The treatment landscape for type 2 diabetes mellitus (T2DM) has broadened greatly over the past decade with innovative therapies now targeting several distinct pathways involved in the metabolic regulation of blood glucose levels. The advent of these treatments has sparked a new race in the pharmaceutical industry to demonstrate clinical and cost-effectiveness benefits compared with standard-of-care therapies.
One noticeable trend in the development of new oral anti-diabetic products is the increase in fixed-dose combination therapy (FDCT) products, which aim to increase efficacy in lowering glycated hemoglobin (A1C) and blood glucose while reducing the side effects of the individual agents used. Several FDCT products combining metformin with a sulfonylurea, thiazolidinedione, or dipeptidyl peptidase-4 (DPP-4) inhibitor are already on the market. Other products that combine these medications with newer agents, such as the sodium-glucose co-transporter 2 (SGLT-2) inhibitors, are either in late-stage clinical trials or under FDA review. While the goal of preserving or increasing market share for a product is common among developers of these combination therapies, the benefits of these products to patients will no doubt come under increasing scrutiny from payers.
PATIENT ADHERENCE WITH FDCT
One rationale for developing FDCT products is the benefit of increasing patient adherence to prescribed medication regimens. By reducing a patient’s pill burden, especially for those with additional comorbidities requiring dual or triple therapy, an FDCT product may offer a more convenient administration option compared with loose-dose combination therapy (LDCT) with individual products.
Several studies have evaluated the impact on adherence rates of switching patients from dual therapy to FDCT. One retrospective cohort analysis of 7570 FDCT users and 14,762 LDCT users in the Texas Medicaid prescription claims database showed a 12.4% increase in patient adherence.1 A separate study focusing on patients treated with pioglitazone and metformin found an 8.9% increase in adherence when switching from LDCT to FDCT,2 and analyses of 17 different studies conducted between 1998 and 2009 yielded similar results, with improvements in adherence ranging from 10% to 13% with FDCT compared with LDCT.3
The increased adherence seen with FDCT products translated into improved clinical outcomes and cost-effectiveness for patients. Several studies analyzing the effect of nonadherence to prescribed oral anti-diabetic regimens on glycemic control found increased risks of all-cause hospitalization and mortality due to complications from poorly treated diabetes.3 The subsequent economic burden of these complications was also evaluated, and a retrospective analysis of 100,000 patients with T2DM found annual increased healthcare costs of $336 and $1509 for nonadherent metformin and sulfonylurea users, respectively, compared with adherent users.3 These figures were obtained even after accounting for the increased cost of medication that comes with improved adherence, showing that the medication cost was more than offset by the cost savings from averted hospitalizations.3 The cost of an FDCT product (Actoplus Met, pioglitazone/ metformin) compared with its analogous LDCT products was also studied, and the FDCT product was found to be $0.26 less per tablet compared with the LDCT products, leading to a cost savings of approximately $8 per patient per month with FDCT therapy.2
CMS REIMBURSEMENT POLICIES FOR FDCT PRODUCTS
Despite these findings, which support the clinical efficacy and economic benefits of FDCT therapy, a cost-cutting battle continues over the formulary inclusion status of these products in Medicare Prescription Drug Benefit Program (Part D) plans. CMS proposed a change for 2015, struck down in June 2014, that would have made FDCT products exempt from being required on the formularies of Part D plans. The rationale given for this change was that because all individual medications in a given therapeutic class would be included on the formulary as single-entity products, requiring the inclusion of FDCT products would be redundant and unnecessary.
The proposed change would also have both encompassed protected therapeutic classes such as anticonvulsants and antineoplastics, which traditionally include all medications in the class on formulary without restrictive prior authorization requirements,4 and removed the protected designation for immunosuppressants, antidepressants, and antipsychotics, which would reduce the number of medications on formulary for these classes in a bid to lower drug costs. CMS proposed that antiretroviral medications be excluded from this exception, under the rationale that nonadherence to treatment in this therapeutic class presented far more serious clinical consequences than in other cases. As such, CMS concluded that the benefit of increased adherence with antiretroviral FDCT products would warrant formulary inclusion in addition to the single-entity products.4 For now, there are no active proposals to exempt FDCT therapies in protected drug classes from required formulary inclusion. However, it remains to be seen what future guidance CMS will issue regarding FDCT medications, as the agency continues to pursue costcutting strategies while considering the potential clinical and economic benefits of these products.
FDA POSITION ON FDCT PRODUCTS
The proposed changes to Medicare Part D regarding FDCT products come even as the FDA has reconsidered exclusivity rules for such therapies. In recognition of the clinical and cost-effective benefits provided by FDCT products, the FDA finalized an industry guidance in October 2014 that extended exclusivity to 5 years for newly approved FDCT products that combine a New Chemical Entity (NCE) with previously approved components. This benefit, however, will not apply retroactively; any FDCT products approved prior to finalization of the guidance will still have the former 3-year period of exclusivity. In making this change, the FDA noted the benefits of FDCT products, such as improved patient adherence and clinical outcomes, as well as advantages in certain therapeutic areas, such as anti-infectives in combating drug resistance. As such, the FDA considered the change in exclusivity rules an incentive to encourage the development of novel FDCT products.5
David Yao is a PharmD candidate at the Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey.
1. Cheong C, Barner JC, Lawson KA, et al. Patient adherence and reimbursement amount for antidiabetic fixed-dose combination products compared with dual therapy among Texas Medicaid recipients. Clinical Therapeutics. 2008;30(10):1893-1907.
2. Barner JC. Adherence to oral antidiabetic agents with pioglitazone and metformin: comparison of fixed-dose combination therapy with monotherapy and loose-dose combination therapy. Clinical Therapeutics. 2011;33(9):1281-1288.
3. Garcia-Perez LE, Alvarez M, Dilla T et al. Adherence to therapies in patients with type 2 diabetes. Diabetes Ther. 2013;4:175-194.
4. CMS. Contract year 2015 policy and technical changes to the Medicare Advantage and the Medicare Prescription Drug Benefit Programs. https://www.federalregister.gov/articles/2014/01/10/2013-31497/medicareprogram-contract-year-2015-policy-and-technicalchanges-to-the-medicare-advantage-and-the#h-41 Published January 10, 2014.
5. Food and Drug Administration. New chemical entity exclusivity determinations for certain fixed-combination drug products: guidance for industry. https://www.federalregister.gov/articles/2014/10/16/2014-24597/new-chemicalentity-exclusivity-determinations-for-certain-fixedcombination-drug-products-guidance Published October 2014.