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Necessity of strengthening the current clinical regulatory for companion diagnostics: An institutional comparison of the FDA, EMA, and MFDS.

ABSTRACT: Companion diagnostics (CDx), which is essential in precision medicine, is changing to a personalized treatment approach. CDx is a test that identifies patients who can benefit from a specific drug and those who experience side effects of drugs for safe and effective treatment. Conversely, when CDx has inadequate diagnostic performance or has not been adequately validated in a particular treatment, treatment prediction based on diagnostic results is not possible. Given the importance of CDx for the clinical use of biomarkers, strict regulation is essential. Regulators are providing more stringent regulations and are developing or revising guidelines. For example, the EU's In Vitro Diagnostic Regulation has defined CDx for the first time, raising awareness of the importance of CDx. However, if a new clinical performance test needs to be performed to meet the latest specifications or requirements for clinical data, problems such as securing clinical samples or institutions, cost, and time may occur. Therefore, an efficient clinical regulatory process may be required to meet stringent regulatory requirements. This study examines the need to strengthen the current clinical regulatory framework for CDx through an institutional comparison of regulatory agencies (FDA, EMA, and MFDS).

SUBMITTER: Kang SL

PROVIDER: S-EPMC10474566 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Necessity of strengthening the current clinical regulatory for companion diagnostics: An institutional comparison of the FDA, EMA, and MFDS.

Kang Su Lim SL Woo Jae Hyun JH Kim Na Hyeon NH Kwon Ji Yean JY Kim Sung Min SM

Molecular therapy. Methods & clinical development 20230816

Companion diagnostics (CDx), which is essential in precision medicine, is changing to a personalized treatment approach. CDx is a test that identifies patients who can benefit from a specific drug and those who experience side effects of drugs for safe and effective treatment. Conversely, when CDx has inadequate diagnostic performance or has not been adequately validated in a particular treatment, treatment prediction based on diagnostic results is not possible. Given the importance of CDx for t ...[more]

PMID: 37663648

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Project description:Companion diagnostics are an indispensable part of personalized medicine and will likely continue to rapidly increase in number and application to disease areas. The first companion diagnostics were launched in the 1980s and in the face of significant initial skepticism from drug developers as to whether segmenting a drug's market through a diagnostic was advisable. The commercial success of drugs such as Herceptin® (trastuzumab) and Gleevec® (imatinib), which both require testing with companion diagnostics before they can be prescribed, has moved the entire companion diagnostic field forward. From an initial start of a handful of oncology drugs with corresponding diagnostics, the field has expanded to include multiple therapeutic areas, and the number of combinations has grown by 12-fold. Based on drugs in clinical trials, the rapid growth will likely continue for the foreseeable future. This expansion of companion diagnostics will also have a global component as markets in Europe will evolve in a similar but not identical pattern as the US. One of the greatest challenges to future growth in companion diagnostics is aligning the incentives of all stakeholders. A major driver of growth will continue to be the economic incentives for drug developers to pair their products with diagnostics. However, diagnostic companies are caught between the conflicting demands of two major stakeholders, pharmaceutical companies on one hand and payers/providers on the other. Regulators are also becoming more demanding in aligning development time lines between drugs and diagnostics. In order to survive and prosper, diagnostic companies will need to think more broadly about companion diagnostics than the historical match between a specific drug and a single diagnostic. They will also have to continue the process of consolidation and global expansion that the industry has already begun. Despite these potential obstacles, companion diagnostics have become one of the hottest areas of deal making in the diagnostic space in recent years, and the future trends continue to look bright.

Project description:BackgroundOver the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences.ResultsCFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data.ConclusionsRegulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients' eligibility and access: FDA's approach was more mechanistic/biology-driven while the EMA's one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.

Dataset Information

Necessity of strengthening the current clinical regulatory for companion diagnostics: An institutional comparison of the FDA, EMA, and MFDS.

Publications

Necessity of strengthening the current clinical regulatory for companion diagnostics: An institutional comparison of the FDA, EMA, and MFDS.

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