participate without adverse consequence such as denial of services
Inclusion of women and minorities
Scientific merit of the proposed study
Is the design minimally adequate to answer the research questions? Are benefits worth the risk?

37. Review Criterion #1
The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk.
Is the hypothesis clearly stated?
Is the study design appropriate to prove the hypothesis?
Will the research contribute to the generalizable knowledge, and is it worth exposing subjects to risk?

38. Review Criterion #2
The risks to the subjects are reasonable in relation to anticipated benefits, if any, and the importance of knowledge that may reasonably be expected to result.
What does the IRB consider the level of risk to be?
Is there a prospect of direct benefit to subjects?

39. Review Criterion #2 (cont.)
Risk is a probabilistic concept referring to the likelihood that a study-related harm (or adverse event) will occur.
Risks are not just physical; they can be psychological, social, or economic.
Risks vary with frequency, intensity and reversibility.

40. Review Criterion #2 (cont.)
“Benefit” is also probabilistic, referring to the likelihood of a good outcome A benefit may be classified as either “direct” or “indirect”.

41. Review Criterion #3 Risks to the subjects are minimized.
Does the research design strive to reduce risk?
How can safety be maximized?

42. Review Criterion #4 Subject selection is equitable.
Who are the subjects of the research?
Are these subjects appropriate for the research protocol?

43. Review Criterion #5
Informed consent is obtained from subjects, or from their legally authorized representative.
Does the informed consent document contain the required elements?
Is the consent document understandable to subjects?
Who will obtain informed consent? When will it be obtained, and in what setting?

44. Review Criterion #6
Additional safeguards are required for subjects likely to be vulnerable to coercion or undue influence.
Are appropriate protections in place for vulnerable subjects (e.g., children, pregnant women, individuals with diminished capacity?)

45. Review Criterion #7
There are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
Are there any special privacy and confidentiality issues to consider?
Will personal health information be collected? If so, will these data be protected to the greatest extent possible from access or use?

46. Full Board Review of Research
Except for expedited reviews, proposed research is reviewed at a convened (i.e., full board) IRB meeting.
At a full board meeting, the majority of IRB members must be present, and at least one member must be “nonscientific” and “unaffiliated” with the institution.

47. Full Board Review Process
Initial review: New research proposals
Continuing review: Progress of previously approved studies on (at least) an annual basis
Research that was not approved at previous IRB meeting (termed “deferred”)
Full board revisions: review changes to previously approved research proposals (termed “modifications”, “amendments”)

48. The IRB Meeting Quorum. IRBs may not convene without a quorum.
A quorum is defined as the majority of voting members, including at least one member whose primary concerns are in non-scientific areas.
Voting. Voting options are “yes” to approve, “no” to disapprove, or abstention. When the vote is not unanimous – the majority opinion rules. The minority opinion is important, and thus, is recorded in the minutes.
Conflicts of interest. Members who are conflicted must recuse themselves from the research discussion and vote.

49. IRB Decision-making Approved Deferred Disapproved
Approved pending revision
Disapproved

50. Approved. There are no additional issues which need to be addressed, and the research can go forward.
Approvable pending revisions. There are additional issues that must be addressed, but they are minor, and do not require re-review by a full board.
Deferred. The study approval is deferred, as there are substantive (non-minor) issues which need to be addressed. These studies must be re- reviewed at a full board meeting.
Disapproved: The project is unapprovable as currently designed. This categorization is reserved for research that is seem by the board as intrinsically problematic (unethical).

51. FDA Regulation
21 CFR 50. requirements for informed consent
21 CFR 56. requirements for the IRB

52. Much of the FDA regulation is identical to DHHS regulation
DHHS vs. FDA Regulation
Much of the FDA regulation is identical to DHHS regulation
Differences center on “applicability”
DHHS – based on federal funding
FDA – based on use of FDA-regulated product ( i.e., drug, device, biologic)

53. III. Informed Consent

54. Basic Elements of Informed Consent
A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation…
A description of procedures to be followed
Identification of any procedures which are experimental
In addition to defining “informed consent” I want to quickly review the basic elements of informed consent as promulgated by our federal government in the Code of Federal Regulation 45 CFR
This regulation directs us to obtain informed consent from all prospective subjects or the subject’s legally authorized representative in accordance with specific parameters relating to consent document content and context (that is process for the conduct of consent).
Bear with me while I quickly present the 8 basic elements of informed consent [READ SLIDE]
45CFR General Requirements for Informed Consent

55. Basic Elements of Informed Consent
A description of any foreseeable risks or discomforts to the subjects
A description of any benefits to the subject or to others which may reasonably be expected from the research
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject
[READ SLIDE]

56. Basic Elements of Informed Consent
A statement describing the extent, if any, to which the confidentiality of records identifying the subject will be maintained
[READ SLIDE]

57. Basic Elements of Informed Consent
Any compensation… or medical treatment… if injury occurs…
(7) An explanation of whom to contact for answers to pertinent questions about the research and research subject’s rights…
(8) A statement that participation is voluntary
[READ SLIDE]
The feds provide “additional considerations”…other important optional elements,
However, to keep with time, I will not present these.

58. 35 + years and counting…
Cassileth,B. et al., NEJM, April 1980
Informed Consent - Why are Its Goals Imperfectly Realized?
“We explored reasons for the failure of patients to recall major portions of the information on consent forms and in oral explanations about consent.”
“Within one-day of signing the consent form, 200 cancer patients completed a test of recall…”
“Only 60% understood the purpose and nature of the procedure, and only 55% correctly listed even one risk or major complication.”
So --- here’s “the rub”, “the conundrum”, “the challenge” for all of us who tirelessly work within the field of medicine, clinical research, and research administration……
So I ask you this ---- Is Informed Consent doomed to be an “oxymoron”?
------Why are it’s goals imperfectly realized – even today?
Why are we missing the mark?!! [OPEN QUESTION TO AUDIENCE]

59. Current Discourse on Consent for Research
Consent forms are too long
Consent forms are too dense
Consent forms are written at too high a reading (grade) level
Consent forms are primarily designed to protect the Institution
[READ SLIDE]
Anything else can we add to this list??

60. Low Literacy Levels in the U.S.
National Assessment of Adult Literacy Study
US Department of Education (1992, 2003)
Large national survey
Survey measured prose, document and quantitative skills
40% of sample was at “basic” or “below basic” level for all 3 categories
Concluded that the “average American reads at a 7th or 8th grade reading level”
National survey -- 15% of sample of 19,000 participated
Defining ADULT LITERACY – different definitions by different agencies
Ability to read several thousand simple words (4th grade level)
Able to use basic sources of written information such as a warning label (not package insert) – do not take this drug is you are pregnant
PROSE —knowledge and skills needed to search and use information from continuous text
DOCUMENT ---access and assimilate information from non-continuous text in various formats
QUANTITATIVE SKILLS ---- numeracy, perform computations, use numbers embedded in written materials…If your headache persists more than 5 days, consult a doctor. Do not take more than 4 tablets in 24 hours.
DEPT OF ED survey in line with literacy findings from a National Center for Education Statistics survey: 47% of US population (approx 90 million adults) is estimated to have low literacy levels.
Tie this is with the literacy level required to comprehend a research consent form.
NCI – readability est ranging from grade 12.0 to 17.5
******A word on readability estimates : flesh kincaid or SMOG
THERE IS HOPE --- mention Johns Hopkins study, conducted in their oncology center
Study initiated by the IRB in which the IRB started a program of discussing reading assessment results with each investigator. Over time, they were able to increase the percentage of oncology consent documents written at an 8th grade level or below from 6% to 37%.

61. Full Disclosure vs. Comprehension and Retention
Now let’s consider…the concept of “shorter” is optimal in terms of the consent form length?
How may of us have either experienced this directly when recruiting subjects, or heard this comment form a member of an investigative team…
The study candidate….does not read the form, just wants to sign
The study candidate….reads only the first couple of pages and then stops reading, flips to the back for signature
This I was told from an investigator just this week. The last patient he attempted to enroll in a study, would not read beyond the 3rd paragraph. He wanted to sign on, but did not want to continue reading along with the investigator.
OK. Much of this is consent process technique. But much has to do with the document itself.
Is our goal of full disclosure (risk, benefits, alternatives, financial COI, HIPAA policy, etc) hindering our efforts to maximize understanding (comprehension) of the research?
[Open question to Group]
Comprehension
Information

62. IV. Challenges, criticisms and institutional culture

63. Criticisms Variation Greene & Geiger, 2006:
Time to final approval ranged from 5 to 798 days
Achieving consistency among 65 hospital registries added over a year to their project timeline
17% of the budget was consumed by IRB review-related costs
Variable IRB requirements yielded higher refusal rates among sites that required an explicit opt-out procedure as part of the local protocol
From: Greene SM, Geiger AM. A review finds that multicenter studies face substantial challenges but strategies exist to achieve Institutional Review Board approval. J Clin Epidemiol 59(8) (2006):

64. From: Shah S., et al. “How Do Institutional Review Boards Apply the Federal Risk and Benefit Standards for Pediatric Research?”

65. From: Shah S., et al. “How Do Institutional Review Boards Apply the Federal Risk and Benefit Standards for Pediatric Research?”

66. Tensions & Questions
Does heightened protection of vulnerable populations limit research on vulnerable populations in suboptimal ways?
Do “scandals” lead to “over-enforcement” or “over-regulation”?
Does intensive regulation lead researchers to avoiding certain studies, involving novel approaches or vulnerable populations?

67. Time Effort Money Decrease Variable Interpretation Of Regulations
Cost to Researchers
Time
Effort
Money
Decrease
subject enrollment

68. V. The Common Rule: Revisions anticipated in 2019!

69. Proposed Regulatory Changes
Some critics, including potential and former research subjects, object to research performed on a person’s biospecimens without consent – as highlighted in the book, The Immortal Life of Henrietta Lacks.

70. Proposed Regulatory Changes
Ensuring Risk-Based Protections
New Mechanism for Protecting Subjects from Informational Risks
Calibrating the Levels of Review to the Level of Risk
Revised Approach to Expedited Review
Moving Away From the Concept of Exempt
Streamlining IRB Review of Multi-Site Studies
Improving Informed Consent
Improving Consent Forms
Waiver of Informed Consent or Documentation of Informed Consent in Primary Data Collection
Strengthening Consent Protections Related to Reuse or Additional Analysis of Existing Data and Biospecimens

71. (proposed changes, continued…)
Question 45: Under what circumstances should future research use of data initially collected for nonresearch purposes require informed consent? Should consent requirements vary based on the likelihood of identifying a research subject?

72. (proposed changes, continued…)
Question 47: Should there be a change to the current practice of allowing research on biospecimens that have been collected outside of a research study (i.e.,‘‘left-over’’ tissue following surgery) without consent, as long as the subject’s identity is never disclosed to the investigator?

73. (proposed changes, continued…)
Question 57: Should some types of genomic data be considered identifiable and, if so, which types (e.g., genomewide SNP analyses or whole genome sequences)?

74. V. Cased-based class exercises

75. Group Discussion of IRB Cases

76. IRB Case #1 You are a seasoned IRB member reviewing a new protocol.
A researcher is conducting a study at 5 universities in the United States The proposal has already been approved at the other 4 sites. The informed consent form says that will be using “an experimental drug treatment.” However, this is an experimental agent, not yet proven to work.
One IRB member says that the consent form should be changed to say “an experimental drug”- dropping the word “treatment” But the PI says that mandating such a change will hold up the entire project at all of the other sites, since they “all must use the same consent forms.”
As an IRB member, how might your respond?

77. IRB Case #2 You are a seasoned IRB member reviewing a new protocol.
A researcher is conducting a study of violence among adolescents. He will be recruiting the siblings of individuals who have been charged with a violent crime. He will draw a blood sample from them and their siblings. He will then examine DNA, and will administer pencil and paper tests of depression, anxiety, and attitudes toward violence among both groups. He will follow all study participants for 5 years.
Any concerns? What questions might you ask the researcher?

78. IRB Case #3
A researcher wants to study a new anti-depressant, and compare it to placebo, for the treatment of dysthymia, which is mild chronic depression.  He says that a large placebo response exists for treatment of depression.  He will follow study participants with dysthymia for one year.  
Prior to beginning the study all subjects must undergo a “washout” period, in which they are gradually taken off any medication they currently may be on for their depression.
You are either a:
--- member of a group of patients with dysthymia, or
--- member of the research team, or
--- member of the IRB.
A meeting is being held to discuss the proposal.  Do you have any concerns, and if so, what might they be?

79. Public Responsibility in Medicine and Research (PRIM&R)
For initial and continuing education in research ethics, this organization is a great resource.

80. Comments & Questions