FDA Lawyers Blog

This blog is a second part to a blog here, describing Annual Conference for the Food and Drug Law Institute ("FDLI") held on April 23 and 24, 2013, its in Washington, D.C.

On the first day, FLH Partner Brian J. Malkin spoke on a panel discussing the priorities for the Center for Biologics Evaluation and Research ("CBER"). The two key CBER presentations came from Diane Maloney, J.D.., Associate Director for Policy, and Mary Malarkey, Director, Office of Compliance and Biologics Quality. The panel also included Michael S. Reilly, Executive Director, Alliance for Safe Biologic Medicines, and Mark S. Robbins, Ph.D., Vice President, Clinical Regulatory Affairs, DiaMedica USA, Inc. and was moderated by Scott Cunningham, Partner, Covington & Burling LLP. A key issue raised by panel was the status of biosimilars. Reilly, for example, was concerned that there may be misinformation about biosimilars, especially because there is no public information concerning biosimilars applications being considered in the United States. Malkin asked when FDA planned to issue additional guidance, because FDA's guidance has so far been very general and concerns pre-investigational or pre-biosimilars application stages, not the key issues of interchangeability and naming that have been debated. Maloney explained that CBER and the Center for Drug Evaluation and Research ("CDER") have been discussing strategy, even though there still have been no filed biosimilar applications, and would issue additional guidances. At the same time, Malkin and others acknowledged that at the state level, legislators have been passing bills that specifically prohibit substitution of biosimilars for their referenced counterpart, unless FDA deems the biosimilar "interchangeable" and naming issues and more persist.

A question was raised about a pending Citizen Petition that includes an argument that it was a taking for biosimilar applicants to file applications referencing biologic products before the passage of the Biologics Price Competition and Innovation Act ("BPCIA") (March 23, 2010). In this Petition, Abbott argued that before this date, when biologics license applications ("BLAs") were submitted, their sponsors had "reasonable, investment-backed expectations that the trade secrets in their applications would not be used to approve competing products." Abbott asserts, therefore, that FDA's use of trade secrets in these BLAs to support biosimilar approvals "would constitute a taking under the Fifth Amendment to the U.S. Constitution. FDA should not implement the BPCIA in any manner that would raise constitutional issue." While most panel members declined to respond, Malkin hazarded a guess that based on comments FDA has made (see for example here) and in the context of FDA's Citizen Petition response for a similar issue concerning 505(b)(2) new drug applications (where a similar takings argument has been made), FDA wanted to decide that there was no "taking," but FDA has not answered the petition in part because no biosimilar application has been filed to date.

Treatment for HIV/AIDS generally requires patients to take a large number of drugs. For HIV therapy, for example, at least three active drugs, usually from two different classes are required to suppress the virus, allow recovery of the immune system, and reduce the emergence of HIV resistance. As a consequence, medicines are being developed that combine these drugs into fixed dosages, thus providing a combination therapy that simplifies dosing and helps patient compliance.

Gilead Citizen Petition by FDA Lawyers Blog

Gilead Sciences ("Gilead") has developed a new fixed dose combination ("FDC"), STRIBILD®, which contains four distinct drugs: elvitegravir ("EVG"), cobicistat ("COBI") , emtricitabine ("FTC") and tenofovir disoproxil fumarate ("TDF"). EVG and COBI have not been approved before by FDA but both FTC and TDF have been.

Generally when a drug containing a new active ingredient is approved for the first time by FDA, it is considered a new chemical entity ("NCE"), which enables it to receive 5 years of market exclusivity, preventing third parties referencing that drug for their own applications for 5 years (or 4 years if their application includes a Paragraph IV certification / patent challenge).

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 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 March 29, Rep. Frank Pallone, Jr. (D-NJ) introduced in the House a Bill aimed at raising the reporting level of the Office of Generic Drugs ("OGD") in FDA and implementing a temporary "fix" of the 180-day exclusivity forfeiture situation affecting applicants unable to obtain tentative approvals within 30 months from filing. The Bill (H.R. 4332), co-sponsored by Rep. Brett Guthrie (R-KY) is called, "Generic Drug Application Review Fairness Act of 2012".

First, the Bill would elevate OGD to a "separate office" within the Center for Drug Evaluation and Research ("CDER") with direct reporting authority to the Director of CDER, currently Janet Woocock, M.D. OGD is presently part of the Office of Pharmaceutical Science. If enacted, this change would follow a new trend to elevate certain groups within CDER, presumably to empower the separate offices more than in the current hierarchy. A recent elevation from "Division" to "Office", for example, occurred last year for the former Division of Drug Marketing, Advertising and Communications ("DDMAC"), now known as the Office of Prescription Drug Promotion ("OPDP") within the Office of Medical Policy. As proposed, OGD would then be on equal hierarchical par with the Office of New Drugs ("OND") and presumably have more clout when it comes to issues such as resources, funding, or scientific decisions within its purview, such as bioequivalence.

As a temporary fix of OGD's backlog of abbreviated new drug applications ("ANDAs"), the Bill initially would provide 60 months for first applicants with 180-day exclusivity eligibility to obtain a tentative approval. The current forfeiture provision, enacted by the in 2003 under the Medicare Prescription Drug, Improvement, and Modernization Act ("MMA") states that a first applicant to submit a "Paragraph IV" patent challenge will forfeit its 180-day exclusivity in the following situation:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

21 U.S.C. § 355(j)(5)(D)(i)(IV).

by Brian Malkin

On March 12, AstraZeneca Pharmaceuticals LP ("AstraZeneca") sued FDA in the District Court for the District of Columbia requesting declaratory and injunctive relief to prevent FDA from granting final approval to generic versions of Seroquel® (quetiapine fumarate) or Seroquel XR® (extended-release quetiapine fumarate). In its complaint (including AstraZeneca's original citizen petitions, FDA response, and other documents related to the Seroquel® products' new drug applications ("NDAs")), AstraZeneca asserts that FDA could, based on FDA's denial of AstraZeneca's citizen petitions, approve generic versions of both products as early as March 27, 2012, after the pediatric exclusivity associated with a product patent expires.

Aside from whether AstraZeneca's arguments have merit, the heart of the issue appears to be whether AstraZeneca has standing to sue FDA when FDA denied its citizen petitions on March 7, 2012. FDA denied AstraZeneca's petitions "without comment on whether [FDA] will take the actions that [AstraZeneca] request[s]." While FDA's actions on citizen petitions are typically considered final agency action, in this case, FDA only has tentatively approved several generic applicants referencing both Seroquel® and Seroquel XR®. Specifically, FDA stated in its response:

FDA has not yet made a final determination with respect to whether to approve or not approve any ANDA relying on Seroquel or Seroquel XR as the RLD. FDA's decision to approve or not approve a specific application will be based on the particular facts that are applicable to that application at the time of the decision. The periods of exclusivity described above for Seroquel or Seroquel XR may or may not apply or be relevant to the Agency's final decisions with respect to any individual application and its labeling depending on the particulars of an ANDA and the timing of its approval. Such decisions are made by the Agency on a case-by-case basis in the normal course of the review process.

by Brian Malkin

On January 23, The Wall Street Journal published a debate whether innovation would be sparked in the pharmaceutical industry by a further form of patent term extension. While it is clear that patent protection is key for innovators to protect their blockbuster products from generic competition, it is not so clear whether extending patent protection for this class of products drives or hinders innovation.

Josh Bloom, Director of Chemical and Pharmaceutical Sciences at the American Council on Science and Health, a health-care education and advocacy group based in New York, took the position that the pharmaceutical industry needs more and longer patent term protection to help support basic research and development that produces needed breakthrough products. According to Bloom, there are "far fewer" scientists engaged in pharmaceutical research than there were 10 years ago, in part because longer development times have translated to less time left on patents following new product approvals. Bloom describes this as an approaching "financial crisis" or "patent cliff" where a series of patents will soon expire for some of the most profitable innovator drugs, translating to lost profits on branded products approaching an estimated $160 billion in 2015.

Unlike the "steady stream of blockbuster drugs" in the 1990s, Bloom observes, newer products that treat more complicated diseases have required more clinical studies with more subjects, adding costs and extending development times. Extending the patents on current blockbusters would postpone the patent cliff and provide additional research time for more innovative products, Bloom speculates. Generic drugs, Bloom says, "contribute nothing to innovation. . . . [y]et they take up to 90% of sales away from the comparable brand-name drugs." But Bloom wants to discourage pharmaceutical companies from merely developing line extensions for current therapies and would propose that new products receive five year extensions, whereas patents for line extensions would only receive three years of extension.

by Brian Malkin

On October 5, FDA's David T. Read, Regulatory Counsel, Office of Generic Drugs ("OGD"), Center for Drug Evaluation and Research, presented a snapshot of generic drug applications and approvals since the Hatch-Waxman Amendments and the challenges going forward.

Acknowledging that OGD has a backlog of over two thousand abbreviated new drug applications ("ANDA") with a median 27.88 month review cycle, Read cited to a number of factors contributing the problem. First, OGD needs more resources (i.e., reviewers) to get rid of the backlog, which may be helped by the promised Generic Drug User Fee Act ("GDUFA") once it becomes law. Read explained that 505(q) citizen petitions (petitions that FDA must respond to within 180 days because they interfere with generic drug approvals among other things) and products with increased complexity also contributed to the problem. Read cited FDA's response to the enoxaparin citizen petition as an example of the enormous drain on resources caused by complex issues (in that instance, tough questions of "sameness").

In addition to GDUFA, Read explained that other potential solutions could include the better prioritization of ANDAs, and increased communication of the need for higher quality ANDAs and generic products. Here, Read mentioned ongoing complaints about antiepileptic drugs where practitioners and others continued to complain breakthrough seizures occurring in brand-to-generic switches, generic-to-generic switches, and generic-to-brand switches. The problem, Read noted, was that the "data stinks": meaning that the complaint of breakthrough seizures is based on anecdotal data rather than well-controlled studies.

Frommer Lawrence & Haug LLP Partner Brian J. Malkin will speak on a hot issue concerning 180-day exclusivity for first Paragraph IV applicant generics, "Exclusivities and Forfeitures: New Developments, Controversies and Concerns" at the American Conference Institute's 12th Annual Maximizing Pharmaceutical Patent Life Cycles Conference New York City, held from October 4-5, 2011. Now that FDA has issued a number of forfeiture rulings, some of which have been successfully challenged in court, FDA has started issuing decisions without offering an opportunity for public comments. Come and find out the latest developments in this area and how it may affect your pharmaceutical product development.

FDA Lawyers Blog readers may obtain a $200 discount by mentioning FDA Lawyers Blog and using the code "FDA 200". You may register for the conference here.

by Andrew M. Nason

Two proposals included in President Obama's 2012 budget could lead to increased competition between generic drugmakers and large brand-name pharmaceutical companies. One proposal would allow the Federal Trade Commission ("FTC") to stop controversial "pay-for-delay" settlements of drug patent challenges. A second proposal would speed up the availability of generic biologic drugs by cutting the marketing exclusivity of brand biologics from twelve years to seven years. Both proposals face a tough challenge to pass through the divided Congress, as similar proposals previously have run into tough opposition from lawmakers.

The budget seeks to eliminate "pay-for-delay" deals, under which brand-name and generic drugmakers settle patent challenges with payoffs to the generic challengers that delay lower-cost generic drugs from reaching the market. Both brand-name and generic manufacturers have defended the controversial deals, claiming they can lead to early introduction of generic drugs while eliminating the uncertainty of litigation. The Generic Pharmaceutical Association ("GPhA") called the proposal regarding the settlements "misguided." While the White House claims such a ban would save $8.8 billion in federal funds over the next ten years, GPhA believes the Congressional Budget Office used several faulty assumptions to arrive at this number. On the brand side, Pharmaceutical Research and Manufacturers of America ("PhRMA") president John J. Castellani stated, "the President's proposed restrictions on certain types of patent settlements could reduce incentives for future medical innovation. . . . Restricting such settlements, which already are subject to review by the [FTC] and Department of Justice, could discourage pro-consumer settlements that do not delay generic entry past patent expiration, but instead often bring generics to market years before patent expiration."

In contrast to the provision regarding settlements, the proposal regarding biologics predictably met with mixed reviews among generic and brand manufacturers. Biologics--medicines derived from proteins manufactured in living cells--can be far more complex and expensive to manufacture than traditional pharmaceuticals. The White House says its proposal "strikes a balance between promoting affordable access to medication while at the same time encouraging innovation to develop needed therapies." It also would save, according to White House estimates, $2.3 billion by 2021. GPhA lauded the proposal, saying "a 12-year exclusivity period would provide unwarranted monopolies for brand biopharmaceuticals, which would delay the savings that could result from the earlier introduction of biogenerics." PhRMA disagreed, stating that disrupting the current balance achieved by the biosimilars provision of the health care reform law could "seriously threaten innovative companies' ability to fund research on future treatments and cures."

by Mark P. Walters

On December 13, the U.S. Government, in a joint brief filed by the Solicitor General and the Department of Justice, and Teva, in a separate brief, urged the Supreme Court not to grant certiorari to Apotex's petition for writ of certiorari regarding 180-day, generic drug forfeiture under Federal Food, Drug, and Cosmetic Act ("FD&C Act") (21 U.S.C. § 355(j)(5)(D)). As reported in our previous blog, Apotex filed its petition, arguing that based on "unilateral" action by the holder of the challenged patent to delist a patent from the Orange Book, Teva had forfeited its 180-day exclusivity.

Apotex's petition followed a final decision by the D.C. Circuit, where the Circuit Court rejected Apotex's challenge to Teva's claim of market exclusivity, following a long-running battle over Merck's decision to delist U.S. Patent No. 5,608,075 ("the '075 patent") from Cozaar® ((losartan potassium)'s entry in the Orange Book. Merck's decision to delist the '075 patent led FDA in 2009 to take the position that market exclusivity had been forfeited under the plain language of the statute.

The Government agrees with Apotex that the D.C. Circuit erred, when it held that Merck's unilateral action, delisting a patent subject to a paragraph IV certification and allowing such a patent to expire for nonpayment of fees, may serve as basis for forfeiture of the first ANDA applicant's presumptive 180-day period of marketing exclusivity. Notwithstanding this error, the Government claims that "FDA has applied the MMA's forfeiture provisions on only a few occasions, and the D.C. Circuit is the only court of appeals to have construed those provisions." As a result, argues the Government, "[i]f future controversies materialize, they are likely to be heard by another court of appeals, giving the Court greater assurance that the question presented is of recurring significance and the legal issues have fully percolated in lower courts."

Taking a decidedly different approach from the Government, Teva argues that Apotex's petition should be denied because it is moot. According to Teva, Apotex's complaint sought only prospective relief challenging Teva's entitlement to 180-day marketing exclusivity. And since Teva's 180 days of exclusivity have come and gone, Teva claims that Apotex "can't turn back time," and there is thus no case or controversy left for the Court to resolve. Teva further argues that this case "would be a poor vehicle to address the question it purports to present, because it arises in the interlocutory context of a preliminary injunction proceeding." In any event, argues Teva, the D.C. Circuit got it right, "because Apotex's interpretation of the statute would allow brand companies to manipulate the exclusivity incentive despite the absence of any suggestion in the text, history, or structure of the statute that Congress intended to give brand companies that power."

by Mark P. Walters

In early October, Apotex filed a writ of certiorari, asking the U.S. Supreme Court whether a generic drug manufacturer may forfeit marketing exclusivity under the forfeiture provisions of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") (21 U.S.C. § 355(j)(5)(D)) based on "unilateral" action by the holder of the challenged patent to delist a patent from the Orange Book. At issue is generic Cozaar® (losartan potassium), Merck's blockbuster angiotensin II receptor antagonist.

Earlier this year, the D.C. Circuit finally rejected Apotex's challenge to Teva's claim of market exclusivity following a long-running battle over Merck's decision to delist U.S. Patent No. 5,608,075 ("the '075 patent") from Cozaar®'s entry in the Orange Book. Merck's decision to delist the '075 patent led FDA in 2009 to take the position that market exclusivity had been forfeited under the plain language of the statute. Teva sued FDA in June 2009 to regain exclusivity, and, after losing at the district court level, Teva obtained a ruling from the D.C. Circuit in March 2010 that "FDA's interpretation [of the forfeiture provisions] is inconsistent with, and thus foreclosed by, the statutory scheme," and the case was remanded for further proceedings.

On remand, FDA informed the D.C. Circuit that it had learned that the '075 patent expired prior to Teva's lawsuit filing due to Merck's failure to pay maintenance fees for the '075 patent after it delisted the patent. Initially, FDA solicited comments on whether a brand name drug manufacturer could unilaterally cause its patent to expire and, thus, force a forfeiture of a first ANDA applicant's right to 180-day market exclusivity. Reluctantly relying on the D.C. Circuit's interpretation of the forfeiture provisions, FDA ultimately answered this question in the negative.

In its petition for certiorari, Apotex offers a spirited rebuke of the D.C. Circuit's interpretation of the forfeiture provisions in an attempt to invoke the High Court's discretionary jurisdiction in favor of consumers. This case would appear to be the first Hatch-Waxman case taken by the Supreme Court on issues arising from post MMA amendments to the statute. The last time the U.S. Supreme Court took a case relating to the Hatch-Waxman Act was Merck v. Integra, 545 U.S. 193 (2005), dealing with the safe harbor provisions for clinical research prior to applying for market approval under the FD&C Act.

by Charles J. Raubicheck and Brian J. Malkin

On March 26, FDA issued a decision granting Teva 180-day exclusivity for generic versions of Merck's Cozaar® (losartan potassium) and Hyzaar® (losartan potassium and hydrochorothiazide). FDA appeared reluctant to grant exclusivity, because Merck requested that the single patent for Cozaar® and Hyzaar® be delisted, and the patent expired due to Merck's failure to pay maintenance fees--both usual circumstances where a first-to-file abbreviated new drug application (ANDA) applicant forfeits its 180-day exclusivity.

FDA reasoned that the D.C. Circuit's March 2, 2010 decision in Teva Pharms, USA, Inc. v. Sebelius mandated this outcome. The court found the Hatch-Waxman 2003 amendments "structurally" do not permit new drug application (NDA) holders to deprive first ANDA applicants from obtaining 180-day exclusivity by unilaterally delisting a patent. Similarly, FDA determined that just because a patent expires due to the NDA holder's unilateral decision to not pay maintenance fees, the first applicant should not be deprived from 180-day exclusivity.

Charles J. Raubicheck will speaker at the American Conference Institute's FDA Boot Camp in New York on March 24-25, 2010. He will speak on FDA "Non-Patent Exclusivities" for pharmaceuticals.