For many things in life, details matter. Take cooking, for instance: add the wrong ingredient or combine your ingredients in the wrong order, and you may have an unexpected disaster rather than a prize-winning pie. Trust me, you don’t want to eat a cake made with baking soda when the recipe calls for baking powder.

NCE Exclusivity for Combination Drug Products

For many years, the same rule applied to new chemical entity (NCE) exclusivity for fixed-combination drug products. Under FDA’s longstanding policy, if a company mixed the active ingredients together in the wrong order, NCE exclusivity would not be awarded. Specifically, if a company obtained approval of a new active moiety for the first time in a fixed-combination drug product rather than as a single-entity drug product, FDA refused to grant NCE exclusivity to the drug. But if the company reversed the order by getting approval of the single-entity product first, then both the single-entity and combination products could be protected by NCE exclusivity. FDA based this policy on its interpretation of the term “drug” in the relevant statutory provision to mean “drug product.” See 21 U.S.C. § 355(c)(3)(E)(ii). Under this interpretation, FDA typically made only a single NCE exclusivity determination for the combination product as a whole. And if any active ingredient in that combination had been previously approved, then the entire combination was not eligible for NCE exclusivity.

FDA, however, changed its policy in 2014 in response to several Citizen Petitions. In a final guidance document announcing its new policy, FDA explained that, going forward, it would interpret the term “drug” to mean “drug substance” or “active ingredient” rather than "drug product." This new interpretation allows FDA now to make NCE determinations individually for each active ingredient in a fixed combination drug product rather than once for the combination as a whole. The upshot, of course, is a broader standard for granting NCE exclusivity. FDA explained that interpreting the applicable statutory and regulatory provisions “to permit broader availability of 5-year NCE exclusivity for certain fixed-combinations would further incentivize the development of these important products.”

Special Rules for Combinations Containing "Old Antibiotics"?

But what happens if a new active moiety is added to a fixed-combination drug that contains an “old antibiotic”? “Old antibiotics,” also known as “pre-repeal antibiotics,” are antibiotic active ingredients that were the subject of a marketing application (approved or pending) received by FDA before November 21, 1997. Because antibiotics have a different regulatory history than non-antibiotic drug products, special exclusivity rules have always applied to drugs containing “old antibiotics.” Do special rules also apply to NCE exclusivity for fixed-combination drugs that contain an “old antibiotic”? In other words, are "old antibiotics" the wrong ingredient for this particular exclusivity recipe? Or can applicants rely upon FDA’s new, 2014 policy which states that the order of approval no longer matters?

FDA, unfortunately, has sent mixed signals. In a report to Congress on implementation of the Generating Antibiotic Incentives Now (GAIN) Act, FDA states that an exclusivity determination is still “pending” for two fixed-combination drugs containing “old antibiotics” – Vabomere and Avycaz -- approved several years ago. However, FDA also states that it granted both NCE exclusivity and a GAIN extension to Zerbaxa, another fixed-combination drug that likewise contains an “old antibiotic.” Why the inconsistent treatment of what look like similarly situated products?

While we do not know for certain, we have a hunch. Zerbaxa was approved first -- right after FDA adopted its new fixed-combination policy -- and FDA’s Exclusivity Summary indicates that the Agency explicitly applied that new policy in granting NCE exclusivity. There is no indication, however, that FDA considered the issue of whether special rules should apply because Zerbaxa contains an “old antibiotic,” i.e., tazobactam. When FDA subsequently approved Vabomere and Avycaz, however, it appears that the “old antibiotic” issue bubbled to the surface. In the Vabomere Exclusivity Summary, for example, FDA states that even though its new fixed-combination policy would normally result in NCE exclusivity, the fact that Vabomere contains an “old antibiotic,” i.e., meropenem, means that the NCE determination is uncertain. The review division thus referred the 5-year exclusivity assessment to the CDER Exclusivity Board for further consideration. So far, no word (at least publicly) from the Exclusivity Board.

Same Policy Goals, Different Statutory Language

From a public health and policy standpoint, there is no basis for treating combinations containing "old antibiotics" differently than those containing previously approved non-antibiotic active ingredients, like antacids or beta blockers. On the contrary, there may be an even greater public health need to spur the development of new antibiotic drug products to treat resistant pathogens, including fixed-dose combination antibiotics.

The problem, however, is that the statutory language governing “old antibiotics” may be more difficult for FDA to reinterpret than the NCE exclusivity provisions. Under applicable statutory provisions, “old antibiotics” are in a special category all their own and are not eligible for any Hatch-Waxman exclusivity periods except as permitted by 21 U.S.C. § 355(v). Under that provision, a New Drug Application (NDA) submitted after October 8, 2008 “in which the drug that is the subject of the application contains an antibiotic drug” that was approved prior to November 21, 1997 is eligible for only 3-year exclusivity. It is not eligible for NCE exclusivity.

To get around this limitation for fixed-dose combination drugs containing an "old antibiotic," FDA would need to interpret the term “drug” to mean “drug substance” rather than “drug product,” just as it did with the NCE exclusivity provision. However, that may be difficult because of differences in the statutory language between the antibiotic and NCE exclusivity provisions. In the provision governing “old antibiotics,” the statute refers to a “drug” that is the subject of an application and that “contains” an “antibiotic drug.” 21 U.S.C. § 355(v)(1)(B)(i). FDA previously has explained that the term “antibiotic drug” in related legislation refers to a specific antibiotic active ingredient or drug substance, not to an antibiotic drug product. According to FDA, this interpretation is necessitated by Congress’s use of the word “contains” in the statute: “drug products do not contain drug products; rather; drug products contain drug substances.” The same reasoning, however, could apply in reverse and make it difficult for FDA to interpret the “drug that is the subject of the application” as used in 21 U.S.C. § 355(v)(1)(B)(i) to mean the “drug substance” that is the subject of the application, since drug substances typically do not “contain” drug substances, even antibiotic drug substances.

Baking Soda versus Baking Powder

If the term “drug” in the antibiotic provisions must be interpreted to mean “drug product,” FDA’s 2014 policy regarding NCE exclusivity for fixed-combination drugs generally likely will not apply to fixed-combination products that contain “old antibiotics.” In such cases, the old rules will apply, making it necessary for sponsors to obtain approval of a single-entity product containing the new active moiety first in order to obtain NCE exclusivity for either product. In this scenario, "old antibiotics" will be the regulatory equivalent of baking soda when the recipe for obtaining NCE exclusivity calls for baking powder.

It will be interesting to see how FDA navigates this issue and whether it will need to, at some point, modify its decision to grant NCE exclusivity to Zerbaxa. There is certainly precedent for FDA changing an exclusivity decision after the fact based upon a new policy or legal interpretation. We will continue to monitor the situation with interest.