Commentary/Response to Damkier et al.

We take notice of the article by Damkier and colleagues in this issue of Pharmacoepidemiology and Drug Safety. In their commentary, the authors contest EMA's pharmacovigilance risk assessment committee (PRAC) recommendation of precautionary measures for valproate-containing medicines and urge the European Medicines Agency for greater transparency in its communication of risks. There are many points made by the authors with which we entirely agree. EMA agrees that transparency is pivotal for trust between clinicians, academics, regulatory authorities and patients. We strive toward publicly communicating how our scientific committees come to their recommendations, and for that reason we published on our website the public health statement referred to by Damkier and colleagues. Publication of the statement in plain language immediately after the PRAC recommendation ensured that key stakeholders (patients and healthcare professionals) were appropriately informed without delay. We also published materials detailing the PRAC assessment, study methodology and analyses as soon as the administrative and quality standards required of such document were met: EMA's post-authorisation safety studies webpage presents the final study report, PRAC assessment report and the direct healthcare professional communication, and the HMA-EMA Catalogues present the final protocol. Taken together, these materials transparently and comprehensively present the outcome of the PRAC assessment to all target audiences. EMA also agrees that collaboration between regulatory agencies, academia, healthcare professionals and patient representatives is essential, and the Agency routinely interacts with different stakeholders (Patients and consumers/healthcare professionals/international agreements). As presented in the assessment report and public health statement, input from patients, healthcare professionals and experts was collected by the PRAC on the proposed measures; a stakeholder meeting was held on 16 November 2023, followed by an expert meeting on 4 December of the same year. Experts agreed that the strength of the evidence for neurodevelopmental disorders after paternal valproate exposure was limited and advised a precautionary approach, suggesting healthcare professionals and patients be informed in a timely way due to the seriousness of the potential risk. Finally, EMA agrees that measurements of neurodevelopmental outcomes are complex, and this is carefully reflected in the PRAC review. The PRAC considered not only the findings of the post-authorisation safety study, but also existing evidence from scientific literature (1, 2, 3, 4) and the views of patients and clinical experts expressed during the stakeholder and expert meetings. The marketing authorisation holders for valproate-containing medicines provided additional information. The review of all these data ultimately resulted in the current recommendation, including guidance for healthcare professionals and for patients who need these medicines. We consider that the outcome of the assessment reflects all available information, including input from patients, healthcare professionals and subject matter experts. In addition, we have transparently disclosed all relevant materials underpinning the PRAC recommendation. We will continue to monitor the safety of valproate-containing medicines and take appropriate action when emerging evidence warrants it. The authors declare no conflicts of interest.