Risk minimisation measures and measuring their effectiveness
Risk minimisation prevents or mitigates the risks of a medicine, through routine measures such as the product information and the legal status and, where those are not enough, through additional measures such as educational programmes and controlled access. In the EU the additional measures are governed by Module XVI of the good pharmacovigilance practice (GVP) guidelines and its addenda. They shape the choice of tools, the plan for disseminating them and the evaluation of their effectiveness, and each of these places demands on the writers of the risk management plan, the risk minimisation materials, the studies that measure effectiveness and the periodic safety update report.
Routine and additional risk minimisation
Risk minimisation is essential to ensure safe and optimal patient care. Its activities are used as barriers in medical practice to prevent or mitigate risks to the patient, the healthcare provider or public health. It intends to prevent an adverse drug reaction causally related to the use of a medicine from occurring, or to reduce the probability that it occurs. It also intends to minimise the severity of such a reaction if it occurs and to mitigate the clinical outcome in the patient. For a football team, for example, the most important risk may be that the opposing team scores too many goals, and the best risk minimisation is a good goalkeeper and a good defensive strategy, the benefit being that the team wins. As that example shows, minimising the occurrence or the outcome of a risk has a very large impact on the benefit-risk balance.
Risk minimisation is a complex process, and so are the pharmacovigilance documents related to it. So it is important for a pharmacovigilance writer to understand the concepts of risk minimisation and pharmacovigilance well.
Risk minimisation activities are categorised as routine or additional, the two types the EU regulatory framework generally recognises. Routine risk minimisation includes the product information, such as the summary of product characteristics, and the legal status, such as over-the-counter or prescription-only. The labelling can also be a routine activity, especially where the risk is a medication error, since it might carry symbols or wording that make patients aware of the correct use of a specific formulation. The pack size and the prescription status are also routine activities, and they intend to control the use of a medicine, for example by making the patient present more often at the pharmacy or to the prescribing physician. Additional risk minimisation includes activities such as educational programmes, restricted access and pregnancy prevention. Additional measures are typically educational: educational materials in writing, audio or video, and the direct healthcare professional communication. GVP Module XVI deals exclusively with the additional measures and the measurement of their effectiveness.
Within the risk management plan and the periodic safety update report, the evaluation of important risks provides a conclusion on their impact on the authorised patient population and on the appropriate strategy to manage them in the post-marketing environment. Most of the time routine risk minimisation is considered sufficient to manage risks, but where the seriousness or likelihood of occurrence of a risk is not sufficiently managed by routine activities, additional risk minimisation may be necessary. Additional risk minimisation then requires a detailed plan and a periodic evaluation of its effectiveness, to ensure that the measures meet their defined goals and objectives without causing an unacceptable burden on patients and healthcare providers. So Module XVI also details the requirements and approach to generate metrics to assess that effectiveness.
Module XVI and its revisions
Module XVI was first published on 28 February 2014 and revised on 25 April 2014 (Rev 1) and on 30 March 2017 (Rev 2). The EMA issued a draft third revision (Rev 3) for public consultation in February 2021; one account gives the date as 1 February in its text and as 3 February in its table of the module's history. The draft Rev 3 was planned to come into effect in the fourth quarter of 2021 or the first quarter of 2022. At the end of 2021, after a round of public consultation, Rev 3 was under finalisation, so the changes it proposes could be modified in the final version. Addendum I, on educational materials, was first published on 15 December 2015 and had no revisions. Addendum II, on methods for effectiveness evaluation, was first released for consultation on 3 February 2021, and it was planned to come into effect in the fourth quarter of 2021 or the first quarter of 2022.
Since the module's first publication, stakeholders had outstanding questions about implementing it, and the development of risk minimisation measures in particular revealed unclear areas such as the design, target audience, objectives and effectiveness measurement of risk minimisation tools. Module XVI Rev 2 was issued along with Module V Rev 2. Because Module V Rev 2 described the routine risk minimisation tools, Module XVI Rev 2 focused on additional measures, so the two second revisions complement each other and must be read together. Rev 2 still revealed a need for further practical guidance and clarifications. The draft Rev 3 clarifies the role of risk minimisation in risk management planning and in its impact on the benefit-risk balance of medicinal products, the role of the related effectiveness evaluation, the role of risk communication, dissemination and implementation, and the role of healthcare professionals and patients in risk minimisation. Addendum II provides guidance to stakeholders to monitor the outcomes of risk minimisation measures, and it was being finalised along with Module XVI Rev 3.
One practitioner welcomes Rev 3 as an evolution of the regulations defining additional risk minimisation and the measurement of effectiveness, reflecting the experience gained since the first version came into effect in 2014. On this view, the greater detail of Rev 3 has helped resolve some of the outstanding questions marketing authorisation holders faced with previous versions, and its added information on the target audience and objectives of risk minimisation tools and its expanded consideration of effectiveness measurement should help teams design focused and relevant risk minimisation. More guidance on digital intervention and dissemination would still be helpful, to acknowledge the important role those platforms now play in society. The accumulated knowledge and experience is being included in national guidelines for risk minimisation, with the ultimate goal of protecting patients and public health.
Additional risk minimisation tools
The draft Rev 3 further clarifies the types, objectives and target audiences of the different additional risk minimisation measures. Measures such as educational programmes, direct healthcare professional communications, controlled access and pregnancy prevention programmes are addressed in detailed sections that outline considerations for the target audience, such as the specific types of information relevant for physicians or for patients, and that describe the situations in which each measure should be considered. These sections guide how the objectives of risk minimisation need to be aligned with the choice of tools. Educational materials are further stratified, with specific reference to guides, checklists, risk awareness forms, demonstration kits, patient diaries and patient cards. Controlled access programmes are stratified too, and include controlled prescription and supply systems and centre accredited systems. The tools are not new, but one practitioner welcomes their specific mention and the individualised considerations for each type as helping clarify the appropriate use of the different interventions.
Medical writers working on the materials, such as educational guides or checklists, should consider the objectives the guideline defines for the various tools, to ensure that appropriate information is included. In project management, they need to prompt project team members to provide their respective expertise to design the risk minimisation tool. Templates developed for use within the organisation can improve internal and external communication when the interventions are created and implemented.
The risk minimisation dissemination plan
The draft Rev 3 clearly describes the need for a risk minimisation dissemination plan. The plan complements the information in the risk management plan's Part II module VII and Part V, such as the root cause, the risk factors and the proposed measures to prevent and mitigate important risks, and it should give in-depth details of the objectives, target audience, implementation strategy and milestones. The EMA included no standard template for the dissemination plan in the draft guideline, so marketing authorisation holders can develop a company-customised template to support a harmonised approach to implementing risk minimisation plans that acknowledges the company's situation and way of working. The risk management plan and Annex II of the European public assessment report should be aligned with what the risk minimisation plan details on the root causes of risks, the stakeholders who should receive the interventions, the implementation strategy and the milestones.
Plans for additional risk minimisation should be submitted to national competent authorities as part of the national negotiation before the launch of the product. Medical writers who prepare risk management plans and risk minimisation proposals should be aware of the need to submit the proposal to the national competent authorities.
Evaluating effectiveness
Evaluating the effectiveness of risk minimisation strategies is a key objective of post-marketing surveillance. GVP Module XVI Addendum II recommends that regulatory authorities and marketing authorisation holders apply appropriate study designs and data sources to determine whether risk minimisation measures achieve their intended safety outcomes and reduce the incidence or severity of adverse drug reactions. Reviews in the pharmacovigilance literature emphasise that few post-marketing studies are specifically designed to assess the impact of such measures, which underscores the importance of structured methodologies to evaluate their effectiveness.
The draft Rev 3 expands and clarifies the requirement to evaluate the effectiveness of risk minimisation measures. It specifies that effectiveness evaluations should be focused, meaning that the approach to assessing effectiveness should be aligned with the objectives, target audience and milestones of the risk minimisation activity. It emphasises how and when evaluation should occur, including a close interaction between prospective planning in the risk management plan, targeted endpoints in the post-authorisation safety study and appropriate regulatory follow-up. The evaluation of effectiveness and regulatory follow-up also benefit from patient and healthcare provider input, which the draft also emphasises for the design and evaluation of risk minimisation.
Under the draft, evaluation should take place at defined intervals of 1, 3 and 5 years after the risk minimisation activity is first implemented. These timeframes will be defined according to the type of intervention, agreed with the EMA and national competent authorities, reflected in the risk management plan and aligned with post-authorisation safety study activities. A detailed timeline for measuring effectiveness will help support the appropriate approach to risk minimisation over the lifecycle. Planned timelines for evaluation will also help establish the relevance of risk minimisation measures through a timely demonstration of whether important risks and their minimisation have become routine knowledge integrated into clinical practice.
A new section of the draft details the need to evaluate both the intended and the unintended outcomes of a risk minimisation activity. Marketing authorisation holders must understand whether the activity is having the desired effect, such as an appropriate change in clinical knowledge about how to mitigate a risk, and this desired outcome should be evaluated against any unintended consequence of the risk minimisation. Evaluating both aims to ensure that risk minimisation is fit for purpose and does not place an unacceptable burden on the intended stakeholders. For example, patients might stop taking the medicine because the requirement of the risk minimisation activity is too difficult to follow.
In the initial guideline, an effectiveness evaluation could be categorised as either a process indicator, such as dissemination or changes in knowledge or behaviour, or an outcome indicator, such as an actual change in the incidence of the risk. The draft addresses effectiveness evaluation in more depth, with a hierarchy of three levels: dissemination and risk awareness, behavioural change, and health outcomes. It sets out considerations and expectations for the data to be collected for qualitative and quantitative assessments of each level. Measuring the effectiveness of risk minimisation can be considered a post-authorisation safety study, so the expectations for such a study need to be fulfilled. The draft Addendum II gives detailed consideration to study design and protocol preparation.
Effectiveness in the study documents, the risk management plan and the periodic safety update report
Post-marketing safety writing places growing emphasis on evaluating the effectiveness of risk minimisation, and Module XVI and its related addenda set clear expectations for measuring the real-world impact of the measures, requiring structured methodologies and predefined metrics. This has expanded the scope of safety writing to include analytical plans, methodology descriptions and the interpretation of evaluation results.
Medical writers who write protocols and study reports should be aware of the added requirements for studies used to measure the effectiveness of risk minimisation. The endpoints in study protocols should be focused and aligned with the objectives of the risk minimisation activity, and any interim and final study reports should clearly describe whether the objectives of the measure were met. This calls for close cooperation between medical writers and epidemiologists when the study documents are developed. The guideline recommends different methodologies, which should be considered when a protocol is prepared.
The evaluation of effectiveness should be accurately and appropriately documented in the risk management plan and assessed in the periodic safety update report. The milestones documented in the risk management plan should be carried into the organisation's lifecycle management plan. In the risk management plan, the description of effectiveness should focus on how the outcome informs risk minimisation and pharmacovigilance planning; in the periodic safety update report, it should focus on how the implemented measures affect the safety and benefit-risk balance of the product. The medical writer should ensure continuity from the objectives of the risk minimisation measures to the endpoints in the protocol, the conclusions in the study report, further planning in the risk management plan and communication in the periodic safety update report.