Safety Reports:PSUR/PBRER

Index

1. What is a Periodic Safety Update Report (PSUR)?2. Objective of the PSUR3. Periodicity, EU Reference Dates and Data lock Points4. Exemption from submitting PSURS5. EU single assessment of PSUR (PSUSA) 6. Summary of GVP Module VII7. How to review a PSUR/PBRER

Safety Reports: PSUR/PBRER

1. WHAT IS A PERIODIC SAFETY REPORT (PSUR)?

Periodic safety update reports (PSURs) are pharmacovigilance documentsintended to provide an evaluation of the risk-benefit balance of a medicinalproduct for submission by marketing authorisation holders at defined timepoints during the post-authorisation phase.

PBRER (Periodic Benefit Risk Evaluation Report) are referred to as PSUR since implementation in Europe via GVP module VII.

2. OBJECTIVE OF THE PSUR (1)

To present a comprehensive and critical analysis of new or emerging information on the risks and, where pertinent, new evidence of benefit to enable an appraisal of overall benefit risk. To contain an evaluation of new relevant information that became available to the MAH during the reporting interval, in the context of cumulative information:

• Examine whether new information is in accord with previous knowledge of the benefit risk profile

• Summarises relevant new safety information that may impact the benefit risk profile

• Summarises any important new efficacy and effectiveness information • Conduct an integrated Benefit/Risk evaluation (where new important safety

information has emerged)

2. OBJECTIVE OF THE PSUR (2)

This evaluation of risk-benefit assessment should be undertaken in the context of ongoing pharmacovigilance and risk management:

Module VII: Post-authorization safety studies

Module V: Risk management systems

3. PERIODICITY (1)

PSUR must be prepared at the following intervals:

• Immediately upon request• Every six months from authorisation until product placed on the market• Every six months for first two years on the market• Annually for the next two years• Thereafter every 3 years

Exception – frequency and dates of submission are laid down as a condition of the MAor determined otherwise in the list of Union Reference Dates (EURD List).Submit:

• By day 70 for intervals up to 12 months• By day 90 for intervals in excess of 12 months

3. INTERNATIONAL BIRTH DATE AND DATA LOCK POINT (2)

The date of the first marketing approval for the medicinal product in any country in the world is the International Birth Date (IBD). Data lock point is the date designated as the cut-off for data to be included, based on IBD.

The EU Reference Dates List is a comprehensive list of activesubstances and combinations of active substances for which PSURsshall be submitted:• Legally binding • Periodicity defined on a risk-based approach

The EU Reference Dates List was put in place in order to facilitate theharmonisation of Data Lock Points (DLPs) and frequency ofsubmission of PSURs for medicinal products containing the sameactive substance or the same combination of active substancessubject to different marketing authorisations, authorised in more thanone Member State.EMA has published the list of Union reference dates and frequency ofsubmission information which will be legally binding when Module VIIbecomes effective 2 July 2012.

3. EU REFERENCE DATES LIST (3)

EU reference dates list

3. EU REFERENCE DATES LIST (4)

The EURD list is a living document which will be amended wheneverconsidered necessary by the PRAC, the CHMP or CMDh in response tothe emergence of relevant new safety information, newly authorisedsubstances and requests received from MAHs. Substances can beadded or removed as appropriate. The EURD list is updated on amonthly basis; MAHs should therefore maintain an awareness of thecurrent status of the list. PSURs shall also be submitted at any timeimmediately upon request by the regulatory authorities.

3. EU REFERENCE DATES LIST (EURD List) (5)

3. EU REFERENCE DATES LIST (EURD List) REGULATORY NETWORK (6)

11

The Co-ordination Group for Mutual Recognition andDecentralised Procedures – Human, examine any questionrelating to marketing authorisation of a medicinal product intwo or more Member States in accordance with the mutualrecognition procedure or the decentralised procedure.

Executive body of the EuropeanUnion responsible for proposinglegislation, implementingdecisions, upholding the Union'streaties and day-to-day running ofthe EU.

Helps protect and promote health in Europe by evaluating medicines for both human and veterinary use.

Heatlh Authorities of each Member State

The Committee for Medicinal Products for Human Use is thecommittee at the EMA that is responsible for preparingopinions on questions concerning medicines for human use.

CHMP

The committee at the EMA that is responsible for assessingand monitoring safety issues for human medicines.

EMA

PRAC

National Competent Authorities (NCA)

4. EXEMPTION FROM SUBMITTING PSURS

Generics, well-established use, and traditional herbal medicinalproducts are exempted from submitting PSURs except in thefollowing circumstances: The marketing authorisation provides for the submission of

PSURs as a condition. PSURs is (are) requested due to concerns relating to PV data or

due to the lack of PSURs relating to an active substance afterthe MA has been granted (e.g. when the “reference” medicinalproduct is no longer marketed).

For the products where PSURs are no longer required to besubmitted routinely, it is expected that marketing authorisationholders will continue to:• Evaluate the safety of their products on a regular basis and

Report any new safety information that impacts on the benefit-risk profile or the product information.

5. EU SINGLE ASSESSMENT OF PSUR (PSUSA) (1)

PSUSA is a PSUR single assessment of substances contained incentrally authorised product(s) AND nationally authorisedproducts. This assessment lead to legally binding outcomes:maintenance, variation, suspension, revocation of the marketingauthorisation.

Objectives: harmonise and strengthen the safety and benefit-riskreview of medicines across the EU; increase the shared use ofresources between competent authorities; Assessment by thePRAC with CHMP involvement (for CAP and CAP/NAP) or CMDh(for NAP) in case of regulatory action.

5. EU SINGLE ASSESSMENT OF PSUR (PSUSA) (2)

5. EU SINGLE ASSESSMENT OF PSUR (PSUSA) (3)

The EMA publishes a list of outcomes for NAPs on their websitewhile outcomes for CAPs are published as part of each medicine’sEuropean public assessment report (EPAR). Any changes to theproduct information as a result of the PSUR assessment areimplemented without subsequent variation for CAPs and throughthe appropriate variation at national level for NAPs.http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000620.jsp&mid=WC0b01ac0580902b8d

6. SUMMARY OF GVP MODULE VII

Module VII includes guidance on the objectives, format and contents of thePSUR, as well as recommendations for quality systems for PSURs and trainingof staff members on the PSUR process.

Overall ContentPSURs should provide greater emphasis on analysis of case reports; toinclude:

scientific evaluation of the benefit-risk profile summaries of relevant scientific/clinical data including literature searches available sales/prescription data to calculate patient exposure

The reaction terms used in the PSUR should be in accordance with theMedDRA terminology.

7. HOW TO REVIEW A PSUR/PBRER

Review by an experienced person who knows the drug and who knowsdrug safety.HIGH QUALITY /AUDITS/ INSPECTIONS

• All promises and commitments made to the Health Agencies (HAs), whether inthe PSUR itself or in accompanying emails or communications should be noted.Responses to HAs.

• Make sure you have in hand the appropriate labels (CCSI, national labeling etc.).• The reviewer should be aware of any current concerns (safety signals, special

populations, new or removed indications, any actions taken for safety reasons bythe company or another health agency, any label changes for safety reasonsanywhere in the world….)

• Careful review of the SAEs/ADRs:• In which SOCs have most SAEs/ADRs occurred?• Any surprises or signals in the listed SAEs/ADRs?• Any surprises or signals in the unlisted SAEs/ADRs?• Any surprises or issues in the fatal SAEs/ADRs?• Are there any findings in specific patient populations as defined by disease, age,

vulnerable groups etc?

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