Articles Posted in Citizen Petitions

multipills.jpgOn February 21, 2014, FDA issued a Draft Guidance that will now permit a fixed combination drug product containing a new active ingredient plus a previously approved active ingredient to qualify for New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 By virtue of the new Draft Guidance, the Agency is changing its interpretation of pertinent sections of the Federal Food, Drug, and Cosmetic Act and its own regulations.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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Jnj.jpgJohnson and Johnson (“J&J”) recently joined the discordant chorus of stakeholders and commentators who have weighed in on the issue of naming for biosimilar products. On the one hand, some advocate for shared International Non-Proprietary Naming (“INN”) system names between a biologic approved under Section 351(k) of the Biologics Price Competition and Innovation Act of 2010 (“BPCIA”) and the reference protein product (“RPP”). Conversely, others argue that biosimilars and RPPs should be assigned unique INNs. Whether biosimilar products are given the same or unique names matters: biosimilar products with unique names will likely require independent marketing and detailing (i.e., automatic substitution will not be available). For its part, J&J requests that FDA “require biosimilars to bear nonproprietary names that are similar to, but not the same as, those of their reference products or other biosimilars.”

J&J cites to its experience with Eprex®/Erypo® recombinant human erythropoietin (epoetin alfa), to inform its position on biosimilar naming. In particular, J&J identified four considerations that arose from its experience: (1) reliable pharmacovigilance mechanisms are necessary for postmarket safety; (2) products may undergo clinically-meaningful changes over time; (3) effective pharmacovigilance can only occur when it is possible to identify the product administered to a patient; and (4) switching products can interfere with determining which product is responsible for any given adverse effect. For example, J&J received reports of erythopoetin antibody-mediated pure red cell aplasia in Thailand between 2004-2007 but were unable to pinpoint the adverse event reports to a specific epoetin product due to incomplete documentation and frequent product switching.

Based on this experience, J&J argues that giving a biosimilar product the same name as the RPP would interfere with pharamacovigilance. For example, J&J states that, “to the extent that adverse event reports identify a product solely by nonproprietary name, shared names would complicate if not prevent tracing a safety signal to a specific product.” J&J also states that physicians may submit adverse event reports that incorrectly identify the responsible product if switching occurs without the knowledge of the physician.
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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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lingual.jpgOn October 31, 2013, FDA responded to a Citizen Petition filed by G. Pohl-Boskamp GmbH & Company KG (“Pohl”) on December 16, 2010. The petition requested that FDA require particular showings prior to approval of an abbreviated new drug application (“ANDA”) for a generic version of Pohl’s Nitrolingual® Pumpspray (nitroglycerin lingual spray). Nitrolingual® Pumpspray is a metered dose spray indicated for acute relief of an attack or prophylaxis of angina pectoris, i.e., chest pain, due to coronary artery disease.

In its Citizen Petition, Pohl requested that FDA require ANDA applicants to show in vivo bioequivalence studies evaluating the concentration of active ingredient (nitroglycerin or “TNG”) and its two metabolites, 1,2- and 1,3-glyceryl dinitrate (“1,2-DNG” and “1,3-DNG”, respectively) in plasma. FDA “effectively granted” Pohl’s request in 2012 with issuance of revised Draft Bioequivalence Recommendations for Nitroglycerin Metered Spray/Sublingual products (“the 2012 Revised Recommendations”). FDA recommended that data for TNG as well as 1,2-DNG and 1,3-DNG be submitted as supporting evidence since these metabolites may contribute to the pharmacological activity of Nitrolingual® Pumpspray.

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Written by Shelly Fujikawa. Ph.D

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FDA also effectively granted, in the 2012 Revised Recommendations, Pohl’s request for in vivo bioequivalence studies to use a confidence interval approach for TNG, the parent substance. This ruling thereby prohibited substitution for a confident interval approach only for the active metabolites, 1,2-DNG and 1,3-DNG. Pohl argued and FDA agreed that TNG can reliably and accurately be measured using analytical methods employing gas chromatography.
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duelingsquirrels.jpgOn October 24, 2013, FLH Partner Brian J. Malkin was quoted on an Inside Health Policy article “FDA Denies Shared REMS Petition; But Guidance, Rulemaking A Possibility”. Some background on this topics may be found in a previous blog here.

Building upon a recent presentation made at the FDA public meeting on Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (“REMS”) held in FDA’s White Oak campus on July 25-26, 2013, Mr. Malkin suggested another way that FDA could find the resources to assist in the collaboration between innovator and generic companies to develop shared REMS programs: user fees from generic drug companies to help fund the process and development of guidance and initiate a notice-and-comment rulemaking.

FDA’s decision to the Prometheus Citizen Petition said FDA may consider regulation or guidance as it gains more experience with the development of shared REMS, particularly in an environment where there is only the innovator’s product prior to generic entry. FDA’s response, however, denied the request for rulemaking at the present moment. FDA’s response suggested that FDA thought a shared REMS was possible because it has been accomplished before, despite the innovator’s concerns for resource commitments and potential risks arising from antitrust law and product liability. To the extent that FDA listed examples where a shared REMS worked, however, there were few contentious issues concerning patents such as patents on the REMS itself or complexities involved in obtaining the innovator’s product without circumventing or avoiding the REMS for bioequivalence testing purposes. FDA also denied Prometheus with an opportunity to directly participate in the process to determine whether FDA would waive the requirement for ANDA applicants to agree to a single, shared REMS with the innovator for a product with a REMS with elements to assure safe use. In this regard, FDA said that it would invite comments, however, from both innovator and generic companies on the process to develop a single, shared REMS. FDA reserved the right to determine by specific request or on its own whether a waiver should be granted based on its evaluation of the burdens and benefits to create a single, shared REMS.
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rapaflo.jpgEarlier this month, FDA denied a Citizen Petition filed by Watson Laboratories Inc. (now part of Actavis, Inc. or “Actavis”) on May 10, 2013, requesting that FDA deny any abbreviated new drug applications (“ANDAs”) it receives for a generic version of Rapaflo® (silodosin) Capsules unless the applicant demonstrates bioequivalence for both silodosin and its metabolite KMD-3213G. Watson requested that bioequivalence for both the drug and its metabolite be measured using a strict statistical evaluation of the standard pharmacokinetic measures of area under the plasma concentration-time curve (“AUC”) and peak drug concentration (“Cmax”). Watson further requested that FDA revise its draft guidance on bioequivalence testing for silodosin capsules to require a demonstration of bioequivalence for both silodosin and KMD-3213G.

On October 8, 2008, FDA approved Watson’s new drug application (“NDA”) for Rapaflo®, 4 mg and 8 mg, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (“BPH”). BPH is a noncancerous enlargement of the prostate that makes urination difficult and uncomfortable. Sandoz Inc. (“Sandoz”) recently filed an ANDA for generic Rapaflo®.

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Written by Shelly Fujikawa. Ph.D

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Silodosin is an alpha-1 adrenergic receptor antagonist and undergoes extensive metabolism. Its main metabolite is a glucuronide conjugate, KMD-3213G, which has been shown in vitro to be active. KMD-3213G has an extended half-life (approximately 24 hours) and reaches plasma exposure approximately four times greater than that of silodosin.
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newport.jpgOn October 17, 2013, concurring with the end to the government shutdown, FDA responded to a Citizen Petition filed by Lorillard Tobacco Company, Inc. (“Lorillard”). The Petition requested that FDA exercise enforcement discretion to allow the marketing of new tobacco products introduced after March 22, 2011 that are the subject of reports intended to demonstrate substantial equivalence and compliance with the Federal Food, Drug & Cosmetic Act (“FD&C Act”) Section 906(j)(1)(A)(i) (“SE Report”). Lorillard specifically asked that FDA exercise enforcement for two of its tobacco products that were the source of SE Reports and for similarly-situated tobacco products where the SE Report had been submitted at least 90 days prior to introduction in the market. As a preliminary matter, FDA said that requesting enforcement discretion in a citizen petition is not “within the scope of the FDA’s citizen petition procedures,” yet FDA elected to address the concerns underlying the request for a policy of enforcement discretion. FDA also indicated that it had issued orders for both Lorillard products, SE0003730 and SE0003731.

Lorillard had submitted SE Reports for its two new products, non-menthol versions of its 2007 Newport Lights Menthol, in October 2011. FDA indicated it its Technical Project Lead Memoranda for the products that both products had amendments and responses to deficiencies, with the most recent response dated February 8, 2013, and FDA’s response dated June 25, 2013. The new products differed from the grandfathered predicate products by: 1) absence of menthol, 20 presence of fire standard compliant cigarette paper, and 3) changes to design features to maintain consistency of smoke delivery. FDA’s reviews included chemistry, engineering, toxicology, social science, addiction, and an environmental assessment. FDA found the two new products to be substantially equivalent because: 1) the exclusion of menthol would not adversely impact initiation, dependence, or cessation of use, 2) the depth of inhalation would be equivalent and not raise different questions of public health, and 3) constituents in smoke delivered from the comparison products maintains an equivalent risk to the user and does not raise different questions of public health.

FDA agreed with Lorillard’s assertion that the FD&C Act did not mandate a timeframe for FDA’s response to an SE Report. FDA said that it has been “working diligently” to provide feedback to parties to address filing deficiencies, which have been significant and omnipresent, as well as “working expeditiously” to review SE Reports. FDA further intends to “establish performance measures” to include specific timeframes for SE Report review phases. In addition, FDA has conducted and webinars to provide information concerning observed deficiencies to the tobacco product industry to help to improve future submissions and reduce the number of review cycles. FDA described the SE Report review process as “can be complex” with “a wide range in the quality and completeness,” which further requires a review of the product to determine if it complies with the FD&C Act.

Interestingly, FDA’s response to Lorillard’s two referenced SE Reports via the Technical Project Lead Memoranda were just a day short of one year after the Petition was filed. Time will tell whether FDA provides more definitive timeframes for reviewing such SE Reports and how industry addresses the perceived review cycles in terms of filing their SE Reports before intended marketing of the new tobacco products.

duelingsquirrels.jpgOn October 7, 2013, in the midst of the government shutdown, FDA responded to a Citizen Petition filed by Prometheus Laboratories, Inc. (“Prometheus”) concerning shared risk evaluation and mitigation strategies (“REMS”), FDA Docket No. FDA-2013-P-0572. In its Petition, Prometheus requested “complete notice and comment rulemaking establishing the standards and processes for a single, shared REMS [Risk Evaluation and Mitigation Strategies]” and waivers for the requirement for a single, shared REMS. Prometheus also requested that it be given notice and the opportunity to engage in any process used by FDA to determine whether to grant a waiver from the requirement for a single, shared REMS for Lotronex® (alosetron hydrochloride). Additional details concerning their Petition may be found in a previous blog here.

As with many citizen petition responses these days, FDA granted the Petition in part and denied it in part, but for now the requests were essentially denied. First, FDA said that it was still deciding whether to initiate notice-and-comment rulemaking or issue guidance for single, shared REMS system development and denied this request at this time. Instead, FDA described how it has handled other single, shared REMS with elements to assure safe use (“ETASU”) where the statute mandates innovator and generic companies to work together to implement a single, shared REMS rather than having multiple programs that create an additional healthcare burden. First, FDA said that it notifies both the innovator and generic companies of the single, shared REMS requirement. The Petition states that then:

FDA has expected that negotiation of the single, shared REMS would begin promptly thereafter, and would proceed concurrently with the review of the ANDA [abbreviated new drug application] application. . . .

In addition to monitoring the IWG’s [industry working group’s”] progress on developing a REMS, FDA has acted to help ensure that sponsors were cooperating and that there were no obstacles to developing a single, shared system. When a company indicated to the Agency that another company (brand or generic) was not receptive or responsive to such efforts, the Agency has held teleconferences, individually or jointly, with firms involved, and/or has asked them to come to FDA for face-to-face discussions to help facilitate resolution of any issues that were preventing moving forward on a single, shared system. . . .

Unlike the elements of the REMS, which are reviewed and approved by FDA, cost-sharing, governance, and other business issues relating to the implementation of single, shared REMS are left to the discretion of the sponsors.

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redbloodcells.jpgAMAG Pharmaceuticals (“AMAG”) recently filed a Citizen Petition requesting that FDA apply more stringent bioequivalence standards to potential generic versions of its Feraheme® (ferumoxytol) Injection. Feraheme® is a non-biologic complex drug (“NBCD”) indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Specifically, AMAG requested that FDA: (1) refrain from approving any generic products referencing Feraheme® until post-marketing studies evaluating the therapeutic equivalence another IV iron replacement product to its reference listed drug (“RLD”) are complete (Nulecit™ to its RLD Ferrlecit®); (2) require sponsors of generic Feraheme® to show bioequivalence using a comparative study in patients with clinical endpoints; and (3) require generic Feraheme® sponsors to demonstrate bioequivalence using the additional assays being evaluated in the Nulecit™ post-marketing studies.

Ferumoxytol is a colloidal crystal of polynuclear ferric oxyhydroxide encased within a carbohydrate. It is a large, complex chemical entity (approximately 750 kDa) and its chemical structure has not been fully characterized. The carbohydrate serves to encase and sequester the iron moiety until it is taken up by its site of action, the macrophages of the reticular endothelial system (“RES”). In other words, the iron becomes bioavailable only inside the macrophage vesicles. This sequestration function is important because free iron is toxic and causes oxidative stress. Indeed, iron is normally sequestered in the body (e.g. hemoglobin, ferritin) because of this toxicity.

AMAG requests that FDA refrain from approving any generic Feraheme® products until the Nulecit™ post-marketing studies demonstrate that the standards currently established for generic IV iron replacement products are sufficient to therapeutic equivalence. FDA approved Nulecit™ as a generic version of Ferrlecit® in 2011. However, FDA issued a “Sources Sought” notice in April 2013 to determine the availability of third-party businesses to evaluate the therapeutic equivalence of Nulecit™ to Ferrlecit®. In particular, FDA proposed studies of: (1) in vitro phagocytosis to compare RES uptake of generic and RLD; (2) the time-dependent iron content in the major target organs and a comparison of biodistribution in animal models; (3) a prospective, randomized, 2-way crossover study to compare non-transferrin bound iron levels in hemodialysis patients treated with generic and RLD products. AMAG argues that a moratorium on generic approvals of IV iron products is reasonable pending the outcome of these studies. In addition, AMAG requests that FDA require prospective generic applicants perform these studies.
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Thumbnail image for mortar and pestle.jpgOn May 10, FDA denied a Citizen Petition submitted on behalf of Endo Pharmaceuticals Inc. (“Endo”). The Petition requested that FDA: (1) determine that Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OP”) were discontinued for safety reasons, (2) refuse to approve any pending abbreviated new drug application (“ANDA”) for a generic version of OP, and (3) suspend and withdraw the approval of any ANDA referencing OP as the reference listed drug. By statute, if a drug was withdrawn from sale for reasons of safety or effectiveness, FDA must refuse to approve any pending ANDA and suspend or withdraw any approved ANDA referencing the drug.

FDA initially approved the New Drug Application (“NDA”) for OP held by Endo on June 22, 2006. The approved label advised that the product should be swallowed whole and warned against crushing, chewing, snorting, or injecting the dissolved product to prevent uncontrolled delivery, overdose, and death. FDA approved two ANDAs referencing OP in December 2010. Generic versions of the product entered the market in July 2011 and January 2013, respectively.

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Written by Shelly Fujikawa. Ph.D

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FDA approved an NDA for a reformulated version of OP, also called Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OPR”), held by Endo on December 9, 2011. FDA found that OPR could still “dose dump” and approved a label for ORP that was virtually identical to the approved label for OP. Endo ceased shipping OP on May 31, 2012 and submitted the present petition in August 2012 which was subsequently supplemented with preliminary postmarketing data and analysis concerning the abuse of OP, generic versions of OP, and OPR.
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