1. 1 Safety of Cell Therapies Derived from Human Embryonic Stem Cells CTGTAC #45 April 10, 2008

2. 2 Public Scientific Discussions Advisory Committee Meetings Advisory Committee Meetings Human Stem Cells as Cellular Replacement Therapies for Neurological Disorders. July 13-14, 2000. Human Stem Cells as Cellular Replacement Therapies for Neurological Disorders. July 13-14, 2000. Unrelated allogeneic hematopoietic stem/progenitor cells from placental/umbilical cord blood for hematopoietic reconstitution February 27, 2002. Unrelated allogeneic hematopoietic stem/progenitor cells from placental/umbilical cord blood for hematopoietic reconstitution February 27, 2002. Allogeneic Pancreatic Islets for Type 1 Diabetes October 9-10, 2003 Allogeneic Pancreatic Islets for Type 1 Diabetes October 9-10, 2003 Cellular Products for the Treatment of Cardiac Disease March 18- 19, 2004 Cellular Products for the Treatment of Cardiac Disease March 18- 19, 2004 Cellular Products for Joint Surface Repair March 3-4, 2005 Cellular Products for Joint Surface Repair March 3-4, 2005 Draft Guidance for Industry for minimally manipulated, unrelated allogeneic cord blood, and the regulatory approach to minimally manipulated unrelated allogeneic peripheral blood stem/progenitor cells. March 30, 2007 Draft Guidance for Industry for minimally manipulated, unrelated allogeneic cord blood, and the regulatory approach to minimally manipulated unrelated allogeneic peripheral blood stem/progenitor cells. March 30, 2007 Workshops Workshops FDA/NIST Sponsored Workshop In Vitro Analyses of Cell/Scaffold Products December 6-7, 2007 FDA/NIST Sponsored Workshop In Vitro Analyses of Cell/Scaffold Products December 6-7, 2007

3. Stem Cell-based Products: Scientific Considerations and Safety Evaluation Properties of embryonic stem cells Properties of embryonic stem cells Self renewal Self renewal Pluripotency Pluripotency Differentiation in culture Differentiation in culture Safety Evaluation Safety Evaluation Inappropriate differentiation Inappropriate differentiation Tumorigenicity Tumorigenicity Ectopic tissue formation Ectopic tissue formation StemCellStemCell ImmatureCellsImmatureCells MatureCellsMatureCells tumorigenicity 2

4. 4 Safety Assessment 21 CFR, part 312.23(a)(8): Pharmacologic & Toxicologic Studies “…adequate information about the pharmacological & toxicological 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.”

5. 5 Focus Safety issues regarding the use of cellular products derived from human embryonic stem cells Safety issues regarding the use of cellular products derived from human embryonic stem cells Discussion from CTGTAC and additional expert panelists Discussion from CTGTAC and additional expert panelists

6. 6 Discussion Issues.. Inappropriate Differentiation/Tumorigenicity Preclinical safety assessment Preclinical safety assessment Animal species/model selection criteria Animal species/model selection criteria Clinically relevant study designs Clinically relevant study designs Site of cell implantation Site of cell implantation Fate of cells after administration Fate of cells after administration Cell dose extrapolation from animal to human Cell dose extrapolation from animal to human Study duration Study duration

7. 7 Discussion Issues.. Product Characterization Characteristics related to safety Characteristics related to safety Ability to predict inappropriate differentiation/tumorigenicity Ability to predict inappropriate differentiation/tumorigenicity Sensitivity/specificity of assays to distinguish degree(s) of cell differentiation Sensitivity/specificity of assays to distinguish degree(s) of cell differentiation

8. 8 Discussion Issues.. Clinical Trial Design What tools exist for monitoring the fate of infused cells during clinical trials? What tools exist for monitoring the fate of infused cells during clinical trials? Where do the cells go in the body? Where do the cells go in the body? Can we monitor inappropriate cellular differentiation in the body? Can we monitor inappropriate cellular differentiation in the body? Cell dose levels: Cell dose levels: Balancing possibility of therapeutic effect with need to ensure maximum safety Balancing possibility of therapeutic effect with need to ensure maximum safety

9. 9 Overview Guest Presentations Guest Presentations Dr. Carpenter, Novocell Dr. Carpenter, Novocell Dr. Dinsmore, ACT Dr. Dinsmore, ACT Dr. Lebkowski, Geron Dr. Lebkowski, Geron Dr. Isacson, Harvard Dr. Isacson, Harvard Dr. Bulte, Johns Hopkins Dr. Bulte, Johns Hopkins Open Public Hearing Open Public Hearing Panel Discussion of FDA Questions Panel Discussion of FDA Questions

10. 10 Thanks to all participants! CTGTAC #45