FDA Lawyers Blog

On February 20-22, 2013, the Generic Pharmaceutical Association ("GPhA") held its 2013 Annual Meeting attracting over 600 attendees to see how the nation's health and regulatory issues will impact the generic industry and consumers who use generic medicines. While some events are for GPhA members only, a majority of the events are open to all attendees and were held in a single room or exhibit hall. Most of the main events were held in a slickly-decorated room filled with stars, comets, and planets.

While the Meeting covered a lot of territory, recurrent themes appeared to emphasize that the generic industry has come of age, where it joins its big-pharma brothers in having an office on par level with the Office of New Drugs ("OND") in FDA's Center for Drug Evaluation and Research ("CDER") and now pays user fees to speed up generic drug approvals. GPhA's members announced that they are ready to develop high quality generic versions of specialty pharmaceuticals and biologics, some of which may require the expenditure of hundreds or more millions of dollars to develop, obtain approval for, and market. At the same time, GPhA appears to hold onto the notions that that they can continue to settle cases with reverse payments that the Federal Trade Commission ("FTC") views as so-called "pay-for-delay" settlements that are presumptively anticompetitive. GPhA also believes that manufacturers should be allowed to sell generic versions of products with the same labeling as the innovator, when the innovator or generic companies that manufacture and sell the product are aware of safety information not presently included in the FDA-approved labeling.

Kicking off the meeting with a "State of the Association", GPhA President and CEO Ralph G. Neas described generic drugs as the "backbone of the pharmaceutical industry." Neas expressed the Association's confidence that FDA will "come through" and help the industry understand what will be expected of it to develop biosimilars and interchangeable biosimilars, which are the future to save lives and money.

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.

On May 17, Osmotica Pharmaceutical Corp. ("Osmotica") filed a somewhat unusual citizen petition requesting that FDA refuse to approve Sun Pharma Global Inc.'s ("Sun's") 225 mg Venlafaxine Hydrocholoride Extended-Release Tablets because of the size of Sun's tablets.

Wyeth Pharmaceuticals Inc. ("Wyeth") (now Pfizer Inc. ("Pfizer") first obtained FDA approval for Venlafaxine Hydrochloride, an antidepressant sold under the trade name Effexor®, in 1993. Wyeth's patent for the compound expired in 2008, although it still holds Orange Book-listed patents for methods of using extended release venlafaxine. In 1997, FDA approved Wyeth's Extended-Release Capsules, 37.5 mg, 75 mg, 100 mg, and 150 mg, under NDA No. 020699. As an aside, Wyeth's decision to list the method-of-use patents in the Orange Book and to assert them against generic competition has led to allegations of antitrust violations.

Osmotica's 505(b)(2) application (NDA No. 022104) for Venlafaxine HCl Extended Release Tablets, 37.5 mg, 75 mg, 150 mg, and 225 mg, received FDA approval in 2008, referencing Wyeht's Effexor XR® capsules. Later the same year, FDA granted Osmotica's citizen petition requesting that FDA require ANDA applicants, specifically Sun, to submit new ANDAs and conduct new bioequivalence studies using Osmotica's tablets, rather than Wyeth's capsules, as the reference listed drug ("RLD"), because it is the most similar pharmaceutical equivalent (i.e., an extended-release tablet). Sun, an Indian Corporation, subsequently obtained FDA approval for tablets on three of Ostmotica's four dosage strengths, 37.5 mg, 75 mg, and 150 mg. Sun's Venlafaxine HCl Extended Release Tablets have an AB-therapeutic equivalence rating to Osmotica's product (i.e., a generic substitute product).

On March 27, FDA granted final approval to 10 drug companies for their generic versions of AstraZeneca's Seroquel® (quetiapine fumarate) tablets. Seroquel® is used to treat the symptoms of schizophrenia and to treat and prevent mania or depression in patients with bipolar disease. Seroquel® is AstraZeneca's second-best selling drug, generating $5.83 billion in revenue in 2011.

On March 28, 2012, the majority, if not all, of the ANDA filers launched their products. Also on March 28, 2012, AstraZeneca filed a complaint against FDA stating that it is entitled to exclusive rights for Seroquel® until December 2, 2012, and FDA's approval of these ANDAs was unlawful and will cause AstraZeneca irreparable harm. AstraZeneca had filed another law suit against FDA prior to the ANDA approvals, but this suit was dismissed without prejudice on March 23, 2012 based on a lack of ripeness (see our blog on this here). The Court held that AstraZeneca could seek a new action "[s]hould the FDA ever give final approval to a competing generic in a manner that is not to AstraZeneca's liking." Four days later, FDA provided Astrazeneca with notice of approval of the ANDAs for Seroquel®, and AstraZeneca filed the current suit on March 28, 2012.

Similar to the arguments made in the first suit, AstraZeneca claims that it is entitled to a three-year new-patient- population exclusivity period as a result of a labeling change that FDA mandated in the supplemental NDAs that were approved on December 2, 2009. AstraZeneca argues that it is improper for FDA to approve any ANDAs prior to December 3, 2012, because AstraZeneca has exclusive rights to the clinical data that FDA required to be added to its Seroquel® and Seroquel XR® labels.

by Andrew S. Wasson

As promised, ViroPharma filed a complaint in the United States District Court for the District of Columbia for a declaratory judgment and injunctive relief, as well as a motion for a temporary restraining order and/or preliminary injunction against FDA. ViroPharma's lawsuit responds to FDA's decision to mostly deny ViroPharma's Citizen Petition with regard to its Vancocin® (vancomycin hydrochloride) product and the simultaneous approval of three generic vancomycin hydrochloride capsule products (Akorn, Strides Arcolabs Ltd., and Watson Pharmaceuticals) (see our blog here. ViroPharma previously sued FDA in September 2010, only to have the court dismiss ViroPharma's suit for a lack of standing.

In the present action, ViroPharma alleged that: (1) FDA violated the Section 706(A) and (D) of the Administrative Procedure Act ("APA") by adopting and applying in vitro dissolution testing as the bioequivalence method in approving the generic vancomycin products, and (2) FDA violated Section 706 of the APA and the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(c)(3)(E)(iv) and (j)(5)(F)(iv)) by denying ViroPharma's request for the three-year period of regulatory exclusivity. ViroPharma alleged that FDA's actions have been arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.

In particular, ViroPharma characterized the use of in vivo testing as the "traditional" approach to testing for bioequivalence. ViroPharma stated that, "[e]xcept in very limited circumstances, regulations adopted by FDA to implement the statute requires 'bioequivalence' to be demonstrated through in vivo testing, i.e., clinical testing on humans." What is more, ViroPharma alleged that drugs that act locally in the gastrointestinal tract should be treated differently for bioequivalence standards (clinically efficacy and safety endpoints). According to ViroPharma, prior to 2006, FDA consistently held that it would require generic applicants to demonstrate bioequivalence through the use of in vivo studies with clinical endpoints.

by Brian Malkin

On April 9, FDA simultaneously denied ViroPharma's Citizen Petition regarding bioequivalence and labeling requirements for generic Vancocin® capsules (vancomycin hydrochloride)
and approved three generic applications to Akorn, Strides Acrolabs Ltd. and Watson Pharmaceuticals. In an unprecedented 87-page response (with index), FDA responded to a myriad of arguments presented in ViroPharma's original Citizen Petition dated March 17, 2006, as well as its 20 additional supplements and 16 submissions to a public docket for FDA's Draft Vancomycin Bioequivalence Guidance.

FDA's response provides numerous insights into FDA's decision-making process for bioequivalence determinations in addition to FDA's affirmation of its draft generic Vancocin recommendation as "scientifically sound" and "the most accurate, sensitive, and reproducible approach for demonstrating bioequivalence for generic vancomycin capsules." For generic Vancocin® FDA will continue to permit in vitro dissolution data alone to demonstrate bioequivalence for generic Vancocin® capsule versions that contain the same active and inactive ingredients in the same amounts ("Q1/Q2"). Non-Q1/Q2 formulations must perform clinical endpoint studies in patients with Clostridium difficile Associated Diarrhea.

FDA's decision secondarily answered an issue raised in a later supplement regarding certain labeling changes to Vancocin® that was supported with clinical data, which FDA determined would not be eligible for 3 years of clinical data exclusivity because it is not a new indication. According to FDA, "old" antibiotics, such as vancomycin, may only obtain 3-year new data exclusivity for a significant new use or new indication, not for "refinements in labeling related to previously approved used for Old Antibiotics."

by Brian Malkin

On February 7, United States District Judge Amy Berman Jackson granted defendant FDA's motion for summary judgment and denied plaintiff Sanofi-Aventis's ("Sanofi's") cross-motions in Sanofi's challenge of FDA's decision of a citizen petition filed by Sanofi regarding generic versions of Lovenox® (enoxaparin sodium injection), a blood thinning drug. As we reported here in our coverage of FDA's response to Sanofi's citizen petition, Sanofi had requested that FDA withhold generic approvals until enoxaparin had been fully characterized, for any abbreviated new drug application ("ANDA") referencing Lovenox® that did not use an equivalent manufacturing process or did not show proof of equivalent safety and efficacy through clinical trials.

In that decision, FDA had concluded that enoxaparin had been adequately characterized to approve generic applications derived from natural sources and that five criteria would be sufficient to demonstrate "sameness" of enoxaparin in generic products compared to Lovenox®. In FDA's opinion, these elements would demonstrate sameness of enoxaparin, including its 1,6-anhydro ring structure, without (a) the need for a complete characterization of all of the different polysaccharides of exoxaparin, (b) using the same manufacturing processes by Sanofi, or (c) clinical trial data to demonstrate safety and efficacy. FDA's administrative record showed later, however, that while the Office of Generic Drugs ("OGD") supported this five-part test, the Office of New Drug Quality Assessment ("ONDQA") thought that the test was insufficient and the only way to demonstrate enoxaparin sameness was to fully characterize all of the different polysaccharides of enoxaparin.

Following FDA's decision on the citizen petition, FDA approved Novartis's/Sandoz's version and Sanofi filed a complaint that included a motion for a temporary retraining order ("TRO") and preliminary injunction ("PI") to prevent the sale of Sandoz's version and have FDA withdraw approval of Sandoz's version. Since then, the District Court consolidated and denied Sanofi's TRO/PI motion, based on the Court's finding that Sanofi was unlikely to success in its three claims. When these same claims were reviewed by the Court as part of FDA's motion for summary judgment, the Court concluded that all of Sanofi's contentions could be answered in terms of statutory construction:

1. the FDA acted within its statutory authority when it called for Sandoz to file immunogenicity data as part of its ANDA;


2. it did not unlawfully depart from agency precedent by approving a generic before the listed drug had been fully characterized; and


3. it reasonably found that the active in the generic drug was the same as the active ingredient in Lovenox.

by Brian Malkin

On May 6, FDA published in the Federal Register a Notice announcing the public availability of a new guidance, Submission of Summary Bioequivalence Data for ANDAs. The Guidance was published to help abbreviated new drug application ("ANDA") applicants better understand FDA's thinking for how to comply with FDA's final rule, "Requirements for Submission of Bioequivalence Data" that published in the Federal Register on January 16, 2009. The Final Rule requires ANDA applicants to submit data from all bioequivalence studies conducted by the applicant on the drug product formulation submitted for approval, rather than the prior practice that permitted applicants to submit only the successful bioequivalence studies. This Guidance follows a draft version of the Guidance issued on July 16, 2009, for which FDA received "few" and "minor" comments that FDA did not address in the Federal Register Notice.

Submission of Summary Bio Equivalence Data for ANDAs Guidance

The Guidance addresses the following topics: (1) the types of ANDA submissions covered by the Final Rule, (2) a recommended format for summary reports of bioequivalence studies, and (3) the types of drug formulations that FDA considers to the "same" drug product formulation for different dosage forms based on differences in composition. The Guidance applies to bioequivalence studies conducted during preapproval and postapproval but does not address what formulations FDA considers to be the "same" drug product formulation based on differences in manufacture.

The Guidance explains that the following ANDA submissions must now include all bioequivalence studies conducted on the same drug product formulation: (1) original ANDAs, (2) ANDA amendments, (3) ANDA supplements that require bioequivalence studies under 21 C.F.R. § 320.21(c), (4) ANDAs submitted under a suitability petition, and (5) ANDA annual reports. The Guidance addresses differences in composition to consider when determining when a dosage form is the "same" drug product in the categories: (1) immediate release, (2) extended-release, (3) semi-solid, and (4) other complex dosage forms, such as transdermals, injectable suspensions, and suppositories. FDA states in the Guidance that FDA's definition of "same drug product formulation" (21 C.F.R. § 320.1(g)) applies whether the products are manufactured at the same or different manufacturing sites.

FDA's format for summary reports will be posted online at FDA's Generic Drugs: Information for Industry web page, as well as a model data summary tables consistent with a common technical document ("CTD") formatted application under the heading "Generic Drug Development, Abbreviated New Drug Application (ANDA) Submissions, and Review Information". Electronic or written comments on the Guidance may be submitted at any time.

by Andrew S. Wasson

ViroPharma's suit against FDA was dismissed by the United States District Court for the District of Columbia due to a lack of standing on April 15, 2011. ViroPharma sued FDA in September 2010, seeking a declaratory judgment that FDA violated the Administrative Procedure Act ("APA") by allegedly adopting new bioequivalence standards without conducting notice-and-comment rulemaking (see previous blog here). FDA moved to dismiss under Sections 12(b)(1) and 12(b)(6) of the Federal Rules of Civil Procedure on the grounds that the court lacked subject matter jurisdiction because of "lack of standing and ripeness and that the plaintiff has failed to state a claim upon which relief can be granted."

ViroPharma Complaint Dismissed

At root, ViroPharma objected to what it perceived as FDA's emerging, less-stringent bioequivalence standards for locally-acting GI drugs. In FDA's response to Cobalt's Citizen Petition for Precose® (acarbose), FDA found that in its discretion it could accept in vitro studies under 21 C.F.R. § 320.24 to support bioequivalence (rather than requiring only in vivo studies). The implication, of course, was that FDA would take the same stance with regard to ViroPharma's own locally-acting gastrointestinal ("GI") product Vancocin® (vancomycin). Indeed, in 2006, FDA published draft bioequivalence guidelines (still not finalized) for Vancocin® which allowed generic applicants to submit in vitro data. Currently, eleven generic applicants have filed against Vancocin®, however, FDA has not approved any application to date.

The District Court for the District of Columbia determined that ViroPharma lacked standing despite alleged (1) future lost profits from generic competition and (2) current harms to ongoing business operations. With regard to the first alleged harm, the Court found that ViroPharma must show that it "substantially probable" that FDA's actions will cause harm in the form of lost profits due to generic competition. FDA countered, however, that ViroPharma would not suffer such an injury unless FDA actually approves a vancomycin ANDA or the approval was based on the disputed interpretation of the regulations. The Court agreed with FDA, finding that it could not assume that FDA would ultimately approve any of the filed ANDAs, and that even if it did, that such approval would be based on the challenged interpretation. Finally, the Court dismissed standing based on the alleged current harms as being "highly nebulous in both character and degree" and a "far cry" from the required "concrete and compartmentalized" injury required for standing. Therefore, the Court granted FDA's motion to dismiss.

It is interesting to note that in so ruling a number of core issues remain unaddressed. The court did not address the appropriate bioequivalence standard for vancomycin or other locally-active GI drugs (although it is unlikely that the Court would have gotten to this issue even if ViroPharma had standing). Also unaddressed, and more interesting from an administrative law perspective, was FDA's latitude in determining its standards of review. On the one hand, FDA needs the ability to update decisions based on new technology and circumstances. On the other hand, stakeholders need some amount of stability in order to act and to justify investment. It is a delicate balance. But whether that balance was reached in this situation will be a question put off for another day.

by Charles J. Raubicheck

FDA is imposing a new approval hurdle on makers of generic versions of the popular sleep medication Ambien CR® (zolpidem tartrate). In an October 13th decision on a Sanofi-Aventis citizen petition, the agency found that the standard criteria for a generic to prove bioequivalence to Ambien CR® (area under the curve (AUC) and maximum concentration (Cmax)) are not sufficient. The added pharmacokinetic parameter partial AUC must be satisfied as well.

Partial AUC is a measurement of the amount of the active ingredient in an extended-release tablet such as Ambien CR® that is absorbed into the bloodstream shortly after dosing. FDA says that generics must measure the level of the active ingredient zolpidem 1.5 hours after the drug is taken, because most people fall asleep at that point and must absorb enough zolpidem by then to maintain sleep over a 7-8 hour period.

However, this barrier does not appear to have slowed generic approvals. On the same day as FDA's decision, FDA approved a generic Ambien CR® 6.25 mg tablet (tentative approval for 12 mg tablet) filed by Actavis and tentative approvals for generic Ambien CR® 6.25 mg and 12 mg tablets filed by Synthon Pharmaceuticals, Inc.--evidently based on a partial AUC 1.5 hour analysis already conducted by the companies. More approvals are expected to follow.

by Andrew S. Wasson

On September 10, Pennsylvania-based ViroPharma sued FDA in the United States District Court for the District of Columbia over FDA's willingness to accept in vitro data to support generic ANDA filings against its Vancocin® (vancomycin) capsules product. According to the complaint, "[a]n important factor" for ViroPharma to acquire Vancocin® from Eli Lilly in 2004 was the expectation that generic applicants would be forced to undertake rigorous studies with clinical safety and efficacy endpoints, or at least provide in vitro data correlated with in vivo datapoints.

39209531 Viropharma Complaint

Imagine ViroPharma's surprise when it read a report from Canadian stock analysts Infinium Capital reporting that FDA would consider accepting in vitro data alone in a generic vancomycin application. ViroPharma also cites the report in the complaint. According to ViroPharma's complaint, this was the "first public disclosure of FDA's new bioequivalence standard for vancomycin and was the first ViroPharma itself learned of the new standard." FDA announced in a GPhA Technical Conference in October 2009 and in an updated guidance that FDA will no longer respond to individual letters requesting bioequivalence determinations. Apparently, information leaks, such as this one, may have led to FDA's current policy to notify all applicants at one time regarding its bioequivalence recommendations.

ViroPharma fought back by filing a declaratory judgment last month seeking a determination that the FDA violated the Administrative Procedure Act (APA) by adopting allegedly new bioequivalence standards "without observance of procedure required by law." See 5 U.S.C. § 706(2)(D). In particular, ViroPharma argued that FDA improperly laid the foundation for its course by its decision in Cobalt's citizen petition relating to Precose® (acarbose). In FDA's decision, FDA denied Cobalt's request that FDA consider only in vivo data unless one of the limited biowaiver exceptions are satisfied. See 21 U.S.C. § 320.22. FDA noted that the statute and regulations afforded FDA wide latitude in accepting in vivo data, in vitro data or both. Ultimately, FDA found that in vitro data may be appropriate if a generic application for a locally-acting product contained qualitatively and quantitatively the same inactive ingredients as the reference-listed drug.

Here, ViroPharma argued that FDA's decision in the acarbose petition effectively amended the biowaiver exceptions in 21 U.S.C. § 320.22 and that FDA did so without the notice-and-comment period required by the APA. Thus, ViroPharma requested: (1) that the court declare that any generic applicant seeking waiver of in vivo testing requirements meet one of the criteria in 21 U.S.C. § 320.22; (2) FDA amended its regulations by accepting in vitro data under 21 U.S.C. § 320.24 even if none of the 21 U.S.C. § 320.22 exceptions are met; and (3) FDA amended its regulations without notice-and-comment rulemaking and therefore violated the APA.

by Charles J. Raubicheck

At an April 13 meeting, FDA's Advisory Committee for Pharmaceutical Science and Clinical Pharmacology discussed tighter bioequivalence standards for generic formulations of certain extended-release drugs. The dialogue centered on requiring a demonstration of bioequivalence for partial areas under the curve (AUC), at time intervals when onset of delivery of the active drug ingredient is necessary for early clinical response. For such drugs, in addition to total AUC, bioequivalence would be measured at 3 hours after administration under fasting conditions, and at 4 hours following administration under fed conditions. Such tighter bioequivalence measurements could result in larger subject populations to achieve target confidence intervals.

This approach has been referred to in the industry as "matching the drug delivery curve." The specific drugs mentioned were Concerta® and Ambien CR®. Johnson & Johnson, manufacturer of Concerta®, has requested FDA to take this action in a pending citizen petition.