In recognition of the increasingly important role fixed-combination products play in treating cancer, cardiovascular, and infectious diseases, the FDA has issued draft guidance that significantly departs from its historical interpretation of the five-year NCE exclusivity provision. Currently, the Agency's regulations state that it is precluded from accepting ANDA or 505(b)(2) applications for drug products containing the same "active moiety as in the new chemical entity" until the five-year NCE exclusivity period lapses. 21 CFR 314.108(b)(2). The new draft guidance focuses on the Agency's evolving interpretation of the term "drug" in the eligibility clause of the five-year NCE exclusivity statutory provisions to improve incentives for producing new drugs in fixed-combinations, a practice that is often safer and more effective. 

FDA promulgated its five-year NCE exclusivity regulations more than 20 years ago. Since that time, FDA has interpreted the term "drug" to mean a drug product that "contains no active moiety that has been [previously] approved by FDA." 21 CFR 314.108(a). This interpretation of the statute and regulations removes incentives for industry to produce new drugs in fixed-combination with ingredients that have already been approved. The presence of the previously approved drug ingredient makes the product ineligible for five-year NCE exclusivity. Even the manufacturer that produces the new drug in stand-alone form is entitled to exclusivity only for any subsequent combination products for the same five-year window, beginning on the date the new drug was initially approved, known as the "umbrella period." 

The draft guidance sets forth that FDA will change its interpretation of the term "drug" in the five-year NCE statute and its regulatory definition of new chemical entity, such that the exclusivity determination will be made for each drug substance in a drug product, not for the drug product as a whole. Thus, fixed-combination applications under section 505(b) of the FD&C Act will be eligible for five-year NCE exclusivity for a new drug even if it contains a previously approved drug.

The draft guidance acknowledges recent changes in the field of fixed-combination therapy. The Agency notes that fixed-combinations have become increasingly common, especially in the last decade, with the rate of NDA approvals up significantly. Fixed-combination approvals are also aimed at an increasingly diverse set of therapeutic areas, with mounting evidence showing that they "improve treatment response, lower the risk of developing resistance, and lower the rates of adverse events." FDA received several petitions in 2013, asking it to revise its interpretation of the five-year NCE exclusivity provisions with respect to certain fixed-combinations. Petitioners pointed out that the existing interpretation might lead to suboptimal drug development strategies. 

For example, an applicant may submit an NDA for a single-entity product first to preserve its right to exclusivity over any subsequent combination product, even if the single-entity product is less effective or safe than the fixed-combination form. FDA agrees with the petitioners, concluding that "the new interpretation urged by the petitioners would be beneficial to the public health" and now seeks to align its interpretation to optimize exclusivity incentives with public health goals. However, if the Agency's draft guidance is finalized in current form, these petitioners of approved products would not see relief. FDA indicates that it intends to apply the new interpretation prospectively once adopted and that it will have no effect on fixed-combination drug products that were approved before adoption of the new interpretation. 

FDA does not propose amending its regulations. Rather, it proposes that it will change how it administers the NCE exclusivity regulations upon finalization of the guidance document. Because the proposed change is a "more than a minor nature" change to existing policy, FDA is required to solicit and consider public comments before finalizing the guidance. The 60-day comment period ends on April 25. 

A copy of the draft guidance document is available here

A copy of the Federal Register Notice announcing the availability of the Draft Guidance for Industry on New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products is available here