Abstract
Introduction
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This article advocates and expounds upon the practice of petitioning FDA and engaging in litigation stemming from FDA's decision. The article first provides an overview of the citizen petition and private correspondence process, as well as a primer on the litigation that typically results from FDA's response. The article then describes three recent examples of FDA litigation, relating to generic valganciclovir, celecoxib, and vancomycin products. These examples provide a thorough overview of typical and atypical petition fact patterns and demonstrate the value in both challenging and defending an FDA decision before the courts.
Citizen Petitions and Private Correspondence With FDA
The right to petition the federal government is enshrined in the First Amendment. Additionally, the Administrative Procedures Act provides for petitions requesting an agency to issue, amend, or repeal a rule. 1 Each federal agency has its own rules and procedures for petitioning. Petitioning FDA regarding drug development and marketing is most commonly done through citizen petitions and, to a lesser extent, private correspondence submitted to the Agency through a new drug application (NDA) or abbreviated new drug application (ANDA). The rules governing how to properly prepare and submit a petition to FDA are found in FDA's regulations, 2 FDA guidance documents, 3 and the Food, Drug, and Cosmetic Act (FDCA). 4
Any interested party may petition FDA to issue, amend, or revoke an order or regulation. For example, a party may petition FDA regarding bioequivalence guidelines, labeling requirements and regulations or decisions governing approval, marketing exclusivity, and the forfeiture of such exclusivity. Additionally, a party may petition FDA to take or refrain from certain administrative actions, such as granting or revoking exclusivity for a drug product, or granting or denying approval of a drug product. FDA must approve the petition, deny the petition, or provide a tentative response indicating why the Agency has been unable to reach a decision. 5
Drug manufacturers have increasingly taken advantage of the citizen petition process over the past decade. 6 This sharp rise in drug-related citizen petitions led to a backlog in the review of NDAs and ANDAs. The backlog resulted because the Agency must consider not only the substance of any pending application concerning a particular product, but also the merits of the petition and its effect on the application. This incentivized NDA holders to submit citizen petitions as a tactic for delaying generic competition. 7 To illustrate, suppose that one or more ANDAs are set for approval upon the expiration of an NDA holder's market exclusivity. Faced with the imminent prospect of generic competition, the NDA holder could, on the eve of expiration, effectively extend its exclusivity by submitting a petition raising some issue pertaining to the pending ANDAs.
Congress addressed the potential abuse of the petition process by adding Section 505(q) to the FDCA as part of the Food and Drug Administration Amendments Act of 2007 (FDAAA). 8 Section 505(q) applies to petitions requesting FDA to take any form of action related to a pending ANDA, 505(b)(2) “paper NDA,” or biosimilar application. The provision states that approval of pending applications should not be delayed due to a citizen petition unless a delay is necessary to protect public health. The number of so-called 505(q) petitions filed annually has remained steady since the passage of the FDAAA. 9 Nevertheless, the Agency remains concerned that the FDAAA has not prevented the filing of petitions intended to delay approval of an application. 10
Further compounding the situation is the enactment of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA). Section 1135 of FDASIA shortened the deadline for FDA to respond to 505(q) petitions from 180 days to 150 days. This shortened time for FDA to evaluate the issues raised by a petition and formulate a response has significantly impacted the Agency, resulting in a redirection of resources from other initiatives. 11 The tighter deadline also led to the increased issuance of non-substantive responses, such as rejections because the issues raised in the petition were purportedly premature or responses wherein FDA summarily rejects a petition with no substantive discussion.
Another means of bringing an issue to FDA's attention is via private correspondence. Citizen petitions are open to the public for viewing and commentary, whereas private correspondences are kept strictly between the Agency and the submitting party. A drug manufacturer might therefore choose to use private correspondence in situations where it is preferable to keep the subject matter of the communication private.
Litigating Issues Decided by FDA
In many cases, FDA's response to an issue raised in a citizen petition or private correspondence has an immediate and substantial impact on one or more parties. An aggrieved party can sue the Agency in order to prevent the FDA action from taking effect. Likewise, a party that stands to benefit from FDA's decision may wish to intervene on the side of the Agency in order to ensure that its interests are adequately represented in the litigation.
To successfully obtain a preliminary injunction or a temporary restraining order against the FDA action, the moving party must show that it is likely to succeed on the merits, that it is likely to suffer irreparable harm in the absence of preliminary relief, that the balance of equities weighs in its favor, and that equitable relief is in the public interest. 12 Likelihood of success on the merits is perhaps the most difficult showing because FDA's decisions are administrative actions and are reviewed under the deferential Chevron framework. 13 Thus, when a party challenges an FDA decision as being contrary to the Agency's governing statutes and regulations, a reviewing court must first determine if the applicable statute or regulation is clear on its face. If the applicable law is not facially clear, courts will often defer to FDA's decision so long as the Agency acted upon a reasonable interpretation of the applicable law. This deference can govern even where the applicable law is open to other equally reasonable interpretations proffered by the challengers. If the challenging party loses at the preliminary injunction stage, it can be difficult to overcome this deference if the case proceeds to a final hearing on the merits.
Challenging FDA's response to a citizen petition can be an uphill battle, but, as illustrated by the celecoxib matter discussed below, it is not insurmountable. Similarly, a party benefitting from FDA's decision might feel buoyed by the deference owed to the Agency and thus be content to sit on the sidelines and let the litigation play out. Such complacency could, however, prove to be quite damaging. This is because FDA's interest in defending its own decision usually has little or no bearing on the pecuniary interests of drug manufacturers. Accordingly, companies that stand to gain from FDA's decision should strongly consider intervening on the side of the Agency in order to ensure that their interests are adequately represented in court.
The three recent cases discussed below each involved challenges to FDA's decisions on issues raised in citizen petitions or private correspondence. The valganciclovir case presents a unique situation where both private correspondence and a citizen petition prompted FDA action on a pending ANDA, and the ANDA holder subsequently moved to enjoin FDA's action from taking effect. The case provides a straightforward overview of the typical mechanics of petitioning FDA and litigating FDA actions. The facts underlying the celecoxib matter are more complex. Nevertheless, the case illustrates that, despite the obstacle of Chevron deference, challenging an FDA decision on generic drug development is a worthwhile endeavor, especially when the challenger can muster strong statutory support for its position. Finally, the vancomycin matter provides an example of an NDA holder using the citizen petition process over a number of years in an attempt to forestall generic competition.
Recent Examples of FDA Litigation
Valganciclovir
Generic drugmaker Ranbaxy Laboratories (“Ranbaxy”) sued FDA after the Agency revoked tentative approval for its valganciclovir ANDA, which was directed to a generic version of Valcyte®. FDA's revocation of Ranbaxy's tentative approval was precipitated by correspondence submitted by Endo Pharmaceuticals (“Endo”) and a citizen petition filed by Dr. Reddy's Laboratories (“Dr. Reddy's”). Endo and Dr. Reddy's sought to market their own generic products but were stymied by Ranbaxy's claim to 180-day marketing exclusivity.
FDA granted Ranbaxy tentative approval for valganciclovir in 2008, despite ongoing concerns regarding the company's compliance with current good manufacturing practices (cGMP) at its manufacturing sites. Ranbaxy was the first company to file a Paragraph IV certification for this product, and thus held the right to 180-day marketing exclusivity. Ranbaxy's exclusivity claim prevented FDA from granting final approval to other generic applicants, so Endo (via private correspondence) and Dr. Reddy's (via citizen petition) asked FDA to reexamine Ranbaxy's approval status in light of the company's ongoing noncompliance with cGMPs. In a Letter Decision responding to these inquiries, FDA stated that it erred in granting tentative approval when Ranbaxy's cGMP compliance status was in doubt and, accordingly, rescinded the company's tentative approval. 14 The Agency also determined that Ranbaxy was no longer eligible for 180-day exclusivity because it failed to obtain tentative approval within 30 months of submitting its ANDA. On the same day it issued its Letter Decision, FDA granted final approval to Endo and Dr. Reddy's. In order to protect their approval status, Dr. Reddy's and Endo intervened as defendants in Ranbaxy's subsequent suit against FDA. 15
Ranbaxy argued that FDA misinterpreted its own statutes and regulations concerning the requirements for tentative approval. Specifically, the company accused FDA of acting outside of its powers in rescinding tentative approval based on cGMP compliance, asserting that the FDCA only requires compliance with cGMPs for the purpose of securing final approval. In other words, Ranbaxy argued that, for the purpose of gaining tentative approval, an applicant's present ability to comply with cGMPs has no relevance. Ranbaxy asserted that the FDCA instead requires only a blueprint for compliance at the tentative approval stage. Ranbaxy thus moved for a TRO and PI to enjoin FDA's actions, arguing that the Agency abused its discretion in revoking tentative approval based on noncompliance with cGMPs.
FDA and defendant-intervenors Endo and Dr. Reddy's asserted that the provisions on tentative approval clearly require present ability to comply with cGMPs. Specifically, defendant-intervenors argued that the substantive requirements for tentative approval are identical to those for final approval because tentative approval is appropriate only for situations where an ANDA is otherwise ready for final approval but exclusivity or blocking patents prevent FDA from granting final marketing approval. 16 The defendants further argued that, to the extent that the provisions might be considered ambiguous, FDA's interpretation requiring present ability to comply with cGMPs was reasonable, whereas Ranbaxy's “blueprint for compliance” interpretation was directly contrary to the underlying purposes of the governing statutes.
In the D.C. Circuit, the factors for granting preliminary equitable relief are judged on a sliding scale. 17 If a movant cannot convincingly demonstrate a particular factor, such as irreparable harm, the movant must make a strong showing on the other factors. 18 At the time of the hearing to resolve Ranbaxy's TRO/PI motion, the patent covering valganciclovir was set to expire in a mere four months, which meant that any exclusivity to which Ranbaxy could be entitled to would be extinguished. Ranbaxy, however, made no showing as to if and when it expected to receive final FDA approval. The court thus found it highly unlikely that Ranbaxy would even be able to take advantage of any right to exclusivity, and consequently found no basis for the company's claim that it would suffer irreparable harm absent injunctive relief. 19 The court also deferred to FDA's interpretation of the ambiguous tentative approval provisions, noting that Ranbaxy's interpretation “placed form over substance” and would undermine congressional intent. 20 Specifically, Ranbaxy's interpretation would allow an ANDA filer with pervasive compliance issues to indefinitely block other generic competitors, thereby hindering access to low-cost generic medications.
The court echoed this sentiment in its Memorandum Opinion granting summary judgment to FDA and the defendant-intervenors. In rejecting Ranbaxy's challenges, the court deferred to FDA's interpretation of the tentative approval provisions and stated: “[b]y [Ranbaxy's] logic, an applicant could state in its [application] that it planned to manufacture a generic drug in an outhouse behind the applicant's house using a child's chemistry set, and the FDA would have no power to deny tentative approval.” 21
The valgancivloir case is representative of a typical FDA litigation, and there are several takeaways. First, the case illustrates that private correspondences are a viable alternative to citizen petitions, as FDA's Letter Decision to Ranbaxy reflected issues raised in Endo's private correspondence with the Agency. Second, the case underscores the value in actively intervening on the side of FDA instead of merely relying on the Agency and Chevron deference. In this matter, Ranbaxy raised arguments regarding whether FDA had the authority to revoke tentative approval that it granted years earlier by virtue of a “mistake” that was known to the Agency at the time approval was granted. If Endo and Dr. Reddy's had not intervened and provided additional arguments, particularly as to the propriety of FDA's decision and the lack of harm to Ranbaxy, the court may very well have sided with Ranbaxy.
Finally, the case illustrates the types of arguments that a court will consider in determining whether an FDA action should be enjoined. Likelihood of success on the merits is dictated by Chevron deference. Further, because Ranbaxy was seeking preliminary equitable relief that disrupted the status quo, the court required Ranbaxy to present a high quantum of concrete evidence demonstrating irreparable harm. Because Ranbaxy failed to present evidence as to if and when it could bring its product to market, the court discounted the company's harm arguments as unsubstantiated speculation. Finally, in opposing the injunction, it was important that the injunction would have blocked less expensive generic products from the market, which was argued to be against the public interest.
Celecoxib
In 2014, Mylan Pharmaceuticals, Inc. (“Mylan”), Watson Pharmaceuticals, Inc. (“Watson”) and Lupin Pharmaceuticals, Inc. (“Lupin”) challenged an FDA Letter Decision determining that original and reissued patents provide a “single bundle of patent rights” and that a reissued patent therefore cannot be the basis for a new period of 180-day exclusivity. 22 This Letter Decision, though purporting not to be a determination with respect to any particular pending applications, followed a series of letter writing and private meetings between the companies and FDA inquiring into how the Agency would treat their ANDAs for celecoxib, which was a generic version of the blockbuster drug product Celebrex®.
Pfizer produces Celebrex®, which was originally covered by U.S. Patent Nos. 5,426,823 (“the ’823 patent”), 5,563,165 (“the ‘165 patent”), 5,972,986 (“the ’986 patent”) and 5,760,068 (“the ’068 patent”). In 2003, Teva filed an ANDA containing Paragraph IV certifications to the ’823, the ’165, and the ’068 patents, and Pfizer subsequently sued Teva for patent infringement. In 2007 the District Court for District of New Jersey found the patents valid and infringed. 23 Then, in 2008, the Federal Circuit reversed in part, deeming claims of the ’068 patent invalid. 24 The following year, Mylan, Watson, and Lupin filed ANDAs for celecoxib containing Paragraph IV certifications. On March 7, 2013, the Patent and Trademark Office reissued the ’068 patent as RE44,048 (“the ’048 patent”). On the same day, Mylan, Watson, and Teva filed Paragraph IV certifications to the ’048 patent. As mentioned above, the companies then engaged in letter writing and private meetings with FDA in order to determine whether filing Paragraph IV certifications to the reissued patent entitled them to 180-day marketing exclusivity under the rules in place prior to the 2003 Medicare Prescription Drug Improvement and Modernization Act (MMA). 25
On April 24, 2014, FDA issued a Letter Decision stating that original and reissued patents provide a “single bundle of patent rights,” and thus a reissued patent cannot be the basis for a new period of 180-day exclusivity. FDA accordingly determined that only Teva was entitled to 180-day exclusivity with respect to generic Celebrex®, by virtue of its status as the first company to file a Paragraph IV certification to the original ’068 patent.
Mylan filed suit against FDA in the Northern District of West Virginia and sought injunctive and declaratory relief regarding FDA's Letter Decision. Watson and Lupin intervened as plaintiffs, and Teva intervened as a defendant. The district court consolidated the hearing on the plaintiffs' preliminary injunction motion with a trial on the merits. The court found that the applicable statutes on first filer exclusivity were ambiguous. The court thus deferred heavily to FDA's “bundle of rights” interpretation and subsequently granted judgment in favor of FDA and dismissed the case. 26
The plaintiffs appealed the decision to the U.S. Court of Appeals for the Fourth Circuit. The Fourth Circuit held that the lower court should never have reached the second step of the Chevron analysis because the applicable pre-MMA provisions on exclusivity are facially clear and FDA's “bundle of rights” interpretation contravened this clear mandate. 27 The court noted that, although the Hatch-Waxman Act does not define “patent” or mention reissued patents, the statute is not ambiguous regarding exclusivity triggers because the pre-MMA provisions on 180-day exclusivity state that exclusivity runs from “the date of a decision of a court in an action … holding the patent which is the subject of the certification to be invalid or not infringed.” 28
The celecoxib matter illustrates the value of litigating unfavorable FDA decisions even in view of the deferential standard applied by the courts. Despite the district court's emphasis on the deference owed to FDA's interpretation of the pre-MMA 180-day exclusivity provisions, the plaintiffs won by pursuing the case on appeal and convincing the Fourth Circuit panel that they had clear statutory support for their position. This case is a good example of how framing the issues properly and clearly demonstrating that the Agency has acted contrary to statute or regulations is key to challenging FDA decisions in court.
Vancomycin
In 2012, ViroPharma filed suit against FDA after the Agency denied ViroPharma's citizen petition 29 regarding bioequivalence and exclusivity claims related to its Vancocin® (vancomycin) product. 30 ViroPharma petitioned FDA to stay approval of any ANDAs for generic Vancocin relying on in vitro bioequivalence data, arguing that this would result in generics that are less safe and effective than the brand product. ViroPharma was essentially challenging FDA's recent decision to amend the bioequivalence guidelines for vancomycin to permit generic applicants to establish bioequivalence through in vitro dissolution studies. ViroPharma also petitioned FDA to confirm ViroPharma's right to additional three-year exclusivity under 21 U.S.C. § 355(j)(5)(F)(iv). 31 ViroPharma argued that it was entitled to additional exclusivity based upon its submission of a supplemental new drug application in 2011 for a label change reflecting new clinical data. The supplement did not, however, seek to add any new indications or conditions of use.
After the petition had been pending for over six years, and after considering numerous submissions by ViroPharma, FDA denied the petition in a comprehensive letter ruling. 32 In response to ViroPharma's bioequivalence claims, FDA highlighted the Agency's scientific reasoning in adopting in vitro testing guidelines for vancomycin and downplayed ViroPharma's concerns regarding the effectiveness of in vitro testing. In response to ViroPharma's exclusivity claims, FDA determined that 21 U.S.C. § 355(v)(3)(B) limits the availability of new clinical data exclusivity for certain antibiotics, including vancomycin. FDA reasoned that, for antibiotics like vancomycin to obtain exclusivity based on new clinical data, the data must support a “significant new use” for the old antibiotic, such as a new indication or condition of use. Because ViroPharma's data did not support approval for any new indications or conditions of use, FDA determined that the company was not entitled to additional exclusivity.
On the same day it issued its letter, the Agency approved vancomycin ANDAs submitted by Akorn, Inc. (“Akorn”), Strides Acrolab Limited (“Strides”), 33 and Watson. ViroPharma subsequently filed suit against FDA in the U.S. District for the District of Columbia, moving for a TRO and PI requiring FDA to withdraw the recent ANDA approvals for vancomycin products. Akorn, Alvogen, and Watson intervened as defendants. At the TRO/PI hearing, the court first noted that the FDCA provisions governing bioequivalence and new data exclusivity are not facially clear. 34 The judge deferred to FDA's interpretation, emphasizing not only the court's duty under Chevron, but also the Agency's competency to evaluate scientific data within its area of expertise and to interpret its governing statutes according to their underlying purpose. 35 Because of the deference owed to FDA's interpretation, the court held that ViroPharma was unlikely to succeed on the merits. 36
As to irreparable harm, the court held that ViroPharma's alleged reputational injury from potentially unsafe generic products and alleged financial injury from increased generic competition were too speculative to justify preliminary equitable relief. 37 Additionally, the court noted that ViroPharma's harm argument was severely undercut by public statements made by a financial officer, wherein the officer predicted continued profits despite increased generic competition. 38 The court also found that the balance of hardships favored the defendant-intervenors, as their products had already hit the market. 39 Finally, the court found that the increased generic competition was in the public interest, and therefore in the favor of FDA and defendant-intervenors. 40
The vancomycin case demonstrates an attempt by an NDA holder to use the citizen petition process and subsequent litigation as a means to delay generic competition, and illustrates the value of intervening on the side of FDA in order to protect approval in the face of such tactics. Further, this case provides additional insight into the arguments that courts generally favor and disfavor in cases challenging an Agency decision. As mentioned above, courts considering whether to enjoin an FDA action require a particularized showing of irreparable harm absent injunctive relief, and rosy statements made by the plaintiff's financial officers can undercut such arguments.
Conclusion
Drug manufacturers should strongly consider using citizen petitions and private correspondence to proactively resolve concerns surrounding product development and marketing. Because FDA decisions often coincide with critical determinations on marketing exclusivity and approval, the resulting litigation is on a very compressed schedule. The TRO/PI hearing will often take place within days of the filing of the complaint, and any separate hearing on the merits will often take place within weeks. Consequently, companies intending to petition FDA should be fully prepared to quickly litigate FDA's decision either as a plaintiff (in the event of an unfavorable decision) or as a defendant-intervenor (in the event of a favorable decision). The compressed schedule combined with the highly complex statutory subject matter at play present unique and difficult litigation challenges. The foregoing discussion provides a roadmap for navigating these challenges and illustrates that despite these obstacles, a concerted effort in petitioning FDA and litigating the results can pay huge dividends for drug developers.