By Kurt R. Karst –
It was just last week when one orphan drug exclusivity labeling carve-out case (presumptively) came to an end when the U.S. Court of Appeals for the District of Columbia Circuit ruled for FDA in the context of a generic version of FUSILEV (levoleucovorin) for Injection (see our previous post here). Little did we know, however, that just a few days prior to that June 3, 2016 D.C. Circuit decision AstraZeneca Pharmaceuticals LP (“AstraZeneca”) submitted a Citizen Petition (Docket No. FDA-2016-P-1485) to FDA (dated May 31, 2016) raising yet another orphan drug exclusivity labeling carve-out issue. The petition immediately reminded us of that famous quote from Don Michael Corleone in The Godfather: Part 3 – “Just when I thought I was out, they pull me back in" – where the “I” is “FDA” and the “they” is “AstraZeneca.”
AstraZeneca’s petition was posted on regulations.gov earlier this week and concerns FDA approval of ANDAs and 505(b)(2) applications for generic and “follow-on” versions of the company’s blockbuster drug CRESTOR (rosuvastatin calcium) Tablets, 5 mg, 10 mg, 20 mg, and 40 mg, which FDA approved on August 12, 2003 under NDA 021366. The petition stems from FDA’s May 27, 2016 approval of Supplement 033 to CRESTOR NDA 021366 adding a new indication: “for treatment of pediatric patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total C, nonHDL-C and ApoB as an adjunct to diet, either alone or with other lipid-lowering treatments.” AstraZeneca will presumably be granted a period of orphan drug exclusivity for this use until May 2023 based on an earlier orphan drug designation for the drug for pediatric HoFH.
According to AstraZeneca:
First, carving out AstraZeneca’s protected pediatric HoFH labeling from the labeling of a product marketed under an ANDA or section 505(b)(2) NDA would present substantial safety and efficacy risks. Although FDA may in some instances approve ANDAs that omit protected pediatric labeling, FDA has made clear that a carve out is inappropriate when, as here, the protected pediatric labeling is “necessary for the safe use of the drug.” Crestor® is labeled for treatment of HoFH in adult and pediatric patients, and for treatment of heterozygous familial hypercholesterolemia (“HeFH”), a related but far less severe condition. In many instances, the recommended dosage and course of treatment differ between adult HoFH and pediatric HoFH patients, and likewise between HeFH and HoFH patients. Given these differences, there are substantial risks that doctors would over- or under-treat pediatric HoFH patients if generic or other rosuvastatin calcium omitted AstraZeneca’s protected pediatric HoFH labeling.
Second, irrespective of whether a carve out would present a safety risk, FDA lacks legal authority to carve out pediatric labeling protected by orphan drug exclusivity. Together, the Hatch-Waxman Act’s same-labeling requirement and FDA’s pediatric-labeling regulations impose a categorical rule: pediatric labeling information subject to orphan drug exclusivity may not be omitted from generic-drug labeling. The Best Pharmaceuticals for Children Act, 21 U.S.C. § 505A(o), permits the carve out of labeling protected only by patent and Hatch-Waxman exclusivity—and therefore provides no basis for carving out labeling protected by orphan drug exclusivity. FDA also possesses several other “general” carve-out authorities, see 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7), but those authorities are inapposite in light of FDA’s subsequently adopted pediatric-labeling rules and Congress’s enactment of section 505A(o). Indeed, prior to the passage of section 505A(o), FDA concluded that it lacked authority to carve out protected pediatric labeling in circumstances nearly identical to those presented here. FDA and the United States District Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to carve out pediatric labeling protected by orphan drug exclusivity. However, that conclusion is incorrect for the reasons given above and in Part II.B of this Citizen Petition.
As noted above, AstraZeneca’s petition once again raises our old friend FDC Act § 505A(o). That provision, titled “Prompt approval of drugs under section 355(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage Provision” (or Section 11 of the Best Pharmaceuticals for Children Act) states:
(1) General rule – A drug for which an application has been submitted or approved under section 355(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 352 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 355(j)(5)(F) of this title.
(2) Labeling – Notwithstanding clauses (iii) and (iv) of section 355(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 355(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—
(A) a statement that, because of marketing exclusivity for a manufacturer—
(i) the drug is not labeled for pediatric use; or
(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and
(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.
FDC Act § 505A(o) was front and center in an April 2015 FDA Letter Decision concerning approval of ANDAs for generic versions Otsuka Pharmaceutical Co.’s (“Otsuka’s”) ABILIFY (aripiprazole) with labeling that omitted information concerning pediatric patients and protected by orphan drug exclusivity. And, as noted above, that FDA Letter Decision led to litigation and a May 2015 decision in favor of FDA (which supported a labeling carve-out by generics) by the U.S. District Court for the District of Maryland (see our previous posts here and here).
In the petition, AstraZeneca first asserts that the carve-out situation presented as a result of the recent approval of Supplement 033 for pediatric HoFH meets a three-part policy FDA laid out in the Agency’s April 2015 ABILIFY Letter Decision:
FDA has adopted a safety and efficacy policy (the “Policy”) that squarely applies to AstraZeneca’s protected pediatric HoFH labeling. Under the Policy, a generic drug is “misbranded” and “will not [be] approve[d]” where
- the reference-listed drug “is approved in adults and pediatric patients for the same indication”;
- “the pediatric information is protected by exclusivity and is significantly different from the information regarding use in adults for the same indication”; and
- “a carve-out of [the] pediatric information while the adult information is retained in the ANDA labeling may result in a potential safety risk to pediatric patients.”
Astra Zeneca argues that each criterion above is met in the case of CRESTOR. “Unlike Abilify, Crestor® meets all three of the Policy’s criteria and is therefore entitled to de facto exclusivity for the duration of AstraZeneca’s seven-year period of orphan drug exclusivity,” says AstraZeneca.
And regardless of whether or not the “Policy” applies here, says AstraZeneca, FDA may not carve out orphan drug exclusivity-protected pediatric HoFH information from ANDA and 505(b)(2) labeling because the Agency lacks the authority to do so, despite what the District of Maryland ruled in Otsuka, which is “incorrect and should be overturned.”
[N]one of FDA’s carve-out authorities applies to pediatric labeling protected by orphan drug exclusivity, regardless of a factual inquiry into whether the omitted labeling raises a safety issue. . . .
[First, ] FDA’s pediatric-labeling regulations mandate that dosing, specific indications, and safety data pertaining to pediatric uses “must appear in all prescription drug labeling.” 21 C.F.R. §§ 201.57(a), (a)(6)–(7), (a)(13), (c)(2)(i)(B), (c)(3)(i)(H) . . . . These FDA pediatric-labeling regulations create a barrier to approval of a generic drug when (i) the reference-listed drug is approved for one or more pediatric indications and (ii) at least one of those pediatric indications is protected by patent, Hatch-Waxman, or some other form of exclusivity. . . .
[Second,] [b]ecause section 505A(o) does not address other forms of exclusivity—including exclusivity afforded by the Orphan Drug Act, 21 U.S.C. § 360cc(a)—the barrier to generic-drug approvals presented in the Glucophage precedent remains with respect to orphan drug exclusivity.
[Third,] [FDA’s] general carve-out regulations [(i.e., 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7))] do not fill the void left by section 505A(o) for at least five reasons [detailed later in the petition].
AstraZeneca, which pushed FDA to quickly approve Supplement 033, wants FDA to act promptly on the company’s petition. Why? July 8, 2016 is the date that pediatric exclusivity applicable to U.S. Patent No. RE 37,314 listed in the Orange Book for CRESTOR expires, and when FDA is expected to approve multiple and currently tentatively approved ANDAs for generic CRESTOR. FDA already approved one ANDA – Watson Laboratories, Inc.’s (“Watson’s”) ANDA 079167; approved on April 29, 2016 (see here and here) – for generic CRESTOR. According to AstraZeneca, however, that ANDA approval was authorized because the company “granted Watson a patent license and a selective waiver of all periods of exclusivity applicable to FDA’s May 27, 2016, approval of the pediatric HoFH indication and labeling with respect to Watson’s marketing of its generic rosuvastatin product.”
Watson is apparently one of several “first applicants” eligible for 180-day exclusivity, which would have been triggered on May 2, 2016 when the company commercially marketed its generic CRESTOR. FDA notes in the approval letter for ANDA 079167 that Watson may have forfeited eligibility for 180-day exclusivity for failure to obtain timely tentative approval, but that “[a]t least one first applicant remains eligible for 180-day generic drug exclusivity for Rosuvastatin Calcium Tablets, 5 mg, 10 mg, 20 mg, and 40 mg,” thus setting up a Nateglinide-like situation (see our previous post here).
If FDA does approve ANDAs for generic CRESTOR on July 8, 2016, then it seems likely that litigation will ensue – probably not in the U.S. District Court for the District of Maryland given that court’s Otsuka decision – and FDA’s carve-out authority under FDC Act § 505A(o) will once again be tested.