ICH V1 An FDA Update Min Chen, M.S., RPh Office of Drug Safety Center for Drug Evaluation and Research FDA January 21, 2003

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  • ICH V1An FDA UpdateMin Chen, M.S., RPhOffice of Drug SafetyCenter for Drug Evaluation and ResearchFDAJanuary 21, 2003

  • ICH E2C V1 Expert Working GroupNeed of an Addendum to E2C was defined as topic V1 in early 2002 in BrusselsInterim meeting held in June 2002 in London- First draftStep 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 20023 regional regulatory agencies to publish for commentsEMEA 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, 2003U.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 1997Not 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- OverviewSynchronization of National Birthdates with the International BirthdatesUse of the latest version of the reference safety informationSubmission of executive summaries as part of the PSUROptions to submit summary bridging reports and addendum reportsHandling of solicited reports

  • Next Steps to the AddendumStep 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 314.80Reporting 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 (Contd)Required Componentsnarrative summary and analysis of interval expedited reportsFDA Form 3500A with an index consisting of a line listing of all non-expedited reports for intervalhistory 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 analysis2. Narrative discussion of actions taken3. Index line listing4. FDA Form 3500As or VAERS forms

  • Summary of Content in the AddendumIntroduction-provides further clarifications, guidance or increased flexibility beyond that provided in E2CAddendum to be used with E2C

  • 1.1 Objectives PSURs contain proprietary informationConfidentiality of the data and conclusions stated in Title pageA more comprehensive safety or risk-benefit analysis can be prepared and submitted as a stand alone documentin addition to the usual safety analysis in PSURresults 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 regimensSeparate PSURsfixed combinationstwo or more different formulations, e.g., systemic vs topical

  • 1.4.4 IBD and frequency of review and reportingWhen use local approval date, may submit prepared IBD-based PSUR plus:line-listings and/or summary tabulations covering the additional period (6 mo for a longer duration PSUR)

  • Synchronization of national birthdates with the IBDIBD unknown, MAH can designate the IBD and notify the Regulatory AuthoritiesDifferent approval dates in regions, MAH may negotiate a mutually acceptable birth month and day

  • Summary Bridging ReportsCIOMS V - p. 154-6Concise document that integrates two or more PSURs to cover a specified periodformat identical to the usual PSURsummary highlights and overview of data

  • Addendum ReportsAn update to the most recently completed PSUR, requested by Regulatory Authorities outside of the usual IBD cycleSummarize the safety data between interval:IntroductionChanges to the CCSISignificant regulatory actionsLine listing and summary tabulationsConclusions

  • Restart the ClockDecision should be discussed with the Regulatory Authority A new clinically dissimilar indicationA previously unapproved use in a special patient populationA new formulation and/or new route of administration

  • Time Interval between the Data Lock Point and the SubmissionRA sends comments to the MAH on:non-compliancesafety issues need further evaluationadditional analysis or issues of content identifiedAdditional time for SubmissionLarge number of reportsIssues raised by RA or MAH for further analysis

  • 1.4.5 Reference Safety InformationCCSI at the beginning of the period used for 6 month and 1 year reportsThe latest CCSI at the end of the period used for longer period of reports

  • 2.1 Executive SummaryOverview of PSUR when neededAt the beginning of the PSURExample in CIOMS V p.333

  • 2.5 Patient ExposureDifficulty in estimating patient exposure data is discussedConsistent in methods of calculation Extrapolations may be used based on information from a period that does not fully cover the periodAvoid patient exposure data that overlap time periods in a summary bridging report

  • 2.6 Presentation of Individual Case HistoriesContain a description and analysis of selected cases containing new or relevant information and grouped by SOCsDescribe criteria used to select cases for presentationConsumer and other non-healthcare professional reports in separate listings and analysisSolicited reports are handled as from clinical trials, clearly identified in analysis

  • 2.9 Overall Safety EvaluationDiscussion and analysis should be organized by SOCRelated terms should be reviewed together for clinical relevance