4.1 Introduction

The pharmacovigilance documents associated with risk evaluation and management are often required components of Marketing Authorization Application (MAA) and New Drug Application (NDA) submissions, and thus could have been included in Chapter 3 (Pharmacovigilance Medical Writing for Marketing Authorization). However, they have been accorded a stand-alone chapter as they are ‘living’ documents, which are continually updated and amended throughout the medicinal product’s post-marketing life, as and when warranted by the emergence of new safety information.

In the EU, the Risk Management Plan (RMP) is a mandated component of the MAA for most medicinal products. The EU RMP outlines all safety information yet to be established for the medicinal product and describes the processes that will be utilized by the company to acquire this information. Furthermore, the RMP outlines the measures that will be applied by the company to minimize the product’s determined risks and how the effectiveness and success of these endeavors will be determined.

In effect, the EU RMP, when submitted at the time of application for marketing authorization, affords both the sponsor and regulatory authority the opportunity to proactively plan all required pharmacovigilance activities before the medicinal product is actually licensed for use by the public. As new safety data is gathered during the medicinal product’s early post-marketing life, this document is updated, either upon the initiative of the Marketing Authorization Holder (MAH) or at the behest of the regulators, to further fine-tune understanding of the product’s safety profile and resulting impact on the benefit-risk balance. As such, the EU RMP prepared at the time of application for marketing authorization remains a live document that will continue to be updated in the course of the medicinal product’s post-marketing life.

In the US, the Risk Evaluation and Mitigation Strategies (REMS) Report can be requested by the Food and Drug Administration (FDA) as part of the registration or authorization process for any medicinal product considered as requiring additional risk management processes. In effect, the REMS Report serves the same purpose in the US as the EU RMP in the EU. Although the REMS Report came into effect as a pharmacovigilance document in 2007, the FDA can also request a REMS Report for medicinal products authorized prior to 2007, if considered necessary due to new safety data. As an alternative, it is also possible for the sponsor or MAH to proactively prepare and submit a REMS Report without a specific request from the FDA.

Preparation of the EU RMP and REMS Report involves a significant degree of pre-submission discussion and correspondence between the applicant (i.e. MAH or sponsor) and the regulators, which serve to guide the applicant on the regulators’ views regarding acceptable risk minimization measures for the medicinal product.

The Benefit-Risk Evaluation Report, which presents a cumulative assessment of the medicinal products’ benefits (in specific indications) weighed against the associated risks, is developed during the pre-authorization period. As with other pharmacovigilance documents utilized in risk evaluation and management, the Benefit-Risk Evaluation Report continues to be updated and amended throughout the medicinal product’s life cycle, and is required for product authorization, with subsequent updating and amendment usually required at other critical decision-making points, such as registration of new indications, license renewal, and, on occasions, of product withdrawal.

A summary of the key pharmacovigilance documents required for risk evaluation and management is presented below (see Figure 1.1):

• EU RMP (EU only);
  
• REMS Report (US only);
  
• Benefit-Risk Evaluation reports.

4.2 The EU Risk Management Plan

The general principles of the EU RMP are summarized in Table 4.1.

Table 4.1 General principles of the EU Risk Management Plan.

4.2.2 When are EU Risk Management Plans Prepared?

EU RMPs can be prepared and submitted at any time during the medicinal product’s pre- and post-marketing life cycle. EU RMPs are prepared or updated on the following occasions:

• at the time of the initial MAA (i.e. at the time of product registration/authorization);
  
• application for registration of new indications or changes to approved use (e.g. new dose, new route of administration, or a modified manufacturing process for biotechnology products);
  
• authorization of treatment for a special treatment population (e.g. paediatrics and the elderly);
  
• identification of a new safety concern;
  
• upon request from the relevant competent authority;
  
• within 60 days of important pharmacovigilance or risk minimization activity milestones being achieved or availability of new data from studies.

4.2.3 Data Sources for the EU Risk Management Plan

A summary of the data required for preparation of EU RMPs and the company departments usually responsible for the provision of these data are presented in Table 4.2. As noted with other documents, the precise designations of the departments/functions may vary from company to company.

Table 4.2 Source data for the EU Risk Management Plan.

4.2.4 Review of the EU Risk Management Plan

As with all other pharmacovigilance documents, the preparation of the EU RMP involves contributions from a multidisciplinary team, which is tasked with participation in document planning, provision of data from their respective departments, and review and approval of the RMP. A summary of the team that should be involved in preparation of the EU RMP is presented in Table 4.3.

Table 4.3 The EU Risk Management Plan review team.

4.2.5 A Timeline – Planning for the EU Risk Management Plan

As a general rule, preparation of an EU RMP can be divided into the following four key activities:

• RMP planning and collation of source data;
  
• writing of the draft EU RMP;
  
• review of the EU RMP;
  
• QC, finalization, and approval of the EU RMP.

An example timeline appropriate for preparation of the EU RMP is presented in Figure 4.1.

Figure 4.1 Example timeline for EU Risk Management Plan preparation

4.2.6 Generic Model of the EU Risk Management Plan

A generic model EU RMP template, based on guidelines and format recommended by the European Medicines Agency [3] is presented in this section.

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