From Safety Signal to Regulatory Action: How the PRAC Signal Process Works

A safety signal can lead to a change in product information, additional risk minimisation measures, further investigation, or a major regulatory decision. The outcome depends on the evidence, the seriousness of the potential risk, and its implications for the medicine’s benefit–risk balance.

For marketing authorisation holders (MAHs), understanding this process is essential. Identifying a potential safety concern is only the beginning. The next steps involve evaluating the evidence, understanding the regulatory response, and ensuring that any required actions are implemented.

The European Medicines Agency (EMA) publishes PRAC recommendations on safety signals, providing a practical way to follow how emerging safety concerns translate into regulatory action.

What Is a Safety Signal in Pharmacovigilance?

A safety signal is information suggesting a new potentially causal association between a medicine and an adverse event, or a new aspect of a known association, that warrants further investigation. Signals may emerge from spontaneous adverse reaction reports, clinical studies, scientific literature, observational data, or other sources.

A signal does not automatically mean that a medicine has caused the reported event. The event may have another explanation, including the patient’s underlying condition or concomitant medication. The purpose of signal management is to examine the evidence and determine whether further investigation or action is justified.

How the PRAC Signal Process Works

The EU signal management process includes several connected activities. Although they can be described as stages, signal management is an ongoing process, and urgent concerns may require action without waiting for every activity to be completed in sequence.

1. Signal detection

Potential safety signals are identified from available sources, including individual case safety reports, the literature, clinical studies, and safety databases.

2. Signal validation and confirmation

The available information is reviewed to determine whether there is sufficient evidence to justify further analysis. The assessment considers the strength of the evidence, clinical relevance and whether the association is already known.

3. Analysis and prioritisation

The evidence is examined in more detail, and the signal is prioritised based on factors such as seriousness, potential impact on public health, and possible effects on the medicine’s benefit–risk balance.

4. Assessment and recommendation

PRAC evaluates the available evidence and recommends whether regulatory action, further investigation or another response is appropriate.

5. Implementation and follow-up

The relevant regulatory bodies and MAHs act on the recommendations, where applicable. Safety monitoring continues, and new evidence may lead to further assessment.

PRAC, the Pharmacovigilance Risk Assessment Committee, plays a central role in evaluating safety concerns. However, its recommendation is not always the final legally binding decision. The next steps depend on the medicine’s authorisation status and the regulatory procedure being used.

For centrally authorised medicines, recommendations to amend product information are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement. For nationally authorised medicines, recommendations are communicated to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), while national competent authorities oversee implementation. Other procedures, such as formal EU-wide referrals, may involve additional decision-making steps.

What Can Happen After a Safety Signal Is Assessed?

Not every signal requires the same response. The regulatory outcome depends on the evidence, the clinical implications and whether existing measures adequately control the risk.

1. Updating the product information

One possible outcome is an amendment to the Summary of Product Characteristics (SmPC) and package leaflet. This may involve adding a new adverse reaction, strengthening a warning, clarifying contraindications or providing more specific advice to healthcare professionals and patients.

Real example: Varicella vaccines, July 2025

Following a case of encephalitis with a fatal outcome after vaccination with Varilrix, PRAC reviewed the available evidence from clinical trials, scientific literature and post-marketing use. It recommended updating the product information for the Varicella vaccine, as well as for relevant measles, mumps, rubella, and varicella combination vaccines.

The changes provided more detail about the severity of encephalitis, including the rare reports of fatal outcomes. They advised patients and caregivers to seek prompt medical attention if symptoms suggestive of encephalitis developed. No additional risk minimisation measures were considered necessary.

This example illustrates an important point: a serious reported event can lead to a more explicit description of a known risk rather than the introduction of a new restriction or suspension.

2. Introducing additional risk minimisation measures

Sometimes, updating the product information alone may not be sufficient. Additional risk minimisation measures may be needed to help ensure that the medicine is used appropriately and that important risks are understood.

Depending on the assessment, these measures can include educational materials for healthcare professionals or patients, controlled-access arrangements, or direct healthcare professional communication (DHPC).

Real example: Ixchiq, 2025

Ixchiq is a live attenuated vaccine against chikungunya. In May 2025, the European Commission requested an EU-level review under Article 20 of Regulation (EC) No 726/2004 following concerns about serious adverse reactions.

During the review, temporary restrictions were introduced for vaccination in people aged 65 years and older. In July 2025, PRAC recommended lifting that temporary restriction while emphasising that the vaccine should be used only when there is a significant risk of chikungunya infection and after careful consideration of the benefits and risks.

The recommendation also involved updating the product information and communicating the findings to healthcare professionals. The CHMP endorsed the recommendation, and the European Commission issued its final decision in September 2025.

The case demonstrates that regulatory action can evolve as the evidence is assessed. Initial precautionary restrictions may be revised, while other conditions for safe use remain in place.

It also illustrates why it is important to distinguish a routine signal recommendation from a formal referral or review procedure. The Ixchiq case was an Article 20 review, not simply a routine product-information update following a signal.

3. Requesting further data or continuing the assessment

A signal may remain unresolved after the initial assessment. In such cases, regulators may request supplementary information, additional analyses or further investigation before reaching a more definitive conclusion.

This does not necessarily mean that the concern has been dismissed. It may mean that the available evidence is insufficient to establish the nature or magnitude of the risk, or to determine which regulatory action would be proportionate.

For MAHs, this can require a coordinated response involving pharmacovigilance, medical, regulatory affairs and other relevant teams. The company may need to review new data, prepare an assessment, respond to regulatory questions or implement any required follow-up activities.

The key distinction is that a request for more evidence is itself a regulatory outcome, even when it does not immediately change the product information.

4. Suspending or revoking a marketing authorisation

In more serious situations, the evidence may raise concerns that cannot be adequately addressed through warnings or additional risk minimisation measures. Regulatory authorities may then consider suspending or revoking a marketing authorisation.

These are major interventions and should not be presented as routine outcomes of the PRAC signal process. They may follow broader benefit–risk reviews or formal referral procedures.

Real example: Oxbryta, 2024

In September 2024, EMA recommended suspending the marketing authorisation for Oxbryta (voxelotor), a medicine for sickle cell disease. The recommendation followed emerging safety data from registry-based studies indicating a higher occurrence of vaso-occlusive crises during treatment, alongside concerns arising from clinical trial data, including an imbalance in deaths.

The CHMP recommended suspension as a precaution while the available evidence was reviewed. The company separately decided to withdraw and recall the medicine from markets where it was available.

Oxbryta provides an example of a major regulatory intervention prompted by serious safety concerns. However, it is important to describe it accurately: the suspension recommendation came from the CHMP as part of a broader review, rather than as a routine PRAC signal recommendation.

For comparison, the ulipristal acetate medicine Esmya, used for uterine fibroids, underwent a review of serious liver injury risk. In 2020, PRAC recommended revoking its marketing authorisation because the risks outweighed the benefits and the risk could not be adequately controlled. This was also a formal benefit–risk review, illustrating how a regulatory process can lead to a decision more far-reaching than an update to the product information.

What Should Marketing Authorisation Holders Do After a PRAC Recommendation?

For MAHs, monitoring the emergence of a signal is only one part of the responsibility. Once a recommendation is published, the company needs to determine whether it affects its products and what actions are required.

A practical response should include the following activities:

• Review the recommendation. Confirm the active substance, affected products, nature of the safety concern and recommended action.
• Assess the impact on the product portfolio. Determine which authorised products and product information documents may be affected, including relevant national authorisations.
• Coordinate implementation. Involve pharmacovigilance, regulatory affairs, medical and other relevant teams to prepare and submit the required changes or information.
• Check communication requirements. Determine whether a DHPC, educational materials or other risk minimisation measures are required.
• Track deadlines and completion. Maintain appropriate records of regulatory commitments, submissions, approvals and implementation activities.
• Continue monitoring. Assess whether new evidence changes the understanding of the risk or requires further action.

EMA explicitly expects MAHs to monitor its published PRAC recommendations and take action in accordance with the applicable recommendations. The precise implementation route depends on the type of authorisation and the procedure involved.

A robust internal process helps ensure that a published recommendation does not remain simply an item on a regulatory news feed. It becomes an assessed and tracked action with clear ownership and documented completion.

Why Continuous Safety Monitoring Matters

The examples show that a safety concern can lead to different regulatory outcomes. A known risk may require clearer warnings; another concern may justify additional measures or restrictions; and a more serious change in the benefit–risk balance may lead to suspension or revocation.

The challenge for pharmacovigilance teams is to recognise relevant information, evaluate it in context and understand when it may require action. Scientific literature, spontaneous reports, regulatory publications and other safety sources all contribute to this work.

Continuous literature monitoring and regulatory intelligence can help teams identify emerging evidence and follow developments after an initial signal has been assessed. However, identifying a publication or regulatory update is only the starting point. The information still needs to be evaluated for relevance, assessed against the available evidence and translated into appropriate action.

Conclusion

The PRAC signal process is an important part of the EU pharmacovigilance system, but it should not be understood as a single, predictable pathway. Its purpose is to ensure that emerging safety concerns are assessed and that regulatory responses reflect the available evidence and the medicine’s benefit–risk balance.

For MAHs, effective signal management means more than detecting a potential risk. It means following the assessment, understanding the resulting recommendation, implementing required measures and continuing to monitor the safety profile of authorised medicines.

The transition from a safety signal to regulatory action is therefore not just a regulatory milestone. It is an ongoing process that connects evidence, decision-making and the practical protection of patients.