By Riëtte van Laack –

On Nov. 13, 2014, DOJ announced another Consent Decree of permanent injunction regarding the manufacture and distribution of dietary supplements.

Under the Consent Decree, contract manufacturer SciLabs, Inc. and its CEO Paul Edalat are prohibited from the manufacture and distribution of dietary supplements until FDA has determined that the company is in compliance with the dietary supplement GMPs.

According to the complaint, inspections in 2012, 2013, and 2014 revealed that SciLabs violated the dietary supplement GMP requirements causing the dietary supplements, distributed under the brand All Pro Science, to be adulterated.  In January 2013, FDA issued a Warning Letter alleging numerous violations of the GMP requirements observed during the 2012 inspection.  FDA claims that SciLabs expressed its intent to comply but the company did not provide documents to support the corrective actions.  Moreover, according to DOJ, the company failed subsequent inspections in 2013 and 2014.  Based on this record, DOJ concluded that “unless restrained by [the] Court, Defendants [would] continue to violate” the GMP requirements. 

The Consent Decree appears to, at least temporarily, put the company out of business.  The company must recall and destroy all products manufactured since August 2012 and any inventory.  In addition, the company must shut down until it has taken all required corrective actions and FDA confirms, in writing, that the company is in compliance.  The Consent Decree specifies that, if the company wants to reopen, it must hire an independent GMP expert to help with compliance issues.  The expert must certify to FDA that the company has corrected all deficiencies and is in compliance with GMP requirements.  Only once FDA confirms that it agrees with the expert may the company reopen for business.  In addition, SciLabs must “have paid all costs of FDA’s inspections, investigations, supervision, analyses, examinations, and reviews.”

Once the company resumes manufacturing, it must retain an independent expert to conduct audit inspections at least every 6 months for a period of five years.  

Earlier this year, at least three other dietary supplement manufacturers entered into similar consent decrees (see here, here, and here).  Similar to SciLabs, those companies allegedly failed several inspections and, all but one, received a warning letter alleging violation of GMPs but, according to FDA, failed to take the appropriate corrective actions. 

These cases show that FDA will aggressively pursue violators of the dietary supplement GMP requirements.   Because the consent decrees include a recall provision, a shut-down provision, and a requirement that FDA confirm that they are in compliance before they can reopen, the companies may well end up being put out of business permanently. 

FDA does not bring a lot of injunction cases per year.  Four (or more) injunctions related to dietary supplement GMP suggests that this area is a high enforcement priority for the Agency.

By Kurt R. Karst –       

Earlier this week, Mallinckrodt Inc. (“Mallinckrodt”) filed a Complaint and Motion for Temporary Restraining Order (later supplemented) in the U.S. District Court for the District of Maryland challenging FDA’s November 12, 2014 decision to downgrade from “AB” to “BX” the Therapeutic Equivalence (“TE”) rating for the company’s generic version of CONCERTA (methylphenidate HCl) Extended-Release Tablets, 27 mg, 36 mg, and 54 mg, which the Agency approved on December 28, 2012 under ANDA 202608.  FDA also downgraded the TE rating for another generic version of CONCERTA approved on July 9, 2013 under ANDA 091695 and marketed by Kudco Ireland Ltd.  Both drugs were downgraded after FDA issued a revised ANDA bioequivalence guidance earlier this month, and after FDA stated, based on “[a]n analysis of adverse event reports, an internal FDA re-examination of previously submitted data, and FDA laboratory tests,” that the generic versions of CONCERTA “have raised concerns that the products may not produce the same therapeutic benefits for some patients as [CONCERTA].”  FDA has asked both ANDA sponsors to either confirm, within 6 months, the bioequivalence of their products using the Agency’s revised bioequivalence standards, or voluntarily withdraw their products from the market.

By way of background, TE ratings are used to determine the substitutability of two drug products.  Pharmaceutically equivalent prescription drug products (i.e., generally drug products in the same strength, route of administration, dosage form, and containing the same active ingredient) are identified in the Orange Book with either an “A” or “B” therapeutic equivalence code designation.  “A-rated” drug products are considered to be to therapeutically equivalent to other pharmaceutically equivalent products, because there are no known or suspected bioequivalence problems, or such problems have been resolved with adequate evidence supporting bioequivalence.  “B-rated” drug products are not considered to be therapeutically equivalent to other pharmaceutically equivalent drug products, because actual or potential bioequivalence problems identified by FDA have not been resolved by adequate bioequivalence evidence. 

Drug products assigned an “A” rating fall under one of two categories: (1) those active ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, and for which bioequivalence to the Reference Listed Drug (“RLD”) is presumed and considered self-evident based on other data in an application or by a showing that an acceptable in vitro dissolution standard is met; or (2) those active ingredients or dosage forms presenting a potential bioequivalence problem, but the applicant’s approved application contains adequate scientific evidence establishing (through in vivo and/or in vitro studies) the bioequivalence of the product to a selected RLD.  Drug products that fall under the first category are assigned a therapeutic equivalence code depending on the dosage form.  These codes include “AA,” “AN,” “AO,” “AP,” or “AT.”  Drug products that fall under the second category are coded “AB” (the most common code assignment).

Drug products assigned a “B” rating are designated “BC,” “BD,” “BE,” “BN,” “BP,” “BR,” “BS,” “BT,” “BX,” or “B*,” generally according to dosage form.  According to the Orange Book Preface, a “BX” code is “assigned to specific drug products for which the data that have been reviewed by the Agency are insufficient to determine therapeutic equivalence under the policies stated in this document.  In these situations, the drug products are presumed to be therapeutically inequivalent until the Agency has determined that there is adequate information to make a full evaluation of therapeutic equivalence.”

In recent year, FDA actions concerning TE ratings have been the focus of some controversy – generally in the context of 505(b)(2) applications – with a couple of Citizen Petitions and a lawsuit against FDA (see our previous posts here and here).  FDA also downgraded the TE ratings, and then withdrew the approvals, of two ANDAs for Bupropion Hydrochloride Extended-Release Tablets, 300 mg, after concerns about therapeutic equivalence were raised (see here and here).

According to Mallinckrodt, FDA’s TE rating downgrade for generic CONCERTA effectively takes the drug off the market because TE ratings are used in many states (see here) for purposes of substitution.  “That determination by FDA means that (depending on the jurisdiction) it is either unlawful or unacceptably risky for pharmacists to fill a prescription by substituting Mallinckrodt’s generic for the brand-name drug Concerta®,” says Mallinckrodt. 

Mallinckrodt also alleges that FDA exceeded its statutory authority by effectively taking the company’s drug off the market without providing Mallinckrodt with a hearing. “The FFDCA provides only one mechanism for taking a generic drug off the market: withdrawing (or suspending) ANDA approval under 21 U.S.C. § 355(e). . . . FDA has no statutory authority to take a drug off the market through other actions not specified in section 355(e).”  Citing the DC Circuit Court’s recent decision in Ivy Sports Medicine, LLC v. Burwell, 767 F.3d 81 (D.C. Cir 2014), pet. for reh’g en banc filed Nov. 11, 2014 (see our previous post here), Mallinckrodt says that that conclusion “flows directly from a recent D.C. Circuit decision construing the parallel statutory requirements governing FDA’s authority to remove a medical device from the market (following an earlier FDA decision that authorized marketing the device).”

Mallinckrodt asserts that FDA’s action has violated the company’s rights under the Fifth Amendment to the U.S. Constitution.  “The statutory hearing rights . . . derive from an underlying constitutional right to notice and a hearing guaranteed by the Fifth Amendment’s Due Process Clause. . . .  When it reclassified Mallinckrodt’s methylphenidate ER, FDA eviscerated the company’s property right in its ANDA by effectively taking the drug of the market.  FDA had no constitutional authority to impair Mallinckrodt’s property right without giving Mallinckrodt notice and an opportunity to be heard.”

Mallinckrodt’s five-count Complaint seeks both injunctive and declaratory relief from the court, including an injunction setting aside FDA’s actions, and prohibiting its future actions, and a declaratory judgment declaring that FDA has acted unlawfully. 

Update:

• On November 19th, the court issued a notice confirming that a hearing on Mallinckrodt's Motion for Temporary Restraining Order is scheduled for Tuesday, November 25, 2014, at 9:00 AM before Judge Deborah K. Chasanow.  FDA's Opposition is due by 4 p.m. on November 20th.

By Allyson B. Mullen –

Late last week, the Department of Justice ("DOJ") obtained criminal charges from a grand jury sitting in the United States District Court for the Western District of Texas against Vascular Solutions, Inc. ("VSI") and Howard Root, VSI’s CEO, for off-label promotion of the company’s Vari-Lase devices.  The Indictment alleges a conspiracy to defraud the U.S. government, along with distributing adulterated and misbranded medical devices. 

According to the Indictment, this case involves VSI’s promotion of its Vari-Lase laser ablation devices, which includes lasers, consoles, needles, fibers, sheaths, and other accessories.  The Vari-Lase devices were cleared for treatment of superficial veins.  VSI did not have clearance for treatment of perforator veins.  In 2006, however, a competitor of VSI’s obtained clearance for treatment of perforator veins. 

In response to this clearance, the government alleges that VSI began systematically promoting Vari-Lase for treatment of perforator veins.  In fact, the Indictment claims that VSI created a new “Short Kit,” a modified version of the cleared device that was specifically intended for perforator vein treatment.  The Indictment alleges that VSI unsuccessfully sought 510(k) clearance of the Short Kit, which included an expanded indication for a use that would have included perforator veins.  The Indictment further alleges that the company performed a clinical study of perforator vein treatment with laser ablation that showed poor safety and effectiveness.  Nevertheless, the government contends that VSI promoted the Short Kit and other Vari-Lase devices for the off-label intended use of perforator vein treatment. 

The Indictment goes on to allege that Mr. Root oversaw and encouraged the entire promotional campaign.  In addition, the government claims that Mr. Root was responsible for reviewing and approving various key training materials that were essential to the company’s off-label promotional activities.  The Indictment specifically claims that VSI and Mr. Root’s promotional practices were misleading because they misrepresented and concealed relevant facts regarding the Short Kit, including, telling physicians that Medicare would reimburse for perforator vein procedures performed with VSI’s devices.

As of now, we have only heard the government’s side of the case, and as we all know, there are almost always two sides to every story.  It is worth noting that this is the second case against the company on these facts this year.  According to the DOJ news release, in July of this year, VSI settled a civil case with the government, in which VSI paid $520,000 “to resolve allegations that it caused false claims to be submitted to federal health programs by marketing a medical device for the ablation (or sealing) of perforator veins without FDA approval and despite the failure of its own clinical trial.”  The civil case appears to relate to the same marketing practices that form the basis of the criminal case that was initiated last week. 

The civil case was brought in the Western District of Texas, which is the same venue where the criminal case was filed.  This is of particular note because it is representative of how the government often investigates and brings criminal cases against drug and device companies.  When a relator brings a qui tam case, the government often conducts a criminal investigation in the very same judicial district, whether or not the company is based in that district.  In fact, quite often these days the decision regarding which judicial district will conduct a criminal investigation and possible criminal prosecution is often based solely on where the relator’s counsel is based.  Qui tam counsel will often file cases in a judicial district where they live, not where the company is headquartered or even where their own client lives. 

This forum shopping starkly contrasts with “the old days” when FDA criminal cases were almost always brought in the company’s principal place of business.  This trend is troubling for companies because they are being forced to travel around the country defending against not only civil, but now also criminal cases.  This is another reminder of why there can be painful consequences when companies are investigated for off-label promotion practices.

By Michelle L. Butler & Alan M. Kirschenbaum –

On November 13, 2014, the Health Resources and Services Administration (“HRSA”) withdrew the 340B program “mega-rule” it had submitted for review to the Office of Management and Budget.  In a previous blog post we reported on a federal court decision vacating HRSA’s regulation implementing the orphan drug exclusion under the 340B program.  The court had ruled that the statute did not grant HRSA authority to issue regulations on the orphan drug exemption.  Although that case did not directly involve the mega-rule, HRSA has apparently concluded, as we foresaw in our blog post, that the holding in that decision also would preclude the issuance of the mega-rule.  (See here for an update on HRSA’s orphan drug rule.  We note that a scheduling order was just entered with summary judgment briefing to conclude in March 2015.) 

In place of the mega-rule, it appears that HRSA intends to issue guidance, as it has traditionally done in the past.  On its website,  HRSA states: “In 2015, HRSA plans to issue a proposed guidance for notice and comment that will address key policy issues raised by various stakeholders committed to the integrity of the 340B program.  HRSA is also planning to issue proposed rules pertaining to civil monetary penalties for manufacturers, calculation of the 340B ceiling price, and administrative dispute resolution.”  It is safe to assume that the proposed guidances will, at a minimum, address the topics that were originally intended to be included in the mega-rule – i.e., the definition of an eligible patient; compliance requirements for contract pharmacy arrangements; hospital eligibility criteria; and eligibility of off-site facilities.

By Kurt R. Karst –      

Last Friday, Ranbaxy Laboratories, Ltd. and Ranbaxy, Inc. (“Ranbaxy”) filed a Complaint and a Motion for a Temporary Restraining Order and Expedited Preliminary Injunction in the U.S. District Court for the District of Columbia challenging FDA’s November 4, 2014 Letter Decision stripping Ranbaxy of tentative approvals for the company’s ANDAs for generic versions of VALCYTE (valganciclovir) Tablets, 450 mg (Ranbaxy ANDA 078078), and NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg (Ranbaxy ANDA 077830).  In that same decision, FDA ruled that Ranbaxy forfeited eligibility for 180-day exclusivity for Valganciclovir Tablets pursuant to FDC Act § 505(j)(5)(D)(i)(IV) because Ranbaxy failed to obtain timely tentative approval within 30 months of ANDA submission.  As we previously reported, FDA approved two ANDAs for generic VALCYTE – one from Dr. Reddy’s Laboratories (ANDA 203511), and another from Endo Pharmaceuticals (ANDA 200790) – after stripping Ranbaxy of its tentative approval and cxclusivity eligibility.

FDA states in the November 4, 2014 Letter Decision that the Agency rescinded the tentative ANDA approvals because of the compliance status of the facilities identified in the ANDAs.  Specifically, FDA states:

At the time of FDA’s February 5, 2008 [tentative approval] letter [for Esomeprazole Magnesium Delayed-release Capsules, 20 mg and 40 mg], the Paonta Sahib facility had been the subject of a Warning Letter issued on June 15, 2006, based on the CGMP violations observed during FDA’s February 20-25, 2006 inspection at the Paonta Sahib facility and taking into account Ranbaxy’s March 20, April 20, and May 25, 2006 responses.  Accordingly, at the time of the tentative approval letter, the compliance status of the Paonta Sahib facility was Official Action Indicated (OAI), which is an inspection conclusion reflecting that “objectionable conditions were found and a regulatory action is recommended.”  Under such circumstances, Center for Drug Evaluation and Research Office of Compliance (CDER Compliance) will not recommend approval.  The overall compliance status for ANDA 077830 was “withhold,” and the ANDA should not have been tentatively approved at that time due to the inspectional status. . . .

At the time of FDA’s June 20, 2008 [tentative approval] letter [for Valganciclovir Hydrochloride Tablets USP, 450 mg], the Dewas facility had been the subject of a January 28 – February 12, 2008 inspection that found significant deviations from CGMP in the manufacture of sterile and non-sterile finished products and in the manufacture and control of APIs, and that resulted in the issuance of a Warning Letter on September 16, 2008.  The Paonta Sahib facility had been the subject of the Warning Letter issued on June 15, 2006, and the Paonta Sahib Batamandi (Unit II) facility had been the subject of a March 3-7, 2008 inspection that found many significant deviations from CGMP in the manufacture of finished drug products, and that resulted in the issuance of a Warning Letter on September 16, 2008.  Accordingly, at the time of the tentative approval letter, the compliance status of the Dewas facility was “potential” OAI and the status of the Paonta Sahib facility was “OAI” and the ANDA should not have been tentatively approved at that time due to the inspectional status.

Ranbaxy alleges in its court filings that “FDA has no power to correct an alleged ‘mistake’ it made six years ago,” that “FDA’s Letter Decision conflicts with the plain language of the statute’s failure-to-obtain TA forfeiture trigger, which merely requires the first-filer to receive a TA letter from the Agency within the 30-month deadline,” and that “FDA’s Letter Decision cannot be squared with the plain text and structure of the statutory provisions that set forth the exclusive requirements for obtaining TA, on one hand, and final approval, on the other.”

A hearing on Ranbaxy’s Motion for a Temporary Restraining Order is scheduled for November 19th at 2:00 PM.  Both Dr. Reddy’s (represented by Hyman, Phelps & McNamara, P.C.) and Endo have intervened in the case.

By Douglas B. Farquhar –

For years, one of the frustrations for attorneys challenging FDA in court (including us, many times) has been the degree of deference that federal courts have accorded to FDA interpretations of the Federal Food, Drug, and Cosmetic Act.  This happens when FDA says that FDCA provisions are ambiguous, and a court agrees.  But a recent and unusual statement by U.S. Supreme Court Justice Antonin Scalia (joined by Justice Clarence Thomas) invites the right party, in the right civil case, to challenge a federal agency’s interpretation of ambiguous provisions of a statute, like the FDCA, that address both criminal and administrative violations.  The statement may not only open the door – but illuminate the path – for a successful challenge, in a civil or administrative enforcement case, to FDA interpretations of FDCA provisions that have both administrative enforcement and criminal implications.  And there are plenty of provisions like that.

Historically, the so-called “rule of lenity” prohibits agency interpretations from turning ambiguous criminal statutory provisions into an acceptable basis for sending people to prison.  The principle is that it is unfair to impose harsh sanctions on an individual when an individual, examining the governing law, could reasonably believe that he or she was allowed to do what he or she did.

Douglas F. Whitman, the defendant in the case that was the subject of the recent statement by Justice Scalia, had been convicted of a violation of federal law, as interpreted by the Securities and Exchange Commission.  He appealed his conviction.  The Second Circuit Court of Appeals affirmed his conviction, deferring to the SEC on an interpretation of the relevant provision of the Securities Exchange Act.  Justice Scalia, agreeing with the decision that the Supreme Court should not further review the case (Whitman had filed a petition for a writ of certiorari), noted that the decision of the Second Circuit was consistent with numerous prior decisions in which courts “have deferred to executive interpretations of a variety of laws that have both criminal and administrative applications.”  But Justice Scalia questions whether those cases were correctly decided.  Is it appropriate, he asks, to apply a rule of lenity with regard to application of ambiguous laws in criminal cases (thus allowing courts to decide on their own whether statutory provisions are ambiguous, and to interpret statutes as they deem fit, even when in conflict with the agency interpretation), but to make courts follow the agency say-so when the same provisions are applied in administrative decisions?  Those decisions, in Justice Scalia’s view, are contrary to “many cases” holding that a law with “both criminal and civil applications” should apply a rule of lenity “in both settings.”  If the “rule of lenity” were applied to the FDCA in the civil setting, that could mean, for example, that the court and the relevant parties would not be compelled to accept FDA’s interpretation in an FDA enforcement action brought in federal court – such as a seizure of drugs or medical devices that FDA contends are adulterated, or an injunction against a company or an individual under like circumstances.

Justice Scalia did not think that the Whitman case was the appropriate platform to address these issues, because of the “procedural history of the case.”  But he is explicitly sending a signal that he wants the Supreme Court to address the issue of whether agencies are entitled to deference “when a petition properly presenting the question comes before us” – even in a civil setting (when, for example, an affected party challenges an agency enforcement decision).  In a blogpost discussing a prior Supreme Court decision, we asked the same question about interpretations of ambiguous statutory provisions that have both criminal and administrative implications.

None of the cases cited by Justice Scalia dealt with provisions of the FDCA, but it is hard to think of a reason that the same principles he discusses would not apply to the FDCA.  Courts frequently defer to FDA on interpretations of the FDCA, especially in cases dealing with the Hatch-Waxman Amendments (see, e.g., Apotex, Inc. v. FDA, 414 F. Supp. 2d 61 (D.D.C. 2006); Purepac Pharm. Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004)), but also in at least one case about whether dietary supplements are adulterated.  This violation could result in criminal liability for distribution of adulterated dietary supplements (under Section 301(a) of the FDCA, 21 U.S.C. § 331(a)).

Justice Scalia’s invitation should not be ignored by an FDA-regulated company or individual who wants to challenge, for example, an enforcement action taken on the basis of an ambiguous provision of the FDCA, where that provision has criminal, as well as administrative, implications.  Judge Scalia is wondering whether it makes sense for a court not to defer to an agency interpretation of an ambiguous statutory provision in the criminal context, but to defer to the same agency interpretation of the same provision in the civil or administrative context.  Maybe that does not make sense.

By Andrew J. Hull* & William T. Koustas –

With the January 1, 2015 implementation of the Drug Supply Chain Security Act (DSCSA) looming over the heads of both FDA and industry, the Healthcare Distribution Management Association (HDMA) held its annual track-and-trace conference November 10-12, 2014.  Foremost on everyone’s mind was the pending and highly anticipated draft guidance from FDA—due on November 27th—regarding implementation of the new law and the creation of a national database for monitoring drug transactions throughout the supply chain.  Throughout the conference, manufacturers, distributors, and other members of the drug supply chain expressed concern over the current lack of guidance from FDA regarding compliance with federal product tracing laws with only 49 days until the DSCSA is set to begin to take effect.

Dr. Connie Jung, Acting Associate Director for Policy and Communications for the Office of Drug Security, Integrity, and Recalls in FDA’s Center for Drug Evaluation and Research, Office of Compliance, once again spoke at the conference and attempted to address some of their concerns.  Dr. Jung suggested that FDA expects supply chain members to begin complying with the DSCSA on January 1st, but was less confident about FDA’s ability to release the long-awaited draft guidance on time.  Dr. Jung stressed that FDA is diligently working to produce the draft guidance by the November 27th statutory deadline (Thanksgiving Day), but she was very reluctant to commit to the timing of its release.  Dr. Jung was less reluctant with regard to the development of the wholesaler and third-party logistics provider (3PL) databases.  She was much more confident that these databases would be running by the statutory deadlines, January 1st and November 27threspectively.

Dr. Jung also addressed numerous questions in a lively Q&A session.  Most significantly, she hinted that FDA would likely view an advanced shipment notification (ASN) system as an appropriate system to pass tracing information required under the DSCSA, and she stated that FDA would have to issue further guidance regarding proper reporting requirements for potentially fraudulent transactions.

Another highlight of the HDMA conference was HDMA’s own discussion and analysis of the federal preemption issues and ongoing state initiatives to comply with the DSCSA.  Specifically, HDMA expressed its opinion that the DSCSA preemption provision for wholesale distributor and 3PL licensing set both a floor and ceiling on state law licensing requirements, similar to the DSCSA’s preemption of state pedigree laws.  This analysis seems to run counter to FDA’s interpretation (see our previous post here) that indicates that states must only meet the minimum standards set forth by federal law.  HDMA also stated that several states (AZ, CA, CO, FL, ID, KS, MD, OK, OR, and VA) have already begun the process of updating existing licensing laws.  Most states, however, seem to be waiting for FDA to issue regulations before revising their own laws.

All in all, the members of the drug supply chain at the HDMA conference represented a level of anxious anticipation for more specific direction from FDA regarding the drug-tracing provisions of the DSCSA and a feeling that they will be more than thankful if the draft guidance actually comes as promised on Thanksgiving Day.  We here at HPM will continue to watch for the pending draft guidance and keep you posted with any new developments over the next couple of weeks.

* Not admitted in D.C.  Work supervised by the Firm while D.C. application pending.

By James E. Valentine* & James C. Shehan – 

On November 4, 2014, FDA’s Office of Health and Constituent Affairs and an Agency-wide working group posted a notice requesting comments generally on all its various patient engagement activities and specifically on FDASIA Section 1137— the provision on Patient Participation in Medical Product Discussions.

Section 1137 directs FDA to “develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions, including by—(1) fostering participation of a patient representative who may serve as a special government employee in appropriate agency meetings with medical product sponsors and investigators; and (2) exploring means to provide for identification of patient representatives who do not have any, or have minimal, financial interests in the medical products industry.”

The FDA Patient Representative Program allows patients and caregivers to become Special Government Employees (SGEs) and thereby participate in advisory committee meetings about medical products and serve as consultants to review divisions to provide input at FDA-sponsor meetings during the clinical development process.  The Program’s genesis was the HIV/AIDS activism movement in the 1980’s and it was expanded and made formal by President Clinton’s cancer initiative in the 1990’s.  According to Heidi Marchand, Pharm.D., FDA Assistant Commissioner for Health and Constituent Affairs, whose office administers the Patient Representative Program, since 2012, Patient Representatives have served on advisory committee meetings for over 150 medical products and participated in 22 FDA-sponsor product development meetings.

This notice comes on the heels of a flurry of recent activity in the arena of patient advocacy in medical product development and review, albeit not activity specifically focused on Sec 1137.  In October alone, FasterCures, BIO, NORD, and DIA hosted meetings and workshops to discuss the role of patient engagement with industry and FDA.  CTTI has embarked on a project to understand best practices for effective engagement with patient groups around clinical trials (see here).  Meanwhile, on Capitol Hill, the proposed 21st Century Cures legislation continues to contemplate expanding the role of patients in the medical product development process (see our previous post here).  In addition, FDA has spent the last couple of years piloting new initiatives to more systematically collect patient input (i.e., CDER/CBER Patient-Focused Drug Development, CDRH Patient Preferences Initiative).  Each of these efforts seeks to find ways for the patient voice to be better heard. 

FDA’s Federal Register notice is worded broadly and seeks input on all of its patient engagement activities, not just those specified in Section 1137, recognizing that all the tools for obtaining the patient perspective collectively contribute to FDA’s understanding of the patient perspective. 

While not its exclusive focus, the newly established public docket represents an opportunity to weigh in on FDA’s implementation of Section 1137 via the Patient Representative Program.  For those interested in providing comments, this public docket (here) is open until December 4, 2014.

MassBIO is hosting a Patient Advocacy Summit on November 10th (agenda here) where HP&M’s Jim Shehan will be participating in a panel on access issues.

*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.

By Michelle L. Butler –

We previously reported that FDA had filed a notice of appeal in Depomed Inc. v. U.S. Department of Health and Human Services et al., Case No. 1:12-cv-01592.  In another turn of events, on November 6, 2014, FDA filed an unopposed motion to dismiss the appeal.  The motion was granted and the appeal was dismissed by the Court of Appeals for the D.C. Circuit on November 7, 2014.  The Order from the Court of Appeals was docketed in the District Court’s docket on November 10, 2014. 

Apparently FDA has decided it will operate its orphan drug program within the strictures of the Depomed decision.  What effect this will have on other aspects of the program remains to be seen.

By Jamie K. Wolszon & Jeffrey N. Gibbs –

On November 6, Alberto Gutierrez, the head of the office in charge of regulating in vitro diagnostics at FDA’s Center for Devices and Radiological Health (CDRH), discussed the two Laboratory-Developed Test (LDT) draft guidances with members of a federal advisory committee devoted to laboratory issues.  (We previously reported on the draft guidances, which FDA released on October 3, here and here).  Dr. Gutierrez fielded several questions from the advisory panel members, and –even though he was interrupted by fire alarms–provided some additional insights on how the agency plans to regulate LDTs, although a plethora of questions remain to be answered.

Dr. Gutierrez, Director, Office of In Vitro Diagnostics and Radiological Health (OIR), at CDRH, discussed the draft guidances during the second day of the November 5-6 Clinical Laboratory Improvement Advisory Committee (CLIAC) meeting in Atlanta, Georgia.  CLIAC, which is managed by the Centers for Disease Control and Prevention (CDC), provides scientific and technical advice and guidance to the Department of Health and Human Services (HHS) related to laboratory issues.  The CLIAC discussion comes on the heels of an October 23 FDA webinar on the topic (previously blogged on here). 

Key points include:

• No Premarket Review Grace Period for New Highest-Risk LDTs Introduced after Final Guidance Issued.  Dr. Gutierrez stated that the need for premarket review for new LDTs that fall into the highest-risk category goes into effect the moment the final LDT guidance is published.  Those highest-risk category tests are LDTs with the same intended use as cleared/approved companion diagnostics, LDTs with the same intended use as approved Class III medical devices, and certain LDTs for determining safety and effectiveness of blood or blood products.  The draft guidance states that for the highest risk LDTs already on the market, the laboratory will have 12 months to submit an application.  That statement implies that new LDTs would not receive a similar grace period.  Dr. Gutierrez is now explicitly stating that LDTs that fall within the highest-risk category not on the market at the time the final guidance is issued will not receive a grace period from the premarket review requirements.  The upshot is that if the LDT guidance goes into effect as written, laboratories will want to begin marketing their tests before the guidance is issued.
• Determining Risk.  FDA will publish a priority list for the timeframe for premarket submissions for the remaining high-risk LDTs in year two.  FDA will publish a priority list for moderate-risk LDTs in year four.  The agency will consult advisory panels to determine these priority lists.  However, according to Dr. Gutierrez’s slides, FDA anticipates that after the highest-risk LDTs identified in the draft guidance, the next group of high-risk devices for which the agency will seek premarket submissions/applications include “devices that act like companion diagnostics; screening devices for serious diseases/conditions intended for use in asymptomatic patients without other confirmation; and diagnostics for certain infectious diseases with high-risk intended uses.”  
• In response to a question about how FDA would determine whether an LDT was high or moderate risk, Dr. Gutierrez stated that the risk depends on both the analyte and the intended use.  For instance, with a biomarker for cancer, if the test is intended to screen asymptomatic patients to determine who has cancer, this would be a high-risk test because if there is a false negative, then the clinician will miss cancer. If there is a false positive, the patient will needlessly undergo medical procedures that may result in morbidity or mortality for the patient.  The same biomarker for cancer monitoring is likely to be moderate risk, he suggested.  Monitoring involves multiple longitudinal assessments, so a false result is less risky to the patient.  Dr. Gutierrez also stated that only a small portion of IVD kits are Class III devices, and he expects that the same ratio will apply for LDTs.   
• LDTs Subject to Prohibition against False and Misleading Statements.  Dr. Gutierrez indicated that even if an LDT already on the market is not subject to premarket review yet under the phased timeline, if the company makes a statement about the test that “is not credible,” FDA can immediately initiate enforcement action.  Essentially, on the day the guidance takes effect, LDTs will be subject to the misbranding provision under Section 502(a) of the Federal Food, Drug, and Cosmetic Act, which prohibits false and misleading claims.
• Notification.  Dr. Gutierrez stated that the agency was considering having a link between the National Institutes of Health (NIH) registry of LDTs and FDA’s notification database, so that if a laboratory’s test already was registered with NIH, the laboratory would not have to duplicate that information, but would only need to complete a few fields where the information was not previously provided.  He also said that the agency has yet to decide whether to make the FDA notification database public.  He added he did not see any reason why it should not be public, as the agency can redact information such as information that could have public security implications.  In response to questions about whether the agency should require notification for LDTs that meet the “Traditional” LDT category, Dr. Gutierrez noted that this was an area where the agency solicited specific comment and that the agency was “moving toward” not requiring notification for LDTs that fall into the Traditional LDT category. 
• Manufacturing Information.  As to whether a laboratory submitting a PMA for a Class III LDT would need to include manufacturing information in the application, as is required for IVD kits, Dr. Gutierrez stated that the draft guidance as currently drafted does require such manufacturing information.  However, Dr. Gutierrez stated that the agency is reconsidering this area.  He noted that when the Quality System Regulation (QSR) went into effect in the 1990’s there was a phase-in period during which the inspections focused on education as opposed to enforcement.  The agency is considering whether a similar approach would make sense here. 
• Will there be another draft guidance before a final guidance issues? Dr. Gutierrez said that whether there will be another draft guidance issued before a final guidance is issued will be justified “by the number of changes we make to” the current proposal.  FDA issued two separate draft guidances when it was considering the In Vitro Diagnostic Multivariate Index Assay (IVDMIA) proposal.  That proposal affected significantly fewer tests than this current proposal and was much less sweeping in scope and impact. 
• January 2015 Public Meeting.  FDA will hold a two-day meeting in January 2015 to discuss the draft guidances.

CLIAC Deliberation of “Off-Label” Use of Waived Tests by Waived Laboratories.  On November 5, panel members, FDA and Centers for Medicare & Medicaid Services (CMS) representatives extensively discussed the “off-label” use of waived tests by waived laboratories.   

Under CLIA, a laboratory is either waived, moderate-complexity or high-complexity, with waived laboratories subject to the least amount of controls.  Waived laboratories are not subject to routine inspections.  A waived laboratory is only supposed to perform tests that are categorized by FDA as waived.  These waived tests are supposed to be simple enough so that they can be performed reliably and accurately in these less sophisticated laboratories.  We reported on FDA’s guidance on administrative procedures for categorization here.

Daralyn Hassan, a representative from CMS, explained that the majority of laboratories in the United States are waived.  Specifically, 66 percent of CLIA laboratories possess a certificate of waiver.  This represents a great increase, according to Ms. Hassan, from the 1990’s, when only around 20 percent of laboratories were waived.  CMS initiated a pilot program in 2002 under which the agency had inspected two percent of the waived laboratories in all 50 states.  The inspectors uncovered a number of problems in these waived laboratories during those inspections, which were announced before the inspector arrived.  CMS found that, among other issues, multiple waived laboratories were performing waived tests for off-label uses.  She said that devices used outside of the manufacturer’s requirements or intended use are considered to be test modification/off label use, and modified tests are no longer considered waived. 

FDA representatives indicated that the way FDA is dealing with the issue is to seek more narrow indications for use.   Prakash Rath, an OIR representative, said that FDA cleared indications for use are often broad, but the waived use is very narrow, and waived labs end up using the test for off-label populations or sample matrices.  Dr. Rath added that “given the only control is labeling, FDA’s approach is to request clearance/approval within a narrow intended use that may include training.”  He asked the committee to consider what else can be done to avoid the “off-label” use of waived tests by waived labs. 

Dr. Gutierrez concurred that “where we are going to is narrower intended uses.”  This conforms with our own recent experiences with OIR. 

Dr. Gutierrez noted that while the agency considers labeling to be only control it has in waived testing, the labeling must be at a seventh-grade level.  Given the requirement for a seventh-grade reading level, narrowing the intended use may not give the agency enough control over the waived testing:  He is not certain the indications for use are well enough understood to provide a successful control in the waived setting.

CLIAC agreed to make two recommendations to HHS on the issue.  First, CLIAC will recommend that the HHS facilitate development of a non-punitive and non-regulatory self-assessment checklist type tool and recommend it for use by all current CLIA-waived labs.  The committee also recommended that CMS continue to consider potential changes to address this issue and report back to the committee on this issue.

Hyman, Phelps & McNamara, P.C. has once again been ranked as a “Tier 1” law firm in the area of “FDA Law” (both nationally and in Washington, D.C.) by the folks over at U.S. News & World Report, who teamed up with Best Lawyers for the 2015 “Best Law Firms” rankings.  More than 12,000 law firms are ranked in 74 practice areas nationally and in as many as 120 practice areas on the metropolitan lists.  “[R]ankings are based on a rigorous evaluation process that includes the collection of client and lawyer evaluations, peer review from leading attorneys in their field, and review of additional information provided by law firms as part of the formal submission process,” according to U.S. News. The 2015 list of America’s Best Law Firms can be searched here, or viewed here (we’re noted on page 45).

In addition to the honors from U.S. News & World Report, LMG Life Sciences recently listed HP&M as “Highly Recommended” in the areas of Pharmaceuticals and Medical Devices.  Here’s what they had to say about us:

Hyman Phelps & McNamara represents one of — if not the most well-respected regulatory boutique firms catering to clients in the life sciences.  Tellingly, when asked for a summary of the preeminent regulatory attorneys active in the industry, one industry peer responded, “Hyman Phelps as a whole comes to mind before any-one else.”  Various practitioners with the firm inspired the praise of their peers with Jeff Gibbs, Bob Dormer and Alan Kirschenbaum the most regular recipients of accolades.  One industry peer said of Kirschenbaum, “he is absolutely top notch,” while the firm generally was described as “the most rounded FDA practice” with respondents highlighting its work on behalf of food manufacturers and pharmaceutical companies in particular.

In fact, the firm’s ability to handle all matters under the jurisdiction of the FDA, from food to drugs and devices to cosmetics, affords clients access to a substantial knowledge base exemplified through the experience of attorneys with specialized practices in every area related to the FDA as well as complementary agencies like the DEA.

One client summed up the general consensus concerning Hyman Phelps succinctly: “there are many Washington firms that focus entirely on regulatory work, with the best example of that type of dedicated practice being Hyman Phelps.”

Wow!  We’re blushing. 

By Allyson B. Mullen –

On November 3, 2014, the law firm of McKenna Long & Aldridge LLP filed suit on behalf of Plymouth Direct, Inc. (Plymouth) and Natures Pillows, Inc. (NPI) in the United States District Court for the District of Columbia against FDA claiming that FDA unlawfully detained multiple shipments of the companies’ medical device, the BeActive® Brace, that were imported into the U.S. 

According to the companies’ Complaint, BeActive is manufactured in China and sold by Plymouth and NPI in the United States through retail and mail order channels.  BeActive is a wrap brace that puts pressure on the wearer’s calf muscle, thereby reducing tension on the sciatic nerve, which can reduce lower back pain.  In April 2014, Plymouth and NPI’s supplier (Base4 Group Inc.) sent an email to FDA with BeActive’s packaging and labeling and sought FDA’s opinion as to the product’s classification (see court document here).  Based on the information provided in the court filings, the draft labeling explained that the brace was used to apply pressure to the calf muscle to relieve back pain – the device’s fundamental principle of operation.  FDA responded stating that BeActive was a Class I, 510(k)-exempt, Limb Orthosis, pursuant to 21 C.F.R. § 890.3475. 

Plymouth and NPI began selling BeActive in August 2014.  The Complaint states that between September 27, 2014 and October 20, 2014, FDA subjected seven shipments of the product to Detention without Physical Examination because BeActive lacked 510(k) clearance.  Specifically, FDA indicated that BeActive’s claim that it can relieve back pain caused by pregnancy and piriformis syndrome requires 510(k) clearance.  In addition, FDA indicated that BeActive could be an acupressure device because of how the product achieves its intended effect, and acupressure devices could be subject to 510(k) premarket notification requirements (see court document here).   FDA subsequently released all seven shipments on the grounds that although the product appeared violative, the violation was a minor violation. 

According to the Complaint, two more BeActive shipments were detained on October 28, 2014 – six days before the Complaint was filed.  As part of the detention, FDA indicated that it was in the process of adding BeActive to an Import Alert for failure to have a 510(k) clearance. 

In an effort to resolve the import detentions, the Complaint states that Plymouth and NPI proposed changing BeActive’s packaging, labeling, and promotional materials to remove the “objectionable” claims.  In addition, the companies offered to file a 510(k) for BeActive, provided that they could continue selling while the 510(k) was pending.  The Complaint reports that these proffers were made between October 24 and 28, 2014, and as of the date of the Complaint, FDA had not responded. 

The Federal Food, Drug, and Cosmetic Act (the FD&C Act) establishes procedures for the FDA and U.S. Bureau of Customs and Border Protection (CBP) to work together to admit or deny import of medical devices into the U.S.  Through this process, set out in the statute and regulations, FDA or CBP can take samples of devices to determine if they are adulterated or misbranded.  21 U.S.C. § 381(a). If samples are taken, the medical devices must be held until they are cleared for sale into interstate commerce.  21 C.F.R. § 1.90.  These procedures also allow for an informal hearing if import is denied.  21 C.F.R. § 1.94.  In addition, as an alternative to the process in the statute and regulations, FDA has created the “Detention without Physical Examination” process in its Regulatory Procedures Manual.  Through the Detention without Physical Examination process, FDA does not actually take samples of the devices.  Rather, FDA requires the recipient of the devices to hold the devices while the importer provides documentation demonstrating that the devices do not meet the criteria for import refusal. 

The Detention without Physical Examination process is the method employed by FDA in this case, and it is also the method most commonly used to detain imports of medical devices subject to enforcement action (e.g., a Warning Letter that includes an import alert).  FDA believes this process is less burdensome on FDA’s resources than having to take physical samples of products that are delivered into the U.S., when FDA has already determined that the product is adulterated or misbranded.  Thus, if a court found this process to be unlawful, it could significantly change the way that FDA and CBP handle import detentions of medical devices.

Additionally, this case raised an interesting question about how FDA handles enforcement actions that are based on a regulatory finding that is contrary to an earlier FDA opinion.  At least according to Plymouth and NPI’s recital of the facts in this case, FDA concluded that BeActive was 510(k) exempt after reviewing draft copies of the product’s packaging and labeling.  FDA’s import detention, however, was based on the premise that BeActive lacked 510(k) clearance (which would not be necessary if the product is 510(k) exempt).  Based on the materials provided in the court filings, the specific claims for piriformis syndrome and pregnancy that FDA objected to were not included in the packaging and labeling reviewed by FDA in April.  However, the April labeling appeared to explain that the device operated by applying pressure to the calf muscle to relieve back pain.  Therefore, at least from an outsider’s perspective, it appears that FDA changed its mind as to the device classification based on the devices mode of action, even though FDA knew the mode of action when it reviewed the device’s labeling in April.  Certainly, if FDA did change its mind regarding the device classification based on the mode of action without any explanation to the company, this action would appear to be arbitrary and capricious.

Given the very short timeframe in which these facts have transpired, we wonder if FDA considered Plymouth and NPI’s offer to modify BeActive’s packaging, labeling and promotional claims before the companies filed this lawsuit.  This offer was likely made about a week and a half before the companies filed this suit.  However, it appears to have worked in Plymouth and NPI’s favor. 

While the information regarding the two most recent shipments of BeActive in FDA’s import system has not been updated, this case was voluntarily dismissed by the companies on November 6, 2014.  We can assume that, based on the voluntary dismissal, that FDA and the companies likely came to an agreement to release the detained product and a pathway forward for future shipments.

Although we will not have any legal resolution as to the interesting questions raised by this case, it is a recent example of a lesson that can often be forgotten in a regulatory framework where companies usually want to work with the Agency to resolve disputes – sometimes litigation is the answer.  Particularly when it comes to import alerts and detentions that companies have trouble (or cannot) resolve with FDA, history shows us that litigation can be a very effective tool.  A recent review by HPM of cases in which companies challenged an FDA import alert or detention in court showed that the company typically prevailed.  In fact, in most of these cases, soon after the case was filed, it was dismissed, usually, if not always, because the import alert or detention was vacated by FDA.   

By Kurt R. Karst –      

We learned this week that FDA finally approved ANDAs for generic versions of Hoffmann-LaRoche, Inc.’s VALCYTE (valganciclovir) Tablets, 450 mg (NDA 021304).  We don’t usually post on FDA’s daily ANDA approval activities, but the valganciclovir ANDA approvals are of special significance. . . . and might foreshadow another FDA action on a long-awaited generic version of AstraZeneca LP’s NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg (NDA 021153).

Ranbaxy Laboratories, which entered into a Consent Decree with FDA and the Department of Justice in January 2012, was believed to be the first applicant eligible for 180-day exclusivity for generic VALCYTE.  Indeed, the company acknowledged this in a 2008 press release after FDA tentatively approved the company’s ANDA, stating “Ranbaxy believes that it has First-to-File status on Valganciclovir tablets, thereby providing a potential of 180-days of marketing exclusivity, offering a significant opportunity in the future.”  (Interestingly, that tentative approval was recently removed from FDA’s website.)  But it appears almost certain that the company’s data integrity and manufacturing problems prevented FDA from granting final ANDA approval. 

Meanwhile, generic competition was stalled because of Ranbaxy’s eligibility for 180-day exclusivity.  Frustration mounted by many people seeking generic competition, and earlier this year, our firm submitted a Citizen Petition to FDA requesting that the Agency take action to remove Ranbaxy’s block on competition for generic VALCYTE, as well as for generic NEXIUM and DIOVAN (valsartan) Tablets (see our previous posts here and here).  (FDA later approved Ohm Laboratories Inc.’s [Ranbaxy’s] ANDA 077492 for generic DIOVAN and granted 180-day exclusivity.)

According to FDA’s ANDA approvals for generic VALCYTE:

The Agency determined today that the applicant who was first to file a substantially complete ANDA with a paragraph IV certification to the remaining patent listed for the reference listed drug (RLD) has forfeited its eligibility for 180-day generic drug exclusivity under section 505(j)(5)(B)(iv) of the act.

Our presumption was that FDA stripped Ranbaxy of 180-day exclusivity eligibility under the terms of the Consent Decree, which states in relevant part:

If Corporate Defendants have not completed their substantial completeness submissions pursuant to paragraph XIV.A, audit plans pursuant to paragraph XIV.B.1, and audits pursuant to paragraph XIV.B.2, for each of the following Excepted Applications by the following dates, Corporate Defendants shall, upon written notification from FDA, be deemed to have relinquished any claim to 180-day exclusivity for such Excepted Application(s) and shall not interpose any objection in any forum to FDA’s approval of any other ANDAs held by other sponsors for the drugs subject to such Excepted Application(s) after such date: ANDA 1, by December 31, 2012; ANDA 2, by January 31, 2013; ANDA 5, by July 31, 2013; and ANDA 4, by September 30, 2014.

But according to a press report, FDA informed Ranbaxy that the Agency’s tentative approval decision was “in error because of the compliance status of the facilities.”  “The FDA also told the Indian drugmaker there were no ‘data integrity’ issues related to the company's filings for the two drugs,” continues the report.  In other words, Ranbaxy forfeited eligibility for exclusivity under FDC Act § 505(j)(5)(D)(i)(IV) for failure to obtain timely tentative approval within 30 months of ANDA submission.  (In the case of generic DIOVAN, where FDA granted 180-day exclusivity, any failure to have obtained timely tentative approval was excepted – see here.)

FDA’s action on Ranbaxy’s ANDA for generic VALCYTE necessarily raises the question as to whether or not the Agency is poised to take a similar action with respect to Ranbaxy’s ANDA for generic NEXIUM.  When FDA tentatively approved the company’s ANDA in 2008, Ranbaxy commented in a press release that it “believes that it has a FTF (First to File) status on the drug, providing it with a potential 180 days marketing exclusivity, thereby offering a significant opportunity in the future.” 

Although recent press reports (see here) say that Ranbaxy continues to believe it has 180-day exclusivity, FDA’s action on generic VALCYTE calls that belief into question.  Moreover, we note that FDA recently removed from its Drugs@FDA website any mention of the company’s tentative ANDA approval for generic NEXIUM, just as with generic VALCYTE.  

By Kurt R. Karst –      

Last week when this blogger reported on the lawsuit filed by Amgen, Inc. (“Amgen”) in the U.S. District Court for the Northern District of California alleging that Sandoz Inc. (“Sandoz”), in its efforts to obtain approval of a Section 351(k) application for a biosimilar version of NEUPOGEN (filgrastim), unlawfully refused to follow the patent resolution procedures outlined in the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), I had it in the back of my mind that something more might be in the works.  A citizen petition perhaps?  As it turns out, that thought was prescient. 

In an October 29, 2014 Citizen Petition (Docket No. FDA-2014-P-1771), Amgen asks FDA to adopt policies and procedures to require biosimilar applicants – before their applications are accepted for review by FDA – to certify to the Agency that they will comply with PHS Act § 351(l)(2)(A) (42 U.S.C. § 262(l)(2)(A)) by providing the reference product sponsor with a copy of the 351(k) application “and such other information that describes the process or processes used to manufacture the biological product that is the subject of such application” within 20 days after FDA informs the biosimilar applicant that its 351(k) application has been accepted for review.  “This certification should be required for all biosimilar applications that have not been accepted for review by the FDA,” says Amgen. 

According to Amgen, what’s at stake here goes way beyond delays in the initiation of patent infringement litigation – it’s the entire fabric of the BPCIA that is is in jeopardy, including biosimilar exclusivity:

Non-compliance with subsection (l)(2)(A) vitiates the entire scheme that Congress created.  If the biosimilar applicant does not disclose the biosimilar application and manufacturing information, the reference product sponsor may not know that an application referencing its product has been submitted.  Even if the reference product sponsor learns of this filing from other sources (e.g., the press), its ability to identify relevant patents is undermined as it may not have the information describing the biosimilar product and its manufacture necessary for meaningful judicial resolution and that should have been exchanged under subsections (l)(2) through (l)(5).  This, in turn, prevents or delays the initiation of court proceedings to enforce infringed patents.  A patent infringement action commenced by means other than as set out in subsections (l)(2) through (l)(6) also may call into question the biosimilar applicant’s obligation to notify FDA, and public notice via the Federal Register may not result. 

The timely initiation of patent litigation under (l)(6) also affects the Agency’s administration of other portions of BPCIA. Pursuant to subsection (k)(6), the sponsor of the first biosimilar product to be designated an “interchangeable” biosimilar product earns a period of exclusivity that will expire on the earliest of five defined dates . . . .  This exclusivity is implemented by the Secretary withholding designation of another biosimilar product as being “interchangeable” until the expiration of the first of these five periods to occur.

Delays in compliance with subsection (l)(2)(A) will delay commencement of, or possibly even eliminate, litigation under subsection (l)(6).  That, in turn, delays the expiration of the periods specified in subsection (k)(6)(B), rendering those potential expiration dates inapplicable.  That result would frustrate a clearly stated Congressional intent. 

Moreover, writes Amgen, a decision by FDA to stand on the sidelines makes the Agency culpable:

By not implementing measures to ensure timely compliance with the subsection (l)(2)(A) disclosures, FDA is contributing to that uncertainty to the detriment of the legitimate interests of reference product sponsors, subsequent biosimilar applicants who may wish to seek an interchangeability designation, and the public.

The remedy Amgen seeks – a certification of compliance with PHS Act § 351(l)(2)(A) – is well within the Agency’s authority, according to the company.  “FDA has the power to remind parties of existing statutory duties without going through any particular level of formality,” writes Amgen.  “Similarly, FDA has broad authority to determine the manner in which parties present themselves or their viewpoints to the agency.  Thus, either as a matter of interpretative or procedural authority, FDA has the power to require that biosimilar applicants certify compliance with subsection (l)(2)(A).”

Whatever the merits of Amgen’s Citizen Petition, we are eager to find out what FDA thinks.  But it may be some time until the Agency responds to Amgen.  Although the petition includes a certification pursuant to FDC Act § 505(q), we question whether or not FDA will deem Amgen’s petition a “505(q) petition” subject to the statutory 150-day response deadline. 

Briefly, under the version of FDC Act § 505(q) in effect since 2012, FDA cannot delay approval of a pending ANDA, 505(b)(2) application, or 351(k) biosimilar application as the result of a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  (See our previous post here for additional background on FDC Act § 505(q).)  Amgen’s petition, however, does not seem to apply to Sandoz’s 351(k) application.  As noted above, Amgen’s “ask” of FDA is for a certification of compliance with PHS Act § 351(l)(2)(A), but only for “biosimilar applications that have not been accepted for review by the FDA” (emphasis added).  Sandoz’s 351(k) application does not fit the bill because the application was already accepted by FDA.  Unless there is another 351(k) application pending at FDA that could be affected by Amgen’s petition, the Agency might simply put the petition on a backburner and respond at a later date. 

By Michelle L. Butler & Kurt R. Karst –

On November 3, 2014, just short of the 60-day deadline, FDA filed a notice appealing to the U.S. Court of Appeals for the District of Columbia Circuit the Final Judgment and Order entered on September 5, 2014 by the U.S. District Court for the District of Columbia in Depomed Inc. v. U.S. Department of Health and Human Services et al., Case No. 1:12-cv-01592.  As we previously reported, the District Court granted Depomed’s Motion for Summary Judgment and ordered FDA to recognize orphan drug exclusivity for Gralise (gabapentin) Tablets “without requiring any proof of clinical superiority or imposing any additional conditions on Depomed.” 

While the filing of the Notice of Appeal answers one of questions arising from the Court’s decision – namely, will FDA accede to the decision – many questions remain.  For example, we know that FDA is still granting orphan drug designations.  (Indeed, according to FDA’s Orphan Drug Designations and Approvals database, the Agency has granted 50 orphan drug designations since September 6, 2014 – the day after the District Court’s decision.)  However, we don’t know if FDA has changed its view on the necessity of articulating a plausible hypothesis of clinical superiority in order to obtain designation of a second drug containing the same active moiety as an approved drug for the same orphan indication. 

We also don’t know for sure what FDA’s views are on the scope of orphan drug exclusivity post-Depomed.  Post-Depomed, one issue is whether or not orphan drug exclusivity applies broadly, such that FDA is prohibited from approving any marketing application for a drug containing the same active moiety for the same indication, including an ANDA for a generic version of a brand-name drug that does not itself have a period of orphan drug exclusivity remaining.  For example, it could be argued that orphan drug exclusivity applicable to Gralise for postherpetic neuralgia prevents FDA from approving ANDAs for generic Neurontin for postherpetic neuralgia. 

We will continue to monitor the case and FDA’s activities and will post further information as it becomes available.