Overview
A drug is authorized by an agency only when it demonstrates a positive risk-benefit balance or safety profile for the target population. It is a key component of Pharmacovigilance (PV) to safeguard public health. However, information on drug safety gathered from clinical trials is limited and, at times, not relevant to the larger population that shall consume the drug once it has been marketed. Consequently, information available at the time of approval is usually sufficient only to provide a preliminary assessment of the balance between benefit and risk. Thus, Regulatory Authorities have mandated the submission of a Risk Management Plan as part of drug safety surveillance.
What is a Risk Management Plan?
A risk management plan (RMP) is a legally binding document that ensures that the product’s benefit outweighs its risks throughout its life cycle [1]. An RMP aims to identify and characterize risks and outline interventions to prevent or alleviate these risks.
The RMP has three basic components:
- safety specification, which elaborates the current knowledge of the safety profile of the drug,
- the pharmacovigilance plan, which aims to add to the knowledge of suspected risks and fill gaps where knowledge is absent; and
- an assessment of the requirement for risk-minimization activities.
Data collected from non-clinical and clinical studies provide the synopsis of the safety profile that makes up the safety specifications. Information that is not known at the time, such as long-term safety, use in a pediatric population, and use in special populations such as renal impaired or pregnant, is also included in the risk management plan. The risks are classified into important identified risks, important potential risks, and missing information.
Safety specification forms the foundation of the pharmacovigilance plan that roadmap the routine or additional activities required to be conducted in the post-authorization phase.
Routine minimization or more
The nature of the risk determines if routine risk minimization measures such as conveying risk information in Package Leaflets and Summary of Product Characteristics, limiting pack size, or restricting the distribution by label status is enough for mitigating these risks or if some more effective interventions are required. These interventions could be simple as an educational program where a patient alert card or a prescribes brochure is distributed to increase awareness of the risk or can be complex such as a control access program or pregnancy prevention program.
The choice of additional risk minimization measures largely depends on the seriousness and frequency of the risk and its impact on the patient’s health. Hence, one can agree that there cannot be a ‘one-size-fits-all’ approach in risk mitigation, and careful expertise consideration should be given to determine if the mitigation goal can be achieved with routine minimization measures or of what intensity of the additional risk minimization measure is required. Development, execution, and evaluation of the effectiveness of risk minimization measures are key elements of risk management. The estimation of the effectiveness of these measures enables early and prompt corrective actions if needed. As the drug is being used more over time, and more information and experience are gained for the drug post-marketing, these measures may require modifications. This would result in more stringent interventions, or these measures may become obsolete.
Accordingly, a risk management plan is not a ‘one-off’ document but rather a live and ever-evolving document that requires thorough examination and understanding, making risk minimization a complex process.
Risk Management Guidelines: EU vs. US
While many countries have their respective guidelines for the format and content of risk management plans, most countries worldwide accept this EU format with additional requirements captured in country-specific annexures. The startling difference can be noted in the USFDA’s risk minimization method.
European RMP
Stringent regulatory agencies around the world have implemented guidelines for RMPs. For example, in Europe, the acceptable format of an RMP is elaborated in EMA’s Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems [1,2].
US REMS
For the USFDA, a Risk Evaluation and Mitigation Strategy (REMS) is developed to monitor the balance between the risks and benefits of the drug [3]. REMS requirements comprise a communication plan, medication guides, communication plans, elements to ensure safe use (ETASU), and a timetable for implementing and assessing REMS.
Risk Management Plan and Risk Evaluation and Mitigation Strategy both provide an impactful direction in assuring patient safety with medicinal products.
RMP and REMS capabilities at DDReg
As part of its risk minimization and management services, the medical and pharmacovigilance team conducts a meticulous review of resources, including publications, product labels, medical literature, and more, to provide tailored recommendations for risk minimization measures. The team continuously evaluates product risks and develops country-specific safety documentation. Additionally, the medical and pharmacovigilance experts compile, author, and conduct compliant quality checks of RMPs, supports REMS, review patent portfolios & technological pipelines, and develop and implement additional risk minimization measures.
References and further reading:
[1] European Medicines Agency. Guideline on Good Pharmacovigilance Practices (GVP): Module V- Risk management systems. 2017
[2] European Medicines Agency. Guidance on the format of the risk management plan (RMP) in the EU- in integrated format. 2018
[3] United States Food and Drug Administration. Risk Evaluation and Mitigation Strategies (REMS). 2021