Given the growing importance and prevalence of fixed-dose combination (FDC) drugs, the FDA is rethinking the exclusivity for those that combine a new chemical entity (NCE) with previously approved components.

In the past, the agency limited the exclusivity for such products to three years, but as a response to three citizen petitions, it issued a draft guidance, published in Monday’s Federal Register, that would extend the exclusivity to five years – but not retroactively.

That’s bad news for Gilead Sciences Inc., which had been pushing for five-year exclusivity for its HIV drug Stribild. The FDA, which has been holding off on determining the length of the drug’s exclusivity, made it clear in its response to Gilead’s petition that the drug – a combination of two new active moieties, elvitegravir and cobicistat, and two previously approved components, emtricitabine and tenofovir disoproxil fumarate – would receive three years of exclusivity in keeping with the policy in place at the time of its approval in August 2012. (See BioWorld Today, Aug. 27, 2012.)

The policy change spins on the interpretation of the word “drug” in the exclusivity provisions of the 1984 Hatch-Waxman Amendments to the Federal Food, Drug and Cosmetics Act (FDCA). Those provisions allowed five years of exclusivity for drugs with NCEs and three years for new drugs that contained active moieties that had already been approved.

In denying the longer exclusivity to FDCs that paired an NCE with an older drug, the FDA interpreted “drug” as the finished drug product. But Gilead and other sponsors of such combinations said “drug” should be interpreted as the drug substance.

In its citizen petition urging a change, Gilead noted that the FDA’s interpretation “pre-dates the significant advances in medicine in which FDC therapies have been recognized as essential for the treatment of HIV/AIDS and other critical diseases” and added that a new interpretation “is necessary to keep pace with advances in medical science.” (See BioWorld Today, Jan. 25, 2013.)

The FDA, which recognizes the therapeutic benefit of FDCs, agreed. “Recent changes in drug development, particularly in the field of fixed-combination development in the last 20 years, and the importance of fixed-combinations to key therapeutic areas – such as HIV, cardiovascular disease, tuberculosis and cancer – warrant revisiting our current policy,” it said in its joint response to the petitions filed by Gilead, Ferring Pharmaceuticals Inc. and Bayer Healthcare Pharmaceuticals Inc.

The agency noted the value of FDCs in improving adherence to dosing regimens, ensuring better patient outcomes and fighting drug resistance in anti-infectives. It also acknowledged the growing number of FDCs hitting the market. Since the agency finalized its policy on exclusivity 20 years ago, it has approved 19 FDCs that contained an NCE and older drug; more than half of those were approved in the past seven years.

INCENTIVE, NOT REWARD

Given the promise of FDCs and their potential impact on public health, the FDA is considering the longer exclusivity as an incentive to encourage their development, which can be a costly and time-consuming process as it generally involves trials demonstrating efficacy against each of the components separately, as well as against placebo.

Since the longer exclusivity is intended as an incentive, it’s not needed for drugs that have already been developed, the FDA said in denying two more years of exclusivity for Stribild, Ferring’s Prepopik (sodium picosulfate, magnesium oxide and citric acid) and Bayer’s Natazia (estradiol valerate and dienogest).

A retroactive application of a new policy also would burden companies relying on the old policy to develop generics of the three FDCs, the agency added.

At least one abbreviated new drug application has been filed for Natazia, an oral contraceptive that lost exclusivity in May 2013. The three-year exclusivity for Prepopik, approved to cleanse the colon in preparation for a colonoscopy, ends July 16, 2015. Comments on the draft guidance are due by April 25. If the FDA finalizes the guidance, a bill introduced in the House last year may stall in committee.

The Combination Drug Development Incentive Act, H.R. 2985, would have amended the FDCA to grant five-year exclusivity to new combinations of drugs so long as the sponsor was required to evaluate the FDC in new clinical trials. (See BioWorld Today, Aug. 7, 2013.)

The longer exclusivity is just part of the battle for FDCs though. As a cost-saving move, the Centers for Medicare & Medicaid Services recently proposed changes to Medicare Part D that don’t recognize the public health benefits of FDCs. The proposed rule would allow Part D plans to exclude FDCs for most of the protected drug classes. (See BioWorld Today, Jan. 8, 2014.)

“Because all drugs in the category or class of clinical concern would be on the formulary as single-entity products, we do not believe it is necessary, in most cases, to require inclusion of the fixed-dose combination or co-packaged products,” CMS said in the 678-page rule.

The exception would be antiretrovirals, as the rule would require all Part D formularies to include not only all single-entity antiretrovirals, but also all FDA-approved FDC and co-packaged antiretrovirals.