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

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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!