Biomarker qualification at the European Medicines Agency: a review of biomarker qualification procedures from 2008 to 2020

Regulatory qualification of biomarkers facilitates their harmonised use across drug developers, enabling more personalised medicine. This study reviews various aspects of the European Medicines Agency's (EMA) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into 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 analysed 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 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

Changes and determination of dosing recommendations for medicinal products recently authorised in the European Union

Introduction: The quantity and quality of data for determining the dose and treatment schedule of medicinal products is directly related to how safe and efficacious these medicines are and how successful they can be used to treat patients. Areas covered: This review provides an analysis of dose-related label modifications of recently approved drugs. It shows which areas could benefit from a better dose-exposure-response understanding, both during initial assessment and after marketing authorisation. This analysis highlights regulators' considerations in dosage evaluations and provides reflections for drug developers on how to ensure best possible dose selection in the interest of the patients. Expert opinion: Using modelling and simulation, pharmacogenomics, population pharmacokinetics, physiologically based pharmacokinetic models and drug-drug interaction studies in conjunction with well-designed clinical trials will improve the understanding of the pharmacology of medicines, of the physiology of the disease and of the dose-exposure-response relationship during drug development. More focus should be given to the investigation of dose and regimens for special populations before applying for marketing authorisation. Consequently, regulators could review dose-exposure-response data with more certainty and better define dose recommendations in the label

Cancer Drug Development and the Evolving Regulatory Framework for Companion Diagnostics in the European Union

The European Union (EU) legal framework for medical device regulation is currently under revision. The European Commission has proposed a new framework to ensure that medical devices serve the needs and ensure the safety of European citizens, aiming for a framework that is fit for purpose, more transparent, and better adapted to scientific and technological progress. The proposed new framework is described as an evolution of the current regime keeping the same legal approach. An important proposed change is that companion diagnostics will no longer be considered as low risk and subject to self-certification by the manufacturer. According to the new proposal, companion diagnostics will be classified as high individual risk or moderate public health risk (category C) and require conformity assessment by a notified body. It has also been proposed that evidence of the clinical utility of the device for the intended purpose should be required for companion diagnostics. In this article, we review the EU legal framework relevant for companion diagnostics, describe the proposed changes, and summarize the available scientific guidance from the European Medicines Agency and its regulatory experience with cancer drug development including companion diagnostics. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development.

Biosimilars: what clinicians should know.

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators