By Kurt R. Karst –      

There have been rumors floating around Washington, DC for a few months that efforts were afoot to introduce legislation to amend the FDC Act to address the availability of products subject to a restricted distribution program to generic drug and biosimilar manufacturers for purposes of conducting studies necessary to pursue approval of a marketing application.  Those rumors turned into reality with the September 18th introduction of H.R. 5657, the Fair Access for Safe and Timely Generics Act of 2014 (“FAST Generics Act”).  Introduced in the U.S. House of Representatives by Congressmen Steve Stivers (R-OH) and Peter Welch (D-VT), the bill would “increase consumer access to generic drugs, boost market competition and ultimately save consumers money,” according to a press release announcing the introduction of the FAST Generics Act.  The Generic Pharmaceutical Association, which sponsored a paper published in July 2014 on restricted distribution programs and generic drug competition, applauded the introduction of the bill in a press release.

In case you’re not familiar with the topic of the FAST Generics Act, the issue concerns drug and biological products covered by restricted distribution programs – either under a Risk Evaluation and Mitigation Strategies (“REMS”) program with Elements To Assure Safe Use (“ETASU”) under FDC Act § 505-1, or under a restricted distribution program adopted and implemented by a brand-name manufacturer.  In most cases, in order for a generic drug (or biosimilar) manufacturer to submit a marketing application to FDA, the company must first conduct studies comparing its proposed product to the brand-name reference product.  In order to do so, the generic drug manufacturer must first obtain reference product sample.  Normally drug product sample is easily obtained through various market channels.  Products under a restricted distribution program, however, are tightly controlled (often because of a safety concern) and are not readily available.  If a generic drug sponsor is unable to obtain sample for equivalence testing, then it is unable to seek marketing approval from FDA.

Current law states that “[n]o holder of an approved covered application shall use any element to assure safe use required by [FDA] under [FDC Act § 505-1(f)] to block or delay approval of an application under section 505(b)(2) or (j) or to prevent application of such element under [FDC Act § 505-1(i)(1)(B)] to a drug that is the subject of an [ANDA].”  In June 2009, Dr. Reddy’s Laboratories, Inc. submitted a Citizen Petition (Docket No. FDA-2009-P-0266) to FDA requesting that the Agency “establish procedures to facilitate the availability of generic versions of drug products subject to a [REMS] and enforce the FDC Act to prevent companies from using REMS to block or delay generic competition.”  FDA responded to the petition in August 2013 saying, among other things, that decisions to take enforcement action are made at the Agency’s discretion on a case-by-case basis and that FDA “agrees that issues related to ensuring that marketplace actions are fair and do not block market competition would be best addressed by the FTC,” to which FDA has been referring complaints related to restricted distribution programs. 

In 2012, as Congress was considering legislation that was ultimately enacted as the FDA Safety and Innovation Act (“FDASIA”), there was a push to amend the law to address REMS and generic competition.  Specifically Section 1131 of Senate-passed S. 3187 would have amended FDC Act § 505-1 to state that:

Notwithstanding any other provision of law, if a drug is a covered drug, no elements to ensure safe use shall prohibit, or be construed or applied to prohibit, supply of such drug to any eligible drug developer for the purpose of conducting testing necessary to support an application under [FDC Act § (b)(2) or § 505(j) or PHS Act § 351(k)] if the Secretary has issued a written notice described in paragraph (2), and the eligible drug developer has agreed to comply with the terms of the notice.

That provision was not enacted as part of FDASIA.  As one legislative bulletin issued at the time stated, “[s]ome controversy surrounded this provision since it could have [led] to the FDA forcing drug sales between brand and generic manufacturers.”  In addition, then-FTC Commissioner J. Thomas Rosch objected to including the provision in FDASIA.  Referring to both REMS legislation advocated by FTC staff that would “give the FTC jurisdiction to challenge the refusal of a pioneer drug company to provide product samples to generic manufacturers if the FDA determined that the generic company’s protocols were safe,” and to the REMS provisions in S. 3187, Commissioner Rosch commented that “[n]either proposal should be tacked on to other legislation on the Senate floor and should instead be considered by the Help Committee on their own merits” (see our previous post here). 

Meanwhile, issues concerning ETASU REMS, restricted distribution programs, and generic competition were being debated in court in the context of antitrust law (see our previous posts here, here, and here).  None of the earlier court challenges resulted in a decision, because the cases were settled.  Earlier this year, however, Mylan Pharmaceuticals Inc. filed a lawsuit alleging that Celgene Corporation violated federal and state antitrust laws by preventing generic competition for Celgene’s drug products THALOMID (thalidomide) Capsules and REVLIMID (lenalidomide) Capsules (see our previous post here).  That case is still pending, with a Motion to Dismiss filed by Celgene (Opposition and Reply briefs are available here and here).

The 17-page FAST Generics Act would amend the FDC Act to add Section 505-2, titled “Competitive Access to Covered Products for Development Purposes.”  Proposed FDC Act § 505-2 would add several provisions, including:

(b) COMPETITIVE ACCESS TO COVERED PRODUCTS AS A CONDITION ON APPROVAL OR LICENSING.—As a condition of approval or licensure, or continuation or renewal of approval or licensure, of a covered product under section 505 of this Act or section 351 of the Public Health Service Act, respectively, the Secretary shall require that the covered product’s license holder not adopt, impose, or enforce any condition relating to the sale, resale, or distribution of the covered product, including any condition adopted, imposed, or enforced as an aspect of a risk evaluation and mitigation strategy approved by the Secretary, that restricts or has the effect of restricting the supply of such covered product to an eligible product developer for development or testing purposes. 

(c) COMPETITIVE ACCESS TO COVERED PRODUCTS OTHER THAN REMS PRODUCTS FOR DEVELOPMENT PURPOSES.—No license holder shall adopt, impose, or enforce any condition relating to the sale, resale, or distribution of a covered product that interferes with or restricts access to reasonable quantities of a covered product by an eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product unless the license holder generally adopts, imposes, or enforces lawful conditions relating to the sale, resale, or distribution of a covered product, with respect to other buyers of the covered product.

(d) COMPETITIVE ACCESS TO REMS PRODUCTSFOR DEVELOPMENT PURPOSES.—

(1) PROHIBITED USE OF REMS TO RESTRICTACCESS.—With respect to a REMS product, no aspect of a risk evaluation and mitigation strategy under section 505–1 shall prohibit or restrict, or be construed or applied to prohibit or restrict, the supply of such REMS product to an eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the REMS product’s license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the REMS product.

(2) SINGLE, SHARED SYSTEM OF ELEMENTS TO ASSURE SAFE USE.—With respect to a REMS product, no license holder shall take any step that impedes—

(A) the prompt development of a single, shared system of elements to assure safe use under section 505–1; or

(B) the entry on commercially reasonable terms of an eligible product developer into a previously approved system of elements to assure safe use.

(e) PROCEDURES FOR OBTAINING ACCESS TO COVERED PRODUCTS.—

(1) COMPETITIVE ACCESS.—Notwithstanding any other provision of law, in the case of an eligible product developer that has an authorization to obtain a covered product in effect . . . , no license holder shall adopt, impose, or enforce any other condition relating to the sale, resale, or distribution of such covered product that interferes with or restricts access to reasonable quantities of the covered product by the eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product, unless the license holder generally adopts, imposes, or enforces lawful conditions relating to the sale, resale, or distribution of a covered product, with respect to other buyers of the covered product.

A violation of a requirement or prohibition in any of the above-proposed sections would be treated, in the case of a REMS product, as a violation of the product’s REMS, and would be a prohibited act under proposed FDC Act § 301(ddd).  Also, an “eligible product developer” (i.e., a person seeking to develop an ANDA, 505(b)(2) application, or a BLA) that has authorization for access to a covered product from FDA and that is aggrieved by a violation of one of the above-proposed sections “by a license holder or any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product[,] may sue such license holder for injunctive relief and treble damages (including costs and interest of the kind described in section 4(a) of the Clayton Act (15 U.S.C. 15(a)).”

In addition to laying out the procedures for an interested party to obtain an authorization to procure a covered product, the FAST Generics Act would give FDA the authority to prohibit, limit, or otherwise suspend a transfer of a covered product to an eligible product developer because such transfer would present an imminent hazard to the public health, and would shield NDA and BLA holders from liability for any claim arising out of an eligible product developer’s development or testing activities conducted under proposed FDC Act § 505-2, “including a claim arising out of a failure of the eligible drug developer to follow adequate safeguards to assure safe use of the covered product.”

Finally, the bill would require various reports from FDA and from the FTC on the implementation of proposed FDC Act § 505-2, and would amend FDC Act § 505-1(i)(1)(B) concerning waiver of the single, shared REMS requirement (see our previous post here).  If enacted, the bill would apply to all NDAs and BLAs, regardless of whether or not those applications were approved before, on, or after the date of enactment of the FAST Generics Act. 

By Kurt R. Karst –      

There are mortal sins and there are venial sins.  In the latest guidance documents FDA announced (here and here) earlier this week – a final guidance on ANDA Refuse-to-Receive (“RTR”) standards and a draft guidance on ANDA RTR for lack of proper justification of impurity limits – FDA focuses on the mortal sins of ANDA submission that will generally result in the Office of Generic Drugs (“OGD”) refusing to accept an ANDA for review.  Indeed, the phrase “FDA will refuse-to-receive an ANDA” (followed by or preceded by some example) appears not less than 24 times in FDA’s final ANDA RTR standards guidance. 

Both ANDA RTR guidances were issued on the eve of a September 17th public meeting on implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”).  FDA requested comment at the meeting on the ANDA RTR impurity limits draft guidance and other recent guidances on GDUFA implementation (see our previous posts here, here, and here).  FDA also solicited comment on “GDUFA Implementation Related to Generic Drug Exclusivity” and “GDUFA Implementation and Potential First Generics.”  Although very few comments (see here) were submitted to FDA in response to the Agency’s solitation, we understand that the public meeting was well attended and included statements from an array of generic drug industry stakeholders, including the Generic Pharmaceutical Association (see here and here).  The September 17th public meeting follows a solitication from FDA earlier this year seeking input and suggestions on ways to improve the quality of ANDAs and on how to best communicate those suggestions to the generic drug industry (see our previous post here).  About a dozen comments have been submitted to the docket FDA established for that solicitation.

FDA’s ANDA RTR standards guidance finalizes a draft version of the guidance released in October 2013.  In addition to providing greater clarity around major deficiencies (i.e., mortal sins) that will generally result in an RTR decision and minor deficiencies (i.e., venial sins) that can be easily corrected, the guidance makes several important changes to the draft version.  Bob Pollock from Lachman Consultants covers those changes in his recent post. 

In the ANDA RTR impurity limits draft guidance – a guidance FDA presumably issued in draft form and separate from the ANDA RTR standards guidance because the issue was not addressed in the draft ANDA RTR standards guidance – FDA lays out serious deficiencies in impurity information that could cause FDA to RTR an ANDA. The deficiencies described in the draft guidance include: “(1) Failing to justify proposed limits for specified identified impurities in drug substances and drug products that are above qualification thresholds; (2) failing to justify proposed limits for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) above identification thresholds.” 

As Bob Pollock notes, the position FDA takes in the draft guidance “is consistent with past Guidance issued by OGD on the requirements for justification of impurity limits, but, in the past, OGD has not stated that if such justification is lacking, they will issue an RTR letter rather than handling the issue as a review issue.”  This is an important observation, because it shows that OGD is making an effort to clarify the sometimes fuzzy line between what constitutes a deficiency for ANDA RTR purposes, and what is properly an ANDA review issue (and not an RTR issue).  Indeed, we’re likely to see more follow-on, issue-specific guidances like the ANDA RTR impurity limits draft guidance as the new ANDA filing and review groups within OGD hash things out and establish brighter lines between ANDA filing and review issues.  FDA says as much in the notice announcing the ANDA RTR impurity limits draft guidance: “FDA intends to develop additional guidance documents further clarifying the enhanced refusal to receive standards.”

By James E. Valentine* –

On September 10, 2014, the FDA hosted its 3rd Annual Patient Network Meeting, “Under the Microscope: Pediatric Drug Development,” to explore challenges related to pediatric drug development.  The Patient Network is a program run out of FDA’s Office of Health and Constituent Affairs “to bring the unique perspectives of patients, family members, caregivers, and patient advocates to the decision-making processes of the FDA.”

The meeting consisted of a series of educational and interactive panel discussions, which discussed current regulations that encourage pediatric product development, as well as ways to advance pediatric drug development.  While the meeting focused on patients and patient advocates, the discussions also included perspectives from regulators, industry, and academia.

Dr. Lynne Yao, Associate Director of the Pediatric and Maternal Health Staff in FDA’s Center for Drug Evaluation and Research’s Office of New Drugs, and Dr. Dianne Murphy, Director of FDA’s Office of Pediatric Therapeutics, set the stage for further discussion by presenting the historical framework and challenges for pediatric product development.  There was a consensus that the Pediatric Research Equity Act ("PREA") and the Best Pharmaceuticals for Children Act ("BPCA") have helped facilitate the studies to support approved pediatric labeling (see here), and that the permanent reauthorization in FDASIA was a positive step forward. 

Dr. Robert “Skip” Nelson, Deputy Director and Senior Pediatric Ethicist of FDA’s Office of Pediatric Therapeutics, provided an overview of the ethical framework and regulatory protections for children in research, consisting of (1) scientific necessity, (2) appropriate balance of risk and benefit, (3) parental permission, and (4) child assent. 

Throughout the course of the panel discussions, a series of challenges to pediatric product development arose from both the regulatory and industry perspectives.  An underlying problem is that pediatric studies, like studies of orphan drugs, enroll subjects from a small population.  As a result, there are fewer subjects to enroll in studies, and there may be a limited ability to recoup costs of development and formulations. 

Additionally, it is more difficult to conduct pediatric trials due to the need for multicenter and often international studies in order to enroll adequate numbers of patients, as well as the need for special facilities, equipment, nurses, laboratories, and expertise.  Also, studies require many age subsets or subset analyses because pediatrics covers a wide range of organ developmental maturation, which may affect drug pharmacokinetics, efficacy, and safety.  Other challenges include the need for juvenile animal studies, age-appropriate pediatric formulations, and age-appropriate and validated pediatric endpoints and assessment tools.

Some recommendations from patients, regulators, industry, and academia included:

• A need for the entire pediatric community to insist on incorporation of evidence based treatment sufficient to support pediatric labeling;
• Development of simplified pediatric networks to conduct appropriate clinical trials;
• Education of caregivers about the importance of clinical trial enrollment, understanding the role of a control arm, and the option and ramifications of “opting out;”
• The need for flexibility by FDA in the design of pediatric studies, especially to relieve the tension with formulation development; and
• Increased patient and caregiver input in FDA and industry’s planning and decision-making (i.e., caregiver input on protocols, caregiver participation in protocol simulations).

Ultimately, there was accord among the meeting participants that you protect children not from studies but with studies. 

For more information, the full meeting agenda can be found here and the speaker bios and presentations can be found here.

*Not admitted to practice in Washington, D.C.

FDA’s 510(k) review is based upon the concept of substantial equivalence.  This approach has been much criticized, but in a new article published in the Food and Drug Law Journal and authored by Hyman, Phelps & McNamara, P.C. Director Jeffrey K. Shapiro, Mr. Shapiro concludes that substantial equivalence review is a powerful regulatory tool allowing FDA to ensure that the broad range of moderate risk devices reach the market based upon a reasonable assurance of safety and effectiveness. 

The article, titled “Substantial Equivalence Premarket Review: the Right Approach for Most Medical Devices,” examines substantial equivalence review in detail, looking at its historical development, the operative legal framework, the specific decision steps FDA follows to reach a substantial equivalence determination, and the strengths of the system in fostering efficiency, predictability, and adaptability in the premarket review of medical devices.  The article rebuts the Institute of Medicine’s call to scrap substantial equivalence review (see our previous post here), and rebuts a published study finding that substantial equivalence review results in a disproportionate share of serious recalls.  The article argues that a better public 510(k) database is needed to improve the predictability of substantial equivalence review.  Mr. Shapiro concludes by calling for targeted reform of a basically sound system rather than wholesale condemnation as critics have suggested. 

The integrity of Generally Recognized As Safe (“GRAS”) determinations, and FDA’s reliance on the voluntary GRAS notification process, has come under attack.  Critics allege that, among other things, GRAS determinations employ outdated science; GRAS determinations are rife with conflicts of interest; the safety of food ingredients should be assessed in the same way that pesticides are assessed for safety; GRAS determinations are never re-visited; and the data supporting GRAS determinations are secret.  At the upcoming ISRTP Workshop on GRAS determinations, truly qualified experts will explain the facts and dispel the fictions circulating in the ongoing debate.  Attendees will have ample opportunity to question the experts.  The Workshop will be held on October 13-14, 2014 in Washington, D.C.  Space is limited so rush to register.  A copy of the Workshop agenda and registration information are available here.        

By Larry K. Houck & Andrew J. Hull –

Last week, the Drug Enforcement Administration (“DEA”) published its final rule implementing the Secure and Responsible Drug Disposal Act of 2010 (“Disposal Act”).  79 Fed. Reg. 53,520 (Sept. 9, 2014).  A post appeared here when DEA issued its notice of proposed rulemaking back in December 2012.  DEA considered 192 comments in response to the notice of proposed rulemaking.  The disposal regulations become effective October 9, 2014.

DEA’s final rule significantly expands the options available to ultimate users to dispose of their controlled substances.  Prior to implementation of the final rule, ultimate users (e.g., patients) could only dispose of unused, unwanted and expired controlled substances by destroying the drugs themselves (e.g., by flushing), by surrendering the drugs to law enforcement agencies or by requesting assistance from DEA.  As a result of these limited options, unused controlled substances accumulated in household medicine cabinets, creating a significant risk of diversion or accidental ingestion.  The Disposal Act amended the Controlled Substances Act, requiring DEA to implement regulations permitting ultimate users to deliver the medication to third parties for disposal.  The ultimate goal of the regulation is to decrease unused pharmaceutical controlled substances in households, thereby reducing the risk of diversion and harm.  Some highlights of the new regulation include the following:

Ultimate Users.  The final rule allows ultimate users to continue disposing their unused or outdated controlled substances through previously allowed methods (mentioned above), and creates three other options.  Ultimate users may: (1) drop off the drugs at take-back events overseen by law enforcement agencies; (2) send the drugs to a law enforcement agency or authorized collector operating a mail-back program; or (3) drop the drugs at a collection receptacle maintained by a law enforcement agency or an authorized collector.

Law Enforcement Agencies.  The rule specifically allows law enforcement agencies to conduct take-back and mail-back programs, and maintain collection receptacles at their physical location.

Registrants and Reverse Distributors.  Manufacturers, distributors, reverse distributors, narcotic treatment programs (“NTPs”), hospitals and clinics with on-site pharmacies and retail pharmacies can modify their DEA registrations to become “collectors” (defined as registrants “authorized” to “receive a controlled substance for the purpose of destruction”).  As authorized collectors, they may operate mail-back programs to receive and destroy schedule II-IV controlled substances received from ultimate users.  To operate a mail-back program, they must make packages available to the ultimate user.  Collectors operating mail-back programs must also destroy the drugs onsite.  We anticipate that the on-site destruction requirement will deter many registrants from becoming authorized collectors via a mail-back program.  Authorized collectors permitting take-backs on their premises may install, manage and maintain a collection receptacle for schedule II-IV controlled substances delivered by ultimate users.  Controlled substances collected in this manner may be destroyed onsite or may be transferred to a reverse distributor.  The final rule establishes new recordkeeping and safety requirements for registrants serving as authorized collectors.

Registered NTPs that become authorized collectors may maintain collection receptacles at their registered locations.  The NTPs must maintain the collection receptacles in a securely locked room with limited access that contains no other controlled substances.  Hospitals/clinics with on-site pharmacies, as well as retail pharmacies, that become authorized collectors can also maintain collection receptacles inside their registered locations or at long term care facilities. They may also conduct mail-back programs.

Controlled substances collected through take-back events, mail-back programs and collection receptacles may be comingled with non-controlled substances.  Collectors cannot individually count or inventory the controlled substances they collect through collection receptacles.

DEA has modified  DEA Form-41 (“Registrants Inventory of Drugs Surrendered”), to allow registrants who dispose of controlled substances to account for the destruction of collected controlled substances.

Reverse Distributors. The final rule clarifies the definition of “reverse distribute” and “reverse distributor,” as well as security, inventory and recordkeeping requirements applicable to all entities that reverse distribute controlled substances.  Reverse distributors are now defined as “entities registered with the Administration as [] reverse distributor[s]” (i.e., persons permitted to acquire controlled substances in order to return them to manufacturers or to destroy them). (Specified entities who reverse distribute are not just those registered as reverse distributors).

Destruction.  DEA does not mandate that collectors use a particular destruction method so long as they render the controlled substances “non-retrievable.”  DEA defines “non-retrievable” as “the condition or state…following a process that permanently alters that controlled substance’s physical or chemical condition or state through irreversible means and thereby renders the controlled substance unavailable and unusable for all practical purposes.”  Controlled substances rendered non-retrievable are no longer subject to regulation by DEA.

Costs/Benefits.  DEA recognizes that collection and disposal of controlled substances is voluntary and costly.  DEA notes that costs to collectors may be offset by potential benefits of providing these services, including “increased consumer presence” at the registered locations.

Caveats.  Registrants considering voluntarily becoming authorized collectors must be aware of heightened recordkeeping and other responsibilities.  The voluntary nature of authorized collector status does not obviate a registrant’s duty to comply with these heightened requirements, especially because the additional security and recordkeeping requirements relate to preventing diversion.  See, e.g., Fred Samimi, M.D., 79 Fed. Reg. 18,698, 18,709-10 (Apr. 3, 2014). Second, registrants who take on the responsibility of destroying collected controlled substances should proceed with caution as they develop certain destruction methods.  DEA specifically stated that it would not require registrants to use any particular method of destruction.  DEA’s specific standard of “non-retrievable,” as well as its detailed definition of the same, must guide registrants in fulfilling their responsibilities.  Registrants should be wary of not only the cost of destruction but also the risk of developing a method that DEA may later find does not meet DEA’s interpretation of “non-retrievable.”

Final Word.  Registrants contemplating the merits of becoming collectors should consider the benefits to the community and themselves by assuming these additional responsibilities.  The diversion and abuse of unused and outdated controlled substances is a significant problem, and DEA’s development of this disposal program as part of a congressional mandate, has the potential to address this issue.  Registrants should not, however, accept these new, voluntary responsibilities without also considering the additional recordkeeping and security requirements – not to mention costs – associated with them.

By Michelle L. Butler & Kurt R. Karst –

As we recently reported, the U.S. District Court for the District of Columbia granted Depomed Inc.’s ("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.”  The court’s Memorandum Opinion is now available.  This decision, which finds that “the plain language of the exclusivity provisions of the Orphan Drug Act requires the FDA to recognize exclusivity for any drug that the FDA has designated and granting marketing approval,” Mem. Op. at 33 (emphasis added), has far-reaching implications for FDA’s orphan drug program (and perhaps beyond).

The facts of the case are discussed in our previous posts (here and here).  The court, in its September 5th opinion, decided the case on Chevron Step 1 grounds, which means that the court determined that “the plain language of the Orphan Drug Act requires the FDA to recognize exclusivity for Gralise.”  Id. at 18.  The court stated that the statute

employs the familiar and readily diagrammable formula, ‘if x and y, then z.’  Congress has crafted its command to the Secretary of the FDA in a manner that sets forth two circumstances – a drug that has been designated for a rare disease or condition, and the FDA’s approval of a marketing application for that drug – that, if present, result in a particular consequence: a seven-year period of abstinence regarding marketing approval for other such drugs.

Id. at 20.  Importantly, the court described the orphan drug exclusivity incentive not as a benefit conveyed to manufacturers, but rather as “a restriction of the FDA’s ability to approve the marketing of other such drugs for the same rare disease or condition (referred to herein as ‘new such drugs’) when a drug that has been designated as an orphan drug is approved for marketing.”  Id.  The court asserted that the statute “does not permit or invite discretion on the part of the FDA regarding whether or not to continue authorizing new such drug marketing applications once an orphan drug has been so designated and approved,” citing the fact that the statute specifically identifies only two exceptions to the grant of exclusivity.  Id. at 21 (citing 21 U.S.C. § 360cc(b), which provides exceptions if the manufacturer of a drug with marketing exclusivity cannot assure availability of the drug or provides written consent for approval of other applications).

The court rejected FDA’s arguments that the statute was ambiguous under the circumstances presented, and, therefore, permitted FDA to impose its clinical superiority requirements.  Id. at 22-26.  Among other things, the court stated that

[t]ry as they might, Defendants cannot square their insistence that the FDA has the discretion to address this situation with the fact that, under the statute, Congress did not give the FDA any discretionary authority to grant or deny exclusivity at all – rather, as mentioned previously, Congress forbade the FDA from granting any further approvals when the statutory conditions were met.

Id. at 25.  The court also stated that the structure of the statute “suggests that the intent of Congress was to provide the FDA with a merely ministerial role in the exclusivity process” and operated “by removing FDA discretion to approve the marketing of certain other drugs.”  Id. (emphasis in original).

The court also rejected FDA’s policy arguments that giving effect to the plain language of the statute would lead to an absurd result.  FDA argued that (1) affirming exclusivity for Gralise could permit Depomed to cut off new gabapentin entrants to the market without providing any benefit in the treatment of post-herpetic neuralgia ("PHN") and (2) such an interpretation could result in serial exclusivity for the same drug.  Id. at 27.  The court rejected both arguments.  As to FDA’s first policy argument, the court commented

This policy argument misses the mark by a mile.  To the extent that Defendants’ contention is that Congress never would have intended for a “me too” drug like Gralise to get a benefit that the legislature devised to entice new entrants into the rare-disease treatment market, Defendants’ point is unfounded—nothing in the statute even remotely suggests that Congress intended to incentivize only one sponsor to produce a particular drug (although Congress certainly could have specified as much), and general market forces provide a plausible reason for a legislative scheme that deliberately incentivizes multiple manufacturers of the same pharmaceutical product.  Nor can it be said that permitting Depomed to grasp the brass ring of exclusivity for Gralise is unfair to the manufacturers of the prior iterations of the drug, since each had every opportunity to seek exclusivity and failed to do so.  If, on the other hand, Defendants are making the . . . argument that it would be ‘absurd’ for the same drug as others already on the market to be permitted to cut off the development of new and improved versions, that result appears to be a function of granting a drug marketing exclusivity in any event – i.e., the statute plainly incentivizes investment in drugs for rare disease and conditions precisely because it prevents new (and potentially better) drugs from being adopted and marketed for that same condition – and this is inherent in the exclusivity statute. 

Id. at 29 (emphasis in original).  As to FDA’s second policy argument, that also fell flat with the court:

The second potentially absurd result that Defendants identify is a variation on this same theme—and fails for the opposite reason. . . .  As far as this Court can tell, Defendants are worried that interpreting the statute to mandate exclusivity whenever a drug has obtained designation and approval could lead to a situation in which sponsors that have exclusivity for a particular drug could simply tweak their formulation for that drug and resubmit applications for designation and approval after the initial exclusivity period has expired, thereby gaining successive exclusivity periods. . . .  However, under the statutory scheme as it currently exists, this result would only occur if the FDA permitted it to happen.

Id. at 30 (emphasis in original). 

Taken together, the court’s statements about the effect of exclusive approval could potentially be read to put in jeopardy FDA’s “same drug” regulations, which permit FDA to ignore a previously approved drug’s exclusivity in order to approve a “clinically superior” drug with the same active moiety that will be marketed for the treatment of the same orphan disease.  The court does not explicitly reach this conclusion, but some of the court’s statements about Congressional intent in providing for exclusivity and FDA’s lack of discretion with regard to matters of exclusivity could be read to suggest that, once exclusivity is granted, other drugs with the same active moiety for the same orphan indication cannot be approved during that period of exclusivity.  On the other hand, the court’s statements are generally in the context of whether FDA can decline to grant exclusivity in the first place as opposed to whether the exclusivity, once granted, is inviolable.

Interestingly, the court also notes that

as luck would have it for the FDA, the agency has the ability and the opportunity to control the circumstances under which marketing exclusivity attaches because the FDA is responsible for determining when to designate a drug as an orphan drug under section 360bb, and it is also the agency that has the duty of deciding when and under what circumstances a drug will be approved for marketing.

Id. at 21.  The court seems to be suggesting that, if FDA is unhappy with this turn of events, it can affect whether a drug ultimately obtains exclusivity by applying a stricter standard at the designation step.  Indeed, the court later states that “FDA could require designation applicants to show clinical superiority before granting their product orphan-drug designation. . . .”  Id. at 30. 

There are many initial questions raised by this decision, and there are likely more that will arise as we continue to think through the implications.  Here’s a short list of some of our initial questions:

• Will FDA appeal the decision?  What will the Agency do in the meantime – perhaps seek a stay of the decision?
• What effect will the decision have on pending ANDAs for gabapentin (citing Neurontin as the reference listed drug) that currently include the PHN indication, as well as ANDAs for generic Neurontin approved after the January 28, 2011 approval of Gralise?  Language in the opinion about the scope of exclusive approval suggests that FDA cannot approve any applications (including ANDAs) that contain the same active ingredient (gabapentin) as Gralise for the orphan indication during the period of orphan drug exclusivity.  Would the sponsors of those pending ANDAs need to now “carve out” the PHN indication?
• What effect will the decision have on other drugs with orphan drug designations that obtained approval but were unable to obtain orphan drug exclusivity due to an inability to demonstrate clinical superiority?  Will FDA now grant exclusivity to those drugs?
• What effect will the decision have on FDA’s ability to approve a second drug during a period of orphan drug exclusivity on the basis that the second drug is not “such drug” as the approved drug (i.e., is not the “same drug” under FDA’s regulations) on the basis that it is clinically superior to the approved drug? 
• What effect will the decision have on FDA’s designation process?  Will FDA impose a higher bar at the designation step for drugs that are claimed to be clinically superior?  How can a higher bar to designation be squared with other benefits under the Orphan Drug Act (e.g., tax credits)?  
• What effect will the decision have on FDA’s orphan drug regulations?  If FDA accedes to the court’s reasoning, the current regulations, at least with respect to FDA’s recognition of exclusive approval at 21 C.F.R. § 316.34(c), would need to be revised.  Would FDA take a new look at the clinical superiority requirements more broadly?

By Jennifer D. Newberger –

On August 19, 2014, FDA finalized its guidance document, “FDA Decisions for Investigational Device Exemption Clinical Investigations,” which was issued in draft in June 2013.  The final guidance is largely similar to the draft, with the exception of the pre-decisional IDE process.  As we noted in our blog post on the draft guidance, it was not clear how the pre-decisional IDE process would actually benefit sponsors, since the timeframe for review was essentially the same as without the process. 

In the Federal Register notice announcing the draft guidance, FDA specifically sought feedback on the utility of the pre-decisional process.  In its notice announcing the final guidance, FDA stated:  “Some commenters expressed support for the proposal and felt that it might shorten the time to full approval of pivotal IDE studies. Other commenters expressed concern that the Pre-Decisional IDE process itself might be too time-consuming or require extensive FDA resources that could be better allocated elsewhere. Based on the comments received and FDA’s consideration of the points raised, FDA will not pursue the Pre-Decisional IDE at the present time.”  79 Fed. Reg. 49089, 49090 (Aug. 19, 2014). 

There are two other changes that relate to how information will be conveyed by FDA to the IDE sponsor.  In both the draft and final guidance, FDA states that, if it “identifies concerns unrelated to subject safety which the Agency believes should be addressed to enable the study to support the sponsor’s stated goals (e.g., a future marketing application or future study), FDA intends to communicate these ‘study design considerations’ [SDCs] to the sponsor.” 

In the draft guidance, FDA proposed that these SDCs be included in a section of the IDE decision letter.  In the Federal Register notice announcing the final guidance—but not in the final guidance itself—FDA states that it will provide the SDCs in a separate attachment included with the IDE decision letter.  It is doing so because it “believes that sponsors and other stakeholders may misinterpret SDCs included in the body of a decision letter as issues that are required to be addressed.”  The SDC letter will state:  “These recommendations do not relate to the safety, rights or welfare of study subjects, and they do not need to be addressed in order for you to conduct your study.’’ Id.

FDA also intends to convey “future considerations” in a separate letter.  “Future considerations” are “issues or recommendations that FDA believes the sponsor should consider in preparing for a marketing application or a future clinical investigation but which FDA does not deem necessary to address to enable the current study to support its stated goals.”

One thing that unfortunately did not change from the draft guidance is the language FDA uses with respect to the study design assessment.  The final guidance states that FDA’s decision letter will specify whether FDA believes that “the study design is adequate and may support a future marketing approval or clearance, if it is successfully executed and meets its stated endpoints without raising unforeseen safety concerns.”  Guidance, at 12 (emphasis added).  It is not clear why FDA cannot say that if the study design is adequate, it will support a future marketing approval or clearance, if it meets its endpoints and does not raise unforeseen safety concerns.  The statement about the endpoints and safety concerns is not even the entire caveat FDA provides; the guidance also states that “FDA intends to consider changes to its assessment of the study design only if the sponsor materially changes the device or the study design or important issues relevant to a determination of safety or effectiveness have emerged since it approved the IDE.”  FDA therefore seems to have given itself sufficient “outs” and should be willing to state “will” rather than “may.”  Also, it is interesting to note that FDA only “intends” to change its assessment if certain circumstances arise; it will not commit to only changing its position in those circumstances.  Given all of the qualifying language with respect to a statement that a study design is adequate, FDA is not guaranteeing that a successful study will yield a clearance or approval.  On the other hand, FDA should need to shoulder a high burden to justify changing its views.

By Jennifer M. Thomas & Anne K. Walsh –

French device maker PREVOR won another victory against FDA in litigation involving FDA’s interpretation of the statutory definition for “device.”  The first suit, as readers may recall (see our previous post here), resulted in a finding from District Court Judge Rosemary Collyer that FDA had acted arbitrarily and capriciously in classifying PREVOR’s Diphoterine® Skin Wash (“DSW”) as a combination product to be regulated as a drug.  The Court flatly rejected FDA’s interpretation of the “device” definition, and remanded the matter to FDA to make a new determination in compliance with her opinion.  In its subsequent decision, however, FDA boldly rejected the Court, the law, and FDA precedent, when it introduced a wholly new standard for interpreting the “device” definition (“meaningfully contributes”). So Prevor sued FDA again (see our previous post here).

In the September 9, 2014 opinion, Judge Collyer rightfully rejected FDA’s second attempt to evade the plain statutory language with a novel standard.  She adopted PREVOR’s plain meaning of “achieves,” and rejected FDA’s contention that “meaningfully contributes” is synonymous with “achieves.”  The Court also provided an evaluation of the context and legislative history of the “device” definition to support its decision.  Importantly, Judge Collyer found that “[t]he statute does not demand that FDA quantify the exact contribution of a product’s ultimate goal [in order to classify it as a drug].  However, it does require more than simply finding that the product would not work as claimed without chemical action.”  Slip Op. at 19 n. 7.

In its 23-page opinion, the Court rejected FDA’s decision and its reasoning as being “based on an erroneous and unreasonable interpretation of the law,” and remanded the case to FDA “to determine a standard that complies with the statutory requirements and to classify DSW accordingly.”  We do not know whether FDA will accept the Court’s ruling, but if so, we believe the right result is that FDA should regulate DSW as a device.

Hyman, Phelps & McNamara, P.C. (attorneys Jeffrey N. Gibbs, John R. Fleder, Anne K. Walsh, and Jennifer M. Thomas) represent PREVOR.  Amici curiae in the case include Alcoa, United Steel Workers of America, and the Washington Legal Foundation.

By Riëtte van Laack –

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

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

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

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

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

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

By Kurt R. Karst –      

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

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

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

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

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

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

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

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

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

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

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

By Ricardo Carvajal –

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

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

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

By Kurt R. Karst –    

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Updates:

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

By Kurt R. Karst –  

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

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

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

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

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

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

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

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

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

By Kurt R. Karst –      

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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