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
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