ICH V1 An FDA Update

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ICH V1An FDA Update

• Min Chen, M.S., RPh
• Office of Drug Safety
• Center for Drug Evaluation and Research
• FDA
• January 21, 2003

2
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

3
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

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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

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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

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Next Steps to the Addendum

• Step 3 - Collecting comments for further EWG
  discussions
• Reach Step 4
• Each regulatory agency publication as final
  guideline

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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

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Current Postmarketing Periodic Reporting
Requirement in US (Contd)

• 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

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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

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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

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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

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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

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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 (lt3 mo for 6 month PSUR, lt6
  mo for a longer duration PSUR), or
• and Addendum Report (gt3 mo for 6 mo PSUR, gt6 mo
  for a longer duration PSUR)

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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

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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

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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

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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

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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

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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

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2.1 Executive Summary

• Overview of PSUR when needed
• At the beginning of the PSUR
• Example in CIOMS V p.333

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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

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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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2.9 Overall Safety Evaluation

• Discussion and analysis should be organized by
  SOC
• Related terms should be reviewed together for
  clinical relevance