Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response

Abstract

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit-risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy-effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy-effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.

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“…As described above, this approach poorly predicts findings of subsequent evidence accumulation. The focus on HRs from clinical trials is further complicated by the 'efficacy-effectiveness gap', the commonly observed discrepancy between clinical trial results and the performance of a treatment in real-world practice [10]. For welldocumented reasons -including healthcare system characteristics, clinical trial measurement methods and complex interactions between a drug's biological effect and contextual factors -clinical trials do not always predict realworld outcomes [11].…”

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“…Furthermore, clinical practice may vary on a regional or national level. These differences can lead to a discrepancy between the observed efficacy of interventions in RCTs and their effectiveness in clinical practice, a phenomenon often referred to as the efficacy-effectiveness gap [6,7].…”

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“…15 In the case of vaccines, the effectiveness is lower than the efficacy, which is accounted for by a large set of requirements and potential failures in the vaccination operation (e.g. cold chain, application quality, selection of the subjects, etc.)…”