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

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)

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)

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.

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).

 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. Overview of BSD/UCH IRB: A Period of Growth

 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. Overview of BSD/UCH IRB: Supplemental Form C

9-7-04: Protocol 13472A submitted to the IRB : 1 st IRB Pre-review generated: Administrator communicates to PI that submitted Form C indicates study involves > minimal risk with direct benefit to children with disorders of puberty and inquires re: healthy children. U of C Review of 13472A: Timeline of Events Leading to 407 Review

Oct. ’04: Further communications between PI and administrative staff indicate PI’s belief that study represents only minimal risk to healthy subjects, but feels compelled by IRB to designate > minimal risk. U of C Review of 13472A: Timeline of Events Leading to 407 Review

: 1 st 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). U of C Review of 13472A: Timeline of Events Leading to 407 Review

:Pending-Conditional (PC) letter issued :Response to PC letter received :PI informs IRB that GCRC has requested changes to the protocol, thus, necessitating review again by the Committee :2 nd IRB Meeting; full approval granted (healthy subjects not to be enrolled)

U of C Review of 13472A: Timeline of Events Leading to 407 Review :Protocol forwarded to Associate Vice-President of Research for 407 review consideration : 1 st continuning review completed : FDA Pediatric Ethics Subcommittee meets

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

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;

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.

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)

Shah et al. JAMA 2004; 291(4):476-82

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.

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.

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 Overview of BSD/UCH IRB