IRB 101: Highlights of the History of Human Subjects Protections

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IRB 101Highlights of the History of Human
Subjects Protections
Columbia University Medical Center IRB 2008 - 2009
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Objective

• Provide an overview of the events that have led
  to the system of protections that are currently
  in place to protect individuals who volunteer for
  research.
• Summarize the applicable regulations for the
  protection of human subjects.

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Pre-20th Century

• Medical practice developed from medical research
• No formal, widely-accepted codes
• Reliance on morals, ethical principles of
  culture, Hippocratic Oath

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20th Century

• 1900 Walter Reeds Yellow Fever experiments
• 1898 Spanish American War
• 968 soldiers killed in combat
• 5000 died of disease, mostly Yellow Fever
• United States Army Yellow Fever Commission
• Major Walter Reed
• Conducted experiments outside of Havana
• Proved that the mosquito transmits Yellow Fever
• First systematic use of informed consent in
  research

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Elements present in Yellow Fever Consent Form

• Autonomy (respect for persons) gives his
  consentfor the reasons and under the
  conditions
• Voluntary Participation being in the enjoyment
  and exercise of his own free will
• Risks In case of the development of yellow
  fever in him, that he endangers his life to a
  certain extent.
• Benefits He will receive from the said
  commissioner the greatest care and the most
  skillful medical service.
• Compensation he will receive the sum of 100 in
  American gold . . .
• Study withdrawal conditions The undersigned
  binds himself not to leave the bounds of this
  camp during the period of the experiments and
  will forfeit all right to the benefits named in
  this contract if he breaks this agreement.

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1932 PHS Study of Syphilis

• Significant health problem
• No initial intent to deny treatment
• Complete physical exam, medical history taken
• Followed for 6-8 months without treatment
• New follow-on study started in late 1933
• New procedures to strengthen scientific validity,
  control group
• No information provided about true nature of
  study government doctors were examining people
  for bad blood
• Penicillin accepted as curative treatment in
  1943
• Not provided
• Exemption from draft to keep subjects in study

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1939-1944 Nazi Experimentation

• Findings of the Tribunal
• In every single instance appearing in the record,
  subjects were used who did not consent to the
  experiments
• In no case was the experimental subject at
  liberty of his own free choice to withdraw from
  any experiment.
• All of the experiments were conducted with
  unnecessary suffering and injury and but very
  little, if any, precautions were taken to protect
  or safeguard the human subjects from the
  possibilities of injury, disability, or death.
• In every one of the experiments the subjects
  experienced extreme pain or torture, and in most
  of them they suffered permanent injury,
  mutilation, or death, either as a direct result
  of the experiments or because of lack of adequate
  follow-up care.

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THE NUREMBERG CODE

• from Trials of War Criminals before the
  Nuremberg Military Tribunals under Control
  Council Law No. 10. Nuremberg, October 1946April
  1949. Washington, D.C. U.S. G.P.O, 19491953.
• First Tenet - The voluntary consent of the human
  subject is absolutely essential.

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Nuremberg Code and Voluntary Consent

• This means that the person involved should
• Have legal capacity to give consent
• Situated as to be able to exercise free power of
  choice, and should have sufficient knowledge
  and comprehension of the elements of the subject
  matter involved as to enable him to make an
  understanding and enlightened decision.
• This latter element requires that before the
  acceptance of an affirmative decision by the
  experimental subject there should be made known
  to him the nature, duration, and purpose of the
  experiment
• The method and means by which it is to be
  conducted
• All inconveniences and hazards reasonably to be
  expected
• The effects upon his health or person which may
  possibly come from his participation in the
  experiment.

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Investigator Responsibility

• The duty and responsibility for ascertaining the
  quality of the consent rests upon each individual
  who initiates, directs or engages in the
  experiment. It is a personal duty and
  responsibility which may not be delegated to
  another with impunity.

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1946, 1950-53 Fernald School

• Massachusetts Institute of Technology researchers
  and Fernald staff members
• Studies with radioisotopes at the school
• The first study, in 1946, exposed seventeen
  students to radioactive iron.
• The second study exposed fifty seven subjects to
  radioactive calcium between 1950 and 1953.

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Fernald Consent Documents

• Misleading information implies benefits
• No mention of radioisotopes
• Coercive
• Active consent not required

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Late 1950s

• Thalidomide Tragedy
• Approved in Europe as sedative
• Not approved in U.S.
• Samples provided to U.S. physicians paid to study
  safety and efficacy
• 1962 Amendments to U.S. Food, Drug and Cosmetic
  Act (Kefauver-Harris Amendments)

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1956-72 Willowbrook

• New York University researchers
• Willowbrook State School for the Retarded,
  located on Staten Island
• Residents were injected with a mild form of
  hepatitis serum
• The researchers hoped to find a treatment for the
  virus by studying the disease in its earliest
  stages

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1961 Milgram Obedience Study

• Recruitment by newspaper ad
• 4.50 for one hour's work
• Psychology experiment investigating learning and
  memory
• Involved deception
• Individuals were asked to give what appeared to
  be real electric shocks to another person
• The researchers wished to test how far subjects
  would follow the orders of an experimenter
• Post-experiment interview

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1960s

• 1964 Declaration of Helsinki Expansion on
  Informed Consent
• In any research on human beings, each potential
  subject must be adequately informed of the aims,
  methods, sources of funding, any possible
  conflicts of interest, institutional affiliations
  of the researcher, the anticipated benefits and
  potential risks of the study and the discomfort
  it may entail. The subject should be informed of
  the right to abstain from participation in the
  study or to withdraw consent to participate at
  any time without reprisal. After ensuring that
  the subject has understood the information, the
  physician should then obtain the subject's
  freely-given informed consent, preferably in
  writing. If the consent cannot be obtained in
  writing, the non-written consent must be formally
  documented and witnessed.
• 1966 NIH Policies for the Protection of Human
  Subjects issued
• Established the IRB as one mechanism through
  which human subjects would be protected.

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1970s

• 1972 Syphilis study exposed
• Study stopped in March 1973 and treatment
  provided
• 1974 National Research Act passed (raised NIH
  policy to regulation)
• Required regulations for protection of human
  subjects
• Informed consent
• Institutional Review Boards
• Created National Commission for the Protection of
  Human Subjects of Biomedical and Behavioral
  Research
• 1979 Belmont Report published by National
  Commission
• Respect for persons (informed consent)
• Beneficence (minimize risk, evaluate risk/benefit
  ratio)
• Justice (selection of subjects)

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Acknowledgement of History of Violation of
Ethical Principles

• - Lack of Informed Consent (no respect for
  persons)
• Convenience sample bearing burden of research
  (injustice)
• Causing harm to subjects (maleficence)

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1981

• Based on Commissions reports and
  recommendations
• Significant revisions to HHS and FDA human
  subject regulations
• Clarified IRB role
• No change in general principles of review
• DHHS regulations codified at Title 45 Part 46 of
  the Code of Federal Regulations (45 CFR 46)
• Effective 1/16/81 revised 3/4/83 6/18/91
• 1991 revision involved adoption of Federal Policy
  for Protection of HS Common Rule (Subpart A)
  by 16 agencies
• Subparts B,C,D adopted 1978, 1978, 1983
  respectively
• FDA regulations codified at Title 21 Parts 50
  (1980), 56 (1981)
• Additional regulations for drugs, devices, device
  classification

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Differences between HHS and FDA regulations

• Comparison of FDA and HHS Human Subject
  Protection Regulations
• http//www.fda.gov/oc/gcp/comparison.html
• Consult with IRB staff if uncertain about
  application.

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Summary

• Formal codes for protection of human subjects
  relatively recent
• Subsequent to abuses of human subjects in
  research
• Limited in extent of protection

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IRB 101IRB Review CriteriaandTips for
Submission
Columbia University Medical Center IRB 2008-2009
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Objectives

• Describe how submissions are routed for review
• Provide return criteria
• Explain the requirements for approval
• Demonstrate where in RASCAL information should be
  entered
• Provide tips for a complete and accurate
  submission.
• Facilitate more timely review through a better
  understanding of the IRB review process and
  review criteria.

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Submission Process New Protocols

• Protocol submitted to the IRB (submitted/Log-in
  queue)
• Administrative review conducted by IRB staff
• Reviewer form guides review
• Performance standards provide timeline
• Review comments entered into Notes.

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Submission process New Protocol (2)

• Protocol will be accepted (logged in/Chair
  queue) if complete.

PI submits protocol
Submitted (Log-in queue) Staff review
Logged in (Chair queue)
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Submission process New Protocol (3)

• Return Criteria at log-in stage
• Cancer Center is not listed in Facilities
  section, and the research is cancer-related
• PI is not qualified
• Consent and/or Assent is not attached, and a
  waiver has not been requested
• Recruitment material is mentioned, but not
  attached
• Study instruments are described, but are not
  attached
• Sponsors protocol, IDB, or Package Insert is
  not attached
• Grant, contract, or other documentation of
  funding agreement is not attached
• There is insufficient information to make
  required determinations.

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Submission process New Protocol (4)

• Protocol will
• be returned (returned/
• Investigator queue)
• if one or more
• return criteria
• are met.

PI revises protocol
Correspondence from Chair to PI
PI submits protocol
Correspondence from team to Chair
Submitted (Log-in queue) Staff review
Correspondence from logger to team
Returned (Investigator queue) PI receives
protocol
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Submission process New Protocol (4)

• Overview

PI revises protocol
Correspondence from Chair to PI
PI submits protocol
Correspondence from team to Chair
Submitted (Log-in queue) Staff review
Correspondence from logger to team
Logged in (Chair queue)
Returned (Investigator queue) PI receives
protocol
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RASCAL tip Review IRB Submission Manual

• Posted on Columbia Universitys Office for
  Clinical Trials website
• http//www.columbiaclinicaltrials.org

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RASCAL tip Clarity

• Describe clearly and accurately what will be done
  at this site or under the direction of a Columbia
  investigator
• Identify related procedures that will be or have
  been done elsewhere or previously
• Provide clear descriptions of relationships
• Accurately describe funding mechanisms
• Consistently and precisely describe data
  collection.

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Submission Process Renewals

• Renewals
• Similar process, different form Return
  criteria
• Clean copies of consent documents or study
  instruments not attached
• Enrollment information not provided
• Documents or fields not updated
• Conditions of previous approval not satisfied
• All required attachments not provided.

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RASCAL tip Review attachments

• Archive superceded, reference, HIPAA documents
• Review content of attachments for currency,
  accuracy, outdated approval stamps, and inclusion
  of new requirements
• Review correspondence from previous approval.

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Submission Process Modifications

• Modifications
• Similar process, summary of modification,
  assessment of revision in all applicable
  documents
• Return criteria
• Clear explanation of changes not provided
• Description of modification does not match
  changes in documentation
• Changes are described but not incorporated
• Supporting documentation not attached.

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Submission Process Adverse Event ReportsReview
New IRB Unanticipated Problems Policy

• Unanticipated problem report
• Similar process, reconciliation of
  investigator assessment with UP policy
• Return criteria
• All required documentation not attached
• Event does not meet criteria to be reported
  individually
• Investigators assessment does not comport with
  supporting information.

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RASCAL tip Name files logically
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RASCAL tip Include Correspondence

• Cover letter with initial submission.
• Correspondence or attached response with
  resubmissions.
• Attached letter to IRB to explain unusual or
  complex collaborations, centers, affiliations,
  procedures, etc.

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IRB Review

• Low risk protocols may be eligible for exemption
  (6 categories)
• Minimal risk protocols may be eligible for
  expedited review (9 categories)
• Protocols that are not exempt or cannot be
  expedited require review by the full Board
• Time required for review is dependent upon the
  type of review, complexity and risk level of
  procedures, and other factors
• Chair schedule
• IRB meeting schedule
• Completeness of submission
• Other required approvals
• Recommendation
• Submit as soon as all protocol materials are
  available
• Allow 60 days for renewal of full Board protocol

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Review Process Overview

• Logged in
• (Chair queue)
• Chair reviews or distributes

Distributed then Assigned to Meeting
Exempt or expedited
Full Board
Approve
Approve
Return
Pending
Return
Defer
Disapprove
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Criteria for IRB approval of research 45 CFR
46.111 and 21 CFR 56.111

• (a) In order to approve research covered by this
  policy the IRB shall determine that all of the
  following requirements are satisfied

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1) Risks to subjects are minimized (i) by
using procedures which are consistent with sound
research design and which do not unnecessarily
expose subjects to risk, and (ii) whenever
appropriate, by using procedures already being
performed on the subjects for diagnostic or
treatment purposes.

• Criteria for IRB approval of research

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• New protocol considerations
• Research versus clinical care?
• Design features?
• Types of risk physical, social, psychological,
  economic?
• Risks reduced or managed to the extent possible?
• Safeguards incorporated?
• Potential for statistical validity demonstrated?
• Investigators competent?
• Inclusion and exclusion criteria clearly defined?
• Renewal
• Is it the determination of the IRB, based on an
  evaluation of reported enrollment, adverse
  events, and unanticipated problems, that risks
  are still minimized?

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• Modifications
• Risks still minimized?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Change to protocol and/or consent form needed to
  reflect new risks?

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• Modifications
• If another subject group is being added, or
  inclusion/exclusion criteria is being revised,
  does subject selection remain equitable?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Change to protocol and/or consent form needed,
  i.e., is risk to a particular group increased
  such that inclusion/exclusion criteria need to be
  revised or consent documents need to be updated?

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RASCAL entry Research Page
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RASCAL entry Study Description attachments

• 1. Study Purpose and Rationale.2. Study Design
  and Statistical Procedures.3. Study
  Procedures4. Study Drugs or Devices5. Study
  Questionnaires6. Study Subjects.7.
  Recruitment8. Confidentiality of Study Data9.
  Potential Risks10. Potential Benefits11.
  Alternatives

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Criteria for IRB approval of research(2)
Risks to subjects are reasonable in relation to
anticipated benefits, if any, to subjects, and
the importance of the knowledge that may
reasonably be expected to result. In evaluating
risks and benefits, the IRB should consider only
those risks and benefits that may result from the
research (as distinguished from risks and
benefits of therapies subjects would receive even
if not participating in the research). The IRB
should not consider possible long-range effects
of applying knowledge gained in the research (for
example, the possible effects of the research on
public policy) as among those research risks that
fall within the purview of its responsibility.
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• New protocol considerations
• Acceptable risk/benefit ratio?
• Ethically acceptable to expose participants to
  risk of harm?
• Available alternatives?
• Renewals
• Is it the determination of the IRB that risks are
  still reasonable in relation to anticipated
  benefits?
• Have any subjects been seriously harmed?
• Should any new information be provided to
  subjects?

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• Modifications
• Risks still reasonable in relation to anticipated
  benefits?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Change to protocol needed to ensure that
  risk/benefit ratio is still acceptable?
• Change to consent process needed to notify
  participants of new risks?

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RASCAL entry Study Description attachments

• 1. Study Purpose and Rationale.2. Study Design
  and Statistical Procedures.3. Study
  Procedures4. Study Drugs or Devices5. Study
  Questionnaires6. Study Subjects.7.
  Recruitment8. Confidentiality of Study Data9.
  Potential Risks10. Potential Benefits11.
  Alternatives

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RASCAL tip 11 Elements

• Ensure that all 11 elements of a research
  protocol are addressed in the Study Description
  and/or attached protocol
• Study Description may be the only protocol or
  serve as an overview of a sponsors protocol
• Avoid See attached protocol as the Board
  members will receive the Study Description but
  not attached protocols.

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Criteria for IRB approval of research (3)
Selection of subjects is equitable. In making
this assessment the IRB should take into account
the purposes of the research and the setting in
which the research will be conducted and should
be particularly cognizant of the special problems
of research involving vulnerable populations,
such as children, prisoners, pregnant women,
mentally disabled persons, or economically or
educationally disadvantaged persons.
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• New protocol considerations
• Easy availability, compromised position, or
  susceptibility to manipulation a factor?
• If potential benefit, particularly for conditions
  with no effective treatment, are recruitment
  methods and enrollment criteria objective?
• Are ethnic groups neither under- or
  over-represented?
• Are women and children included where
  appropriate?
• Renewals
• Has the actual selection/enrollment of subjects
  represented an equitable distribution of the
  benefits and burdens of the research (versus the
  anticipated study population)?

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RASCAL entry Subjects Page
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RASCAL entry Subjects Page
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RASCAL tip Subject Selection

• Select Special Populations options thoughtfully
• Understand why/when vulnerability exists
• Justify inclusion of vulnerable groups
• Consider and include additional protections, or
  exclude group, as appropriate
• Select Recruitment options accurately
• Text or documentation must be included in
  submission

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Criteria for IRB approval of research (4)
Informed consent will be sought from each
prospective subject or the subject's legally
authorized representative, in accordance with,
and to the extent required by 45 CFR 46.116 or 21
CFR 50.
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• New protocol considerations
• Are procedures for an ongoing process described?
• When and by whom will consent be obtained?
• How will competency be addressed?
• Is surrogate consent proposed, and if so, is it
  acceptable?
• Is a waiver of consent requested, and if so, is
  justification provided?
• Not permitted under most circumstances by FDA.
• Renewals
• Has consent been obtained from enrolled subjects?
• Is the consent process adequate or are changes
  required (to the process or the form/forms)
  before additional subjects may be enrolled?
• Is there new information that should be, but has
  not yet been, conveyed to enrolled subjects so
  that they may make an informed choice about
  continuing their participation?

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• Modifications
• Does the consent form need to be revised to
  reflect change(s) proposed in the modification?
• Do enrolled subjects need to be advised of the
  proposed change, e.g., if there are new
  procedures?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Is there new information that may affect enrolled
  or prospective subjects willingness to enroll or
  continue participation, and should be
  incorporated into the consent process/form?

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Basic elements of informed consent

• (1) 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 the procedures to
  be followed, and identification of any procedures
  which are experimental
• (2) a description of any reasonably foreseeable
  risks or discomforts to the subject
• (3) a description of any benefits to the subject
  or to others which may reasonably be expected
  from the research
• (4) a disclosure of appropriate alternative
  procedures or courses of treatment, if any, that
  might be advantageous to the subject
• (5) a statement describing the extent, if any, to
  which confidentiality of records identifying the
  subject will be maintained

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Basic elements of informed consent (2)

• (6) for research involving more than minimal
  risk, an explanation as to whether any
  compensation and an explanation as to whether any
  medical treatments are available if injury occurs
  and, if so, what they consist of, or where
  further information may be obtained
• (7) an explanation of whom to contact for answers
  to pertinent questions about the research and
  research subjects' rights, and whom to contact in
  the event of a research-related injury to the
  subject and
• (8) a statement that participation is voluntary,
  refusal to participate will involve no penalty or
  loss of benefits to which the subject is
  otherwise entitled, and the subject may
  discontinue participation at any time without
  penalty or loss of benefits to which the subject
  is otherwise entitled.

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Additional elements of informed consent

• (1) a statement that the particular treatment or
  procedure may involve risks to the subject (or to
  the embryo or fetus, if the subject is or may
  become pregnant) which are currently
  unforeseeable
• (2) anticipated circumstances under which the
  subject's participation may be terminated by the
  investigator without regard to the subject's
  consent
• (3) any additional costs to the subject that may
  result from participation in the research
• (4) the consequences of a subject's decision to
  withdraw from the research and procedures for
  orderly termination of participation by the
  subject
• (5) A statement that significant new findings
  developed during the course of the research which
  may relate to the subject's willingness to
  continue participation will be provided to the
  subject and
• (6) the approximate number of subjects involved
  in the study.

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RASCAL entry Consent Form Builder
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RASCAL tip Select Layout Review Form
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Waiver criteria 45 CFR 46.116(d)

• (1) the research involves no more than minimal
  risk to the subjects
• (2) the waiver or alteration will not adversely
  affect the rights and welfare of the subjects
• (3) the research could not practicably be carried
  out without the waiver or alteration and
• (4) whenever appropriate, the subjects will be
  provided with additional pertinent information
  after participation.

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Waiver criteria 45 CFR 46.116(c)

• (1) the research or demonstration project is to
  be conducted by or subject to the approval of
  state or local government officials and is
  designed to study, evaluate, or otherwise
  examine (i) public benefit or service programs
  (ii) procedures for obtaining benefits or
  services under those programs (iii) possible
  changes in or alternatives to those programs or
  procedures or (iv) possible changes in methods
  or levels of payment for benefits or services
  under those programs and
• (2) the research could not practicably be carried
  out without the waiver or alteration.

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RASCAL entry Subjects Page
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Criteria for IRB approval of research

• (5) Informed consent will be appropriately
  documented, in accordance with, and to the extent
  required by 45 CFR 46 46.117 or 21 CFR 50.27.

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• New protocol considerations
• Is use of a written consent document proposed?
• Does the consent document contain required
  elements, exclude exculpatory language, and
  include optional elements where appropriate?
• Is waiver of written documentation of consent
  requested, and if so, is justification provided?
• Will a copy of the form be provided to subjects?
• If verbal consent will be obtained, are
  appropriate procedures proposed?
• Renewals
• Has consent been appropriately documented for
  enrolled subjects?
• Have subject complaints about the consent process
  been received?

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Waiver of written documentation criteria 45 CFR
46.117(c)

• (1) The only record linking the subject and the
  research would be the consent document and the
  principal risk would be potential harm resulting
  from a breach of confidentiality. Each subject
  will be asked whether the subject wants
  documentation linking the subject with the
  research, and the subject's wishes will govern
  or
• (2) The research presents no more than minimal
  risk of harm to subjects and involves no
  procedures for which written consent is normally
  required outside of the research context.

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Criteria for IRB approval of research

• (6) When appropriate, the research plan makes
  adequate provision for monitoring the data
  collected to ensure the safety of subjects.

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• New protocol considerations
• Is a data and safety monitoring plan needed?
• Are proposed data and safety monitoring
  procedures adequate?
• Will the consent process be monitored?
• Renewals
• Has the IRB been informed of any unforeseen
  problems or accidents that may have occurred?
• Do reports of adverse events and monitoring
  bodies reflect that the data are being adequately
  monitored?
• Should the IRB request that progress reports be
  submitted at regular intervals, more often than
  annually?

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• Modifications
• Does the modification revise procedures in such a
  way that the data and safety monitoring plan, or
  other oversight of the study, needs to be
  revised?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Is more frequent or different monitoring needed
  as a result of the unanticipated problem?

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RASCAL entry Study Description attachments

• 1. Study Purpose and Rationale.2. Study Design
  and Statistical Procedures.3. Study
  Procedures4. Study Drugs or Devices5. Study
  Questionnaires6. Study Subjects.7.
  Recruitment8. Confidentiality of Study Data9.
  Potential Risks10. Potential Benefits11.
  Alternatives

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Criteria for IRB approval of research

• (7) When appropriate, there are adequate
  provisions to protect the privacy of subjects and
  to maintain the confidentiality of data.

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• New protocol considerations
• In what manner will data be gathered and
  maintained (anonymously, de-identified, coded,
  identifiable)?
• Are procedures for collecting and storing
  identifiable data adequate to reduce risk of
  breach of confidentiality?
• If data will be transmitted to another site, are
  procedures appropriate?
• Does the consent document adequately reflect data
  confidentiality issues and potential breaches?
• Are research personnel trained in privacy
  practices?
• Renewals
• Have there been complaints from subjects, or
  reports of unanticipated problems related to
  privacy and confidentiality?

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• Modifications
• Is more sensitive information being collected,
  such that the measures in place to protect
  confidentiality need to be enhanced?
• Reports of Unanticipated Problems
• Unanticipated, related, and suggests increase in
  risk?
• Has a breach of confidentiality occurred, which
  requires reassessment of plans to protect
  confidential data?

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RASCAL entry Study Description

• 1. Study Purpose and Rationale.2. Study Design
  and Statistical Procedures.3. Study
  Procedures4. Study Drugs or Devices5. Study
  Questionnaires6. Study Subjects.7.
  Recruitment8. Confidentiality of Study Data9.
  Potential Risks10. Potential Benefits11.
  Alternatives

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IRB 101Vulnerable Populations
Columbia University Medical Center IRB 2008-2009
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Criteria for IRB approval of research 45 CFR
46.111 and 21 CFR 56.111

• When some or all of the subjects are likely
  to be vulnerable to coercion or undue influence,
  
• such as children, prisoners, pregnant women,
  mentally disabled persons, or economically or
  educationally disadvantaged persons,
• additional safeguards have been included in
  the study to protect the rights and welfare of
  these subjects.

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• New protocols considerations
• Is information included for the required
  determinations of Subparts B (pregnant women,
  fetuses), C (prisoners), and D (children and
  minors) to be made?
• Do consent processes adequately address the needs
  of vulnerable subjects, e.g., translations,
  legally authorized representatives?
• How will competency to provide consent be
  determined?
• Are procedures in place to address loss of
  cognitive ability during the trial?
• Renewals
• Are the determinations required by the Subparts
  still acceptable?
• Should competency be reassessed?

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Subpart B Pregnant Women Human Fetuses
(46.204) Assessment of risks made by the IRB

• Where scientifically appropriate, preclinical
  studies, including studies on pregnant animals,
  and clinical studies, including studies on
  non-pregnant women, have been conducted and
  provide data for assessing potential risks to
  pregnant women and fetuses.
• The risk to the fetus is caused solely by
  interventions or procedures that hold out the
  prospect of direct benefit for the woman or the
  fetus or, if there is no such prospect of
  benefit, the risk to the fetus is not greater
  than minimal and the purpose of the research is
  the development of important biomedical knowledge
  which cannot be obtained by any other means.
• Any risk is the least possible for achieving the
  objectives of the research.

86
In English

• If the study involves greater than minimal risk
  to the fetus, there must be a prospect for direct
  benefit for the mother or the fetus. There must
  also be preclinical studies assessing the
  potential risk, and the study must be designed to
  minimize risk to the extent possible.
• If the study involves no benefit to the mother or
  fetus, the risk to the fetus must be minimal and
  the least possible to achieve the objectives of
  the research. Further, the research must be
  designed to develop important biomedical
  knowledge that cannot be obtained any other way.

87
Consent Requirements for Research
Involving Pregnant Women Human Fetuses

• If the research holds out the prospect of direct
  benefit to the pregnant woman, the prospect of a
  direct benefit both to the pregnant woman and the
  fetus, or no prospect of benefit for the woman
  nor the fetus and the risk to the fetus is
  minimal, consent of ONLY the pregnant woman is
  required.
• If the research holds out the prospect of direct
  benefit to the fetus only, then the consent of
  the pregnant woman AND the father must be
  obtained. The father's consent need not be
  obtained if he is unable to consent because of
  unavailability, incompetence, or temporary
  incapacity or the pregnancy resulted from rape or
  incest.
• Each individual providing consent is fully
  informed regarding the reasonably foreseeable
  impact of the research on the fetus or neonate.

88
Additional Requirements for Research Involving
Pregnant Women and Human Fetuses

• For children as defined who are pregnant, assent
  and permission are obtained in accord with the
  provisions of subpart D.
• No inducements, monetary or otherwise, will be
  offered to terminate a pregnancy.
• Individuals engaged in the research will have no
  part in any decisions as to the timing, method,
  or procedures used to terminate a pregnancy.
• Individuals engaged in the research will have no
  part in determining the viability of a neonate.

89
Research Involving Neonates - Non-viable or of
Uncertain Viability (46.205)Research involving,
after delivery, the placenta, the dead fetus or
fetal material (46.206)

• Additional considerations apply and
  determinations must be made.
• Consult with the IRB before submitting for
  tailored guidance.

90
Research Not Otherwise Approvable (46.207)

• The IRB finds that the research presents a
  reasonable opportunity to further the
  understanding, prevention, or alleviation of a
  serious problem affecting the health or welfare
  of pregnant women, fetuses or neonates and
• The Secretary, after consultation with a panel of
  experts in pertinent disciplines and following
  opportunity for public review and comment,
  including a public meeting announced in the
  FEDERAL REGISTER, agrees with the above
  determination or disagrees with the IRBs
  conclusions and finds the research approvable
  according to current regulations

91
Subpart C Prisoners Relevant Definitions

• Prisoner - any individual involuntarily confined
  or detained in a penal institution, including
• individuals sentenced to such an institution
  under a criminal or civil statute
• individuals detained in other facilities by
  virtue of statutes or commitment procedures which
  provide alternatives to criminal prosecution or
  incarceration in a penal institution and
• individuals detained pending arraignment, trial,
  or sentencing.
• In other words..
• A resident of a drug rehabilitation center who is
  in treatment as an alternative to jail would
  qualify as a prisoner.
• Children in juvenile detention halls qualify as
  prisoners.
• If subjects enroll in the research and are then
  incarcerated, subpart C applies.

92
Subpart C Prisoners Relevant Definitions

• Minimal risk" is the probability and magnitude
  of physical or psychological harm that is
  normally encountered in the daily lives, or in
  the routine medical, dental, or psychological
  examination of healthy persons.
• Minimal risk means that the 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.

93
Prisoners IRB Review

• Prisoner representative must be present.
• The majority of the Board must have no
  association with the prison.
• For research funded by DHHS, the institution must
  certify to the Secretary that the required
  findings under subpart C have been made. The
  research cannot commence until OHRP has approved
  the research.

94
Prisoners Approvable Categories of Research

• Study of the possible causes, effects, and
  processes of incarceration, and of criminal
  behavior, provided that the study presents no
  more than minimal risk and no more than
  inconvenience to the subjects.
• Study of prisons as institutional structures or
  of prisoners as incarcerated persons, provided
  that the study presents no more than minimal risk
  and no more than inconvenience to the subjects.

95
Prisoners Approvable Categories of Research

• Research on conditions particularly affecting
  prisoners as a class
• (for example, vaccine trials and other research
  on hepatitis which is much more prevalent in
  prisons than elsewhere and research on social
  and psychological problems such as alcoholism,
  drug addiction, and sexual assaults)
• provided that the study may proceed only after
  the Secretary has consulted with appropriate
  experts including experts in penology, medicine,
  and ethics, and published notice, in the FEDERAL
  REGISTER, of his intent to approve such research.

96
Prisoners Approvable Categories of Research

• Research on practices, both innovative and
  accepted, which have the intent and reasonable
  probability of improving the health or well-being
  of the subject.
• In cases in which those studies require the
  assignment of prisoners in a manner consistent
  with protocols approved by the IRB to control
  groups which may not benefit from the research,
  the study may proceed only after the Secretary
  has consulted with appropriate experts, including
  experts in penology, medicine, and ethics, and
  published notice, in the FEDERAL REGISTER, of the
  intent to approve such research.

97
Prisoners Required findings by the IRB

• The research under review represents one of the
  previously mentioned categories of research.
• Any possible advantages accruing to the prisoner
  through his or her participation in the research,
  
• when compared to the general living conditions,
  medical care, quality of food, amenities and
  opportunity for earnings in the prison,
• are not of such a magnitude that his or her
  ability to weigh the risks of the research
  against the value of such advantages in the
  limited choice environment of the prison is
  impaired.

98
Prisoners Required findings by the IRB

• The risks involved in the research are
  commensurate with risks that would be accepted by
  non-prisoner volunteers.
• Procedures for the selection of subjects within
  the prison are fair to all prisoners and immune
  from arbitrary intervention by prison authorities
  or prisoners.
• Unless the principal investigator provides to
  the Board justification in writing for following
  some other procedures, control subjects must be
  selected randomly from the group of available
  prisoners who meet the characteristics needed for
  that particular research project.

99
Prisoners Required findings by the IRB

• The information is presented in language which is
  understandable to the subject population.
• Adequate assurance exists that parole boards will
  not take into account a prisoner's participation
  in the research in making decisions regarding
  parole, and each prisoner is clearly informed in
  advance that participation in the research will
  have no effect on his or her parole.

100
Prisoners Required findings by the IRB

• Where the Board finds there may be a need for
  follow-up examination or care of participants
  after the end of their participation, adequate
  provision has been made for such examination or
  care, taking into account the varying lengths of
  individual prisoners' sentences, and for
  informing participants of this fact.

101
Children Subpart D of 45 CFR 46 and 21 CFR 50

• Risk Determination
• Parental Permission Requirements
• Assent Requirements
• Wards?

102
Research with Children

• When children or minors will be subjects, the IRB
  must determine and provide the basis for their
  determination of
• 1. Category of research
• 46.404/50.51 Research not involving greater
  than minimal risk.
• 46.405 /50.52 Research involving greater than
  minimal risk but presenting the prospect of
  direct benefit to the individual subjects.
• 46.406 /50.53 Research involving greater than
  minimal risk and no prospect of direct benefit
  to individual subjects, but likely to yield
  generalizable knowledge about the subject's
  disorder or condition.
• 46.407 /50.54 Research not otherwise
  approvable which presents an opportunity to
  understand, prevent, or alleviate a serious
  problem affecting the health or welfare of
  children.

103
Research with Children (2)

• 2. Requirements for parental permission
• One or both parents may provide permission for
  research in categories 46.404/50.51 and
  46.405/50.52.
• Both parents must provide permission for
  research in categories 46.406/50.53 and
  46.407/50.54.
• 3. Whether assent should be obtained
• Considering age and maturity of the children
• Evaluating whether effective alternatives are
  available
• 4. Whether wards will be involved
• An advocate must be provided for each ward that
  is enrolled

104
Subpart D Minimal Risk Research Section 404
Research

• Risk Determination
• In order for a study to be categorized under
  section 404(DHHS) or section 51(FDA), the
  research has to pose minimal risk to the children
  involved.
• The regulators define minimal risk as the
  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.
• The CUMC IRBs interpret this to apply to the
  daily lives of normal children.
• The permission of one parent must be obtained
  unless consent is waived by the IRB.
• The assent of the child is obtained or the IRB
  has waived the assent requirements.

105
Subpart D Research presenting Greater than
Minimal Risk with potential for Direct Benefit
Section 405 Research

• Risk Determination
• The risk is justified by the anticipated benefit
  to the subjects
• The relation of the anticipated benefit to the
  risk is at least as favorable to the subjects as
  that presented by available alternative
  approaches.
• Adequate provisions are made for soliciting the
  assent of the children or the IRB has waived the
  assent requirements.
• Permission of one parent is obtained unless
  waived by the IRB.

106
Subpart D Research presenting Greater than
Minimal Risk with No anticipated Direct Benefit
Section 406 Research

• Risk Determination
• The risk represents a minor increase over minimal
  risk
• The intervention or procedure presents
  experiences to subjects that are reasonably
  commensurate with those inherent in their actual
  or expected medical, dental, psychological,
  social, or educational situations
• The intervention or procedure is likely to yield
  generalizable knowledge about the subjects'
  disorder or condition which is of vital
  importance for the understanding or amelioration
  of the subjects' disorder or condition
• Adequate provisions are made for soliciting the
  assent of the children.
• Permission of BOTH parents is obtained unless one
  parent is deceased, unknown, incompetent, or not
  reasonably available, or when only one parent has
  legal responsibility for the care and custody of
  the child.
• WARDS

107
Subpart D Research Not Approvable according to
Sections 404, 405 or 406 (FDA 51, 52, or
53) Section 407 Research

• Risk Determination
• The research presents a reasonable opportunity to
  further the understanding, prevention, or
  alleviation of a serious problem affecting the
  health or welfare of children and
• Referral to DHHS for secretarial consultation
• The Secretary, after consultation with a panel of
  experts in pertinent disciplines (for example
  science, medicine, education, ethics, law) and
  following opportunity for public review and
  comment, agrees with the above determination or
  disagrees with the IRBs conclusions and finds
  the research approvable according to current
  regulations.
• Adequate provisions are made for soliciting the
  assent of the children.
• Permission of BOTH parents is obtained unless one
  parent is deceased, unknown, incompetent, or not
  reasonably available, or when only one parent has
  legal responsibility for the care and custody of
  the child.

108
Inclusion of Wards in Research

• If wards are to be enrolled in sections 406 or
  407 research
• Detailed information about the proposed informed
  consent process as well as detailed information
  regarding the identity and authority of any
  individual who will provide consent must be
  provided to the IRB.
• The research must be
• Related to their status as wards or
• Conducted in schools, camps, hospitals, etc. in
  which the majority of the subjects involved in
  the research are not wards.
• An advocate for each ward must be appointed to
  act on behalf of the child. The advocate must
  have the background and experience to act in the
  best interest of the child throughout the
  research and cannot be associated in any way with
  the research, the investigator or the guardian
  institution.
• In NY, the Administration for Childrens Services
  (ACS) must agree to the inclusion of wards in the
  research and permission must be obtained from the
  person designated by ACS for each ward who is
  enrolled.

109
Parental Permission Waiver Options

• Parental permission can be waived
• If the research a) poses no more than minimal
  risk b) does not negatively impact upon the
  rights and/or welfare of the subjects c)
  renders it impracticable to obtain consent and
  d) provides for informing subjects of any
  additional pertinent information upon completion
  of the research.
• If the research protocol is designed for
  conditions or for a subject population for which
  parental or guardian permission is not a
  reasonable requirement to protect the subjects
  (for example, neglected or abused children), and
  an appropriate mechanism for protecting the
  children who will participate as subjects in the
  research is substituted.

110
Assent Requirements

• In general
• Applies to children 7 and older who are capable
  of assenting
• When determining capability, ages, maturity level
  and psychological state must be taken into
  account.
• Ages 7 through 11 Written or verbal
• Ages 12 through 17 Written
• A separate age appropriate assent can be provided
  or the child can co-sign the parental consent.

111
Exceptions from Assent Requirements

• Waiver of assent is granted by the IRB in
  accordance with 46.116.
• The intervention or procedure involved in the
  research holds out a prospect of direct benefit
  that is important to the health or well-being of
  the children and is available only in the context
  of the research.

112
IRB Submissions

• If your research involves vulnerable subjects
• RASCAL questions
• Ensure your protocol submission includes adequate
  information for the IRB to make the
  determinations required as outlined in the
  previous slides.
• As always, call the IRB office (contact
  information for individual staff on website) with
  any questions.

113
References

• DHHS OHRP - Subpart B (Pregnant women, human
  fetuses and neonates) http//www.hhs.gov/ohrp/huma
  nsubjects/guidance/45cfr46.htmsubpartb
• DHHS OHRP - Subpart C (Prisoners)
  http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  fr46.htmsubpartc
• DHHS OHRP - Subpart D (Children)
  http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  fr46.htmsubpartd
• FDA - Subpart D (Children) http//www.accessdata.f
  da.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
  Part50showFR1subpartNode211.0.1.1.19.4

114
Research with Other Vulnerable Individuals

• When inclusion of subjects with a specific
  vulnerability is proposed
• Justify selection of this group
• Include plans for additional protections
  relative to vulnerability
• If status is variable, include plans for
  periodic assessment
• Clearly describe any special consent procedures
• Provide local or expert documentation, as
  applicable.

115
IRB Actions

• Approve
• Require modifications
• defer to Chair as pending or
• defer to Board as returned
• Defer
• Suspend enrollment
• Suspend the study
• Terminate
• Reportable to OHRP and/or FDA, as applicable,
  sponsor, subjects, institution

116
An IRB may also

• Impose additional precautions or reassess special
  requirements previously imposed
• e.g., the IRB has the authority to observe or
  have a third party observe, the consent process
  as well as the research itself 45 CFR 46.109(e)
  and 21 CFR 56.109(f)

117
Summary

• IRB Review Criteria
• Tips for Submitting
• RASCAL

118
IRB 101Case Study
Columbia University Medical Center IRB 2008-2009
119
Initial submission

• Industry-sponsored, Phase III, double-blind,
  randomized clinical trial to study the effects of
  Drug A on Type 2 diabetes mellitus.
• The subjects will be patients already in the care
  of either Dr. PI or Dr. Co-I, or will be
  recruited from patients in the care of other
  endocrinologists at the medical center.
• It is anticipated that all subjects will be
  English-speaking.
• Subject compensation Subjects will be paid
  1,500 for the entire study. Payment will be
  received at the end of the entire study after all
  study procedures have been completed.
• In each phase of the study, subjects will receive
  a radioactive isotope to detect a newly
  identified protein that has been shown to affect
  insulin production in animal studies.
• Six out of seven members of the study team have
  completed required GCP and HIPAA training via the
  RASCAL online testing center.
• Level of review?
• IRB considerations?

120
First modification

• Revised consent form based on a request from the
  Radiation Drug Research Committee that a
  statement required by the FDA to collect an
  additional blood sample to assess a new toxicity
  that was found in a phase II study and that is
  possibly associated with the isotope' regarding
  the limits for radiation exposure be included.
  This change was made in the consent form under
  the Procedures and "Risks" sections.
• Level of review?
• IRB considerations?

121
Second modification

• 1) Revision of the blood pressure inclusion
  criterion to accept patients with blood pressure
  lt 140/90 mm Hg on blood pressure lowering
  therapy. (The current IRB-approved protocol
  requires a blood pressure lt 130/90 on therapy.)
• 2) Submission of a recruitment flyer for IRB
  approval. The flyer will be posted at sites
  accessible to potential study subjects and will
  be used to expedite and expand patient
  recruitment.
• Level of review?
• IRB considerations?

122
Third modification

• 1) Spanish patient recruitment flyer.
• 2) Consent form translated in Spanish.
• Each of the Spanish documents has been translated
  from its approved English counterpart by the
  investigator.
• Level of review?
• IRB considerations?

123
Fourth modification

• 1) Addition of two co-investigators to the study
  team.