FDA Perspective on the Development of Cellular Therapies for Repair and Regeneration of Joint Surfaces - Preclinical Pe

1. FDA Perspective on the Development of Cellular Therapies for Repair and Regeneration of Joint Surfaces - Preclinical Perspective Richard D. McFarland Ph.D., M.D. Medical Officer CBER/OCTGT/DCEPT/PTB mcfarlandr@cber.fda.gov CTGTAC # 38 March 3, 2005

2. Scope of Talk • CBER-CDRH Collaboration on Joint Surface Repair Products • Framework for FDA Preclinical Review Of Cellular Products for Joint Surface Repair • General- Preclinical Study Design and Review • Specifics- Cellular Products for Joint Surface Repair • Introduction to Preclinical Discussion Questions

3. CBER-CDRH Collaboration on Cartilage Repair Products • FDA Critical Path Initiative • http://www.fda.gov/oc/initiatives/criticalpath/ • CBER Stakeholder meeting, Fall 2004 • CBER-CDRH Joint Team- Fall 2004 • CTGTAC Meeting #38- March 2005

4. CBER-CDRH Joint Team • Monthly Collaborative Meetings • Shared Educational Activities • Internal • Outreach • Composite Review Teams • Pre-IND, pre-IDE meetings • IND, IDE • BLA, PMA, 510K

5. FDA Review Framework for Joint Repair Products • Parallels prudent product development • Dependent on characteristics of specific product • Cellular • Device • Combination • Preclinical studies designed to support use of specific products • Framed by regulations • IND (21CFR 312), BLA (21 CFR 601) • IDE (21CFR 812), PMA (21 CFR 814)

6. Goals of Preclinical Evaluation • Provide rationale for proposed therapy • Preliminary risk/benefit assessment • Recommend safe starting doses and escalation schemes for humans • Identify “at risk” patient populations • Identify parameters for clinical monitoring • Discern mechanism of action • Characterize product and compare to normal tissues • Qualification of analytical tests used during manufacturing and lot release

7. Routine Preclinical Questions • Does the submission contain sufficient information to assess risks to the subjects in the proposed trial? • Were adequate preclinical studies performed? • Were data submitted in sufficient detail to conduct an independent review? • If sufficient data are present, are the risks to human subjects from product administration reasonable?

8. Potential Sources of Data to Support Initiation of Clinical Trials • Safety Assessment in Animal Model • GLP-compliant toxicology studies • Well-controlled studies conducted “in house” • Cross reference to data on identical/similar product previously submitted to FDA • In vitro studies • Previous human experience • Published data in peer-reviewed journals

9. Perils of Using Published Animal or Human Studies as Sole Support for Initiation of Clinical Trials • Often they were not designed to answer a toxicologic question, and therefore, adequate toxicology endpoints may not have been incorporated into the design • Often do not contain sufficient detail of study design, toxicities, study dropouts, etc., to allow for independent review

10. Potential Animal Study Designs • Pharmacology or “proof of concept” studies in animal model of disease • Toxicology studies in healthy animals • Hybrid pharmacology-toxicology study design • Animal model of disease • Toxicology endpoints

11. Toxicology Study Design • Appropriate controls • Mimicking clinical treatment as closely as possible • Product, ROA, formulation, device, dose regimen, etc… • Reasonable group size • Endpoints • Mortality, clinical observation, hematology, serum chemistry, gross pathology, histopathology, body weights, food consumption etc…

12. Potential Characteristics of “Ideal” Animal Model for Cellular Therapies for Joint Surface Repair • Similar characteristics to humans • Anatomy • Biomechanics • Pathophysiology • Cell biology • Immune tolerance to human cells • Allows use of clinical cellular product

13. “Ideal” Animal Model for Cellular Therapies for Joint Surface Repair • Unfortunately an “ideal” model does not exist. • Therefore, we (FDA and sponsors) must understand the capabilities and limitations of the available models

14. Established Animal Models for Joint Surface Repair Products • Numerous species have been reported in scientific literature introducing inherent interspecies variation including: • Body and Joint Size • Anatomic Features • Gross • Microscopic • Cell Biologic Features • Physiologic Features • Applicability for regulatory use therefore also varies

15. Established Animal Models for Joint Surface Repair Products • Analogous cellular products from animal source can provide data for assessment of safety • Potential processing, formulation, and storage differences between animal and human products • Limited characterization of the animal cellular product introduces uncertaintyin the extrapolation to human studies

16. Preclinical Issues for Committee Discussion • Committee is asked to provide FDA insights with respect to the following specific issues through their discussion this afternoon • Discussion will help guide FDA in future decisions in this product area

17. Animal Models for Prediction of Safety and Clinical Activity • Exploration of dose and allometric scaling • Significance of interspecies differences for use analogous animal cells to model human chondrocytes • Anatomy • Cell physiology • Methods for evaluation of intraarticular toxicity and /or cartilage formation • Non-invasive imaging modalities • Biomechanical tests • Arthroscopic biopsy • Need for tumorigenicity studies of cultured chondrocyte cellular products

18. Pivotal Toxicology Study Design • Support for exploratory clinical trials • Animal model(s) • Study duration • Support for licensing application • Animal model(s) • Study duration • Appropriateness of measures of systemic toxicity such as clinical pathology tests and histopathology • Cellular products • Modified cellular products that may secrete molecules capable of producing systemic toxicities

19. Allogeneic Cellular Products • Potential additional safety concerns beyond those posed by an autologous product should be addressed