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Focus on Regulation

FDA Denies 5-Year Exclusivity to “Stable Esters” and Confirms Structure-Based Approach to Exclusivity

For sponsors developing new chemical structures based on previously approved active ingredients, two new FDA decisions offer a clear – though hardly satisfying – standard for determining whether a new structure will be awarded 5-year “new chemical entity” (NCE) exclusivity.  In two letter decisions issued on the same day, the agency firmly explained that NCE exclusivity will not be awarded to a new structure that relies on an ester bond to link a new appendage to a previously approved active ingredient. 

Ordinarily, this would not be newsworthy.  It has long been the case – indeed, it is memorialized in the governing statute – that new esters of previously approved active ingredients are, at most, entitled to 3-year marketing exclusivity.  However, FDA had also recognized that in exceptional cases, it could award NCE exclusivity to a “stable ester.”  That is, where an ester-based appendage is critical to the physiological or pharmacological action of the drug substance, the entire molecule, including the ester, would be considered the active drug substance and would be eligible for NCE exclusivity.

On May 29, 2012, the agency reversed its award of NCE exclusivity to Torisel (temsirolimus), an ester form of the previously approved drug Rapamune (sirolimus).  The exclusivity had been awarded and published in 2007 and appeared to have stood the test of time.  The reversal surfaced in a June 21, 2012, memorandum addressed to the NDA for Torisel.  On the same day, May 29, 2012, the agency resolved that Veramyst (fluticasone furoate), an ester form of fluticasone propionate, would not receive NCE exclusivity, and placed the decision in the administrative file for the NDA on June 21, 2012. 

The letter decisions represent a step backward for companies seeking to improve upon the vast library of approved compounds through innovative structural chemistry.  Under FDA’s ruling, even if a novel ester appendage can fundamentally change the pharmacokinetics or pharmacodynamics of a previously approved drug, the entire linked molecule will not be eligible for NCE exclusivity.  The agency came down strongly on the side of enforcing a bright-line structural test, rather than one that would require the agency to assess the chemical activity of the esterified molecule.  Because intellectual property protection over the base compound may long since have expired, the elimination of the potential to earn NCE exclusivity for a novel, ester-linked compound can be costly.

The Stable Ester Analysis

The Food, Drug, and Cosmetic Act awards NCE exclusivity “for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other [NDA].”  21 USC 355(j)(5)(F)(ii); 21 USC 355(c)(3)(E)(ii).  Id.  Thus, a drug will not earn NCE exclusivity if FDA has already approved the same active ingredient in another drug product.  By regulation, FDA has interpreted the term “active ingredient” in this context to mean “active moiety,” which is defined as:

the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.

21 CFR 314.108(a). Although this definition primarily contains a structure-based analysis, the concluding clause – and previous FDA actions and statements – apparently led FDA to take an activity-based approach to defining the active moiety – i.e., defining the esterified molecule as the active moiety – in specific cases. 

The idea that a stable ester could qualify for NCE exclusivity, even where the underlying structure had previously been approved, arose from a small number of FDA decisions and internal agency documents.  For example, FDA granted NCE exclusivity to ISMO (isosorbide mononitrate) in 1991, on the basis that the esterified molecule itself was a new active moiety, even though the underlying molecule (isosorbide) had previously been approved.  Relying on this decision, FDA later acknowledged that an ester appendage can, under certain circumstances, be considered an integral part of the active moiety:

Ordinarily, an ester of an approved drug is not considered a new active moiety, as most ester linkages are rapidly cleaved in vivo to provide the de-esterified molecule circulating in the blood. However, there can be exceptions to this. An ester that is stable, both in vitro and in vivo, is considered to be the active moiety, because the de-esterified molecule is devoid of activity (e.g., organic nitrates, in which the nitrate esters are the active moieties and the parent molecules (glycerol, isosorbide) are inert).

Draft Manual of Policies and Procedures (MAPP) 7500.3 “Drug and Application Classification” (distinguished in Actavis Elizabeth USA LLC v. FDA, infra).

FDA appeared to be following, if not broadening, the stable ester analysis when it approved Torisel (temsirolimus) on May 30, 2007.  Although temsirolimus is an ester of the previously approved moiety, sirolimus, FDA awarded NCE exclusivity to Torisel, presumably on the basis that the entire temsirolimus molecule was an independent, pharmacologically active moiety.  See, e.g., Torisel Package Insert (“Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division.”).  Unlike isosorbide mononitrate, where the underlying molecule is inert, in the Torisel case, FDA awarded exclusivity for an esterified version of a molecule that is known to be therapeutically active.

At about the same time (April 2007), FDA approved Veramyst (fluticasone furoate) without making any exclusivity determination for the product.  Veramyst’s active ingredient is an ester of fluticasone, which FDA had approved in numerous products over the previous decade.  Veramyst’s sponsor had sought NCE exclusivity, arguing that the entire esterified fluticasone furoate molecule was responsible for the pharmacological activity of the product, and should be considered a unique active moiety.  See Statement of Claimed Exclusivity in Veramyst Administrative and Correspondence Documents, at pdf pages 9-19.  Although agency review documents noted the prior approval of fluticasone, FDA made no decision on exclusivity at the time of approving Veramyst, or for the next five years (the period during which the NCE exclusivity would have run).

The Veramyst and Torisel Exclusivity Determinations

The Torisel and Veramyst letter decisions confirm that the agency will apply a “chemical-structure-based” rule, rather than an “activity-based” approach, in determining the active moiety of a new product for purposes of NCE exclusivity.  In other words, FDA will look only to the chemical bond between the base molecule and its appendages, and will not consider whether the underlying molecule is therapeutically active, or how the appended portions are cleaved off in vivo or otherwise behave in the body.

In asserting this bright-line rule, FDA relied heavily on its 2009 exclusivity determination regarding Vyvanse (lisdexamfetamine), which had been challenged in court and upheld.  Lisdexamfetamine is composed of a lysine appendage covalently attached via amide bond to dextroamphetamine, a moiety that had previously been approved by FDA.  FDA granted Vyvanse NCE exclusivity, consistent with the regulations, which define non-ester covalently bonded appendages to be part of the active moiety.  In concluding that lisdexamfetamine itself was a new active moiety eligible for NCE exclusivity, FDA expressly did not take into account the pharmacological activity of lisdexamfetamine, including whether and how the lysine appendage cleaved off in the body.  FDA’s determination was upheld by the DC Circuit in Actavis Elizabeth LLC v. FDA, 625 F.3d 760, 765 (D.C. Cir. 2010).

The Torisel and Veramyst exclusivity determinations emphasize that the agency interprets its regulation not to permit the activity-based approach underlying the stable ester analysis:

FDA’s regulatory definition of active moiety has for eighteen years categorically excluded ester appendages, regardless of the in vivo activity of the particular ester at issue.  Hence, Veramyst (fluticasone furoate) is comprised of an active moiety, fluticasone, that is modified with an ester bonded appendage.  Before approving Veramyst, the Agency approved products that contain fluticasone modified with a different ester (fluticasone propionate).  Under the Agency’s interpretation of its regulations, the active moiety in these products is also fluticasone.  Therefore, Veramyst contains a previously approved active moiety, fluticasone. Accordingly, FDA determines that Veramyst is not a NCE and is not entitled to five years of exclusivity.

Veramyst Exclusivity Determination at 2; see also Torisel Exclusivity Determination at 2 (rescinding Torisel’s exclusivity in virtually identical terms).

In these decisions, FDA dismissed the isosorbide mononitrate exclusivity as non-precedential, because that decision was made before the agency finalized its exclusivity regulations in 1994. The fact that FDA awarded NCE exclusivity to isosorbide mononitrate in 1991 – before the regulations were finalized – strongly suggests that the statute does not prohibit the award of NCE exclusivity for a stable ester. This leaves open the possibility of refining the regulatory standard by notice-and-comment rulemaking, or interpreting it by guidance, to allow the agency to consider the functional role of an esterified molecule or ester link.

With the two new letter decisions, FDA can now explain its past NCE decisions based on a structure-only test. The test is easy for the agency to administer and has the virtue of certainty. Looking forward, however, the structure-only test may undervalue the contributions of innovative pharmaceutical chemistry, where esters can be used to create new molecules with clinically important differences in pharmacokinetics and functional ACTIVITY.