Referral Procedures: How the EU Safeguards Medicines

Ensuring the safety and efficacy of medicines is paramount in the European Union. One key mechanism that regulatory authorities use to manage and harmonize decisions on human medicines is the referral procedure. Referral procedures are critical in the European Medicines Agency’s (EMA) framework. They address safety concerns, efficacy issues, and the need for consistent regulation across member states. This article explores the different types of referral procedures, their purposes, and their impact on public health.

What Are Referral Procedures?

Referral procedures initiate formal processes to resolve concerns about medicines that affect multiple EU member states. Various parties, including national regulatory authorities, the European Commission, or the pharmaceutical company holding the marketing authorization, can trigger these procedures. The primary goal is to ensure that medicines are safe, effective, and available under the same conditions across the EU.

Types of Referral Procedures

Article 31 Referral

Article 31 of Directive 2001/83/EC is invoked when there is a need to harmonize regulatory actions across the EU. This usually occurs if there are divergent national medical decisions. This procedure is often used when concerns arise about a medicinal product’s safety, efficacy, or quality.

Case Example: Pseudoephedrine-Containing Medicinal Products

Pseudoephedrine, a common decongestant in many over-the-counter cold and flu medications, was linked to severe but rare vascular events, including posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS).

In 2023, several EU member states raised concerns about these risks, leading to an Article 31 referral by the EMA to assess whether the benefits of pseudoephedrine still outweighed the risks. The Pharmacovigilance Risk Assessment Committee (PRAC) reviewed medical data, safety reports, and research studies. They recommended updating the medicine’s information to include warnings about the risks of PRES and RCVS. They also advised against using the medicine in people who are at higher risk, such as those with heart problems. Additionally, they emphasized the importance of educating healthcare providers and patients about these risks and how to spot early signs of issues. Finally, they encouraged prompt reporting of any side effects.

Article 107i Referral: Urgent Safety Concerns

Article 107i triggers action when new safety data or adverse drug reactions create an urgent need for intervention. This referral is unique in its focus on rapidly addressing serious safety concerns.

Case Example: Metamizole-containing medicinal products

In 2024, the EMA initiated a review of medicines containing the painkiller metamizole due to concerns that existing measures to minimize the known risk of agranulocytosis might not be sufficient. The Finnish medicines agency requested the review. This was in response to ongoing reports of agranulocytosis despite recent efforts to strengthen risk minimization strategies in Finland. In light of the latest reports, the company marketing the only metamizole-containing medicine authorized in Finland requested the withdrawal of its marketing authorization for safety reasons.

PRAC will now review the risk of agranulocytosis for all metamizole-containing medicines authorized in the EU for their different authorized uses and their existing risk minimization measures. The Committee will assess agranulocytosis’s impact on the medicines’ benefit-risk balance and recommend whether their marketing authorizations should be maintained, varied, suspended or revoked across the EU.

The Referral Process: How It Works

The referral procedure begins when a member state, the European Commission, or a marketing authorization holder raises concerns. The issue is then assessed by the relevant Committee within the EMA, such as the PRAC or the Committee for Medicinal Products for Human Use (CHMP), depending on the nature of the referral.

1. Initiation: The referral is formally initiated, and the concerned parties are notified.
2. Assessment: The EMA committee conducts a thorough assessment, reviewing all available data, including clinical trials, pharmacovigilance reports, and scientific literature.
3. Recommendation: Based on the assessment, the Committee makes a recommendation, which could involve updating product information, restricting or suspending the product, or other regulatory actions.
4. Final Decision: The recommendation is reviewed by the European Commission or the relevant national authorities, who make the final, binding decision across all member states.

Impact of Referral Procedures

Referral procedures are crucial for maintaining a high drug safety and efficacy standard across the EU. They align regulatory decisions across all member states, preventing discrepancies that could jeopardize patient safety. Moreover, these procedures enhance transparency and trust in the regulatory system. They achieve this through scientific assessments and public communication of the outcomes.

Referral procedures can significantly change pharmaceutical companies’ marketing and monitoring practices. While this can be challenging, it ultimately helps ensure their products meet the stringent safety and efficacy standards required in the EU.

Conclusion

Referral procedures are vital to the EU’s regulatory framework for human medicines. They promptly address safety concerns and harmonize decisions across all member states. Understanding the different types of referral procedures and their implications is essential for pharmacovigilance specialists. This knowledge helps them navigate the complex regulatory landscape and contribute to the ongoing protection of public health.