FDA Lawyers Blog

In an effort to further investigate the position in emerging economies, FDA commissioned the Institute of Medicine ("IOM") to study and identify the core elements of food, drug, medical product, and biologics regulatory systems in developing countries with a view to identifying the main gaps in those systems and to design a strategy for FDA and other stakeholders, which can be used to strengthen the food and medical products regulatory systems abroad. FDA is under relentless pressure to increase the number of inspections it carries out of foreign medicinal product manufacturers. However, FDA cannot do this without help and without substantial improvements in the capacity of their counterpart agencies, particularly those in emerging economies.

The report compiled by the IOM Committee on Strengthening Core Elements of Regulatory Systems in Developing Countries and entitled "Ensuring Safe Foods and Medical Products Through Stronger Regulatory Systems Abroad" put forward several recommendations as to how the United States can play its part in helping strengthen the regulatory systems in low- and middle-income countries by promoting cross-border partnerships, including government, industry, and academia, to foster regulatory science and build a core of regulatory professionals. In putting together their report IOM staff travelled to China, Brazil, South Africa, and India to meet with regulators, representatives of regulated industry, academics, and health and development workers.

The IOM recommended that the FDA should use enterprise risk management to assist its inspection, training, regulatory cooperation, and surveillance efforts and should facilitate training for regulators in developing countries. The objective being workforce training and professional development through an ongoing, standard regulatory science and policy curriculum. The IOM stated that, "[E]nsuring the safety of food and medical products imported from around the world is a difficult task, and one that the FDA has executed fairly successfully so far. There is no reason to believe that their luck will hold over the next 10 years without substantive improvements in the capacity of their counterpart agencies abroad."

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.

On April 24, at the Food and Drug Law Institute's ("FDLI's") 55th Annual Conference 2012, reflecting on history of the FDA and FDLI, FDA Commissioner Margaret A. Hamburg, M.D., noted that dating back to the first FDLI/FDA informal conference back in 1957, FDA continues to regulate an "enormous scope" of products with a continuing need for more resources. Hamburg said that FDA is now at a "turning point"--there is a need to develop medical countermeasures for biological threats either natural- or terrorism-oriented, such as new antibiotics, and there are needs for new product such as treatments for type II diabetes and obesity. At the same time FDA is poised for various riders expected to be added to the four user fee bills presented to Congress. Some of those riders include new provisions for accelerated approval, increased authorities for FDA to regulate products or component of products made overseas (e.g., 85% of the active ingredients are manufactured outside us and 40% drug products are made outside the United States), increased monitoring for drug shortages, and strengthening FDA's rare disease program. Hoping to create a "brand" for FDA, Hamburg said there is a need for stronger and more sophisticated science to help bolster reliance by the world on FDA's decision-making as the "gold standard."

Following Hamburg, three of FDA's relatively-new Deputy Commissioners discussed key issues confronting each of them. Michael R. Taylor, Deputy Commissioner for Foods, said that he believes resource allocation is important. Taylor's key issues include antimicrobial resistance, nutrition labeling, nanotechnology, chemical contaminants, a new strategic plan for foods and veterinary medicine, and executive leadership management--all with a need to involve stakeholders in the process. Stephen P. Spielberg, M.D., Deputy Commissioner for Medical Products and Tobacco, said that he is excited to be working at FDA at a time when the medical community is better understanding the causes of diseases. He is looking at the potential for more synergies between the centers and also looking at his own responsibilities, including how to help prevent children from initiating smoking and becoming addicted to nicotine. Deborah M. Autor, Deputy Commissioner for Global Regulatory Operations and Policy, said she is interested in "leap frogging" and developing an enterprise management where domestic and foreign inspection are handled the same in an increasingly global environment with statutes and regulations drafted with domestic manufacturing primarily in mind. Autor is hoping that manufacturers take a better look at the supply chain and components that go into their products, while developing better risk analytics to maintain quality.

Following a discussion on FDA regulatory science and a lunch session highlighting FDLI's new upcoming conference in Brazil, each of the FDA centers presented their outlooks for the upcoming year. Presenting for the Center for Drug Evaluation and Research ("CDER"), Deputy Center Director, Douglas C. Throckmorton said that a key priority will be to finalize and implement the requirements of FDA's requested user fees. CDER plans to fill a number of key senior leadership position: an additional Deputy Center Director and directors for the Office of Generic Drugs, the Office of Biostatistics, the Office of Clinical Pharmacology, and the Office for Surveillance and Epidemiology. In addition,

Off-label communications cost a major biopharmaceutical company $322 million dollars just this week. As the very definition of "off-label" hangs in the balance and the tension surrounding liability reaches a fever pitch, the American Conference Institute's ("ACI's") 8th Advanced Summit on Off-Label Communications provides a forum for in-house executives from leading pharmaceutical and device companies to unite with preeminent outside counsel and current and former government prosecutors to give the most comprehensive view of the new off-label landscape, including the major FDA guidance developments and evolving first amendment case law shaking the industry.

Here are the top 3 reasons why you need to join ACI to discuss the nuances of the new landscape:

1. Identify specific off-label triggers of government scrutiny... Featuring a DOJ enforcement panel including:

Marilyn May Assistant United States Attorney Healthcare Fraud Coordinator U.S. Attorney's Office, Eastern District of Pennsylvania

Sondra L. Mills (Invited)
Trial Attorney, Consumer Protection Branch
U.S. Department of Justice

David S. Schumacher
Assistant U.S. Attorney
U.S. Attorney's Office, District of Massachusetts

Wendy L. Weiss
Assistant United States Attorney
Chief, Civil Fraud Section
U.S. Attorney's Office, Central District of California

Plus don't miss the customized post-conference Master Class on Creating a Culture of Compliance: Best Practices for Working with the FDA and DOJ in an Off-Label Investigation, featuring insights from former government prosecutors who have worked on the front lines of an off-label settlement.

2. Prepare for more individual prosecutions stemming from off-label practices... Featuring an FDA keynote address on The Park Doctrine and Off-Label Promotion:

Eric M. Blumberg Deputy Chief Counsel for Litigation Office of the Chief Counsel, U.S. Food and Drug Administration

3. Learn how the free speech defense is shifting the boundaries of what's fair and foul in off-label communications as you benchmark your protocols against those of counsel from:

Abbott Laboratories * Biomet * Digitas Health * Endo Pharmaceuticals * Lundbeck Pharmaceuticals * Novo Nordisk * NuPathe * Pfizer * Purdue Pharma * Sanzoz *Zimmer and many more...

FDA Lawyer's Blog readers are entitled to a discount when referencing the code: FDA 200

For more information, please visit ACI's website.

The increasing globalization of clinical research has had the effect that most clinical trials are conducted somewhere else in the world, under a different regulatory framework, and in a different cultural setting from the jurisdiction for which the resulting data is likely to be used. Regulators, healthcare professionals, and patients worldwide all rely on the same or similar trial data when making decisions on whether or not to approve a medicine. The European Medicines Agency ("EMA") has issued a reflection paper, which proposes to enhance international cooperation in the regulation of clinical trials and provides practical steps to enable regulators to be assured that ethical and GCP standards have been applied, both during the development and during the marketing-authorization-application phases.

The EMA considers that the best approach for achieving these objectives is "to ensure that a robust framework exists for the oversight and conduct of clinical trials, no matter where in the world the clinical investigators' sites are located and patients recruited." Hence, there is a "need for cooperation between Supervisory Bodies involved in the supervision of clinical trials and the need to extend and link networks to support these activities in particular in countries where the ethics and regulatory systems/aspects are not fully developed/available." All clinical trials from phase I to phase IV (including BE/BA studies) are required to meet internationally agreed ethical and data quality standards or their equivalent. The EMA points out that these standards have to be addressed before and during the conduct of the clinical trials and not by assessment and inspection at the time of evaluating the Marketing Authorization ("MA"), because by this time the trials will have been completed, and in some cases several years earlier.

The ultimate objective is to obtain international cooperation and standardization in the regulation of clinical trials and to permit trials of medicinal products only if the trial is authorized by the national regulatory authority or by the concerned Ethics Committee(s) in that country and that the authority takes action against violations. The paper lists several other key objectives such as requiring Ethics Committees to be truly independent, professionally sound and adequately resourced. A survey of the distribution of patients used in pivotal trials between January 2005 and December 2010 showed that Africa provided 2.76% of the patient total, Middle East/Asia/Pacific 8.7% (with India 1.6%, Israel 1.2%, Philippines and Thailand around 1.0%), Australia 1.5%, Central/South America 8.5% (Brazil 2.5%, Argentina 2% and Mexico 1.3%), Russia 2.8%, USA 30%, and EU/EEA/EFTA 39.4%.

FLH Partner Brian Malkin will attend the Food and Drug Law Institute's ("FDLI's") Annual Conference in Washington, D.C. on April 24-25. For 55 years, FDLI's Annual Conference has been considered the venue for food and drug law lawyers and professionals to hear from FDA and industry about new and emerging topics covering all the products FDA regulates. FDLI has reported that this year's event is expected to draw more than 600 attendees, who will hear directly from FDA's key leaders including Commissioner Margaret Hamburg; Deputy Commissioners Deborah Autor, Stephen Spielberg, and Michael Taylor, various representatives from FDA's six product Centers; newly-appointed Chief Counsel Eliabeth Dickinson, as well as a number of former Chief Counsels. An updated agenda is available here.

FDA Lawyers Blog is a Media Partner of FDLI's 55th Annual Conference. Prior to FDLI's Annual Meeting, Mr. Malkin will participate in a FDLI Monograph Committee Meeting on April 23 and will be working out of Frommer Lawrence & Haug LLP's Washington, D.C. office next week. Mr. Malkin looks forward to seeking you and catching up at FDLI's Annual Conference this year.

On April 10, FDA published a press release announcing its approval of Amyvid™ (Florbetapir F 18 Injection), manufactured for Avid Radiopharmaceuticals (a fully-owned subsidy of Eli Lilly. Amyvid™ is used to detect brain plaques associated with cognitive impairment, or when the ability to think clearly and rationally has decreased. Amyvid™ is radiolabeled with Fluorine-18, and after injection the Fluorine binds to any β-amyloid plaques that are present in the brain. β-Amyloid is a protein produced in patients with Altzheimer's Disease and other cognitive impairments, and it clumps together with brain cells to form plaques in the brain. The brain plaques affect communications between neurons, and the neurons eventually die. β-Amyloid plaques are one of two hallmarks for Altzheimer's Disease, the second being neurofibrillary tangles, which are aggregates of hyperphosphorylated tau protein. The most common theory on the cause of Altzheimer's Disease, the "amyloid hypothesis," states that the accumulation of β-Amyloid peptide in the brain initiates the pathogenesis of the disease. The theory further states that the imbalance between the production of β-Amyloid and the lack of clearance from the body causes the disease to progress, and also causes the neurofibrillary tangles.

After Amyvid™ injection, a 10-minute PET (Positron Emission Tomography) scan is performed to measure the level of β-Amyloid plaque density. A negative result demonstrates sparse (1-5) or no plaques, which is not consistent with an Altzheimer's diagnosis. A positive scan shows moderate (6-19) to frequent (20 or more) plaques, which is consistent with a diagnosis of Altzheimer's. A positive scan does not always signify Altzheimer's; it can also represent other cognitive impairment. Like other diagnostic tests, false positives also occur. Elderly patients with normal cognitive ability may have brain plaques, resulting in a positive scan.

While Amyvid™ can rule out an Altzheimer's diagnosis, a positive result does not mean that the patient has Altzheimer's Disease, or any cognitive impairment. Further, the results of an Amyvid™ scan show the patient's current situation, and do not provide any information regarding future development of Altzheimer's or other cognitive impairment. Some doctors remain unsure of the amyloid hypothesis, and wish to wait until there is more evidence to determine whether the hypothesis is valid. It is also important to note that there are currently no drugs on the market that successfully remove the amyloid plaques. At least one critic has said that without the drugs to remove the plaques, is there any point of using a drug to detect the plaques? On the other hand, Dr. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research stated, "Until now, the brain content of β-amyloid neuritic plaques could only be determined with a brain biopsy or examination of the brain at autopsy. This imaging agent is one tool to help physicians in the assessment of their patients by serving as an adjunct to other diagnostic evaluations."

On April 16, the Federal Circuit affirmed a SDNY decision to dismiss Bayer's claims of patent infringement against three generic defendants. The basis of the Federal Circuit's affirmation lay in its conclusion that the abbreviated new drug applications ("ANDAs") for generic Yasmin® submitted by the defendants sought approval for only contraceptive use and the patent-at-issue did not claim the use of the drug for that purpose alone.

Bayer produces and markets Yasmin® (drospirenone/ethinyl estradiol), an oral contraceptive. Bayer's U.S. Patent No. 5,569,652 ("the '652 patent") is a method-of-use patent listed in the Orange Book. The '652 patent contains two independent claims, which recite that the claimed method achieves three effects simultaneously: a contraceptive effect, an anti-androgenic effect, and an anti-aldosterone effect. The defendants filed ANDAs with the FDA to market generic versions of Yasmin® and certified that the '652 was invalid or not infringed. Bayer responded by filing suit against the ANDA applicants pursuant to § 271(e)(2), alleging that the defendants' generic forms of Yasmin® would induce infringement of the '652 patent.

Two of the defendants moved for judgment of non-infringement on the pleadings under Fed. R. Civ. P. 12(c). They argued that their ANDAs sought approval for contraception and not for the other two uses claimed in the '652 patent. Their motions were granted by the SDNY, which explained that "the FDA had approved the use of Yasmin® only for oral contraception, and not for the simultaneous treatment of three conditions, which was the use claimed in the '652 patent."

On April 11, Arkansas State Court Judge Tim Fox entered judgment on fines totaling $1.2 billion against pharmaceutical giant Johnson & Johnson and its subsidiary Janssen Pharmaceuticals (collectively "J&J") for wrongdoing surrounding their prescription antipsychotic medication, Risperdal® (risperidone). (No. CV07-15345.) FDA originally approved Risperdal® in 1993 for the treatment of psychotic disorders like schizophrenia.

Arkansas Attorney General Dustin McDaniel alleged, among other things, that J&J violated Arkansas' false claims act and deceptive trade practices act in marketing and selling Risperdal®. In particular, he alleged that J&J caused improper reimbursement for prescriptions covered by Medicaid by falsely asserting that Risperdal® was safer and more effective than comparable medications and not adequately warning about serious side effects, including diabetes and neurological complications. According to the complaint, J&J sold and marketed Risperdal® for off-label uses, including the treatment of bipolar disorder, dementia, and mood, and anxiety disorders.

After a jury determined that J&J violated the Arkansas False Claims Act and Arkansas Deceptive Trade Practices Act, Fox evaluated damages. He found nearly a quarter million instances in which J&J violated the Arkansas False Claims Act, based on the number of Risperdal® prescriptions written in the state. He also found nearly 5,000 instances in which J&J violated the Arkansas Deceptive Trade Practices Act, based on the number of Risperdal® direct mailings to Arkansas physicians. As a result, he held that J&J improperly induced the state to spend Medicaid funds for Risperdal® prescriptions. The statutory minimum penalties--ranging from $2500 to $5000 per violation--resulted in a judgment of $1.2 billion. J&J has moved for a new trial, contending that the fines dwarf actual Medicaid payments for Risperdal®, which J&J argues are no more than $8.1 million. J&J further contends that the state showed no evidence that any patient suffered actual harm, that any doctor was misled into writing a prescription that was not warranted, or that any prescription did not warrant reimbursement. The Arkansas False Claims Act, however, requires only that a person "[k]nowingly makes or causes to be made any false statement or representation of a material fact in any application for any benefit or payment under the Arkansas Medicaid program." J&J may be better off trying the Eighth-Amendment route. See United States ex rel. Bunk v. Birkart Globistics GmbH & Co., Nos. 1:02cv1168 & 1:07cv1198, 2012 U.S. Dist. LEXIS 18445 (E.D. Va. Feb. 14, 2012).

A recent study has linked current FDA regulatory policy and physician prescribing patterns to a branded product's ability to maintain market share for its reformulations of an existing product. The study suggests that the continued preservation of market share by a branded product may lead to higher drug costs and may ultimately undercut the healthcare system's ability to realize substantial savings in an emerging era of healthcare austerity.

The study focused on Abbott Laboratories branded fenofibrate product (Tricor® and later a delayed-release version Trilipix®), which is used to treat cardiovascular disease. Abbott's branded product has dominated the market share for the last decade, even after the launch of generic version of fenofibrate. According to one of the study's leaders, Nicholas S. Downing, "Abbott's efforts to preserve the market share of its branded formulations of fenofibrate was legal. Thus, current policy could be seen as a factor that contributed to the continued use of branded fenofibrate."

Furthermore, Downing also points to the prescribing habits of physicians as another contributing factor to the continued dominance of Abbott's branded fenofibrate. "Had clinicians prescribed generic formulations as they became available, the healthcare system could have realized substantial savings."

While the unanimous Supreme Court's decision (see our previous blog post here) made it clear that "Caraco may bring a counterclaim seeking to 'correct' Novo's use code 'on the ground that' the [method of use] patent 'does not claim an approved method of using the drug,'" Justice Sonia Maria Sotomayor's concurrence indicates that the Court has neither answered all the questions nor fixed all the problems associated with the counterclaim provisions. She initially noted "the counterclaim can only lessen the difficulties created by an overly broad use code; it cannot fix them." The concurrence summarized how a generic manufacturer now will be able to challenge an overbroad use code: "submit an ANDA with a paragraph IV certification . . . wait for the brand [to sue], file a counterclaim, litigate the counterclaim, and, if successful [in obtaining a corrected use code] . . . file an ANDA with a section viii statement."

Sotomayor, however, identified two problems with this process. First, the process introduces a delay and litigation expense that the statutory scheme does not envision when the generic applicant deliberately carves out uses protected by a patent and files a section viii statement. Second, there is no guarantee that it would be in the interest of a brand company to instigate a lawsuit against the generic applicant that files a Paragraph IV certification when a section viii statement is initially not available for an overly broad use code that overlaps with an indication for the listed method of use patent. In this case, the generic applicant may obtain approval for the broader use(s) and then be at risk for a claim of induced infringement for selling a product with a label "that suggests that the product be used for a patented method of use."

Sotomayor concluded by criticizing FDA's minimal guidance on this issue. She highlighted how "remarkably opaque" FDA's guidance on what is required of a brand manufacturer when submitting use codes and even noted that "FDA's opacity" was part of the reason this case came to the Supreme Court. While recognizing that Novo's interpretation of the counterclaim provision is erroneous, Sotomayor expressed some sympathy for the drug company, because it only changed its use code to "correspond" to new labeling required by FDA. She noted that a fix to this statutory scheme likely would require a fix from Congress or FDA, and that "[a]bsent greater clarity from FDA concerning what is required of brand manufactures in use codes, Congress' fears of undue litigation may be realized."

Over a year ago, prior to the Court's ruling and Sotomayor's observations, FLH Partners Brian J. Malkin and Andrew S. Wasson published a FDLI Policy article, "Should FDA Undertake More Than a Ministerial Role With Respect to Patent Information?" In this article, Malkin and Wasson noted that for many years FDA has argued that it lacks the resources and expertise to review patents substantively, calling its hands-off role as "ministerial." While many courts have upheld FDA's position, they note, it is not the case that courts have mandated that FDA take this position. Instead, the authors suggest that hiring a few competent patent attorneys, trained in biotechnology or the pharmaceutical sciences, could result in the more efficient administration of the Hatch-Waxman Act Amendments to the Federal Food, Drug, and Cosmetic Act. Following Sotomayor's concurrence, perhaps their recommendations should be considered again.

On April 17, the Supreme Court issued its decision that is likely to have far reaching consequences in pharmaceutical litigation regarding method of use patents. The Court's ruling overturned the Federal Circuit's April 2010 Novo Nordisk v. Caraco decision, most recently blogged on here, which had held that 21 U.S.C. § 355(j)(5)(C)(ii)(I) ("the counterclaim provision") did not provide an avenue for Caraco to compel Novo Nordisk ("Novo") to modify the "patent use code narrative" associated with a patent listed in FDA's Orange Book for Prandin® (repaglinide). A unanimous Supreme Court, with a concurrence by Justice Sonia Maria Sotomayor, instead held that "a generic manufacturer may employ [the counterclaim provision] to force correction of a use code that inaccurately describes the brand's patent as covering a particular method of using the drug in question."

The Court, through Justice Elena Kagan, principally addressed the construction of two statutory phrases found in the counterclaim provision; namely, the "patent does not claim . . . an approved method" phrase and the "patent information submitted . . . under subsection (b) and (c)" phrase. Regarding the first phrase, the Supreme Court addressed whether the "not . . . an" language in the counterclaim provision meant "not any" (the view of Novo and the Federal Circuit) or "not a particular one" (the view of Caraco). Kagan noted that the correct meaning of "not . . . an" depends on context and provided a number of real life examples to make her point. Here, the Court found that the context in the statute supported Caraco's interpretation of "not a particular one."

Kagan explained that the Hatch-Waxman framework, specifically 21 U.S.C. § 355(j)(2)(A)(viii) ("section viii"), provides generic drug companies with a mechanism to seek approval for less than the referenced drug's uses, when those uses are listed for patents in FDA's Orange Book. In essence, the aim of this statutory scheme is to prevent one patented use from blocking the marketing of a generic drug for other non-patented uses. According to the Court's reasoning, Congress's reasons for establishing the section viii carve-out and counterclaim provisions would be frustrated by Novo's reading of "not . . . an." The Court noted that Congress could have drafted that counterclaim provision to cover Novo's interpretation by using "not . . . any" instead of "not . . . an." Kagan elaborated, "We think that the 'not any' construction does not appear in the relevant counterclaim provision because Congress did not mean what Novo wishes it had." The Court concluded that Congress meant for the counterclaim provision to aid the statutory scheme of "facilitating the approval of non-infringing generic drugs under section viii." The Court next addressed Novo's argument that Caraco's counterclaim to correct patent information must fail because a use code is not "patent information submitted by the [brand] under subsection (b) or (c)" of section 21 U.S.C. § 355(j)(5)(C)(ii)(I). Dismissing the fact that the statute does not define "patent information," the Court readily held that a use code is "patent information," such meaning that "fits under any ordinary understanding of the language."

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.

For more than 50 years, the Food and Drug Law Institute's ("FDLI's") Annual Conference has provided the venue for food and drug law professionals to discuss and debate emerging topics, as well as participate in valuable education programs. At this year's event, more than 600 attendees will hear directly from FDA leadership including Commissioner Hamburg; Deputy Commissioners Autor, Spielberg, and Taylor; representatives from FDA's six product Centers; Chief Counsel Dickinson and former Chief Counsels.

Programming at the Conference addresses a range of topics including: regulatory science; global developments and emerging markets; economic, legal and regulatory challenges of innovation; social media and mobile apps.

Join FDLI for the largest networking opportunity for food and drug law professionals. We look forward to seeing you at the 2012 FDLI Annual Conference next week.

FDA Lawyers Blog is a Media Partner of FDLI's 55th Annual Conference.

On July 12, Frommer Lawrence and Haug LLP Partner Brian Malkin
will kick off and speak on biosimilars, biobetters, and generic drugs at Q1 Productions' Conference, "Regulatory Clearance & Commercialization of Generic Drugs & Biosimilars" in Alexandria, Virginia.

Q1 Productions Regulatory Clearance & Commercialization of Generic Drugs & Biosimilars

First, Mr. Malkin will kick off a panel: "Preparing for the Evolution of the Generic Drug and Biosimilar Industry", which seeks to relate the new biosimilars legislation and related FDA guidances to the "patent cliff" transitioning to the development of a biosimilars market with new opportunities for innovative products. In the afternoon, Mr. Malkin will conclude the biosimilars track with a presentation, "Biobetters and Extending into the Marketplace Beyond Patent Expiration," where Mr. Malkin will examine the opportunities for developing biobetters amidst the landscape of a developing biosimilars market, including assessing the risks and benefits, as well as the resources, for developing biobetters.

Mr. Malkin is pleased to work with Q1 Productions, which focuses on developing programs targeted to its audiences to provide strategic and timely information and solutions for attendees. More information about the conference and Q1 Productions may be obtained here.

by Ami E. Simunovich, Pharm.D., R.Ph.

Prescription drug abuse continues to be a leading form of drug abuse in the United States. In its ongoing efforts to curb prescription drug abuse, the U.S. Drug Enforcement Administration ("DEA") served administrative inspection warrants to six Florida Walgreens pharmacies and one of its distribution centers in Jupiter, Florida. According to the DEA, these inspection warrants were issued to determine if the Walgreens facilities are violating federal laws and regulations and dispensing controlled substances outside the scope of their DEA registrations.

Pharmacies and wholesalers that dispense or distribute controlled substances must register with the DEA. The DEA can subject any of its registrants to an inspection to ensure compliance with provisions of the U.S. Control Substance Act related to the distribution of controlled substances. Under the U.S Controlled Substance Act, a warrant can be issued if there is probable cause. "The term 'probable cause' means a valid public interest in the effective enforcement of this subchapter or regulations thereunder sufficient to justify administrative inspections of the area, premises, building, or conveyance, or contents thereof, in the circumstances specified in the application for the warrant."

According to DEA Special Agent in Charge Mark R. Trouville, "[T]his latest regulatory action continues DEA's effort to rid Florida of the prescription drug abuse epidemic. DEA is concerned about the recent significant rise in the number of oxycodone tablets purchased by Walgreens in Florida."

by Howard E. Rosenberg, Ph.D.

Doshi et. al. ("Doshi") in a recent publication in PLoS Medicine highlighted their difficulties in obtaining full clinical trial data surrounding the approval of the influenza antiviral Tamiflu® (oseltamivir). Their interest in the drug was aroused when they began examining claims for the utility of drug and the differing ways that the World Health Organization ("WHO"), FDA and other health authorities around the globe interpreted the effectiveness and thus the recommended method of treatment plans for the drug. The information that was freely available to Doshi came from published trial data and meta-analyses but this proved to be unsatisfactory, as it did not allow them to really examine how the differing understandings of the drug's effectiveness and treatment patterns were decided upon by the world health authorities.

Widening their research into clinical trial reports and published data provided for other drugs that had subsequently been withdrawn or turned out to be unsatisfactory (e.g., rosiglitazone, rofecoxib, etc.), when it became clear to them that what they needed to see original clinical trial data without any "spin" attached. They pointed out that although published randomized clinical trials ("RCTs") are considered the "gold standard" source of synthesized evidence, their conclusions are vulnerable to distortion when the trial sponsors have strong interests that might benefit from suppressing or promoting selected data. From their point of view, a better method to independently assess drugs would be to enable the access and review of the clinical trial documentation and reports sent to the government drug regulators. However, these reports are historically treated as commercial confidential documents, impeding additional scrutiny by independent researchers. As a result, Doshi was unable to get all the data they required for their Tamiflu® project, despite putting in a great effort trying to get key documents released by government regulators.

A group of European regulators have replied to the Doshi article, agreeing that clinical trial data should not be considered commercial confidential information, particularly as most patients enrolling in clinical trials do so with an assumption of contributing to general medical knowledge, and that non-disclosure of complete trial results undermines this. They see many potential advantages in having public disclosure, for example, in enabling the development of predictive models for patient selection to appropriate treatments and the potential for better individualized therapeutic decisions.

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 April 4, Senator Michael Bennett (D-CO) announced that a draft Bill introduced by himself and Senators Orrin Hatch (R-UT) and Richard Burr (R-NC) on March 26 has been included a Senate Committee bipartisan plan to help advance important medical and bioscience breakthroughs through certain FDA reforms. The Committee is called the Senate Health Education Labor and Pension Committee, which seeks to implement FDA reforms as part of a larger FDA reauthorization. The Bill, now described as a "discussion draft," is called the Advancing Breakthrough Therapies for Patients Act.

The Bill amends Section 506 of the Federal, Food, Drug and Cosmetic Act ("FD&C Act") by creating a new "breakthrough therapy" designation to provide more flexibility for these types of drugs to encourage their development and approval. At the request of a sponsor, a drug, alone or in combination with one or more drugs, may be designated as a "breakthrough" drug, if intended to treat serious or life-threatening diseases or conditions and preliminary evidence suggests that the drug may demonstrate substantial improvements on one or more clinically-significant endpoints over existing therapies. Within 60 calendar days of the sponsor's request, FDA must determine whether the drug meets the "breakthrough therapy" criteria. If FDA agrees that the drug meets the "breakthrough therapy" criteria, then FDA may take appropriate actions to expedite development and review of the drug. Such actions include holding meetings with the drug sponsor throughout the drug development process and providing timely advice to the sponsor regarding the drug development plan. In addition, the Bill enables a collaborative, cross-disciplinary approach by senior managers and review staff at FDA to help craft a clinical program that minimizes the number of patients enrolled in studies, shortens the duration of studies, and reduces the number of clinical studies, when scientifically appropriate. A "breakthrough therapy" may further seek fast-track product designation, accelerated approval, and priority review to help speed the review process.

Drugs that receive accelerated approval under these provisions may be subject to either post-approval studies to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical benefit, or be required to submit all promotional materials related to the product during the approval period and at least 30 days prior to dissemination of any materials. FDA may withdraw approval on an expedited basis if the sponsor fails to conduct any required post-approval study, such studies fail to verify the predicted effects or benefits, or the sponsor disseminates false or misleading promotional materials about the product.

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 30, FDA denied the Natural Resources Defense Council, Inc.'s ("NRDC's") Citizen Petition to remove the chemical bisphenol A ("BPA") from food packaging and other products where it comes in contact with food. NRDC said that BPA may be found in a wide variety of the liners of metal food cans and hard plastic containers such as baby bottles.

As we previously reported here, on August 19, 2011, NRDC sued FDA for declaratory and injunctive relief for FDA to grant the citizen petition and issue a regulation prohibiting the use of BPA in food packaging. NRDC's original Citizen Petition was filed in October 2008 yet remained unanswered by more than 1000 days, as of the complaint filing date. According to NRDC's complaint, FDA should have responded to its type of petition within 90 days and had a maximum time of 180 days to respond. NRDC had asserted that FDA's failure to respond to NRDC's Petition prolonged its members from unwanted exposure to BPA in food packaging. FDA's failure to respond to the Petition, NRDC further claimed, denied NRDC from seeking judicial review, if necessary.

NRDC's latest suit on this Petition resulted in a Consent Judgment, where FDA agreed to issue a final decision to NRDC's Citizen Petition "on or before March 31, 2012" as the "settlement of all claims that were asserted, or could have been asserted . . . related to the allegations in the Complaint." NRDC was also awarded $10,500 as "attorney feed and costs arising out of this Action" in a Stipulation and Order that followed the Consent Judgment.

by Julie E. Kurzrok

On March 27, the FDA approved Affymax's Omontys® (peginesatide) for use in adult dialysis patients with anemia caused by chronic kidney disease. Anemia is a condition characterized by a decrease in the level of red blood cells in the body. Healthy red blood cells carry oxygen to the body's organs and tissues, and when the level of red blood cells is decreased, the organs are not able to function properly. The kidneys produce the hormone erythropoietin, which directs the bone marrow to produce enough red blood cells to support the body. Diseased kidneys do not produce enough erythropoietin, and as a result, the bone marrow does not produce enough red blood cells, causing anemia. There are currently close to 400,000 patients on dialysis, and almost all of them have anemia.

Amgen has held a monopoly on the anemia market, yielding close to $40 billion since Epogen®'s (epoetin alfa) approval in 1989. Amgen supplies the same drug under the name Procrit® to Johnson and Johnson for use in chemotherapy patients with anemia and for non-dialysis kidney patients. Amgen also produces the drug Aranesp®, a longer-lasting anemia drug used mainly in non-dialysis patients, which has made close to $26 billion in sales since it entered the market.

Omontys® is a synthetic erythropoietin-stimulating agent that assists the body in increasing red blood cell production. Prior to the approval of Omontys®, the only treatment choice for dialysis patients with anemia was Amgen's Epogen®. Epogen® is an injection usually given between one to three times weekly. Omontys®, on the other hand, is an injection given once monthly, which has demonstrated equivalent safety and efficacy to Epogen® treatment.