美国FDA已审批应用的干细胞化妆品

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Clinical Review BLA 125348源自文库
TABLE OF CONTENTS 1. EXECUTIVE SUMMARY………………………………………………………6 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 DISCIPLINES…………………11 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 DATA………..19 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 STUDIES……………………………………………22 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
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 patient’s own cultured living fibroblasts in Dulbecco’s Modified Eagles Medium at a concentration of 1.0 – 2.0 x 107 cells/mL. Placebo: Dulbecco’s Modified Eagle’s 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:
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Clinical Review BLA 125348 7.7.3 Basal Cell Carcinoma 7.7.4 Allergic Reactions 7.7.5 Herpes Simplex and Injection-Site Paresthesia 7.7.6 Unresolved Adverse Events 7.8 Safety Profiles in Subgroups 7.9 Safety Conclusions 7.10 Review of Commercial Training Manual (To be used in the labeling) 8. ADVISORY COMMITTEE MEETING………………………………………...75 8.1 Summary and Discussion of Advisory Committee Meeting (bulleted texts summarizing the AC members’ discussion) 8.1.1 Efficacy 8.1.2 Safety 8.1.3 Product Safety 8.1.4 Injection-Site Adverse Events 8.1.5 Tumor Formation 8.1.6 Race and Ethnicity 8.1.7 Geriatric (> 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 RECOMMENDATIONS……………………………………………81 9.1 Recommendations for Pre-Approval Actions 9.2 Recommendations for Labeling and Post-Approval Actions 10. APPENDICES……………………………………………………………………85 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
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)
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: Branch Chief: Office Director: Bruce Schneider, M.D. Changting Haudenschild, M.D. Wilson Bryan, M.D. Celia Witten, Ph.D., M.D.
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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 TRIALS…………………………………52 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 in Studies 005 and 006 7.1.5 Twelve-Month Long-Term Safety Assessment in Studies 005 and 006 7.2 Safety Results of Study IT-R-001 7.3 Safety Results of Study IT-R-002 7.4 Safety Results of Studies IT-R-003A and IT-R-003B 7.5 Safety Results of Study IT-R-007 7.6 Analysis of Integrated Safety Information 7.6.1 Overview, Extent of Exposure and Methodology of Assessment 7.6.2 Adverse Events in > 1% Safety Population 7.6.3 Adverse Events in < 1% Safety Population 7.6.4 Severity of Adverse Events 7.6.5 Duration of Adverse Events 7.6.6 Comparison of Adverse Events in Pivotal Trials with Integrated Safety Data 7.7 Significant Adverse Events 7.7.1 Injection-Site Ischemia 7.7.2 Injection-Site Nodules