Change Dosing Regimens To Lower Drug Costs? It's Possible, Researchers Say

August 9, 2019
Allison Inserro

The August issue of JAMA Oncology features a Viewpoint that puts forth a free-market solution to lower high drug costs by changing dosing regimens without hurting efficacy using the approach of interventional pharmacoeconomics (IVPE).

The August issue of JAMA Oncology features a Viewpoint that puts forth a free-market solution to lower high drug costs by changing dosing regimens without hurting efficacy.

The authors propose the idea of interventional pharmacoeconomics (IVPE) and present 4 strategies. The idea of IVPE comes from traditional pharmacoeconomics, which typically focuses on the value and affordability of pharmaceutical interventions.

In the absence of complete regulation of drug prices, an IVPE approach could save tens of billions of dollars annually, they write.

The first strategy is to lower the dose of a drug; the authors give the example of oral oncology drugs with poor bioavailability that are taken while fasting. In the example of abiraterone, 72 patients were randomized to the standard daily dose of 1000 mg of abiraterone fasting or 250 mg with food. The primary end point of noninferiority of prostate-specific antigen change was met; there was also evidence of equivalence of target (CYP17A) inhibition and prostate-specific antigen progression-free survival.

It also describes ibrutinib, used in chronic lymphocytic leukemia. The drug is formulated as 140-mg capsules; the authors say it is likely that a two-thirds reduction in cost can be obtained by demonstrating the comparability of 140 mg and 420 mg daily. Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase and its maximum clinical effect occurs at doses below the labeled dose of 420 mg. A small pilot study has shown that dose reductions from 420 mg to 140 mg maintain efficacy and Bruton tyrosine kinase occupancy while lowering inhibition of platelet function, a marker of bleeding risk.

Less frequent dosing is a second way to reduce costs, such as in the case of injectable drugs. This would not happen by dose reduction, since they are supplied in single-dose vials. But the authors suggest that less frequent dosing will maintain efficacy, cutting prescribing costs and maybe adverse reactions. The authors give the example of a standard 3-weekly regimen of trastuzumab, which yields trough serum concentrations in excess of the target trough of 20 μg/mL. That suggests that the interval between doses could be increased, with potential cost reductions of 50% or more.

A reduced duration of treatment is another possible strategy, and the article cites multiple trials of imatinib discontinuation for chronic myelogenous leukemia. A shorter duration of treatment has also been studied for trastuzumab in HER2-positive breast cancer in the Persephone trial, which demonstrated that a 50% reduction in the duration of trastuzumab treatment does not compromise efficacy in the adjuvant setting.

A fourth strategy is therapeutic substitution. The authors say off-label bevacizumab is more than 95% cheaper than the FDA—approved alternatives ranibizumab and aflibercept for age-related macular degeneration and as such is the most commonly prescribed vascular endothelial growth factor inhibitor. A publicly funded randomized trial of bevacizumab and a smaller antibody, ranibizumab, demonstrated no difference in efficacy. Widespread use of bevacizumab resulted in an estimated reduction in overall Medicare spending of more than $17 billion.

IVPE may also be linked with reduced adverse reactions. For example, ceritinib, a drug used for anaplastic lymphoma kinase—rearranged lung cancer, causes significant gastrointestinal adverse reactions. Giving a lower dose (450 mg) with food reduced adverse reactions and maintained the efficacy of the previous standard dose (750 mg administered while fasting).

For biologics and biosimilars, less frequent administration may also result in a shorter duration of serious adverse reactions, particularly immune-related ones. Therapeutic drug monitoring has been used to guide the frequency of infliximab administration for patients with inflammatory bowel disease and has been proposed as a guide for nivolumab administration frequency. A shorter duration of trastuzumab is also linked with fewer cardiac toxic effects.

These ideas should capture the attention of payers such as governments, healthcare systems, and self-insured corporations, say the authors, who propose Bayesian noninferiority trial designs as the most efficient to determine the possibilities, “especially in settings where there is a strong pharmacological rationale and/or promising preliminary clinical results.” The use of biomarkers, such as tumor size and soluble biomarkers in inflammatory diseases, are reasonably likely to predict efficacy while demonstrating the increased value of lower-cost regimens.

While a typical noninferiority study is the usual approach, they are expensive and time-consuming approach and can never prove absolute equivalency, the authors note.

In addition, strict payer policies may be required to restrict certain treatment strategies when the results of studies justify an IVPE approach; the authors say they do not expect word to reach providers. And although there is the risk that the pharmaceutical industry will just raise drug prices in response, the authors suggest that off-label dosing strategies would be created. Price increases for the on-label dosing strategy has the potential to stir public anger, given the current focus on drug prices overall.


Ratain MJ, Goldstein DA, Lichter AS. Interventional pharmacoeconomics—a new discipline for a cost-constrained environment. JAMA Oncol. 2019;5(8):1097-1098. doi:10.1001/jamaoncol.2019.1341.