Unique Risks, Benefits, and Challenges of Developing Drug-Drug Combination Products in a Pharmaceutical Industrial Setting

Abstract

Treatment with a single drug targeting a specific receptor is no longer considered optimal in the treatment and management of complex diseases such as HIV/AIDS, diabetes, and cardiovascular disease. Potential health benefits may arise from the use of affordable, multiple-target, fixedratio drug combinations, which concomitantly reduce multiple risk factors without increasing the risk of adverse effects. Main goals for development of fixed-dose drug combinations may largely be based on the following concepts: treatment of two closely related diseases (e.g., hyperlipidemia and hypertension), patients insufficiently controlled by optimally dosed individual monotherapies, and substitution of fixed-dose combination versus free combination. Success in creating and developing the bestin- class commercial combination products requires a multifaceted approach including the following: 1) treatment paradigms in therapeutic area; 2) patient compliance and impact of personalized medicine; 3) shifts in market and cost drivers; 4) preclinical and pharmaceutical development and manufacturing; 5) competitive intellectual property landscape; and 6) clinical development and regulatory filing strategy. Assessment of risks and probability of success of specific drug combinations and drug delivery technologies are needed in order to arrive at the proper recommendation and risk mitigation plans. Personalization of combination therapy is rationalized on the theoretical premise of division of clinical responders from partial or nonresponders to drugs in diseases for which known biomarkers exists. Combination drug therapies with individualized optimization are likely to become a major future focus. A comprehensive review of industrial practice and literature is presented with the goal of developing a best practices roadmap in the feasibility assessment of drug combination therapies.