IRB Presentation to the Pediatric Ethics Subcommittee of the FDA regarding

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• IRB Presentation to the Pediatric Ethics
  Subcommittee of the FDA regarding Gonadotropin
  Releasing Hormone (GnRH) Agonist Test in
  Disorders of Puberty
• Marc Garfinkel, M.D.
• Vice Chair, BSD IRB, Committee C
• Assistant Professor of Surgery
• Section of Transplantation
• Director, Islet Cell Program
• University of Chicago

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Objectives

• To provide an overview of the University of
  Chicago Biological Sciences Division/ University
  of Chicago Hospitals Institutional Review Board
  (BSD/UCH IRB)
• Provide an overview of the review process for IRB
  Protocol Gonadotropin Releasing Hormone (GnRH)
  Agonist Test in Disorders of Puberty (UC IRB
  13472A)

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Overview of Human Research Protections at The
University of Chicago/UCHospitals

• 3 Functional areas of IRBs
• Biomedical/Clinical Research (BSD/UCH)
• Social Services/Chapin Hall (School of Social
  Services Administration)
• Social Behavioral Sciences (Humanities, GSB,
  Law)

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Overview of BSD/UCH IRB

• The IRB is charged with the responsibility for
  review, approval and surveillance of all research
  involving human subjects carried out in the BSD
  and the University of Chicago Medical Center.
  This review and surveillance is conducted to
  assure the protection of the rights and welfare
  of all research subjects, including volunteers
  and patients. Occurs regardless of federal
  funding.
• Currently, there are over 2000 active protocols
  involving human subjects at The University of
  Chicago falling under BSD IRB surveillance.
• Of these protocols, approximately 200 involve
  children.

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Overview of BSD/UCH IRB

• 3 Committees (A, B, C) that meet monthly
• IRB Committees are composed of faculty
  scientists, non-scientists, and community
  members. Committee membership is drawn from a
  variety of backgrounds, including Ethics,
  Pediatrics, Cardiology, Cancer, Surgery, Nursing,
  Pharmacy, Teaching, and Law.
• Committees are supported by administrative staff
  (Administrators of Regulatory Compliance).

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Overview of BSD/UCH IRBA Period of Growth

• Approximate doubling of active protocols since
  2000
• Since 2000, the BSD IRB staff have doubled in
  size from 6 to 12 full time staff members
• Since 2001, BSD IRB Committees have tripled from
  1 to 3 Committees that meet separately on a
  monthly basis (Committees A, B C)
• The BSD IRB is currently implementing an
  electronic submission system.

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Overview of BSD/UCH IRBSupplemental Form C

• All protocols involving children as subjects
  require submission of Form C along with Protocol
  Submission Form
• Form asks investigators to identify
• Justification benefits to pediatric subjects (if
  any).
• Risk/benefit assessment (with opportunity to
  characterize research into one of 3 approvable
  categories according to sub-Part D).
• Consent/assent confirmation.

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U of C Review of 13472A Timeline of Events
Leading to 407 Review

• 9-7-04 Protocol 13472A submitted to the IRB
• 9-24-04 1st IRB Pre-review generated
  Administrator communicates to PI that
  submitted Form C indicates study involves gt
  minimal risk with direct benefit to children
  with disorders of puberty and inquires re
  healthy children.

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U of C Review of 13472A Timeline of Events
Leading to 407 Review

• Oct. 04 Further communications between PI
  and administrative staff indicate PIs belief
  that study represents only minimal risk to
  healthy subjects, but feels compelled by IRB to
  designate gt minimal risk.

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U of C Review of 13472A Timeline of Events
Leading to 407 Review

• 11-9-04 1st IRB Meeting receives
  Pending- Conditional approval
• Finds that research involving children with
  prepubertal disorder can be approved under
  45CFR46.405, but classifies research as minor
  increase over minimal risk with no prospect of
  direct benefit for healthy children or their
  disorder (as they have none), thus requiring a
  407 review prior to approval.
• No debate regarding ethical conduct of research
  or opportunity of this study to contribute to
  understanding of condition (serious problem
  affecting the health or welfare of children).

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U of C Review of 13472A Timeline of Events
Leading to 407 Review

• 11-23-04 Pending-Conditional (PC) letter
  issued
• 11-29-04 Response to PC letter received
• 12-20-04 PI informs IRB that GCRC has
  requested changes to the protocol, thus,
  necessitating review again by the Committee.
• 1-11-05 2nd IRB Meeting full approval granted
  (healthy subjects not to be enrolled)

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U of C Review of 13472A Timeline of Events
Leading to 407 Review

• 3-4-05 Protocol forwarded to Associate
  Vice-President of Research for 407 review
  consideration
• 11-8-05 1st continuning review completed
• 11-15-05 FDA Pediatric Ethics Subcommittee
  meets

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Overview of 13472A

• IRB Deliberations regarding Subpart D
• Children with prepubertal disorder
• Study is greater than minimal risk, thus, not
  approvable under 46.404
• Study offers the prospect of direct benefit if it
  provides a better diagnostic characterization of
  their disorder, thus, approved under 46.405

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Overview of 13472A

• IRB Deliberations regarding Subpart D
• Children without prepubertal disorder
• Study deemed greater than minimal risk, thus, not
  approvable under 46.404
• Study does not offer the prospect of direct
  benefit, thus, not approvable under 46.405

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Overview of 13472A

• Children without a disorder/condition, cont.
• Healthy children do not have a disorder or
  condition, thus, not approvable under 46.406
• Thus, can only be approved under 46.407,
  research not otherwise approvable which presents
  an opportunity to understand, prevent, or
  alleviate a serious problem affecting the health
  or welfare of children.

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Overview of 13472A

• IRB Challenges when reviewing 13472A
• Defining Minimal Risk-Application of the
  minimal risk standard is difficult as what
  classifies as minimal risk is not specified and
  has been interpreted differently by different
  people.
• Note the variance in response by IRB chairs when
  asked to classify risk level of various
  procedures in healthy 11- year- olds (Shah et al.
  JAMA 2004 291(4)476-82)

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Shah et al. JAMA 2004 291(4)476-82
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Final Comments

• As evidenced by literature and our own
  deliberations, we, like other institutions,
  struggle with the interpretation and application
  of the regulations regarding pediatric subjects
  enrollment.
• We seek the guidance and appreciate the oversight
  provided by the 407 panel.

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Overview of BSD/UCH IRB

• The University and IRB are sensitive to issues
  regarding vulnerable populations such as
  children.
• As such, a new training program to emphasize
  research with pediatric populations was made
  effective on September 1, 2005.

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Overview of BSD/UCH IRB

• In addition,
• The IRB submission forms have been expanded to
  ensure that the appropriate findings are made in
  regards to Subpart D.
• Application of Subpart D during review of
  protocols emphasized for IRB staff and Committee
  members