1. Cellular Therapies for Cardiac Diseases – FDA Preclinical Perspective Richard D. McFarland Ph.D., M.D. CBER/OCTGT/DCEPT BRMAC # 37 March 18-19, 2004

2. Scope of Talk Framework for FDA Reviews Preclinical Models for Cardiac Diseases Introduction of Scientific Speakers

3. FDA Review is Product- based Parallels prudent product development Dependent on characteristics of specific product Preclinical studies designed to support use of specific products Clinical trial design supported by manufacturing, preclinical data Framed by regulations

4. Investigational New Drug (IND) Regulations 21 CFR312.23 (8) Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations…..

5. IND Regulations 21CFR312.23 (8)(ii)(b) For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review…..

6. Goals of Preclinical Evaluation Provide rationale for proposed therapy Discern mechanism of action Identify “at risk” patient populations Recommend safe starting doses and escalation schemes for humans Preliminary risk/benefit assessment Identify parameters for clinical monitoring

7. Use of Preclinical Models of Cellular Therapies Scientific rationale with the cellular product intended for clinical use Understanding of cell function, trafficking and differentiation Modelling of routes of administration

8. Characteristics of Ideal Animal Model for Cardiac Cell Therapies Similar pathophysiology to humans – Improves predictability of human risks Similar anatomy to humans – Allows modeling of catheter use with clinical catheter – Allows for dose exploration Immune tolerance to human cells – Allows use of clinical cellular product

9. Syngeneic Animal Models of Cardiac Diseases Can provide useful data for assessment of safety – Analogous cell source from animals Potential processing, formulation, and storage differences Limited product characterization introduces uncertainty

10. Complexity due to Innovative Delivery Systems Intraoperative transepicardial injection (usually CABG) Catheter-mediated transendocardial injection Catheter-mediated via cardiac vein

11. Small Animal Models in Published Literature Cryoinjury or coronary artery ligation primarily used to generate damaged myocardium Immunocompromised animals available (mouse and rat) Species used – Mouse – Rat – Rabbit

12. Large Animal Models in Published Literature Ameroid constrictor primarily used to generate ischemic area Amenable to catheter administration Amenable to clinical monitoring modalities Species used – Dog – Sheep – Pig

13. Potential Sources of Data to Support Initiation of Clinical Trials Preclinical studies specifically designed to support a clinical trial Other potential sources – Existing animal studies designed to answer other questions – In vitro studies – Clinical trials using the “same” product

14. Using Published Animal or Human Studies as Sole Support for Intiation 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 Published reports must provide sufficient information for independent review

15. Use of Published Studies (cont’d) Protocols must be sufficiently detailed – Specifics of the route of administration Catheter specifics such as identity, flow rates and pressures Location of injection in relation to ischemic region – Must contain details of “routine” monitoring and analytical plans

16. Use of Published Studies (cont’d) Data must be presented in sufficient detail – In-process and lot-release data (manufacturing) – Complete study reports for animal and clinical studies

17. Use of Published Studies (cont’d) Cellular products used in published reports may not be comparable to the intended clinical product – Insufficient data to allow comparability assessment – Editorial constraints

18. Regulatory Challenges 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 unreasonable and significant?

19. Afternoon Speakers Focus on cells – Doris Taylor, University of Minnesota – Silviu Itescu, Columbia University Focus on devices – D. Nick Jensen, FDA/CDRH – Robert Lederman, NIH/NHLBI