Is the Issuance of a Pediatric Written Request a Condition Precedent to FDA Awarding Pediatric Exclusivity? A New Citizen Petition Pushes FDA to Answer the Question

By Kurt R. Karst –

Ever since the FDC Act was amended in November 1997 by the the FDA Modernization Act (“FDAMA”) to add a new section creating a period of “pediatric exclusivity,” we’ve had more than a passing interest in the provision.  In fact, it was the topic of this blogger’s first law review article published in 2000 (see here).  Under FDC Act § 505A, now referred to as the Best Pharmaceuticals for Children Act (“BPCA”), pediatric exclusivity provides for a 6-month add-on to unexpired periods of patent and non-patent exclusivities listed in the Orange Book for a sponsor’s drug (i.e., active moiety) (as least insofar as an initial grant of pediatric exclusivity is concerned) if the sponsor has conducted pediatric studies.  The BPCA is the “carrot” in the carrot and stick metaphor often used to describe the two pediatric testing statutes.  The other statute – the so-called “stick” – is the Pediatric Research Equity Act (“PREA”), codified at FDC Act § 505B, and under which FDA can require sponsors to conduct pediatric testing for on-label uses.  (PREA was enacted after FDA’s so-called “Pediatric Rule” was struck down in court – see Association of American Physicians and Surgeons, Inc. v. FDA, 226 F.Supp.2d 204 (D.D.C. 2002).)  Together, the BPCA and PREA have been recognized by the U.S. Government Accountability Office and others as an ongoing success. 

Over the years, the BPCA has undergone several changes.  Most recently, in July 2012, the FDA Safety and Innovation Act (“FDASIA”) made the BPCA permanent.  Prior to that, FDC Act § 505A was reauthorized and amended generally every 5 years along with each iteration of the Prescription Drug User Fee Amendments.  For example, the 2007 FDA Amendments Act (“FDAAA”) authorized the BPCA for another 5 years and also tweaked some of the language in the process. 

Notwithstanding changes in the BPCA, folks have always considered one thing to be true: in order to obtain a period of pediatric exclusivity, FDA must first issue a Pediatric Written Request (“PWR”) laying out the studies to be conducted in pediatric subjects.  Indeed, FDA’s initial guidance document announced in July 1998 and revised in September 1999, titled Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act, said as much: “In general, a 505(b)(1) (21 U.S.C. 355(b)(1)) application will qualify for pediatric exclusivity if all of the following have occurred: 1. The Agency issued a Written Request for pediatric studies . . . .”  But a recent Citizen Petition (Docket No. FDA-2014-P-0830) submitted to FDA on behalf of Merz North America calls into question the long-held belief that issuance of a PWR is a condition precedent to FDA awarding pediatric exclusivity – at least with respect to Merz’ (formerly Shionogi Pharma, Inc.’s) orphan drug CUVPOSA (glycopyrrolate) Oral Solution, which FDA approved on July 28, 2010 under NDA No. 022571 to reduce chronic severe drooling in pediatric patients (aged 3-16) with neurologic conditions associated with problem drooling (e.g., cerebral palsy).

According to the petition:

Merz’ predecessor fulfilled the requirements for six-month pediatric exclusivity pursuant to FFDCA § 505A(h) as it existed at the time [FDA] approved Cuvposa in 2010.  The pediatric studies were performed as required under a provision of law and regulations (i.e., for NDA approval), and thus satisfied the requirements for pediatric exclusivity under § 505A(h) without a formal written request from FDA.  Although FDA waived the pediatric study requirements under the [PREA] based on Cuvposa’s orphan drug status, the Agency failed to consider that Cuvposa was still eligible for six-month pediatric exclusivity.  Accordingly, this exclusivity period should now be recognized and attached to the remaining Cuvposa orphan drug exclusivity and patent periods.

Alternatively, says Merz:

[I]f FDA determines that a written request for pediatric studies was required pursuant to § 505A(h) in 2010, then FDA’s 2001 meeting of the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee ("2001 AC Meeting" or "Meeting") legally constitutes this written request.  The conclusions of the AC and the direction provided to FDA and the sponsor satisfy the legal and policy reasons for the written request.  The Agency did not consider this fact and therefore did not consider the eligibility of Cuvposa for six-month pediatric exclusivity.  Accordingly, this exclusivity period should now be
recognized and attached to the remaining Cuvposa orphan drug exclusivity and patent periods.

The key to the first argument for pediatric exclusivity for CUVPOSA, says the Petitioner, is FDC Act § 505A(h), which was initially codified at FDC Act § 505A(i) in 1997.  That provision has undergone several changes since 1997, initially stating:

(i) Relationship to regulations.  Notwithstanding any other provision of law, if any pediatric study is required pursuant to regulations promulgated by the Secretary and such study meets the completeness, timeliness, and other requirements of this section, such study shall be deemed to satisfy the requirement for market exclusivity pursuant to this section.

Then changing to the following with the 2007 FDAAA:

(h) Relationship to pediatric research requirements.  Notwithstanding any other provision of law, if any pediatric study is required by a provision of law (including a regulation) other than this section and such study meets the completeness, timeliness, and other requirements of this section, such study shall be deemed to satisfy the requirement for market exclusivity pursuant to this section.

And finally to the following with the 2012 enactment of FDASIA:

(h) Relationship to pediatric research requirements.  Exclusivity under this section shall only be granted for the completion of a study or studies that are the subject of a written request and for which reports are submitted and accepted in accordance with subsection (d)(3).  Written requests under this section may consist of a study or studies required under section 355c of this title [FDC Act § 505B].

The difference between the 2007 statute,which was in effect when FDA approved CUVPOSA, and the 2012 (and current) version is significant for two reasons, says Merz:

First, it includes language referencing written requests which was not present in that particular subsection when Cuvposa was approved.  Second, it facially narrows the relationship between studies conducted for pediatric exclusivity and for other required purposes.  The previous language broadly referenced pediatric studies conducted as required by another provision of law or regulation, but the new language only references PREA studies by name as being eligible for pediatric exclusivity. . . .

For Cuvposa to have been eligible for pediatric exclusivity under § 505A(h) in 2010, two requirements must have been met.  First, the pediatric studies performed must have been "required by a provision of law (including a regulation)."  Second, the studies must also have met the pediatric exclusivity requirements.  Cuvposa met the first hurdle for receiving pediatric exclusivity under § 505A(h) because the sponsor was required to complete pediatric studies for NDA approval under both the FFDCA and the regulations. . . . Cuvposa also cleared the second hurdle for pediatric exclusivity under § 505A(h) — that the studies meet the "completeness, timeliness, and other requirements" for exclusivity.  The completeness requirement was certainly met because, if not, then the NDA would not have been approved.  The timeliness factor is not relevant here, because the studies were completed as required for NDA approval.  As far as any of the "other requirements" — a written request, internal review of the request, and internal review of the completed studies — none of these were required for Cuvposa to be eligible for exclusivity under § 505A(h).

And even if FDA sticks to its long-held position that a PWR is a condition precedent to awarding pediatric exclusivity, then Merz says that requirement was already met by virtue of the 2001 AC Meeting concerning the design of clinical trials to study anti-muscarinics for drooling in children with cerebral palsy and other neurologic diseases.  According to the Petitioner, the 2001 AC Meeting “addressed the most critical elements of a written request, including pharmacokinetic studies; clinical study design including patient selection and related ethical issues; clinical study outcomes; dose titration, including safety/risk/benefit balancing; and labeling issues,” and the meeting conclusions “provided the roadmap for Cuvposa development and approval.”  In addition, says Petitioner, “the meeting satisfies the historical purpose of the written request — to provide sponsors with information regarding the conduct of pediatric studies to qualify for exclusivity.”