Should Free Speech Protections Include an Exception for Exclusivity-Protected Information?

Should Free Speech Protections Include an Exception for Exclusivity-Protected Information?

By Kurt R. Karst –     
As we previously noted, the intersection of exclusivity and off-label promotion issues is not common, but quite an interesting issue nevertheless. The intersection of these issues was raised earlier this year when Egalet Corporation (“Egalet”) issued a press release saying that the company had received correspondence from FDA stating that the Agency “‘does not object’ to Egalet’s stated plans for distribution of materials [concerning the company’s ARYMO ER (morphine sulfate) Extended-release Tablets] that are ‘based on the intranasal abuse-deterrence data in its original NDA submission’ if the communications are directed only to healthcare professionals, include appropriate disclosures and are otherwise truthful and non-misleading.”  You see, although Egalet conducted intranasal route of abuse clinical studies with ARYMO ER (approved under NDA 208603), FDA determined that 3-year exclusivity granted to Inspirion Delivery Technologies, LLC’s (“Inspirion’s”) MORPHABOND (morphine sulfate) Extended-release Tablets (NDA 206544) – for which Daiichi Sankyo, Inc. (“Daiichi”) holds U.S. marketing rights – prevented the Agency from approving ARYMO ER with labeling describing abuse-deterrence via the intranasal route of abuse.
FDA’s comments to Egalet have apparently bled over into comments submitted to the Agency by AbbVie Inc. (“AbbVie”) and Daiichi concerning a January 2017 draft guidance, titled “Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers” (Docket No. FDA-2016-D-2285).
According to AbbVie’s comments, “beyond-the-label communications” are justifiably restricted in one particular narrow circumstance:

A flexible approach to beyond-the-label communications . . . will serve the public interest by enabling more informed coverage and treatment decisions. Providing these additional avenues for manufacturer communications also furthers First Amendment values by respecting the rights of manufacturers to engage in truthful and nonmisleading speech about their products. . . .  In one narrow situation, however, we believe a different conclusion is warranted: that a specific legitimate government interest justifies appropriate limits on certain beyond-the-label communications.  This narrow situation involves the federal statutory scheme in place to incentivize biopharmaceutical industry research and development efforts through grants of non-patent regulatory exclusivity to innovative sponsors, in particular circumstances. . . .
In very narrow circumstances, however, beyond-the-label communications could undermine these sorts of regulatory exclusivity granted to a given company. This could happen if an innovator’s product were approved for an unprotected use but also for a supplemental use protected by orphan exclusivity or, in the case of a new drug, three-year exclusivity.  In these situations, FDA might approve another company’s product for the unprotected uses but allow that company to carve out from its labeling the protected uses. That other company might then choose to promote its drug for the protected use (subject to infringement claims under any applicable patents), which could lead to sales for the protected use—directly undermining the exclusivity.  Appropriate regulation of beyond-the-label communications in these circumstances would directly advance the government’s legitimate interest in preserving incentives for innovation made possible by exclusivity.  Indeed, courts that have upheld FDA’s authority to approve products with labeling carve-outs have assumed that only the innovator could promote for the protected use.  Moreover, no less restrictive alternatives (such as a disclaimer) would be effective in preserving the incentive.  The constitutional analysis in these narrow circumstances thus leads to a different result. In this specific situation, then, we believe FDA could justify a speech restriction.

Although AbbVie does not identify a particular product, the company’s focus on orphan drug exclusivity may be a veiled reference to AbbVie’s HUMIRA (adalimumab). In September 2016, FDA approved Amgen, Inc.’s (“Amgen’s”) AMJEVITA (adalimumab-atto) (BLA 761024), the first biosimilar version of HUMIRA (see our previous post here).  Amgen’s AMJEVITA was approved with labeling omitting information on uses that are protected by periods of orphan drug exclusivity applicable to HUMIRA. 
Comments submitted to FDA on the draft guidance by Daiichi are specific to the off-label use/exclusivity controversy:

Data exclusivity thus derives all of its value from the scope of the labeling for the drug. If the Draft Guidance were interpreted to permit a competitor to communicate data about a condition of use of a product with the same active moiety for which another company has data exclusivity, then the value of the data exclusivity to the original innovator would be severely undermined, if not destroyed.
In these circumstances, [Daiichi] believes that the First Amendment analysis is different than in the typical communication with a healthcare professional. . . . Where exclusivity rights are not at stake, the Central Hudson analysis weighs in favor of protecting truthful and non-misleading communications to sophisticated health care professionals about medicines and puts the burden on the government to show that it has important interests that the speech regulation directly advances in a narrowly tailored manner. . . .  Where intellectual property rights, such as exclusivity rights, are at stake, the prohibition on truthful and non-misleading communications directly advances the government’s interest in protecting those rights and preserving incentives for innovation. . . .  Allowing a competitor to communicate the infringing data, by itself, causes immediate competitive injury and undermines the carefully framed statutory exclusivity framework.  No amount of disclosure can cure that infringement.  Thus, the only alternative in this narrow circumstance is to restrict the speech. . . . 
FDA should thus make clear that the guidance provided does not apply to any communications that would infringe on the intellectual property rights of another company, including data exclusivity rights. In those circumstances, the only rule that would be consistent with statutory mandates is to restrict the communication, even if the communication is truthful and non-misleading.

Neither the Pharmaceutical Research & Manufacturers of America (“PhRMA”), nor the Biotechnology Innovation Organization (“BIO”), has yet entered the fray in any appreciable way.  BIO’s comments to FDA on the draft guidance only briefly mention exclusivity:

BIO does not believe that FDA’s modernizing its current framework to appropriately broaden communications will detract from the sound incentives for pursuing label expansions. This is due to the value of having information on the FDA-approved labeling, the simplicity of ‘on label’ detailing, and incentives such as regulatory exclusivity and eligibility for reimbursement.

Whether FDA will address off-label promotion vis-à-vis exclusivity in another version of the guidance is unclear; however, the Agency may be hesitant to do so in detail given the controversial nature of the topic and the possibility of litigation over the matter.

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User Fee Reauthorization Moves One Step Closer to Reality with House Committee Passage

User Fee Reauthorization Moves One Step Closer to Reality with House Committee Passage

By Kurt R. Karst –
On June 8, 2017, after a long mark-up session, the House Energy and Commerce Committee unanimously (54-0) passed H.R. 2430, the FDA Reauthorization Act of 2017 (“FDARA”). The Senate version of the bill, S. 934, passed out of the Health, Education, Labor, and Pensions Committee last month (see our previous post here).  Both bills would, in enacted, reauthorize an alphabet soup of user fee programs that fund much of FDA’s operations, including PDUFA, GDUFA, BsUFA, and MDUFA.
During the House Energy and Commerce Committee mark-up session, several amendments were added to the bill that passed out of the House Energy and Commerce Subcommittee on Health in May. Those amendments include:

An amendment from Reps. Ryan Costello (R-PN) and Scott Peters (D-CA) on medical device servicing;
An amendment from Reps. Ryan Costello (R-PN) and Scott Peters (D-CA) concerning FDA’s review process for medical imaging devices with contrast agents;
An amendment from Rep. Mimi Walters (R-CA) concerning a process for medical device manufacturers to request that FDA reclassify accessories based on their intended use;
An amendment from Rep. Jan Schakowsky (D-IL) establishing a voluntary pilot project to gather timely and reliable information on medical device safety and effectiveness; and
A sense-of-Congress amendment by Rep. Schakowsky (D-IL) urging the Department of Health and Human Services to work with Congress to take administrative actions and enact legislation to lower the costs of prescription drugs by increasing generic and biosimilar competition and preventing anticompetitive behavior.

Chairman Greg Walden (R-OR) also offered a package of technical corrections that passed.  Among other things, the package of technical corrections amends provisions included in the Health Subcommittee version of H.R. 2430 concerning Competitive Generic Therapies and a new 180-day exclusivity regime (see our previous post here).  
Several other amendments failed to garner the votes necessary for inclusion in the user fee reauthorization bill. Those proposed amendments include the Pharmaceutical Information Exchange Act, which seeks to “improve patient access to emerging medication therapies by clarifying the scope of permitted health care economic and scientific information communications between biopharmaceutical manufacturers and population health decision makers,” a revised version of Rep. Morgan Griffith’s (R-VA) Medical Product Communications Act concerning off-label use, and an amendment from Rep. Peter Welch (D-VT) concerning drug importation.  Rep. Welch also offered the Fair Access for Safe and Timely Generics Act concerning Risk Evaluation and Mitigation Strategies, but withdrew the amendment after debate.
H.R. 2430 will now move to the House Floor where further changes may be made to the bill. Differences between the House and Senate versions of FDARA will need to be ironed out before the bill can be sent to the President for his signature.  

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Adieu, “Orange Book FR Safety or Effectiveness Determinations List”; Hello, “Orange Book Patent Listing Dispute List”

Adieu, “Orange Book FR Safety or Effectiveness Determinations List”; Hello, “Orange Book Patent Listing Dispute List”

By Kurt R. Karst –       
The Orange Book has undergone – and continues to undergo – a lot of change as a result of FDA’s October 2016 promulgation of final regulations (effective as of December 5, 2016) to implement parts of the December 8, 2003 Medicare Modernization Act (“MMA”).  We pointed out some of those changes in our annual review of the Orange Book (see our previous post here), as well as in a subsequent post on changes made to the Orange Book reflecting new FDA guidance, titled “Referencing Approved Drug Products in ANDA Submissions.”  Most recently, we delved into the new “Reference Listed Drugs by ANDA Reference Standard List” (see our previous post here), which is intended to “assist applicants submitting an ANDA to seek approval of a generic drug in identifying an RLD when an ANDA [Reference Standard] has been selected.”  Last week, we became aware of some additional changes to the Orange Book . . . and one in particular that we had been waiting for. 
First, FDA has discontinued publishing the “FR Notice Determination of Safety or Effectiveness List.” (The “FR” in the title is short for “Federal Register.”)  FDA had published the list for many years (most recently in December 2016), and it was a helpful resource to determine what withdrawn drug products were the subject of an FDA determination (since 1995) that withdrawal was not for reasons of safety or efficacy.  (Although the Orange Book continues to include the standard ““**Federal Register determination that product was not discontinued or withdrawn for safety or efficacy  reasons**” next to a particular discontinued drug product, the “FR Notice Determination of Safety or Effectiveness List” included additional details about each discontinued drug product.)  Now, the website that housed that list simply states “This list is no longer published,” and refers readers to the new “Reference Listed Drugs by ANDA Reference Standard List” (see here).
Second, and of greater interest to Orange Book followers, is the new “Orange Book Patent Listing Dispute List.” The list implements FDA’s new method-of-use patent/patent use code patent challenge regulations and fulfills FDA’s new requirement to “promptly post information on its Web site regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the patent listing dispute.”  The new patent challenge procedures are laid out at 21 C.F.R. § 314.53(f)(1) and state:  

(f) Correction of patent information errors—(1) Requests by persons other than the NDA holder. If any person disputes the accuracy or relevance of patent information submitted to the Agency under this section and published by FDA in the list, or believes that an NDA holder has failed to submit required patent information, that person must first notify the Agency in a written or electronic communication titled “314.53(f) Patent Listing Dispute.” The patent listing dispute communication must include a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for FDA to send to the applicable NDA holder. For a dispute regarding the accuracy or relevance of patent information regarding an approved method of using the drug product, this statement of dispute must be only a narrative description (no more than 250 words) of the person’s interpretation of the scope of the patent. This statement of dispute must only contain information for which the person consents to disclosure because FDA will send the text of the statement to the applicable NDA holder without review or redaction. The patent listing dispute communication should be directed to the Office of Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620 Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the email address listed on the Agency’s Web site at http://www.fda.gov.
(i) Communication with the NDA holder—(A) Drug substance or drug product claim. For requests submitted under this paragraph (f)(1) that are directed to the accuracy or relevance of submitted patent information regarding a drug substance or drug product claim, the Agency will send the statement of dispute to the applicable NDA holder. The NDA holder must confirm the correctness of the patent information and include the signed verification required by paragraph (c)(2)(ii)(R) of this section or withdraw or amend the patent information in accordance with paragraph (f)(2) of this section within 30 days of the date on which the Agency sends the statement of dispute. Unless the NDA holder withdraws or amends its patent information in response to the patent listing dispute, the Agency will not change the patent information in the Orange Book.
(B) Method-of-use claim. For requests submitted under this paragraph (f)(1) that are directed to the accuracy or relevance of submitted patent information regarding an approved method of using the drug product, FDA will send the statement of dispute to the NDA holder. The NDA holder must confirm the correctness of its description of the approved method of use claimed by the patent that has been included as the “Use Code” in the Orange Book, or withdraw or amend the patent information in accordance with paragraph (f)(2) of this section, provide a narrative description (no more than 250 words) of the NDA holder’s interpretation of the scope of the patent that explains why the existing or amended “Use Code” describes only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product, and include the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute. The narrative description must only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction.
(1) If the NDA holder confirms the correctness of the patent information, provides the narrative description required by paragraph (f)(1)(i)(B) of this section, and includes the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute, the Agency will not change the patent information in the Orange Book.
(2) If the NDA holder responds to the patent listing dispute with amended patent information in accordance with paragraph (f)(2) of this section, provides the narrative description required by paragraph (f)(1)(i)(B) of this section, and includes the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute, FDA will update the Orange Book to reflect the amended patent information.
(ii) Patent certification or statement during and after patent listing dispute. A 505(b)(2) application or ANDA must contain an appropriate certification or statement for each listed patent, including the disputed patent, during and after the patent listing dispute.
(iii) Information on patent listing disputes. FDA will promptly post information on its Web site regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the patent listing dispute.

The inaugural “Orange Book Patent Listing Dispute List” includes only a single patent listing dispute (concerning PRADAXA (dabigatran etexilate mesylate) and U.S. Patent No. 9,034,822); however, we expect the list to grow.

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Amgen SENSIPAR Pediatric Exclusivity Dispute is Put on Ice While FDA Dispute Resolution Process Proceeds

Amgen SENSIPAR Pediatric Exclusivity Dispute is Put on Ice While FDA Dispute Resolution Process Proceeds

By Kurt R. Karst –      
Amgen Inc.’s (“Amgen”) nearly two-week-old lawsuit filed against FDA in the U.S. District Court for the District of Columbia challenging the Agency’s denial of a period of 6-month pediatric exclusivity under the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A) applicable to SENSIPAR (cinacalcet) Tablets (NDA 021688) is on hold while Amgen seeks resolution of its claim that the company met the requirement for granting exclusivity by using FDA’s Formal Dispute Resolution process.
As we previously reported, Amgen alleges in the company’s Complaint and Motion for Temporary Restraining Order and/or Preliminary Injunction that FDA violated the Administrative Procedure Act when the Agency, among other things, “acted contrary to the plain terms of its governing statute by faulting Amgen for its failure to fulfill ‘one criterion’ of several study requests, when the statute requires merely that the studies ‘fairly respond’ to the Agency’s [Written Request for pediatric studies].”  Amgen’s lawsuit set off a flurry of activity from each party to the litigation, including a Motion to Dismiss from FDA and supplemental briefs (here and here).  A Motion Hearing was held last Friday where Judge Randolph D. Moss took the matter under advisement.
But on Monday, June 5, 2017, the case was put on hold with a Stipulation and Order signed by Judge Moss. According to the Order, “FDA will accept resubmission of Amgen’s May 25, 2017 request for dispute resolution on June 5, so long as that request is substantially similar to Amgen’s May 25, 2017 request,” and the Agency must respond with a decision by June 26, 2017. “[S]hould reconsideration uphold the May 22, 2017, decision [denying pediatric exclusivity], Amgen shall respond to the reconsideration decision by July 3, 2017; and FDA shall issue a decision on dispute resolution by August 2, 2017,” says the Order.  If FDA, after reconsideration, deems that the studies met the terms of the Written Request for pediatric studies, then “FDA will update the Orange Book to reflect pediatric exclusivity on the first business day following the acceptance.”  If FDA once again denies Amgen pediatric exclusivity, then we’ll probably see the parties back in court. 
Regardless of whether FDA decides to grant pediatric exclusivity, or if the exclusivity is ordered granted by a court, the Order states that “any future decision requiring FDA to accept Amgen’s study reports for Sensipar (cinacalcet) under 21 U.S.C. § 355a(d)(3) . . . shall be deemed to relate back, nunc pro tunc, to May 22, 2017, the date of FDA’s initial determination.”  As we previously explained, a “relate back” decision is important here, because pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity an application holder may have under the FDC Act, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.  Here, U.S. Patent No. 6,011,068 listed in the Orange Book for SENSIPAR expires on March 8, 2018.  Nine months prior to that date is June 8, 2017. 

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First Generic Drug Price Gouging Prohibition to Become Law in Maryland

First Generic Drug Price Gouging Prohibition to Become Law in Maryland

By David C. Gibbons & Alan M. Kirschenbaum –
Maryland will become the first state in the United States to enact a law prohibiting “price gouging” by generic pharmaceutical manufacturers. H.B. 631, 437th Gen. Assemb., Reg. Sess. (Md. 2017) (hereinafter, “the Bill”). The Bill was passed by the Maryland General Assembly on April 20, 2017 and, on May 26, Maryland Governor Larry Hogan sent a letter to the Speaker of the House stating that he would allow the bill to become law without his signature.
There are two essential provisions of the Bill. First, it prohibits a generic drug manufacturer or wholesale distributor from engaging in price gouging in the sale of an “essential off-patent or generic drug.” An essential off-patent or generic drug, for purposes of the Bill, is a prescription drug (1) with no unexpired marketing exclusivity under the Federal Food, Drug, and Cosmetic Act; (2) that either appears on the World Health Organization’s model list of essential medicines or is designated as essential for treating a life-threatening or certain chronic health conditions by the Maryland Secretary of Health and Mental Hygiene; (3) is actively marketed in the United States by three or fewer manufacturers; and (4) is available for sale in Maryland. Prohibited price gouging, according to the Bill, is an “unconscionable increase” in the price of such prescriptions drugs. This term is defined as a price increase that is “excessive and not justified” by the manufacturing cost or costs associated with expanding access to the drug for the purpose of promoting public health, and which results in patients having “no meaningful choice” whether or not to purchase the drug because of its importance to their individual health and insufficient market competition. The Bill exempts wholesale distributors from the price gouging prohibition when the price increase is “directly attributable” to additional costs imposed on the distributor by the manufacturer.
Second, the Bill authorizes the Maryland Medical Assistance Program (“MMAP”) to notify the Maryland Attorney General (“AG”) of a price increase when the Wholesale Acquisition Cost (“WAC”) of a prescription drug increases by at least 50% from the WAC within the preceding one-year period or when the price paid by MMAP would increase by at least 50% from the WAC within the preceding one-year period and the WAC for either a 30-day supply or a full course of treatment exceeds $80.
At the request of the AG, the manufacturer of a drug so identified must provide a statement justifying the price increase within 45 days of such request. The AG may also require a manufacturer or distributor to provide records or documents relevant to a determination of whether the price increase violates the Bill’s prohibition on price gouging. The AG may seek a court order compelling a justification statement or document disclosure.
In addition, the Bill allows the AG to seek other remedies, including:

Restraining or enjoining violations of the Bill;
Obtaining monetary relief to consumers, based on violative price increases;
Requiring the manufacturer or distributor to sell the drug to Maryland State health plans or programs at the price at which it was available in the year prior to the violative price increase; and
Imposing a civil penalty of up to $10,000 per violation.

The Bill has not been without controversy. Governor Hogan indicated, in his letter to the Speaker of the House, that “legal and constitutional concerns” with the Bill have been raised by his Chief Counsel. This places the Governor at odds with the AG, who championed the Bill, but largely echoes concerns raised by generic drug manufacturers through the Association for Accessible Medicines, the generic manufacturers’ trade association. The Governor stated that one issue concerns the fact that the Bill only addresses generic products, and not patented drugs and medical device drug delivery systems, which, according to the Governor, comprise a significant share of the market and “are often times the most expensive and essential pharmaceuticals.” He also stated that the Bill may suffer from defects under the U.S. Constitution. First, the Governor stated that the Bill potentially implicates the Constitution’s dormant commerce clause by regulating interstate commerce—that is, drug prices negotiated “outside of Maryland.” Second, the Bill may violate the Fourteenth Amendment due process clause due to the vagueness of the terms “unconscionable increase” and “excessive.”
The Bill will become effective on October 1, 2017. We will continue to monitor enforcement of this law and similar developments in other states.
 

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Letter Signed by 65 Members of Congress Urges FDA to Reconsider “Office Stock” Restrictions for Section 503A Compounders

Letter Signed by 65 Members of Congress Urges FDA to Reconsider “Office Stock” Restrictions for Section 503A Compounders

By Karla L. Palmer –
A recent letter from 65 members of Congress to FDA’s Commissioner Gottlieb has caused a bit of a buzz in the pharmacy compounding world. The letter, dated May 23, 2017, expresses the Congressional signers’ “strong disappointment” with FDA’s recently issued Final Guidance for Industry titled, “Prescription Requirement under 503A of the Food Drug and Cosmetic Act.” The Final Guidance, published on December 30, 2016 (see our previous post here), addresses the so-called “prescription requirement” in FDCA Section 503A, including FDA’s policies requiring compounding only after the receipt of a prescription for an identified individual patient, limited compounding before the receipt of such a prescription (referred to as “anticipatory compounding”), and the prohibition on compounding for office use (referred to as “office stock”).  FDA has consistently asserted since the passage of the 2013 Drug Quality and Security Act that, in order for compounders to obtain Section  503A’s exemptions from new drug, adequate directions for use and cGMP requirements, each compounded formulation must be prepared for an individually identified patient pursuant to a prescription or order, and the compounder may not engage in compounding for office stock.  Proponents of those that believe state-licensed pharmacies should be permitted to engage in compounding for office stock if it is permissible under state law assert that Congress’ plain use the term “distribution” in Section 503A and various Congressional statements prior to and at the time of the Act’s enactment demonstrate Congress’ clear intention to permit state-licensed pharmacies to engage in compounding for office stock.  
The bi-partisan letter (led by Rep. Chris Stewart (R-Utah) and Rep. Buddy Carter (R-Ga.), urges FDA to rethink its decision restricting pharmacies from engaging in compounding for office stock. The Letter  states that FDA’s policies are contrary to the plain language of Section 503A as amended by the DQSA.  In addition,  it asserts that FDA ignored congressional intent, stakeholder input, and clear directives in FY 2016 funding legislation about office use compounding, and added to the Final Guidance language that attempts to redefine the terms “dispense” and “distribute,” ignoring their commonly accepted “definitions both in existing law and in pharmacy practice.”  The Letter accuses FDA of “doubling down” on FDA’s “misinterpretation of the statute and will further exacerbate the patient access problems as more state licensed and compliant pharmacies are forced to cease compounding office-use medications to the providers in their communities who rely on them.” 
Calling the Final Guidance “regulatory overreach,” the Letter lastly seeks the rescission of the Final Guidance, and requests FDA to issue a proposed rule that adheres to “congressional intent” and “plain language of the underlying statute.”

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Amgen Sues FDA After Agency Denies Pediatric Exclusivity for SENSIPAR

Amgen Sues FDA After Agency Denies Pediatric Exclusivity for SENSIPAR

By Kurt R. Karst –
The drought is over! It’s been several months since we’ve seen a new dispute over non-patent exclusivity filed against FDA in a court.  But with a May 25, 2017 Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction filed in the U.S. District Court for the District of Columbia, Amgen Inc. (“Amgen”) has ended the drought.  And the dispute concerns a rarely litigated statutory provision: 6-month pediatric exclusivity granted (or denied, as the case is here) under the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A).  In fact, we’re only aware of one similar case in the 20 years since FDC Act § 505A has been around: Merck & Co. v. FDA, 148 F. Supp. 2d 27 (D.D.C. 2001) (here) . . . and that case didn’t turn out too well for FDA.  (Of course, there was the initial case of National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999) (here), but that case concerned the applicability and scope of, and not the eligibility for, pediatric exclusivity under FDC Act § 505A.) 
By way of background, FDC Act § 505A provides an additional six months of patent and non-patent exclusivity to pharmaceutical manufacturers that conduct acceptable pediatric studies of new and currently-marketed drug products identified by FDA in a Written Request (“WR”) for which pediatric information would be beneficial. Pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity (e.g., 5-year, 3-year, and 7-year orphan drug exclusivity) an application holder may have under the FDC Act, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.  An important aspect of pediatric exclusivity is that it provides additional marketing exclusivity not just for the pediatric indications or formulations, but for all protected indications and formulations of that sponsor’s drug.  Thus, pediatric exclusivity attaches to the patent and non-patent marketing exclusivity for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted, and not to a specific drug product. 
Amgen’s lawsuit centers around FDA’s March 22, 2017 Letter Decision denying the company pediatric exclusivity for SENSIPAR (cinacalcet) Tablets (NDA 021688).  FDA approved SENSIPAR on March 8, 2004 for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis, and for the  treatment of hypercalcemia in patients with parathyroid carcinoma. 
In May 2010, FDA issued Amgen a WR – a condition precedent to obtaining pediatric exclusivity – “to obtain the information needed to understand (and describe in labeling) the safety and effectiveness of the long term use of cinacalcet in children 28 days to < 18 years of age,” says FDA in the Agency’s Letter Decision. “The main objective of WR was to establish the benefits of  cinacalcet use for the chronic treatment of hyperparathyroidism (HPT) secondary to end-stage  renal disease in pediatric patients receiving either hemodialysis or peritoneal dialysis, and to adequately characterize the risks associated with this intended use in pediatric patients,” according to the Agency.  The WR was amended several times over the years, and, as finally amended, requested that Amgen conduct four pediatric studies.  Amgen conducted the studies – and an additional five studies – and submitted them to FDA last November.  But the company also had some difficulty with one of the studies.  “FDA’s [WR] asked that Study 3 involve a minimum of 15 patients who would be treated for either 26 weeks or, if a patient received a kidney transplant during the study, 12 weeks prior to transplant,” but Amgen was able to enroll only 11 patients for at least 12 weeks, and only four patients met all study completion criteria.  Amgen’s two-count Complaint alleges that FDA violated the Administrative Procedure Act (“APA”) in multiple ways, and that FDA’s interpretation of FDC Act § 505A (and the Agency’s failure to provide fair notice about its interpretation) violates the procedural due process guarantees of the Fifth Amendment to the United States Constitution. . . as well as the APA: FDA’s decision violated the [APA] in as many ways as that Act can be violated. First, the agency acted contrary to the plain terms of its governing statute by faulting Amgen for its failure to fulfill “one criterion” of several study requests, when the statute requires merely that the studies “fairly respond” to the Agency’s [WR]. Second, the agency also violated the statute by conflating the standard for accepting study reports with the different, separate, and more rigorous statutory standard for assessing a drug’s safety. Third, by denying pediatric exclusivity, FDA deviated from its treatment of similarly situated sponsors and broke with the agency’s longstanding practice, without explanation. Fourth, FDA’s denial of pediatric exclusivity lacks any logical basis, because it is premised on Amgen’s failure to achieve an impossible goal set by the agency – one that the agency itself cemented by refusing to accommodate amendments to the relevant study.  And fifth, FDA violated Amgen’s due process rights by changing the agency’s interpretation of the statute without providing Amgen advance notice of its newfound interpretation.  To support its case, Amgen points to the Merck decision linked to above.  “In addition to text, context, and purpose, Amgen has precedent on its side,” says the company.  In that case, which concerned MEVACOR (lovastatin), FDA denied pediatric exclusivity because Merck met only 14% of the study enrollment requirement.  But the DC District Court concluded that Merck’s studies “fairly responded” to the WR, and that FDA impermissibly denied pediatric exclusivity for “failure to meet a single term of the [WR].”  Amgen is seeking emergency relief, and a Temporary Restraining Order or Preliminary Injunction by June 6, 2017. Why that date?  Because June 8, 2017 is the date that is nine months before the March 8, 2018 expiration of U.S. Patent No. 6,011,068 listed in the Orange Book for SENSIPAR.  As noted above, the BPCA provides that pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.  

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If Everyone’s Unhappy, Maybe You’re Doing Something Right… Comment Period on FDA’s Biosimilar Interchangeability Guidance Closes

If Everyone’s Unhappy, Maybe You’re Doing Something Right… Comment Period on FDA’s Biosimilar Interchangeability Guidance Closes

By Sara W. Koblitz –
The comment period on FDA’s Draft Guidance Considerations in Demonstrating Interchangeability With a Reference Product recently closed (Docket No. FDA-2017-D-0154), and it seems like everyone has something to say about the guidance. With over 50 comments submitted, some very technical in nature, FDA has some deep reading to do before finalizing anything. Commenters ranged from biologics and biosimilar manufacturers to third-party payers and trade associations.
Most commenters addressed the same points: the distinction between interchangeability and biosimilar, switching studies, use of foreign reference products, and the necessity of demonstrating interchangeability in all indications or uses and in all presentations. Questions are raised throughout the comments about what interchangeability actually means: is it a higher standard or just an additional data requirement? Is it therapeutic equivalence? And everyone is nervous about whether FDA will use labeling or nonproprietary naming or something totally new to indicate that a biosimilar is interchangeable. The commenters were also torn on the use of foreign reference products – mostly breaking down into a cost compared to safety argument.
Interestingly, almost all of the comments complimented FDA on its “flexible approach” to interchangeability, but proceeded to ask FDA for more precise testing requirements. Some want more human factor requirements while others want more in-depth switching study requirements. And comments really want FDA to lay out its plan for post-marketing changes to innovators after findings of interchangeability.
A lot of these questions are familiar to commenters, as they echo the questions that have arisen during the rocky implementation of the Hatch-Waxman Act and the abbreviated new drug pathway. Questions about whether interchangeability needs to apply to all conditions of use seem like they are a direct response to the common practice of skinny-labeled generics. And questions about exclusivity when multiple applications for interchangeability are submitted and ready for approval on the same day smacks of post-MMA questions that have taken FDA years to address. There is a lot of overlap in the biologic and drug industry, so a lot of these players have been burned before. Hence, the push for clarity, I presume.    
It’s clear that FDA is not going to be able to please everyone with its interchangeable procedures. With so many commenters asking for diametrically opposed standards, there will be some tough decisions to make. And as we have seen in the Hatch-Waxman context, the trade-off between innovation and access is complicated. The one thing that all of the commenters have made pretty clear though is that they want FDA to take action and give some clear direction to manufacturers here. With the plain language of the BPCIA already subject to multiple interpretations, industry is really relying on FDA for some semblance of clarity here. As the Rolling Stones so eloquently said “you can’t always get what you want, but if you try sometimes, well you just might find, you get what need.” Maybe these comments will push FDA to give industry the clarity it needs, but one can only hope.

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Coalition of Consumer Advocates Challenges FDA’s GRAS Notification Final Rule

Coalition of Consumer Advocates Challenges FDA’s GRAS Notification Final Rule

By Ricardo Carvajal –
A coalition of consumer advocates filed a lawsuit challenging FDA’s final rule that formally established the GRAS notification system.  The complaint alleges that the rule “unlawfully subdelegates statutory authority to private parties,” that the “secret GRAS system is contrary to the FDCA,” and that the “criteria for GRAS determinations are contrary to the FDCA.”  Plaintiffs ask the court to vacate the rule and direct the agency to “correct the legal deficiencies found by the court.”
The lawsuit was foreshadowed in critical press releases issued by two of Plaintiffs shortly after issuance of the final rule, and is the latest parry in Plaintiffs’ years-long battle to call attention to alleged deficiencies in FDA’s oversight of the GRAS exception.  The central allegations and arguments in the complaint have been previously raised and addressed in one or another context, so we won’t belabor them here (see, for example, FDA’s memorandum submitted to the court in prior litigation, and our prior postings here and here).  Essentially, Plaintiffs fault FDA for not imposing certain requirements on industry that FDA lacks any apparent statutory authority to impose.  For those seeking an antidote in the form of a more constructive take on the GRAS system, we suggest this supplemental issue of Regulatory Toxicology and Pharmacology. 
The merits of Plaintiffs’ case may be entirely beside the point.  Industry should expect that the litigation will be used as a cudgel in the court of public opinion as it unfolds.  In the interim, FDA will be forced to expend its scarce resources to defend Plaintiffs’ dubious claims – a result that seems unlikely to advance the cause of food safety.

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DEA Administrative Decisions Update: Has DEA Established New Grounds for Summary Disposition?

DEA Administrative Decisions Update: Has DEA Established New Grounds for Summary Disposition?

By John A. Gilbert, Jr. & Andrew J. Hull –
Numerous prior DEA final orders have been based on a summary disposition. Summary disposition is a procedure used by government counsel to seek a recommended decision by the Administrative Law Judge (“ALJ”) to revoke a DEA registration without proceeding to a hearing on the facts. It is similar to summary judgment in federal court, and is used when there are undisputed facts that are dispositive of a matter. The aforementioned DEA cases have all used summary disposition in cases where it is undisputed that a practitioner has lost state authority to handle controlled substances (see our previous post here).
However, a recent administrative decision by the DEA Acting Administrator appears to expand the basis whereby DEA will grant summary disposition to allegations of material falsification of an application for DEA registration. To our knowledge, DEA has never used summary disposition to adjudicate a matter other than loss of state authority. Yet the Administrator’s decision in Richard J. Blackburn, D.O., 82 Fed. Reg. 18669 (Apr. 20, 2017), holds that an allegation of material falsification of an application—at least in that case—can be properly decided on summary disposition.
Material falsification of an application for DEA registration is an independent and discretionary ground for granting an application or revoking a registration. 21 U.S.C. § 824(a)(1). The Administrator’s decision in this case is noteworthy because, unlike loss of state authority where the agency believes state licensing is a prerequisite to maintaining a DEA registration, proof of material falsification can be overcome by acceptance of responsibility by the registrant and remedial actions. See The Lawsons, Inc., 72 Fed. Reg. 74334, 74338-39 (Dec. 31, 2007).
In the present matter, DEA issued an Order to Show Cause to the physician in September 2016, proposing the denial of the physician’s application for DEA registration on two separate grounds: loss of state authority and material falsification of his application. The physician requested a hearing, and explained in his request that “any irregularities in his application were done by mistake.” 82 Fed. Reg. at 18670. DEA moved for summary disposition on both grounds, though it had originally indicated that it believed a hearing was necessary for the material falsification allegation. The physician failed to respond to DEA’s motion, and the ALJ deemed the summary disposition motion as unopposed.
The ALJ granted the summary disposition motion as to the loss of state authority, but declined to grant the motion on the material falsification allegation because the physician had earlier specifically denied this allegation. The government contended in its exceptions to the ALJ’s recommended decision that there was no dispute that multiple answers to the physician’s application were false (the physician had surrendered a state license, but indicated that he had never surrendered a professional license for cause, and had provided a state license number when, in fact, he did not hold a state license).
On review, the Administrator agreed with the ALJ regarding the summary disposition related to loss of state authority. However, finding that the practitioner had falsified his application, he ruled that the ALJ erred in not granting summary disposition on the material falsification allegation, and stated that the “Government was entitled to summary disposition on the allegation that Respondent materially falsified his . . . application.” Id. at 18673. He also held that the physician had waived his right to present evidence refuting the government’s prima facie showing on material falsification and on the issue of remediation by failing to respond to the government’s motion. Id. at 18671-72.
There are a few important takeaways. First, the issue of whether the material falsification allegation should be decided on summary disposition had little immediate practical effect as the Administrator was still going to deny the application on loss of state authority. The government likely sought a ruling on this ground so that the final order could have preclusive effect in a future hearing if the physician ever reobtained his state license and applied again for a DEA registration. So, the intent may not have necessarily been to establish a new standard.
Second, the physician likely would have saved himself from summary disposition on the material falsification ground if he had responded to the government’s summary disposition motion as directed by the ALJ.
Third, and finally, regardless of whether the facts of this case may have been unique in providing a basis for summary disposition on the material falsification issues, all registrants, including manufacturers, distributors, and practitioners, should be on notice of DEA’s potential use of summary disposition on material falsification grounds in future cases. In our opinion, the bright line where a practitioner either does or does not have a current state license is not the same case as responses to DEA liability questions on an application related to whether the applicant has been subject to prior disciplinary actions, suspensions, surrenders, or even convictions. Often, it is not as evident whether the answer to these questions is “Yes” or “No.” Thus, a broad application of summary disposition in cases where DEA believes that an applicant has provided the wrong answer to such questions and where the registrant is not permitted the opportunity to put on evidence of acceptance of responsibility and remedial actions, would shortcut current agency precedent and due process protections.

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