Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 January 2024

12 January 2024

Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures

EMA’s safety committee (PRAC) is recommending precautionary measures for the treatment of male patients with valproate medicines. These measures are to address a potential increased risk of neurodevelopmental disorders in children born to men treated with valproate during the three months before conception. Neurodevelopmental disorders are problems with development that begin in early childhood. Valproate medicines are used to treat epilepsy and bipolar disorder. In some EU Member States they are also authorised to prevent migraine headaches.

In reaching its conclusion, the PRAC reviewed data from a retrospective observational study carried out by companies that market valproate as an obligation following a previous review of valproate use during pregnancy. The committee also considered data from other sources, including non-clinical (laboratory) studies and scientific literature, and consulted patients and clinical experts.

The PRAC latest recommendations come in addition to restrictions and other measures that are already in place to avoid valproate exposure in pregnancy, because exposed babies are at high risk of malformations and developmental problems. These measures were endorsed following a referral of valproate and related substances in 2018.

More information is available in EMA’s public health communication.

New safety information for healthcare professionals: new precautionary measures for valproate-containing medicines

The PRAC also discussed a direct healthcare professional communication (DHPC) for valproate medicines.

The DHPC will inform healthcare professionals about the potential risk of neurodevelopmental disorders in children of fathers treated with valproate in the three months prior to conception. It is recommended that valproate treatment in male patients is started and supervised by a specialist in the management of epilepsy, bipolar disorder or migraine. Valproate treatment of male patients should be reviewed regularly to consider whether it remains the most suitable treatment, particularly when the patient is planning to conceive a child.

The DHPC for valproate medicines will be forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). When adopted, the DHPC will be disseminated to healthcare professionals by the marketing authorisation holder, according to an agreed communication plan, and published on the direct healthcare professional communications page and in national registers in EU Member States.

Start of safety review of CAR T-cell medicines

The PRAC started a signal procedure to review data on secondary malignancies related to T-cells (cancers that begin in a type of white blood cells called T-cells), including T-cell lymphoma and leukemia, for the six approved chimeric antigen receptor (CAR) T-cell medicines.

CAR T-cell based gene therapy products belong to a type of personalised cancer immunotherapies where patients' white blood cells (T-cells) are reprogrammed and reinjected to attack the cancer.

Six CAR T-cell products are approved in the European Union (EU): Abecma, Breyanzi, Carvykti, Kymriah, Tecartus and Yescarta. These medicines are used to treat blood cancers such as B-cell leukemia, B-cell lymphoma, follicular lymphoma, multiple myeloma and mantle cell lymphoma in patients whose cancer has come back (relapsed) or has stopped responding to previous treatment (refractory).

A secondary malignancy is when a patient who has cancer (current or previous) develops a second cancer different from the first cancer.

For all six CAR T-cell products, secondary malignancies were considered as an important potential risk at the time of their authorisation and included in the Risk Management Plans (RMPs). Close monitoring is already in place and the marketing authorisation holders of the approved medicines are required to regularly submit interim results from the imposed long-term safety and efficacy studies and as part of the Periodic Safety Update Reports (PSURs).

The PRAC is now reviewing all available evidence, including information on 23 cases of various types of T-cell lymphoma or leukemia in EudraVigilance, the EU database of adverse reactions to medicines, and will decide on the need for any regulatory action.

Agenda

Agenda of the PRAC meeting 8-11 January 2024

Draft Reference Number: EMA/PRAC/545005/2023

PRAC statistics: January 2024

PRAC statistics: January 2024

Glossary:

• Safety signal assessments. A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under 'Signal management'.
• Periodic safety update reports, abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under 'Periodic safety update reports: questions and answers'.
• Risk management plans, abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation. RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under 'Risk-management plans'.
• Post-authorisation safety studies, abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under 'Post-authorisation safety studies'.
• Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under referral procedures.
• Summary safety reports have been introduced as part of the enhanced safety monitoring of COVID-19 vaccines. Marketing authorisation holders are required to submit these reports to EMA, starting on a monthly basis. Their submission complements the submission of PSURs. For more information see Pharmacovigilance plan of the EU Regulatory Network for COVID-19 vaccines. 

Ongoing referrals

Procedure	Status	Update
Hydroxyprogesterone-containing medicinal products – Article-31 referral	Under evaluation	PRAC continued its assessment