Developing combination drugs in preclinical studies.

Although combination drugs have been available for many years, it is only recently that preclinical guidelines have been released by the Food and Drugs Administration (FDA) and EMEA and as yet they are not part of the ICH process. In addition, the World Health Organisation and FDA have issued guidelines for combination drugs developed specifically to treat HIV infections. Depending on the type of combination (marketed drug/marketed drug; marketed drug/NME and NME/NME), the scope and complexity of studies can 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 preclinical data available may suffice; particularly when the components have a history of co-administration 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 programme of studies will be required for the NME, and a study of up to 90 days 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 that arise when developing combination drugs, we recommend that, whenever possible, the preclinical study strategy is discussed with the regulatory authorities.