Financier Worldwide published an editorial by FLH Partner Brian J. Malkin on shared REMS in its October 2013 edition entitled, “Will the FDA provide more guidance or manage the process to share risk evaluation and mitigation strategies (REMS)?”. Prior to FDA’s response to the Prometheus Citizen Petition reported in our blog here, Mr. Malkin discussed his opinion whether FDA would undertake a more proactive process to manage shared risk evaluation and mitigation strategies (“REMS”). Mr. Malkin’s analysis includes an overview discussion of the issue, namely negotiating the process whereby innovator and generic companies can work together to implement a shared REMS program. In the past, such negotiations have been particularly problematic when elements of the REMS were protected by patents or the negotiating parties were involved in a Hatch-Waxman litigation scenario.
Earlier 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 Watson further requested that FDA revise its draft guidance on bioequivalence testing for silodosin capsules to require a demonstration of bioequivalence for both silodosin and KMD-3213G.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®.
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.
FLH Partner Brian J. Malkin’s Chapter, “Free Speech and Off-Label Drug Promotion: Should Recent Cases Change Your Business Practices?” is now available as part of an Aspatore Special Report, Navigating Recent Off-Label Promotion Developments: Understanding Government Regulations and the Potential Impact of Noteworthy Cases published on September 1, 2013. FLH and FDA Lawyers Blog bring to you as a special benefit a link to Mr. Malkin’s Chapter for your review and use available here.
Mr. Malkin’s Chapter provides an overview of the off-label promotion issue as well as addresses some of the most recent cases that have called into question FDA’s statutory scope of authority over such discussions. Broadly speaking, FDA permits unaffiliated doctors to prescribe and speak about offlabel uses of products approved by FDA for marketing but has limited the ability of a product’s sponsor or individuals acting on the sponsor’s behalf to do so. In some instances, violations have resulted in convictions for criminal felonies involving prison time and substantial fines, even in to the billions of dollars. A recent Second Circuit Case, United States v. Caronia, however, held that truthful, nonmisleading off-label promotion is constitutionally protectable commercial speech. FDA’s decision to not appeal the decision and official position that the ruling is very narrow and business is as usual has further complicated the issue. Mr. Malkin’s chapter takes a look at how FDA has proceeded since Caronia and provides “takeaways” for counsel when considering their products and marketing materials.
On 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.
On 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.
Based on data submitted by Watson Pharmaceuticals Inc. (“Watson”) (recently merged with Actavis Inc. (“Actavis”)), FDA announced last week that Watson’s generic bupropion hydrochloride (“HCl”) extended-release (“ER”) 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL® 300 mg, the reference listed drug (“RLD”). Therapeutically equivalent drugs generally may be substituted for each other with the expectation that the substituted product will produce the same clinical effect and safety profile when used according to the labeling. Watson has agreed voluntarily to withdraw this product from the distribution chain.
Last year, FDA also reviewed data indicating that Budeprion XL 300 mg (bupropion hydrochloride extended-release tablets), manufactured by Impax Laboratories, Inc. (“Impax”), and marketed by Teva Pharmaceuticals USA, Inc. (“Teva”), is not therapeutically equivalent to Wellbutrin XL® 300 mg. Impax requested that the Agency withdraw approval of Budeprion XL 300 mg extended-release tablets. Impax and Teva stopped shipping the product and issued detailed information to their customers.
FDA has changed the Therapeutic Equivalence Code in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) for the Impax and Watson products from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence). FDA does not anticipate a drug shortage.
Last week, the European Parliament voted on a draft for the Tobacco Products Directive (TPD) and declined to accept the European Commission’s proposal to regulate electronic cigarettes (“e-cigarettes”) as medicines. The majority of Members of European Parliament (“MEPs”) supported using a mixture of tobacco regulation (e.g., controls on promotion) and medicines-style regulation (e.g., reporting of adverse reactions) for all nicotine products (including medicines), and applying medicines regulation to products that make medicinal claims.
However, just prior to the Parliament’s decision the United Kingdom (“UK”) Medicines and Healthcare Products Regulatory Agency (“MHRA”) had announced that the UK government would regulate e-cigarettes and other nicotine-containing products (“NCPs”) as medicines. After the vote the MHRA stated that it still believed that medicinal regulation of NCPs is in the best interests of the public health, and they will continue to encourage companies voluntarily to seek a medicinal license for their NCPs. Comparable nicotine replacement products (e.g. gums, patches, inhalator), for example, are licensed as medicines.
Earlier the Commission on Human Medicines (“CHM”) working group on NCPs had concluded that the NCPs currently on the market do not meet appropriate standards of safety, quality, and efficacy. Their study found that nicotine levels can vary considerably from the labeled content, and the amount of nicotine per product can differ from batch to batch. Regarding e-cigarettes, which deliver nicotine via a cartridge, there is also no data concerning the manufacture of the cartridge or device to suggest consistent nicotine doses across multiple cartridges or multiple devices. Additionally, the cartridges may contain potentially toxic elements at unexpectedly high doses, which could produce adverse effects, particularly in vulnerable patient groups.
Last night, the George Washington University Law School (“GW Law”) hosted a celebration event for the newest Commissioner to be sworn into the International Trade Commission (next week), its own GW Law Professor F. Scott Kieff. Kieff was nominated by President Obama to serve on the U.S. International Trade Commission (“ITC”). GW Law’s event was called “Law in Action in the Nation’s Capitol” and featured an informal panel presentation where Kieff and others shared their experiences and the impact that their outside work has had on their academic careers. Joining Kieff were John M. Whealan, Dean for Intellectual Property Studies, former Deputy General Counsel for Intellectual Property Law and Solicitor at the United States Patent and Trademark Office; William E. Kovacic, Global Competition Professor of Law and Policy, Director of the Competition Law Center, former Commissioner at the Federal Trade Commission; Jonathan R. Siegel, F. Elwood and Eleanor Davis Research Professor of Law, Special Counsel to the Administrative Conference of the United States; Spencer A. Overton, Professor of Law, former Principal Deputy Assistant Attorney General at the Department of Justice in the Office of Legal Policy; and The Honorable Randall R. Rader, Professorial Lecturer in Law, Chief Judge of the U.S. Court of Appeals for the Federal Circuit.
Kieff studied molecular biology and microeconomics at the Massachusetts Institute of Technology and also did research on molecular genetics at the Whitehead Institute prior to earning his J.D. at the University of Pennsylvania. Kieff spent two years as a clerk for the Hon. Giles S. Rich, United States Court of Appeals for the Federal Circuit in Washington, D.C. and then moved on to the Chicago offices of Jenner and Block, where he was a trial lawyer and intellectual property specialist.
On October 8, 2013, FDA published a press release announcing its approval of Bayer HealthCare Pharmaceuticals, Inc.’s (“Bayer’s”) Adempas® (riociguat) to treat two types of Pulmonary Hypertension (“PH”): (1) chronic thromboembolic pulmonary hypertension (“CTEPH”) and (2) pulmonary arterial hypertension (“PAH”). PH is an increase in blood pressure of the pulmonary arteries. Normal pressure in the pulmonary arteries is 8-20 mm Hg and PH occurs when the pressure is 25 mm Hg or higher. The World Health Organization (“WHO”) has divided PH into five groups. Group 1 (PAH), Group 2 (PH with left heart disease), Group 3 (PH associated with lung disease), Group 4 (PH caused by blood clots (includes CTEPH)), and Group 5 (PH caused by other diseases). Adempas® is the first drug approved in the U.S. to treat two types of PH, specifically Groups 1 and 4.
“Adempas is the first in its drug class approved to treat pulmonary hypertension and the first drug of any class to be shown to be effective for patients with CTEPH,” said Norman Stockbridge, director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research (“CDER”). In CTEPH, blood clots travel from the body and clog the pulmonary arteries, forming more clots and increasing resistance to blood flow. In PAH, the pulmonary arteries become narrowed or tightened restricting blood flow. CTEPH and PAH both cause the heart to work harder to pump blood through the lungs, and this increased strain often causes shortness of breath, fatigue, weakness, and sometimes heart failure.
Adempas® is a guanylate cyclase stimulator which catalyzes the synthesis of cGMP, the signal for relaxation of smooth muscle. Relaxation of smooth muscle causes vasodilation, increased blood flow, and reduced blood pressure. The standard treatment for CTEPH is a complex surgery to clear the clots from the arteries, but for patients with inoperable CTEPH or recurrent CTEPH after surgery, Adempas® is the first and only FDA-approved drug treatment. FDA approved Adempas® with the goal of helping affected patients increase their ability to exercise.
On September 30, 2013, before the federal government shut down hit, FDA published a new guidance, “ANDA Submissions-Refuse-to-Receive Standards“. FDA’s guidance explains many of the principles that have been articulated in FDA’s “ANDA [Abbreviated New Drug Application] Checklist for Completeness and Acceptability of an Application” (“ANDA Checklist”), which is reviewed quarterly basis (calendar year) and updated on an “as needed” basis. The Guidance reported that refusal-to-receive decisions (“RTRs”) “underscore the need for improvement in the quality of original ANDAs.” Between 2009 and 2012, FDA’s Office of Generic Drugs (“OGD”) refused to receive 497 ANDAs, the Guidance explains. RTRs occurred with regard to original submissions, in 2009 – 12%; 2010 – 18%; 2011 – 15.5%, and 2012-9.4% (estimated). The most common reasons for RTRs included serious bioequivalence deficiencies and serious chemistry deficiencies, with other lead causes being format or organizational flaws, clinical deficiencies, and inadequate microbiology. As a result, FDA believes that it would help to clarify its RTR criteria to help improve ANDA quality.
First, FDA noted that as part of its threshold determination for filing, FDA reviews ANDAs following the ANDA Checklist, which is formatted to mirror the organization of the Electronic Common Technical Document (“eCTD”). As a matter of general policy, FDA will notify an applicant if it will issue a RTR and provide the applicant with the opportunity to withdraw its ANDA, amend to correct the deficiencies, or take no action. FDA intends to work with applicants if there are fewer than ten minor deficiencies, with such notification by phone, e-mail, or facsimile. If the applicant can correct the deficiencies within five business days and FDA so finds, then FDA will still receive the application from its original receipt date; if not so corrected, FDA will RTR the application. FDA will issue an RTR, however, if the application contains more than ten minor deficiencies or one or more major deficiencies.