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29. Periodic Safety Update Reports (PSURs)/Periodic Benefit-risk Evaluation Reports (PBRER)

29. Periodic Safety Update Reports (PSURs)/Periodic Benefit-risk Evaluation Reports (PBRER)

Periodic safety update report (PSUR) provides a periodic and comprehensive assessment of the worldwide safety data of a marketed drug.

Over time it was recognized that the risk of the marketed drug should be assessed in the light of its benefits and change in the risk estimate overtime. Consequently, the report name was changed to Periodic Benefit-Risk Evaluation Report (PBRER).

PBRER are mandatory for all approved medicinal products.

This report provides an analysis of the safety, efficacy, and effectiveness of the product over its lifecycle. Most information will likely be related to safety, but information on any new limitations of the medicine and alternative treatment areas also needed to be included.

In simple terms, PBRER means submitting safety information to Regulatory authorities periodically. But in practice the Regulatory requirements make the process much more complex.

How to prepare PBRER:

Single PBRER for an Active Substance: The report should provide information on all approved indications, dosage forms, and regimens for the active substance, with a single DLP.

PBRER for Fixed-Dose Combination Product: For combinations of substances also marketed individually, information for the fixed combination may be reported either in a separate PBRER/PSUR or included as separate presentations in the report for one of the individual substances, depending on the circumstances. 

Products Manufactured and/or Marketed by More than One Company: Each MAH is responsible for submitting PSURs for its own products.

When companies are involved in contractual relationships (e.g., licensor-licensee), respective responsibilities for preparation and submission of the PSUR to the regulatory authorities should be clearly specified in the written agreement.

Risk-benefit evaluations: The PBRER should:

  • critically examine information received since last PBRER to see if there are new signals that have led to potential or current risks or update information on previous risks
  • summarise any new information on the safety, efficacy and effectiveness of the product that could affect its risk-benefit balance
  • provide an integrated benefit-risk analysis from the date of an interventional clinical trial (in any country) for all authorised indications 
  • summarise any risk minimisation actions implemented or planned during the reporting interval
  • outline plans for signal or risk evaluations including timelines and/or proposals for additional pharmacovigilance activities
  • Need to include results of any new studies carried out on the safety of product around off-label use, with a summary of their impact.

Source of report must be included to help demonstrate risk-benefit evaluation. These may include:

  • non-clinical studies
  • spontaneous reports (e.g. reports on the marketing authorisation holder’s safety database)
  • active surveillance systems (e.g. sentinel sites)
  • investigations of product quality
  • product usage data and drug utilisation information
  • clinical trials, including research in unauthorised indications or populations
  • observational studies, including registries
  • patient support programs
  • systematic reviews and meta-analysis
  • marketing authorisation holders’ sponsored websites
  • published scientific literature or reports from abstracts, including information presented at scientific meetings
  • unpublished manuscripts
  • licensing partners, other sponsors or academic institutions and research networks
  • competent authorities (worldwide)

Format and Presentation: 

The recommended table of contents, including section numbering, for the PBRER is provided below: 

Title Page: It contains the label of the medical product, the description number, the name and address of the Marketing authorisation holder, the global birth date with the name of the nation, the report date. 

Executive Summary: It contains a concise summary of the most important information contained in the report. 

Table of Contents

  1. Introduction
  2. Worldwide Marketing Approval Status
  3. Actions Taken in the Reporting Interval for Safety Reasons
  4. Changes to Reference Safety Information
  5. Estimated Exposure and Use Patterns

5.1 Cumulative Subject Exposure in Clinical Trials

5.2 Cumulative and Interval Patient Exposure from Marketing Experience

6. Data in Summary Tabulations

6.1 Reference Information

6.2 Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials

6.3 Cumulative and Interval Summary Tabulations from Post-Marketing Data Sources

7. Summaries of Significant Findings from Clinical Trials during the Reporting Period

7.1 Completed Clinical Trials

7.2 Ongoing Clinical Trials

7.3 Long-Term Follow-up

7.4 Other Therapeutic Use of Medicinal Product

7.5 New Safety Data Related to Fixed Combination Therapies

8. Findings from Non-Interventional Studies 

9. Information from Other Clinical Trials and Sources 

10. Non-Clinical Data

11. Literature

12. Other Periodic Reports

13. Lack of Efficacy in Controlled Clinical Trials 

14. Late-Breaking Information

15. Overview of Signals: New, Ongoing, or Closed 

16. Signal and Risk Evaluation

16.1 Summary of Safety Concerns

16.2 Signal Evaluation

16.3 Evaluation of Risks and New Information

16.4 Characterisation of Risks

16.5 Effectiveness of Risk Minimisation (if applicable)

17. Benefit Evaluation

17.1 Important Baseline Efficacy/Effectiveness Information

17.2 Newly Identified information on Efficacy/Effectiveness

17.3 Characterisation of Benefits

18. Integrated Benefit-Risk Analysis for Approved Indications

18.1 Benefit-Risk Context – Medical Need and Important Alternatives

18.2 Benefit-Risk Analysis Evaluation

19. Conclusions and Actions 

20. Appendices

Refer below document for complete guidance.

http://academy.gmp-compliance.org/guidemgr/files/E2C_R2_STEP4.PDF

Regulatory Requirement for Submission of PSUR in different countries 

The need for the submission of a PBRER and the frequency of report submission to regulatory authorities are subject to national or regional regulatory requirements, and usually depend on such factors as approval dates, the length of time the product has been on the market, and the extent of knowledge of the benefit-risk profile of the product. 

The PBRER format and content are intended to apply to periodic reports that cover reporting periods of 6 months or longer. 

Once a drug has been marketed for several years, national or regional regulation may allow the frequency of submission to be extended to longer time intervals, e.g., greater than one year for products considered to have an established and acceptable profile or considered to be low risk; however, more frequent PBRERs may continue to be required in other regions. 

As a result, the following scenarios may be encountered by MAHs:

  1. PBRERs may be required on 6-monthly, annual, and less frequent submission timetables simultaneously across different regions.
  2. Changes in reporting frequency may also apply after important additions or changes in clinical use are approved (e.g., new indication[s] and/or new population[s]). In these circumstances, it is possible that the reporting interval will be shortened, even for older products with a previously reduced frequency of PBRER submission.
  3. An ad hoc PBRER may be requested by a regulatory authority 

Reference documents:

  • CIOMS II: International Reporting of Periodic Drug-Safety Update Summaries
  • ICH E2C: Periodic Benefit-Risk Evaluation Report
  • GVP Module VII: Periodic safety update report
  • 21 CFR 314.80(c)(2) and 600.80(c)(2)
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