Top tips for writing the best benefit-risk reports
It is important to stay abreast of the latest requirements in pharmacovigilance in order to meet the needs of the regulators. Here, Seema Jaitly cuts through the confusion to provide a step-by-step guide to writing a Periodic Benefit Risk Evaluation Report (PBRER).
At the end of 2012, the Periodic Benefit Risk Evaluation Report (PBRER) superseded the longstanding Periodic Safety Update Report (PSUR), to better reflect drug safety needs in an evolving pharmacovigilance environment. As the title suggests, the PBRER is an evaluation of the benefits of the product against the risks to ensure that the benefit-to-risk ratio is still positive for the product. This review is carried out on a regular basis, depending on the type of drug and the risks associated with it.
While everyone was used to writing a PSUR (Periodic Safety Update Report), the format of the PBRER is very different. Although the thinking process behind the preparation of both documents should have been similar, a lot of PSURs were not up to the mark and hence the advent of the PBRER has meant a re-learning of analysis and assessment of interval against cumulative data for a lot of pharmacovigilance personnel.
When embarking on the preparation of the PBRER, you need to understand the interval data. It is essential that you know what you are looking at, i.e. how the data has been retrieved from the database. This will enable you to identify potential gaps and ensure that they are addressed appropriately.
The interval data should be reviewed against the cumulative data and anything that looks 'odd' should be reviewed further. Although the PBRER does not require narratives and line listings routinely, the regulator is only seeing the summary table and anything that looks out of place needs to be explained. For example, this could be a relative increase in a specific event or even a few events of a particular reaction. Even if an event is listed you should pay attention to increased frequencies and ensure these are assessed and described in the PBRER if seen. For example, if you have a hypnotic, you may have a report from a poisons unit that has many reports with your product and skews the data so it seems that there is an increase in overdose with your product. This would need to be described in the report.
Previous assessment report
You should always review the previous assessment report for the last report as it is essential that the actions requested are carried out. This should really be assigned when the assessment report is first received but there may be requests to monitor or analyse certain areas in the next PBRER. When this is requested a validation step should be carried out to decide whether these requests are considered signals or not. If they are then a full work-up should be presented in section 15 and 16.2. If not, then a separate section can be presented in section 15 as these would then be considered non-valid signals. Either way there needs to be justification of why the allocation has been made.
The literature should be reviewed regularly to ensure that any articles that refer to new important safety information are identified and explained within the report, although in the previous PSUR format this was required. One thing to bear in mind is that there may be information relevant to your important risks that need to be reviewed and added to section 16.3 or cross-referred. Additionally information on patterns of use would need to be retrieved and summarised within section 5 or cross-referred.
Description of signals is a new concept within the PBRER and has meant that the process needs to be extremely clear within companies so that the relevant signals can be identified and discussed appropriately. The signal process consists of detection, validation, assessment and recommendations for action. Any signals that are new, ongoing or closed during the interval need to be included in the report. Only valid signals should be included and therefore the company tracking system should ensure that it is easy to see the validation status, and also the dates for the other steps in the process so the signals are described in the appropriate sections. When a signal has been closed, i.e. the assessment has been performed, then the outcome can be refuted, identified risk or potential risk, and for the latter two the signal should be described in the relevant sections in 16.3.
If you have a product that does not have a Risk Management Plan (RMP) then you will need to pull out the important potential and identified risks. As a general guide, contraindications and warnings and precautions tend to be the important risks. However, judgement should always be used to ensure the relevant risks are identified. The appropriate risks would be those having a significant impact on individual and public health where perhaps additional pharmacovigilance activities for characterisation or additional risk minimisation activities may be required. This can be quite an onerous task, but the European Medicines Agency (EMA) is starting to publish the public summary of the RMP for products and, if yours is a generic product, it would be worthwhile to check the EMA website and if a public summary is available for the innovator, to align the important risks and missing information.
The responsibility for the benefit section can often lie with the medical department rather than the pharmacovigilance department. Usually a literature search is carried out for the interval to identify any relevant articles or changes to guidelines that need to be included. The baseline used is the indication(s) in the reference information and this is then used to build on for further PBRERs. For older products efficacy data can be an issue as they may not be readily accessible. In these cases old studies identified through the literature and guidelines are often used.
In this section the risks and benefits are brought together. There are different ways of doing this, one way is through use of a value tree and the other through the BRAT framework. In both the benefits of the drug, taking into account other products available, no treatment is reviewed against the pertinent risks to ensure the benefit:risk is still positive.
1. ICH HARMONISED TRIPARTITE GUIDELINE, PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER); E2C(R2), Dec 2012.
2. Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report. 22 June 2012.
About the author:
Dr Seema Jaitly qualified in Medicine from Charing Cross and Westminster Medical School in 1992 and worked in hospital medicine for four years. She has worked in the pharma industry for over 18 years at CROs and companies spanning clinical research, medical affairs, pharmacovigilance and the EU QPPV role. In 2010 she founded Essjay Solutions to offer pharmacovigilance services, consultancy and contracting services.
She is currently studying for an MSc in epidemiology with the London School of Hygiene and Tropical Medicine.
Patients as partners in medicines development – the EUPATI project