Drug Safety Evaluation

Alberto Lodola

We define "combination drugs" as "fixed-dose combinations" (FDCs), that is, two or more drugs (marketed or not) combined in a single pill or two or more separate drugs packaged together. FDCs have been available commercially for many years but only relatively recently have nonclinical development guidelines been released by a number of regulatory authorities and the World Health Organization; as yet there are no ICH guidelines specific to combination drugs. In general however, the ICH guidelines for monotherapy development provide a framework for FDC development. Depending on the type of drug combination (marketed drug/marketed drug; marketed drug/NME and NME/NME) the scope and complexity of toxicity studies will vary greatly. In all cases however, a key issue is the potential for pharmacokinetic and/or toxicologic interaction between the components. For a marketed drug/marketed drug combination a detailed review of the nonclinical data available may suffice, particularly when the components have a history of coadministration at about the same dose and ratio as that of the proposed combination. For a marketed drug/NME combination, in addition to a review of the data for the marketed drug, a full ICH program of studies will be required for the NME, and a study of up to 90-day duration (in one species) for the combination. With an NME/NME combination each component will require a full ICH battery of studies and a combination study in one species. In all cases additional studies may be needed to address data gaps. Given the many novel and complex issues which arise when developing FDCs we recommend that, whenever possible, the nonclinical study strategy is discussed with the regulatory authorities.