By Riëtte van Laack –

On April 9, 2015, FDA published a proposal to amend the regulations regarding registration of food facilities.  The proposal addresses a multitude of issues: codification of certain self-implementing provisions of the Food Safety Modernization Act 0f 2011 (FSMA), amendment of the regulations as directed by FSMA (e.g., to amend the definition of retail establishment), and update and improvement of the food facility registration system. 

The Bioterrorism Act of 2002 amended the Federal food, Drug, and Cosmetic Act (FDC Act), adding section 415, which directs FDA to issue regulations to require registration of facilities engaged in the manufacturing, processing, packing or holding food for consumption in the United States.  FDA issued implementing regulations in 2003. FSMA amended section 415 to require that facilities submit additional registration information to FDA and renew their registration every two years. 

Under the current regulation, food facilities that manufacture/process, pack, or hold food for consumption in the United States must register with FDA.  However, retail food establishments, farms, restaurants, and certain other entities are exempt from the requirement to register.  FDA proposes to amend the definition of a retail food establishment to increase the number of establishments that are considered retail food establishments (and therefore are not required to register).

Currently, the regulation defines a retail food establishment as “an establishment that sells food products directly to consumers as its primary function.”  Whether the primary function is selling food directly to consumers depends on whether the annual monetary value of sale of food products directly to consumers exceeds the annual monetary value of sales of food products to all other buyers.  FDA proposes to amend the regulation so that the sale of food directly to consumers from an on-farm establishment will include direct sales by the establishment at direct sales platforms such as roadside stands, farmers’ markets, Community Supported Agriculture (CSA) programs, and other direct-to-consumer sales platforms, including door-to-door sales; mail, catalog and Internet order, including online farmers markets and online grocery delivery; religious or other organization bazaars; and State and local fairs.  This expansion of sales direct to consumers applies only to on-farm establishments.

FDA further proposes to codify certain self-implementing provisions of FSMA that have been effective upon enactment of FSMA (i.e., provide e-mail address for the contact person or U.S. agent, bi-annual renewal of registration and assurance that FDA will be permitted to inspect the facility at the times and in the matter permitted by the FDC Act).  In addition, FDA proposes to add certain new requirements that the Agency anticipates will improve the food facility registration system.

• All food facility registrations will be required to be submitted to FDA electronically.  FSMA authorizes FDA to require electronic registration no earlier than 5 years after enactment of the law, i.e., not before Jan. 4, 2016.  Among other things, electronic registration will reduce time and cost of processing forms, reduce registration errors, and reduce search and retrieval time. This provision will include a waiver for establishments that cannot register electronically.  
• Registrations will be required to identify the type of activity conducted at the facility for each food product category.
• FDA proposes various measures to assure that the food facility registration database is up to date by verifying accuracy of certain information submitted in registrations and reducing the time for updates and cancellation of registration from 60 to 30 days. For example, to prevent any uncertainty whether a US agent is authorized to register a foreign facility, FDA will not register the facility until it has been able to verify that the U.S. agent is indeed authorized.

The proposed rule does not address the suspension of food facility registration provisions of FSMA.  FDA intends to address these provisions in a separate rulemaking.

Public comments on FDA’s proposed rule may be submitted electronically or by regular mail until June 8, 2015.

By Kurt R. Karst –      

Some days we feel like the “Dickie V” (Dick Vitale) of the Hatch-Waxman and Biosimilars worlds – enthusiastically calling play-by-play on litigation and other FDA happenings, just like the Basketball Hall of Fame broadcaster does for college basketball games.  (And while we’re on that topic, this blogger can’t help but express his disappointment in Wisconsin’s loss to Duke in the championship game – Go Badgers!)  But even Dickie V needs a break from the detailed play-by-play once in a while.  And today is our break.  Instead of putting out one of our typically detailed posts, we’re just going to give our readers brief updates on a couple of cases we’ve been following and that we’ve previously detailed.  After all, like Dickie V, who is now 75 years old, we too at the FDA Law Blog are getting old, having just celebrated our 8th anniversary.

First off is Otsuka Pharmaceutical Co., Ltd.’s (“Otsuka”) two-count Complaint and Motion for Summary Judgment filed against FDA in the U.S. District Court for the District of Maryland concerning ABILIFY (aripiprazole).  As we previously reported, Otsuka alleges in Count I that FDA impermissibly broadened a recent supplemental approval for ABILIFY to include treatment of all patients with Tourette’s disorder, instead of treatment of pediatric patients with Tourette’s Disorder.  In Count II, Otsuka alleges that FDA is precluded from approving generic versions of ABILIFY on April 20, 2015 (when a period of pediatric exclusivity associated with U.S. Patent No. 5,006,528 expires) based on FDC Act § 505A(o) (concerning the inclusions and omission of protected pediatric information in generic drug labeling) and the fact that the labeling of ABILIFY is “loaded with pediatric information.” 

In a Motion to Dismiss filed earlier this week, FDA argues that Otsuka’s case is unripe, that the company lacks standing, and that there hasn’t been any final agency action to challenge in the first place.  According to FDA:

FDA has made no determination with respect to the issues raised in Otsuka’s January 21, 2015 letter and, to the extent it ultimately finds it necessary to decide these issues, would only do so if, and when, it approves any generic versions of Abilify.  In order to make any generic Abilify approval decisions, however, the agency may also need to consider other potentially important parts of the regulatory scheme, which Otsuka’s letter does not take into account.  These may include the scope of the permissible difference to the same labeling requirement in the statute (see 21 U.S.C. § 355(j)(2)(A)(v)), regulations (see 21 C.F.R. § 314.94(a)(8)(iv)), and applicable case law, as well as the effect of 21 U.S.C. § 355A(o) on labeling that is protected by both Hatch-Waxman and orphan exclusivity.  FDA may also deem it important to consider arguments potentially raised by generic drug sponsors.

In addition, even when FDA has tentatively approved an ANDA,any number of events may nevertheless prevent or delay final approval (e.g., a pre-approval inspection that reveals manufacturing deficiencies or a change in standards governing impurity are just two examples).  FDA will consider all relevant factors, in making any future decisions on these matters.  However, FDA will make these final determinations at the time that it approves any generic versions of Abilify (and not before).

FDA also makes some hay out of a recent Otsuka Motion to Compel Supplementation of the Administrative Record, saying that the company is attempting to change the action challenged in Count I.  (Later in the day on April 8th, the District Court issued a Memorandum Opinion granting Otsuka's motion.)

Intervenor-Defendants Apotex Inc. and Apotex Corporation, and Teva Pharmaceuticals USA, Inc. take a tack similar to FDA in their combined Motion to Dismiss, but they also address the substantive legal issues raised by Otsuka:

[T]he ultimate question Otsuka’s motion poses is whether FDA has authority to approve ANDAs that carve out the orphan indication for Tourette’s disorder (whether or not the indication includes any reference to a pediatric population).  FDA’s authority to do so is clear. Otsuka’s motion rests on a myopic view of FDA’s authority to approve ANDAs that carve out portions of brand-name drug labeling—a view that is belied by the FDCA as a whole, the Orphan Drug Act, agency regulations entitled to deference, and clear Fourth Circuit authority.  Otsuka’s claims must fail because FDA has authority to approve ANDAs carving out a Tourette’s disorder indication, and that authority is not abrogated or constrained by Section 505A(o).

Other Intervenors-Defendants, Alembic Pharmaceuticals Limited, Alembic Limited, Alembic Global Holdings SA and Alembic Pharmaceuticals, Inc., filed a brief Memorandum opposing Otsuka’s Motion for Summary Judgment.

Second up today is an update on Amgen Inc.’s (“Amgen”) appeal to the U.S. Court of Appeals for the Federal Circuit (Case No. 2015-1499) of a March 2015 decision from the U.S. District Court for the Northern District of California concerning Sandoz Inc.’s  (“Sandoz”) biosimilar version of Amgen’s NEUPOGEN (filgrastim) and the applicability and interpretation of various provisions of the the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  As we previously reported, the District Court denied Amgen’s Motion for a Preliminary Injunction (as well as an earlier filed Motion for Judgment on the Pleadings or, in the Alternative, Motion for Partial Summary Judgment) and ruled, among other things, that the BPCIA’s “patent dance” procedures are not mandatory for Section 351(k) biosimilar applicants, and that the statutory 180-day notice of first commercial marketing can come well before biosimilar licensure. 

Amgen asked the Federal Circuit for and was granted an expedited briefing schedule, with briefing to be completed by the end of April 2015.  Amgen lays out the company’s arguments in its Opening Brief filed last week, and asks the Federal Circuit to address four issues:

1. Whether the district court erred in holding that, under the [BPCIA], Sandoz . . .may elect not to comply with the requirement that it “shall provide” to Amgen, the reference product sponsor (or, “RPS”), a copy of its biologics license application (“BLA”) and information describing “the process or processes used to manufacture the biological product that is the subject of such application.” 42 U.S.C. § 262(l)(2)(A).

2. Whether the district court erred in holding that Sandoz may comply with the requirement that the Applicant “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k)” by giving notice before the biological product becomes “licensed.” 42 U.S.C. § 262(l)(8)(A).

3. Whether the district court erred in holding that where Sandoz refused to provide its BLA and manufacturing information and provided untimely notice of commercial marketing, Amgen cannot compel Sandoz’s compliance and its sole remedy is a declaratory judgment on patent issues under 42 U.S.C. § 262(l)(9).

4. Whether the district court erred in denying Amgen’s motion for a preliminary injunction based on an erroneous interpretation of the BPCIA and an erroneous finding of no irreparable harm.

Another case raising similar issues is brewing in the U.S. District Court for the District of Massachusetts.  In that case, Janssen Biotech, Inc. (“Janssen”) is challenging Celltrion, Inc.’s and Hospira, Inc.’s biosimilar version of Janssen’s REMICADE (infliximab).  On April 8, 2015, Janssen filed a Motion for Partial Summary Judgment and a Preliminary and Permanent Injunction. 

By Kurt R. Karst –      

It’s not all that often that we see the Patent and Trademark Office (“PTO”) dismiss or deny a request to extend the term of a patent covering a medical device, though such actions on a Patent Term Extension (“PTE”) request do come up from time to time (see our previous posts here and here).  The PTO’s recent dismissal of a PTE request for U.S. Patent No. 5,762,599 (“the ‘599 patent”) filed by Vesiflo Inc. (“Vesiflo”) and covering the company’s inFlow Intraurethral Valve-Pump and Activator (“inFlow”) device for a replaceable urinary prosthesis for use in female adults who cannot contract the muscles necessary to push urine out of the bladder presents an interesting moment of zen in the PTE world. 

The inFlow device was reviewed by FDA through the de novo classification process and is the subject of an October 14, 2014 Classification Order, which FDA announced on the same day.  The de novo process, formally known as Evaluation of Automatic Class III Designation, is established by FDC Act § 513(f)(2).  It was added to the statute by the 1997 FDA Modernization Act (“FDAMA”), as modified by the 2012 FDA Safety and Innovation Act (“FDASIA”), to address novel medical devices that lack a predicate device but pose only a low-to-moderate risk, making them ill-suited to the PMA process under FDC Act § 515 (see our previous post here).  Vesiflo utilized the de novo process after a long history of being shut out of other marketing routes for its inFlow device.  As stated by Vesiflo in its PTE application:

[T]he applicant sought FDA approval for over 17 years prior to the De Novo Petition (DEN130044) being granted on October 14, 2014.  Throughout the process, the FDA maintained its stance that the InFlow™ device required § 515 approval and was a class III device.  The initial IDE (G970029) was performed from 1997 to 2000 in accordance with § 515 for a class III device.  The applicant subsequently prepared for submission and attempted to file pre-PMAs under § 515 in 2002 and 2011, an application under § 513(g) in 2005, and an application under § 510(k) in 2006, but the FDA, based on the actions of the Urology Branch Chief Janine Morris, refused to accept of any of the applications.  It was not until 2013 that the FDA changed its stance, when it down-classified the InFlow™ to class II based on its re-examiniation of the safety data from the pivotal (IDE) trial and agreed to accept a submission under §513(g), rather than under § 515 as it had been treated for the prior seventeen years.  Ultimately, DEN 130044 was filed and approved based on the same data from G970029 that was originally submitted in 2002.

Shortly after FDA handed down the October 14, 2014 Classification Order, Vesiflo requested a PTE for the ‘599 patent.  But just a few months later, on March 4, 2015, the PTO dismissed the request, concluding that the ‘599 patent is ineligible for a PTE.

Under the PTE statute at 35 U.S.C. § 156, the owner of record of a patent (or its agent) must submit a PTE request to the PTO “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use.”  For a medical device, the “regulatory review period” is defined at 35 U.S.C. § 156(g)(3)(B) to be the sum of:

(i) the period beginning on the date a clinical investigation on humans involving the device was begun and ending on the date an application was initially submitted with respect to the device under section 515, and

(ii) the period beginning on the date an application was initially submitted with respect to the device under section 515 and ending on the date such application was approved under such Act or the period beginning on the date a notice of completion of a product development protocol was initially submitted under section 515(f)(5) and ending on the date the protocol was declared completed under section 515(f)(6).

Thus, the definition of “regulatory review period” for a medical device requires that an application for a medical device be submitted under FDC Act § 515 – i.e., a PMA – and also that the PMA be approved.  And that’s where Vesiflo’s troubles began and ended.  According to the PTO’s dismissal decision:

Since no application under section 515 of the FFDCA was filed with FDA, the time period in § 156(g)(3)(B)(i) has not ended.  Turning to the § 156(g)(3)(B)(ii) period, since no application was filed under either 515 or 515(f)(5), the regulatory review specified in § 156(g)(3)(B)(ii) did not begin nor did it end.  Instead, an order under 513(f)(2) of the FFDCA for applicant’s medical device was issued October 14, 2014.  This means that the triggering event in §156(d)(1) has not occurred since the product was not reviewed under “the provision of law”—section 515 of the FFDCA —under which the applicable “regulatory review period” occurred —the regulatory review period as defined in 35 U.S.C. 156(g)(3)(B)(i) and (ii).

Vesiflo’s ineligibility for a PTE also doomed the company’s hopes for an interim PTE, requested pursuant to 35 U.S.C. § 156(e)(2), on the ‘599 patent.  Citing legislative history and the Federal Circuit’s decision in Somerset Pharmaceuticals, Inc. v. Dudas, 500 F.3d 1344 (Fed. Cir. 2007), the PTO concluded that an interim extension cannot be granted if a patent is not eligible for extension under 35 U.S.C. § 156(a).

By Alexander J. Varond –

After six years of operating under its May 2009 “Guidance for Industry: Formal Meetings Between the FDA and Sponsors of Applicants,” FDA refreshed its guidance.  On March 11, FDA announced its draft guidance entitled “Formal Meetings Between the Food and Drug Administration and Sponsors or Applicants of Prescription Drug User Fee Act (PDUFA) Products.”

Despite the amount of time that passed since the last version was issued, the draft guidance makes relatively few changes.  This is fairly impressive, given the importance of FDA meetings; but this also speaks to the relative maturity of the PDUFA program—now in its fifth incarnation.  We posted an in-depth discussion about the 2009 guidance here.

In the chart below, we provide a brief overview of each meeting type and highlight the changes made by the draft guidance document.

Table 1:  Summary of Meeting Types and an Overview of Changes

The draft guidance also clarifies the appropriate timeframe for scheduling meetings.  In the 2009 guidance FDA stated “If a sponsor or applicant requests a meeting date that is beyond [30/60/75] days from the date of the request receipt, we will work with the sponsor or applicant to determine the earliest agreeable date.”  (Emphasis added).  The last clause has been made more specific, such that the scheduling requirement is now “If a request for a meeting date that is beyond [30/60/75] days from the date of the request receipt, the meeting date should be within 14 calendar days of the requested date.”  (Emphasis added).

By Kurt R. Karst –      

Last week, the U.S. Court of Appeals for the Federal Circuit ruled in Apotex Inc. v. Daiichi Sankyo, Inc., saying that there is subject matter jurisdiction to hear a declaratory judgment action of non-infringement for a disclaimed Orange Book-listed patent.  The decision reverses a January 2014 decision from the U.S. District Court for the Northern District of Illinois. 

As we previously reported (here and here), the case stems from a November 2012 Complaint for Declaratory Judgment filed by Apotex, Inc. (“Apotex”) in an effort to obtain a court decision triggering the 75-day statutory period under the failure-to-market forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb) and that could ultimately result in a forfeiture of 180-day exclusivity eligibility for purported first-filer Mylan Pharmaceuticals Inc. (“Mylan”) for its generic version of Daiichi Sankyo Inc.’s (“Daiichi”) BENICAR (olmesartan medoxomil) Tablets approved under NDA 021286.  The patent at issue – U.S. Patent No. 6,878,703 (“the ‘703 patent”) – is apparently the only remaining exclusivity-bearing patent, and, as a result of the patent being disclaimed, is listed in the Orange Book with a “Patent Delist Request Flag.”  For those in need of some good bedtime reading, the briefs filed in the Federal Circuit are available here (Daiichi); here and here (Apotex); and here and here (Mylan).

By way of a quick review, under the 180-day exclusivity failure-to-market forfeiture provisions added to the statute by the 2003 Medicare Modernization Act (“MMA”), there must be two events – or “bookends” – to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is:

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant

That event has already happened with respect to generic BENICAR given the April 25, 2006 date on FDA’s List of Paragraph IV Patent Certifications: the “earlier of” date under (aa) is October 25, 2008. 

The other bookend – the (bb) part of the equation – provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval).”  We emphasize that last portion for a reason, which we’ll get to in due course.  But for now, let’s put a pin in it.  

Returning to the BENICAR case, the Federal Circuit nicely summarized the position of the parties:

Apotex asserted that it has a concrete stake in securing the requested declaratory judgment because, under the governing statutory provisions, the requested judgment would allow it to enter the market earlier than it could without the judgment. . . .  According to Apotex, a court judgment of non-infringement would cause Mylan to forfeit the exclusivity period if Mylan has not marketed its drug 75 days after appeal rights are exhausted (certiorari aside) and Apotex has obtained tentative approval for its generic product from the FDA. . . .

Daiichi and Mylan did not dispute that an earlier-than-otherwise Apotex entry into the market would likely have the identified effects, to Apotex’s benefit and Daiichi’s and Mylan’s detriment.  But Daiichi argued that no controversy exists because it could not now assert the disclaimed ’703 patent against Apotex.  Mylan added arguments based on the fact that Apotex lacked (and lacks) a “tentative approval” from the FDA for its ANDA.  Specifically, Mylan argued that redress of Apotex’s delayed-market-entry injury is unduly speculative before tentative approval is in hand.  Mylan also made an argument based on the fact that tentative approval is a necessary statutory condition for the forfeiture of Mylan’s presumptive exclusivity period based on the declaratory judgment requested here. § 355(j)(5)(D).  It argued that the forfeiture provision should be read to mean that, for a declaratory judgment brought by a second ANDA filer to cause forfeiture, the second ANDA filer must have had tentative FDA approval when it brought the declaratory-judgment action.  Under that interpretation, Mylan contended, the present action cannot provide Apotex forfeiture relief—even if Apotex could file an identical declaratory-judgment action as soon as it obtains tentative approval.

The Illinois District Court granted Daiichi’s Motion to Dismiss the Apotex Complaint, reasoning that “both Daiichi and Apotex no longer hold any meaningful interest in the now disclaimed patent” and that the continued listing of the ‘703 patent in the Orange Book “does not create a case or controversy by which Apotex may seek a declaratory judgment regarding a nonexistent patent.”  In addition, the Illinois District Court denied Mylan’s Motion to Intervene as moot in light of the court’s decision to grant Daiichi’s Motion to Dismiss.  Apotex subsequently appealed, and Mylan cross-appealed the District Court’s denial of intervention. 

On appeal, the Federal Circuit, after confirming Mylan’s right to be a party in the case “because of its obvious stake in the dispute,” reversed the Illinois District Court’s dismissal of Apotex’s Complaint for lack of a case or controversy.  Citing and quoting the U.S. Supreme Court’s decision in MedImmune, Inc. v. Genentech, Inc., 549 U.S. 118 (2007), the Federal Citcuit concluded that “the facts alleged, under all the circumstances, show that there is a substantial controversy, between parties having adverse legal interests, of sufficient immediacy and reality to warrant the issuance of a declaratory judgment.”  From there, the Federal Circuit addressed four issues:

1. whether Daiichi’s disclaimer of the patent means that the parties lack concrete stakes in the dispute over the declaratory judgment; 
2. whether the alleged harm is traceable to Daiichi; 
3. whether the real-world impact is too contingent on future events—specifically, FDA tentative approval of Apotex’s ANDA; and 
4. whether Apotex’s alleged harm would not be redressed even if Apotex receives the requested judgment because ultimate relief is independently blocked by the statutory standards for triggering forfeiture of Mylan’s exclusivity period.

Our friends over at the Patent Docs blog nicely summarized each point identified by the Federal Circuit leading to the Court’s holding – that “Apotex has alleged facts supporting the conclusion ‘that there is a substantial controversy, between parties having adverse legal interests, of sufficient immediacy and reality to
warrant the issuance of a declaratory judgment’” – so we refer you to that blog post for that discussion.  That means we get to spend the rest of our time on other aspects of the Federal Circuit’s decision that we find interesting.  And you’ll hardly be suprised that by “other aspects” we mean 180-day exclusivity.  (Now you can take out the pin noted above.)

In its decision, the Federal Circuit performs its own mini-forfeiture analysis, identifying October 2008 as the month when the (aa) bookend date occurs under the failure-to-market provisions at FDC Act § 505(j)(5)(D)(i)(I).  As to the (bb) bookend date, the Federal Circuit, referring to that provision says:

This provision, which separates the tentative-approval phrase from its specification of certain forfeiture-triggering dates, including the non-infringement-finality date of (AA), admits of a simple reading.  There are two requirements for forfeiture: a court must have entered a final decision of non-infringement that is no longer appealable (certiorari aside), and the second (or later) filer must have received tentative approval.  The first filer forfeits its exclusivity if it has not entered 75 days after those two requirements are satisfied.  Under that reading, Apotex can trigger forfeiture in this case by obtaining the judgment it seeks here and by obtaining tentative approval, if it does both early enough in relation to Mylan’s market entry.

This and other statements in the Court’s decision seem to indicate a preference for a non-draconian interpretation of the statute.  Under a draconian interpretation, if a subsequent applicant first obtains a court decision and then obtains tentative approval, one reading of the statute is that the court decision does not trigger the 75-day period.  Why?  Because the order of events is critical under this interpretation.  That is, for the 75-day period to be triggered, an applicant must have tentative approval at the time there is a court decision.  If not, then the court decision has no effect and there is not a (bb) event.  Other, less draconian interpretations could also result under this permutation: (1) that the 75-day period is retroactive to the date after the court decision; or (2) that the 75-day period begins on the day after the date on which a subsequent applicant completed the statutory criteria (i.e., the 75-day period begins after the date a subsequent applicant obtains tentative approval). 

Continuing on, the Federal Circuit says something interesting:

Tentative approval is required before a second filer can actually trigger forfeiture, because exclusivity should not be lost unless the second filer is on the verge of having an approved product to deliver the benefits of competition.  It would be arbitrary, in terms of the discernible policy, to require tentative approval earlier.  Thus, for this case, the purpose of requiring tentative approval has nothing to do with Apotex’s approval status at the time it brought the declaratory-judgment action, and it has everything to do with its approval status when forfeiture is triggered.  Our interpretation—the 75-day clock for Mylan starts to run when Apotex has both tentative approval and a no-longer-appealable judgment of non-infringement—fits the concrete function of the provision . . . . [(Emphasis added)]

Putting aside the order of events (i.e., a final court decision and tentative approval), the Court’s conclusion (emphasized above) is pretty clear under the statute:  if “any other applicant” (i.e., a subsequent applicant) obtains tentative approval and that same subsequent applicant obtains a final court decision, then the 75-day period under FDC Act § 505(j)(5)(D)(i)(I)(bb) is triggered.  Eligibility for 180-day exclusivity would be forfeited (provided there is a subitem (aa) event) unless a first applicant timely commercially markets its drug product.   

But the Federal Circuit does not consider another option . . . .  It’s possible that FDA will interpret the “any other applicant (which other applicant has received tentative approval)” to mean that if a subsequent without tentative approval, like Apotex, obtains a court decision, then both the court decision and tentative approval requirements are met because a different subsequent applicant previously obtained tentative approval.  Under that interpretation, the 75-day period under FDC Act § 505(j)(5)(D)(i)(I)(bb) begins to run after the court decision be comes final.  Eligibility for 180-day exclusivity would be forfeited 75 days later (provided there is a subitem (aa) event), unless a first applicant commercially markets before the 75-day date. 

Interestingly, that’s exactly the tentative approval situation with generic BENICAR.  Although FDA has not tentatively approved Apotex’s ANDA, the Agency has approved ANDAs submitted by two other subsequent applicants: ANDA 090237 (Sandoz) and ANDA 091079 (Teva).  If Apotex obtains a final court decision on the ‘703 patent because the company it is now able to pursue a declaratory judgment action (and if Apotex still doesn’t have tentative approval at that time), then FDA will once again be put in the position of having to make a decision on how best to interpret the 180-day exclusivity failure-to-market forfeiture provisions.

By James E. Valentine*, Josephine M. Torrente & Frank J. Sasinowski –

On March 31, 2015, FDA’s Center for Drug Evaluation and Research (“CDER” or the “Center”) finalized its Guidance for Industry: Critical Path Innovation Meetings, establishing an enduring function of the Center to facilitate Critical Path Innovation Meetings (“CPIMs”).  The CPIM program is a tool for external stakeholders, including industry, academia, patient advocacy groups, or the government, to request a meeting to discuss a drug development methodology or technology with CDER outside of the context of review for any particular product or application. 

CPIMs are a venue to seek “[FDA’s] perspective on the potential use of proposed new tools and methods in drug development” and “advise requesters of issues to consider in pursuing their work . . . .”  FDA Guidance for Industry: Critical Path Innovation Meetings, at page 3 (Apr. 2015).  CPIMs also provide an opportunity to discuss with CDER follow-up activities, such as initiatives with consortia and/or wider engagement of the scientific community (e.g., public workshops).  The scope of the CPIM program is broad, and can concentrate on addressing any number of challenges in drug development and strategies. 

Meeting Topics 

While the program’s focus may change over time, CDER provided a preliminary list of topics:

1.      Biomarkers in the early phase of development.

CPIMs can serve as a venue for discussing the potential of proposed biomarkers, as well as the type of questions FDA may have related to proposed biomarkers.  This type of meeting may be of particular interest to prospective submitters to the Biomarker Qualification Program.

2.      Clinical outcome assessments (“COAs”) in the early phase of development.

CPIMs can also provide a forum for discussing potential approaches to developing COAs, such as patient-reported outcomes, that can support marketing approval and labeling claims.  This type of meeting could answer questions related to the development or selection of COAs in preparation for the qualification process.

3. Natural history study designs and implementation.

Here, CPIMs could assist those interested in the design of natural history studies in ways that maximize the potential to generate data, which will help in the design of interventional clinical trials and drug development programs.  Dr. Janet Woodcock, the director of CDER, has recently been advocating for greater adoption of patient registries, particularly by patient groups, to systematically collect natural history information to aid drug developers and FDA in determining if a drug has an effect.  One such use of natural history information is to leverage it as a historical control in a single-arm clinical trial.

4. Emerging technologies or new uses of existing technologies.

These types of meetings could help drug developers understand the strengths and weaknesses of technologies in relation to their various potential uses at different stages of drug development.  For example, on March 20, 2015, the National Institutes of Health and FDA hosted a public scientific workshop to discuss dystrophin protein quantification methodologies for use in Duchenne Muscular Dystorphy (“DMD”) therapy developemnt.  Under the CPIM program, stakeholders in any disease area may be able to initiate discussions with CDER that could ultimately result in similar public workshops.

5. Innovative conceptual approaches to clinical trial design and analysis.

Such CPIMs could provide a venue to discuss conceptual and general regulatory issues concerning various design and analytical approaches to clinical trials.  In particular, CPIMs may be a valuable forum for discussing, for instance, novel adaptive or enrichment study designs for classes of therapeutic targets.

Requesting a Meeting

To request a CPIM, one must first develop a proposal containing background material, the purpose of the meeting, steps that have already been taken to advance the project, any specific questions for FDA, and the desired outcome of the meeting.  Requests can be submitted electronically here.  The program is administered by the Office of Translational Sciences, which will respond to requests within 14 days. 

If a meeting request is granted, the requester will also be responsible for developing a final preparation package to submit to FDA at least two weeks before the meeting date.  CDER commits to sending a meeting summary to the requester within 60 days of the meeting.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application is pending.

By Jennifer D. Newberger –

Federal Sunshine Law:  On March 31, 2015, CMS issued an email notice that the Open Payments data submission period will remain open until midnight on Friday, April 3, 2015, “to accommodate all applicable manufacturers and group purchasing organizations (GPOs) that are in the final stages of data submission.”  The original deadline for submission was March 31, 2015.

West Virginia:  On March 24, 2015, West Virginia’s Governor, Earl Ray Tomblin, signed into law S.B. No. 267, which repeals the Prescription Drug Advertising Expense Reporting requirement.  That law had required pharmaceutical manufacturers doing business in the state of West Virginia to disclose all expenditures for advertising and promotion of prescription drugs in West Virginia.  The repeal goes into effect on June 11, 2015.  Based on information on the website for the Governor’s Office of Health Enhancement and Lifestyle Planning (GO HELP), and a discussion with a responsible West Virginia official, manufacturers will still be expected to submit reports due on April 1, 2015, for expenditures made in 2014.

By Ricardo Carvajal & Diane B. McColl –

FDA announced a “strategy to establish ingredient definitions and standards for animal food,” pursuant to a statutory directive in the Food and Drug Administration Amendments Act of 2007 (FDAAA).  As indicated in one of our prior postings, this effort has been in the works for years, but FDA’s recent announcement gives a better indication of the direction in which the agency is headed.   

The stated goal of the strategy is “to align AAFCO ingredient listings with the agency’s regulatory process and requirements.”  To that end, it appears that FDA intends to launch a comprehensive review through which the agency will establish as its own standards and definitions any AAFCO definitions for ingredients that are “approved by the agency as food additives” or “recognized as GRAS.”  For other AAFCO definitions, FDA will review the scientific literature to determine whether that literature supports food additive approval or GRAS affirmation, and will approve or affirm those substances (apparently on the agency’s own initiative).  Where data are lacking to support either of these actions, FDA will require submission of a food additive petition “to allow continued legal use” of the substance. 
 
The planned review is reminiscent of the type of review that FDA initiated for substances used in human food in the wake of the 1958 Food Additives Amendment – a resource-intensive effort that was never completed.  The planned review can therefore be expected to extend years into the future.  FDA’s announcement states that “[t]he agency intends to work closely with industry during this transition to minimize disruption to animal food production.“  It’s not clear whether that close working relationship will extend to staving off a proliferation of class action litigation targeting the marketing of food ingredients under AAFCO definitions that FDA concludes are neither approved food additives nor GRAS.  The marketing of such ingredients could be vulnerable to lawsuits targeting “unlawful” business practices under state law, as is feared could happen with respect to human food ingredients that FDA deems subject to a change in regulatory status (partially hydrogenated oils come to mind, as laid out in this posting by the Washington Legal Foundation). 
 
For now, AAFCO’s new ingredient definition review process remains in operation – in fact, the Memorandum of Understanding between AAFCO and FDA that facilitates that process was recently renewed.   If anything, AAFCO suggests that demand for its new ingredient definition review process is expected to increase as a result of FSMA, and that the MOU will help AAFCO accommodate that increased demand.  At this time, it’s not clear how FDA will manage the strain of that increased demand on CVM’s resources, or how the continuation of AAFCO’s new ingredient definition review process will be squared with the planned review announced by FDA.

By Kurt R. Karst –      

Over the past few months we’ve seen various pieces of the 21st Century Cures Initiative discussion draft released as stand-alone bills in both the U.S. House of Representatives and the U.S. Senate (see our FDA Legislation Tracker).  One section of the discussion draft that caught our attention was Section 1241 (on pages 118-122), titled “Extended Exclusivity Period For Certain New Drug Applications and Abbreviated New Drug Applications.”  As we noted back in January 2015 (see our previous post here), Section 1241 would continue a trend of “exclusivity stacking” started in 1997 with the creation of 6-month pediatric exclusivity by extending a period of 3-year new clinical investigation exclusivity by two years if the NDA sponsor provides certain information. 

Section 1241 recently emerged from the House as a stand-alone bill with a sponsor and a name.  Earlier this month, Rep. Gus Bilirakis (R-12) introduced H.R. 1353, the “Promoting Access for Treatments Ideal in Enhancing New Therapies Act of 2015” (or “PATIENT Act of 2015”).  The PATIENT Act of 2015 is substantively identical to Section 1241 of the 21st Century Cures Initiative discussion draft.  We’re not sure if it will be included in the much-anticipated Version 2.0 of the 21st Century Cures Initiative, but we thought it would be worth taking a closer look at the bill. 

H.R. 1353 is relatively straightforward.  It would amend the statutory sections governing the period of 3-year new clinical investigation exclusivity created by the Hatch-Waxman Amendments, which are found in both the ANDA (FDC Act § 505(j)(5)(F)(iii)-(iv)) and 505(b)(2) application (FDC Act § 505(c)93)(E)(iii)-(iv)) provisions, to add new clauses.  Those proposed clauses state that 3-year exclusivity is extended by two years if the NDA sponsor provides documentation to FDA demonstrating either that the new clinical investigations conducted or sponsored by the NDA applicant and determined by FDA to be essential to the approval of the NDA (or Supplemental NDA) support the approval of a new indication or use for the NDA’d drug, or that the drug that is the subject of the NDA (or Supplemental NDA) has been reformulated or redesigned so that the drug can reasonably (as determined by FDA in consultation with the applicant) be expected:

1. to promote greater patient adherence to an approved treatment regime relative to the previously approved formulation or design of the drug;
2. to reduce the public-health risks associated with the drug relative to the previously approved formulation or design of the drug;
3. to reduce the manner or extent of side effects or adverse events associated with the previously approved formulation or design of the drug;
4. to provide systemic benefits to the health care system relative to the previously approved formulation or design of the drug; or
5. to provide other patient benefits that are comparable to the benefits described in items 1 through 4 above.

Not later than 180 days after the enactment of the PATIENT Act of 2015, FDA would be required to promulgate final regulations to implement the Act, including regulations establishing a process under which FDA would consult with NDA sponsors who claim eligibility for the 2-year extension based on one of the five items noted above.

Though the first provision extending exclusivity by two years based on the approval of a new indication or use of a previously approved drug would cover a lot of changes, it is the second provision concerning drugs reformulated or redesigned that really seems to be the focus of the PATIENT Act of 2015. 

There are a lot of changes that can be placed into the reformulation and redesign buckets identified in the bill, including, for example, the development of abuse-deterrent opioid formulations, and the change in or elimination of an excipient.  But does the added incentive proposed by the PATIENT Act of 2015 also create a reverse incentive?  That is, with the possibility of added exclusivity, is there an incentive for companies to start at the bottom and work their way to the top, obtaining multiple approvals and periods of exclusivity along the way for product improvements?  And to the extent an older version of a drug is determined by FDA to have been withdrawn for reasons of safety or effectiveness, that drug would no longer be available as a listed drug for ANDA or 505(b)(2) submission purposes.  Perhaps those types of issues would be part of the proposed FDA consultation process, but the PATIENT Act of 2015 seems to envision a process in which FDA is confined to consider a new drug vis-à-vis the previously approved formulation or drug design. 

By Kurt R. Karst –      

Last week marked the 5th anniversary of the March 23, 2010 enactment of the Affordable Care Act (“ACA”).  Title VII of the ACA, the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), amended the Public Health Service Act (“PHS Act”) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed reference biological product.  Over the past few years, much of industry’s focus has been on FDA’s creation and implementation of the biosimilar pathway (see our previous posts here, here, and here), and on the legal battles over the “patent dance ” provisions (see our previous posts here and here).  But there’s another set of provisions in the BPCIA that folks have begun eyeing with increased interest: the so-called “transition provisions.”  And a new bill introduced last week by Representative Michael Burgess (R-TX), the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” (H.R. 1576), seeks to get the Government Accountability Office (“GAO”) involved in evlauating the provisions before they come into play. 

The transition provisions are at Section 7002(e) of the BPCIA and account for a change made to the statutory definition of “biological product” at PHS Act § 351(i) to include a “protein (except any chemically synthesized polypeptide).”  That change brings into the fold of biologics (and thus biosimilars) regulation a larger grous of products, including several natural source proteins like insulin, hyaluronidase, menotropins, and human growth hormones, that have been regulated as drugs under the FDC Act.  Specifically, BPCIA § 7002(e) states:

(e) PRODUCTS PREVIOUSLY APPROVED UNDER SECTION 505.—

(1) REQUIREMENT TO FOLLOW SECTION 351.—Except as provided in paragraph (2), an application for a biological product shall be submitted under [PHS Act § 351] (as amended by this Act).

(2) EXCEPTION.—An application for a biological product may be submitted under section [FDC Act § 505] —

(A) such biological product is in a product class for which a biological product in such product class is the subject of an application approved under such section 505 not later than the date of enactment of this Act; and

(B) such application—

(i) has been submitted to the Secretary of Health and Human Services (referred to in this subtitle as the “Secretary”) before the date of enactment of this Act; or

(ii) is submitted to the Secretary not later than the date that is 10 years after the date of enactment of this Act.

(3) LIMITATION.—Notwithstanding paragraph (2), an application for a biological product may not be submitted under [FDC Act § 505] if there is another biological product approved under [PHS Act § 351(a)] that could be a reference product with respect to such application (within the meaning of such section 351) if such application were submitted under [PHS Act § 351(k)].

(4) DEEMED APPROVED UNDER SECTION 351.—An approved application for a biological product under [FDC Act § 505] shall be deemed to be a license for the biological product under such section 351 on the date that is 10 years after the date of enactment of this Act. 

Thus, an application for a biological product must be submitted under PHS Act § 351 subject to the exceptions at BPCIA § 7002(e)(2) during the 10-year transition period that ends on March 23, 2020. 

The “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” is, at least in part, an effort to get ahead of the curve before BPCIA § 7002(e) comes into play by asking the GAO to study some of the unique challenges presented by FDA’s evaluation of generic versions of complex drug products.  The bill sets out two broad questions for the GAO to consider:

1. With respect to nonbiologic complex drug products that have not been fully characterized . . . , whether the listing of such drugs as reference products in generic drug applications presents unique challenges in meeting approval standards that are significantly different than the challenges presented by generic drug applications that list small-molecule reference products.
2. With respect to biological products that are within the scope of the exception under section 7002(e)(2) of Public Law 111-148 (relating to temporary authority for the approval of biological products under [FDC Act § 505], whether the listing of such biological products as reference products in generic drug applications presents unique challenges in meeting approval standards that are significantly different than the challenges presented by generic drug applications that list small-molecule reference products.

The term “complex drug products that have not been fully characterized” is further defined in the bill to mean a drug for which: (1) the active ingredient has molecular diversity; (2) scientific analytic methodologies are unable to fully identify the molecular structures and physiochemical properties of the active ingredient; and (3) the nature of the active ingredient is not understood sufficiently to identity both the the molecular components of the drug that are involved in producing the therapeutic effect, and the mechanisms of action that produce such effect.

If the GAO determines, after consulting with FDA and “appropriate public and private entities,” that the answer to the questions above is that “significantly different challenges are presented for patients when reference products are nonbiologic complex drug products that have not been fully characterized or when reference products are biological products that are within the scope of the exception under [BPCIA § 7002(e)(2)],” then that determination triggers a series additional considerations, including:

1. What degree of characterization of the proposed generic version and the reference product should be required in order to determine the safety and effectiveness of the generic version;
2. What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product;
3. What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product;
4. What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product;
5. Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product; and 
6. Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.

Ultimately, consideration of these questions is intended to address whether FDC Act § 505(j) (concerning ANDAs) needs to be amended “to establish provisions that expressly address the approval of copy versions of nonbiologic complex drug products that have not been fully characterized, provisions that expressly address the approval of copy versions of biological products that are within the scope of the exception under [BPCIA § 7002(e)(2)], or both,” whether other changes to the law (i.e., FDC § 505(b)(2) and PHS Act § 351) need to be made, and whether FDA should develop a policy document “providing a comprehensive statement of general principles on the evidence that is necessary to obtain the approval of such Administration for proposed generic versions of reference products that are nonbiologic complex drug products that have not been fully characterized or that are biological products.”  The GAO report addressing each of these issues would be due not later than two years after the enactment of the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015.”

With or without the passage of H.R. 1576, we’re likely to see some interesting questions and controversies crop of with the BPCIA’s transition provisions.  For instance, what happens if FDA approves an A-rated generic version of a biological product that come March 2020 will be deemed a license under the PHS Act?  Does that A-rating transition into an interchangeable biological product or not given the statutory requirements for interchangeability?  And what about the applicability of pediatric exclusivity to patents currently listed in the Orange Book for biological products that will be deemed licensed under the PHS Act?  Does that exclusivity simply disappear given the BPCIA's pediatric exclusivity limitation and lack of a patent listing mechanism?  Also, how will FDA treat any ANDAs or 505(b)(2) applications pending review on March 23, 2020? 

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a junior to mid-level associate with substantive experience in medical devices and other areas of food and drug law and regulation to assist with a growing practice.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jwasserstein@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

By James C. Shehan –

Events keep on coming at a furious pace in the biosimilar world, with two new developments in the battle between Amgen and Sandoz over the latter’s hopes to launch its recently approved Zarxio, a biosimilar version of the former’s Neupogen (filgrastim). 

On March 25, 2015 FDA denied an Amgen Citizen Petition that requested FDA to require biosimilar applications to include certifications that applicants will timely comply with section 351(1)(2)(A) "by providing the reference product sponsor with a copy of the biosimilar application and information that describes the process(es) used to manufacture the biosimilar product that is the subject of that application.”  This petition was filed in October 2014 (see our previous post here) and Momenta’s comments opposing it (cited by FDA) were filed the following month.  As summarized by FDA, Amgen’s position largely flows from its interpretation of the statute as making the patent dance a mandatory process, while Momenta’s position is based on interpreting the patent dance as optional.

Having laid out these opposing views, FDA declines to require the certification requested by Amgen while refusing to endorse either interpretation.  Instead, the Agency makes plain that it has no intention of getting involved in a fight that it believes it can avoid.

FDA’s reasoning starts with the wording of the statute itself: “Neither section 351(k) nor section 351(1) requires FDA to impose a certification requirement as part of the biosimilar review process.”  The agency highlights that in this respect the BPCIA is “in contrast” to the Hatch-Waxman Act “Section 505(b) requires new drug application sponsors to identify certain patents for listing by FDA.  Consistent with section 505(b)(1), FDA publishes these lists in its Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book). Sections 505(b)(2)(A) and 505(j)(2)(A)(vii) of the FD&C Act require 505(b)(2) and ANDA sponsors, respectively, to certify each patent submitted for the listed drug referenced in the Orange Book.  Because of this contrast, FDA concludes that imposing a certification “is a matter of regulatory discretion and not compelled under the PHS Act.”  For good measure, FDA asserts that the Amgen petition “implicitly acknowledges” that this is a matter of FDA discretion.

In support of its conclusion, FDA characterizes the patent dance procedures as “parallel to, but separate from, the FDA review process.”  As further support, the Agency notes that the BPCIA “generally does not describe any FDA involvement in monitoring or enforcing the information exchange by creating a certification process or otherwise,” although it does acknowledge grudgingly in a footnote that it has a duty to receive and publish certain patent infringement lawsuit complaints in the Federal Register.  Tying up with a bow its determination to stay clear of patent dance fights to the extent possible, FDA consigns the issue to the judicial system “These competing interpretations of section 351(1) are the subject of litigation that may clarify how section 351(1) should be interpreted.”

Speaking of that litigation (see our posts here, here, and here), Amgen has now filed an appeal to the Federal Circuit of the lower court’s denial of its request for a preliminary injunction to block the launch of Zarxio.  The parties have requested an expedited schedule for the appeal with oral argument projected for June.  Amgen has also requested an injunction during the pendency of the appeal.  Sandoz has agreed to not launch Zarxio until the earlier of May 11th or a Federal Circuit ruling on Amgen’s request for an injunction pending appeal. 

During the long five years between BPCIA passage and Zarxio’s approval, long stretches could pass without significant developments in the US biosimilar world.  It seems that those days are past.

By Alexander J. Varond –

On March 23, Representative G.K. Butterfield (D-NC) introduced H.R. 1537, the “Advancing Hope Act of 2015.”  The Advancing Hope Act would reauthorize the rare pediatric disease priority review voucher (“Pediatric Voucher”) program, which is slated to sunset in March 2015.  Rep. Butterfield’s press release can be found here.  We discussed the Pediatric Voucher program and its sunset clause here.  The bill would also amend the tropical disease priority review voucher (“Tropical Disease Voucher”) program.

The Advancing Hope Act would modify the definition of “rare pediatric disease” to specifically include “any form of sickle cell disease” and “any pediatric cancers.”  This appears to be in response to various requests for the inclusion of sickle cell disease submitted to FDA’s docket for its Draft Guidance on the Pediatric Voucher program and efforts by Kids v. Cancer.  We discussed the Draft Guidance here.  The Advancing Hope Act would also eliminate the possibility of receiving a Pediatric Voucher after a Tropical Disease Voucher was issued for the same drug or biological product.

The Advancing Hope Act also addresses the Tropical Disease Voucher program and would exclude drugs that have been “approved for commercial marketing for any tropical disease indication by a government authority outside of the United States for more than 24 months before the application is submitted.”  Such a limitation, however, could prove problematic for a number of reasons.  We discuss two of these reasons below.

First, the World Health Organization’s Prequalification Programme relies on regulatory findings from a select number of regulatory agencies (e.g., FDA, EMA, Health Canada).  WHO’s website explains:

The Prequalification Programme, set up in 2001, is a service provided by the World Health Organization (WHO) to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis.  From the outset, the Programme was supported by UNAIDS, UNICEF, UNFPA and the World Bank as a concrete contribution to the United Nations priority goal of addressing widespread diseases in countries with limited access to quality medicines.

Prequalification was originally intended to give United Nations procurement agencies, such as UNICEF the choice of a range of quality medicines. With time, the growing list of products (i.e. medicines) that have been found to meet the set requirements has come to be seen as a useful tool for anyone bulk purchasing medicines, including countries themselves and other organizations.  For instance, the Global Fund to Fight AIDS, Tuberculosis and Malaria disburses money for medicines that have been prequalified by the WHO process.

Eliminating incentives for sponsors to seek FDA approval would likely slow WHO’s efforts to prequalify medicinal products and, therefore, could have a significant impact on global health.

Second, adding this exclusion to the Tropical Disease Voucher program would remove incentives for sponsors to further develop, manufacture, and seek U.S. approval of drugs that, at some point, were approved outside of the United States but are no longer manufactured.  FDA’s Draft Guidance on the Tropical Disease Voucher program addresses a variety of reasons the program was enacted.  Among these is the concern that “[a]lthough these tropical diseases are rare in the United States, intercontinental jet transport, immigration, tourism, and military operations are increasing the direct impact these diseases have on the health of Americans.”  Without these incentives, it is unlikely sponsors would seek approval in the United States.  If confronted with a health emergency for a tropical disease in the United States, stocks of a drug approved outside the United States might be unavailable.  Even if they were available outside the United States, they would not have been determined to be safe or effective in the United States.

By Kurt R. Karst –   

Does FDA has the authority to approve a new indication for an approved drug when that new indication has not been shown to be safe and effective by adequate and well-controlled studies submitted by the sponsor of the application?  And under what circumstances can FDA omit from generic drug labeling protected pediatric information included in the labeling of a Reference Listed Drug approved for multiple indications?

Those are the two core questions posed in a lawsuit Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Development & Commercialization, Inc., and Otsuka America Pharmaceutical, Inc. (collectively, “Otsuka”) filed earlier this week against FDA in the U.S. District Court for the District of Maryland concerning the atypical antipsychotic blockbuster drug ABILIFY (aripiprazole).  ABILIFY is approved under several NDAs (NDA 021436, NDA 021713, NDA 021729, and NDA 021866) in various dosage forms (tablets, oral solution, orally disintegrating tablets, and injection) for:

1. the treatment of schizophrenia;
2. the acute treatment of manic and mixed episodes associated with bipolar I disorder;
3. the maintenance treatment of bipolar I disorder;
4. use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder;
5. the treatment of irritability associated with autistic disorder;
6. the acute treatment of agitation associated with schizophrenia or bipolar disorder (manic or mixed); and . . . most recently and most importantly for the issues at hand . . .
7. the treatment of Tourette’s disorder (or is it, as discussed below, the treatment of pediatric patients with Tourette’s Disorder?). 

Each version of ABILIFY is listed in the Orange Book with several patents expiring years from now; however, it was widely expected that FDA might approve ANDAs for generic versions of ABILIFY come April 20, 2015 when the period of pediatric exclusivity associated with U.S. Patent No. 5,006,528 (listed in the Orange Book as a drug product, drug substance, and method-of-use patent) expires.  But that shouldn’t happen says Otsuka in the company’s March 24, 2015 Complaint and Motion for Summary Judgment.  And a decision needs to be made soon to avoid irreparable harm, according to Otsuka’s Motion to Expedite the court proceedings. 

By way of background – and we’ll try to keep things as simple as possible (ha-ha!) – FDA, on January 25, 2006, designated Otsuka’s ABILIFY as an orphan drug for the “[t]reatment of Tourette’s syndrome.”  Meanwhile, Otsuka conducted Phase 3 clinical trials of aripiprazole in pediatric patients with Tourette’s Disorder demonstrating that the drug is safe and effective for use in pediatric patients.  In February 2014, Otsuka submitted Supplemental NDAs to FDA seeking approval for the treatment of pediatric patients with Tourette’s Disorder.  On December 12, 2014, FDA approved the Supplemental NDAs stating, among other things, that “[t]hese ‘Prior Approval’ supplemental new drug applications provide for labeling revisions based upon two adequate and well-controlled trials that demonstrate the efficacy for the new indication in pediatric patients with Tourette’s Disorder.”  Not long after that, FDA’s Orphan Drug Designations and Approvals database was updated to show the “Orphan Approval Status” as “Approved for Orphan Indication,” and the “Approved Labeled Indication” as “Treatment of pediatric patients with Tourette’s.”  FDA’s Orange Book (Cumulative Supplement No. 2, Feb. 2015) was then updated to reflect the addition of a period of orphan drug exclusivity expiring on December 12, 2021.      

So far, so good; just the typical approval and outcome you’d expect.  But then things got interesting. . . really interesting . . . .   

As stated in Otsuka’s court filing:

Counsel for Otsuka thereafter wrote to FDA’s Chief Counsel setting forth the company’s position that FDA’s approval of Abilify of an orphan indication for treatment of pediatric patients with Tourette’s Disorder meant that FDA was precluded from approving an ANDA for a generic version of Abilify for any indication pending the expiration of Otsuka’s statutory seven-year period of orphan drug market exclusivity for the new indication.  Id. ¶ 22, Att. E.  As counsel’s letter explained, none of the narrow exceptions to the general “same labeling rule” that requires generic drugs to contain the same information on their labels as their respective brand-name predicate (or reference listed) drug were applicable and, therefore, the general “same labeling rule” controlled.  Id. Att. E. [(Emphasis added; copies of the various attachments referenced are available here.)]

The position set forth by Otsuka’s counsel concerns FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act.  The provision, titled “Prompt approval of drugs under section 355(j) when pediatric information is added to labeling,” 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)0, 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.

This section of the law has come up in the past.  It has been used as a basis to delay approval of competing products until the expiration of exclusivity (see here), but it also facilitated ANDA approvals with pediatric information (e.g., sildenafil).

According to Otsuka, because FDC Act § 505A(o) refers only to protected pediatric labeling information protected by patent or 3-year exclusivity, “[t]he statute undeniably does not allow the omission of pediatric information protected by orphan drug exclusivity, which is granted pursuant to Section 527 of the FDCA (21 U.S.C. § 360cc).”

After receiving the above-referenced correspondence from Otsuka’s counsel, FDA changed course, alleges Otsuka, for an “improper extra-legal reason”: to prevent a result that would bar generic competition.  According to Otsuka:

On February 24, 2015, FDA sent Otsuka a letter, informing Otsuka that “as the first sponsor of [aripiprazole] to obtain marketing approval for this indication, [Otsuka] is entitled to seven years of orphan-drug exclusive approval . . . for treatment of Tourette’s disorder.”  Id. ¶ 23, Att. F.  That same day, FDA sent Otsuka a “corrected” approval letter, in which FDA went further and, without explanation or elaboration, advised that its earlier December 12, 2014, approval letter “contained an error in the ‘indications’ section,” an “error” FDA purported to change unilaterally by changing (broadening) the approved indication from treatment “in pediatric patients with Tourette’s Disorder” to treatment of “patients with Tourette’s Disorder.”  Id. ¶ 23, Att. A. [(Emphasis in original)]

Feeling forced into a corner, and with the threat of generic competition right around the corner, Otsuka sued, alleging violations of the Administrative Procedure Act (“APA”) and the FDC Act by FDA stemming from the Agency’s “corrected” approval.  Specifically, Otsuka alleges first that FDA violated the APA by abusing its discretion and by acting in an arbitrary and capricious manner that is contrary to the law when the Agency reversed its original approval decision:

This claim rests firmly on three closely related contentions.  First, when FDA approved a broader indication that that which Otsuka requested and when this broader indication was not supported by Otsuka’s adequate and well-controlled studies, FDA acted well outside its authority under the FDCA.  Second, FDA’s broadened approval is arbitrary and capricious because it is without factual or evidentiary support.  Otsuka conducted clinical trials with pediatric patients only and FDA does not conduct its own independent clinical trials to determine the safety and efficacy of a requested new indication.  Third, FDA “corrected” and broadened its original approval for a legally impermissible reason. FDA’s “corrected” its decision for reasons altogether unrelated and extraneous to the proper use of Abilify in the treatment of Tourette’s Disorder. Instead of operating within the boundaries of the FDCA’s approval provisions, FDA acted – and improperly so – in an effort to seek to deny Otsuka the rights and benefits to which it is entitled under the Orphan Drug Act.

Otsuka’s first contention is particularly interesting to us.  Indeed, we’ve seen at least one recent instance in which FDA decided on its own to broaden the indication for a drug over the objection of the NDA sponsor.  That happened with the August 13, 2013 approval of NDA 204308 for EPANED (enalapril) for oral solution, 1 mg/mL, for the treatment of hypertension (see here). The sponsor had pursued approval (and obtained orphan drug designation) for the treatment of hypertension in pediatric patients; however, FDA refused to approve the drug for anything less that treatment of hypertension in adults and children. 

Otsuka, in Count Two of the company’s Complaint, assumes (without conceding) the validity of FDA’s “corrected” (and broadened) approval and alleges that FDA is precluded from approving any generic versions of ABILIFY on April 20, 2015 based on FDC Act § 505A(o) and the fact that ABILIFY’s labeling is “loaded with pediatric information.”  “FDA is barred from omitting from the generic’s label the ample and multiple pediatric references in the FDA-approved Abilify label for the broadened population at large indication,” says Otsuka.  “Those references are protected by orphan drug exclusivity, and pediatric information pertaining to orphan drug exclusivity is not a category of information that Congress permitted to be omitted.”

Given the intense interest in the drug and what is likely a long line of ANDA applicants for generic ABILIFY, we’ll probably see some interventions in the case.  A conference call between the parties and the court was held on Wednesday, March 25, 2015 at 3:00 PM.  Afterwards, the court issued a Scheduling Order setting a hearing on April 14, 2015 at 10:00 AM for Otsuka's Motion for Summary Judgment and any cross-motions.

By Riëtte van Laack & Ricardo Carvajal -