Risk Management System
04 Apr 2018
Pharmacovigilance, in simple terms, can be defined as the processes and science of monitoring the safety of medicines and taking steps to reduce the associated risk. Therefore, the assessment of benefit versus risk must begin right from the preclinical evaluation of a medicinal product, and must extend throughout its entire life cycle.
Risk management aims to ensure that the benefits of a particular medicinal product (or a series of medicinal products) exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole. This can be achieved either by increasing the benefits or by minimising the risks associated. The main focus of risk management is to minimise the risk.
A risk management system is a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise the risks relating to medicinal products, including the assessment of the effectiveness of those interventions. This requirement can be fulfilled by the preparation of a risk management plan (RMP).
The risk management cycle
Risk management has three stages which are interrelated and reiterative:
- Characterisation of the safety profile of the medicinal product including what is known and not known.
- Planning pharmacovigilance activities to characterise risks, identify new risks and increase the knowledge about the safety profile of the medicinal product.
- Planning and implementation of risk minimization and mitigation and the assessment of the effectiveness of these activities.
Figure 1: The risk management cycle
The principles of risk management are the same regardless of the type of product, stakeholder or territory. However, the actions and responsibilities within each step of the cycle will vary according to whether the stakeholder is an applicant/marketing authorisation holder, competent authority, healthcare professional (HCP) or patient. Other players may be involved in the risk-benefit management such as:
- Patients’ organisations (providers of essential support and information to those living with medical conditions, as well as their families and carers)
- Educated societies
- Health economists
- National safety organisations
- Environmental advisors
- Occupational health professionals
- Pharmaceutical distributors
Essential components of any risk management cycle:
- To identify and analyze the risk(s): The safety concerns are categorized into important identified risks, important potential risks and missing information. To identify the new safety concerns or to further characterise the known safety concerns including elucidation of risk factors, pharmacovigilance activities are performed. These activities can be divided into routine pharmacovigilance activities and additional pharmacovigilance activities. Routine pharmacovigilance activities include: case processing (collection of cases from different sources including spontaneous, literature and regulatory authority cases); follow up of safety reports for missing information and for information on the progress and outcome of the cases; generation of aggregate reports with cumulative analysis of data from all sources; management and evaluation of cases with exposure to medicinal products during pregnancy; handling of customer communications/medical inquiries; periodic signal detection and management activity; and literature review activity. Additionally, use of specific questionnaires as a follow-up to a reported suspected adverse reaction is considered to be routine pharmacovigilance. Additional pharmacovigilance activities may be non-clinical studies, clinical trials (Post-authorisation safety studies [PASS]) or non-interventional studies such as drug utilisation studies, and registries. A safety concern may have no, or a number of, additional pharmacovigilance activities associated with it depending upon its nature, the degree to which it has already been characterised, and the feasibility of studying it.
- To prevent or minimise the risk(s): Each safety concern is considered on a case-by-case basis and depending upon the severity of the risk, healthcare setting, indication, pharmaceutical form, target population and its impact on public health, the risk minimisation activity/measure is decided. A safety concern may be addressed using more than one risk minimisation measure. Risk minimisation activities can be divided into routine risk minimisation activities and additional risk minimisation activities. Routine risk minimisation measures/activities include the provision of information of risks into product labeling (eg. SmPC, the PIL), the pack size(s) modification or limitations, changing the legal status of the product, restricted prescription and special medication prescription. Additional risk minimisation measures/activities include educational programmes for HCPs, caregivers and patients (such as educational material, direct healthcare professional communication letter [DHPC letter], patient alert card), controlled access programmes, controlled distribution systems, pregnancy prevention programme etc. The evaluation of effectiveness of additional risk minimisation measures facilitate early corrective actions if needed and indicate modification over time.
Pharmacovigilance planning and risk management in the EU
In the EU, the RMP consists of seven parts. Certain parts of the RMP, in particular the safety specification, are subdivided into modules so the content can be tailored to the specifics of the medicinal product, and the modules added/removed or re-used in other documents (e.g. PSURs).
- Part I: provides the administrative information on the RMP and an overview of the product(s) covered within it.
- Part II: provides a synopsis of the safety profile of the medicinal product(s) and includes what is known and not known about the medicinal product(s). It contains a summary of the important identified risks of a medicinal product, important potential risks, and missing information.
- Part III: provides a plan to identify and/or characterise the risks identified in the safety specification. It does NOT include actions intended to reduce, prevent or mitigate risks.
- Part IV: provides post-authorisation efficacy study details for the medicinal product(s) where efficacy may vary over time, patients in whom this assumption of constant efficacy may not be true, and where post-authorisation longer term efficacy data is necessary.
- Part V: provides the risk minimisation plan with details of the risk minimisation measures which will be taken to reduce the risks associated with individual safety concerns.
- Part VI: provides a summary that includes key elements of the RMP with a specific focus on risk minimisation activities. A summary of the RMP for each medicinal product shall be made publically available and is written in layman language so that non-HCPs can also understand the concerns with the product.
- Part VII: provides the annexures which include interface between RMP and Eudravigilance/EPITT, current/proposed SmPC and PIL, worldwide marketing authorisation status, synopsis of on-going and completed clinical studies, specific adverse event follow-up forms, details of proposed additional risk minimisation activities with mock up examples, and referenced material.
Pharmacovigilance and risk management are highly regulated, and an indispensable part of the pharmaceutical product life cycle. Benefit and risk must be continually assessed with an updated knowledge of the pharmaceutical product. Building risk management plan requires a systematic approach to ensure that all safety aspects are monitored and addressed properly. Building risk management plans require thorough knowledge, experience and niche expertise on each pharmacovigilance system elements.
GVP Module V – Risk management systems (Rev 1). EMA/838713/2011. Updated April 2014; cited 25th Mar 2016.Available from: