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PSURs – How They Should Be Used. E. Stewart Geary, M.D. Eisai Co., Ltd. National Regulatory Conference 2005 Subang Jaya, Selangor, Malaysia 6-7 September, 2005. Outline. History of the PSUR Non-ICH PSURs Content and Use of PSUR Future Developments: DSUR. History of PSUR. - PowerPoint PPT Presentation
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PSURs – How They Should Be Used
E. Stewart Geary, M.D.
Eisai Co., Ltd.
National Regulatory Conference 2005
Subang Jaya, Selangor, Malaysia
6-7 September, 2005
PSUR National Regulatory Conference 2005
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Outline
• History of the PSUR
• Non-ICH PSURs
• Content and Use of PSUR
• Future Developments: DSUR
History of PSUR
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History of ICH PSUR
• CIOMS II Working Group– Began work in November 1989 after completing
CIOMS I– Harmonize report format for aggregated safety
information– Published Report in 1992
• ICH Topic E2C– Step 4 November 1996
• ICH E2C Addendum– Step 4 February 2003
Non-ICH PSURs
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Types of PSUR
• FDA: Postmarketing Periodic Adverse Drug Experience Report
• Japan: Anzenteikihoukoku
• ICH: PSUR
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FDA: Postmarketing Periodic Adverse Drug Experience Report
• Described in – 21 CFR 314.80 (c) (2)– 21 CFR 600.80 (c) (2)
• Submit quarterly for first 3 years then yearly forever– 30 days to prepare quarterly report, 60 days to
prepare annual report
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FDA: Postmarketing Periodic Adverse Drug Experience Report
• Contains – An analysis of safety issues
– A history of actions taken (PI changes)
– Scientific literature
– MedWatch forms: all individual AE reports which were received during that period and have not already been submitted to FDA as 15 day reports
• No line listings• No cumulative tabulations
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FDA: Postmarketing Periodic Adverse Drug Experience Report
• Proposal to change to the ICH PSUR format in the “tome”– Proposed Rule of March 14, 2003
• Unclear when or if this Rule will be implemented
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Japan: Anzenteikihoukoku
• Periodic report focused on local safety experience
• The PSUR is to be included as an appendix to this report
• Only produced in Japanese– Limited/No use outside of Japan
Content and Use of PSUR
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Content and Use of PSUR
• Principles
• Content
• CIOMS V Recommendations
• E2C Addendum
• Use?
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PSUR Principles
• One PSUR for one active substance– Multiple indications, doses and even formulations will usually be
covered in one PSUR
• Interval data for the period covered– Except for cumulative tabulations and table of worldwide
regulatory status
• Create as a “stand alone” report• Interval covered changes as product matures
– Every 6 months for first 2 years– Every 1 year for next 3 years– Every 5 years subsequently (changing to every 3 years)
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PSUR Content (1)
• Introduction• Worldwide Market Authorization Status
– Dates of authorization and launch by country• Regulatory actions taken for safety
– During the time interval– For safety: withdrawal, restrictions, failure to renew
• Changes to CCDS/CCSI• Patient Exposure
– Data available on exposure vary internationally– An estimate
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PSUR Content (2)
• Presentation of Cases– Select individual case series for discussion as needed
– For a mature product with no new safety issues, there might be no cases or issues selected for individual discussion
– Frequently highlighted issues• Deaths
• Liver disorders
• Renal disorders
• Cardiac arrhythmias or other cardiovascular events
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PSUR Content (3)
• Line listings– Determine “listed” or “unlisted” according to the
CCDS, not the locally approved label– A single line for each case– Line Listings
• Spontaneous, Serious, Unlisted Reports• Spontaneous, Serious, Listed Reports• Spontaneous, Non-serious, Unlisted Reports• Clinical Trial, Serious, Reactions• Literature Serious and Unlisted Non-serious reactions• Regulatory Serious Reactions
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PSUR Content (4)
• Tabulations– Summary Tabs: Numbers of all reports for the interval
period
– Cumulative Tabs: Numbers of serious & unexpected reports since international birthdate
• Studies– Newly analyzed company-sponsored studies (i.e.
completed)
– Targeted safety studies ongoing during reporting period
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PSUR Content (5)
• Other Information– Efficacy-related information for products used to treat
serious or life-threatening diseases (lack of effect)– Late-breaking information (after data-lock period)
• Overall safety evaluation– Drug-drug interactions, pregnancy exposure, overdose,
abuse• Conclusion
– Has the overall safety profile changed?• CCDS/CCSI as an appendix
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CIOMS V PSUR recommendations
• Company choose the International Birthdate• Summary Bridging Reports
– Concise document integrating two or more PSURs• Addendum report
– Update to most recent PSUR when a regulatory authority requests a PSUR outside usual reporting cycle
• 5 year PSUR– Submit 5 one-year PSURs with bridging document
• Simplification of PSUR– Abbreviated PSUR prepared when only a small number of AEs are
received during the reporting period• Eliminate line listings for very large PSUR
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E2C Addendum (1)
• Followed CIOMS V• When a PSUR is needed outside IBD cycle,
submit the already prepared PSUR plus:– Line listing + summary tabulation for periods up to 6
months– Addendum report for periods > 6 months
• Summary Bridging Report– “Bridges” 2 or more PSURs– Does not contain new safety information– 10 x 6 month PSUR + Bridging Report = 5 yr PSUR
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E2C Addendum (2)
• Addendum Report– Summarize safety information between most recent
PSUR and Regulatory Authority’s requested cut-off date
– May follow a simplified presentation
• 30 day extension to 60 day preparation period• Use latest CCSI to determine “listedness” for
PSURs covering > 1 year• Present non-healthcare professional (consumer)
reports in separate line-listings
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PSUR: Use
• Opportunity for re-assessment of safety profile– Not the only time
• Assessment and rationale for updating CCDS/CCSI– Driving updates of Package Inserts worldwide
• Rationale for why events have not been added to CCDS/CCSI
• Opportunity to open discussions on label changes
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PSUR: Use
• Background on total exposure (denominator)
• Interim snapshot of safety reports
• Cumulative numbers of safety reports
• CCDS/CCSI
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PSUR Use: Caution!• Confidential information• Does not explain all prior safety issues
– CCDS/CCSI does give company’s view of safety profile
• Line-listings provide limited information for assessing a case
• Very difficult to change format of line listings– Validated computer outputs
• Causality for events cannot be determined based on information in a PSUR– Central problem for PV: what events are really due to use of the
medicinal product?
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PSUR Use: Unofficial Feedback
• Original CIOMS group thought PSUR would be very short (<10 pages)– In fact they are very long for major products
• “Line-listings not very useful”• Exposure calculations are very rough
estimates– Data available does not exactly match PSUR
periods
Development Safety Update Report
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DSUR
• The PSUR is designed to report on cumulative safety information after product launch
• There are requirements in the US and EU for annual reports during drug development– “IND Annual Report”
– “EU Annual Safety Report”
• Harmonize the format and content of a periodic safety report to be used during development
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DSUR Issues
• Similar to PSUR– Periodicity?– Line listings?– Tabulations?– Events or reactions?– Handling of blinded reports?
Thank you for your kind attention!