1. Animal Models for Porcine Xenotransplantation Products Intended to Treat Type 1 Diabetes or Acute Liver Failure CTGTAC #47 May 14, 2009

2. Xenotransplantation Any procedure that involves the transplantation, implantation, or infusion into humans of: 1) live cells, tissues, or organs from a nonhuman animal source or 2) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs. DHHS (2001). PHS Guideline on Infectious Disease Issues in Xenotransplantation FDA (2003). Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans

3. FDA Activities in the Xenotransplantation Field Regulated under Section 351 of the Public Health Service (PHS) Act (42.U.S.C.262) and the Federal Food, Drug and Cosmetic Act (21 U.S.C. 321) Regulated under Section 351 of the Public Health Service (PHS) Act (42.U.S.C.262) and the Federal Food, Drug and Cosmetic Act (21 U.S.C. 321) Collaboration among PHS Agencies (i.e, CDC, BARDA) within the Dept. of Health and Human Services (DHHS) Collaboration among PHS Agencies (i.e, CDC, BARDA) within the Dept. of Health and Human Services (DHHS) Published guidances Published guidances Public advisory committee meetings Public advisory committee meetings FDA/CBER Biological Response Modifiers Advisory Committee (BRMAC) Xenotransplantation Subcommittee FDA/CBER Biological Response Modifiers Advisory Committee (BRMAC) Xenotransplantation Subcommittee [DHHS] Secretary’s Advisory Committee on Xenotransplantation (SACX) [DHHS] Secretary’s Advisory Committee on Xenotransplantation (SACX) International participation – sharing of information and collaboration International participation – sharing of information and collaboration WHO WHO OECD OECD EMEA EMEA

4. Use of Porcine Xenotransplantation Products in Humans Potential to replace failed organ, glandular, or tissue function for conditions in which human-derived organs, cells, or tissues are in limited supply Potential to replace failed organ, glandular, or tissue function for conditions in which human-derived organs, cells, or tissues are in limited supply Acute Liver Failure (ALF) & Type 1 Diabetes (T1D) - the need for cellular treatment options significantly exceeds the supply of human-derived differentiated cells Acute Liver Failure (ALF) & Type 1 Diabetes (T1D) - the need for cellular treatment options significantly exceeds the supply of human-derived differentiated cells Porcine source animals are plentiful Porcine source animals are plentiful

5. Use of Porcine Xenotransplantation Products in Humans: Potential Risks Transmission of known pathogens Transmission of known pathogens Potential for introducing a new infectious disease into the general population Potential for introducing a new infectious disease into the general population Potential zoonotic risks to personal contacts and healthcare professionals Potential zoonotic risks to personal contacts and healthcare professionals Potential for adverse inflammatory and immunological responses of the host to the product or its secreted proteins Potential for adverse inflammatory and immunological responses of the host to the product or its secreted proteins Potential for rejection of the source animal cells/tissues/organs and any associated adverse effects Potential for rejection of the source animal cells/tissues/organs and any associated adverse effects Risks of using immunosuppressive agents in an attempt to prolong the transplanted graft Risks of using immunosuppressive agents in an attempt to prolong the transplanted graft

6. Safety is Always Primary… One of FDA’s primary objectives in reviewing an application is, in all phases of the investigation, to assure the safety and rights of human subjects One of FDA’s primary objectives in reviewing an application is, in all phases of the investigation, to assure the safety and rights of human subjects How are Preclinical Studies Integrated into the Proposed Clinical Plan? Provide adequate information from pharmacology & toxicology studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, & scope of animal and other tests required varies with the duration & nature of the proposed clinical investigations. Provide adequate information from pharmacology & toxicology studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, & scope of animal and other tests required varies with the duration & nature of the proposed clinical investigations. IND Regulations [21 CFR 312.23 (a)(8)]

7. Goals of Preclinical Evaluation Provide rationale for proposed therapy (potential for benefit) Provide rationale for proposed therapy (potential for benefit) Discern mechanism of action/toxicity Discern mechanism of action/toxicity Preliminary risk/benefit assessment Preliminary risk/benefit assessment Identify “at risk” patient populations Identify “at risk” patient populations Recommend safe starting clinical dose level, dose escalation scheme, and dosing regimen Recommend safe starting clinical dose level, dose escalation scheme, and dosing regimen Identify parameters for clinical monitoring Identify parameters for clinical monitoring

8. To Achieve these Goals… An understanding of the biological actions of the xenotransplantation product following administration in animals that model the intended clinical disease to the extent possible (pathophysiology, metabolically, immunologically) will potentially help to mitigate some of the risks to humans enrolled in clinical trials

9. Discussion Issues: Animal Models of ALF Discuss the limitations and capabilities of available animal models of ALF to evaluate the safety and clinical activity of bioartificial liver assist devices containing porcine cells/tissues as a bridge to spontaneous recovery or liver transplant. Discuss the limitations and capabilities of available animal models of ALF to evaluate the safety and clinical activity of bioartificial liver assist devices containing porcine cells/tissues as a bridge to spontaneous recovery or liver transplant. Ability of model to recapitulate the clinical manifestations/lab abnormalities of ALF Ability of model to recapitulate the clinical manifestations/lab abnormalities of ALF Treatment duration Treatment duration Ability to repeat the treatment Ability to repeat the treatment Study endpoints - what is considered a clinically meaningful effect? Study endpoints - what is considered a clinically meaningful effect? The robustness of the response The robustness of the response

10. Discussion Issues: Animal Models of T1D Discuss the ability of available animal models of T1D to evaluate the safety and clinical activity of porcine islet cell transplantation. The robustness of the model Discuss the ability of available animal models of T1D to evaluate the safety and clinical activity of porcine islet cell transplantation. The robustness of the model Ability of model to recapitulate the immunological and metabolic manifestations of T1D Ability of model to recapitulate the immunological and metabolic manifestations of T1D Treatment duration Treatment duration Need for/ability to re-transplant Need for/ability to re-transplant Study endpoints - what is considered a clinically meaningful effect? How long should the effect persist? Study endpoints - what is considered a clinically meaningful effect? How long should the effect persist? Requirements for specific immunosuppression regimens Requirements for specific immunosuppression regimens

11. We will not: Discuss specific products or proposals Discuss specific products or proposals Discuss animal husbandry issues Discuss animal husbandry issues Discuss product manufacturing issues Discuss product manufacturing issues Discuss genetically engineered source animals* Discuss genetically engineered source animals* Provide definitive assessments of data Provide definitive assessments of data Make definitive policy decisions Make definitive policy decisions *FDA/CVM (2009). Guidance for Industry: Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs at http://www.fda.gov/cvm/Guidance/fguide187.pdfhttp://www.fda.gov/cvm/Guidance/fguide187.pdf

12. Preclinical Issues for Committee Discussion Committee is asked to provide FDA with insights regarding the use of animal models to support the development and regulatory evaluation of xenotransplantation products for the treatment of ALF and T1D Committee is asked to provide FDA with insights regarding the use of animal models to support the development and regulatory evaluation of xenotransplantation products for the treatment of ALF and T1D Discussion will help guide FDA decisions regarding preclinical models in future applications for this product area that may be submitted for review in this product area Discussion will help guide FDA decisions regarding preclinical models in future applications for this product area that may be submitted for review in this product area

13. Guest Presentations Dr. Ira Fox Dr. Ira Fox Director of the Center for Innovative Pediatric Regenerative Therapies; University of Pittsburgh Director of the Center for Innovative Pediatric Regenerative Therapies; University of Pittsburgh 'Animal Models for Evaluation of Porcine Cells/Tissues to Treat Patients with Acute Liver Failure' Dr. Bernhard Hering Dr. Bernhard Hering Scientific Director of the Schulze Diabetes Institute, Dept.of Surgery; University of Minnesota Scientific Director of the Schulze Diabetes Institute, Dept.of Surgery; University of Minnesota 'Animal Models for Evaluation of Porcine Islet Products to Treat Patients with Type 1 Diabetes'