Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2005 Good Review Practices Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2005 Good Review Practices TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. GENERAL GUIDANCE ON THE CLINICAL SAFETY REVIEW .......................... 2 A. Introduction....................................................................................................................................2 B. Explanation of Terms ....................................................................................................................3 C. Overview of the Safety Review .....................................................................................................4 D. Differences in Approach to Safety and Effectiveness Data ........................................................4 E. Identifying and Assembling Source Materials for the Safety Review.......................................6 F. Identifying Major Concerns at the Outset...................................................................................7 G. Auditing Source Materials ............................................................................................................8 H. The Purpose of Individual Case Review/“Drug-relatedness”....................................................8 III. SPECIFIC GUIDANCE ON THE CONTENT OF THE SAFETY REVIEW............ 9 7.1 Methods and Findings..................................................................................................................11 7.1.1 Deaths .........................................................................................................................................11 7.1.2 Other Serious Adverse Events..................................................................................................15 7.1.3 Dropouts and Other Significant Adverse Events....................................................................16 7.1.3.1 Overall Profile of Dropouts ...................................................................................................16 7.1.3.2 Adverse Events Associated with Dropouts...........................................................................18 7.1.3.3 Other Significant Adverse Events.........................................................................................19 7.1.4 Other Search Strategies ............................................................................................................19 7.1.5 Common Adverse Events..........................................................................................................19 7.1.5.1 Applicant’s Approach to Eliciting Adverse Events in the Development Program...........20 7.1.5.2 Establishing Appropriate Adverse Event Categories and Preferred Terms.....................20 7.1.5.3 Incidence of Common Adverse Events — Assessment of Various Databases...................22 7.1.5.4 Common Adverse Event Tables ............................................................................................23 7.1.5.5 Identifying Common and Drug-Related Adverse Events ...................................................23 7.1.5.6 Additional Analyses and Explorations .................................................................................24 7.1.6 Less Common Adverse Events .................................................................................................25 7.1.7 Laboratory Findings .................................................................................................................25 7.1.7.1 Overview of Laboratory Testing in the Development Program.........................................26 7.1.7.2 Selection of Studies/Analyses for Drug-Control Comparisons of Laboratory Values .....26 7.1.7.3 Standard Analyses and Explorations of Laboratory Data .................................................27 7.1.7.3.1 Analyses Focused on Measures of Central Tendency ......................................................27 7.1.7.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................27 7.1.7.3.3 Marked Outliers and Dropouts for Laboratory Abnormalities......................................28 7.1.7.4 Additional Analyses and Explorations .................................................................................29 7.1.7.5 Special Assessments: Hepatotoxicity, QTc, Others ............................................................29 7.1.8 Vital Signs ..................................................................................................................................30 7.1.8.1 Extent of Vital Signs Testing in the Development Program ...............................................30 7.1.8.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons......................30 7.1.8.3 Standard Analyses and Explorations of Vital Signs Data...................................................30 7.1.8.3.1 Analyses Focused on Measures of Central Tendency ......................................................30 7.1.8.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................30 7.1.8.3.3 Marked Outliers and Dropouts for Vital Signs Abnormalities .......................................30 7.1.8.4 Additional Analyses and Explorations .................................................................................30 7.1.9 Electrocardiograms (ECGs) .....................................................................................................30 7.1.9.1 Extent of ECG Testing in the Development Program, Including Brief Review of Preclinical Results ................................................................................................................................30 7.1.9.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons......................31 7.1.9.3 Standard Analyses and Explorations of ECG Data ............................................................31 7.1.9.3.1 Analyses Focused on Measures of Central Tendency ......................................................31 7.1.9.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................31 7.1.9.3.3 Marked Outliers and Dropouts for ECG Abnormalities.................................................31 7.1.9.4 Additional Analyses and Explorations .................................................................................31 7.1.10 Immunogenicity .......................................................................................................................31 7.1.11 Human Carcinogenicity ..........................................................................................................31 7.1.12 Special Safety Studies..............................................................................................................32 7.1.13 Withdrawal Phenomena/Abuse Potential .............................................................................32 7.1.14 Human Reproduction and Pregnancy Data..........................................................................32 7.1.15 Assessment of Effect on Growth.............................................................................................32 7.1.16 Overdose Experience...............................................................................................................33 7.1.17 Postmarketing Experience......................................................................................................34 7.2 Adequacy of Patient Exposure and Safety Assessments ...........................................................34 7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to Evaluate Safety .....................................................................................................34 7.2.1.1 Study Type and Design/Patient Enumeration......................................................................35 7.2.1.2 Demographics .........................................................................................................................36 7.2.1.3 Extent of Exposure (Dose/Duration).....................................................................................36 7.2.2 Description of Secondary Clinical Data Sources Used to Evaluate Safety...........................36 7.2.2.1 Other Studies ..........................................................................................................................37 7.2.2.2 Postmarketing Experience.....................................................................................................37 7.2.2.3 Literature ................................................................................................................................37 7.2.3