Cardiovascular Polypills Flounder under FDA Regulations


Fixed-dose combination (FDC) products may be grossly underavailable for cardiovascular conditions.

Fixed-dose combination (FDC) products may be grossly underavailable for cardiovascular conditions.

Although solid clinical evidence supports the safety and effectiveness of multiple single-agent drugs to treat chronic diseases such as cardiovascular disease (CVD), diabetes, and hypertension, the real-world efficacy of these regimens is held back by their complexity— a key factor in poor medication adherence and health outcomes.

Combining several medications into 1 polypill can overcome these obstacles. However, strict regulatory hurdles have had a chilling effect on the availability of these adherence-promoting medications.

For instance, to patent a new FDC, manufacturers often must conduct and submit phase 3 studies for FDA approval. In addition, the FDC manufacturing process commonly involves challenges that require specialized expertise. This considerable time, effort, and risk result in a mere 3 years of FDA-imposed market exclusivity for the patent holder.

Recently, the FDA sought to incentivize FDC production by expanding this period of exclusivity to 5 years. However, an important limitation of this exclusivity agreement is the provision that at least 1 medication in the combination must be a new molecular entity.

Under current regulations, many of the most commonly used medications will never become available as FDCs, including the 3 most popular medications for CVD:

· Lisinopril/simvastatin

· Lisinopril/metformin

· Metformin/simvastatin

Additionally, none of the 3 most commonly paired medication classes are available as FDCs:

· Angiotensin-converting enzyme inhibitors/statins

· Beta-blockers/statins

· Biguanides/statins

Unlike HIV/AIDS drug therapy, which is dominated by FDCs, CVD care has been plagued by medication nonadherence and therapeutic complexity exacerbated by the lack of FDCs. Results from a recent study reveal an important yet unrealized opportunity for greater availability of FDCs for CVD.

Using medical and pharmacy insurance claims data from a national commercial insurer, researchers identified patients who in 2012 filled prescriptions for multiple single-agent drugs to treat diabetes, dyslipidemia, and hypertension, or FDCs containing these products.

Of a total of 848,082 patients, two-thirds (67%) filled at least 1 FDC prescription in 2012. Among the 20 most frequently filled pairs of single-agent medications, however, only 3 (lisinopril/hydrochlorothiazide, amlodipine/atorvastatin, and glipizide/metformin) were available commercially as FDCs. Importantly, all 3 of these medications were available in generic forms.

Analyzing the medications more broadly by combinations of drug classes, only 9 of the 20 most frequently paired classes were available commercially as FDCs.

“Utilization of drug combinations to treat cardiovascular conditions does not correspond well with availability of FDCs containing these agents,” the authors concluded. “A concerted set of strategies should be implemented to streamline the development of useful combination products, including expedited approval pathways and increased investment in formulation studies.”

The significance of cardiovascular FDCs was formerly stressed in the global Fixed-dose Combination Drug for Secondary Cardiovascular Prevention (FOCUS).

In that study, researchers randomized patients to receive simvastatin, ramipril, and aspirin in either a polypill or 3 separate dosage forms. The investigators then assessed medication adherence and cardiovascular outcomes over more than 3 years of follow-up.

Compared with the 3 medications administered separately, the FDC significantly improved adherence and subsequently led to fewer cardiac events. After 42 months, cardiac events occurred in 43% of patients receiving 3 medications, compared with 26% of those taking the FDC.

As lead FOCUS study author Valentin Fuster, MD, noted, “Rather than thinking of a polypill as a trivial intervention, it is important to recognize that the polypill is of critical importance.”


1. Wang B, Choudhry NK, Gagne JJ, Landon J, Kesselheim AS. Availability and utilization of cardiovascular fixed-dose combination drugs in the United States. Am Heart J. 2015;169(3):379-386.e1.

2. Castellano JM, Sanz G, Peñalvo JL, et al. A polypill strategy to improve adherence: results from FOCUS (Fixed-dose Combination Drug for Secondary Cardiovascular Prevention) Project. J Am Coll Cardiol. 2014.

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