By James C. Shehan –

Aficionados of pro wrestling can regale you with the exploits of tag teams  like The Bruiser and the Crusher, The Wild Samoans and The Fabulous Freebirds.   The moniker FDA-IRS-FTC is far less colorful and mellifluous than those of WWE stars, but proved more than sufficient recently to take down a Rhode Island man accused of distributing unapproved cancer drugs.  And therein lies an unpleasant lesson for those facing government enforcement actions.

On September 15th, James Feijo pleaded guilty  in federal court in Providence, Rhode Island to selling products not approved by FDA as cancer mitigation and treatment options and to failing to pay ~$220,000 in employment taxes.  But government interest in Mr. Feijo began years earlier and in another agency – the Federal Trade Commission.

In September 2008, the FTC announced enforcement actions against 11 sellers of bogus cancer cures.  One of these 11 companies was Daniel Chapter One, a company owned by Mr. Feijo and his wife Patricia.  Daniel Chapter One was said to market herbal formulations and shark cartilage for the prevention, treatment and cure of cancer, and to mitigate the side effects of radiation and chemotherapy.  The FTC announcement noted that Daniel Chapter One also had received an FDA warning letter.

While six of the eleven companies had agreed to settle, Daniel Chapter One was not among them and so the FTC proceeded with a case before one of its administrative law judges. After an administrative trial, the ALJ in August 2009 upheld the FTC charges of deceptive claims and ordered the company and Mr. Feijo to stop making cancer claims for its products unless it could show that the claims were true, non-misleading and based on reliable scientific evidence.  In December 2009, the FTC Commissioners unanimously upheld the ALJ. 

Mr. Feijo and Daniel Chapter One then asked the U.S. Court of Appeals for the DC Circuit in March 2010 to review the FTC ruling that they were making deceptive claims.  In December 2010, the DC Circuit  ruled in favor of the FTC.  Meanwhile, the FTC asked the Department of Justice to impose civil penalties on Daniel Chapter One and Mr. Feijo for violating the FTC order and in August 2011 the DOJ did so.    A DOJ summary judgment motion for liability was granted in September 2012, leading to a final order of injunctive relief, equitable monetary relief in the amount of $1,345,832.43 and a civil penalty award of $3,528,000.  In the course of that case, Mr. and Mrs. Feijo were held in contempt of a court order for, among other things, continuing during 2011 to make claim that their products treat or cure cancer.   

The Feijos’s continued defiance of the FTC appears to have triggered the government to involve other federal agencies.  In April 2014, following an investigation by the Rhode Island FDA Task Force and the IRS’s Criminal Investigation unit, a grand jury indictment issued charging Daniel Chapter One and Mr. and Mrs. Feijo with 18 counts of tax evasion and six of introducing an unapproved new drug into interstate commerce.  This was followed by the afore-mentioned plea agreement, under which Mr. Feijo will plead guilty to one count of willful failure to collect, account for or pay a tax, punishable by up to five years imprisonment, and one count of introduction of an unapproved new drug into interstate commerce., punishable by up to one year imprisonment.   Sentencing is set for January 12, 2016. 

Enforcement activity by any one federal agency is a daunting prospect.  But when a tag team of several agencies becomes involved, almost any defendant will be pinned to the mat.

By Kurt R. Karst – 

One day in the future, reporting on biosimilar patent dance challenges lodged pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) will be considered passé.  Such challenges will be as commonplace as Hatch-Waxman Paragraph IV challenges.  Indeed, earlier this week, FDA released a report that the Agency has held nearly 90 meetings with more than 50 companies interested in biosimilars, and last week, CDER Director Janet Woodcock testified before a Senate Committee that as of July 31, 2015, 57 proposed biosimilar products were in FDA’s Biosimilar Product Development Program.  But we’re not yet even close to that future date.  Today, each BPCIA patent dance lawsuit holds the potential to alter the future course of the law.  And because of that potential, we try to keep a close eye on the biosimilars scene. 

BPCIA-related lawsuits come in many flavors, several of which we have not yet even tasted.  (Consider, for example, the palate-expanding experience that awaits us when the duo of Amgen and Allergan face off against Roche and Genentech over a biosimilar version of Avastin (bevacizumab) – see here – or when FDA is eventually challenged over the Agency’s implementation of the law.)  Initially, there were the declaratory judgment cases filed by biosimilar applicants (see our previous post here).  Then there were the challenges alleging that biosimilar applicants violated the BPCIA for failure to participate (or to cooperate) in the patent dance process and for providing inadequate or ineffective notice of commercial marketing (see our previous post here).  More recently, there has been a post-patent dance challenge involving a biosimilar version of Amgen’s NEULASTA (pegfilgrastim) – see here – and that also involves an allegation of ineffective notice.  For the most part, courts are still working on sorting out the second wave of BPCIA lawsuits involving participation in the patent dance process (PHS Act § 351(l)(2)-(l)(7)) and the timing of 180-day commercial notice (PHS Act § 351(l)(8)).  Both issues are in dispute in a recent Complaint filed by Amgen against Hospira concerning a biosimilar version of EPOGEN (epoetin alfa) (BLA 103234). 

Amgen’s Complaint (Case No. 1:15-cv-00839-RGA) – the first BPCIA-related Complaint filed in the U.S. District Court for the District of Delaware – alleges that Hospira violated PHS Act §§ 351(l)(8)(A), (l)(2)(A), and (l)(4) after Hospira engaged Amgen upon FDA notification that the Agency accepted Hospira’s BLA for a biosimilar version of EPOGEN.  (The Complaint also alleges infringement of three patents, one of which was included in Amgen’s disclosure under PHS Act § 351(l(3)(A).)  These issues, insofar as they concern the mandatory or voluntary nature of the patent dance process and the timing of notice, were tackled by the U.S. Court of Appeals for the Federal Circuit in a July 21, 2015 decision, but the decision has been appealed. 

According to Amgen, “Hospira has chosen to ignore certain statutory requirements of the BPCIA that Congress put in place to protect innovators such as Amgen.  Rather than follow the requirements of the BPCIA, Hospira has selectively decided to comply with certain provisions while refusing to comply with others.”  First, Amgen alleges that “[a]lthough Hospira provided a copy of the Hospira BLA to Amgen, it did not provide Amgen with the other information describing the processes used to manufacture the Hospira Epoetin Biosimilar Product as required by § 262(l)(2)(A),” and that Hospira has repeatedly refused to provide information specifically identified by Amgen.  None of the correspondence identified in Amgen’s Complaint is attached to the Complaint, so we’re unclear what that information is exactly.  Is it information included in a Drug Master File (i.e., a submission of information to FDA to permit the Agency to review such information in support of a third party’s submission without revealing the information to the third party), or in some other submission to FDA?  “By unlawfully withholding the information required by 42 U.S.C. § 262, Hospira has thereby frustrated the statutory purpose and deprived Amgen of the opportunity to seek redress for potential infringement.  Amgen may therefore seek to assert additional patents following eventual receipt of Hospira’s manufacturing information to be produced in discovery in this action under the Federal Rules,” says Amgen in its Complaint. 

Notwithstanding the alleged absence of certain information from Hospira, Amgen engaged Hospira in the patent exchange process of the patent dance.  But Amgen says that Hospira has failed to cooperate.  After accepting Amgen’s patent list provided pursuant to PHS Act § 351(l)(3)(A), “Hospira refused to engage in any of the negotiations required by [PHS Act § 351(l)(4)(A)]” in violation of the statute, according to Amgen. 

Turning to notice of commercial marketing, Amgen says that the 180-day notice Hospira provided on April 8, 2015 is invalid.  The Federal Circuit recently ruled in a severely split decison that valid notice can only be provided on or after FDA licensure of a biosimilar BLA.  “Despite its obligation under § 262(l)(8)(A), Hospira provided Amgen with a purported (8)(A) notice on April 8, 2015, before Amgen had provided its initial disclosure of patents under (3)(A) and before Hospira received FDA approval for its Hospira Epoetin Biosimilar Product” (emphasis in original), says Amgen.  “In serving a purported ‘notice of commercial marketing’ before its biosimilar product is licensed, Hospira intends to deprive Amgen of the statutory time period for considering the need for and, if appropriate, seeking adjudication of, a potential preliminary injunction motion. Therefore, Hospira intends to continue violating this provision of the BPCIA absent an order of the Court compelling Hospira to comply.”

In addition to patent-specific relief, Amgen has a laundry list of BPCIA-specific relief the company wants from the court.  The relief includes: (1) orders “enjoining Hospira from commercially marketing the Hospira Epoetin Biosimilar Product until Amgen is restored to the position it would have been in had Hospira met its obligations under the BPCIA,”  “enjoining Hospira from continuing to seek FDA review of its [biosimilar] application and/or compelling Hospira to suspend FDA review of its [biosimilar] application until Hospira has obtained permission from Amgen to use the EPOGEN® (epoetin alfa) license or Hospira has restored to Amgen the benefits afforded to Reference Product Sponsors in the BPCIA,” and “requiring Hospira to provide Amgen ‘such other information that describes the process or processes used to manufacture the biological product that is the subject of’ the Hospira BLA; (2) declarations that Hospira’s April 9, 2015 notice of commercial marketing  is ineffective, and that Hospira has violated the BPCIA by failing to provide to Amgen by the statutory deadline certain manufacturing informatin; and (3) an injunction requiring notice of commercial marketing from Hospira to Amgen on or after FDA licensure of Hospira’s EPOGEN biosimilar application and prohibiting Hospira from launching its biosimilar until 180 days after notice is provided. 

By Karla L. Palmer – 

Last week, several congressional representatives announced the introduction of H.R. 3537, the “Synthetic Drug Control Act of 2015.”  If enacted, the Synthetic Drug Control Act would strengthen existing federal law (specifically, the Controlled Substances Analogue Enforcement Act) (“Analogue Act”), which provides that any compound that is chemically or pharmacologically similar to a controlled substance in Schedule I or II under the Controlled Substances Act (“CSA”) must be treated as if it is controlled in that same schedule.   

The significant limitation found in the Analogue Act, which the legislators hope to address with passage of the proposed legislation, is that the Analogue Act currently addresses substances that are substantially structurally and pharmacologically similar to a controlled substance as long as they are intended for human consumption.  (21 U.S.C. § 816 (a “controlled substance analogue shall, to the extent intended for human consumption, be treated, for purposes of any Federal law as a controlled substance in Schedule I.”))  Schedule I substances have a high potential for abuse, have no currently accepted medical use in treatment in the U.S. and there is a lack of accepted safety for their use under medical supervision.  21 U.S.C. § 812(b)(1).  The use of newly derived analogues, which crop up on a very regular basis and include “flakka” and “molly,” are often sold legally in colorful, readily identifiable, and branded packaging. These drugs are distributed by convenience stores, head shops, or online, and, importantly, they typically bear the legal fig leaf ‘not for human consumption’ to avoid regulation by the federal Food and Drug Administration.

The legislation intends to facilitate the prosecution of synthetic drug manufacturers and distributors and make Analogue Act law a more useful tool for law enforcement.  It adds to the end of 21 U.S.C. § 813, which currently states “A controlled substance analogue shall, to the extent intended for human consumption, be treated, for the purposes of any Federal law as a controlled substance in schedule I” the following language: “for purposes of prohibitions, restrictions, and other requirements with respect to manufacture, importation, distribution, and sale.” The bill also removes all references of the term “substantially” from the definition of a controlled substance analogue (21 U.S.C. § 802(32)(A), so that substances may be more readily classified as an analogue without having to show that they have a substantial similarity to their alleged counterpart.  Finally, it adds a detailed and long list of known synthetic drugs identified by the DEA into schedule I, thus bypassing the need for DEA to temporarily place substances in Schedule I on an emergency basis and await scheduling by DEA.  Note that at least one court has noted that the Analogue Act as applied is unconstitutionally vague.  See United States v. Forbes, 806 F. Supp. 232, 234 (D. Colo. 1992).     

To ensure that the legislation targets manufacturers and distributors rather than end users, the Synthetic Drug Control Act narrows the Analogue Act to provide that it should apply to the sale, manufacture, import, and distribution of drugs – not simple possession.  A concern likely remains here, however, because the legislation does not address another loophole in the Analogue Act – the fact that synthetic compounds often are not sold as drugs or “for human consumption,” but are instead sold as non-food products (i.e., bath salts) not intended for human consumption and thus elude a clear FDA regulatory status.  Whether the supplier of the product or substance is a manufacturer, distributor, or end user, the fact that the Analogue Act applies to products for human consumption (and the burden is on law enforcement to demonstrate that the suspect product is intended for human consumption) will likely still be an availing loophole throughout the distribution chain.  One other way to close this loophole is to remove the requirement “intended for human consumption” from Section 813.      

Congressman Jim Himes (CT) made the following statement concerning the importance of this legislation:

Synthetic drugs are being marketed in convenience stores and other markets as a safe, legal alternative to controlled substances . . . . This is far from the truth. Without any serious regulation or enforcement, the manufacturers of these drugs are exploiting a legal loophole to put untested, potentially dangerous drugs on the street, where the people buying them have no idea what sort of effect they’re going to have. The side effects can include aggression, disorientation and hallucination, which can lead to harm for the user and others. We need them off the street.

By Anne K. Walsh & John R. Fleder –

The government has long repeated the mantra that it will hold individuals personally liable for the activities of their corporate employer.  In the FDA-regulated arena, the government has been bolstered by the U.S. Supreme Court precedents set in United States v. Dotterweich, 320 U.S. 277 (1943), and United States v. Park, 421 U.S. 658 (1975), and corporate officials have been well-trained to understand the potential exposure they face from their positions under the Park Doctrine.  In the 1960s to the mid-1980s, FDA requested the Department of Justice to prosecute numerous individuals, which it did mostly in cases involving egregious conduct, such as persistent violations in the face of notice from FDA, or serious injury to the consumers.  Between the mid-1980s and the early 2000s, the government’s focus on individuals languished, except for cases involving allegations of clear fraud, for many reasons described here, but no more.  In the last year alone, several high-level government officials have repeated the clear message that responsible corporate officers are in the crosshairs of DOJ and FDA in both misdemeanor and felony situations.

The latest missive is the strongest statement by DOJ.  In a seven-page memorandum, announced during a highly publicized speech at NYU School of Law, Deputy Attorney General Sally Quillian Yates explicitly revises the “Principles of Federal Prosecution of Business Organizations,” set forth in the U.S.A.M. 9-28.700 et seq. and the civil litigation provisions in USAM 4-4.000 et seq.  It is unclear how these changes will be formally documented in the U.S. Attorney’s Manual, but Ms. Yates makes clear that the guidance will apply immediately, even “to those matters pending as of the date of this memo.”

The memo is not long, and should be required reading for anyone who defends companies and individuals in civil and criminal enforcement actions taken by the government.  The new policy does not reference and is thus not limited to FDA-regulated entities, but applies broadly to “any investigation of corporate misconduct.”  And unlike earlier memoranda addressed at criminal prosecutions, like the 2008 Filip memo, Ms. Yates makes clear that there will be changes to the way the government considers civil corporate matters.  Taking that to the extreme, even a simple negotiation with the government on an FDA regulatory matter could result in potentially implicating individuals before the company can achieve resolution.

And that’s the point of the Yates memo.  The government appears to mean business that it will pursue individuals, and it will incentivize (or penalize, depending how one stands on the issue) companies to turn over facts to help the government with the witch hunt.

Below are each of the six principles and some questions for consideration:

• Companies will not receive any credit for cooperating with the government unless that cooperation includes producing facts relating to the individuals involved in the alleged misconduct.  How many facts are enough?  How many individuals are enough?  How much investigation must a company do before turning over its facts?  What impact will there be on the attorney-client privilege governing that investigation?
• The government is required to focus on potential individual culpability from the inception of an investigation.  Will all involved individuals need to retain separate counsel?  How will that affect the company’s own internal investigation?  And when will the government notify individuals or the company that a particular person is not a focus?
• Civil and criminal government attorneys should be in routine communication about potential conduct that might give rise to culpability.  How will material governed by grand jury secrecy rules be shared?  Will a company have to jointly communicate with both the civil and criminal sides of DOJ?
• The government will not release an individual from liability as part of a corporate resolution.  This appears to document what we have seen as existing practices by government lawyers, so this is not to change the policy.
• Companies cannot resolve a matter until there is a plan to resolve investigations of any individuals.  This could seriously delay corporate resolutions, but of course, that is the stick the government is holding to urge companies to assist with the individual case.
• Government lawyers handling civil cases cannot use an individual’s inability to pay as a factor in deciding whether to bring a case against an individual.  Ms. Yates recognizes that these cases “may not provide as robust a monetary return on the Department’s investment,” but focuses on the long-term deterrent effect of these cases.

As noted earlier, this new policy applies immediately, even to pending matters.  We will just have to see if those in the unfortunate circumstance of being involved in a negotiation that is close to resolution would serve as the guinea pigs for fleshing out how this guidance will be applied.

By Kurt R. Karst –

Finding new ways to incentivize and reward drug development for particular therapeutic needs is all the rage these days.  Over the past few years we’ve seen several new incentives incorporated (and proposed for incorporation) into the FDC Act.  These new incentives are quite different from the standard grants of patent and non-patent marketing exclusivities, including incentives that merely stack exclusivity periods upon one another, such as 6-month pediatric exclusivity (FDC Act § 505A) or 5-year Generating Antibiotic Incentives Now Act exclusivity (FDC Act § 505E) or other proposals under consideration (see our previous posts here and here).  Take, for example, the Rare Pediatric Disease Priority Review Voucher (“Pediatric PRV”) program (FDC Act § 529) and the Tropical Disease PRV (“TD PRV”) program (FDC Act § 524), added to the law in 2012 by the FDA Safety and Innovation Act and in 2007 by the FDA Amendments Act, respectively.  Both PRV programs, which provide for a transferable voucher allowing for a standard 10-month application review to become a 6-month priority review, have been tremendously successful, with several new drug and biologic approvals and PRV sale tags going through the roof (see our previous post here).  There’s also the concept of so-called “wildcard exclusivity” proposed in one version of the 21st Century Cures Act.  A provision in the bill would allow a sponsor to convey a portion of its exclusivity to apply with respect to one or more other drugs (see our previous post here).  Such conveyance could include the sale of exclusivity from one company to another company and would also apply to Orange Book-listed patents.

The latest incentive proposal from Congress comes from Senator Robert Casey (D-PA) in the form of S. 2041, the Promoting Life-Saving New Therapies for Neonates Act of 2015.  If enacted, the bill would amend the FDC Act to add Section 530 to create a transferable “Neonatal Drug Exclusivity Voucher.”  The voucher is kind of a combination of the recent PRV programs and efforts to create “wildcard exclusivity.”  And it’s an idea the President’s Council of Advisors on Science and Technology (“PCAST”) proposed in a September 2014 report as part of a broader initiative announced by The White House to address the growing challenges posed by antibiotic resistance.  In the report, PCAST recommended consideration of a tradable exclusivity voucher to reward successful antibiotic development.  As we noted in a post when the PCAST report was published, “there seems to be a growing chorus of support for wildcard exclusivity that may mean it will gain traction among legislators and find its way into the FDC Act.”  Clearly, momemtum is building for transferable wildcard exclusivity. 

S. 2041 would allow the sponsor of a 505(b)(1) NDA for a new chemical entity or the sponsor of a BLA for a new biological entity intended for the prevention or treatment of a disease or condition of a preterm or full-term neonate (as specificed on a Priority List of Critical Needs for Neonates created under the bill), and that “relies on clinical data derived from studies examining a neonatal population and dosages of the drug intended for that population,” to obtain a “Neonatal Drug Exclusivity Voucher” upon approval of its application.  A “Neonatal Drug Exclusivity Voucher” is defined in the bill to mean:

a voucher issued by [FDA] to the sponsor of a neonatal drug application that entitles the holder of such voucher to one year of transferable extension of all existing patents and marketing exclusivities, including any extensions, for a single human drug with respect to an application submitted under section 505(b)(1) or for a single human biologic product with respect to an application submitted under section 351(a) of the Public Health Service Act, including the 6-month period described in section 505A, the 4- and 5-year periods described in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of section 505, the 3-year periods described in clauses (iii) and (iv) of subsection (c)(3)(E) and clauses (iii) and (iv) of subsection (j)(5)(F) of section 505, the 7-year period described in section 527, the 5-year period described in section 505E, and the 12-year period described in section 351(k)(7).  [(Emphasis added)]

The bill includes some provisos on voucher transferability and use.  For example, a voucher “may not be transferred to, or used for, a drug with respect to which all patents and cxclusivities have expired as of the date of the transfer.”  In addition, each person to whom a voucher is transferred must notify FDA of the change in ownership not later than 30 calendar days after the transfer.  A sponsor intending to use a voucher would be required to notify FDA not later than 15 months prior to loss of patent and exclusivities on the drug to which the voucher would apply, and FDA would then be required to notify the sponsor of its eligibility to redeem a voucher for the intended drug within 30 days of notice of intent to use.  Also, FDA would be able to revoke a voucher if the neonatal drug product for which the voucher was awarded is not marketed in the United States within 365-days from the date of the approval of the neonatal drug.  And, in a change from the current PRVs programs, FDA would be prohibited from assessing a fee  for the exercise of a Neonatal Drug Exclusivity Voucher.

S. 2041 also includes certain limitations on voucher eligibility and use.  For example, a Neonatal Drug Exclusivity Voucher would only be available to a sponsor that submits a marketing application after the enactment of S. 2041.  In addition, the bill provides that FDA “shall limit grants of exclusivity under [proposed FDC Act § 530] to drugs that are not required to complete neonatal studies under section 505B,” the Pediatric Research Equity Act.  And in case anyone thinks about “voucher stacking” (i.e., combining a PRV with a Neonatal Drug Exclusivity Voucher), think again.  S. 2041 says that “ [a] sponsor may not use a neonatal exclusivity voucher on a product for which the sponsor also intends to use a voucher obtained or purchased pursuant to section 524 or section 529.”

As one person (likely Pablo Picasso) once said: “Good artists copy, great artists steal.”  That’s a nice way to characterize the Promoting Life-Saving New Therapies for Neonates Act of 2015.  Senator Casey has taken a pinch of the PRV and a pinch of the concepts underlying “wildcard exclusivity,” mixed them together, and came up with something new. 

S. 2041 has been referred to the Senate Committee on Health, Education, Labor, and Pensions.  Perhaps we’ll see the bill resurface soon as part of the Senate’s counterpart to the House-passed 21st Century Cures bill.  We’re already seeing an uptick in FDA-related legislation introduced in the Senate, perhaps paving the way for the introduction of a larger FDA-related bill (or the release of a draft bill) in the coming weeks.  In addition to the Promoting Life-Saving New Therapies for Neonates Act of 2015, we’ve also seen the recent introduction of the Advancing Targeted Therapies for Rare Diseases Act of 2015 (S. 2030), a bill addressing  national health security (S. 2055), and legislation addressing drug affordability (S. 2023).

The latest issue of the Food and Drug Law Institute’s “Update” magazine features an analysis of the recent case of Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. May 7, 2015), written by Hyman, Phelps & McNamara, P.C. attorneys David C. Gibbons and Jeffrey N. Wasserstein.  The article, titled "Amarin Case Tests Limits of FDA Regulation of Off-Label Promotion," analyzes the regulatory background leading up to the case and where the Amarin case fits within recent First Amendment jurisprudence.

By David C. Gibbons & Anne K. Walsh – 

In the wake of what industry is touting as Amarin’s First Amendment victory (read our Amarin posts here and here), Pacira Pharmaceuticals, Inc. (“Pacira” or the “Company”) filed a suit raising similar claims in the same district court as the Amarin matter.  On September 8, 2015, Pacira filed a Complaint in the U.S. District Court for the Southern District of New York seeking to prevent FDA from bringing an enforcement action against the Company for what it claims is truthful and nonmisleading speech concerning its sole product, Exparel.  (Pacira subsequently filed a Motion for Preliminary Injunction in the case.)  A key issue is whether FDA can limit the scope of a generally approved product to only those specific uses in which the drug has been studied and approved.

Exparel is approved for “single-dose infiltration into the surgical site to produce postsurgical analgesia.”  Exparel (bupivacaine liposome injectable suspension) Label, NDA 022496, 2 (Dec. 2014).  The indication does not limit the surgical site for which Exparel can be used, even though the clinical studies used to gain approval were conducted in two specific types of surgeries:  bunionectomy and hermorrhoidectomy.  According to the Complaint, “Pacira initially felt free to provide truthful and non-misleading information to health care providers about Exparel’s use in surgical sites other than bunionectomy and hemorrhoidectomy.”  Complaint at 45, Pacira Pharms., Inc. v. FDA, No. 15-7055 (S.D.N.Y. Sept. 8, 2015). 

Three years after approval, in September 2014, FDA’s Office of Prescription Drug Promotion (“OPDP”) issued a Warning Letter to Pacira alleging that Exparel was misbranded.  FDA, Warning Letter to Pacira Pharmaceuticals, Inc. (Sept. 22, 2014).  Specifically, FDA took issue with Exparel’s distribution of materials describing the use of Exparel in laparoscopic cholecystectomy and open colectomy surgeries.  Id. at 4.  FDA stated that the promotional materials “suggest[ed] an extensive promotional campaign by Pacira to promote the use of Exparel in surgical procedures other than those for which the drug has been shown to be safe and effective.”  Id. at 3.  According to the Complaint, Pacira did not agree with FDA, but was “compelled to comply with FDA’s demands” because Pacira feared enforcement action.  Compl. at 50.   

The Instant Lawsuit

In its lawsuit, the Company seeks to resume promoting Exparel as it did before the Warning Letter issued.  Compl. at 71-72.  Like Amarin, Pacira identifies in its Complaint specific types of information that it desires to disseminate to healthcare providers, such as the use of Exparel in surgical sites other than bunionectomy and hemorrhoidectomy; the different methods by which Exparel can be administered in these other surgical sites; published studies and reports regarding Exparel’s administration into different surgical sites; and experiences that other physicians have had administering Exparel into other surgical sites to produce postsurgical analgesia.  Compl. at 52-53.

Pacira first argues that under Caronia and Amarin, the First Amendment protects the dissemination of information concerning uses of Exparel in patients undergoing a specific type of surgery other than bunionectomy or hemorrhoidectomy, “even if it constituted an off-label use.”  Id. at 59.  Citing the Amarin decision, Pacira argues that FDA has no constitutional basis to prohibit the dissemination of information concerning specific uses of Exparel, even if not FDA-approved, because it is protected commercial speech.  Id. at 56.  

In the alternative, Pacira argues that the information was not even off-label because the Company held a reasonable and good faith belief that the “broad pain indication” allows the Company to disseminate information on uses consistent with such an indication.  Id. at 57.  Under this argument, Pacira disputes FDA’s conclusions that the dissemination of information about the use of the product to produce postsurgical analgesia in other types of surgeries is outside the scope of the approved indication.  Id. at 57-58.  

Pacira also raises familiar challenges under the Administrative Procedure Act (that FDA’s restrictions are arbitrary and capricious) and the Fifth Amendment (due process).  Pacira asserts that FDA changed its position on Exparel, noting that FDA reviewers originally sought to limit the approval to bunionectomy or hemorrhoidectomy surgeries, but that the final Exparel’s approved label did not contain that limitation.  Id. at 63.  Pacira also focuses on FDA’s requirements for pediatric studies under the Pediatric Research Equity Act (“PREA”), arguing that “FDA could only have reached a conclusion that pediatric studies were required for Exparel if it understood the product’s approved indication to encompass all surgical sites generally, and not just those sites associated with bunionectomies and hemorrhoidectomies.”  Id.   

Predictions

While this case appears to present the same issues as in Amarin, there are unique aspects of this case that, if resolved in Pacira’s favor, could further erode FDA’s authority in this field.  But there also are potential weaknesses that highlight the limitations of Amarin.  

For example, unlike Amarin, Pacira could be at risk of a challenge from FDA given the current posture of the matter.  Based on the company’s decision to discontinue the targeted promotional activities, FDA closed out the Warning Letter in July 24, 2015.  Given that FDA’s close-out letter suggests there is no imminent threat of prosecution against Pacira, the court may find there is no justiciable controversy at issue.  Whether the action is mooted, or whether the company lacks standing, or both, is an issue that was not at play in Amarin. 

Also, Pacira’s argument that its promotional claims are in fact within the approved general indication for postsurgical analgesia raises an issue beyond the scope of Amarin and with broader implication on medical device companies.  Medical device companies frequently face this “general versus specific use” issue because it is not uncommon for a medical device to receive clearance for a general use.  Healthcare practitioners, of course, will use the medical device on specific sites, so the question arises whether medical device representatives can talk to these practitioners about the specific uses directly.  The risk is that FDA may view the specific use as a new intended use requiring a new 510(k) clearance or even premarket approval.  Given the specific claims that Pacira wants to make, medical device companies should be keenly following this litigation to see whether FDA gives any insight on how it views marketing for specific uses.  

Also, the scientific strength of the claims is not as strong as that involved in Amarin.  Pacira does not have completed pivotal phase 3 data on the specific indications for which it would like to promote, and instead seeks to extrapolate data that is not directly involving its drug product.  See Compl. at 44.   

If nothing else, Pacira’s lawsuit tells us that Caronia and Amarin have indeed given courage to other potential First Amendment challengers.  The key will be to see who has the heart to file in a circuit other than the Second Circuit where good precedent exists.  Even a loss could be a win for industry if it creates a circuit split that could result in the issue being decided by the U.S. Supreme Court. 

By Kurt R. Karst –

In a September 10, 2015 Response to a September 2, 2011 Citizen Petition (Docket No. FDA-2011-P-0657) submitted by the National Organization for Rare Disorders (“NORD”), FDA refuses to add a statement to guidance documents concerning orphan drugs that the Agency’s official policy is to afford “special flexibility” to the regulatory review of marketing applications for products for rare diseases.  Despite FDA’s refusal, however – and in what might be characterized as the regulatory equivalent of a “nudge nudge wink wink” – the Agency assures NORD that FDA “remains sensitive to NORD’s concerns and will continue to encourage and support the development and availability of treatments for rare diseases” and outlines the numerous ways in which the Agency addresses the unique concerns related to rare diseases. 

NORD’s petition was triggered by a provision included in the Fiscal Year 2010 FDA Appropriations Act (Pub. L. No 111-80).  As we previously reported, Section 740 of the law required FDA to, among other things, develop “internal review standards” no later than 180 days following issuance of a report by the Agency’s internal expert committee on the review of articles for the diagnosis or treatment of rare diseases.  FDA issued the Report to Congress on June 27, 2011, making the Agency’s “internal review standards” guidance due for issuance no later than December 27, 2011 (see our previous post here).  NORD’s petition requests that FDA’s guidance explicitly include three items: 

• Acknowledgement that the conduct of clinical trials for most orphan drugs is qualitatively and quantitatively different from the conduct of trials for drugs that treat common conditions.
• Acknowledgement that FDA review of marketing applications for most orphan drugs is accordingly qualitatively and quantitatively different from FDA review of applications for articles that treat common conditions.
• In recognition of the above, and notwithstanding the unchanged requirements that articles for rare diseases must demonstrate both efficacy and safety, we request a statement that it will now be FDA official policy to afford special flexibility to the regulatory review of submissions for all orphan drugs.

According to NORD, “[t]his petition does not request any itemization of past actions – rather, through the language of forthcoming guidance, we request the establishment of a policy to direct future actions.”  In addition, NORD requests that FDA “incorporate mandatory training in this new policy and other matters related to orphan drug development for all full-time FDA review professionals”  by making the course administered by CDER’s Associate Director for Rare Diseases, titled “Meeting the Challenges of Rare Disease Drug Review,” a requirement for all CDER and CBER reviewers.

Citing the Agency’s January 2013 final guidance on Humanitarian Use Device Designations (see our previous post here) and FDA’s August 2015 draft guidance on “Rare Diseases: Common Issues in Drug Development” (see our previous post here) – which “acknowledges that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases” – FDA says in the petition response that the guidances meet the publication provisions of Section 740 of the Fiscal Year 2010 FDA Appropriations Act, and that with their issuance, FDA grants the guidance publication request in NORD’s petition.  (FDA also notes that other related guidances are in the near-term pipeline.)  But that’s the extent to which FDA explicitly grants any of the requests in NORD’s petition. 

Moving on to NORD’s request for “explicit acknowledgements” in guidance that both clinical trials and FDA application reviews for orphan drugs are “qualitatively and quantitatively different” from clinical trials or application reviews for products treating prevalent diseases or conditions, and NORD’s request for a statement in guidance on the “special flexibility” FDA applies to the review of applications for orphan drugs, FDA takes an interesting tack.  FDA denies both requests, saying that “the language you suggest may inadvertently limit FDA’s decision-making flexibility or mislead others regarding the standards required for orphan drugs;” however, the Agency then goes on to note the various ways in which the Agency has accorded flexibility to orphan drug reviews, including citing a landmark report authored by Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski on his findings of flexibility in FDA’s review of potential treatments for patients with rare diseases (see our previous posts here and here).  According to FDA:

Although the Agency will not make explicit the suggested acknowledgements in future guidances, FDA has assessed, and will continue to assess, orphan drug development programs on an individual basis, taking into account disease manifestations, the expected results of the intervention, the population under study, and other factors. . . .

For products treating rare diseases, FDA’s record of flexibility during the approval process is indisputable.  Between 2006 and 2015, FDA approved almost 200 such products in multiple therapeutic areas and indications.  In doing so, the Agency assented to a wide variety of clinical development programs, accepted trial populations as low as less than 20, approved treatments that in some instances relied on only one study, and accepted a diverse array of study designs.  For approved products, such factors such as the disease being treated, the intervention proposed, and the population under study can affect the quantity and quality of evidence available.) [sic] In each case, FDA exercised its scientific judgment to determine what level of information would be sufficient to demonstrate compliance with applicable statutory and regulatory standards.

FDA also declines to change the content of the Agency’s “Meeting the Challenges of Rare Disease Drug Review” training course as NORD requested, saying that “in its current iteration, this annual course sufficiently addresses your concerns regarding the unique challenges of orphan drug development.” 

But FDA’s petition response is not done yet.  FDA takes this opportunity to tick off some of the recent ways in which the Agency “has been proactive in addressing the unique concerns related to rare diseases”: 

• Hiring additional staff to the OND Rare Disease Program
• Forming a Rare Disease Council that meets monthly and discusses cross-cutting issues relating to rare diseases (see here at page 60)
• Developing a comprehensive regulatory science database and evaluation tool that allows the Agency to identify best practices and gaps for rare disease development
• Holding public workshops and Patient-Focused Drug Development (PFDD) meetings that address specific topical areas and particular diseases, where approximately 50% of these meetings have been focused on rare diseases (see our previous post here)
• Holding a PDUFA V- and FDASIA-mandated three-day public meeting entitled “Complex Issues in Developing Drugs and Biological Products for Rare Diseases and Accelerating the Development of Therapies for Pediatric Rare Diseases” on January 6- 8, 2014
• Publishing the draft guidance for industry entitled “Rare Pediatric Disease Priority Review Vouchers” in November 2014 (see our previous post here)
• Publishing the guidance for industry entitled “Expedited Programs for Serious Conditions – Drugs and Biologics” in May 2014 (see our previous post here)
• Establishing and participating in numerous conferences, committees, and work groups related to rare disease issues and topics

So, despite FDA's reticence to explicitly state as official Agency policy that FDA affords special flexibility to the regulatory review of submissions for orphan drugs, it seems pretty clear that the flexibility is implied.  That seems to me the messaging going on in FDA's petition response to NORD.  And it's a message repeated by FDA’s Associate Director for the CDER Rare Diseases Program, Dr. Jonathan Goldsmith, who commented in a recent FDA Voice blog post that it is “important to note that FDA regulations provide flexibility in applying regulatory standards because of the many types and intended uses of drugs. Such flexibility is particularly important for treatments for life-threatening and severely-debilitating illnesses and rare diseases.”

By Riëtte van Laack & Etan J. Yeshua –

As we previously reported, when FDA announced a new compliance date for the menu labeling rule, it also announced that it would issue guidance.

On Friday, September 11, FDA issued the promised draft guidance.  The draft guidance is a mix of clarifications of the rule, and answers to certain questions.  Overall, the draft guidance appears to include little “new” information, though. A few noteworthy statements:

• The rule requires that covered establishments provide FDA, “within a reasonable period of time upon request,” with information substantiating nutrient values.  According to the draft guidance, FDA considers “4-6 week” a reasonable period of time to respond to such a request;
• If there is an inconsistency between declaration of nutrient values under the menu labeling rounding rules and under the TTB’s rounding rules for the voluntary Serving Facts on the label, covered establishments may use the value provided in the voluntary Serving Facts statement for an alcoholic beverage labeled consistent with TTB’s rather than with FDA’s rounding rules.
• The guidance includes a helpful table that lists types of establishments and identifies which establishments would and would not be considered “covered establishments.”  In response to questions, FDA clarifies that in-patient only food service facilities in hospitals and prisons are not covered establishments.  Also, complementary hotel breakfast buffets are not subject to the menu labeling rule.

The draft guidance is labeled as Part II.  FDA previously issued Part I.  However, that guidance is not available because the Agency is “revising this guidance document in order to make changes in light of FDA’s issuance of final rules.”  It is unclear when an updated version of Part I will be available. 

Stakeholders would be well-advised to review the draft guidance and submit remaining questions.  FDA invites comments to the draft guidance but, at this time, has not provided a deadline for comments to be considered in finalizing the guidance.  In the constituent update, FDA indicates that it will consider updates to the guidance as needed.  Likely as a result of critical reviews of the final rule and the threat of amending legislation, the Agency states that it is “committed to working collaboratively with establishments covered by the menu labeling final rule , . . . now and in the future, to answer additional questions” and FDA will “work flexibly and cooperatively with individual companies making a good faith effort to comply.”  FDA also plans to provide “educational and technical assistance for covered establishments and for our state, local, and tribal regulatory partners to support consistent compliance nationwide.” 

UPDATE: After we published this post, FDA announced that the deadline for comments to be considered in finalizing the guidance is November 2, 2015.”

By Kurt R. Karst – 

Last week, Senators Amy Klobuchar (D-MN) and Charles Grassley (R-IA) announced the introduction of S. 2019, the Preserve Access to Affordable Generics Act.  The bill is the latest attempt to pass legislation to address pharmaceutical patent settlement agreements (aka “reverse payment agreements” or “pay-for-delay agreements”).  It’s also the first attempt (that we can recall) that Congress has made to pass the Preserve Access to Affordable Generics Act after the U.S. Supreme Court declined to hold, in FTC v. Actavis, Inc., 133 S. Ct. 2233 (2013), that reverse payment settlement agreements are presumptively unlawful, and that “Courts reviewing such agreements should proceed by applying the ‘rule of reason,’ rather than under a ‘quick look’ approach” (see our previous post here).  Since that June 2013 decision, the Federal Trade Commission (“FTC”) has continued to battle with companies in court over patent settlement agreements, sometimes with success (see here and here).  The Supreme Court’s decision has also opened the door on a lot of antitrust litigation (see here).  Despite this uptick in litigation, however, companies continue to enter into patent settlement agreements.  Last December, the FTC issued its most recent report on the topic (see our previous post here), saying that Fical Year 2013 saw 145 final patent settlement agreements filed with the Commission.  This was is a small increase from Fiscal Year 2012, but the 2013 numbers do not account for any potential fallout from the Supreme Court’s decision in Actavis.  “The FTC has kept the pressure on, but Congress should act to end these twisted litigation settlements,” commented Senator Grassley in a press release announcing the introduction of S. 2019.

Unlike the last version of the Preserve Access to Affordable Generics Act, which reminded us of that old saying about insanity (i.e., that insanity is doing the same thing over and over again and expecting different result) (see our previous post here), the latest iteration of the bill changes thing up . . .  but just a little. 

Like the previous versions of the Preserve Access to Affordable Generics Act, S. 2019 would amend the FTC Act to add a new section – Section 27 – to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 27] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product” if “an ANDA filer receives anything of value, including an exclusive license” – a new addition to the bill – and if “the ANDA filer agrees to limit or forego research, development, manufacturing, marketing, or sales of the ANDA product for any period of time.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence” that “the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement,” or, in a new exception, if the value received “is compensation solely for other goods or services that the ANDA filer has promised to provide.”  Previous versions of the bill concerned only ANDA applicants, but in the latest version of the bill, the term “ANDA” is defined to include an application under FDC Act § 505(j) and an application under FDC Act 505(b)(2).  (The bill does not address patent settlement agreements in the context of biosimilar applications submitted to FDA pursuant to PHS Act § 351(k).) 

Gone from S. 2019 are certain “competitive factors” found in previous versions of the bill that fact finders were to consider in determining whether or not the settling parties met the presumption burden noted above.  Instead, fact finders are subject to certain limitations, which also appeared in previous versions of the Preserve Access to Affordable Generics Act.  Specifically, the fact finder shall not presume: (1) “that entry would not have occurred until the expiration of the relevant patent or statutory exclusivity”; or (2) “that the agreement’s provision for entry of the ANDA product prior to the expiration of the relevant patent or statutory exclusivity means that the agreement is pro-competitive, although such evidence may be relevant to the fact finder’s determination under this section.”

Also gone from S. 2019 is the section appearing in previous versions of the bill that the FTC may issue regulations implementing and interpreting the new statutory provisions that would be added by the Preserve Access to Affordable Generics Act.  Of course, the FTC may nevertheless issue implementing regulations if S. 2019 becomes law. 

With the exception of a few additional items, the remainder of S. 2019 is identical to previous versions of the Preserve Access to Affordable Generics Act.  For example, “[e]ach person, partnership or corporation that violates or assists in the violation of [new Sec. 27] shall forfeit and pay to the United States a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”  Also, an agreement that violates propsed Sec. 27 would result in a forfeiture of an ANDA applicant’s 180-day exclusivity eligibility.  (This last penalty would not apply to 505(b)(2) applicants because they are not eligible for – or subject to – 180-day generic drug exclusivity.)

One notable change from previous iterations of the bill is a statute of limitations providing that the FTC “shall commence any enforcement proceeding . . . not later than 6 years after the date on which the partiesto the agreement file” the required notice with the FTC.  Previous versions of the bill gave the FTC only 3 years to initiate an enforcement proceeding.  Another notable change is the addition in S. 2019 of an “Effective Date” provision.  That new provision provides that proposed Section 27(a)(1) concerning enforcement proceedings “shall apply to all agreements . . . entered into after June 17, 2013,” while proposed Section 27(f) concerning penalties “shall apply to agreements entered into on or after the date of enactment of [the Preserve Access to Affordable Generics Act].” 

S. 2019 has been referred to the Senate Judiciary Committee.  The bill will either sit and die in committee, or be taken up as a stand-alone bill or as part of a broader package of legislative proposals.

By Ricardo Carvajal & Riëtte van Laack –

FDA released pre-publication versions of the two final rules on current good manufacturing practice and preventive controls requirements – one governing human food (here), and the other animal food (here).  The pre-publication versions total over 1,500 pages, so will take a while to digest.  To help that process along, FDA has issued fact sheets summarizing the rules’ principal requirements (see here and here), and has scheduled webinars in mid-September and a public meeting scheduled to take place in Chicago on October 20.  In addition, the agency indicated that several guidance documents are forthcoming.

For human food, larger businesses will be expected to comply with CGMP requirements and most preventive control requirements by September 19, 2016, whereas small and very small businesses will have until September 18, 2017, and September 17, 2018, respectively.  However, under certain circumstances, FDA is allowing additional time for compliance with the supply chain program requirements of the rule.  For animal food, larger businesses will be expected to comply with CGMP requirements by September 19, 2016, and with most preventive controls requirements by September 18, 2017; small businesses will have an additional year after these dates, and very small businesses will have an additional two years after these dates.  FDA is also allowing additional time for compliance with the supply chain program requirements of the animal food rule, under certain circumstances.  The range of potentially applicable compliance dates is sufficiently complicated that FDA summarized them in tables included in the final rules (see p. 770 of the human food rule and pp. 556-557 of the animal food rule).

As we work our way through the final rules, we’ll highlight issues that catch our eye. 

The Expert Institute recently informed us that the organization is holding a “Best Legal Blog Competition” and that the FDA Law Blog has been selected to participate in the competition.  From a field of more than 2,000 potential nominees, FDA Law Blog has received enough nominations to join the 250 legal blogs participating in one of the largest competitions for legal blog writing online today. 

Now that the blogs have been nominated and placed into their respective categories, it is up to their readers to select the very best.  With an open voting format that allows participants only one vote per blog, the competition will be a good test of the dedication of each blog’s existing readers. 

Each blog will compete for rank within its category, while the three blogs that receive the most votes in any category will be crowned overall winners.  Voting has already started and closes at 12:00 AM on October 9th, at which point the votes will be tallied and the winners announced.  The competition can be found here.  FDALaw Blog is in the “Niche and Specialty” category.  Thanks for taking a couple of minutes out of your busy schedule to vote!

By Kurt R. Karst –   

It’s been a while since we peeked in on the appeals Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) and Elliott Associates, L.P.,  Elliott International, L.P. and Knollwood Investments, L.P. (collectively “Elliott”) filed with the U.S. Court of Appeals for the District of Columbia Circuit after District Court Judge Ketanji Brown Jackson issued an Opinion and Order in January 2015 upholding FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares.  There’s been some recent court docket activity to report on . . . and there’s more activity on the way in October. 

As we previously posted (here, , and ), Takeda is the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, which FDA approved to prevent and treat gout flares, and that is listed in the Orange Book with several unexpired patents.  The MITIGARE 505(b)(2) NDA did not cite COLCRYS as a listed drug relied on for approval, but rather a different drug: COLBENEMID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) FDA approved under NDA 012383 on July 27, 1961, that is no longer marketed, and for which no patents are listed in the Orange Book.  Takeda sued FDA alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects:

First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products.  Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.  And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process.  [(Emphasis in original)]

Later, Elliott, which has investment interests in COLCRYS, filed a separate Complaint alleging that FDA’s approval of the MITIGARE NDA violated the FDC Act and the APA because Hikma was required to certify to patents listed in the Orange Book for COLCRYS.

Judge Jackson dismissed each of the allegations and ruled for FDA (and Intervenor-Defendants Hikma and West-Ward).  She nicely summarized her ruling on pages 31-32 of her 80-page Opinion:

[T]his Court concludes that Plaintiffs are wrong to characterize FDA’s actions with respect to Mitigare as unauthorized, unsafe, or unreasoned; to the contrary, it is clear on the record presented that FDA’s approval of Mitigare was consistent with the FDCA, the regulations the agency has promulgated pursuant to the FDCA, the Citizen Petition Responses FDA has issued, and the policies and practices under which the agency operates.  Furthermore, the record clearly reveals the reasonableness of FDA’s expert determination that Mitigare is safe and effective as labeled, and it supports the agency’s conclusion that Mitigare’s labeling best reflects current scientific information regarding the risks and benefits of Mitigare—a conclusion that, in any event, is entitled to a high degree of deference.  Consequently, Plaintiffs have failed to establish that summary judgment should be entered in their favor on their APA claims, and this Court finds that Defendants are entitled to summary judgment as a matter of law.

For more in-depth commentary and analysis of Judge Jackson’s decision and the issues presented in the case, see our previous post here.

In their Opening Briefs (here and here) filed in the D.C. Circuit, Takeda and Elliott pitch their appeals as presenting issues that, if not resolved with a reversal of Judge Jackson’s decision, would upset the balance Congress intended to create with the passage of the Hatch-Waxman Amendments: the balance between brand-name incentives, on the one hand, and for prompt approval of high quality and lower-cost generic drugs, on the other hand. 

Springboarding from Judge Jackson’s explanation that it’s not FDA’s reliance on the investigations underlying another drug product that triggers the 505(b)(2) patent certification requirement, but only a 505(b)(2) applicant’s reliance, Takeda frames FDA’s approval of the MITIGARE NDA as violating the APA in at least two ways:

First, FDA approved Hikma’s 505(b)(2) application without requiring Hikma to reference Colcrys and to make the Paragraph IV certifications required by statute.  Under Hatch-Waxman, a 505(b)(2) applicant must certify to patents for each previously approved drug “relied upon by the applicant for approval of the application.”  FDA emptied the statute of effect by permitting an applicant to certify only to those drugs expressly named in its application—even if FDA uses an unnamed drug’s data to approve the application.  That is inconsistent with the statutory text, with common sense, and with FDA’s longstanding interpretation that an applicant must certify to any drugs without which “the application cannot be approved.” . . .  And it is clear that Colcrys was necessary to Mitigare’s approval, despite Hikma’s gerrymandering of its application to avoid mentioning Colcrys. . . .

Second, FDA acted arbitrarily and capriciously in approving Hikma’s 505(b)(2) application without requiring the Mitigare label to include critical safety information it had previously deemed essential.  After Mutual’s groundbreaking studies, FDA determined that information about dose adjustments and a low-dose colchicine regimen was mandatory for all single-ingredient oral colchicine products’ labels.  The Mitigare label omits both types of information.  FDA gave no reasoned explanation for allowing those omissions.  [(Emphasis in original; citations omitted)]

Elliott’s arguments on appeal are more straightforward:

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents was arbitrary and capricious because it violated FDA’s own binding regulation.  21 C.F.R. § 314.50(i)(1)(iii)(B) requires a 505(b)(2) applicant to file “an applicable certification” if “the labeling of the drug product for which the applicant is seeking approval includes an indication that” according to the Orange Book “is claimed by a use patent.” Mitigare’s label contained an indication for “prophylaxis of gout flares.”  Takeda’s Colcrys® use patents are listed in the Orange Book as claiming that very indication.  FDA’s binding regulation accordingly required Hikma to certify whichever of the following was “applicable”: that Takeda had not submitted patent information to FDA, that the patents were expired, or that they were “invalid, unenforceable, or will not be infringed.”  Hikma filed no certification, and FDA’s acquiescence was an unlawful violation of its own regulation. . . .

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents also violated Section 505(b)(2) itself.  The plain language of the statute requires a 505(b)(2) applicant to certify to “each patent … which claims a use for such drug for which the applicant is seeking approval under this subsection.”  The Colcrys® use patents claim the use of colchicine for prophylaxis of gout flares, the precise use of colchicine for which Hikma sought approval.

The Pharmaceutical and Research Manufacturers of America (“PhRMA”), in an amicus brief filed late last month, falls in line with the “upending Hatch-Waxman” theme in the Takeda and Elliott briefs, but PhRMA also addresses Judge Jackson’s interpretation of FDC Act § 505(b)(2) in a more general and overarching sense:

The district court’s decision undermines Hatch-Waxman’s grand bargain by permitting section 505(b)(2) applicants to obtain the Act’s benefits without shouldering any of the corresponding burdens.  Specifically, the district court concluded that a section 505(b)(2) applicant may obtain approval of a follow-on drug—without providing the required patent certification—by omitting any mention of the pioneer drug in its application and relying on FDA to fill in the blanks.  That interpretation cannot be squared with the Act’s structure and purpose. . . . 

The decision below also conflicts with FDA’s regulations and guidance.  First, the district court assumed that a section 505(b)(2) applicant “relie[s] upon” one and only one pioneer drug, but FDA has made clear that section 505(b)(2) applications may rely on more than one drug.  Second, the district court incorrectly concluded that a section 505(b)(2) applicant faces no constraints in deciding which pioneer drug (or drugs) it will “rel[y] upon.”  While applicants have some freedom of choice, FDA has limited that flexibility by concluding that a section 505(b)(2) application may implicitly rely upon a similar pioneer drug.  Third, the district court failed to observe the rule that a section 505(b)(2) applicant may rely on the fact of a pioneer drug’s approval, but not the confidential data underlying that approval. 

FDA’s Opening Brief is due to the D.C. Circuit on October 16, 2015, as is the brief of Hikma/West-Ward.  Takeda and Elliott Reply Briefs are due on October 30, 2015.  We’ll be particularly interested in any discussion from FDA of the Agency’s February 6, 2015 proposed rule implementing certain provisions of the 2003 Medicare Modernization Act (see our previous post here), and specifically FDA’s proposal “to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements.” 

By Kurt R. Karst –

The Order handed down last week by the U.S. Court of Appeals for the Federal Circuit denying Amgen Inc.’s (“Amgen’s”) Emergency Motion For An Injunction Pending En Banc Consideration and Review and Sandoz Inc.’s (“Sandoz’s”) September 3, 2015 launch of the first biosimilar licensed pursuant to the provisions added to the law by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) – a biosimilar version of Amgen’s NEUPOGEN (filgrastim) called ZARXIO (filgrastim-sndz) that FDA licensed on March 6, 2015 under BLA 125553 – are not events marking the end to controversy over various provisions of the BPCIA, but are merely waysides along a highway that may very well end with a decision from the U.S. Supreme Court.  Putting aside Amgen’s recent Emergency Motion (Sandoz’s Opposition Brief is available here), the Federal Circuit’s July 21, 2015 split panel decision (see our previous post here) upholding Sandoz’s position that the complicated exchange of information provisions known as the “patent dance” is a voluntary process that biosimilar (also referred to as an “aBLA”, or abbreviated Biologics License Application) applicants may or may not partake in, but also upholding Amgen’s position that a biosimilar applicant’s notice to the holder of the reference product of an intention to begin commercial marketing in 180 days can occur only after the biosimilar is licensed, has already led to hundreds of pages of briefing.  And there’s likely to be a lot more ink spilled as interested parties continue to chime in at the Federal Circuit. 

For starters, there are the August 20, 2015 Petitions For Rehearing En Banc filed by both Amgen and Sandoz (here and here).  Amgen and Sandoz take the positions one would anticipate them taking.  Amgen argues that the patent dance is a mandatory process, while Sandoz argues that providing 180-day notice of launch after biosimilar licensure (instead of beforehand) creates a new automatic injunction remedy that effectively grants a period of 180-day exclusivity for all biological products beyond what Congress expressly provided in the BPCIA.  On September 8, 2015, Amgen and Sandoz filed Responses (here and here) to one another’s Rehearing Petitions defending each company’s respective wins before the Federal Circuit panel.  According to Amgen, the BPCIA’s text is clear with respect to 180-day notice and the Federal Circuit Panel correctly held that PHS Act § 351(l)(8)(A) requires notice after FDA licensure of an aBLA.  Sandoz’s two arguments for why notice should not have to follow FDA licensure are flawed, argues Amgen:

First, Sandoz argues that notice at the time of FDA approval is superfluous, because FDA licensure is itself a public act.  But the required notice is notice of the timing of first commercial marketing, which cannot be presumed merely from the grant of a license.  It is also notice of the scope of that first commercial marketing: As the Panel noted, it is only upon FDA approval that “the product, its therapeutic uses, and its manufacturing processes are fixed.”

Second, Sandoz argues that the thirty-month stay of approval of a generic drug under the Hatch-Waxman Act confirms, by its absence in the BPCIA, that Congress did not intend litigation to delay approval or marketing of a biosimilar.  The absence of a thirty-month stay under the BPCIA confirms only that Congress did not pattern this part of the BPCIA after the Hatch-Waxman Act.  Instead of conditioning FDA licensure on the outcome or pendency of patent litigation, Congress linked the Applicant’s obligation to provide notice of commercial marketing to the event of FDA licensure.  This makes sense for a statute that uses a standard of biosimilarity, rather than identity, under which the ultimately approved product may differ from the reference product in its structure, manufacture, and uses. Whereas the Hatch-Waxman Act maintains the status quo through a thirty-month stay of FDA approval, the BPCIA vests in the district courts the authority to determine whether to preserve the status quo beyond the 180-day notice period through a preliminary injunction sought by the [Reference Product Sponsor].  Anticipating the increased burden and disruption this would create for the courts, Congress established a defined statutory window of no less than 180 days after FDA approval and before commercial marketing “during which the court and the parties can fairly assess the parties’ rights prior to the launch of the biosimilar product.”  [(Emphasis in original; internal citations omitted)]

According to Sandoz, Amgen’s arguments on the mandatory nature of the patent dance are flawed:

[The BPCIA’s amendments to the law] create artificial acts of infringement, enabling declaratory judgment actions before actual infringement is imminent.  Who can bring such an action, when, and for what relief depends on the actions or inactions of the applicant and the sponsor at each step of a multi-step patent-exchange process regarding the sponsor’s possible patent claims.  Congress carefully spelled out both the action the applicant or sponsor “shall” take as a condition precedent to continue the process, and if that party declines, what follows.  Each step has benefits and burdens for both parties.  Critically, the BPCIA provides no means to force either participant to take any of those steps.  Instead, each step is simply a procedural means to a substantive goal: resolving patent disputes so that biosimilars can be available to patients as soon as possible.

Lining up behind Sandoz are amici curiae Hospira, Inc., Celltrion Healthcare Co., Ltd. and Celltrion, Inc. (collectively “Celltrion”), Mylan Inc. (“Mylan”), and the Biosimilars Council (a division of the Generic Pharmaceutical Association consisting of companies and other stakeholders focused on issues relating to biosimilars). 

Celltrion, which is embroiled in litigation with Janssen Biotech, Inc. (“Janssen”) over a biosimilar version of Janssen’s REMICADE (infliximab) (see our previous post here) says in its brief that the Federal Circuit’s panel decision on 180-day notice “exceeds the judicial role contemplated by Congress in the BPCIA, and calls out for en banc review,” and warns that “[t]he decision has major implications for industry and consumers.” 

Amici file this brief to emphasize three points.  First, review is needed now.  Although the panel’s ruling addresses an issue of first impression, that issue is vital to the competitive structure of the biosimilar industry.  Litigation over the meaning of the ruling continues in the lower courts; further percolation will not advance the law; and settling the issue will spur competition.

Second, the ruling flouts the [BPCIA’s] text and Congress’s purpose in passing it.  In the panel’s view, a potential second phase of litigation—which involves patents that only the sponsor deems relevant—cannot even begin until after FDA approval.  But as even the Biotechnology Industry Organization (“BIO”) has noted, the Act is designed “to identify and resolve patent issues before a biosimilar is approved.” 

Third, the ruling conflicts with a host of cases. . . governing when courts may recognize a private right of action or extra-statutory remedy.  That precedent bars the automatic, bondless injunction entered here—one that not only was granted without any findings that satisfy the traditional requirements for equitable relief, but is unmoored from any patent rights.  [(Internal citation omitted)]

Mylan, which reportedly has “a robust pipeline of biologic products in development, both for the global marketplace and to be submitted for licensure in the United States as biosimilar products under the [BPCIA],” says in its brief that rehearing and reversal of the panel decision on 180-day notice are necessary: 

The majority’s interpretation distorts the statutory scheme, contradicts the plain language, and would produce “real world” outcomes contrary to Congress’ intent.  The consequences cannot be overstated: the majority interpretation would necessarily, in every case where notice is provided, extend the reference product’s monopoly six months past the 12-year market exclusivity Congress granted.  This exclusivity extension, implied from a simple notice provision, disrupts the statutory bargain and improperly delays competition. [(Internal citation omitted)]

Finally, the recently launched Biosimilars Council says in its brief that the Federal Circuit’s panel decision on 180-day notice should not stand:

The panel’s incorrect reading of (l)(8)(A) converts notice into the trigger for an automatic six-month injunction against the marketing of a licensed biosimilar, sub silentio extending to 12 ½ years Congress’s carefully crafted 12-year reference product exclusivity.  This automatic, extra-statutory delay, if left uncorrected, would broadly undercut Congress’s goal of greater competition in biologics markets and dramatically reduce savings to the U.S. healthcare system from biosimilars.  This Court en banc must correct a reading of the BPCIA that Congress could not have intended and that will delay millions of patients’ access to needed treatments. . . .

The clear meaning of 42 U.S.C. § 262(l)(8)(A) is that notice provided under that subsection must occur at least six months “before the date of the first commercial marketing” of the relevant biosimilar, without limiting when notice can first be given.  However, the majority effectively rewrote this straightforward notice requirement to dictate both the earliest and the latest possible time for notice.

The panel’s reading is incorrect because the word “licensed” is clearly intended to modify “the product” that is the subject of notice and not to circumscribe the timing of notice.  Congress used the past-tense “licensed” because the right to commercially market a product, regardless of when notice is given, only exists after FDA licensure.  In other words, the statute simply provides for notice that the applicant intends to market its product once it has been “licensed,” not to limit the earliest date notice can be provided.

There may be a lineup of amici curiae behind Amgen, perhaps including BIO and Janssen, in the days and weeks ahead as we travel further down the highway in this litigation to another wayside.   

By Kurt R. Karst –      

Finger through the “Discontinued Drug Product List” section of the Orange Book and youl’ll quickly realize that there are a lot of drug products no longer marketed.  The “Discontinued Drug Product List” spans 337 pages in the current annual edition of the Orange Book, and more drug products are added each month with the Cumulative Supplement.  You see the additions when the term “DISC” (defined as “Discontinued. The Rx or OTC listed product is not being marketed and will be moved to the discontinuedsection in the next edition.)” is added to a particular drug product listing.  The “Discontinued Drug Product List” encompasses several categories of drugs.  As explained in the Orange Book Preface, it is “a cumulative list of approved products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing.” 

There are various reasons why a company may discontinue marketing a drug product.  Perhaps a brand-name manufacturer has lost interest in a product because of generic competition and loss of market share.  Or perhaps a company obtains approval of an ANDA and is not ready to market the drug because of ongoing patent infringement litigation or because of a settlement agreement that sets a marketing date that is years away.  In either case, the application is put into a coma-like state; it is effectlvely mothballed. 

But just as humans can awake from a coma after many years (here and here), so too can a drug.  Every once in a while you see the notation “CMFD” added to a monthly Orange Book Cumulative Supplement.  That notation is defined as “Change.  The product is moved from the Discontinued Section due to a change in marketing status.”  And just as there are various reasons why a company may discontinue a drug product, there are also several reasons why a drug product may be re-marketed.  For example, perhaps ownership in an NDA or ANDA has been transferred and the purchasing company intends to re-introduce the drug to the market.  In some cases, the approval for a product in the discontinued list has been withdrawn, and it will therefore never awaken from its coma.  (Though the drug can serve as a Reference Listed Drug for an ANDA applicant, provided FDA determines that the brand-name drug was not withdrawn for safety or effectiveness reasons – see our previous post here). 

For many years, the process of moving a drug from the “Discontinued Drug Product List” to the “Prescription Drug Product List” or to the “OTC Drug Product List” – i.e., from “DISC” to CMFD” – was relatively simple.  A company would notify FDA of the change and it would occur.  That changed, however, a couple of years ago after there was “an incident” (about which we don’t know the details) with a drug that was re-marketed after spending some time on the “Discontinued Drug Product List.”  Afterwards, FDA developed a more formal process for when a sponsor wants to have a drug product removed from the “Discontinued Drug Product List.”

When a sponsor notifies FDA that the company intends to remarket a dormant drug, the sponsor will probably receive correspondence from FDA asking a few questions.  That correspondence might look something like this:

Please submit a general correspondence to the application and a courtesy email copy to the Orange Book general inbox (DrugProducts@cder.fda.gov) with the following information:

1) What is the launch date of the product?
2) How long has it been off the market?  When was it last manufactured?
3) Has there been a transfer of ownership since the last manufacturing date?
4) Is the product using the same API supplier/facility, drug product manufacturer/facility and drug manufacturing process/equipment?
5) Will a supplement be needed before the product can be marketed?

We encourage you to submit your request two months before the launch date to allow the Orange Book to process your request in a timely manner.

A company’s responses to these questions ahead of a change to marketing status in the Orange Book gives FDA some cushion to evaluate the re-marketing situation for a particular drug (and presumably, to determine whether or not such a change is appropriate given the particulars of a case).