By Riëtte van Laack –

This case dates back to November 2004, when the FTC filed a complaint in the United States District Court for the Northern District of Georgia, alleging that defendants, including the National Urological Group, Inc., Hi-Tech Pharmaceuticals, Inc., Jared Wheat and Stephen Smith, violated the FTC Act by marketing various dietary supplements with unsubstantiated weight loss claims.  In 2008, the Court entered final judgment and permanent injunctions against the Defendants.  Under the injunction the Defendants were prohibited from advertising weight-loss products with certain claims unless those claims were substantiated by competent and reliable scientific evidence.

In August 2013, the Court entered an order finding that Hi-Tech, Wheat and Smith were in contempt of the permanent injunction because Defendants continued to market supplements with weight loss claims that were not supported by competent and reliable scientific evidence.  In May 2014, the Court issued a sanctions order deciding that Defendants were to pay compensatory damages of $ 40,120,950 (the amount of gross receipts of the alleged violative products) and to recall all products bearing the alleged violative packaging and labels at the retail level. 

In the sanctions order, the Court expressed concern about the Defendants’ lack of diligence and good faith compliance with the permanent injunction.  The Court found that the Defendants ignored advice by counsel that the claims violated the Court’s order, continued to market the alleged violative products even after the Court entered its contempt order, and did not correct the advertising claims on their website until the second day of the sanctions hearing (which was more than 7 months after the contempt order had been issued).  It stated that it would “order coercive incarceration if a complete recall [was] not completed.”

In August 2014, the Court found that Defendants did not complete the ordered recall.  The Court ruled that the evidence showed that it was not until forty-one days after the sanctions order was entered that Defendants began their recall.  Moreover, the Court concluded that there was evidence suggesting that additional products with violative claims entered the market after the sanctions order had been entered.  The Court concluded that Defendants’ actions demonstrate an unwillingness to comply with the sanctions order and that coercive incarceration was needed.  It ordered Wheat and Smith, the Hi-Tech executives with the authority to effectuate a recall, incarcerated until they “purge themselves of their contempt.”  Under the Court’s ruling, they will be incarcerated until they provide evidence that four conditions have been met:

1. No more violative products are available for purchase at retail stores;
2. A recall notice, identifying what is being recalled and including details about the return procedure, is in use.
3. The recall notice has been distributed (via letter or e-mail) to all relevant parties.
4. The recall notice is prominently displayed on each page of the company’s website.  (The order details the manner of display).

The executives were ordered by the District Court to voluntarily surrender themselves last Friday, September 5, 2014.   Nevertheless, the Defendants made one last ditch effort to avoid jail.  They filed an emergency motion for a stay pending appeal and for a writ of mandamus with the United States Court of Appeals for the Eleventh Circuit.  However, on September 4, 2014, that court denied both motions.  (Additional information on the case is available here.) 

By Kurt R. Karst –      

If you guessed that the cover of the publication listing biological products licensed under the Public Health Service Act (“PHS Act”), including licensed biosimilar and interchangeable biological products, would be “purple,” then you guessed correctly.  The “Purple Book,” which is more formally known as “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations,” and that shares a shorthand name with other government publications (see, e.g., here and here), made its debut on FDA’s website on September 9, 2014.  And why purple?  Is it because the cover of the printed edition of the 2014 Code of Federal Regulations is purple (see here)?  No.  According to FDA: 

The “Purple Book” is an easy-to-remember nickname . . . .  Using a color for the nickname of the list draws upon FDA’s long-held practice of using “The Orange Book” to refer to “Approved Drug Products with Therapeutic Equivalence Evaluations” . . . .  Over the years, health care professionals and other stakeholders have come to use the term “Orange Book” in place of this longer, official title.  FDA wanted a similarly user-friendly term for a reference listing biologics, biosimilars, and interchangeable products.  During a meeting, a staff member said, “how about purple?”  Ever since, we’ve called it the “Purple Book.”

Unlike the Hatch-Waxman Amendments, which require the publication of “a list” (i.e., the Orange Book), see FDC Act § 505(j)(7), as well as monthly updates to that list, the Biologics Price Competition and Innovation Act (“BPCIA”) does not require FDA to publish a list of licensed biological products, including applicable patent and non-patent exclusivities.  Nevertheless, FDA has taken the initiative to create a reference guide.  In fact, FDA’s decision to publish the Purple Book is not unlike FDA’s initial, pre-Hatch-Waxman decision to create the Orange Book.  At the time it was created, the Orange Book contained only minimal information – see, e.g., the First Edition (1980) of the Orange Book.

As the formal name of the Purple Book says, it is a compilation of lists.  Two lists in fact: (1) Center for Biologics Evaluation and Research (“CBER”) List of Licensed Biological Products; and (2) Center for Drug Evaluation and Research (“CDER”) List of Licensed Biological Products.  As FDA explains:  

The lists include the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act.  The Purple Book will also enable a user to see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product).  Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.

As you peruse the lists, you’ll notice that a lot of information seems to be missing.  For example, there’s nothing in the “REFERENCE PRODUCT EXCLUSIVITY” or “EXPIRY DATE DATE OF FIRST LICENSURE” columns in the CBER List, and only three entries under those columns in the CDER List – for NEUPOGEN (filgrastim) (BLA No. 103353), PERJETA (pertuzumab) (BLA No. 125409), and GRANIX (tbo-filgrastim) (BLA No. 125294).  Both columns are related, as FDA previously indicated in a draft guidance on Reference Product Exclusivity (see our previous post here).  FDA explains these blanks in a backgrounder on the Purple Book:

Although FDA has not made a determination of the date of first licensure for all 351(a) biological products included on the lists, it does not mean that the biological products on the list are not, or were not, eligible for exclusivity. A determination of the date of first licensure and of when any remaining reference product exclusivity will expire for a biological product submitted under section 351(a) of the PHS Act will generally be made for reasons of regulatory necessity and/or at the request of the 351(a) application license holder.

Once a date of first licensure is determined, then FDA will presumably add that date to the Purple Book, along with any Reference Product Exclusivity (and any attached pediatric exclusivity).  One type of exclusivity that is specifically not included in the new Purple Book is orphan drug exclusivity.  Instead, FDA refers to the Agency’s searchable database for Orphan Designated and/or Approved Products for that information. 

As an aside, we note that the exclusivity listing for NEUPOGEN, with an expiration date of “02/20/03,” resolves the question of whether or not FDA believes the BPCIA's exclusivity provisions apply to reference products licensed prior to the 2010 enactment of the law.  The listing might also provide yet another clue as to how FDA will ultimately rule on a pending Citizen Petition on pre-PBCIA-licensed products (see our previous post here).

There’s no mention from FDA on how the Agency will identify Interchangeable Biological Product Exclusivity under PHS Act § 351(k)(6).  That’s not surprising though.  FDA has not yet approved a highly similar biosimilar product let alone approved an interchangeable biosimilar product.  So, the Purple Book will ultimately need to be changed to accommodate for any such exclusivity.

Similar to the Orange Book, which includes therapeutic equivalence evaluations, the Purple Book includes (again, as the formal title of the publication states) biosimilarity or interchangeability evaluations.  Those evaluations will be identified in a column titled “INTERCHANGEABLE (I)/ BIOSIMILAR (B).”  According to FDA, “[b]iosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated” (emphasis added).  Does this mean that FDA is more or less likely to adopt distinguishable non-proprietary names (see here) for biosimilars?  The tea leaves are not clear on this point.  The CBER and CDER Lists do identify products in alphabetical order by non-proprietary name – and including where a prefix is used  (e.g., filgrastim and tbo-filgrastim, both of which are reference products, are not near one another) – but who knows whether that will apply throughout the lists when biosimilars are added.  Hmmm . . . . Just out of the box and already a possible Purple Book controversy?

By Ricardo Carvajal –

FDA has made no secret of its increasing investment in, and reliance on, databases of genetic information to investigate outbreaks of foodborne illness.  In public presentations, compliance officials have lauded the utility of PFGE and PulseNet, the Whole Genome Sequencing (WGS) Program, the Genome Trakr network and database, and Global Microbial Identifier.  FDA has also been ramping up its environmental sampling, such that the agency is taking samples during multiple inspections to identify potential resident strains of pathogens in specific facilities.

The marriage of all of these resources is evident in the recent CDC announcement, "Multistate Outbreak of Salmonella Braenderup Infections Linked to Nut Butter Manufactured by nSpired Natural Foods, Inc."  According to the announcement, FDA isolated Salmonella Braenderup from environmental samples taken during routine inspections at an nSpired facility, and performed PFGE and WGS on those isolates.  PulseNet was then used to identify “ill persons with the same PFGE ‘fingerprint.’”  Via WGS performed on the clinical isolates, CDC “determined that the bacteria from the ill persons were related to the environmental isolates taken from the firm.”  In subsequent interviews, those persons reported eating a product produced by nSpire, thereby tightening the association.

As FDA continues to build its databases, chances are that we’ll see more investigations following the pattern outlined above.  That trend could get an additional boost from the implementation of FSMA, depending on the nature of any environmental monitoring requirements that are incorporated into the final rule on preventive controls.

By Kurt R. Karst –    

In the 2003 movie “Freaky Friday,” based on the novel of the same name by Mary Rodgers, teenager Anna Coleman (played by Lindsay Lohan) and her mother, Tess Coleman (played by Jamie Lee Curtis), have their souls switched due to an enchanted Chinese fortune cookie.  The food and drug law version of “Freaky Friday” played out last Friday when FDA first found itself on the losing end of a court battle over orphan drug exclusivity (see our post here), and then, hours later, switched places and found itself on the winning end of another court battle over generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection. 

In a Memorandum Opinion and Order granting Motions for Summary Judgment filed by FDA, Mylan, and Par, and denying Hospira’s Motion for Summary Judgment, Judge George Jarros Hazel of the U.S. District Court for the District of Maryland found FDA’s August 18, 2014 Letter Decision permitting the approval of ANDAs for generic PRECEDEX not arbitrary, capricious, or otherwise not in accordance with law, but rather, a decision based on a reasonable and sound interpretation of the FDC Act.  In addition, Judge Hazel found that FDA’s Letter Decsion “was entirely consistent with the FDA’s established practice of approving generic drugs and therefore did not effect a change to settled law.”  As such, the district court said that no new “rule” was created by FDA’s decision and that FDA was not required to follow the Administrative Procedure Act’s (“APA”) formal rulemaking procedures.

The September 5th decision was a turnabout for the court.  A couple of weeks ago Judge Hazel issued a Memorandum Opinion and Order granting Hospira’s Motion for Temporary Restraining Order.  In doing so, Judge Hazel said that Hospira demonstrated that the company is likely to succeed on the merits regarding its contention that FDA violated FDC Act § 505(j)(2)(A)(viii) concerning labeling carve-outs, and with respect to Hospira’s APA claim (see our previous post here). 

Backgound on the case and on FDA’s Letter Decision is available here and here.  Briefly, FDA ruled that ANDA sponsors could omit (i.e., carve out) from their generic drug labeling information protected by U.S. Patent No. 6,716,867 (“the ‘867 patent”) listed in the Orange Book for PRECEDEX.  The ‘867 patent is currently listed in the Orange Book for PRECEDEX with a “U-1472” patent use code defined as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”  (The ‘867 patent was previously listed in the Orange Book with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”) 

Hospira and ANDA sponsor Sandoz, which is eligible for a period of 180-day exclusivity based on a Paragraph IV certification to the ‘867 patent, contended that FDA was prohibited from omitting any labeling information related to the ‘867 patent, because the patent covers both approved uses for PRECEDEX – i.e., (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures – thereby leaving ANDA sponsors with carved-out labeling without an approved use.  Hospira also alleged that FDA violated the APA in announcing a new interpretation of the FDC Act through its Letter Decision. 

FDA, on the other hand, argued that the Agency’s decision to permit a labeling carve-out of information protected by the ‘867 patent – and to approve two ANDAs (one from Mylan (ANDA No. 202881) and one from Par (ANDA No. 203972) with labeling omitting information protected by the ‘867 patent – was permissible and entirely consistent with previous carve-out decision.  According to FDA,

Both the original and the revised use codes are limited to “intensive care unit sedation.”  Although the revised use code includes additional language specifying some of the types of patients that Hospira claims are encompassed within the “intensive care unit sedation” use, i.e., non-intubated ICU patients prior to and/or during surgical and other procedures, it does not broaden the claimed method of use beyond “intensive care unit sedation.” . . .  Nor does the clarified use code and its explicit inclusion of a subset of patients that may undergo procedural sedation somehow expand the patented use to encompass and prevent approval for all patients who seek to use the drug for the separately delineated procedural sedation indication. . . .  FDA previously has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.  The procedural indication and related information in the labeling do not impermissibly disclose the use of Precedex for procedures in the ICU (i.e., for the use covered by the use code).  ANDAs therefore may be approved for the second indication, consistent with how FDA has implemented use codes and allowed carve outs in other circumstances.

In his September 5, 2014 decision, Judge Hazel agreed with FDA on all counts.  With respect to Count I, that FDA violated FDC Act § 505(j)(2)(A)(viii) when the Agency approved ANDAs with labeling omitting information concerning intensive care unit sedation, the court reviewed FDA’s decision under the familiar two-step process of Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837, 842 (1984).  Finding that the statute does not address what constitutes “overlap” between an NDA holder’s patent use code and an ANDA sponsor’s carved-out labeling, Judge Hazel proceeded to Chevron Step Two.  There, Judge Hazel rejected each of Hospira’s arguments that “it was the FDA’s ‘rule’ that ‘if any indication or indications in the generic’s proposed label overlap[ped] ‘at all’ with the brand’s use code as published in the Orange Book, the FDA must reject a section viii statement.’”  That rule, argued Hospira, came from the U.S. Supreme Court in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)), where the Court noted in dicta that “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code.” 

Judge Hazel cited three reasons, however, for rejecting Hospira’s Caraco argument:

[F]irst, notwithstanding the government’s statement in Caraco, the FDA has been consistent in how it has interpreted section viii; second, Hospira’s reading of the Caraco dicta would turn the holding of Caraco on its head; and, third, there is simply no overlap between the ANDA’s carved-out labels and Precedex®’s use code (original or amended).

The district court also relied on previous FDA ANDA labeling carve-out decisions and said that FDA’s decision on generic PRECEDEX is consistent with them:

FDA’s handling of the approval of generic tramadol and generic oxandrolone is entirely consistent with the way the FDA handled the approval of generic Precedex®.  That is, just as the FDA concluded that a labeling carve out was proper for tramadol and oxandrolone notwithstanding the fact that a physician might conceivably use the generic drug for a protected method of use, the FDA, here, concluded that ANDAs for Precedex® may also carve out the protected information (related to use for ICU sedation), and be approved for procedural sedation despite the fact that use for procedural sedation may at times occur in the intensive care unit.  Accordingly, the FDA has not been inconsistent with its past practice.  To the contrary, the FDA has consistently “approve[d] ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.”  That is exactly what the FDA did here.  As such, the Court will decline Hospira’s invitation to deny the FDA the heightened level of deference it is afforded under Chevron step two.

Given the court’s decision on Count I, Judge Hazel easily dispensed with Count II (violation of APA rulemaking requirements):

FDA’s August 18, 2014 decision to authorize the approval of a section viii ANDA whose carved out label omits explicit reference to a protected method of use, despite the fact that, in practice, the generic drug might be used for a protected use, was entirely consistent with the FDA’s past practice. . . .  Accordingly, the Court finds that the FDA’s August 18, 2014 was entirely consistent with the FDA’s established practice of approving ANDA’s and therefore did not effect a change to settled law.  As such, no new “rule” was created by the FDA’s decision and the FDA was therefore not required to follow the formal rulemaking procedures required by the APA when the FDA promulgates a new rule.

During a teleconference in which Judge Hazel announced his Memorandum Opinion and Order, Hospira requested and was denied a Motion for a Stay of the Court’s Order.  It was immediately clear what was coming next: an emergency appeal to the U.S. Court of Appeals for the Fourth Circuit (and a busy weekend for all of the parties involved in the litigation). 

On Saturday morning, Hospira filed an Emergency Motion For Injuction Pending Appeal and a Motion to Expedite the appeal.  On Sunday, briefs opposing the Hospira motions were filed by FDA (here), Mylan (here), and Par (here), to which Hospira later replied (here).  Sandoz filed a brief in support of Hospira’s efforts.  According to Hospira, “ [p]ending the outcome of this appeal, this Court should stay the effectiveness of FDA’s decision, including prohibiting FDA from granting any further generic drug approvals based upon the decision which Hospira challenges in this case, and prohibiting Mylan and Par from the further sale and distribution of their respective generic versions of Hospira’s drug.”

Updates:

• On September 8, 2014, the Fourth Circuit denied Hospira's Emergency Motion For Injuction Pending Appeal and granted the company's Motion to Expedite the appeal.  The court tentatively scheduled the appeal for Oral Argument on the afternoon of October 27, 2014.

By Kurt R. Karst –  

Last week, Connecticut Attorney General George Jepsen announced the submission of extensive comments to FDA that press the Agency to “exercise its discretion to immediately waive the 180-day waiting period and approve the sale” of generic versions of AstraZeneca LP’s NEXIUM (esomeprazole magnesium) Delayed-Release Capsules.  The comments, which seek expedited action from FDA, were filed to the Citizen Petition (Docket No. FDA-2014-P-0594) submitted to FDA earlier this year by Hyman, Phelps & McNamara, P.C. (“HP&M”).  (Coincidentally, the comments were filed on the same day the U.S. District Court for the District of Massachusetts issued a 155-page ruling in In Re: Nexium (Esomeprazole) Antitrust Litigation concerning so-called “reverse payment” settlements.) 

HP&M’s petition, which was submitted to FDA on behalf of a client, requests that the Agency determine that Ranbaxy Laboratories, Ltd. (“Ranbaxy”) has forfeited or is not eligible for first-to-file status for any ANDA subject to FDA’s Application Integrity Policy, including valsartan, esomeprazole magnesium, and valganciclovir hydrochloride, and that FDA immediately approve all tentatively approved ANDAs for these drugs and any other tentatively approved drugs for which final approval is blocked by Ranbaxy’s alleged eligibility for 180-day exclusivity (see our previous post here).  The petition drew comments from both Ranbaxy (here) and Teva Pharmaceuticals USA, Inc. (here).

FDA has not yet substantively responded to the HP&M Citizen Petition.  Shortly after it was submitted to FDA, however, the Agency approved Ohm Laboratories Inc.’s (a subsidiary of Ranbaxy) ANDA No. 077492 for Valsartan Tablets with a period of 180-day exclusivity.  In the ANDA approval letter, FDA notes HP&M’s petition:

This petition requests that FDA determine that Ranbaxy has forfeited or is not eligible for first-to-file status for valsartan, among other drugs, and that FDA must immediately approve all tentatively approved ANDAs for which final approval is blocked by Ranbaxy’s alleged eligibility for 180-day exclusivity.  The agency has not made a decision with respect to this petition, and any such decision, when made, will be announced in the petition docket per the usual procedures.  Because ANDA 077492 is eligible for final approval today regardless of the ultimate decision on the issues raised in the petition, today’s action with respect to ANDA 077492 is taken in order not to further delay the availability of generic valsartan while the issues raised in the petition are under consideration.

Nevertheless, other bottlenecks created by Ranbaxy’s first-filer status and alleged eligibility for 180-day exclusivity for other drug products remain.  In his comments to FDA, Attorney General Jepsen says that immediate action is needed on Ranbaxy’s ANDA for generic NEXIUM:

As the only person advocating for the interest of consumers in this forum, and as the Connecticut official charged with protecting the Connecticut citizens from anticompetitive behavior and securing a competitive marketplace, the Connecticut Attorney General believes that [FDA] should either approve promptly [Ranbaxy’s] generic version of delayed-release 40 mg Nexium (esomeprazole) capsules if it is ready for immediate approval, or alternatively rule that Ranbaxy no longer holds the 180-day exclusivity for that product so that other generic drug makers may be approved and enter the market immediately.  The delay in Ranbaxy approval to market esomeprazole has created a bottleneck preventing other potential generic drug entrants from obtaining final approval of their [ANDAs] and beginning to sell lower cost generic esomeprazole.  The resulting harm to all customers – including federal and state government, municipal and employee health plans and the uninsured – leaves these payers no option to choose lower-priced versions of Nexium and flies in the face of the FDA’s stated goals and regulations designed to promote timely access to less expensive generics. 

Among other things, Attorney General Jepsen urges FDA to utilize its “active pursuit” regulation at 21 C.F.R. § 314.107(c)(3) to determine that Ranbaxy is no longer eligible for 180-day exclusivity for generic NEXIUM.  That regulation states that “if FDA concludes that the applicant submitting the first application is not actively pursuing approval of its abbreviated application, FDA will make the approval of subsequent [ANDAs] immediately effective if they are otherwise eligible for an immediately effective approval.”  FDA has never used its authority to enforce 21 C.F.R. § 314.107(c)(3). 

Attorney General Jepsen delves into the relationship between Ranbaxy and AstraZeneca, noting at one point in his comments that “[b]y the first quarter of 2012, Ranbaxy was formulating finished Nexium capsules for purchase by AstraZeneca and booking substantial sales revenue.”  That almost sounds to us like commercial marketing.  And under the statute (FDC Act § 505(j)(5)(b)(iv)(I)), commercial marketing triggering 180-day exclusivity includes “commercial marketing of the listed drug” by a first applicant.  An FDA regulation (21 C.F.R. § 314.107(c)(4)) states that “commercial marketing commences with the first date of introduction or delivery for introduction into interstate commerce outside the control of the manufacturer of a drug product, except for investigational use under part 312 of this chapter, but does not include transfer of the drug product for reasons other than sale within the control of the manufacturer or application holder.”  Hmmmm . . . . .

This is not the first time Connecticut has put Ranbaxy in its crosshair.  In May 2013, Connecticut announced that it joined with other states and the federal government in a settlement agreement to resolve civil and criminal allegations that Ranbaxy introduced adulterated drugs into interstate commerce and, as a result, false or fraudulent claims were submitted to state Medicaid programs, including Connecticut’s Medicaid program.

By Kurt R. Karst –      

Nearly two years after Depomed, Inc. (“Depomed”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s denial of orphan drug exclusivity for GRALISE (gabapentin) Tablets, the court (Judge Ketanji Brown Jackson) has finally ruled in the case.  And it’s a bit of a shocker!  In an Order handed down last Friday, Judge Jackson denied FDA’s Motion to Dismiss/Motion for Summary Judgment and granted Depomed’s Motion for Summary Judgment (Reply and Opposition briefs available here and here).  In doing so, Judge Jackson ordered FDA to recognize orphan drug exclusivity for GRALISE “without requiring any proof of clinical superiority or imposing any additional conditions on Depomed.” 

Although we’d like to share with you a copy of the court’s Memorandum Opinion, we can’t.  We don’t have it because it was issued under temporary seal.  In an Order To Show Cause, Judge Jackson is giving Depomed and FDA the chance to show cause why his opinion should not be made public in its entirety given that portions of the 771-page administrative record in the case were filed under seal.  Hopefully the decision will be made public later this month.  Until then, we’ll be chomping at the bit to read it!  In the meantime, we can glean some things from the few lines in Judge Jackson’s Septemeber 5, 2014 Order.  But first, some background on the case and the issues involved. . . .

FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  The term “orphan drug” is defined in FDA’s regulations to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act” (i.e., FDA considers a drug to be an orphan drug regardless of whether or not it has been designated as such).  A “clinically superior” drug is a drug shown to have greater efficacy, greater safety, or that provides a major contribution to patient care vis-à-vis the previously approved drug, and, by virtue of its clinical superiority, is not considered the “same drug” as the previously approved orphan drug.

In cases where orphan drug designation has been granted based on a plausible hypothesis of clinical superiority, FDA has determined that, in order to be granted a period of orphan drug exclusivity, clinical superiority must be demonstrated.  FDA explained that the standard for obtaining orphan drug designation is different from the standard for obtaining orphan drug exclusivity in the Agency’s proposed and final orphan drug regulations from 2011 and 2013, respectively (see our previous post here), as well as in an August 2012 Citizen Petition decision (see our previous post here) where FDA noted:

Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.  At approval, the sponsor of a drug which was designated on the basis of a plausible hypothesis of clinical superiority must demonstrate that its drug is clinically superior to the previously approved drug.  Should the sponsor fail to do so, then the subsequent drug will be considered to be the same drug as the previously approved drug, and will not be able to gain marketing approval if the previously approved drug’s orphan-drug exclusive approval period is still running.  Once this exclusivity has expired, the subsequent drug may be approved . . . , but it will not be eligible for orphan-drug exclusivity because the same drug has already been approved for the same orphan indication.

As we previously reported, FDA designated GRALISE as an orphan drug in November 2010 for the management of Postherpetic Neuralgia (“PHN”), and approved the drug product on January 28, 2011 under NDA No. 022544 for the orphan-designated indication.  The designation was based on FDA’s determination that Depomed provided a plausible hypothesis that GRALISE may be clinically superior to NEURONTIN (gabapentin) for the management of PHN.  FDA approved NEURONTIN for PHN many years ago, but the Agency never designated and approved NEURONTIN as an orphan drug.

Despite the orphan drug designation and approval of GRALISE, however, FDA did not grant orphan drug exclusivity.  FDA laid out the Agency’s rationale in a November 2012 Letter Decision sent to Depomed’s counsel after the lawsuit was filed.  According to FDA:

Section 527(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 360cc) generally grants orphan exclusivity to designated drugs upon approval, but does not address eligibility for exclusivity when the same drug has already been approved for the same orphan indication.  FDA interprets this statute to confer exclusivity only to drugs that are designated and not the same as an already approved drug.  By regulation, FDA requires sponsors of orphan-designated drugs to demonstrate the clinical superiority of their drug to the previously approved drug to show that their drug is not the same as the previously approved drug and is therefore eligible for exclusivity.

Gralise obtained orphan designation pursuant to section 526(a) (21 U.S.C. § 360bb) by offering a plausible hypothesis of clinical superiority over the previously approved drug, Neurontin.  But, at the time of approval, Depomed was unable to demonstrate actual clinical superiority.  Nor have any additional Depomed submissions demonstrated Gralise’s clinical superiority over Neurontin. Gralise is therefore the “same drug” as the previously approved drug, Neurontin, and is ineligible for orphan exclusivity.

Depomed’s September 2012 Complaint, seeking declaratory and injunctive relief, alleges that FDA is violating the Administrative Procedure Act by refusing to grant orphan drug exclusivity for GRALISE.  FDA “placed additional hurdles between Gralise and orphan-drug exclusivity by attempting to impose requirements that are found nowhere in the statute and that exist in regulation only for circumstances not present here,” alleges Depomed.  Elsewhere, Depomed lays out with particularity its beef with FDA:

FDA’s course of action with respect to Gralise is a paradigm of arbitrary and capricious decision-making.  From the beginning, FDA has maintained a singular focus on its preferred outcome in this case, and it violated its own regulations and the statute to get there.  The agency began by denying Gralise orphan designation because Depomed had not presented a plausible hypothesis of clinical superiority.  As the record makes clear, FDA did not have a lawful basis for requiring a hypothesis of clinical superiority over a drug that never had marketing exclusivity under the Orphan Drug Act.  No such requirement appears in 21 C.F.R. § 316.25, the regulation that provides the exclusive list of permissible reasons for denying designation requests, and indeed FDA never cited that regulation as a basis for its decisions.  Instead, the agency raised concerns about the uses of taxpayer money and cited an inapplicable regulatory provision on timing. Then, in its second letter, the agency claimed the clinical-superiority hypothesis was in fact required by virtue of still another regulation, although that rule, too, was irrelevant.  Thus, in denying Gralise orphan designation for failure to present a clinical-superiority hypothesis, FDA violated 21 C.F.R. § 316.24, the regulation stating that the agency “will grant” a request for designation if none of the exclusive bases in 21 C.F.R. § 316.25 applies.

FDA followed this unlawful course to its conclusion when it approved Gralise without granting it marketing exclusivity.  The reason FDA gave for this decision was that the data did not prove the clinical-superiority hypothesis the agency had unlawfully demanded in the first place.  This time, the agency’s action was doubly flawed: It violated both the Orphan Drug Act, which provides that marketing exclusivity automatically attaches to a drug designated and approved for its orphan indication, and it violated FDA regulations, which confirm that the agency will record and confirm marketing exclusivity upon approval.

For its part, FDA argued that the Orphan Drug Act is not intended

to reward the development of drugs that merely duplicate drugs already on the market and that offer no benefit to patients over the existing drugs.  Thus, FDA has long interpreted the Orphan Drug Act and its implementing regulations to deny orphan exclusivity to a later-approved “same” drug unless the sponsor demonstrates that its drug is clinically superior to the previously approved drug.  FDA’s interpretation and its past practice are consistent with the statute and its goal of encouraging the development of new treatments for orphan conditions or clinically significant improvements to existing drugs – not just minor modifications to existing drugs that offer no material benefit to patients.

Although we won’t know for sure until we see the Memorandum Opinion what Judge Jackson’s reasoning is for ruling against FDA, it seems that FDA’s all-encompassing definition of “orphan drug” and and the two-step process for first providing a plausible hypothesis of, and then demonstrating, clinical superiority may be in jeopardy.  However, we doubt FDA will take this decision on the chin and will probably appeal it to the D.C. Circuit.  If it stands, then we suspect that FDA’s Office of Orphan Products Development will need to do a lot of backpeddling on designation files where these issues were critical to determinations denying orphan drug designation or orphan drug exclusivity.

In conjunction with Virginia CLE, Hyman, Phelps & McNamara, P.C. Director Ricardo Carvajal and Senior Counsel Brian Donato are presenting a 2-hour CLE telephone seminar that will provide an overview of the Food Safety Modernization Act and its anticipated impact on food businesses.  The seminar is directed to attorneys who serve clients in the food industry, but whose practice does not focus on FDA regulatory matters.  The seminar is scheduled at noon on Tuesday, September 23, and again at noon on October 16.  Registration is available here.  Attorneys licensed in other states may be able to apply for CLE credit in those states (see here).

By Kurt R. Karst –      

It was just a few months ago that we posted on what might have been the first decision in a case involving a counterclaim seeking an order to correct or delete patent information from the Orange Book (and that does not concern a patent use code).  In that case, involving OFIRMEV (acetaminophen) Injection (NDA No. 022450), the U.S. District Court for the Southern District of California denied a Motion for Summary Judgment to remove a patent from the Orange Book.  That decision now appears to have been vacated as part of dismissal of the patent infringement litigation.  Ah, but no worries; there’s yet another patent delisting counterclaim decision to take its place.  But the new decision – this time out of the U.S. District Court for the District of Delaware and involving Avanir Pharmaceuticals’ (“Avanir”) NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) Capsules (NDA No. 021879; approved on October 29, 2010) – is not a denial of an ANDA sponsor’s attempt to seek Orange Book patent delisting.  Instead, it is an Order to delist a patent.  The net effect of the Order, however, is probably zero, and has left us wondering why one of the ANDA sponsors in the case, Par Pharmaceutical, Inc. (“Par”), in particular, pursued the patent delisting with such vigor. 

By way of background, the 2003 Medicare Modernization Act (“MMA”) added provisions to the FDC Act to give ANDA (and 505(b)(2)) applicants the ability to challenge the listing of a patent in the Orange Book for a brand-name reference listed drug.  Prior to the enactment of the MMA, courts had ruled that there was no private right of action to seek Orange Book delisting of an allegedly improperly listed patent. 

The patent delisting counterclaim provisions at FDC Act § 505(j)(5)(C)(ii)(I) applicable to ANDAs state:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under FDC Act § 505(b) or (c)] on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

The MMA also added the same counterclaim provisions at FDC Act § 505(c)(3)(D)(ii)(I) applicable to 505(b)(2) applications.

Outside of the statute’s patent delisting counterclaim provisions, an NDA sponsor may, on its own initiative, request that FDA remove patent information from the Orange Book.  In response, FDA may or may not remove the patent information.  In some instances, FDA continues to list the patent information, but includes a “Patent Delist Request Flag,” which is described by FDA in an Orange Book data file as follows:

Sponsor has requested patent be delisted.  This patent has remained listed because, under Section 505(j)(5)(D)(i) of the Act, a first applicant may retain eligibility for 180-day exclusivity based on a paragraph IV certification to this patent for a certain period.  Applicants under Section 505(b)(2) are not required to certify to patents where this flag is set to Y.  Format is Y or null.

NUEDEXTA is listed in the Orange Book with three patents: (1) U. S. Patent No. 7,659,282 (“the ‘282 patent”) (expiring on August 13, 2026); (2) U.S. Patent No. 8,227,484 (“the ‘484 patent”) (expiring on July 17, 2023); and (3) U.S. Patent No. RE 38,115 (“the ‘115 patent”) (expiring on January 26, 2016).  Only the ‘282 and ‘115 patents were listed in the Orange Book when the first ANDA was submitted to FDA on March 7, 2011 containing a Paragraph IV certification.  Par and Impax Laboratories, Inc. (“Impax”) both certified Paragraph IV to the ‘282 and ‘115 patents (and later to the ‘484 patent as well) and were sued for infringement (here and here).  Par is believed to be the first applicant eligible for 180-day exclusivity. 

Earlier this year, the Delaware District Court ruled in Avanir’s favor, upholding the validity of all three patents, and holding that the proposed ANDA drug products infringe the claims of the ‘282 and ‘484 patents.  At the same time, the court, in response to an earlier counterclaim filed by Par and Impax to “enter an order requiring Plaintiffs to delete the ‘115 patent information that they submitted to the FDA,” said that it had insufficient information to decide on the delisting counterclaim and ordered supplemental briefing on the issue.  Within weeks of that decision, Avanir voluntarily asked FDA to delete the ‘115 patent information from the Orange Book . . . which FDA did by adding a “Patent Delist Request Flag” in relation to the patent information.  Avanir then filed a brief with the court saying that the Par/Impax delisting counterclaims are moot and should be dismissed for lack of subject matter jurisdiction. 

So that was the end of the matter . . . right?  Wrong!

Par and Impax pressed their delisting counterclaims with the court, saying in a brief that the unilateral delisting of the ‘115 patent information was an empty gesture and that an Order from the court is necessary to prevent relisting:

Without a court order, Defendants believe Avanir will not be able to delist the '115 patent.  The FDA will likely decline Avanir’s unilateral request because there is no statutory provision regarding delisting Orange Book patents without a counterclaim. . . .  Without the order provided in the statute and requested by Defendants, Plaintiffs have no barrier against relisting the '115 patent if they can successfully delist it.  Defendants cannot accept Plaintiffs' offer to moot their delisting counterclaims with a letter to the FDA that has not  yet—and may never be—approved.  Even if the FDA accepts the delisting request, nothing bars Plaintiffs from relisting the '115 patent at some point n the future.  

Perplexed that its voluntary patent delisting request did not satisy Par, Avanir shot back in a response brief, saying:

Here, Plaintiffs are at a loss to understand why Par seeks delisting of the ’115 patent, when its continued listing would be intended to protect Par’s own interest in regulatory exclusivity against other generics.  [And, in any case,] Defendants are enjoined from launching their product until 2026 – ten years after the expiration of the ’115 patent.

In any event, what the FDA does or does not do with Plaintiffs’ request is irrelevant to Defendants’ counterclaims.  The statutory remedy is limited to requiring the patent holder—i.e., Plaintiffs—to correct or delete patent information . . . .  The statute does not mandate that the FDA delist the ’115 patent.  Since Plaintiffs have already done what is called for by the statute, Defendants’ counterclaims are moot. . . .  Defendants apparently seek an order requiring Plaintiffs to send another letter to the FDA again requesting delisting of the ’115 patent.  Such an order would be futile.  The FDA has received Plaintiffs initial request and will either delist the patent or not.  A second letter will not change anything.  Indeed, neither Defendants nor Plaintiffs have identified any case where a patent was actually removed from the Orange Book as a result of a delisting counterclaim.  [(Emphasis in oroginal)]

Perhaps not understanding what all the fuss was about given Avanir’s notification to FDA to delist the ‘115 patent information from the Orange Book, the Delaware District Court issued an Order in June 2014 directing the parties in the litigation to “make reasonable efforts to inform [FDA] of the pending request for delisting and of this Court’s request that the FDA provide its views relating to that pending request.” 

Finally, after submitting a joint status report to the Court in which each side sparred with the other and pressed for a dismissal (Avanir) or a delisting Order (Par), the Court issued a delisting Order pursuant to FDC Act § 505(j)(5)(C)(ii)(I)(aa).  In it, the Court recognizes that Par is entitled to such a delisting Order under the statute, but the Court also seems to acknowledge that Avanir can only do so much to “delete” patent information from the Orange Book:

WHEREAS the Court appreciates that Plaintiffs have tried to delete the ‘115 patent from the Orange Book and have failed to do so, yet the law entitles Defendants to an order directing Plaintiffs to try to do so (in this case, to try again to do so); [(Which Avanir did in an August 21, 2014 letter to FDA.)]

IT IS HEREBY ORDERED that Plaintiffs are directed by mandatory injunction under 21 U.S.C. § 355(j)(5)(C)(ii)(I)(aa) to correct within twenty (20) days from the date of this Order and Judgment its improper listing of the '115 patent by submitting to FDA a request enclosing this Order and Injunction to delete the '115 patent from the Orange Book entry for Nuedexta®. . . .  [(Emphasis in oroginal)]

Putting aside for a moment the issue of what it means to delist a patent from the Orange Book, the vigor with which the delisting Order was pursued has perplexed us.  (Though, we note that other strategies pursued by one of the defendants in the case have also perplexed us – see here.)  After all, the ‘115 patent expires more than a decade before the other 180-day exclusivity-bearing patent (i.e., the ‘282 patent) expires on August 13, 2026.  But perhaps an answer lies in a decision by the U.S. Court of Appeals for the Federal Circuit in which that Court ruled that Par’s appeal of the Delaware District Court’s patent infringement decision was premature for lack of a decision on the then-pending patent delisting counterclaim. 

An article set to be published in the Albany Law Review in Spring 2015, titled “Drug Diversion Administrative Revocation and Application Hearings for Medical and Pharmacy Practitioners: A Primer for Navigating Murky, Drug-Infested Waters,” explores the increasingly complex and nuanced practice of administrative law before the Drug Enforcement Administration (“DEA”), and provides a “how to” manual of sorts for counsel undertaking the litigation of a DEA administrative enforcement. 

The article is coauthored by DEA Chief Administrative Law Judge John J. Mulrooney, II, and the latest addition to the ranks of Hyman, Phelps & McNamara, P.C., Andrew J. Hull, who previously served as a judicial law clerk to Chief Judge Mulrooney.  As the authors explain in their article:

One inexorable result of federal efforts to react reasonably to an immense growth in prescription medication dependence is an increasingly complex and nuanced practice of administrative law before the [DEA].  The practice has morphed into a more contested and complicated dynamic that now requires litigation and academic skills that far exceed those previously demanded.  Without an established manual or research resource currently available for this practice, even seasoned administrative practitioners can find themselves overwhelmed by well-trained and seasoned agency trial counsel, experts, and regulators.  Hardened litigators unprepared for the technical nuances of this sophisticated regulatory scheme can unwittingly blunder their clients into irreparable and draconian results.  This is a practice that now requires both skillful litigation and thoughtful study into the statutes, regulations, and precedents from both the agency and the courts of appeal that circumscribe the exercise of powerful discretionary authority that can wreak career-ending consequences on the members of the regulated community.

Chief Judge Mulrooney and Mr. Hull not only provide in their article a general overview of the proceedings and the body of law pertinent to administrative proceedings against medical and pharmacy practitioners, but they also discuss the various bases for revocation or suspension of a DEA license and examine the bases for denial of an application for a DEA license.  They don’t stop there, however.  The article also provides a helpful summary of the process surrounding immediate suspension cases (followed by a discussion of the burdens on the parties and the DEA’s exercise of discretion in sanctioning a party), and an examination of various pre-hearing, hearing, and post-hearing procedures. 

By Kurt R. Karst –      

With the recent litigation surrounding FDA’s approval of ANDAs for generic versions of PRECEDEX (dexmedetomidine HCl) Injection – which litigation has now moved on to Motions for Summary Judgment (see our updates here for the latest briefs) – we’ve had renewed interest in (and requests to update) our popular Generic Drug Labeling Carve-Out Scorecard (a.k.a. the Labeling Carve-Out Citizen Petition Scorecard).  We last updated that scorecard more than two years ago (see here), and we promised to make it a static feature of the FDA Law Blog home page last September when we introduced our Biosimilars State Legislation Scorecard (which also needs to be updated).  So much to do; so little time. . . .  But we found a few minutes to finally draft this post and make a permanent home for the Generic Drug Labeling Carve-Out Scorecard.

This version of the scorecard adds several new FDA decisions (either as a response to a citizen petition, or from an FDA letter decision outside of the petitioning process) and some new (and still pending) citizen petitions. 

Enjoy the scorecard!  And if you're aware of anything you think we missed, then please let us know and we'll take a look and decide whether or not to update the scorecard accordingly.  We note that sometimes determining whether or not a citizen petition submitted to FDA is really about a labeling carve-out issue can be difficult to discern.  Take, for example, a recent citizen petition concerning ProAir HFA (albuterol sulfate) Inhalation Aerosol (Docket No. FDA-2014-P-0404), which FDA responded to late last week.  While the petition does raise, among other things, the issue of 3-year exclusivity eligibility and the effects on generics, that petition is more about the scope of 3-year exclusivity than ANDA labeling carve-outs.  Thus, we would not include a petition like that on our scorecard.

FDA Citizen Petition Responses & Letter Decisions Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket Nos. 2001P-0495/PRC, 2002P-0191/PRC, FDA-2002-P-0003/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Letter Decision (Mar 1, 2004) - SKELAXIN (metaxalone) Tablets
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl)
• FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (Feb. 24, 2011) – XYZAL (levocetirizine dihydrochloride)
• FDA Response, Docket No. FDA-2011-P-0128 (May 11, 2011) – XIBROM/BROMDAY (bromfenac)
• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate)
• FDA Letter Decision, Related to Docket Nos. FDA-2011-P-0662 & FDA-2011-P-0663 (Mar. 27, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2006-P-0007 (Apr. 9, 2012) – VANCOCIN (Vancomycin HCl) Capsules
• FDA Response, Docket No. FDA-2012-P-1018 (Feb. 15, 2013) – COLCRYS (colchicine) Tablets
• FDA Response, Docket No. FDA-2013-P-0247 (Aug. 1, 2013) – RECLAST (zoledronic acid) Injection
• FDA Response, Docket No. FDA-2013-P-1293 (Mar. 10, 2014) – REMODULIN (treprostinil) Injection
• FDA Letter Decision, Docket No. FDA-2014-N-0087 (Aug. 18, 2014) – PRECEDEX (dexmedetomidine HCl) Injection

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)
• FDA Response, Docket No. FDA-2010-P-0614 (May 25, 2011) – COLCRYS (colchicine) Tablets

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2009-P-0581 – BAYTRIL (enrofloxacin) (Animal Drug)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2011-P-0482 – VAGIFEM (estradiol) Tablets 
• Docket No. FDA-2012-P-0632 – COLCRYS (colchicine) Tablets  
• Docket No. FDA-2014-P-1649 – FUSILEV (levoleucovorin) for Injection

Non-Response Denials of Labeling Carve-Out Citizen Petitions

• FDA Response, Docket No. FDA-2011-P-0662 (Mar. 7, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2011-P-0663 (Mar. 7, 2012) – SEROQUEL XR (quetiapine fumarate) 
• FDA Response, Docket No. FDA-2011-P-0823 (May 11, 2012) – CRESTOR (rosuvastatin calcium)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

FDC Act § 505(j)(10) Citizen Petitions and Approval Precedents

• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate) Delayed-Release Tablets
• ANDA No. 076786, Donepezil Hydrochloride Tablets, 5 mg and 10 mg
• ANDA No. 078388, Donepezil Hydrochloride Orally-Disintegrating Tablets, 5 mg, and 10 mg
• ANDA No. 077431, Exemestane Tablets, 25 mg
• ANDA No. 076361, Levofloxacin Tablets, 250 mg, 500 mg, and 750 mg
• ANDA No. 077179, Amlodipine besylate and Benazepril HCl Capsules, 5 mg (base)/40 mg and 10 mg (base)/40 mg

Moot/Withdrawn/“Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426, FDA-2003-P-0081, & 2001P-0481 - SKELAXIN (metaxalone) Tablets; FDA Letter Decision – SKELAXIN (metaxalone) Tablets (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules
• Docket No. FDA-2005-P-0368 (Petition for Reconsideration; Dec. 5, 2006) – OXANDRIN (oxandrolone)
• Docket No. FDA-1997-P-0034 (Legacy FDA Docket No. 1997P-0178) – TORADOL (ketorolac tromethamine)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide); FDA Response (Sept. 30, 2014)
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol) Tablets

By Kurt R. Karst –      

The hope is that years from now (but hopefully not too many years), once the review and performance metrics FDA agreed to as part of the Generic Drug User Fee Amendments are in full effect and 10-month ANDA reviews (resulting in timely tentative and final approvals) are the norm, we’ll look back at posts like this one just to refresh our recollection as to how FDA, in the “dark ages,” went about determining that a sponsor forfeited eligibility for a period of 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(IV).  We’re already in a period of relative calm when it comes to forfeiture, with only a dozen or so FDA decisions so far this year.  But that calm is probably a bit misleading, as forfeiture decisions that would have come up at 30 months after ANDA submission have been delayed to 40 months as a result of the enactment of Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) (see our previous post here).  

It’s been a while since we last posted on an FDA forfeiture decision.  But that’s the topic of today’s post . . . a recent and interesting case concerning generic ACTONEL (risedronate sodium) Tablets approved under NDA No. 020835.  And the case serves as a gentle reminder of FDA’s “our failure is your failure position” when it comes to the failure-to-obtain-timely-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  First things first, however . . . a little statutory background.

Under FDC Act § 505(j)(5)(D)(i)(IV), 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final Agency action on the petition (inclusive of such beginning and ending dates) . . . .” FDC Act § 505(q)(1)(G).  Forfeiture decisions involving this provision have been invariably linked to a change in or review of decision under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has yet to make a stand-alone decision under FDC Act § 505(q), adding a specific number of days to the 30-month forfeiture date. 

FDASIA made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs.  In particular (though not relevant to the case at hand), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months.

FDA’s application of the exception (i.e., the “unless”) provision at FDC Act § 505(j)(5)(D)(i)(IV) was, at first, very narrow and draconian (and it still is to some extent).  For example, FDA explained in an October 2008 Letter Decision that “[t]his express description of the circumstances in which exclusivity will not be forfeited for failure to obtain tentative approval makes it clear that, under other circumstances in which an applicant has failed to obtain tentative approval, regardless of what party might be responsible for that failure, the first applicant will forfeit exclusivity” (emphasis added).  Although FDA still sticks to a “our failure is your failure position,” as we explained in a post back in June 2013, the Agency has shown some willingness to allow a little wiggle room under FDC Act § 505(j)(5)(D)(i)(IV).  In particular, FDA has rejected as too draconian “but for” causation in its application of the statutory forfeiture provision.  As we explained back then:

FDA has determined that even if one of the causes of failure to get tentative approval by the 30-month forfeiture date was a change in or a review of the requirements for approval imposed after the application was submitted, a first applicant will not forfeit eligibility notwithstanding that there may have been other causes for failure to obtain tentative approval by the 30-month forfeiture date that were not caused by a change in or review of the requirements for approval.  That is, to avoid forfeiture, an applicant need only show that acceptability of one aspect of its ANDA (e.g., chemistry, labeling, or bioequivalence) was delayed due, at least in part, to a change in or review of the requirements for approval, irrespective of what other elements may also have been outstanding at the 30-month date.  In other words, “but-for” causation is not required in order to qualify for the exception under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has apparently determined that this interpretation best effectuates the policy embodied in the exception, insofar as it does not penalize first applicants for reviews of or changes in approval requirements imposed after their ANDAs are submitted that cause the failure to obtain approvals or tentative approvals within 30 months, and continues to incentivize applicants to challenge patents by preserving (in many instances) the opportunity to obtain 180-day exclusivity.

In the case of forfeiture of 180-day exclusivity eligibility for generic ACTONEL Tablets, 150 mg, FDA builds on to and hammers home the Agency’s “our failure is your failure position.” 

Teva Pharmaceuticals USA (“Teva”) submitted the first ANDA to FDA – ANDA No. 079215 – containing a Paragraph IV certification for two strengths of generic ACTONEL Tablets: 75 mg and 150 mg.  The first Paragraph IV for the 75 mg strength was submitted on September 10, 2007 as part of the company’s original ANDA submission, and a second Paragraph IV for the 150 mg strength was submitted on August 12, 2008 as part of an amendment to ANDA No. 079215.  Teva’s eligibility for 180-day exclusivity for the 75 mg strength was forfeited pursuant to FDC Act § 505(j)(5)(D)(i)(II) when the company withdrew the strength from ANDA No. 079215 on December 98, 2009, but Teva continued to pursue approval of the remaining 150 mg tablet strength. 

Years passed, and it was not until August 17, 2011 that FDA finally tentatively approved ANDA No. 079215.  This is, of course, more than six months past the date that is 30 months from the August 12, 2008 submission of the 150 mg strength amendment to the ANDA (i.e., February 12, 2011).  (Final ANDA approval was granted on June 13, 2014.) 

Although FDA has not yet posted on the Agency’s Drugs@FDA website a copy of the approval letter for ANDA No. 079215, we were able to get our hands on a copy of FDA’s internal 180-Day Exclusivity Forfeiture Memorandum.  In that memorandum, FDA’s Office of Generic Drugs (“OGD”) details the basis for the Office’s conclusion that Teva forfeited 180-day exclusivity eligibility pursuant to FDC Act § 505(j)(5)(D)(i)(IV), even though as of February 11, 2011, one day prior to the 30-month forfeiture date, all OGD review disciplines had completed review of the ANDA:

We note that although no individual disciplines were outstanding at the 30-month forfeiture date, FDA had not completed its final review of the ANDA by that date.  The decision to approve (or tentatively approve) an ANDA involves not only the disciplines’ evaluations of their respective portions of the ANDA, but final review by [OGD] management.  That final step did not take place by the 30-month forfeiture date, and was complete on August 17, 2011.  We also note that any claim that a company should not forfeit because of the possibility that FDA’s delays caused the company’s failure to obtain tentative approval by the 30-month forfeiture date is unavailing.  Under section 505(j)(D)(1)(IV) of the FD&C Act, exclusivity is forfeited “unless” there is a review of or change in the requirements that has delayed approval or tentative approval of the ANDA.  The statute does not permit, let alone require, either FDA or an ANDA applicant to comb through the ANDA review records and decide whether, had the review been conducted more quickly, the application could have received tentative approval before the 30-month forfeiture date.  Notably, section 1133 of FDASIA . . . , which, among other things, extended the 30-month forfeiture period to 40 months for certain ANDAs, reflects Congress’s understanding both that the length of time that it takes FDA to review an ANDA might contribute to a sponsor’s failure to obtain tentative approval by the 30-month forfeiture date, and that in such instances forfeiture nonetheless may occur.

We’ve always found FDA’s “our failure is your failure position” problematic from a fairness standpoint; however, no company has yet taken FDA to task in a lawsuit challenging the Agency’s interpretation and application of this position.  That’s probably because finding the perfect case is very difficult.  After all, what ANDA file is clean enough from a response timeframe to make such a challenge? 

By Ricardo Carvajal & Diane B. McColl –

The Grocery Manufacturers Association ("GMA") announced an initiative designed to “improve the process and increase transparency for making Generally Recognized As Safe ("GRAS") determinations of ingredients added to food.”  The initiative includes the following five elements:

1. Development by independent technical experts of a publicly available standard to provide guidance on the conduct of ingredient safety assessments.  The standard is intended to be “suitable for accreditation using an independent official accreditation body.”
2. Establishment of a database listing information on GRAS assessments conducted pursuant to the aforementioned standard.  Information in the database will be made available to FDA and other stakeholders.
3. Expansion of GMA’s curriculum of GRAS education and training programs, both with respect to regulatory requirements and the scientific procedures used in safety assessments.  The expertise of the recently established Center for Research and Ingredient Safety (CRIS) will be made available to stakeholders.
4. Adoption of a Code of Practice that addresses the conduct of assessments, maintenance of the GRAS assessment database, and training of employees on GRAS procedures.
5. Outreach to inform stakeholders and consumers of the above-described measures.

The initiative implicitly recognizes that, at least when it comes to food ingredient safety, we live in a “show me” era.  The increased flow of information on safety assessments to FDA and others, coupled with greater clarity about the conduct of such assessments, should help address the principal concerns that have been raised about the current system.

Of course, we also live in a “my way” (or the highway) era.  As we’ve noted in prior postings (here and here), some critics of the current system have pursued a no-holds-barred approach to seeking change, and would prefer nothing less than mandatory premarket approval – a solution that is both unworkable and unattainable.  The GMA initiative effectively calls their bluff.

By Alan M. Kirschenbaum –

We have reported previously (here and here) on PhRMA’s lawsuit challenging a HRSA regulation implementing the orphan drug exclusion that applies to certain types of covered entities under the 340B Drug Discount Program. To recap briefly, the rule had provided that the orphan drug exclusion is applicable only to orphan drugs when used for the rare condition or disease for which that orphan drug was designated, so that covered entities are entitled to 340B discounts when a drug designated as an orphan drug for one indication is used for a different, non-orphan indication. In May, the D.C. District Court vacated the rule on the ground that HRSA did not have statutory authority to promulgate a legislative rule on this subject. Last month, HRSA responded by issuing a substantially identical rule, but characterizing it as an interpretive rule. PhRMA then asked the Court to either order additional briefing on whether the now-interpretive rule is valid, or to vacate the rule.

Today, the Court denied PhRMA’s request, ruling that the new interpretive rule is not the subject of PhRMA’s lawsuit. Accordingly, PhRMA “is free to challenge that interpretive rule, but such a challenge is beyond the scope of the instant action.”

To be continued . . . .

By Jennifer D. Newberger –

On August 20, 2014, CDRH issued a guidance document, “Unique Device Identifier System: Frequently Asked Questions, Vol. 1.”  The purpose, according to the guidance, is to “provide[] clarification of key provisions of the UDI Rule.”  We previously posted on the UDI rule here.

Clarification, in this instance, appears to be little more than a regurgitation of information contained in the rule itself, the preamble to the rule, the UDI website, and the Global Unique Device Identification (GUDID) guidance document.  It is not clear what new insights FDA intended this guidance to impart.  There are parts of the rule that do deserve further clarification, but those issues are not addressed. 

For example, the definition of an implantable device is one that “is intended to remain implanted continuously for a period of 30 days or more.”  21 C.F.R. § 801.3.  By this definition, extended wear contact lenses are considered implantable devices, since they are intended to remain in the eye for 30 days.  Nevertheless, we assume that FDA did not intend to include extended wear contact lenses in the definition of an implantable device.  It would be helpful for FDA to clarify this point, but failed to do so in the FAQ.

Additionally, we have been made aware that many retailers may not be able to read automatic identification and data capture (AIDC) codes for a number of years.  All labels are required to contain a UDI in plain text and AIDC format.  For devices available over-the-counter at retail stores, it is not clear how the presence of a code in AIDC format will benefit the public health (e.g., by facilitating a recall) if the retailer is unable to read the code.  Even though FDA rejected an overall exception to UDI requirements for devices available at retail establishments, it would be helpful to industry for FDA to discuss situations in which a UPC code may suffice as a UDI until retail technology catches up to the AIDC requirement.  Until then, requiring companies to place AIDC codes on retail devices with UPC codes is burdensome with no countervailing public health benefit.

The title of this guidance document states that it is “Vol. 1,” implying that there will at least be a “Vol. 2.”  Hopefully, future UDI guidance documents will do more than repeat information that is already available.

By Kurt R. Karst –      

This blogger’s oldest child started middle school this past week.  Naturally, I was excited to get his impressions of the first day of school.  “Good” was his initial comment – a now all too familiar one-word tween response with which I am still coming to grips.  So I pressed further: “Tell me more.”  “It’s all so different from elementary school,” he said.  “I got 8 pages of homework on the first day!”  While I expressed surprise, what I was really thinking was: “If only life could be that simple again.”  That thought is similar to this blogger’s first reaction after reviewing FDA’s latest draft guidance document issued in preparation for the October 1, 2014 implementation of the review and performance goals agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”): “Controlled Correspondence Related to Generic Drug Development.”  When did every little aspect of generic drug development – even simple correspondence to FDA – become so complicated?  Of course, we know the answer to that question: when GDUFA was enacted.  But just as we get used to new responsibilities as we move through the education process, the generic drug industry will step up to the task of evolving with GDUFA no matter how complicated things get.

So-called “controlled correspondence” has been a mainstay of the generic drug development and approval process for many years now.  It’s how many companies have been able to get answers from FDA’s Office of Generic Drugs (“OGD”) to questions like “What are the bioequivalence requirements for drug X?” and “How close is my formulation to that of the brand-name reference listed drug?”  OGD gets a ton of controlled correspondence each year.  Although the volume of controlled correspondence was reduced with OGD’s decision – after some internal FDA legal wranglings – to publish product-specific bioequivalence recommendations (see our previous post here), OGD continues to receive hundreds (if not thousands) of controlled correspondence requests each year.  Not surprisingly, there’s been a backlog of controlled correspondence awaiting a response from OGD.

For a long time there was no guidance (informal or formal) on how to submit controlled correspondence to FDA – or even what controlled correspondence encompassed.  Eventually, FDA posted some recommendations on the Agency’s website.  And then GDUFA came along . . . .

Early on in GDUFA negotiations it was suggested that timeframes be established for  controlled correspondence between FDA and industry to support application review targets.  Those suggestions were ultimately captured in the GDUFA review and performance goals letter where controlled correspondence was described (below) and where FDA agreed to response metrics.  The following is from the review and performance goals letter:

Controlled correspondence – FDA’s Office of Generic Drugs provides assistance to pharmaceutical firms and related industry regarding a variety of questions posed as “controlled documents.” . . . Controlled correspondence does not include citizen petitions, petitions for reconsideration or requests for stay.

Controlled Correspondence Metrics

• Controlled Correspondence
• FDA will respond to 70 percent of controlled correspondence in 4 months from date of submission in FY 2015.
• FDA will respond to 70 percent of controlled correspondence in 2 months from date of submission in FY 2016.
• FDA will respond 90 percent of controlled correspondence in 2 months from date of submission in FY 2017.
• If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.
• In the case of controlled correspondence which raises an issue or question that is the same as or related to the issue or question that is the subject of one or more pending citizen petitions, or petitions for stay or reconsideration, the above goals will apply from the date FDA issues responses to the pending petitions.

FDA’s draft controlled correspondence guidance, which is announced in an August 27, 2014 Federal Register notice and is the topic of a pre-recorded webinar, puts some meat on the bones of the review and performance goals letter.  We knew the draft guidance would be issued soon.  After all, FDA identified the guidance as a topic for discussion at a public hearing on GDUFA implementation scheduled for September 17, 2014 (see our previous post here). 

The draft controlled correspondence guidance provides, for the first time, a definition of “controlled correspondence” (at least for the purposes of GDUFA): “A correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development.”  It also limits controlled correspondence to inquiries and requests from generic drug manufacturers and related industry.  “Inquiries related to generic drugs submitted by other parties (for example, private citizens, financial firms, or public advocacy groups that are not directly involved in developing generic drug products) should be directed to CDER’s Division of Drug Information,” says FDA in the draft guidance.  From there, FDA puts some controls on what types of controlled correspondence are subject to the GDUFA metrics and when responses may be issued.  For example, FDA says that the goal dates for responding to controlled correspondence concerning issues raised in a pending citizen petition (including a petition for reconsideration or a request for stay) depend on when a petition response is issued:

If a controlled correspondence is submitted that raises an issue that is the same as or related to an issue or question that is the subject of one or more pending citizen petitions, petitions for reconsideration, or requests for a stay, the goal dates set forth in the GDUFA Commitment Letter for controlled correspondence will apply from the date FDA issues responses to the pending petitions.  Likewise, if a citizen petition, petition for reconsideration, or request for stay is submitted that raises an issue that is the same as or related to an issue or question in a pending controlled correspondence, the goal date for that controlled correspondence will apply from the date FDA issues a response to the related citizen petition, petition for reconsideration, or stay request.  For example, if a controlled correspondence is submitted in FY 2015 that relates to an issue in a pending petition, and the Agency responds in FY 2016 to that petition, the 4-month goal date for FY 2015, the year in which the controlled correspondence was submitted, will apply to the controlled correspondence from the 2016 date that the petition is answered.

For controlled correspondence related to matters still under consideration by FDA (e.g., requests for specific approval requirements for an ANDA for a complex drug product for which FDA is still considering the scientific standards for approval), parties may get a non-response response that will close the matter.  According to FDA:

For such questions that call for developing a new policy, FDA will respond to the controlled correspondence to notify the requestor that such a policy is under development, but that the Agency cannot provide information at that time because the matter is still under consideration.  The Agency will consider this response to close the controlled correspondence, and it will not provide additional direct communications to an inquirer on the matter.

Although FDA’s draft guidance does provide some specific examples of what inquiries and topics are appropriate for controlled correspondence (e.g., requests related to inactive ingredients, formulation assessments, and labeling standards for certain container/closure systems), along with general guidance that controlled correspondence should involve “inquiries on a specific element of generic drug development, and not general questions related to product planning,” FDA spends quite a bit of time explaining what topics fall outside the scope of controlled correspondence, as well as what controlled correspondence is excepted from GDUFA goals.  “First, the Agency considers any question related to a pending ANDA a review issue,” says FDA. “Such inquiries will not be treated as controlled correspondence and should be submitted only to the ANDA so they can be included as part of the full administrative record for that application.”  “Second, inquiries that are submitted to FDA that are not directly related to generic drug development will not be considered controlled correspondence for the purposes of GDUFA.” Finally, “general, open-ended, or insufficiently detailed questions related to product development are not the appropriate subject of [controlled correspondence].”

Excepted from the GDUFA goals are three types of inquiries that fall within the definition of controlled correspondence, but that FDA has historically treated differently than other inquiries on generic drug development: (1) requests for bioequivalence study recommendations for a specific drug produc; (2) requests for review of bioequivalence clinical protocols; and (3) requests for pre-ANDA meetings to discuss generic drug development.  “FDA will continue to respond to these inquiries consistent with its current practices, and to exclude these inquiries from the goal dates in the GDUFA Commitment Letter,” writes FDA.

Finally, the draft guidance provides detailed information on how generic drug manufacturers or related industry should go about submitting controlled correspondence, the specific components FDA expects to see in controlled correspondence, and what OGD disciplines might review and respond to controlled correspondence. 

The draft guidance is a lot to digest, but it’s also welcomed detail of an information request process that is intended to result in quicker ANDA approval.  Nevertheless, some questions still remain.  For example, how will FDA’s focus on addressing controlled correspondence submitted in Fiscal Years 2015-2017 affect controlled correspondence submitted during the first two years of GDUFA (and before)?  Will those pending requests be put on a backburner?