FDA Lawyers Blog

Towards the end of last year, FDA added two new final guidances related to the safety reporting requirements for investigational new drug exemptions ("INDs") and bioavailability and bioequivalence ("BA/BE") studies entitled: Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies and Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide. These guidances are intended to explain final rules published on September 29, 2010 that amended the IND safety reporting requirements under 21 C.F.R. Part 312 and added safety reporting requirements for individuals conducting BA/BE studies under 21 C.F.R. Part 320. We blogged on that development then.

A key focus of the new regulations was to add clarifying definitions to certain terms, "adverse event", "suspected adverse reaction", "unexpected" adverse event or reaction, "serious" adverse event or reaction, and "life-threatening", as well as further define reporting requirements. According to the main Guidance (not the one for small entities), sponsors frequently took a broad reading of the phrase "associated with the use of the drug" in the context of the former 21 C.F.R. § 312.32(a), which stated, "there is a reasonable possibility that the experience may have been caused by the drug." With this broad reading, the Guidance continues, "sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event." The Guidance includes three examples of overzealous reporting, including reporting adverse experiences that were manifestations of the underlying disease, common occurrences in the study population independent of drug exposure, or study endpoints. FDA described these types of reporting as a drain on agency resources and "uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection."

Interestingly, this appears to be somewhat of a departure from how FDA had enforced its reporting regulations on clinical investigators. Shortly after I first joined FDA in the 1990s, I was involved in a clinical investigator disqualification proceeding that resulted in a clinical investor being disqualified from further clinical studies because, among other things, he had not timely or accurately reported certain adverse events. While the Presiding Officer took into account that many of the patients had underlying conditions prior to the experimental therapy, the Center for Drug Evaluation and Research ("CDER's") approach appeared to focus on the need for the investigator to report all adverse event associated with the therapy. In this case, the therapy had to do with infusing a drug with a catheter to help dissolve gall bladder and common bile duct stones, which the CDER described as a drug/device. The investigator admitted that he had not immediately reported certain events that occurred as a result of the catheter insertion (most likely not due to the drug) or the patient's underlying conditions, because in his opinion, they were not associated with the drug therapy. At that time, CDER took the approach that the investigator's opinion was irrelevant, because the adverse events were at least temporally associated with the drug/device and therefore had to be timely reported.

FDA Partner Brian J Malkin helped suggest key topics for and was quoted in an FDAnews article published on January 2, 2013, entitled "Landmark Year for Generics Cues Big Changes, Rulings in 2013". First, Mr. Malkin was quoted in a section regarding risk evaluation mitigation strategies. Here, FDAnews wrote:

...But generic-makers failed to win a key provision that would have allowed access to hard-to-obtain products covered under risk evaluation and mitigation strategies (REMS).

... The loss of the REMS provision may be mitigated by the FDA's move to more classwide REMS, a strategy that could keep brand drugmakers from using patents on the plans to block generic competition, Brian Malkin, a partner at Frommer Lawrence & Haug, said.

The Solicitor General has urged the U.S. Supreme Court to deny GlaxoSmithKline's ("GSK's") pending certiorari petition in GlaxoSmithKline v. Classen Immunotherapies, Inc., case number 11-1078 The issue facing the Supreme Court should it grant GSK's petition is whether the Federal Circuit correctly interpreted 35 U.S.C. § 271(e)(1)'s safe harbor as applying to only pre-market approval of generic counterparts. In its amicus brief submitted late last week, the Solicitor General explained that there is no need to clarify the safe harbor provision and voiced concerns that the Classen case would not be the proper vehicle to do so should the Supreme Court feel the need.

The dispute between GSK and Classen involves three patents, U.S. Patent Nos. 6,638,739, 6,420,139, and 5,723,283, which relate to methods of optimizing vaccine immunization schedules to decrease the risk of developing chronic immune-mediated disorders. Classen sued a number of defendants, including GSK, alleging infringement of its patents through various vaccination research projects. GSK's allegedly infringing activities related to its participation in a government study that evaluated a suggested association between the timing of childhood vaccinations and the risk of developing type 1 diabetes. GSK argued, and the district court agreed, that such activity was within section 271(e)(1)'s safe harbor because the information was ultimately submitted to FDA. On appeal, the Federal Circuit reversed, holding that section 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained." Classen Immunotherapies, Inc. v. Biogen Idec at 1070. The Federal Circuit further explained, "§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration." Id. at 1071.

In the amicus brief, United States Solicitor General Donald Verrilli expressed his belief that the Federal Circuit's interpretation of § 271(e)(1) in Classen was incorrect. 35 U.S.C. 271(e)(1) reads:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

This Tuesday, the European Parliament approved European Union ("EU") regulations creating a European patent with unitary effect ("unitary patent") and setting forth related language translation requirements. The unitary patent, granted by the European Patent Office ("EPO"), will be offered in addition to already-existing national patents. It will be effective across the EU (except Spain and Italy) and enforceable with a single court ruling.

If ratified by at least thirteen states including France, Germany, and the United Kingdom, a Unified Patent Court ("UPC") will exercise exclusive jurisdiction over unitary patents. The UPC Agreement will come to vote in February of next year. (Notably, the Court of Justice of the EU ruled last March that a proposed unified patents court would not be compatible with EU treaties.) The unitary patent is set to take effect beginning in 2014 or when the UPC is ratified, whichever is earlier.

European Commissioner Michel Barnier declared the "long-awaited agreement" a "decisive contribution to the implementation of the economic and growth agenda." Barnier let the numbers speak for themselves: "In the United States, in 2011, 224 000 patents were granted, in China 172 000 while here in Europe only 62 000 European patents were delivered. One of the reasons for this difference is without a doubt the prohibitive cost and the complexity of obtaining patent protection throughout the single market."

On December 12, FDA held a meeting of its Drug Safety and Risk Management ("DSaRM") Advisory Committee regarding development of a framework for addressing what risk evaluation and mitigation strategies ("REMS") are appropriate for teratogenic drugs. Teratogenic drugs are drugs that may cause birth defects for developing fetuses. The Food and Drug Administration Amendments Act ("FDAAA") requires FDA to bring to the DSaRM Advisory Committee for review at least one drug with Elements to Assure Safe Use ("ETASU"), and this was the topic chosen for 2012.

According to the opening remarks, FDA has recognized that over the years, its approach regarding the development of risk management programs for teratogenic drugs "appears to be inconsistent." The DSaRM Advisory Committee began with FDA presentations, continued with stakeholder presentations from industry, prescribers, patients, and then ended with the full committee's discussion of the questions to address:

FDA's proposed framework would take as intrinsic factors: (1) scientific evidence of teratogenicity (biological plausibility, non-clinical data, and human data) and (2) drug-product related factors (characteristic of the drug product, efficacy, and safety profile). The proposed extrinsic factors to consider in the framework are (1) drug product-related factors (actual drug use), (2) clinical-use related factors (characteristics of medical condition, patient population profile, and context of care), (3) regulatory factors (regulatory precedent, previous REMS experience, availability of new REMS tools), and (4) anticipated consequences of REMS.

On December 7, 2012, the U.S. Supreme Court granted the Federal Trade Commission's ("FTC's") certiorari petition and will address the question of whether settlements of Hatch-Waxman pharmaceutical patent litigation that include so-called "reverse-payments" are per se lawful unless the underlying patent litigation was a sham or the patent was obtained by fraud or, instead, are presumptively anticompetitive and unlawful.

As previously reported here, the FTC has repeatedly attacked reverse payment agreements between branded and generic pharmaceutical companies, alleging that such settlements--which the FTC also refers to as "pay-for-delay"--are a violation of antitrust laws. There is currently a split in the circuits regarding the legality of these agreements. In the decision now being reviewed by the Supreme Court, FTC v. Watson Pharmaceuticals, Inc. (involving the brand-name drug AndroGel), the Eleventh Circuit held that such settlements are legal so long as they fall within the "scope of the patent" and there is not evidence of sham litigation or fraud in obtaining the patent. Other courts have arrived at similar conclusions, including the Second Circuit (In re Tamoxifen Citrate Antitrust Litigation) and the Federal Circuit (In re Ciprofloxacin Hydrochloride Antitrust Litigation). In contrast, the Third Circuit's recent In re K-Dur Antitrust Litigation decision held that these agreements create a rebuttable presumption that the settlement is anticompetitive. Both Merck and Upsher-Smith filed petitions to the Supreme Court to review the Third Circuit's K-Dur decision; however, the Court has not yet announced whether it will grant those requests.

In AndroGel, the FTC asks the Supreme Court to adopt the Third Circuit's approach. The FTC argues that the "scope-of-the-patent approach in general, and the decision of the [Eleventh Circuit] in particular, reflect a misapplication of federal competition law." Thus, the FTC advocates for the Third Circuit's "approach, [in which] the restraints embodied in reverse-payment agreements are presumed to be anticompetitive, and the antitrust defendants--who, after all, have settled litigation against each other by agreeing not to compete--bear the burden of advancing some countervailing procompetitive virtue." (Internal quotation omitted).

FLH Partner Brian J. Malkin's chapter in the 2013 Edition of Recent Developments in Food and Drug Law published by Aspatore / Thomas Reuters entitled: "Challenges to the Development of a Biosimilars Industry in the United States" is now available as a PDF copy. The chapter takes a hard look at the new biosimilars pathway created by the Biologics Price Competition and Innovation Act of 2009 ("the Biosimilars Act") and attempts to answer the question why no applicant appears to have filed a biosimilars application with FDA more than two and a half years after the Biosimilars Act was enacted. Some of the topics addressed include:

• The Impact of the Biosimilars Act and Approval Issues for Biosimilars


• Biological Innovator Challenges to Biosimilars


• Interchangeability Issues


• Biosimilar Manufacturing Issues


• Patent Litigation and Confidentiality Issues


• The FDA's General Approach Based on Its New Guidances


• The FDA's Inverted Pyramid Approach


• Enforcement/Pharmacovigilance Issues


• Product Shortages, Liability, and Advertising Issues


• Key Takeaways

Biosimilars are defined under the Biosimilars Act as "highly similar" to an innovator's biological product already approved by FDA. Biosimilars are also known around the world as follow-on biologics or biogenerics. Biosimilars are already approved in Europe and other countries and are clearly feasible given current technology and analytical methods. Ultimately, as there are less small molecule targets for generic companies to pursue over time, innovator and generic drug companies alike will be drawn to design, test, and file applications for biosimilars. FDA appears to have hoped that the new biosimilars pathway would create partnerships to form standards for analytic testing of biosimilars. Instead, the high cost and technical skills to reverse engineer the innovator's product and manufacture biosimilars has driven innovator and generic drug companies to form unique partnerships to develop proprietary analytical methods, including methods with either trade secret or patent protection.

On November 19, 2012, FDA issued a draft Guidance entitled, "Electronic Source Data in Clinical Investigations." The Guidance recommends various procedures relating to the electronic capture of source data in clinical investigations in an effort to reduce errors, to provide real-time data access, and to maintain accurate records for inspection by study investigators and FDA.

Clinical Data Guidance

Source data includes all information found in original clinical investigation documents (or certified copies of original documents) and this information is used for the reconstruction and evaluation of clinical trials. Accurate transcription of source data is extremely important, and the Guidance discusses methods of identifying source data, creating easy identification methods for auditing, capturing source data, and reviewing and retaining the data. The Guidance discusses the identification of source data originators, the capture of source data, the creation of data element identifiers, and the investigator's duty to review and retain electronic data.

The Guidance focuses on data entered into electronic case report forms ("eCRFs"). An eCRF is an electronic record, created for all clinical study subjects, that is reported to the study sponsor as per the study protocol. eCRFs contain data elements that are entered into the system by data originators such as investigators, medical devices, and clinical investigation subjects. Data elements are the smallest units of observation made during a clinical investigation and they include observations such as weight, birth date, race, or body temperature. The Guidance recommends that each sponsor and investigator maintain a list of data originators (e.g., people and devices) authorized to enter data elements for each study protocol. These lists limit access to data entry by creating unique user names, passwords, and identifications and by setting time periods for when each data originator can enter data.

Last Friday, the Supreme Court decided to consider the question presented by generic drug manufacturer Mutual Pharmaceutical Co. ("Mutual") whether federal law "preempt[s] state law design-defect claims targeting generic pharmaceutical products because the conceded conflict between such claims and the federal law governing generic pharmaceutical design allegedly can be avoided if the makers of generic pharmaceuticals simply stop making their products." This issue emerges from the First Circuit's affirmation of a $21 million verdict against Mutual in a state law products liability action.

This case originated in the District of New Hampshire, where Karen Bartlett filed suit against Mutual alleging that its anti-inflammatory drug sulindac (reference listed drug: Clinoril®) is "unreasonably dangerous" under New Hampshire products liability law. Bartlett had a severe allergic reaction to the product resulting in the loss of more than 60% of her outer skin layer. The New Hampshire Supreme Court has adopted § 402A of the Restatement (Second) of Torts ("RS (2nd) § 402A"), which imposes strict liability for selling "any product in a defective condition unreasonably dangerous to the user or consumer." Under New Hampshire law, this requires a showing that "the magnitude of the danger outweighs the utility of the product," regardless of whether there is a safer alternative design. Vautour v. Body Masters Sports Indus., Inc., 784 A.2d 1178, 1182-83 (N.H. 2001).

At issue is whether the Drug Price Competition and Patent Term Restoration Act of 1984 ("Hatch-Waxman Amendments") and corresponding FDA regulations preempt design defect claims that are based in state tort law directed towards generic pharmaceutical products, such as Bartlett's New Hampshire claim. The relevant sections of the Hatch-Waxman Amendments require a generic drug manufacturer to show that its product (1) has the same "route of administration," "dosage form," and "strength" as, and (2) is "bioequivalent" to, the brand name drug that its application references, in order to gain FDA approval. See 21 U.S.C. § 355(j)(2)(A). Mutual argues that these "sameness" requirements preclude generic manufacturers from materially altering the design of their products, and that a generic's ability to comply with both federal and state law by withdrawing its product from the market ("the stop selling theory") is not a valid rationale for finding non-preemption.

On November 30, Endo Pharmaceuticals Inc. ("Endo") sued FDA, seeking declaratory and injunctive relief for FDA to determine that Endo's original Opana® ER (oxymorphone hydrochloride extended-release) was withdrawn from sale for safety reasons, because the product is inherently vulnerable to misuse and abuse. The current crush-resistant formulation of Opana® ER, which goes by the same name, was approved in December 2011, and Endo began marketing this formulation, which Endo called "Opana® ER CRF" in its Complaint to distinguish it from its earlier-marketed formulation. For consistency and clarity, this blog will use the same nomenclature. Endo's complaint states that Opana® ER CRF is bioequivalent to Opana® ER but embeds the active ingredient in a polyethylene oxide matrix to make the pill harder and less crushable, as well as more difficult to liquefy and inject.

According to the Complaint, Endo discontinued Opana® ER on May 31, 2012, because it believed Opana® ER CRF to be less susceptible to misuse and abuse. Endo believes that FDA was required to make a determination whether Opana® ER was withdrawn from the market "promptly" (emphasis in original), because, by this time, FDA had already approved two generic versions to be marketed by Impax Laboratories, Inc. ("Impax") and Actavis South Atlantic LLC ("Actavis"). Endo's Complaint further explains that when FDA failed to make a prompt determination. it filed a Citizen Petition, requesting that FDA make the determination that Opana® ER was discontinued for reasons of safety and cannot be a reference listed drug and that only Opana® ER CRF can have generic versions, which must be similarly crush resistant. Endo further filed a second Citizen Petition and supplemented its original Citizen Petition. The second Citizen Petition sought to classify Opana® ER CRF as a separate dosage form to Opana® ER and require generic versions of Opana® ER CRF to be similarly crush-resistant. The supplement to its original petition included data suggesting that Opana® ER CRF resulted in less reports of abuse and diversion, among other things, which is also described in the Complaint.

Endo's Complaint asserts that Opana® ER was safe and effective when used according to its FDA-approved labeling, but it became evident over time that it posed risks to humans. First, when crushed into a fine powder and inhaled or otherwise ingested, the active ingredient could be released very quickly, risking overdose. Opana® ER could also be chewed, either inadvertently or intentionally, also causing an accelerated release of its active ingredient. Approximately one year after introduction of Opana® ER into the market, Endo decided to develop a crush-resistant formulation with a German partner to reduce these potentials for abuse and misuse, the Complaint recounts..

On November 30, 2012, the U.S. Supreme Court decided to consider the question of whether human genes are patentable subject matter. The American Civil Liberties Union ("ACLU"), representing petitioner Association for Molecular Pathology, challenged Myriad Genetics' patents claiming "isolated" DNA molecules. The ACLU's position is that such patents improperly claim laws of nature and, thus, are not patentable. The Federal Circuit Court of Appeals disagreed, however, determining that Myriad's claims to isolated DNA molecules are patent-eligible. Now, the Supreme Court may have the final word.

At issue is the patentability of human genes, i.e., DNA. Natural DNA exists in the human body as one of forty-six large, contiguous DNA molecules. In contrast, isolated DNA is a free-standing portion of a larger, natural DNA molecule. Isolated DNA has been cleaved (i.e., had covalent bonds in its backbone chemically severed) or synthesized to consist of just a fraction of a naturally occurring DNA molecule. The Federal Circuit reasoned that isolated DNA has a "markedly different chemical structure compared to native DNA." This is because isolated DNA results from human intervention to cleave or synthesize a discrete portion of a native chromosomal DNA, which imparts a distinctive chemical identity on that isolated DNA. Thus, the Federal Circuit decided that the "claimed isolated DNA molecules are distinct from their natural existence as portions of their larger entities" and are patent-eligible subject matter.

In its Supreme Court petition, the ACLU argued that patents on isolated DNA improperly claim products and laws of nature because isolated DNA is defined according to a naturally-occurring functional characteristic, namely coding for a naturally-occurring polypeptide. The ACLU alleges that isolated DNA does not have markedly different characteristics from DNA found in nature because both are DNA, their structures are not markedly different, the protein coded by each is the same, and their use in storing and transmitting information about a person's heredity is identical. Based on this, the ACLU believes that isolated DNA is not patentable subject matter.

On November 28-29, 2012, the American Conference Institute ("ACI") held in Boston, Massachusetts, its inaugural conference: "Orphan Drugs and Rare Diseases: Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process". The Conference was well attended and featured a pre-conference boot camp on the Orphan Drug Act as well as a post-conference master class on overcoming clinical trial challenges and proving the safety and efficacy for orphan drugs.

One highlight of the conference was Timothy R. Cote, M.D., M.P.H., Principal, Cote Orphan Consulting (Director of FDA's Office of Orphan Drug Products Development (2007-2011)). Cote provided a back drop for how the Orphan Drug Act came about, emphasizing that while for each individual disease the afflicted patient population is small, when all of the orphan diseases are pooled together, actually the population is sizable and a rapidly-growing area. Dr. Cote described orphan drug development as a "high touch" field where the need for new therapies are often driven by families with afflicted members and typical "big pharma" strategies are less effective. Calling it "scrappy not crappy" science, Cote explained that unlike big pharma projects that involve thousands of patients and hundreds of millions of dollars to develop new therapies, orphan drugs often can be developed for under $10 million--in part because there are so few patients who are candidates for clinical studies and treatment. Cote said while approximately 60% of orphan drug designation requests are approved, the success stories are the products that obtain new drug application approval and win the highly-coveted seven-year exclusivity for the first orphan indication ("a horse race"). More importantly, the basic research required to find cures for orphan drugs often provides valuable medical knowledge in how our bodies work, which he called "pharma karma."

Another highlight of the conference was Christopher-Paul Milne, D.V.M., M.P.H., J.D., Associate Director, Tufts Center for the Study of Drug Development, Tufts University. Milne said that while the initial orphan market was thought of as relatively small, there are often higher rates of return than more "mainstream" diseases, particularly for diseases with more options for treatment. One phenomena that he tracked was the "ultra orphans," where the orphan population for treatment, which is restricted to less than 200,000 when applied for orphan drug designation in the United States, can get closer to the 200,000 number, and sometimes can expand to more mainstream numbers, if the therapy is later found to have non-orphan treatment options. While certain disease areas such as various cancers have good orphan drug representation, other therapeutic areas, such as neurology, have had less success stories, Milne reported. Milne added that amidst the tension of competition versus collaboration, it has often been important for unlikely partners to work together, with the help and motivation of patient groups, such as the National Organization for Rare Diseases ("NORD").

On November 13, 2012, Cumberland Pharmaceuticals Inc. ("Cumberland") sued FDA, the Commissioner of Food and Drugs, and the Secretary of Health and Human Services in federal district court for the District of Columbia for denying Cumberland's Citizen Petition and approving InnoPharma, Inc.'s ("InnoPharma's") abbreviated new drug application ("ANDA") for an acetylcysteine injection. Cumberland asserted that the denial of the Citizen Petition and the approval of InnoPharma's ANDA were "arbitrary, capricious, and abuse of discretion, and not in accordance with law, all in violation of the APA [Administrative Procedure Act]" and "violated the Federal Food, Drug, and Cosmetic Act ('FDCA')," according to its complaint.

Cumberland holds the approved new drug application ("NDA") for the reference listed drug ("RLD"), Acetadote®, indicated to prevent or lessen hepatic injury in adults and children when administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen. The original formulation of Acetadote® contained edentate disodium ("EDTA") as a chelating agent that was believed to be necessary for the stability of the product. FDA approved Acetadote® in January of 2004, but conditioned its approval on Cumberland's agreement to perform post-approval studies to evaluate whether EDTA could be removed from the formulation in view of safety concerns. EDTA has been associated with a significant drop in serum calcium levels, which may result in fatality, hypokalemia, hypomagnesaemia, or hypotension as well as allergic reactions.

As a result, Cumberland developed and obtained approval in January 2011 from FDA for a new EDTA-free formulation after, according to the complaint, surprisingly demonstrating that EDTA was unnecessary to maintain drug stability. Cumberland then withdrew the EDTA-containing formulation from the market.

American Conference Institute (ACI) will be holding its inaugural Legal, Regulatory and Compliance Guide to Orphan Drugs and Rare Diseases in Boston at the Hyatt Regency on November 28-29, 2012. This unique program features a distinguished faculty of over two dozen leading legal and regulatory orphan drugs and rare diseases experts - including the former director of FDA's Office of Orphan Products Development, senior in-house pharmaceutical counsel, leading patient advocates, and preeminent FDA and patent attorneys - who will address the intricacies of the FDA's orphan drug designation process as well as the challenges affecting orphan drug development and commercialization and overall patent portfolio considerations.

The ACI conference provides a comprehensive forum for the industry to discuss the latest legal and regulatory developments affecting orphan products and therapies for rare diseases and to analyze the strategic considerations in drug development aimed at providing patients facing an unmet medical need with safe and effective life changing therapy. In light of recent cases concerning FDA enforcement of orphan exclusivity, the conference will also feature a spotlight session on "Protecting Orphan Drug Designation and Proactively Guarding Against Potential Liability."

More information about this event, including a full agenda, faculty list, and brochure can be accessed at www.AmericanConference.com/orphandrug

FDA Lawyer's Blog discount code: FDA 200

Last week, FDA denied a Citizen Petition filed by Jazz Pharmaceuticals, Inc ("Jazz"). The May 18, 2012 Petition concerned bioequivalence studies relating to Xyrem® (sodium oxybate), Jazz's oral solution indicated for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. Before issuing its decision, FDA received and considered public comment from Roxane Laboratories ("Roxane"), who had an Abbreviated New Drug Application ("ANDA") referencing Xyrem accepted for review in late 2010.

Jazz asked FDA to take three actions. First, Jazz asked FDA to immediately publish in The Orange Book bioequivalence requirements specifying whether in vitro or in vivo bioequivalence studies, or both such studies, are required for ANDAs referencing Xyrem®. Jazz claimed that FDA's failure to have done so within the first 30 days of Xyrem®'s approval was a violation of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") (See 21 U.S.C. § 355(j)(7)(A)(i)-(ii).) and the Administrative Procedure Act ("APA") (See 5 U.S.C. § 706.). FDA disagreed; the Agency found several flaws with Jazz's arguments. First, requiring the publication of bioequivalence data type for ANDAs within 30 days of new drug approval would be inconsistent with other sections of the FD&C Act, as well as certain FDA regulations. Second, adopting Jazz's arguments would require the Agency to generate and evaluate the scientific data needed to understand bioequivalence characteristics at the time the reference listed drug ("RLD") was approved. FDA disfavored this position, because it would prevent FDA from gaining insight into the characteristics of the RLD during its marketing. Many products never face generic competition, or only do so after the development of acceptable bioequivalence methodologies. As such, FDA reasoned it would be a waste of Agency resources to determine what types of bioequivalence studies are needed within the first 30 days of the RLD's approval. Third, there is no indication Congress meant the statute to require what Jazz sought, and no court has construed the statute as requiring as much. Finally, FDA noted that Jazz's interpretation would actually prejudice those who the statute was meant to protect, i.e., the ANDA sponsors. Requiring FDA to publish bioequivalence requirements within 30 days of the RLD approval would diminish FDA's ability to provide ANDA sponsors with information about the best ways to demonstrate bioequivalence.

Next, Jazz asked FDA not accept for review, review, or approve any ANDA referencing Xyrem® unless and until FDA has published bioequivalence requirements in the Orange Book specifying whether in vitro bioequivalence studies, in vivo bioequivalence studies, or both such studies, are required for ANDAs referencing Xyrem®. Jazz argued that to do so would violate the APA. The drug company reasoned that an ANDA must reference an RLD, and an RLD does not become an RLD until FDA issues the bioequivalence requirements. As such, Jazz concluded that an ANDA can only be accepted for review after FDA issues bioequivalence requirements. Accordingly, Jazz asked FDA to set aside its acceptance of Roxane's ANDA because this was "agency action . . . without observance of procedure required by law," "not in accordance with law," "in excess of statutory jurisdiction, authority, of limitations," and "short of statutory right." Again, FDA declined. The Agency claimed that refusing to accept an ANDA on those grounds would conflict with various FD&C Act sections, including Section 505(j)(2)(A), which delineates what information is required in an ANDA and does not list the bioequivalence requirements, as well as certain FDA regulations. It also refused to accept an interpretation of the statute that would punish ANDA applicants, even if in compliance with the statutory requirements, for FDA's failure to publish the bioequivalence requirements.