Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.

Involvement of the European Medicines Agency in multi-stakeholder regulatory science research projects: experiences of staff members and project coordinators.

Background: The European Medicines Agency (EMA) interacts with many different stakeholders involved in the development of drugs, including academic researchers. In recent years, EMA has collaborated more closely with academia, inter alia by taking part in external research projects such as those set up under the Horizon 2020 program in general and the Innovative Medicines Initiative in particular. The aim of this study was to evaluate the perceived added value of EMA's involvement in these projects, both from the perspective of the Agency's participating Scientific Officers and of the coordinators of the consortia that undertook them. Methods: Semi-structured interviews were conducted with the coordinators of 21 ongoing or recently finalized projects in which EMA has participated, as well as with the Agency experts contributing to them. Results: In total, 40 individuals were interviewed, of whom 23 were project coordinators and 17 were EMA staff members. While most of the projects were reported to suffer from delays due to the SARS-CoV-2 pandemic, the consortia adapted to the circumstances and their members still expected to deliver on their objectives. EMA's input into the projects ranged from providing guidance by reviewing documents and attending meetings to creating project materials and disseminating them. The frequency of communication between EMA and the consortia varied widely. The projects generated a diverse set of outputs, which encompassed new or improved medicinal products, methodological standards, research infrastructures, and educational tools. All of the coordinators expressed that EMA's contributions to their projects had increased the scientific relevance of their consortium's work, and the EMA experts found that the knowledge and the deliverables produced by the projects were valuable, taking into consideration the time they had invested into them. In addition, interviewees highlighted some actions which could be taken to increase the regulatory significance of the project outcomes. Conclusion: EMA's engagement in external research projects benefits the consortia conducting them and supports the Agency's mission to foster scientific excellence and advance regulatory science.

Biomarkers in Medicines Development-From Discovery to Regulatory Qualification and Beyond.

Biomarkers are important tools in medicines development and clinical practice. Besides their use in clinical trials, such as for enrichment of patients, monitoring safety or response to treatment, biomarkers are a cornerstone of precision medicine. The European Medicines Agency (EMA) emphasised the importance of the discovery, qualification, and use of biomarkers in their Regulatory Science Strategy to 2025, which included the recommendation to enhance early engagement with biomarker developers to facilitate regulatory qualification. This study explores the journey of biomarkers through the EU regulatory system and beyond, based on a review of interactions between developers and the EMA from 2008 to 2020, as well as the use of qualified biomarkers in clinical trials. Of applicants that used early interaction platforms such as the Innovation Task Force, less than half engaged in fee-related follow-up procedures. Results showed that, as compared to companies, consortia were more likely to opt for the Qualification of Novel Methodologies procedure and engage in follow-up procedures. Our results highlight the importance of early engagement with regulators for achieving biomarker qualification, including pre-submission discussions in the context of the qualification procedure. A review of clinical trials showed that all qualified biomarkers are used in practice, although not always according to the endorsed context of use. Overall, this study highlights important aspects of biomarker qualification, including opportunities to improve the seamless support for developers by EMA. The use of qualified biomarkers in clinical trials underlines the importance of regulatory qualification, which will further enable precision medicine for the benefit of patients.

Biomarker Qualification at the European Medicines Agency: A Review of Biomarker Qualification Procedures From 2008 to 2020.

Regulatory qualification of biomarkers facilitates their harmonized use across drug developers, enabling more personalized medicine. This study reviews various aspects of the European Medicines Agency's (EMA's) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into the EMA's biomarker qualification process and will thereby support future applications. All biomarker-related "Qualification of Novel Methodologies for Medicine Development" procedures that started from 2008 to 2020 were included. Procedural data were extracted from relevant documents and analyzed descriptively. In total, 86 biomarker qualification procedures were identified, of which 13 resulted in qualified biomarkers. Whereas initially many biomarker qualification procedures were linked to a single company and specific drug development program, a shift was observed to qualification efforts by consortia. Most biomarkers were proposed (n = 45) and qualified (n = 9) for use in patient selection, stratification, and/or enrichment, followed by efficacy biomarkers (37 proposed, 4 qualified). Overall, many issues were raised during qualification procedures, mostly related to biomarker properties and assay validation (in 79% and 77% of all procedures, respectively). Issues related to the proposed context of use and rationale were least common yet were still raised in 54% of all procedures. While few qualified biomarkers are currently available, procedures focus increasingly on biomarkers for general use instead of those linked to specific drug compounds. The issues raised during qualification procedures illustrate the thorough discussions taking place between applicants and regulators-highlighting aspects that need careful consideration and underlining the importance of an appropriate validation strategy.

European Medicines Agency support mechanisms fostering orphan drug development.

A legislative framework introducing European public health measures on orphan medicinal products came into force in the European Union in April 2000. The aim of the orphan legislation is to stimulate research and development of medicinal products for rare diseases by providing incentives to the sponsors. Incentives include, among others, an unreserved access to the centralized procedure with a 10-year period of market exclusivity and fee reductions including free scientific advice for drug development. Nine years after the implementation of the orphan legislation, more than 690 products have been designated and 58 have received marketing authorizations in Europe. The orphan designations granted to date cover a wide variety of diseases for which there are either no authorized treatments or only limited treatment options with a need for improvement. At the dawn of the tenth anniversary of the orphan legislation, the aim of this article is to review how the European Medicines Agency has supported the mechanisms fostering development of orphan medicines in the E.U. since 2000.

Animal models for metabolic, neuromuscular and ophthalmological rare diseases.

Animal models are important tools in the discovery and development of treatments for rare diseases, particularly given the small populations of patients in which to evaluate therapeutic candidates. Here, we provide a compilation of mammalian animal models for metabolic, neuromuscular and ophthalmological orphan-designated conditions based on information gathered by the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) since its establishment in 2000, as well as from a review of the literature. We discuss the predictive value of the models and their advantages and limitations with the aim of highlighting those that are appropriate for the preclinical evaluation of novel therapies, thereby facilitating further drug development for rare diseases.

European regulation on orphan medicinal products: 10 years of experience and future perspectives.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.