FDA Appeals PLAN B Ruling to the Second Circuit; Exclusivity Decision On One-Step Supplement Could Reignite Simultaneous Rx-OTC Marketing Debate

By Kurt R. Karst –      

By now everyone knows that FDA has appealed to the Second Circuit (Case No. 13-1690) the April 5, 2013 Memorandum and Order and April 10, 2013 Judgment from Judge Edward R. Korman of the U.S. District Court for the Eastern District of New York that FDA, within 30 days, make levonorgestrel-based emergency contraceptives (e.g., PLAN B and PLAN B One-Step) available Over-the-Counter (“OTC”) and without point-of-sale or age restrictions (see our previous post here).  (Judge Korman recently clarified that the 30-day deadline for compliance with his order runs from the date of his April 10th Judgment and not from his April 5th Order.)  Everyone also knows about FDA’s April 30, 2013 announcement that the Agency approved a supplement to the PLAN B One-Step NDA (NDA No. 021998) making the drug available OTC for women 15 years of age and older.  (The original July 10, 2009 approval of NDA No. 021998 made the drug available OTC to women over 17 years old, and prescription under that age.)  What folks might not yet know – or fully appreciate – however, are some of the statements FDA made in its May 1st Motion for Stay Pending Appeal, which Plaintiffs have until noon on May 6th to respond to, and for which Judge Korman will hear oral argument on at 11AM on May 7th.  (Judge Korman has already advised the parties in the case that in the event he denies a stay pending appeal, he will grant a stay to allow FDA to seek a stay from the Second Circuit.)

As an intial matter, FDA argues in its motion that the remedy Judge Korman ordered is erroneous for (at least) two reasons:

First, the Court exceeded its authority by issuing an order concerning the “one-pill product,” i.e., Plan B One-Step (PBOS), a drug product that was not the subject of the Citizen Petition that is the basis of this action before the Court.  Rather, PBOS was the subject of a supplemental new drug application (SNDA), and the Court recognized it “do[es] not have any authority to review the denial of the Plan B One-Step SNDA for the purpose of granting relief.” Tummino II, 2013 WL 1348656, at *34.  Second, the Court exceeded its authority, under principles of administrative law and the [FDC Act], by issuing a mandatory injunction ordering FDA ‘to make levonorgestrel-based emergency contraceptives available without a prescription and without point-of-sale or age restrictions within thirty days,’ rather than remanding to the agency for further administrative action.  In such a situation, the appropriate remedy is to vacate an administrative agency’s decision and to order the agency to reconsider its decision or provide a more complete explanation.  The Court cannot pretermit the rulemaking process and foreclose public participation in that process by instead immediately mandating a particular substantive outcome.

In support of its motion (and specifically that FDA and the public interest will suffer irreparable harm absent a stay), FDA makes some pretty interesting statements about the effect of Judge Korman’s order on the availability of 3-year marketing exclusivity with respect to the PLAN B One-Step NDA supplement approved on April 30th and submitted by Teva Branded Pharmaceutical Products R&D, Inc. (“Teva”).  According to FDA:

It is undisputed that, based on FDA’s representations regarding the need for additional data to support approving PBOS for use without a prescription by younger age groups, Teva conducted actual use studies that included participation by sufficient numbers of 15 and 16 year olds.  The agency deemed those studies essential to approval of non-prescription use of the drug by those age groups.  The Court nevertheless implies in its decision that FDA cannot grant Teva marketing exclusivity for a change for PBOS from prescription to OTC simply because FDA issued a complete response letter to Teva in December 2011 and Teva chose not to file a petition for review to the court of appeals.  This implication ignored the prospect that, instead of appealing, Teva could file an amended SNDA, which FDA could approve, leading to a grant of exclusivity.  That is what happened when FDA recently approved Teva’s 15-and-up amended SNDA and gave Teva three years of marketing exclusivity for the newly approved use.

To the extent the Court’s decision can be read to deprive Teva marketing exclusivity under the circumstances here – that is, to the extent it can be read to require FDA to also approve generic versions of PBOS for nonprescription use without age restrictions – it will cause irreparable harm to the regulatory process by undermining the benefits to the public and to FDA of the marketing exclusivity that the FDCA affords to drug sponsors.  As noted, such exclusivity provides a critical incentive for drug development that advances FDA’s goal of protecting and promoting public health.  To the extent the Court’s order is construed to eliminate Teva’s entitlement to exclusivity, it undermines the incentive for drug companies to conduct new clinical research studies to support new uses or indications, because it permits competitors to take advantage of the investments of market innovators free of charge.  Such a result would stifle rather than encourage innovation, to the detriment of the public.

FDA’s apparent grant of 3-year exclusivity – notwithstanding the fact that the Orange Book does not yet reflect such exclusivity as made by the appropriate FDA official under the Agency’s delegations of authority (see here) – is further discussed by CDER Director Janet Woodcock, M.D., in a declaration accompanying FDA’s Motion for Stay Pending Appeal (linked to above).  According to Dr. Woodcock:

In connection with its approval of Teva’s amended SNDA, FDA granted Teva three years of marketing exclusivity on the basis of actual use studies Teva conducted in women age 15 and 16 that FDA found essential to its approval.  The approval does not affect the prescription or approval status of Plan B or its generic equivalents.  The generic equivalents to Plan B remain available to those age 17 and older without a prescription and to those under age 17 with a prescription.  Generic equivalents to Plan B are kept behind the pharmacy counter for the prescription product to be lawfully dispensed.

What’s missing here?  That’s right, what’s missing is a reference to whether or not the PLAN B One-Step NDA supplement approved last week – apparently with 3-year exclusivity – affects the approval status of generic versions of PLAN B One-Step approved under ANDAs.  And it might be missing for good reason: the NDA supplement approval seems to raise the thorny issue of simultaneous prescription and OTC marketing of the same drug. 

As we previously discussed, FDA has relied on FDC Act § 503(b), generally, to assert that, absent a “meaningful difference,” the FDC Act does not permit the simultaneous prescription and OTC marketing of the same drug for the same indications, in the same dosage forms, and at the same strength.  FDA has also relied on FDC Act § 503(b)(4), specifically, to contend that a product whose labeling contains the “Rx-only” symbol (legend) where the same drug is approved for OTC use is misbranded and may not be legally marketed.  (FDC Act § 503(b)(4) renders a prescription drug misbranded if it fails to bear the “Rx-only” symbol and an OTC drug misbranded if it does.) 

FDA discussed its interpretation of what constitutes a “meaningful difference” in a September 2005 Advance Notice of Proposed Rulemaking involving PLAN B.  Historically, a “meaningful difference” exists if the Rx and OTC drug products differ in: (1) active ingredient; (2) indication; (3) strength; (4) route of administration; or (5) dosage form.  FDA’s mixed prescription/OTC approval of PLAN B added age as a sixth difference.

To this very day, FDA is still grappling with simultaneous prescription and OTC marketing issues.  On October 24, 2008, FDA issued a Notice for an Opportunity for Hearing (Docket No. FDA-2008-N-0549) on a proposal to withdraw approval of prescription PEG 3350 ANDAs on the basis that the statute prohibits the simultaneous marketing of the same drug as prescription and OTC.  The notice came after FDA approved NDA No. 022015 for OTC MIRALAX (PEG 3350) in October 2006, and after FDA’s Office of Generic Drugs sent letters to ANDA sponsors of prescription PEG 3350 in April 2007 stating that the FDC Act “does not permit both Rx and OTC versions of the same drug product to be marketed at the same time.”  Several ANDA sponsors requested a hearing and submitted comments to FDA challenging both the Agency’s interpretation of the statute to preclude simultaneous prescription and OTC marketing of the same drug, and FDA’s determination that no meaningful difference exists between the Rx and OTC versions of PEG 3350.  FDA has not yet scheduled a hearing; however, in January 2013, Merck & Co., Inc. sent correspondence to FDA requesting that the Agency wrap things up and withdraw ANDA approvals.

So back to the PLAN B One-Step situation . . . .  If FDA has, in fact, granted (or will grant) 3-year exclusivity vis-à-vis the change approved in the April 30th supplement (i.e., OTC use in 15 and 16 year old women), then what about the ANDAs FDA has already approved for generic PLAN B One-Step for prescription use in 15 and 16 year old women?  Is there a simultaneous prescription and OTC marketing issue there that might call into question the ANDA approvals?  This might arise because the ANDA labeling could not simply be amended to conform to the RLD labeling as a result of the exclusivity period, or is not permitted under a labeling carve-out theory.  Or is there a “meaningful difference” to maintain the status quo?  This might arise because pharmacies will keep the generic product behind the counter and control it as an prescription product, as opposed to PLAN B One-Step being available as an OTC drug on “aisle 6” at the local pharmacy.  We don’t have the answers to those questions, but resolution of whether there is a simultaneous prescription and OTC marketing issue in the first place, and then what to do about it if there is, might be an interesting side-show as the Second Circuit takes up Judge Korman’s decision.    

UPDATE:

• On May 6th, Plaintiffs filed a response in opposition to FDA's Motion for a Stay Pending Appeal.