NDA 21-083 Sirolimus Rapamune ®

8/18/99


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Table of Contents

NDA 21-083 Sirolimus Rapamune ®

FDA Review Team for NDA 21-083

FDA Perspective: Sirolimus (Rapamune®)

Study Population

Strengths of Studies 301 and 302

Strengths of Studies 301 and 302

Study Design

Immunosuppression

Prophylaxis

Co-primary Study Endpoints

FDA Statistical Perspective on Efficacy Analyses

Outline of Presentation

Efficacy Failure at 6 months

Efficacy Failure at 6 months Protocol 301

Efficacy Failure at 6 months Protocol 302

Patient and Graft Survival at 12 months

Patient and Graft Survival at 12 months Protocol 301

Patient and Graft Survival at 12 months Protocol 302

Efficacy Failure at 6 months for Various Subgroups

Efficacy Failure: Race

Efficacy Failure: Donor Source

Efficacy Failure: Recipient Gender

Efficacy Failure: No. of HLA Mismatches

“High Risk” Patients

FDA Defined High Risk Subgroup

Efficacy Failure: High Risk Subgroup

Time to Efficacy Failure

Time to Efficacy Failure Protocol 301

Rejections after 60 days but during the first 6 months

Time to Efficacy Failure Protocol 302

Rejections after 60 days but during the first 6 months

Summary of Efficacy

Summary of Efficacy (cont.)

Safety Perspective

Safety Perspective

Summary of Deaths and Graft Losses at 12 months Protocol 301

Summary of Deaths and Graft Losses at 12 months Protocol 302

Deaths

Discontinuations

Post-transplant lymphoproliferative disease (PTLD)

Infection Studies 301 and 302

Opportunistic Infection

Post-transplant diabetes mellitus (PTDM)

Treatment-emergent Adverse Events Occurring with ᡌ % Frequency

Treatment-emergent Adverse Events Occurring with > 5% and ង % Frequency

Hematologic Adverse Events

Hematologic Adverse Events (cont.)

Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura (HUS/TTP)

Liver Function Tests (LFT’s)

Hyperlipidemia

Study 301 Cholesterol Analysis

Study 302 Cholesterol Analysis

Study 301 Triglyceride Analysis

Study 302 Triglyceride Analysis

Use of Lipid-lowering Drugs in Treatment of New-onset Hypercholesterolemia

Renal Function

Important Points about Renal Function Assessment

Mean GFR and Mean Serum Creatinine Analysis at 12 Months

Study 301 Mean GFR Results at 12 Months (337-393 days)

Study 301 Serum Creatinine at 12 Months (337-393 days)

Study 302 Mean GFR Results at 12 Months (337-393 days)

Study 302 Serum Creatinine at 12 Months (337-393 days)

Summary on Exploratory Renal Function Analysis

Renal Function - Additional Questions

Study 301 Mean GFR at 12 Months (337-393 days)

Study 302 Mean GFR at 12 Months (337-393 days)

Study 301 Serum Creatinine at 12 Months (337-393 days)

Study 302 Serum Creatinine at 12 Months (337-393 days)

Renal Function

Renal Function (cont.)

Safety Conclusions for Sirolimus

Questions for the Advisory Committee #1

Questions for the Advisory Committee #2

Questions for the Advisory Committee #3

Author: Rigo Roca