E BC R Overview of FDA Regulatory Issues Darin J. Weber, Ph.D. Office of Cellular, Tissue and Gene Therapies

E BC R Topics How We Got Here – A Timeline Goals of This Meeting Roles of Federal Agencies Introduction to FDA Questions for Discussion Speakers to Set the Stage for Discussion of FDA Questions

E BC R 28 islet INDs since 2000 How We Got Here – Timeline FDA Islet BRMAC 3/2000 Edmonton Protocol in NEJM 7/2000 FDA Letter to Transplant Centers 9/ islet INDs 10/2003 JDRF NIAID NCRR NIDDK Major Funding Sources

E BC R Goals of This Meeting To discuss FDA expectations for manufacturing data and clinical evidence to be provided in a BLA for approval of allogeneic islets as a treatment for Type 1 Diabetes Mellitus. To obtain advice and perspectives from members of the BRMAC about data to be provided in a BLA for allogeneic pancreatic islets To provide a public forum to obtain input from stakeholders interested in this therapy.

Roles of Federal Agencies Health Resource Services Agency (HRSA) Organ procurement & allocation National Institutes of Health (NIH) Funding of basic research and clinical research uses of pancreatic islets Food and Drug Administration (FDA) Regulatory oversight of clinical uses of pancreatic islets Centers for Medicare and Medicaid (CMS) Reimbursement issues

E BC R Islets as a Licensed Product Intro. to Manufacturing Considerations Must have a well established islet preparation process & documented record of product manufacturing consistency Islets prepared in manufacturing facility meeting cGMP requirements Comply with lot release testing requirements under 21 CFR 610 “General Biological Products Standards”

E BC R FDA CMC Question #1 Please discuss the use of manufacturing experience data as a basis for developing pre-defined acceptance criteria for source organs used to prepare islets. Dissociate Lot Release Testing

E BC R Pancreas FDA CMC Question #2 Balancing the need for well controlled manufacturing process with need for manufacturing flexibility: Is it reasonable to expect that criteria or algorithms can be developed, based on data collected during IND studies, to predetermine under what conditions the use of a specific reagent, reagent concentration, or processing method is appropriate? Dissociate Lot Release Testing

E BC R Pancreas FDA CMC Question #3 Assessment of islet potency: –Please discuss any assay or assays that are currently, or could be, performed on the final islet product before patient administration, which may be predictive of the ability of the islets to perform as expected after patient administration. Dissociate Lot Release Testing

E BC R Pancreas FDA CMC Question #4 Comparability of islets prepared with different manufacturing processes: –What should be key measures for demonstrating allogeneic islet product comparability? –Please discuss appropriate analytical assays, bioassays, preclinical studies, and clinical studies that may be required. Dissociate Lot Release Testing

E BC R Islets as a Licensed Product Introduction to Clinical Considerations Approval will be based upon data from domestic (IND) or foreign studies that are: –Well designed, well conducted –Performed by qualified investigators –Conducted in accordance with ethical principles Data must demonstrate safety & efficacy

E BC R FDA Clinical Question #1 Clinical outcome measures –Importance & limitations of: Insulin Independence Hemoglobin A1c, serum c-peptide, mean amplitude of glycemic excursions Acute diabetic complications (hypoglycemic unawareness, hospitalizations, death) Long term diabetic sequelae (nephropathy, neuropathy, etc.) Others

E BC R FDA Clinical Question #2 Clinical development and risk- benefit assessment –Safety data Nature and extent of “long-term” clinical data. –Use of historical control data –Use of clinical data from small subsets of subjects with type 1 DM –Baseline criteria to consider Age, extent and nature of diabetic complications, etc

E BC R Format for this Meeting Day 1: Thursday October 9 th CMC Issues HRSA and FDA Presentations Guest Presentations Open Public Hearing Discussion of CMC Questions Day 2: Friday October 10 th Clinical Issues HRSA and FDA Presentations Guest Presentations Open Public Hearing Discussion of Clinical Questions Thursday October 9 th Update on Research Programs FDA Presentations Closed Session

E BC R Day 1: Speakers (CMC) Overview of Organ Procurement in the U.S. - Dr. James Burdick, HRSA Moving from Investigational to Licensed Islet Products Expectations for Facilities & cGMPs –Dr. Nicholas Obiri, FDA Islet Processing and Product Quality Issues - Dr. Keith Wonnacott, FDA

E BC R Day 1: Speakers (CMC) Islet Processing: Evolution and Current Standards –Dr. Camillo Ricordi, University of Miami Current Status of Islet Characterization and Quality –Dr. Bernhard Hering, University of Minnesota

E BC R Day 2: Speakers (Clinical) Update on Clinical Islet Transplantation –Dr. James Shapiro, University of Alberta Pancreas Allocation Issues –Dr. Jim Burdick, HRSA

E BC R Day 2: Speakers (Clinical) Ethical Considerations in Allogeneic Islet Transplantation –Dr. James Childress, University of Virginia Clinical Development of Islet Products –Dr. Dwaine Rieves, FDA