On December 3, 2012, the United States Court of Appeals for the Second Circuit (which is based in New York City) issued a long-awaited ruling in United States v. Caronia, a case involving off-label promotion.  In a 2-1 82-page decision that involves a vigorous dissent, the Court vacated the criminal conviction of Alfred Caronia, a former sales representative for a pharmaceutical company.  The sales representative was convicted for promoting the drug Xyrem for a use that had not been approved by FDA. 

The Court ruled that “we construe the FDCA as not criminalizing the simple promotion of a drug’s off-label use because such a construction would raise First Amendment concerns.”  The Court concluded that the record  demonstrated that the government had prosecuted Mr. Caronia for “mere off-label promotion.”  Slip Op. at 26.

The Court explained that FDA’s construction of the FDCA legalizes the outcome of off-label use by doctors, but “prohibits the free flow of information that would inform that outcome.”  The Second Circuit concluded that “the government’s prohibition of off-label promotion by pharmaceutical  manufacturers ‘provides only ineffective or remote support for the government’s purpose.’”  Slip Op. at 47.

The Court also ruled that it construes “the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs.”  In addition the Court ruled “that the government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug.”  Slip. Op. at 51.

It goes without saying that this is a very significant ruling that will have wide implications for FDA and the companies and individuals regulated by FDA.  Our firm will provide a more detailed analysis of the ruling in the upcoming days. Our previous post on the case is available here.

By Jennifer D. Newberger –

On November 28, 2012, CDRH issued a report titled “Improvements in Device Review,” addressing progress in the Center since issuance of its “Plan of Action” in January 2011.  The report states that since the Plan of Action, “the speed and predictability of device review have improved for the first time in almost a decade, including significant reductions in the time it takes FDA to review applications and the size of application backlogs.”

A brief review of the Plan of Action and reasons for its implementation may be helpful in understanding the genesis of this recently released report.  In response to concerns raised by industry, consumer groups, and CDRH employees, CDRH began an evaluation of its premarket review process in late 2009.  In August 2010, in response to internal reviews and public feedback, CDRH released two reports.  The first identified problems with its premarket review process, and the second addressed CDRH’s use of science in regulatory decision-making.  The main problem identified in the premarket review process was unpredictability, “including uncertainty about the requirements for approval and the likely length of the review process, as well as inconsistencies and mid-stream changes in what information was required to obtain approval.”  CDRH issued its Plan of Action in January 2011 to address those concerns.  It included 36 action items, many focused on the major causes of unpredictability. 

The November 2012 report assesses progress on those items, including:

• More efficient review of lower risk products;
• Increasing reliance on national and international device studies and standards;
• Enhancing reviewer training;
• Providing better, timelier guidance to CDRH staff and industry on requirements for clearance and approval;
• Reducing unnecessary and inconsistent data requests;
• Promoting greater transparency, interaction, and collaboration between FDA and industry during premarket reviews; and
• Improving CDRH’s understanding of new device technologies.

The report also discusses CDRH’s action to support innovation, including the Innovation Pathway, the Entrepreneurs-in-Residence program, and creating incentives for conducting clinical trials in the U.S.

According to the report, some of the specific positive trends resulting from the Plan of Action include:

• The average time it takes to clear a 510(k) began declining in 2011, for the first time since 2005;
• The backlog of 510(k)s pending for more than 90 FDA-days dropped by almost two-thirds from its high in 2010, dropping for the first time since 2005;
• The percentage of 510(k)s for which CDRH requested additional information during the first review cycle has decreased;
• The average time to reach a decision on a PMA has been reduced by approximately one-third since 2010; and
• The percentage of 510(k)s cleared and PMAs approved has increased since 2010.  FDA attributes this to “improvements in the quality of applications and the consistency of review standards.”

While these initial numbers are encouraging, it is understandable if industry remains cautious.  It is a bit too soon to consider these results to be “trends.”  Though some of CDRH’s action items actually went into effect in 2010, before issuance of the Plan of Action, the results described in the report are based on, at most, one and a half years of data:  all of FY2011, and limited information from FY2012.  It will be interesting to see what the data look like in another year.

Industry can, however, take comfort in the number of efforts underway at CDRH to improve the review process.  There is no question that CDRH has issued a large number of draft and final guidance documents in the last two years, many of which should prove very useful to both industry and CDRH in improving the premarket review process.  Additionally, improvements in reviewer training and the increase in informal interactions are positive steps. 

Hopefully, CDRH will not take the initial results as a necessary sign of success, but will instead continue to work towards improving its premarket review process and relationship with industry.

By Kurt R. Karst –    

Last Friday afternoon, Endo Pharmaceuticals Inc. (“Endo”) filed a Complaint and a Motion for Preliminary Injunction in the U.S. District Court for the District of Columbia seeking declaratory and injunctive relief concerning the company’s non-crush-resistant formulation of Opana® ER approved under NDA No. 021610 (identified in Endo’s Complaint as “Original Formulation Opana® ER”).  Endo alleges that FDA violated the FDC Act and the Administrative Procedure Act by failing to make a determination as to whether Original Formulation Opana® ER, which was discontinued from marketing earlier this year, was withdrawn for reasons of safety.  Endo currently markets a crush-resistant version of Opana® ER approved under NDA No. 201655 (identified in Endo’s Complaint as Opana® ER CRF).  Endo is also seeking a preliminary injunction ordering FDA to make a decision by December 31, 2012 on whether Original Formulation Opana® ER was discontinued for safety reasons.  FDA has approved two ANDAs for generic versions of Original Formulation Opana® ER – ANDA No. 079087 (Impax) and ANDA No. 079046 (Actavis) – and the companies are expected to begin marketing their drug products on January 1, 2013.  In the interim, Endo wants a court order directing FDA to withdraw or suspend those approvals.

The lawsuit follows a pair of citizen petitions Endo submitted to FDA in August. The first Citizen Petition (Docket No. FDA-2012-P-0895) requests that FDA determine that Original Formulation Opana® ER was discontinued for reasons of safety and can no longer serve as the basis of approval for an ANDA, that FDA refuse to approve any pending ANDA for a generic version of Original Formulation Opana® ER, and that FDA suspend and withdraw the approval of any ANDA referencing Original Formulation Opana® ER as its basis for approval.  The second Citizen Petition (Docket No. FDA-2012-P-0951), which was recently supplemented, primarily concerns the requirements to obtain approval of an ANDA for a generic version of Opana® ER CRF, but also brings Original Formulation Opana® ER into the mix.

“FDA has not carried out its responsibility under 21 C.F.R. § 314.161(a) to make a determination sua sponte as to whether Endo discontinued Original Formulation Opana® ER for reasons of safety,” alleges Endo.  That regulation requires FDA to determine, prior to approving a pending ANDA that refers to a drug product that is no longer marketed, and “[w]henever a listed drug is voluntarily withdrawn from sale and [ANDAs] that referred to the listed drug have been approved,” whether such discontinuation was for reasons of safety or effectiveness.  In addition, the statute (FDC Act § 505(j)(4)(I)) and FDA’s implementing regulations ( 21 C.F.R. § 314.127) provide that FDA may refuse to approve an ANDA if the Agency determines that the RLD was withdrawn from sale for reasons of safety or effectiveness, and that FDA can suspend and withdraw approval of an ANDA if the Agency determines that the RLD was withdrawn from sale for reasons of safety (FDC Act § 505(j)(6)). 

“FDA has not taken any action in response to either of Endo’s Citizen Petitions or its recent Supplement that sought to prod the agency into fulfilling its statutory and regulatory obligations, triggered by Endo’s May 31, 2012 Notice that it had withdrawn Original Formulation Opana® ER,” says Endo.  Moreover, Endo alleges that FDA has failed to make the legally required discontinuation determination despite

mounting evidence of the public health crisis caused by abuse and misuse of prescription opioid pain relievers; FDA’s awareness that opioid pain relievers that are manufactured without safety features are more susceptible to abuse; FDA’s exhortations to pharmaceutical companies to invest in innovative crush-resistant formulations of opioid pain relievers; Endo’s data demonstrating the safety benefits of Opana® ER CRF over non-crush-resistant versions of the drug; the documented “squeezing-the-balloon effect,” whereby opioid abusers can be expected to quickly learn of and migrate to generic non-crush-resistant formulations, i.e., those pills that may be readily crushed and snorted; and FDA’s knowledge that a non-crush-resistant generic version of Opana® ER is poised to launch on or about January 1, 2013.

The issue of simultaneous marketing of abuse-deterrent brand-name drugs and non-abuse-deterrent generic drugs has been heating up over the past year – not only here in the United States, but, for example, in Canada as well. 

In addition to Opana ER, FDA has received several citizen petitions (Docket Nos. FDA-2011-P-0473, FDA-2010-P-0540, and FDA-2010-P-0526) requesting that the Agency determine whether the abuse-deterrent version of OxyContin (oxycodone hydrochloride) Controlled-Release Tablets was discontiued for safety reasons.  Congress has also expressed interest in the topic with the introduction of the Stop Tampering of Prescription Pills Act of 2012 (“STOPP Act”) in July.  As we previously reported, the STOPP Act would amend the FDC Act to, among other things, establish new requirements for the approval of brand-name and generic drugs that are otherwise available in a tamper-resistant formulation, and deem the discontinuation of a non-abuse-deterrent drug after the approval of an abuse-deterrent to be a discontinuation for safety reasons.

By Kurt R. Karst –      

The Alliance for Safe Biologic Medicines (“ASBM”), a self-described “organization composed of diverse healthcare groups and individuals from patients to physicians, innovative medical biotechnology companies, and others who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion,” urges FDA in a new paper to adopt unique non-proprietary names for all biological products licensed under the Public Health Service Act (“PHS Act”), and in particular biosimilar versions of reference products (even those that are interchangeable).  The paper, titled “It’s All About the Name: What is the Imperative of Adopting Unique Names For Biologic and Biosimilar Therapeutics?,” appeared in the latest edition of the Food and Drug Law Institute’s “Food and Drug Policy Forum,” and is the latest effort by ASBM and its members to advocate for unique biosimilar naming.  Over the past few months, ASBM and several member organizations have sent letters to FDA (see here) saying that it is essential that each biosimilar licensed under PHS Act § 351(k) have a unique name in order for patients and physicians to easily distinguish between medicines and to track and trace adverse events for such products.

The “naming issue” has been around since well before the March 23, 2010 enactment of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created the biosimilars pathway in the U.S.  For example, in an October 2006 Policy Position on Naming of Biotechnology-Derived Therapeutic Proteins submitted to the World Health Organization (“WHO”), several organizations, including PhRMA and BIO, recommended the assignment of distinct International Nonproprietary Names (“INNs”) to each biotechnology-derived therapeutic protein produced by different manufacturers in order to “accommodate the acknowledged complexity of protein medicinal products and best meet the WHO Objectives for INNs to facilitate safe prescription and dispensing of medicines and preserve patient safety.”  (An INN is the official generic name assigned to a pharmaceutical’s active ingredient by the WHO and applies to each product globally.)  Just a month before, FDA had commented (see here, page 9) to the WHO that “INNs for biologicals should not be used to imply product interchangeability in the absence of credible scientific evidence.  Likewise, however, INNs should not be used to differentiate biological products with the same active ingredient(s) when credible scientific data demonstrate that no pharmacologically relevant differences exist.” 

The BPCIA, as enacted, does not specifically address biosimilar product naming.  Although previous biosimilar legislation did address the issue, such as Representative Henry Waxman’s (D-CA) Access to Life-Saving Medicine Act (H.R. 1038) and Senator Judd Gregg’s (R-NH) Affordable Biologics for Consumers Act (S. 1505) (both from 2007), it was ultimately decided that naming provisions should not be included in the final biosimilars bill.  Given that “hole,” and an intensifying interest in a U.S. biosimilars market, the “naming issue” has taken on a life of its own.  Indeed, it was a much discussed issue at FDA’s November 2010 public hearing on the Agency’s implementation of the BPCIA. 

ASBM makes the point in its FDLI Policy Forum paper that:

The need for clear, defined naming considerations and a system to implement an effective tracking and tracing of all biologics – not just biosimilars – stems from the potential of these products to be unexpectedly altered by the manufacturing process, handling, etc., in a manner that could cause unintended harm to patients.  Whether the products that FDA approves will have the same name or a different name than the originator biologic will determine how well products can be traced back to a patient who has an adverse reaction.

With this backdrop, ASBM outlines what it says are key components that FDA must address in the biologics naming space, and makes four recommendations: 

1. All biologics should receive distinct non-proprietary names;

2. The United States Pharmacopeia should work with FDA to adapt the product monograph system to accommodate the unique attributes of structurally-related, but distinct, biologic medicines;

3. The non-proprietary name of a reference product and product/s biosimilar to it should have a common, shared root but have distinct and differentiating suffixes; and

4. Products designated interchangeable should have a distinct name from the reference product for which they are considered interchangeable to facilitate accurate attribution of adverse events.

On the other side of the fence, the Generic Pharmaceutical Association (“GPhA”) has taken the position that “[c]onsistency, patient safety and sound scientific principles necessitate biosimilars having the same INN as their specific reference product,” and that “[t]here is no evidence that a unique INN will improve the effectiveness of pharmacoviligance.”  Moreover, says GPhA, the BPCIA does not require different names for biosimilars and their reference product counterparts, and requiring different names for interchangeable products effectively make such a determination meaningless. 

By Ricardo Carvajal & John R. Fleder –

On November 26th, Commissioner Hamburg issued an order suspending the registration of the Sunland Inc. food manufacturing facility alleged to be at the heart of the ongoing recall of peanut products potentially contaminated with Salmonella.  Until the order is vacated and the registration is reinstated, Sunland may not introduce food from the facility into interstate or intrastate commerce.  This marks the first time that FDA has exercised this authority, which was conferred on the agency by the Food Safety Modernization Act (“FSMA”), enacted on January 4, 2011.

If FDA determines that food manufactured, processed, packed, received, or held by a registered facility has a reasonable probability of causing serious adverse health consequences or death to humans or animals, FDA can suspend the registration of the facility that (1) created, caused, or was otherwise responsible for such reasonable probability; or (2) knew of, or had reason to know of, such reasonable probability, and packed, received, or held such food.  The authority to suspend a registration cannot be delegated by the Commissioner.

FDA determined that Sunland’s products have a reasonable probability of causing serious adverse health consequences or death to humans, and that the facility created, caused, or was otherwise responsible for the probability.  FDA relied in part on multiple test results purportedly showing that the products manufactured, processed, packed, and held by the facility “are contaminated with Salmonella, or are at risk for contamination with Salmonella, based on the conditions in [the] facility.”  FDA cited both its own product and environmental test results, and those provided to FDA by the facility.  FDA also questioned the facility’s decision to release certain products into commerce:

Your facility distributed at least a portion of eight (8) lots of peanut and almond butter… after composite testing of those lots revealed the presence of Salmonella. Specifically, when composite testing of a lot was positive for Salmonella, individual containers of product from the positive tested lots were re-tested and portions, or all, of these lots were distributed based on the re-test (non-composite) testing. The initial Salmonella positive composite test results were disregarded. At least one of the batches from a lot with initial positive composite test results… that was ultimately distributed, contained a Pulsed Field Gel Electrophoresis (PFGE) pattern that was indistinguishable from the clinical isolates for the outbreak strain Salmonella Bredeney. When a PFGE pattern of an isolate is indistinguishable from the pattern of another isolate from a common source, it is highly likely that the two isolates are the same strain of Salmonella Bredeney.

Sunland has the opportunity to request an informal hearing on reinstatement of its registration.  The request must be submitted within 3 business days after issuance of the order unless Sunland wants a hearing within 2 business days, in which case the request must be submitted within 1 business day.  The request “must present specific facts showing that there is a genuine and substantial issue of fact that warrants a hearing.”  The order states that “[a] hearing will not be granted on issues of policy or law.”  If the request is granted, the hearing will be conducted under the procedures specified in 21 CFR Part 16.

On its website, Sunland issued a statement suggesting that FDA’s decision caught Sunland by surprise.  In a previously issued statement, Sunland denied having released products “that it knew to be potentially contaminated with harmful microorganisms.”

This suspension action specifically, and more generally the FDA’s FSMA suspension authority, raise an interesting question.  If FDA believes that a food company is involved in a situation the agency believes presents “a reasonable probability of serious adverse health consequences” etc., when will the agency use the suspension authority provided in  FSMA and when will it alternatively seek its more traditional remedy of pursuing judicial relief in the form of a seizure action or an injunction case?  When will it impose an administrative detention?  We are unaware of any FDA guidelines that answer these questions.  Although the suspension authority presents the bureaucratic obstacle of requiring the explicit approval of the FDA Commissioner, it also provides FDA with a swift remedy that does not, in and of itself, require involvement from either the Justice Department or a court.  With that said, a suspended company should have the legal right to challenge a suspension order in court, by seeking a temporary retraining order to block the order  from remaining in effect.  We expect many companies to request the expedited hearing provided by FSMA.  Indeed, we expect many companies to pursue both remedies in cases where a company does not believe that the suspension order is legally or factually justified.

Seizure actions and injunction cases initiated by FDA and DOJ often proceed on a litigation calendar that does include expedited procedures.  There is no doubt that suspension orders issued by FDA will lead to expedited litigation when a company challenges an order.  Hopefully, this fact alone will dictate caution by FDA, as it will need to be prepared to defend its order in the administrative hearing provided in 21 CFR Part 16 and also in emergency court proceedings in a suit filed by the suspended entity.

By Bill Koustas & Alan Kirschenbaum –

In July, we reported that Massachusetts had amended its prescription drug and device marketing law to (among other things) allow pharmaceutical and medical device companies to provide “modest meals and refreshments” as part of an informational presentation to health care practitioners outside of the hospital or medical office setting.  (Note that, in this regard, Massachusetts law is less restrictive than the PhRMA Code on Interactions with Healthcare Professionals, which provides that meals offered in connection with informational presentations made by sales representatives or their immediate managers should be limited to in-office or in-hospital settings.)

On September 19, 2012, the Massachusetts Department of Public Health ("DPH") issued a temporary emergency rule to implement the statutory amendments.  The emergency rule amended DPH regulations in two significant ways.  First, in accordance with the statutory amendment, it removed the prohibition against providing meals to health care practitioners outside of the office or hospital setting, while also requiring pharmaceutical and medical device companies to submit quarterly reports detailing any activities where such meals or refreshments are provided.  Second, in light of the physician payment sunshine provisions of the Affordable Care Act, the emergency rule removed the requirement to annually report other permitted gifts to covered recipients after calendar year 2012.

On November 21, 2012, DPH issued a final rule to replace the earlier emergency rule.  The final rule, which will take effect on December 7, 2012, is similar to the emergency rule, but with a few important modifications.  First, the final rule restores the annual reporting requirement for 2013 and subsequent years to the extent that the required information does not duplicate information that is reported to the federal government under the federal sunshine provisions and that is then reported by the federal government to Massachusetts in annual reports.  Since the federal sunshine provisions cover only remuneration provided to physicians and teaching hospitals, annual reports to Massachusetts will still be required for remuneration provided to other “Covered Recipients” under the Massachusetts law – i.e., hospitals, nursing homes, pharmacists, nurse practitioners, and other practitioners and providers who are authorized to prescribe, dispense, or purchase drugs. 

The final rule retains the quarterly reporting requirement for out-of-office meals and refreshments, but does not specify a reporting deadline.  Presumably, DPH will notify manufacturers about the quarterly report deadline in a future communication.  Interestingly, DPH noted in an explanatory memorandum that much of the information reported in the quarterly reports will likely be covered by the federal sunshine provisions and therefore be preempted, but DPH decided to retain the quarterly reporting requirement regardless.

In issuing the final rule, DPH rejected commenters’ requests to place a monetary cap on what is considered a “modest” meal and to exclude alcoholic beverages.  The definition of “modest meals and refreshments” continues to include both food and drinks without restrictions on alcohol, and the benchmark for “modest” remains what a practitioner “might purchase when dining at his or her own expense,” as judged by local standards.

By Kurt R. Karst –

In a recent Complaint for Declaratory Judgment filed in the U.S. District Court for the Northern District of Illinois (Eastern Division), Apotex Inc. (“Apotex”) is attempting to trigger 180-day exclusivity for generic versions of the hypertension drug BENICAR (olmesartan medoxomil) Tablets, 5 mg 20 mg, and 40 mg, under the failure-to-market 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I). The complaint is the latest in a string of thus far unsuccessful attempts by Apotex to obtain an exclusivity-triggering court decision, including exclusivity for generic versions of LEXAPRO (escitalopram) Tablets and LIPITOR (atorvastatin calcium) Tablets (see here).

BENICAR Tablets, which is approved under NDA No. 021286, is listed in the Orange Book with information on two patents: (1) U.S. Patent No. 5,616,599 (“the ‘599 patent”), which is identified as a drug product, drug substance, and method-of-use patent and the pediatric exclusivity for which expires on October 25, 2016; and (2) U.S. Patent No. 6,878,703 (“the ‘703 patent”), which is identified as a method-of-use patent the pediatric exclusivity for which expires on May 19, 2022.  On July 11, 2006, all claims of the ‘703 patent were disclaimed, and, according to Apotex, the patent expired on April 12, 2009 for failure to pay maintenance fees.  In the February 2010 Orange Book Cumulative Supplement (page A-4), a “delist requested” flag was added to the ‘703 patent entry.  FDA did not remove the ‘703 patent from the Orange Book given the existence of a Paragraph IV certification to the patent.  According to FDA’s List of Paragraph IV Patent Certifications, the first ANDA submitted to FDA containing a Paragraph certification to as to either the ‘599 patent or ‘703 patent was April 25, 2006.

According to Apotex, Mylan Laboratories Ltd. (“Mylan”) (formerly Matrix) was the first company to submit an ANDA for generic BENICAR Tablets containing a Paragraph IV certification, and Mylan’s ANDA contained Paragraph IV certifications with respect to both the ‘599 and ‘703 patents.  Patent infringement litigation was initiated against Mylan with respect to the ‘599 patent but not the ‘703 patent.  Mylan failed in its challenge of the ‘599 patent, and in September 2010, the U.S. Court of Appeals for the Federal Circuit affirmed the validy of the patent.  Mylan’s subsequent appeal to the U.S. Supreme Court also failed (see here).  Thus, Mylan’s Paragraph IV certification to the ‘599 patent converted to a Paragraph III certification, preventing ANDA approval until October 25, 2016 when pediatric exclusivity applicable to the patent expires.  FDA tentatively approved Mylan’s ANDA No. 078276 on March 5, 2008.  On September 16, 2009, FDA tentatively approved a second ANDA – Sandoz’s ANDA No. 090237.  FDA has not yet tentatively approved Apotex’s ANDA No. 204089, which was submitted years after the Mylan ANDA, and contains a Paragraph IV certification to the ‘703 patent.  Patent infringement litigation was not initiated against Apotex with respect to the ‘703 patent.

Under the 180-day exclusivity failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), 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 here given the April 25, 2006 date on the List of Paragraph IV Patent Certifications. 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).”  Based on the D.C. Circuit’s March 2, 2010 decision in Teva Pharms USA, Inc. v. Sebelius, a mere patent delisting request is not enough to trigger a forfeiture event under the failure-to-market forfeiture, and in particular under subitem (CC).  Moreover, FDA, in the context of the Teva decision, ruled in a Letter Decision that the Court’s reasoning “appears to preclude a forfeiture of exclusivity on the basis of a patent expiration where the expiration is in the control of the NDA holder,” such as patent expiration for failure topay maintenance fees. 

Given these decisions, a subsequent ANDA sponsor, like Apotex, has limited options to trigger the forfeiture of a first applicant’s 180-day exclusivity eligibility.  Apotex’s Complaint seeks a declaration of non-infringement and a declaration that FDA may approve Apotex’s ANDA No. 204089:

whenever that application is otherwise in condition for approval, without awaiting any further order, judgment, or decree of this Court; that the judgment entered in this case is a judgment reflecting a decision that the patent in suit is not infringed pursuant to 21 U.S.C. § 355 (j)(5)(B)(iii)(I)(aa); and that the thirty-month period referred to in 21 U.S.C. § 355(j)(5)(B)(iii) and any other marketing exclusivity periods to which Plaintiffs might otherwise be entitled (including any pediatric exclusivity) with respect to the ’703 patent are shortened to expire upon the date of entry of judgment in this case . . . .

Given that FDA has not yet tentatively approved Apotex’s ANDA No. 204089, this case, like other declaratory judgment actions before it, raises several questions . . . . and not just about the “case or controversy” requirement under Article III of the U.S. Constitution for a court to have jurisdiction in an ANDA Hatch-Waxman declaratory judgment action.  This case once again raises the question of how FDA might interpret the “which other applicant has received tentative approval” parenthetical at FDC Act § 505(j)(5)(D)(i)(I)(bb).  If a subsequent applicant first obtains a final court decision in its favor and then tentative approval, when does the 75-day period begin?  Is the tentative approval retroactive to the date of the final court decision, or would FDA interpret the statute such that the 75-day period begins on the date on which the subsequent applicant completed the statutory criteria?  Or, might FDA interpret the statute such that the 75-day period does not even begin under such a scenario because a subsequent applicant must have tentative approval at the time there is a final court decision? 

By Kurt R. Karst –      

A Complaint filed earlier this year by Mylan Pharmaceuticals Inc. (“Mylan”) in the U.S. District Court for the Eastern District of Pennsylvania alleging that Warner Chilcott and Mayne violated Sections 1 and 2 of the Sherman Act by engaged in so-called “product hopping” with respect to DORYX  (doxycycline hyclate) caught our attention.  After all, the Complaint opens with the following salvo:

This action is brought as a result of Defendants’ relentless efforts to obstruct and constrain competition through an admittedly “anti-generic strategy.”  Through multiple, concerted, and deliberate anticompetitive tactics commenced as early as 2005, Defendants have harmed [Mylan] and the public by preventing and/or delaying generic competition to Doryx – a delayed-release doxycycline hyclate product prescribed for the treatment of severe acne and other bacterial infections – years earlier.  Defendants have accomplished their anticompetitive goals through the use of various strategies that were intentionally designed to unlawfully interfere with the regulatory process, cause delays in the approval of generic versions of Doryx, and disrupt the market for generic Doryx.  This conduct violates Sections 1 and 2 of the Sherman Act, as Defendants have monopolized and restrained trade in the market for delayed-release doxycycline hyclate products.

We watched as other Plaintiffs – Direct and Indirect Purchasers – joined the case through a consolidation of related cases (see here), and filed the case in our memory bank until such time that something noteworthy (or, in our speak, “blogworthy”) happened.  That day has come. 

Last week, the Federal Trade Commission (“FTC”) filed a Motion seeking leave to file an amicus brief in the case to assist the court in its assessment of whether the Plaintiffs have plausibly alleged exclusionary conduct sufficient to state a claim under Section 2 of the Sherman Act.  In doing so, the FTC also addresses what it says is the “appropriate antitrust framework to apply when assessing allegations that a brand drug reformulation unlawfully delayed or inhibited generic competition.”  But before we get into the case, some background on “product hopping” is necessary.

Back in 2010, FTC Commissioner Rosch defined “product hopping” in a speech (pages 14-17) as the practice of “introducing new patented products with minor or no substantive improvements in the hopes of preventing substitution to lower-priced generics.”  As the FTC explains in its proposed amicus brief, product hopping can work in the following way:

[F]irst, the brand manufacturer makes minor non-therapeutic changes to the brand product, such as a dosage or form change.  Next, prior to generic entry, it removes the original product from the marketplace, or accomplishes this indirectly, such as by recalling supply of the original product or raising the price of the original product by a meaningful amount above the reformulated one.  Such conduct can push patients and physicians to abandon the original product.  In this way, a brand manufacturer can convert existing market demand for the original product to its reformulated product – not because physicians and patients prefer it, but simply because the original product is no longer as available or is more costly.  Once the original version of the brand product is less available or more expensive, physicians will stop writing prescriptions for it.  Because the prescription must contain, among other things, the same dosage and form as the generic for a pharmacist to substitute it for the brand, a product switch will effectively eliminate substitution at the pharmacy counter and thus meaningful generic competition.

(For a discussion of the intersection of patent settlement agreements and product hopping, see Michael A. Carrier’s “A Real-World Analysis of Pharmaceutical Settlements: The Missing Dimension of Product Hopping.”) 

In the case of DORYX, Mylan alleges that Defendants effectuated three successive drug product reformulations to impeded generic competition: first, a conversion from DORYX Capsules to DORYX Tablets; second, from DORYX Tablets in 75 mg and 100 mg strengths to a DORYX Tablets 150 mg strength; and third, from a single-scored version of DORYX Tablets 150 mg to a dual-scored version of DORYX Tablets 150 mg.  (A Warner Chilcott citizen petition related to this third conversion – Docket No. FDA-2011-P-0702 – was denied in February 2012.)  Mylan also alleges that a fourth conversion was in the works – a formulation change of DORYX Tablets 150 mg.  It is these conversions, argues Mylan, that foreclosed the company from competing in the various relevant markets identified in the Complaint and that are anticompetitive.

Warner Chilcott filed a Motion to Dismiss Mylan’s Complaint (and that of the Direct Purchasers) saying that it alleges “nothing more than innovation by Defendants, and the marketing of those innovations once government approvals were obtained,” which is not illegal under the Sherman Act. (Warner Chilcott also filed a Motion to Dismiss the Indirect Purchasers’ Complaint, which has been opposed, and Mayne filed a Motion to Dismiss the Mylan and Direct Purchasers’ Complaints.) According to Warner Chilcott, the DORYX conversions are per se lawful and that product changes (or redesigns or reformulations) can never constitute exclusionary conduct: “such conduct is either competition-enhancing (if the new version represented an improvement), or at worst competition-neutral because one version was replaced by another.” (Italics in original)  As such, argues Warner Chilcott, Plaintiffs’ claims should be dismissed.

Not so, say Mylan and the Direct Purchasers in their Oppositions briefs (here and here).  They cite Abbott Labs. v. Teva Pharms. USA, Inc., 432 F. Supp. 2d 408 (D. Del. 2006), which is referred to as “TriCor,” as articulating the appropriate standard for assessing whether there is a plausible allegation of exclusionary conduct sufficient to state a claim under Section 2 of the Sherman Act.  In TriCor, the Delaware District Court denied a Motion to Dismiss where the brand-name company argued that its product changes were per se lawful.  The court also rejected the suggestion that plaintiffs in that case were required to prove that the “new formulations [of the drug] were absolutely no better than the prior version or that the only purpose of the innovation was to eliminate the complementary product of a rival.” Instead, the district court, citing United States v. Microsoft Corp., 253 F.3d 34 (D.C. Cir 2001) (en banc), said that “if plaintiffs show anticompetitive harm from the formulation changes, that harm will be weighed against any benefits presented by defendants.”

The FTC, in its proposed amicus brief, says that drug product redesigns can constitute exclusionary conduct, and that, like the plaintiffs in Tricor, Plaintiffs in the DORYX case have articulated a plausible claim that the DORYX conversions are unlawful under Section 2 of the Sherman Act.  “The allegations that defendants used product reformulations to manipulate the pharmaceutical regulatory system and thereby suppress generic competition are sufficient to state a claim of exclusionary conduct.  Applying a per se legal standard, as Warner Chilcott effectively advances here, would entitle brand pharmaceutical companies, as a matter of law, to manipulate the FDA regulatory process and undermine state and federal laws that encourage generic competition,” writes the FTC.

By Riëtte van Laack –

In April 2012, a California consumer filed a class action lawsuit against The Hershey Company alleging that Defendant’s Special Dark Chocolate Bars, Special Dark Kisses, Special Dark Cocoa and Cocoa were misbranded because they carried impermissible nutrient content claims, including nutrient content claims about antioxidants and “healthy” claims, and unapproved health claims.  Plaintiff’s action under several California laws includes claims for disgorgement, restitution and punitive damages. 

Defendant filed a motion to dismiss arguing that the action was precluded by § 310 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) (21 U.S.C. § 337(a)), which states that “proceedings for the enforcement, or to restrain violations, of the [FDC Act] shall be in the name of the United States,” thus excluding private enforcement.  However, in an opinion handed down on November 9, the District Court for the Northern District of California rejected this argument because Plaintiff’s action was based on state law provisions that “mirror the relevant sections of the [FDC Act].”

The Court further concluded that Plaintiff’s claims were not preempted because § 403A of the FDC Act expressly allows states to establish requirements for nutritional labeling identical to the FDC Act.  Plaintiff’s action was based on state law provisions that would not require that Defendant undertake food labeling or representations different from the requirements of the FDC Act or FDA regulations.

This decision is yet another reminder that, at least in California, violations of the nutrition labeling requirements of the FDC Act and FDA regulations may result in private actions under state law with far different consequences (including monetary damages) than actions by FDA. 

By Jennifer D. Newberger –

Section 520(b) of the Federal Food, Drug, and Cosmetic Act ("FDC Act") exempts “custom devices” from the performance standards or premarket approval ("PMA") requirements of sections 514 or 515 if certain criteria are met.  The Food and Drug Administration Safety and Innovation Act ("FDASIA"), signed into law in July 2012 (see here), amended section 520(b).  Though Congress may have been trying to make it easier for a manufacturer to qualify for the custom device exemption, the FDASIA amendment appears to have enumerated additional requirements, making it more difficult to meet the exemption.
 
As amended, section 520(b) will exempt devices from the requirements of section 514 or 515 if the device:

1. Is “created or modified in order to comply with the order of an individual physician or dentist” or other specified healthcare practitioner;
2. Must deviate from a requirement of section 514 or 515 in order to comply with the order of the practitioner;
3. “[I]s not generally available in the United States in finished form through labeling or advertising by the manufacturer, importer, or distributor for commercial distribution”;
4. “[I]s designed to treat a unique pathology or physiological condition that no other device is domestically available to treat”;
5. Is intended to meet the special needs of a practitioner “in the course of the professional practice” of the practitioner or  is “intended for use by an individual patient named in such order” of the practitioner;
6. Is made on a case-by-case basis “to accommodate the unique needs of individuals” described above.

Additionally, to qualify as a custom device, the device must be “for the purpose of treating a sufficiently rare condition, such that conducting clinical investigations on such device would be impractical,” production of the device must be limited to no more than five per year of a particular device type, and the manufacturer of the custom device must notify FDA annually about the production of such devices.

Earlier this week, FDA issued a notice stating that the Agency is now seeking “information on and examples of appropriate uses of the custom device exemption.”  77 Fed. Reg. 69,488, 69,488 (Nov. 19, 2012).  In particular, FDA is seeking information related to instances where the manufacturers or healthcare practitioners have used, would like to have used, or plan to use, the exemption; product areas other than orthopedic and dental devices in which the exemption may be useful; and how often custom devices are ordered to due a unique need of the practitioner (as opposed to the patient).

Historically, FDA has taken a very restrictive view of custom devices.  The amended criteria required will result in fewer devices qualifying for the custom device exemption.  Hopefully the comments will provide FDA with a better understanding of the types of patients, practitioners, and circumstances that would result in appropriate use of the exemption.

Hyman, Phelps & McNamara’s Robert A. Dormer will be speaking at the American Conference Institute’s upcoming conference, “Orphan Drugs and Rare Diseases – Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process.”  The conference will take place on November 28th and 29th at the Hyatt Regency in Boston, Massachusetts.  The conference is designed to give practitioners the complete picture of the orphan drugs and rare diseases landscape, including evolving laws and regulations, commercial implications, patent considerations, and the international framework.  Among other things, speakers, including Mr. Dormer, will discuss strategies to offset potential risks inherent to orphan drug development including:

• Understanding and factoring in the unique incentives, including favorable exclusivity, pricing, and tax benefits, for companies who decide to pursue designation; 
• Replenishing product pipelines in the face of the patent cliff through novel therapies;
• Preparing for eventual pharmacovigilance and labeling issues downstream as designation takes off; 
• Designing clinical trials endpoints and proving safety and efficacy in a smaller population; and
• Protecting orphan drug status and keeping competitors at bay.

To view the conference brochure and register for the conference see here.  FDA Law Blog readers may obtain a $200 registration discount by using code FDALB 200.

By Ricardo Carvajal –

The Center for Science in the Public Interest (“CSPI”) is taking on caffeination and fortification of foods with renewed vigor.  In a letter to FDA/CFSAN’s Office of Compliance, CSPI alleges that certain foods to which caffeine is added “appear to violate [FDA’s] determination (21 CFR 182.1180) that caffeine is generally recognized as safe only in cola-type beverages at concentrations of 0.02 percent or less.”  CSPI further contends that “the proliferation of caffeinated foods and beverages could lead to troublesome or serious health problems for children and adults who consume those products – especially when they consume multiple products over the day.” 

CSPI also filed a class action against Dr. Pepper Snapple Group, Inc. alleging that the company’s addition of vitamin E to its carbonated beverages violates FDA’s Fortification Policy at 21 C.F.R. § 104.20.  CSPI contends that both FDA and federal courts have recognized that the Fortification Policy is legally binding.  CSPI further alleges that the products’ labeling is misleading because it implies that the products’ antioxidant content is derived from real fruit (as opposed to vitamin E), and because the products contain insufficient vitamin E to “provide the health benefits that reasonable consumers associate with antioxidants.”

REMINDER:  You can follow us on Twitter @fdalawblog

By Jennifer D. Newberger –

FDA is amending its proposed rule to establish a unique device identification (“UDI”) system, published on July 10, 2012 (see our previous post here), to meet the requirements of section 614 of the Food and Drug Administration Safety and Innovation Act ("FDASIA"), signed into law on July 9, 2012 (see our FDASIA summary and analysis here).  77 Fed. Reg. 69393 (Nov. 19, 2012).  The amendment affects only implantable, life-supporting, or life-sustaining devices, primarily those that are not Class III devices or are not devices licensed under the Public Health Services Act ("PHS Act"), which are affected only as to the direct marking requirement.

FDASIA section 614 amends section 519(f) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), requiring FDA to implement “final regulations with respect to devices that are implantable, life-saving, and life sustaining” within two years of finalization of the UDI rule.  The July 10 proposed rule required all Class III devices and devices licensed under the PHS Act to bear a UDI within one year of publication of the final rule.  The effective date for those devices therefore meets the two year requirement in FDASIA and is not affected by this amendment. 

To comply with the FDASIA requirements, FDA “is now proposing to require all other implantable, life-supporting, and life-sustaining devices (i.e., those that are not already subject to the 1-year effective date) to bear a UDI” within two years of publication of the final rule.  77 Fed. Reg. at 69394.  In other words, any Class II, Class I, or unclassified devices that are implantable, life-supporting, or life-sustaining must also bear a UDI within two years of publication of the final rule, as opposed to three years as originally proposed.  This is unlikely to have a practical effect on Class I devices, since few, if any, are implantable, and by definition they are not life-supporting or life-sustaining.

The proposed rule also requires direct marking of the UDI on certain limited categories of devices, including implantable devices.  The direct marking requirement was to go into effect two years after the date on which the product was otherwise required to bear the UDI.  For Class III implantables, this would have been three years after finalization of the rule, for Class II, five years, and for Class I, seven years.  To comply with amended section 519(f), FDA is amending the proposed rule to require direct marking of all implantable devices, regardless of classification, within two years of finalizing the rule.

The biggest impact of this amendment will likely be on devices, primarily Class II, that are implantable, life-sustaining, or life-supporting, originally proposed to comply with the UDI requirements within three years of the final rule, and now required to comply within two years.  Additionally, the amendment will affect implantable devices of all classes, primarily Class III and II, which now must bear a permanent marking one year and three years earlier than first proposed, respectively.  Comments to the proposed rule closed on November 7, 2012.  It is not clear when FDA will issue the final rule.

By Jess Ritsick & Bill Koustas –

The Healthcare Distribution Management Association (“HDMA”) held its annual Track and Trace Technology Seminar on November 12 – 14, 2012, designed to address drug pedigree and track and trace requirements being developed in the United States and to explore how stakeholders will play a role—and what those roles may be—going forward.  Perhaps most interesting at the conference was the seemingly unanimous support from industry for the implementation of a national pedigree program in some form.  What follows below are some of the highlights of the conference speakers.

HDMA’s General Counsel and Vice President for Government Affairs, Elizabeth Gallenagh, discussed recent developments in track and trace, pedigree, and serialization at the federal level.  In addition to discussing the recent draft track and trace legislation, which we recently blogged about here, she also discussed the work being done by a “bi-partisan, bi-cameral” congressional working group, which brings together legislators, regulators, and industry and is looking to create a national pedigree system within the next year.  Congress tried to include a national pedigree in the most recent round of PDUFA legislation, but that was obviously not successful.  Ms. Gallenagh also noted that HDMA believed that a national pedigree system should have the effect of preempting state track and trace and pedigree systems. 

Turning to the state level, Virginia Herold, the Executive Officer of the California Board of Pharmacy, spoke about California’s state pedigree requirements, which are slated to begin taking effect in 2015—a date which Ms. Herold emphasized would not be pushed back by the Board of Pharmacy.  Ms. Herold expressed her hope that there would eventually be a national pedigree, but punctuated that hope with the fact that California would only be satisfied with a national pedigree system that proves to be “sufficient.”  Interestingly, with all the work done to draft California’s pedigree requirements, Ms. Herold stated there are no requirements for “passing” the pedigree; rather, the relevant information just needs to exist in an interoperable electronic system.  How this will apply practically, e.g., potential for fraudulent pedigrees, remains to be seen.  Ms. Herold also noted that failure to comply with the pedigree requirements may result in a $5,000 fine per transaction.  The California Board of Pharmacy will hold a public hearing on December 4, and a board meeting on December 13, 2012 to address the implementation of the state’s pedigree requirements. 

Lieutenant Commander TJ Christl, FDA’s Acting Director of the Office of Drug Security, Integrity, and Recalls also spoke briefly, and emphasized FDA’s support for a national pedigree and a robust track and trace system.  He emphasized that FDA hopes to work with industry towards a system that suits both the industry and the Agency.  FDA also remains committed to ferreting out counterfeit drugs in the national drug supply.  In that vein, Lieutenant Commander Christl stated that FDA recently sent letters to practitioners and the relevant state boards and agencies regarding the purchase of suspected counterfeit drugs from online retailers.  While the letters were purely informational and not considered enforcement actions, Lieutenant Commander Christl stated that the follow-up on the letters has yielded “successful outcomes.”

By Kurt R. Karst –      

Earlier this week, Cumberland Pharmaceuticals Inc. (“Cumberland”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s November 7, 2012 denial of a Citizen Petition (Docket No. FDA-2012-P-0507) and approval of InnoPharma, Inc.’s (“InnoPharma’s”) ANDA No. 200644 for a generic version of Cumberland’s  acetaminophen overdose treatment, ACETADOTE (acetylcysteine) Injection, 200mg/mL, which is approved under NDA No. 021539.  Cumberland alleges that FDA’s actions violate the FDC Act and the Administrative Procedure Act (“APA”) and requests that the court set aside FDA’s approval of ANDA No. 200644 and order FDA not to accept for review or approve any ANDA for generic ACETADOTE containig edetate disodium (“EDTA”).

FDA approved a formulation of ACETADOTE on January 23, 2004 containing the chelating agent EDTA with a postmarketing study commitment that Cumberland “evaluate the potential benefit of [EDTA] on the stability of the drug product.”  Cumberland conducted the evaluation, and on January 10, 2011, FDA approved a Suppemental NDA for an EDTA-free formulaton of ACETADOTE.  Cumberland then withdrew the EDTA-containing version of ACETADOTE from the market. 

After the issuance and Orange Book listing of information on a patent covering EDTA-free ACETADOTE, and subsequent notices of ANDA Paragraph IV certifications, Cumberland learned that FDA had received and was reviewing ANDAs for EDTA-containing versions of generic ACETADOTE.  In addition, in May 2011, a Citizen Petition (Docket No. FDA-2011-P-0339) was submitted to FDA requesting that the Agency make a determination as to whether the discontinued, EDTA-containing version of ACETADOTE was discontinued for reasons of safety or effectiveness.  Under FDA’s regulations implementing the FDC Act (21 C.F.R. § 314.122 and § 314.161), an ANDA for a generic version of a listed drug that has been voluntarily withdrawn from sale is to be accompanied by a petition seeking a determination as to whether the listed drug was widrawn for safety or effectiveness reasons, and FDA must make such a determination before approving an affected ANDA.

Cumberland’s Citizen petition, which was submitted to FDA in May 2012, requests that FDA not approve any ANDAs for generic ACETADOTE containing EDTA.  Cumberland argues that the EDTA-containing version of ACETADOTE was discontinued for safety reasons.  According to Cumberland, “EDTA has generally been associated with adverse events, such as significant drops in serum calcium levels, which might result in fatality, hypokalemia, hypomagnesemia, or hypotension,” “EDTA has also been associated with adverse events such as syncope, and allergic contact dermatitis,” and “[a]llergic reactions to EDTA may lead to a problematic interruption of therapy that occurs while these reactions are treated.”  FDA says in the Agency’s petition response, however, that available data “do not provide a reasonable basis upon which to conclude that the original, EDTA-containing formulation of Acetadote was unsafe,” and notes that EDTA is a component in several currently marketed drug products – some with higher quantities of EDTA than in “old” ACETADOTE.  FDA concludes that “although there is a theoretical safety concern with EDTA in Acetadote . . . . we have insufficient evidence to conclude that the original formulation was withdrawn for reasons of safety.” 

Given FDA’s determination, as well as a waiver of FDA’s so-called “exception excipient” regulations for generic versions of injectable drug products that differ from the RLD in formulation (something other than a permitted difference in preservative, buffer, or antioxidant), FDA was able to approve InnoPharma’s ANDA No. 200644.  (See our prior post concerning a challenge to the approval of generic ZOSYN for a discussion FDA’s excipient regulations.)

Cumberland alleges in the company’s Complaint that:

FDA’s denial of Cumberland’s Citizen Petition and acceptance for review and approval of InnoPharma’s acetylcysteine injection ANDA is in violation of the FDCA because Cumberland’s original EDTA-containing Acetadote® formulation was withdrawn for reasons of safety and replaced by an EDTA-free formulation.  As such, FDA cannot lawfully approve an ANDA under section 505(j)(4)(H) of the FDCA for acetylcysteine injection containing EDTA because the EDTA-containing formulation was withdrawn for reasons of safety.

FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:

information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94.  Pertinent regulations on inactive ingredient changes for generic parenteral drug products are set forth in 21 C.F.R. § 314.94(a)(9). 

Cumberland also alleges that FDA’s petition denial and ANDA approval “without requiring InnoPharma to demonstrate that an EDTA-containing formulation is as safe as the reference-listed drug . . . is fundamentally inconsistent with the agency’s previous decision to require Cumberland to undertake the postmarketing study of Acetadote® . . . and is thus, arbitrary and capricious.”  Finally, Cumberland alleges that FDA’s waiver of the Agency’s exception excipient regulation permitting the approval of ANDA No. 200644 violates the APA in that it is arbitrary and capricious and otherwise not in accordance with law.