Bayer: FDA's Exclusivity Provisions for Fixed-Dose Combinations Illegal, Should be Longer

| 24 July 2013 |  By 

In addition to patents, drug products approved by FDA are often protected by periods of market exclusivity. For drugs approved through the new drug application (NDA) process, there are two primary types of market exclusivity granted: five years of protection for new molecular entities never before approved by FDA, and three years of protection of non-NME products approved for a new indication.

But as anyone who has ever sought exclusivity can attest, a variety of factors can influence the decision-a fact made clear in a recent Citizen Petition filed by the law firm Ropes & Gray LLP on behalf of Bayer HealthCare Pharmaceuticals Inc (Bayer).

As the petition explains, Bayer currently holds an NDA (#022252) for Natazia, a fixed-dose combination (FDC) of dienogest and estradiol valerate approved in May 2010. Prior to the 022252 NDA, FDA had never approved a product containing dienogest, making it an NME. However, FDA had previously approved an NDA containing estradiol valerate as an active moiety in 1954 under the brand name delestrogen.

As Bayer adds, under existing FDA precedent, the agency typically only grants three years of exclusivity for fixed-dose combinations including an NME and a previously approved moiety.

The Pursuit of Added Exclusivity

Bayer, however, is trying to obtain five years of exclusivity under an NME argument for Natazia, arguing that FDA's treatment of FDCs is "contrary" to the Federal Food, Drug and Cosmetic Act (FD&C Act), the intent of Congress and FDA's own regulations, resulting in "arbitrary outcomes that disfavor FDCs."

"Accordingly, FDA should recognize 5-year exclusivity for drugs that contain any active moiety that has not been approved previously," Bayer writes. The petition goes on to note that two other similar petitions were submitted to FDA earlier in the year, one by Gilead Sciences and the other by Ferring Pharmaceuticals, with Bayer adding that it "fully endorses" the arguments set forth in both petitions.

One of the arguments set forth by Bayer is that its NDA for Natazia was not simply a minor add-on, the likes of which FDA regulations hope to avoid by removing an incentive to "evergreen" a product through subsequent approvals involving add-on moieties.

"Most previous attempts to develop an estradiol-based mono-phasic oral contraceptive failed due to unacceptable outcomes with respect to bleeding," Bayer wrote. Through a development process, the company succeeded in developing a four-phase regimen "incorporating an estrogen step-down and progestin step-up" approach resulting in a safer product that eliminated sensitivity and increased stability.

Further, Bayer notes that the addition of dienogest required "numerous animal and human studies to establish the safety and effectiveness of [the drug]"-including two Phase II trials and five Phase III trials-that ultimately took 11 years and "nearly $200 million" to complete.

This, Bayer notes, results in something of a conundrum: Because the drug contained an NME, it was required to meet an "increased burden" with respect to its clinical trials that an already-characterized moiety would not need to meet. However, because the drug did contain an already-approved moiety, it only received three years-not five-of exclusivity.

Those additional two years, it argues, were always intended by Congress to balance the additional costs and risks of drug development. The petition quotes Henry Waxman (D-CA), one of the authors of the 1984 Hatch-Waxman Amendments to the FD&C Act, as saying that the five-year exclusivity provision "will give the drug industry the incentives needed to develop new chemical entities whose therapeutic usefulness is discovered late when little or no patent life remains."

"Based on this Congressional intent, a combination drug that contains at least one drug substance that has not yet been approved deserves 5 years of exclusivity," Bayer said, adding that the additional costs of drug development for a product containing an NME conceptually demanded NME-like protections as well.

This argument is advanced later in the petition, when Bayer notes the general benefits associated with permitting FDCs to obtain added exclusivity, noting the benefits it can bring to patients when drugs are combined rather than taken separately.

Regulatory Argument: Definitional Insanity

The petition also argues from a regulatory standpoint as well, saying that FDA's current regulatory definition of "drug product" and "new chemical entity" (NCE) have only one meaning of the term "drug" that "makes sense."

Per FDA regulations, "drug product" is taken to mean a "finished dosage form… that contains a drug substance…"

An NCE, by contrast, is defined as "a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the Act."

Bayer's petition argues that the terms "drug" and "drug product" must mean different things in this context, as one cannot substitute the definition for "drug product" into the definition for "drug" in the NCE definition, as that would result in a definition of "a finished dosage form that contains no active moiety."

"To avoid this absurd result, the term 'drug' in the definition of 'NCE' must mean a component of a drug product, or a drug substance," thereby permitting a FDC like Natazia to obtain five years of exclusivity, Bayer concluded.

An Argument only an English Teacher Could Love

In addition, the Citizen Petition argues that the letter of the FD&C Act actually requires the agency to grant five-year exclusivity to FDCs under the understanding that the statute's reference to "a drug" refers not to the whole drug, but rather its component parts.

"If 'drug' means 'finished drug product,' then, consistent with FDA's historical position, Natazia is not eligible for 5-year exclusivity because there is one active ingredient in the finished drug product that has been previously approved (estradiol valerate) and the statute requires that 'no active ingredient' of the finished drug product have been previously approved," Bayer conceded.

However, "If, on the other hand, 'drug' means 'a component of a finished drug product, or a drug substance,' then dienogest is eligible for 5-year exclusivity because no active ingredient within the drug substance dienogest has previously been approved."

The Citizen Petition goes on to cite several instances in which the statute makes the case for the latter interpretation. Curiously, the argument comes down to two small words: "A" and "The."

First, the relevant statute:

[i]f an application submitted under subsection (b) of this section for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b) of this section, is approved after September 24, 1984, no application may be submitted under this subsection which refers to the drug for which the subsection (b) application was submitted before the expiration of five years from the date of the approval of the application under subsection (b) of this section . . .

When the statute refers to "a drug" with no previously approved ingredients, Bayer contends it is an indefinite article-that is, unspecific-whereas a second reference to "the drug" is specific, and in fact refers to the first instance ("a drug").

Bayer's argument, in a nutshell:

"The second occurrence of the term "drug" refers to that to which exclusivity attaches and FDA has made clear in its regulations that 5-year exclusivity attaches to active moieties, not to finished drug products. See 21 C.F.R. § 314.108(b)(2) (stating that when exclusivity attaches, no 505(b)(2) application or ANDA may be submitted for a product "that contains the same active moiety."). Because the second occurrence of the term "drug" refers to active moieties, and because the first and second occurrences of that term as discussed above, must refer to the same thing, the first instance of "drug" must also refers to active moieties rather than to finished drug products."

Under this interpretation, "a drug substance or active moiety" would thus apply to just dienogest-not estradiol valerate-allowing it to obtain the coveted five years of market exclusivity.

FDA now has 180 days to respond, but given the other Citizen Petitions for January 2013-neither of which have yet received a response from FDA-Bayer may receive an indication regarding the success of its petition even sooner than that.

[Editor's Note: If you understood that argument, thank an English teacher.]


Citizen Petition to FDA


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