Biomarker-Driven Developments in the Context of the New Regulatory Framework for Companion Diagnostics in the European Union.

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk-based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll-out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co-development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR.

Evolution of the EU Biosimilar Framework: Past and Future.

The approval of biosimilars in the EU follows a comprehensive scientific assessment based on stringent regulatory standards. While the initial approach to biosimilars was understandably cautious and conservative in that uncharted territory to protect patients' safety, the analytical and scientific progress and accumulated experience with biosimilars continues to reshape regulatory requirements, generally leading to a reduced burden of clinical trials. This trend is expected to continue, for example, by increasingly employing pharmacodynamic endpoints and biomarkers, but much work remains to make this happen, especially for complex molecules with several or unknown mechanisms of action. We reviewed the available guidance and European Public Assessment Reports (EPARs) of biosimilars approved in the EU via the centralised procedure. This review focuses on the nature and extent of clinical confirmation of biosimilarity considered necessary in addition to analytical and functional data. Cases with conflicting results from different parts of the comparability exercise are discussed, with the aim of identifying whether certain elements of the comparability exercise are more important than others in determining biosimilarity. Taken together, analytical and functional comparison is the foundation of any biosimilar development. In addition, pharmacokinetic similarity is an indispensable prerequisite for any biosimilar approval, so careful planning on behalf of the applicant is mandated to avoid potential failure of such studies, for example, because of large interindividual variability, underpowered trial designs or other methodological causes. Comparative pharmacokinetic studies are a basic requirement for biosimilar development and are usually more sensitive than clinical efficacy trials when detecting potential product-related differences. This may explain why a demonstration of equivalent efficacy could not overrule a finding of dissimilar pharmacokinetic profiles in two cases of biosimilar pegfilgrastim. However, the outcome of efficacy trials depends not only on drug exposure but also on proper pharmacological action of the biological substance in vivo. Therefore, the objectives of both types of studies differ. Efficacy trials should usually be designed as equivalence trials to ensure that the efficacy of the biosimilar is neither decreased nor increased compared with the reference product. However, some remaining uncertainty regarding potentially increased efficacy of the biosimilar may be acceptable in exceptional cases, provided that the data from other parts of the comparability exercise clearly support a conclusion of biosimilarity and safety is assured. In contrast, uncertainties regarding potentially inferior efficacy of the biosimilar may not be acceptable at all. We conclude that the EU biosimilar regulatory framework is robust and able to adapt to advancing knowledge and experience and to strike a balance between regulatory standards, patient safety and feasibility of biosimilar development.

The changing world of cancer drug development: the regulatory bodies' perspective.

BACKGROUND: Although not a singular disease entity, advanced cancer continues to be a largely intractable disease and a high unmet medical need situation. Discovery of novel therapeutic modalities, including new drugs targeting cancer, is undoubtedly of major public health interest. METHODS: In this article, we discuss current trends in oncology drug development as these are ultimately reflected in regulatory drug approvals. RESULTS AND CONCLUSIONS: These include the shift to targeted therapies which hold the promise of personalized medicine, but also financial pressures, the call for adaptive licensing which places more emphasis on early access and post-authorization studies (patient registries, prospective interventional and observational studies) and real-life effectiveness studies, as well as the emergence of biosimilars in the oncology treatment armamentarium.

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.