Medicines, medical devices and blood regulation and safety – guidance

Periodic benefit risk evaluation reports for medicinal products

How to submit your periodic benefit risk evaluation report (PBRER), previously a periodic safety update report (PSUR).

Overview

You must submit a periodic benefit risk evaluation report (PBRER) for all approved medicinal products (unless they are covered by the derogation given in Directive 2001/83, Article 107b.3).

The PBRER is a periodic assessment of the risk-benefit balance of the product. You need to do this irrespective of the marketing status of the product (whether it is placed on the market or not). The PBRER provides an analysis of the safety, efficacy, and effectiveness of the product over its lifecycle.

Most information will likely be related to safety, but you should include information on any new limitations of the medicine and alternative treatment areas.

You must not wait for the PBRER submission to notify us of significant new information relating to the safety and efficacy of your product. Follow the good pharmacovigilance practices for guidance on how to report this urgent safety information.

When to submit your PBRER

If you have just been granted an MA you usually need to submit your PBRER:

  • every 6 months until the product is placed on the market
  • every 6 months for the first 2 years after the product is placed on the market
  • once a year for the following 2 years

Check the European reference data (EURD) list for the exact submission date relating to the active substance in your product, which overrides the general cycle above. The cycle may also be different if you were given specific conditions when you applied for your MA. Although these deadlines have been set, MHRA may request a PBRER at any time.

If you cannot find the submission date for your active substance on the EURD list, it is usually because it is only authorised in the UK. Email the European Medicines Agency (EMA) EURDList@ema.europa.eu if you believe this is inaccurate.

Data lock points (DLPs)

Your specific submission date is based on your ‘data lock point’ which is the cut off point for preparing your report (the end of the cycle). If your submission date is not on the EURD list, it will be:

  • 70 days after your DLP if your PBRER covers a period of 12 months or less
  • 90 days after your DLP if your PBRER covers a period of 12 months or more

You may be able to use some of the same modules in the development safety update report (DSUR) and or risk management plan in the PBRER to minimise duplication and improve efficiency. See appendix D in the ICH guidelines for more information.

How to submit your PBRER

Please note the way you submit your PBRER is changing.

PSUR Repository

Under legislation introduced in July 2012, the EMA has established a repository for the submission of PSURs in the EU. This repository also provides safe storage for associated assessment reports, additional data and comments. From 13 June 2016 it will be compulsory for all PSURs to be submitted to the repository. This will apply for all products including those only approved in the UK. From 13 June 2016 there will no longer be submission of PSURs to the MHRA or any other national competent authority.

The repository is now available and you can submit your PBRERs directly to the repository. Repository use will be mandatory from 13 June 2016. From this date all PSURs must be submitted to the repository even if the product is only authorised in the UK. Up until the 13 June you should also submit your PSUR to the MHRA using current procedures.

Further information on the repository, including how to register to use the submission tools can be found here.

Submission to MHRA: up to 13 June 2016

You should submit:

Follow the eCTD format when submitting your PBRER and supporting documents.

Submit your PBRER and documents using Common European Submission Platform (CESP) or on the MHRA portal using the ‘general submission form’. You will need to register if you haven’t already.

Email pharmacovigilanceservice@mhra.gsi.gov.uk if you don’t receive a confirmation email with the reference number for your submission.

Follow the EMA’s guidelines for single assessment procedures too.

How to prepare your PBRER

You should submit 1 PBRER for all medicinal products with the same active substance according to the EURD list. This should include all:

  • authorised indications
  • routes of administration
  • dosage forms and dosing regiments

This applies even if the products have different names and are granted through different procedures (e.g. decentralised).

You should only submit separate PBRERs for different products with the same active substance if this was agreed when your MA was granted. For example when there are different formulations of the active substance with significantly different indications.

You should follow the EMA’s good pharmacovigilance guidelines (GVP VII) and the guidelines by the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use to prepare your PBRER.

Risk-benefit evaluations

The PBRER should:

  • critically examine information received since your 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 - if you don’t know the date or you can’t access the information use the earliest applicable date for clinical developments as a starting point
  • 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

You should also include the results of any new studies carried out on the safety of your product around off-label use, with a summary of their impact.

Efficacy, effectiveness and safety information of the product

To help demonstrate this in your risk-benefit evaluation you need to include sources. 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)

You can include other sources outside of those above to demonstrate the risks and benefits of the medicinal product.

Exemptions

You do not need to submit routine PBRERs if your medicinal product falls under some articles in the European Commission’s directive (2001/83/EC), unless there’s a specific condition in your MA or it’s indicated in the EURD list. These are:

  • article 10.1 generic (previously article 10.1 a ii)
  • article 10.a - well established use (previously article 4.8ii)
  • article 14 - homeopathic medicine
  • article 16a - traditional herbal medicine

See the European Commission’s directive (2001/83/EC) for more information.

How PBRERs are assessed

PBRERs are jointly assessed by MHRA and other European national competent authorities assigned by the Pharmacovigilance Risk Assessment Committee (PRAC) or a member country appointed by the CMDh. PRAC will create 1 report using a single assessment framework for all products with the same active substance and share it with the relevant MA holders.

The PRAC will issue a recommendation for PBRERs for:

  • a centrally authorised product(s)
  • any mix of centrally authorised products, and those under national and EU procedures
  • nationally authorised products reflected in the EURD list

If the PRAC recommends regulatory action e.g. variations to amend the product information, this will need to be endorsed by the CHMP (centrally authorised products or a mix of centrally and nationally authorised) or the CMDh (nationally authorised products).

MHRA will assess products for active substances authorised in the UK only, on an individual basis.