Translating the dose response into risk and benefit

Abstract

When choosing a medicine two aspects determine the balance between benefit and harm (risk-benefit), matching the medicine to the individual and the choice of dose. Knowing the relationship between dose and response allows a calculation of the dose that causes 50% of the maximal effect, the ED₅₀ . Rational drug dosing depends on defining the ratio of the dose to the ED₅₀ . The ED₅₀ of each drug has two scales, whether the effect measured is for efficacy, or safety. Quantifying efficacy is comparatively straightforward. A fall in blood pressure, combined with a statistical and clinically significant reduction in cardiovascular events, might justify the efficacy of an antihypertensive. Measuring a drug's effect on safety is more complex, as this is so often a subjective assessment of a collection of adverse events. Though a science-based therapeutic window defined from in vitro efficacy and safety dose response curves is reassuring, this review discusses how to translate this into dose-dependent risk-benefit based on clinical trial data. Some of the limitations of our knowledge about the choice of dose that optimizes an individual's risk-benefit, or whether no drug is a better option, are discussed. It is important to define these limitations when educating the consumer/patient about the clinical pharmacology that justifies their treatment dose options.

Keywords: EMA; FDA; Phase 1-3; clinical trials; mortality; safety.