FDA REQUIREMENT FOR DOSE-RESPONSE INFORMATION

To advocate that the Food and Drug Administration require drug product manufacturers to (1) identify average dose-response curves for desirable and undesirable effects, and make this information available to healthcare providers; and (2) publish dose-response information, to the extent possible, on factors that lead to differences in pharmacokinetics and pharmacodynamics among individuals; further,

To encourage drug product manufacturers to conduct studies on and publicly report minimum effective dose data.

Rationale

Knowledge of the relationships among dose, drug concentration in blood, and clinical response (effectiveness and undesirable effects) is important for the safe and effective use of drugs. This information can help identify an appropriate starting dose, titration of dosing, and identification of doses that would produce unacceptable side effects or be unlikely to provide added benefit. Important to this understanding is the analysis of the dose–response relationship, particularly with drug levels above the ED50, the dose that provides approximately 50% of the maximum possible drug effect, as efficacy increases only slightly, while adverse effects increase.

Manufacturer dose-finding studies sometimes provide a dose estimate and the range of a drug’s population ED50, but this information appears to have little bearing on prescribing. Many are either not aware of this measurement or do not consult the information after the drug is marketed with recommended dosage guidelines. Often overlooked is the variation in individual ED50 depending on body size, pharmacokinetics, and pharmacodynamics. This variation in ED50 may cause the effective dose to be lower in many patients compared with participants in clinical trials. It is important to note that the ED50 also can alert a clinician to the likely useful and safe dose range and should be more widely available. ED50 should be an important variable in drug approval, marketing, and, most importantly, prescribing. Furthermore, numerous observational studies have shown that providers often prescribe increasingly higher levels of treatment, often without clear clinical indication for such high doses. As such, the FDA recommends that dose-response assessment should be an integral part of drug development, including minimum effective doses.