EMA Draft Guidelines: Reproductive Safety and Predictive Biomarker Assays
The European Medicines Agency (EMA) has released two draft scientific guidelines for public consultation, covering reproductive safety assessment and predictive biomarker assay development throughout the medicinal product lifecycle.
The first guideline addresses the assessment of fertility, pregnancy and breastfeeding risks, while the second provides recommendations for developing, validating and maintaining predictive biomarker assays, including companion diagnostics (CDx).
Consultation deadline: 28 February 2027
The EMA has published Revision 1 of its guideline on reproductive and breastfeeding risk assessment, incorporating updated scientific approaches, clinical evidence and new approach methodologies (NAMs).
Key Updates and Regulatory Expectations
1. Integrated reproductive risk assessment
The guideline introduces a structured approach to assessing potential effects on male and female fertility, pregnancy, embryo-fetal development and breastfed infants. Assessments should integrate non-clinical toxicology, pharmacology, pharmacokinetics and available human clinical evidence.
2. Non-clinical and clinical evidence
The assessment considers reproductive toxicity studies, mechanisms of action, clinical trials, pregnancy registries, epidemiological studies and post-marketing safety data. Qualified in vitro, ex vivo and other NAM approaches may also support risk assessment and, where justified, reduce or replace certain animal studies.
3. Pregnancy and breastfeeding assessment
Pregnancy risk assessments should consider exposure timing, clinical outcomes, biological mechanisms, dose-response relationships and available treatment alternatives.
For breastfeeding, developers should assess active substance and metabolite transfer into breast milk, potential infant exposure, pharmacological properties and reported adverse effects. Effects on breast milk production and composition should also be considered.
4. Risk classification and recommendations
The guideline uses structured classifications, including identified risk, potential risk, unlikely risk and insufficient data, as applicable to fertility, pregnancy and breastfeeding assessments.
Recommendations should balance potential risks against treatment benefits, disease severity and the availability of safer alternatives.
5. Product information updates
The draft provides updated recommendations for the Summary of Product Characteristics (SmPC) and Package Leaflet (PL), particularly SmPC Section 4.6 covering fertility, pregnancy and breastfeeding. Relevant considerations for contraindications, warnings and precautions are also addressed.
Consultation deadline: 31 March 2027
The EMA has released a draft guideline establishing recommendations for predictive biomarker identification, assay development, validation and lifecycle management. It is primarily intended for medicinal product developers and also supports collaboration with IVD and companion diagnostic manufacturers.
Key Updates and Regulatory Expectations
1. Context of use and biomarker development
Developers should define the assay's context of use, intended patient population and role in treatment decisions. The guideline describes exploratory research, patient selection and clinical validation stages in biomarker assay development.
2. Analytical and clinical validation
Analytical validation should establish relevant performance characteristics, including sensitivity, specificity, precision, reproducibility and appropriate cut-off values.
Clinical validation should demonstrate that biomarker status predicts clinically relevant treatment outcomes. Evidence should support appropriate patient selection and the benefit-risk profile of the medicinal product.
3. Sample management and data quality
The guideline addresses sample collection, processing, storage, baseline sampling and missing data. Developers should ensure representative samples and assess potential bias associated with biomarker pre-screening.
4. Assay adaptations and bridging studies
Changes to assay platforms, biomarker panels or cut-off values during development require appropriate justification and evidence that analytical and clinical performance remain suitable. Bridging studies may be needed to demonstrate comparability between assay versions and maintain continuity of clinical evidence.
5. Centralised and decentralised testing
Centralised testing supports consistency through a common testing environment, whereas decentralised testing can provide faster results and operational flexibility. Where multiple laboratories or assays are used, comparable performance should be demonstrated.
6. Companion diagnostics and IVDR requirements
The guideline clarifies the interface between medicinal product regulation and the In Vitro Diagnostic Regulation (IVDR). Companion diagnostics support the identification of patients most likely to benefit from treatment or those at increased risk of serious adverse reactions.
Medicinal product authorisation and CDx certification follow separate regulatory frameworks, with a consultation procedure involving medicinal product authorities as part of notified body assessment.
7. SmPC and post-approval follow-up
Relevant biomarker and assay information should be reflected in the SmPC. Post-authorisation activities should maintain assay reliability and assess changes that could affect biomarker-guided treatment.
References:
Comments