Animal Models for Porcine Animal Models for Porcine Xenotransplantation Xenotransplantation

Products Intended to Treat Products Intended to Treat Type 1 Diabetes or Acute Type 1 Diabetes or Acute

Liver FailureLiver Failure

CTGTAC #47CTGTAC #47May 14, 2009May 14, 2009

XenotransplantationXenotransplantationAny procedure that involves the transplantation, Any procedure that involves the transplantation, implantation, or infusion into humans of: 1) live implantation, or infusion into humans of: 1) live cells, tissues, or organs from a nonhuman animal cells, tissues, or organs from a nonhuman animal source or 2) human body fluids, cells, tissues, or source or 2) human body fluids, cells, tissues, or organs that have had organs that have had ex vivoex vivo contact with live contact with live nonhuman animal cells, tissues, or organs. nonhuman animal cells, tissues, or organs.

DHHS (2001). DHHS (2001). PHS Guideline on Infectious Disease Issues in XenotransplantationPHS Guideline on Infectious Disease Issues in Xenotransplantation

FDA (2003). FDA (2003). Guidance for Industry: Source Animal, Product, Preclinical, and Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Clinical Issues Concerning the Use of Xenotransplantation Products in HumansHumans

FDA Activities in the FDA Activities in the Xenotransplantation FieldXenotransplantation Field

Regulated under Section 351 of the Public Health Service Regulated under Section 351 of the Public Health Service (PHS) Act (42.U.S.C.262) and the Federal Food, Drug and (PHS) Act (42.U.S.C.262) and the Federal Food, Drug and Cosmetic Act (21 U.S.C. 321) Cosmetic Act (21 U.S.C. 321)

Collaboration among PHS Agencies (i.e, CDC, BARDA) Collaboration among PHS Agencies (i.e, CDC, BARDA) within the Dept. of Health and Human Services (DHHS)within the Dept. of Health and Human Services (DHHS)

Published guidances Published guidances Public advisory committee meetingsPublic advisory committee meetings

FDA/CBER Biological Response Modifiers Advisory Committee FDA/CBER Biological Response Modifiers Advisory Committee (BRMAC) Xenotransplantation Subcommittee(BRMAC) Xenotransplantation Subcommittee

[DHHS] Secretary’s Advisory Committee on Xenotransplantation [DHHS] Secretary’s Advisory Committee on Xenotransplantation (SACX)(SACX)

International participation – sharing of information and International participation – sharing of information and collaborationcollaboration

WHOWHO OECDOECD EMEAEMEA

Use of Porcine Xenotransplantation Use of Porcine Xenotransplantation Products in HumansProducts in Humans

Potential to replace failed organ, glandular, Potential to replace failed organ, glandular, or tissue function for conditions in which or tissue function for conditions in which human-derived organs, cells, or tissues are human-derived organs, cells, or tissues are in limited supplyin limited supply

Acute Liver Failure (ALF) & Type 1 Acute Liver Failure (ALF) & Type 1 Diabetes (T1D) - the need for cellular Diabetes (T1D) - the need for cellular treatment options significantly exceeds the treatment options significantly exceeds the supply of human-derived differentiated cellssupply of human-derived differentiated cells

Porcine source animals are plentifulPorcine source animals are plentiful

Use of Porcine Xenotransplantation Use of Porcine Xenotransplantation Products in Humans: Potential RisksProducts in Humans: Potential Risks

Transmission of known pathogensTransmission of known pathogens Potential for introducing a new infectious disease into the Potential for introducing a new infectious disease into the

general populationgeneral population Potential zoonotic risks to personal contacts and Potential zoonotic risks to personal contacts and

healthcare professionals healthcare professionals Potential for adverse inflammatory and immunological Potential for adverse inflammatory and immunological

responses of the host to the product or its secreted responses of the host to the product or its secreted proteinsproteins

Potential for rejection of the source animal Potential for rejection of the source animal cells/tissues/organs and any associated adverse effectscells/tissues/organs and any associated adverse effects

Risks of using immunosuppressive agents in an attempt Risks of using immunosuppressive agents in an attempt to prolong the transplanted graftto prolong the transplanted graft

Safety is Always Primary…Safety is Always Primary… One of FDA’s primary objectives in reviewing an One of FDA’s primary objectives in reviewing an

application is, in all phases of the investigation, to application is, in all phases of the investigation, to assure the safety and rights of human subjectsassure the safety and rights of human subjects

How are Preclinical Studies Integrated into the Proposed Clinical Plan?

Provide adequate information from pharmacology Provide adequate information from pharmacology & toxicology studies…on the basis of which the & toxicology studies…on the basis of which the sponsor has concluded that it is reasonably safe sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. to conduct the proposed clinical investigations. The kind, duration, & scope of animal and other The kind, duration, & scope of animal and other tests required varies with the duration & nature of tests required varies with the duration & nature of the proposed clinical investigations.the proposed clinical investigations.

IND Regulations [21 CFR 312.23 (a)(8)]

Goals of Preclinical EvaluationGoals of Preclinical Evaluation

Provide rationale for proposed therapy Provide rationale for proposed therapy (potential for benefit)(potential for benefit)

Discern mechanism of action/toxicityDiscern mechanism of action/toxicityPreliminary risk/benefit assessmentPreliminary risk/benefit assessment Identify “at risk” patient populationsIdentify “at risk” patient populationsRecommend safe starting clinical dose Recommend safe starting clinical dose

level, dose escalation scheme, and dosing level, dose escalation scheme, and dosing regimenregimen

Identify parameters for clinical monitoringIdentify parameters for clinical monitoring

To Achieve these Goals…To Achieve these Goals…

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

Discussion Issues:Discussion Issues: Animal Models of ALFAnimal Models of ALF

Discuss the limitations and capabilities of Discuss the limitations and capabilities of available animal models of ALF to evaluate the available animal models of ALF to evaluate the safety and clinical activity of bioartificial liver safety and clinical activity of bioartificial liver assist devices containing porcine cells/tissues as assist devices containing porcine cells/tissues as a bridge to spontaneous recovery or liver a bridge to spontaneous recovery or liver transplant. transplant.

Ability of model to recapitulate the clinical Ability of model to recapitulate the clinical manifestations/lab abnormalities of ALFmanifestations/lab abnormalities of ALF

Treatment durationTreatment duration Ability to repeat the treatmentAbility to repeat the treatment Study endpoints - what is considered a clinically Study endpoints - what is considered a clinically

meaningful effect? meaningful effect? The robustness of the responseThe robustness of the response

Discussion Issues:Discussion Issues: Animal Models of T1DAnimal Models of T1D

Discuss the ability of available animal models Discuss the ability of available animal models of T1D to evaluate the safety and clinical of T1D to evaluate the safety and clinical activity of porcine islet cell transplantation. The activity of porcine islet cell transplantation. The robustness of the modelrobustness of the model

Ability of model to recapitulate the immunological Ability of model to recapitulate the immunological and metabolic manifestations of T1Dand metabolic manifestations of T1D

Treatment durationTreatment duration Need for/ability to re-transplantNeed for/ability to re-transplant Study endpoints - what is considered a clinically Study endpoints - what is considered a clinically

meaningful effect? How long should the effect meaningful effect? How long should the effect persist?persist?

Requirements for specific immunosuppression Requirements for specific immunosuppression regimensregimens

We will not:We will not: Discuss specific products or proposalsDiscuss specific products or proposals Discuss animal husbandry issuesDiscuss animal husbandry issues Discuss product manufacturing issuesDiscuss product manufacturing issues Discuss genetically engineered source Discuss genetically engineered source

animals*animals* Provide definitive assessments of dataProvide definitive assessments of data Make definitive policy decisionsMake 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.pdf

Preclinical Issues for Committee Preclinical Issues for Committee DiscussionDiscussion

Committee is asked to provide FDA with insights Committee is asked to provide FDA with insights regarding the use of animal models to support regarding the use of animal models to support the development and regulatory evaluation of the development and regulatory evaluation of xenotransplantation products for the treatment of xenotransplantation products for the treatment of ALF and T1D ALF and T1D

Discussion will help guide FDA decisions Discussion will help guide FDA decisions regarding preclinical models in future regarding preclinical models in future applications for this product area that may be applications for this product area that may be submitted for review in this product areasubmitted for review in this product area

Guest Presentations Guest Presentations

Dr. Ira FoxDr. Ira Fox Director of the Center for Innovative Pediatric Director of the Center for Innovative Pediatric

Regenerative Therapies; University of PittsburghRegenerative Therapies; University of Pittsburgh'Animal Models for Evaluation of Porcine Cells/Tissues to Treat Patients with Acute Liver Failure'

Dr. Bernhard HeringDr. Bernhard Hering Scientific Director of the Schulze Diabetes Institute, Scientific Director of the Schulze Diabetes Institute, Dept.of Surgery; University of MinnesotaDept.of Surgery; University of Minnesota

'Animal Models for Evaluation of Porcine Islet Products to Treat Patients with Type 1 Diabetes'