Value Attribution for Combination Treatments: Two Potential Solutions for an Insoluble Problem

Hundreds of combination therapies for cancer, infectious diseases, and metabolic, cardiovascular, autoimmune, neurological, and other disorders are currently licensed worldwide, and many others are soon to be launched.1 Combination therapy is intended as a combination of multiple drugs, each having a different mechanism of action and used separately (ie, different from fixed combinations). Multimodality treatment is a cornerstone of modern oncology treatment strategy because it targets key pathways in a characteristically synergistic or additive manner and potentially reduces drug resistance, thus, resulting in potentially higher efficacy than the monotherapy approach.2 Pricing and payment of combination therapies are proving challenging for payers and manufacturers, both from a value-for-money and budget-impact perspective. Value should be appropriately attributed to each component for their synergistic effects. In most circumstances, a new drug (add-on) is combined with an existing treatment (backbone): the combination does not substitute but is added to the existing treatment, thus, increasing costs and potentially affecting the cost-effectiveness profile of the overall therapy. In a National Institute for Health and Care Excellence Decision Support Unit report 10 years ago, combination therapies were listed among those potentially subject to the paradox of “not cost-effective at zero price,”3 if a clinically effective add-on medicine to a backbone increases treatment duration. Latimer et al4 have recently discussed the issue in a multistakeholder workshop to identify possible options for addressing these challenges. Improving the design of clinical studies and aligning the cost of constituent therapies to their value were considered the preferred options. Allocating the value to each constituent requires that this contribution is measured. In addition, aligning the cost of constituent therapies to their value requires that this alignment is accepted for both add-on and backbone therapies, which could prove difficult if the marketing authorization holder of the backbone is different from the add-on one. Towse et al5 have further discussed the conditions from which the policy challenge of pricing and valuing combination treatment arises: (1) a higher expected clinical benefit of the combination therapy than each constituent as a monotherapy, associated with extended treatment duration; (2) 2 or more on-patent drugs used in combination and priced to value; (3) 2 or more companies involved, making separate agreements with payers more difficult to reach, while proposing a total treatment cost agreed upon by both, is not allowed because of competition law; and (4) same willingness to pay per health unit gained in the case of combination regimens or single technology interventions, as previously suggested by Latimer et al. 4 At that time, the authors concluded that approaches proposed in the literature were suboptimal since they did not fulfill the following 3 desirable criteria: (1) universality (allowing credible value attribution for a range of configurations); (2) symmetry (meaning the order of backbone vs add-on sequence is not affecting the value attribution between the combination constituents); and (3) completeness (producing an attribution of the combination’s full value between its components).