If you want to apply for a marketing authorization for a pharmaceutical product in Europe, you must have a risk management plan (RMP). According to the European Commission’s Directive 2001/83/EC, the risk management plan describes the risk management system for the medicinal product concerned and should include:

• Characterization of the safety profile of the medicinal product(s) concerned
• Indication of how to characterize further the safety profile of the medicinal product(s) concerned
• Documentation of measures to prevent or minimize the risks associated with the medicinal product, including an assessment of the effectiveness of those interventions
• Documentation of post-authorization obligations that have been imposed as a condition of the marketing authorization

The EU risk management plan contains seven sections, including the Safety Specification, the Pharmacovigilance Plan, and the Risk Minimization Measures. The Safety Specification is key to the RMP and is a summary of everything the developer knows and does not know about the product at the time of writing – the “knowns and known unknowns.” The Pharmacovigilance Plan describes the research which the developer will conduct to turn the unknowns into knowns, while the Risk Minimization Plan is all about preventing or minimizing risks to patients.

For most products, the “known” information in the Safety Specification will come initially from pre-clinical and clinical studies. Clinical trials (the most common type of pre-authorization clinical study) are designed to show efficacy in the trial population. For multiple reasons related to the numbers and types of patients in clinical trials, and the length of the trials, the information they can provide on safety is more limited. The Pharmacovigilance Plan details what formal studies will be done to gain information on the safety of the product – the Post- Authorization Safety Studies (PASS).

What are PASS?

Post-Authorization Safety Studies (PASS), are officially defined as studies designed to identify, characterize, or quantify a safety hazard, confirm the safety profile of an authorized medicinal product, or measure the effectiveness of risk management measures. In effect, PASS are the studies which turn many of the “unknowns” in the safety specification into “knowns.” Less frequently, a PASS will measure if the activities to reduce risk in the risk minimization plan are working.

Although any type of study can be a PASS if it fulfils the above definition, many PASS are non-interventional studies. Non-interventional studies are also known as observational studies because they observe what is happening to patients in the real world as opposed to the controlled environment of a clinical trial.

While all studies included in the RMP are a legal requirement, some studies are occasionally so important to the understanding of the benefit-risk of the medicine that the regulators “impose” them, and they are individually mentioned in the conditions of the marketing authorization.

COVID-19 considerations

Two Covid-19 vaccine manufacturers have applied to the European Medicines Agency (EMA) for conditional marketing authorizations (MAs). Conditional MAs are given when there is an unmet medical need for a serious or life-threatening disease, or when the product is intended for use in emergency situations in response to public health threats. There is enough data to be confident that the benefit-risk is positive, but more data is required to bring the product to a full MA. Conditional MAs usually have PASS requested to provide more data on the wider and more long-term use of the product, so it is likely that these products' RMPs will contain plans for PASS.

Minimizing risks

All medicines in Europe have routine risk minimization. This takes the form of the information provided to doctors (Summary of Product Characteristics) and patients (Patient Information Leaflet), the number of tablets, or size of bottle in a pack, and the legal status about whether it needs to be prescribed, who can do it, and where it can be made available. However, some medicines have risks which require measures that go beyond this to ensure their safe and effective use.

The most common additional risk minimization measure is to provide educational materials about specific risks to healthcare professionals who intend to prescribe or dispense the drug and/or to patients who might be taking the medicine. Another risk minimization measure might be regular monitoring – for example liver function tests. An additional risk minimization tool might be to provide patients with a card which records the results of the tests, as well as the date the next test is due.

Studies to measure the effectiveness of risk minimization measures are included in the definition of a PASS. Most products won’t need a formal study to measure risk minimization effectiveness, but occasionally a risk is so critical to the benefit-risk balance that it is important to know that steps to minimize it are working. Even if a formal study isn’t needed, developers are still expected to state how they will measure effectiveness of their additional risk minimization measures – and to do so!

The life of an RMP

Developers should think of their RMP as a living document that needs to be updated throughout the lifespan of the product. As new knowledge becomes available, the safety specification will change, and the Pharmacovigilance Plan and Risk Minimisation Plan will possibly need to be updated. As the product matures, the number of unknowns will decrease and the number of studies in the Pharmacovigilance Plan will also reduce, until eventually formal studies are no longer needed.

Clinical trials provide the initial backbone of the RMP, but it is data and evidence from the real world which then build the complete profile of the product.