BIOMARKERS A
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www.frontiersin.org/ articles/10.3389/fphar.2021.747194/full Development and qualification of biomarkers are
key to the future of drug development and precision medicine, particularly in oncology. Biomarkers have pleiotropic utility, and approved and experimental biomarkers can be classified based on their clinical uses. Diagnostic biomarkers suggest the presence of a disease or can classify patients into subtypes. Prognostic biomarkers predict the patient’s overall survival, independent of therapy. Pharmacodynamic target and exerted a cellular response. Predictive biomarkers, or ‘responder identification’, indicate how patients are likely to respond to treatment, either in terms of efficacy or toxicity. Biomarker analytical performance is the ability of a biomarker assay to measure the underlying biomarker quantity under a variety of conditions. Clinical performance means the ability of the assay to inform about a clinical condition of interest, while clinical utility is an assay’s ultimate ability to improve clinical outcomes. A validated, predictive biomarker may become a companion diagnostic, defined by the FDA (Food & Drug Administration) device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. Integrating biomarkers into the therapeutic
development process may not only allow for a more rapid translation from preclinical through clinical development, but also allows for less promising projects to be stopped earlier (especially before entering into costly large Phase II/Phase III trials), thus optimising the total cost of drug development, which aligns with health policy bodies looking for value for medicines. Biomarkers
“Analyses show that for genome-targeted therapy, estimated eligibility was 5.1% in 2006, which then rose to 8.8% in 2018, and has since increased to 13.6% in 2020”
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therefore have the potential to increase the efficiency of drug development in several ways: a) by speeding up clinical trials; b) streamlining clinical trials; c) improving our understanding of how new medicines work and may lead to novel approaches to medicine development in both non-clinical and clinical phases; d) improving the ethics of trial recruitment through help to exclude people who won’t benefit from starting a non-helpful treatment, thus providing an ethical benefit; e) improving trial monitoring and stopping unhelpful trials early; and f) speeding up authorisation. Many new biomarkers are being discovered and used during the development of new medicines though genomics (analyses of changes occurring at the gene level), proteomics (analyses of changes on the protein level), and/or metabolomics (analyses of differences in chemical molecules that play an important role in body and cell function). There are advantages of using validated biomarkers as able to be measured earlier, more easily, or frequently, with high precision; or b) they may be less affected by other treatments, reduce the sample size required, and allow researchers to make faster decisions.
Medicines and companion diagnostics Companion diagnostics are tests that are validated and approved for marketing alongside a new medicine and are not the same as the diagnostic biomarkers defined above. The trend is to develop medicines and companion diagnostics together, rather than have both developments happen separately. Choice among trial designs using biomarkers depends on several issues, such as the clinical development phase, the degree of validation of the biomarker, and the need to assess both biomarker-positive and biomarker-negative patients. In this context, there are several types of clinical study examples: a) enrichment designs, which are those that exclude biomarker-negative patients; b) biomarker-positive patients – basket trials, which may be used in one or more cohorts of patients, defined, eg, on the basis of tumour types; c) bridging studies, which are applied when the pivotal clinical trial was conducted with an assay other than the companion diagnostic under validation. This is relevant because the percentage of cancer patients who are eligible for, and respond to, genome-targeted therapies is steadily increasing over time. Between 2018 and 2020,
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