Articles Posted in Exclusivity

multipills.jpgOn February 21, 2014, FDA issued a Draft Guidance that will now permit a fixed combination drug product containing a new active ingredient plus a previously approved active ingredient to qualify for New Chemical Entity (NCE) exclusivity, thereby preventing the filing of generic drug applications referencing the combination product for a period of 5 years. (A fixed combination drug is one containing more than one active ingredient, each in a fixed amount).

FDA’s prior approach, in effect since 1994, had denied NCE exclusivity status to a fixed combination drug product that included an already-approved active ingredient. By virtue of the new Draft Guidance, the Agency is changing its interpretation of pertinent sections of the Federal Food, Drug, and Cosmetic Act and its own regulations. Going forward, FDA will determine NCE exclusivity by considering the newness of each drug substance (active ingredient) in a fixed combination drug product. If one active ingredient is new, NCE exclusivity can be awarded to the entire product.

As reasons for the change, FDA cites: (i) the emergence of combination drug treatment as a standard of care for serious diseases such as cancer, cardiovascular disease and infectious diseases (e.g., HIV), and (ii) the need to encourage the development of fixed combinations to treat these and other diseases, because particular combinations have been shown to improve treatment response, lower risk of resistance and lower rates of adverse events.
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petition.pngIn a previous post, we covered Gilead’s Citizen Petition to the FDA requesting FDA change its policy on how it allocates five years marketing exclusivity. Gilead argued that the current ruling whereby the five year exclusivity cannot be granted if even one active ingredient in the new drug application (“NDA”) has been previously approved should be altered. Stribild®, which has two previously-approved active ingredients and two new active ingredients, is currently precluded from obtaining the five years new chemical entity (“NCE”) exclusivity.

Mylan filed a Comment in Response, supporting FDA’s current FDA interpretation, arguing against the various points raised in Gilead’s Citizen Petition. First, Mylan points out that FDA’s interpretation is not a matter of policy but governed by the plain language of the statute passed by Congress. The relevant statute is “The Drug Price Competition and Patent Term Restoration Act of 1984” (“Hatch-Waxman” or “the Act”) which states in the section dealing with allocation of the five-year new chemical entity (“NCE”) marketing exclusivity: “[I]f an application submitted under subsection (b) of this section for a drug, no active ingredient … of which has been approved in any other application under subsection (b) of this section.” Mylan argued that: (i) despite Gilead’s attempts at re-interpreting the meaning of “drug” and “active ingredient”, the statute still plainly says that there must be no active ingredient in the NDA that has been previously approved for the five year exclusivity to be granted and (ii) when Congress wrote “an application submitted under subsection (b) for a drug”, it reasonably understood the word “drug” as used in this phrase to mean drug product and, not as Gilead would like to believe, a single component of the drug, such as the active ingredient.

As further support, Mylan pointed to the language of the three-year new clinical data marketing exclusivity provision:

Section 505(j)(5)(F)(iii) states:
If an application submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application under subsection (b), is approved after the date of the enactment of this subsection and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under this subsection for the conditions of approval of such drug in the subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) for such drug.
Thus, Mylan argued, taken together the plain language of the statute for both exclusivities leads to the conclusion that the current FDA interpretation is correct.

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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).
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Thumbnail image for thethinker.bmpOn 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.

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Written by Julie E. Kurzrok

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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.
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by Brian Malkin

FDA.jpegOn 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.”
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by Brian Malkin

Thumbnail image for Thumbnail image for house of representatives.jpgOn 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).
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thethinker.bmpOn 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.

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pharmaceuticalresearch.jpgOn 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.
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FDA.bmpOn 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.
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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.