Abstract
Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker’s clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines.
Highlights
The growing field of pharmacogenetics, which studies the effect of genetic biomarkers on the likelihood of treatment response or adverse drug reactions (ADRs) [1], offers an important opportunity to increase the chances of drug benefit and/or reduce the risk of harm [2,3,4,5]
Many drugs are withdrawn from the market due to lack of efficacy and/or ADRs [11,12,13], and the latter are a major cause of hospital admissions, morbidity, and mortality [14,15]
We identified each piece of evidence referenced in the introduction section of a of a protocol or design paper associated with the trial, and extracted details of the publication protocol or design paper associated with the trial, and extracted details of the publication year (Figure year (Figure 1), study design, drug of interest, biomarker used, sample size, country of origin, 1), study design, drug of interest, biomarker used, sample size, country of origin, and the age, sex and the age, sex and ethnicity of participants for each trial
Summary
The growing field of pharmacogenetics, which studies the effect of genetic biomarkers on the likelihood of treatment response or adverse drug reactions (ADRs) [1], offers an important opportunity to increase the chances of drug benefit and/or reduce the risk of harm [2,3,4,5]. A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [6] Both germline and somatic genetic biomarkers are being used increasingly to personalise treatments across a wide range of disease areas, including cancer [7,8], thromboembolic disease [9], and autoimmune disease [10], as well as to diagnose disease and provide patient prognosis. More guidance exists on the evidence required for interventions to be included in a trial than for biomarker inclusion, an integral biomarker assay is just as important a component of the trial [41,42] With this in mind, we undertook a literature review with the aim of reviewing sources of evidence used to justify five previously published pharmacogenetic BM trials. In light of our findings, we reflected on and provided recommendations on how such evidence should be compiled by those planning future BM trials
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