CLINICAL REVIEW Division of Clinical Evaluation, Office of Cellular Tissue and Gene Therapy, Center for Biologics Evaluation and Research _ TITLE AND GENERAL INFORMATION Medical Officers (M.O.) Review Identifiers and Dates: BLA/NDA #: 125348/0 Related IND #: IND (b)(4) Reviewers: Agnes Lim, M.D. Yao-Yao Zhu, M.D., Ph.D. Changting Haudenschild, M.D. Team Leaders: Bruce Schneider, M.D. Changting Haudenschild, M.D. Branch Chief: Wilson Bryan, M.D. Office Director: Celia Witten, Ph.D., M.D. Submission Received by FDA: March 6, 2009 Review Completed: December 9, 2009 Product: Proper Name or Established Name: Autologous human fibroblast cells Proposed Trade Name: azficel-T, formerly known as Isolagen TherapyTM (IT), is identified as IT in this clinical review Product Formulation(s): A sterile suspension of each patients own cultured living fibroblasts in Dulbeccos Modified Eagles Medium at a concentration of 1.0 2.0 x 107 cells/mL. Placebo: Dulbeccos Modified Eagles Medium (DMEM) without phenol red Applicant: Fibrocell Technologies, Inc., formerly known as Isolagen Technologies Inc., is identified as Isolagen in this review Pharmacologic Class or Category: Cell Therapy Proposed Indication: Clinical Review BLA 125348 Isolagen TherapyTM is an autologous cellular product indicated for the treatment of moderate to severe nasolabial fold wrinkles in adults. Proposed Population: Adults Dosage Form(s) and Route(s) of Administration: Isolagen TherapyTM is available in a single dosage form of 1.0-2.0 x 107 cells/mL per 1.2 vial (sufficient to administer 1.0 mL). Up to 2 mL, administered as 0.1 mL per linear cm, are injected intradermally into the nasolabial fold area. Documents Reviewed: (See Section 4.1 in this review) 2 Clinical Review BLA 125348 TABLE OF CONTENTS 1. EXECUTIVE SUMMARY6 1.1 Brief Overview of Clinical Program 1.2 Efficacy Analysis of Studies IT-R-005 and IT-R-006 1.2.1 Demographics 1.2.2 Efficacy 1.3 Safety 1.3.1 Safety Database 1.3.2 Safety Analysis of Studies 1.3.3 Proposed Dosing Regimen and Administration 1.3.4 Drug-Drug Interaction 1.3.5 Special Populations 1.4 Issues Raised at the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) 1.5 Premarket Recommendations 1.6 Postmarket Recommendations 2. SIGNIFICANT FINDINGS FROM OTHER DISCIPLINES11 2.1 Chemistry Manufacturing and Controls (CMC) 2.2 Animal Studies 3. CLINICAL AND REGULATORY BACKGROUND.12 3.1 Health-Related Conditions and Available Interventions 3.2 Important Information from Pharmacologically Related Products 3.3 Commercial Experience 3.4 Regulatory Background Information 4. CLINICAL DATA SOURCES, REVIEW STRATEGY, AND DATA19 INTEGRITY 4.1 Material Reviewed 4.2 Summary of Clinical Studies 4.3 Review Strategy 4.4 Good Clinical Practices (GCP) and Data Integrity 4.5 Financial Disclosure 5. DESIGNS OF CLINICAL STUDIES22 5.1 Studies IT-R-005 and IT-R-006 5.1.1 Primary Endpoints 5.1.2 Secondary Efficacy Endpoints 5.1.3 Key Eligibility Criteria 5.1.4 Study Schema 5.1.5 Observation Period 5.1.6 Randomization Procedure 3 Clinical Review BLA 125348 5.1.7 Re-Biopsy/Manufacturing Failure 5.1.8 Blinding Procedure 5.1.9 Treatment Regimen 5.1.10 Concomitant Medications and Procedures 5.1.11 Training for Study Investigators 5.2 Statistical Analysis 5.2.1 Sample Size Determination 5.2.2 Efficacy Analysis Populations 5.2.3 Efficacy Analysis 5.2.4 Sensitivity Analysis for the Primary Efficacy Endpoints 5.2.5 Secondary Endpoints 5.3 Study IT-R-001 5.4 Study IT-R-002 5.5 Studies IT-R-3A and IT-R-3B 5.6 Study IT-R-007 6. REVIEW OF EFFICACY.36 6.1 Study Results and Efficacy of Study IT-R-005 6.2 Study Results and Efficacy of Study IT-R-006 6.3 Comparison of Efficacy Outcomes Between the Two Studies 6.4 Analysis of Secondary Endpoints 6.5 Clinical Issues 6.6 Efficacy Conclusions 7. OVERVIEW OF SAFETY ACROSS TRIALS52 7.1 Safety Results of Study IT-R-005 and IT-R-006 7.1.1 Method of Assessment 7.1.2 Safety Results of Study IT-R-005 7.1.3 Safety Results of Study IT-R-006 7.1.4 Adverse Events in 1% Safety Population 7.6.3 Adverse Events in 65 years) and Male Population 8.1.8 Physician Training 8.1.9 Post-Treatment Biopsy 8.1.10 FDA Considerations for Elements of Post-Treatment Biopsy Study 9. CLINICAL RECOMMENDATIONS81 9.1 Recommendations for Pre-Approval Actions 9.2 Recommendations for Labeling and Post-Approval Actions 10. APPENDICES85 10.1 Appendix A: Abbreviations 10.2 Appendix B: List of Documents Reviewed 10.3 Appendix C: Photoguide Used with the Evaluator Wrinkle Severity Assessment (Lemperle Scale) 10.4 Appendix D: Advisory Committee Meeting Questions 11. REFERENCES.90 5 Clinical Review BLA 125348 1. EXECUTIVE SUMMARY 1.1 Brief Overview of Clinical Program Isolagen Therapy (IT) is