ICH V1An FDA Update

Min Chen, M.S., RPh

Office of Drug Safety

Center for Drug Evaluation and Research

FDA

January 21, 2003

ICH E2C V1 Expert Working Group

• Need of an Addendum to E2C was defined as topic V1 in early 2002 in Brussels

• Interim meeting held in June 2002 in London- First draft

• Step 2 document or Addendum completed in September 2002 in Washington DC

Status of V1 Addendum • ICH Steering Committee signed off the Step 2

document in September 2002• 3 regional regulatory agencies to publish for

comments– EMEA published for comments on EU website in

September 2002, comments collected (http://www.ich.org/ich5e.html)

– MHLW published in Japanese November 2002, comments deadline Jan. 10, 2003

– U.S. published in FR on December 31, 2002, comments deadline Jan. 24, 2003

PSURs (Periodic Safety Update Reports) Present Situation in U.S.

• Adopted ICH E2C Guideline published in FR May 1997

• Not required format for periodic reports yet

• Draft Reporting Guidance published 3/2001 allows companies through waiver request submitting periodic reports in E2C format

V1 Step 2 Document- Overview

• Synchronization of National Birthdates with the International Birthdates

• Use of the latest version of the reference safety information

• Submission of executive summaries as part of the PSUR

• Options to submit summary bridging reports and addendum reports

• Handling of solicited reports

Next Steps to the Addendum

• Step 3 - Collecting comments for further EWG discussions

• Reach Step 4

• Each regulatory agency publication as final guideline

Current Postmarketing Periodic Reporting Requirement in U.S.

• 21 CFR 314.80• Reporting timeline

– quarterly for first three years, then annually

– upon written notice, FDA may extend or re-establish the cycle at different times, e.g., new major supplement approvals or other conditions

Current Postmarketing Periodic Reporting Requirement in US

(Cont’d)• Required Components

– narrative summary and analysis of interval expedited reports

– FDA Form 3500A with an index consisting of a line listing of all non-expedited reports for interval

– history of actions taken

Current Draft Reporting Guidance re: Periodic Reports

• Information required and contained within a report should be divided into 4 sections:– 1. Narrative summary and analysis– 2. Narrative discussion of actions taken– 3. Index line listing– 4. FDA Form 3500As or VAERS forms

Summary of Content in the Addendum

• Introduction-– provides further clarifications, guidance or

increased flexibility beyond that provided in E2C

– Addendum to be used with E2C

1.1 Objectives

• PSURs contain proprietary information

• Confidentiality of the data and conclusions stated in Title page

• A more comprehensive safety or risk-benefit analysis can be prepared and submitted as a “stand alone” document– in addition to the usual safety analysis in PSUR– results of the risk-benefit analysis be included in

the next PSUR

1.4 General Principles1.4.1 One report for one active

substance • All indications, dosage forms and regimens

• Separate PSURs– fixed combinations– two or more different formulations, e.g.,

systemic vs topical

1.4.4 IBD and frequency of review and reporting

• When use local approval date, may submit prepared IBD-based PSUR plus:– line-listings and/or summary tabulations

covering the additional period (<3 mo for 6 month PSUR, <6 mo for a longer duration PSUR), or

– and Addendum Report (>3 mo for 6 mo PSUR, >6 mo for a longer duration PSUR)

1.4.4.1 Synchronization of national birthdates with the IBD

• IBD unknown, MAH can designate the IBD and notify the Regulatory Authorities

• Different approval dates in regions, MAH may negotiate a mutually acceptable birth month and day

1.4.4.2 Summary Bridging Reports

• CIOMS V - p. 154-6

• Concise document that integrates two or more PSURs to cover a specified period– format identical to the usual PSUR– summary highlights and overview of data

1.4.4.3 Addendum Reports

• An update to the most recently completed PSUR, requested by Regulatory Authorities outside of the usual IBD cycle

• Summarize the safety data between interval:– Introduction– Changes to the CCSI– Significant regulatory actions– Line listing and summary tabulations– Conclusions

1.4.4.4 Restart the Clock

• Decision should be discussed with the Regulatory Authority – A new clinically dissimilar indication– A previously unapproved use in a special

patient population– A new formulation and/or new route of

administration

1.4.4.5 Time Interval between the Data Lock Point and the

Submission• RA sends comments to the MAH on:

– non-compliance– safety issues need further evaluation– additional analysis or issues of content identified

• Additional time for Submission– Large number of reports– Issues raised by RA or MAH for further analysis

1.4.5 Reference Safety Information

• CCSI at the beginning of the period used for 6 month and 1 year reports

• The latest CCSI at the end of the period used for longer period of reports

2.1 Executive Summary

• Overview of PSUR when needed

• At the beginning of the PSUR

• Example in CIOMS V p.333

2.5 Patient Exposure

• Difficulty in estimating patient exposure data is discussed

• Consistent in methods of calculation

• Extrapolations may be used based on information from a period that does not fully cover the period

• Avoid patient exposure data that overlap time periods in a summary bridging report

2.6 Presentation of Individual Case Histories

• Contain a description and analysis of “selected” cases containing new or relevant information and grouped by SOCs

• Describe criteria used to select cases for presentation

• Consumer and other non-healthcare professional reports in separate listings and analysis

• Solicited reports are handled as from clinical trials, clearly identified in analysis

2.9 Overall Safety Evaluation

• Discussion and analysis should be organized by SOC

• Related terms should be reviewed together for clinical relevance