Why did the European Medicines Agency (EMA) request changes to the RMP template and format with the new Pharmacovigilance legislation? A central theme in the new legislation is the evaluation of risks of product in the context of their benefits, and the new RMP helps to document both sides of the benefit-risks story.

The new RMP template captures some of the new data reporting requirements which are imbedded in the legislation (e.g. the collection of evidence on both the risks and the benefits of medicinal products, as well as on the off-label use of products). It also includes a new module entirely devoted to the collection of post-marketing efficacy data in post-authorisation efficacy studies (PAES).

Will all companies affected by these changes?Starting July 2012, all applicants submitting a Marketing Authorisation Application (MAA) are required to submit an RMP. This includes novel products, generics, and homeopathic medicines.

What are the main changes to the RMP template? The content and the overall spirit of the RMP as a Pharmacovigilance planning document have largely been preserved as compared to the previous RMP. For instance, the detailed section on Safety Specification was left intact, with only major change being the collection of data on health-related quality of life (HRQOL). Many of the headers will sound familiar as they were once a part of the previous RMP.

Overall Structure and Format:  The RMP is now modular, so that the EMA may only require particular modules to be updated depending on the needs of the product. 

The criteria used by the EMA will be a recurring theme which stems from the new legislation which is ‘risk-proportionality’ – the greater the risk, the more information may be required of the product, both in terms of the volume and depth of information but also in the number of modules required. Generic products, for example, which would have a long history of the product being on the market would have a much more abbreviated requirement than say a new molecular entity (NME).

Increased Emphasis on Product Benefit-Risk Profile:

Any plans to collect additional information on the benefits of the drug would need to be reported in an entirely new section in the RMP called ‘Plans for Post-authorisation Efficacy Studies’ where if there are concerns that the benefit profile of the product differs in the real-world setting as compared to the randomized controlled trials setting, the company may be provide evidence to this effect. A possible reason to conduct a post-authorization efficacy study, for instance, would be to try and identify which subpopulations of patients would benefit most from the drug.

Another change to the RMP is that the template is now much more prescriptive in terms of how the information needs to be presented. There are very detailed instructions provided (in green text) within each section, and many more headers and subheaders have been added to the previous version of the RMP.

The requirement for information on population not studied in trials, including off-label use, is another prominent feature of the RMP. The structure of the RMP makes it more clear compared to the previous version exactly what information is available from trials, what populations were excluded from trials and constitute missing information, and where the gaps are in knowledge, particular to populations who are generally omitted from trials, such as those with co-morbid conditions, the elderly and children. For instance, the company is now required to discuss the ability of their RCTs to detect rare, delayed adverse events and the implications for the target population. Companies are now required to estimate the prevalence of off-label use by country and document the source of information.

Each module reminds us how the risks being described feed into the overall safety concerns. The focus on the list of safety concerns reminds the applicant that all of the activities which accompany the Pharmacovigilance plan coupled and the risk minimisation plan should be centred around the list of safety concerns. So in this way, the RMP feels much more integrated.

Companies should be mindful that the RMP is a living document that changes over time to reflect the benefit-risk profile of products. Another new feature of the RMP, albeit is not a direct part of the template, is the possible input of comments on the RMP from the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC was formed as part of the new legislation to help evaluate and monitor the robustness of the Pharmacovigilance plans, and can require the client to perform additional post-marketing studies to fill any gaps in knowledge or evaluate the safety or efficacy of products over its product lifecycle.

On the whole, the RMP does feel much more integrated within itself, but also more integrated with the Periodic Benefit-Risk Evaluation Report (PBRER) which makes it very clear that the RMP is the Pharmacovigilance planning document and the PBRER is the reporting document that reflects the pharmacovigilance plan and the risk minimisation activities outlined in the RMP.

Do you have any practical advice for companies who will need to submit an RMP under the new template?

Study the new template – concepts have transferred over but the presentation of information has changed; some sections are much more detailed than before.

Allow yourself enough time to complete the various elements of the RMP – the RMP could end up being several hundred pages long; you may need to work with your biostatisticians to generate new tables to fit the requirements of the RMP template. New analyses always take longer than planned.

Where can I find out more about the new RMP?

The GVP guidance document of interest is Module 5, called Risk management systems and there’s a template which accompanies the GVP. You may also be interested in the newly released module which can also be downloaded from the EMA website at www.ema.europa.eu.

About the Expert:

Dr. Joseph Kim joined Quintiles in 2011 and currently serves as Senior Director of Benefit-Risk Management. He was trained in the US and the UK, receiving his PhD in Epidemiology at the University of Minnesota and has worked as a medical statistician and epidemiologist for the past 15 years. He holds an honorary appointment with London School of Hygiene and Tropical Medicine (teaching pharmacoepidemiology and pharmacovigilance for the past 10 years). Dr Kim as conducted academic research leading to publications at London School of Hygiene and Tropical Medicine, Karolinska Institute, Stockholm University and University of Minnesota and is a Fellow and Chartered Statistician of the Royal Statistical Society.