FDA Lawyers Blog

The U.S. Food and Drug Administration ("FDA") announced last Tuesday that it would not approve any generic versions of the original formulation of the prescription narcotic painkiller OxyContin® ("original Oxycontin®"). OxyContin® is a brand name for oxycodone hydrochloride, an opiate-based pain medication. Original Oxycontin® has been marketed by Purdue Pharma since 1995 and is notorious for its user misuse and abuse.

OxyContin® contains a large amount of oxycodone because it is designed to release the pain-relieving drug over an extended 12-hour period. However, original Oxycontin® can easily be crushed and then snorted or injected (or even sprinkled on food) to produce a rapid and intense euphoric high. The abuse of original OxyContin® in this manner can lead to addiction and dependence and has reportedly earned the product the nickname "hillbilly heroin." Its accessibility has magnified abuse rates; FDA reports that half a million people over age twelve began using original OxyContin® for non-medicinal purposes in 2008 alone. According to the Center for Disease Control, the death toll from prescription painkiller overdoses tripled in the first decade of the 21st century, and such overdoses "now kill more Americans than heroin and cocaine combined."

In addition to a patent for original OxyContin, which expired on Tuesday, Purdue Pharma also owns a patent for a reformulated, abuse-deterring version ("reformulated Oxycontin®"). This newer version was designed to resist being crushed and to form a gel that is difficult to inject when dissolved. Notably, FDA approved an updated label for this product last week, specifying the tablets' crush-resistant properties and warning of the fatal risks of misuse. (The label information is available here.) Purdue withdrew original OxyContin® from the market when its new version was approved in 2010 but retained the trade name.

On January 16, 2013, FLH Partner Brian J. Malkin was quoted in FDAnews article: "Alabama Supreme Court: Brand Drugmakers Can Be Held Liable for Generic-Drug Labeling". The Alabama Supreme Court recently held that Pfizer Inc. ("Pfizer") could be sued for injury caused by a generic version of its drug. FDAnews asked Mr. Malkin how this could affect branded drug manufacturers makers and whether this decision would contradict federal laws and court rulings. Below is an excerpt from that story:

The Alabama court decision raises the question of whether states or the federal government should have had jurisdiction over the matter, Brian Malkin, a Partner at Frommer Lawrence & Haug told DID.

"If it is fraud, it is fraud on a national level so you would think the case should have gone to the FDA," Malkin said. He has noticed a tension between state-specific and FDA authority in this arena and has noted a couple of cases where states seem to be taking on areas that are traditionally in the FDA's realm. The Mutual v. Bartlett generic preemption case set to be heard by the Supreme Court this spring also began at the state court level, Malkin said (DID, Dec. 3, 2012).

On October 5, FDA sent a warning letter to Avon Products, Inc. ("Avon") concerning the cosmetic company's online promotion of its anti-aging skin care products. The letter, which FDA posted last week, objects to Avon's marketing claims for a variety of its anti-wrinkle products. Specifically, it warns that they "appear to be intended for uses that cause these products to be drugs under section 201(g)(1)(C) of the Federal Food, Drug, and Cosmetic Act ['FD&C Act']."

The cited statutory provision (21 U.S.C. § 321(g)(1).) defines "drug" to include "articles (other than food) intended to affect the structure or any function of the body of man or other animals." FDA asserts that Avon's marketing claims indicate that the creams and serums listed in the letter are intended to affect the structure of human skin tissue, in which case they would fall under that definition. For example, the company's website describes that the Anew Clinical Advanced Wrinkle Corrector as "formulated to boost shock-absorbing proteins to help strengthen skin's support layers," and "start rebuilding collagen in just 48 hours." While it is not out of the ordinary for anti-wrinkle products to claim to reduce the appearance of wrinkles and fine lines, FDA believes that Avon's statements go too far. According to the letter, the products are "not generally recognized among qualified experts as safe and effective for the above referenced uses" and are thus new drugs, requiring marketing approval.

Congress has prohibited the introduction of new drugs into interstate commerce without filing, and subsequent approval of, a new drug application ("NDA") as stated in 21 U.S.C. § 355(a). A new drug application ("NDA") must include, among other things, "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use." Id. at § 355(b)(1). Other requirements address labeling information and manufacturing controls. Id. The warning letter asks Avon to review its website and product labels and requests a response within 15 days of receipt (October 20) detailing the steps the company has taken to correct the alleged violations. At least some of the accused descriptions still seem to remain on Avon's website.

On July 26, FLH Partner Brian J. Malkin was interviewed and quoted in FDAnews' article: "Jazz Petitions FDA, Alleges Agency Wrongly Accepted Xyrem ANDA" available here (subscription required for full story). Malkin and another FDA attorney, David Rosen, were both quoted in the article to provide some color surrounding Jazz's latest Citizen Petition regarding generic Xyrem® (sodium oxybate):

Despite Jazz's arguments, David Rosen, an attorney at Foley & Lardner, questions whether the FDA actually accepted an incomplete application. The FDA, including the Office of Generic Drugs, is well aware of REMS requirements and wouldn't accept an ANDA application if it was deficient on its face, Rosen told DID, noting there is more than one way to put appropriate controls in place for drugs. "The FDA has been taking [ANDA] filings seriously," he said, adding he is confident the FDA is good at judging completed applications.

And Brian Malkin, an attorney at Frommer Lawrence & Haug, explained that because Jazz's Xyrem REMS is still pending and not yet accepted by the agency, generic filers would typically only be required to include the "same essential elements" of a risk management plan in their ANDA application, a flexible approach that could have been satisfied by Roxane. ANDA filers for companies with approved REMS are held to a different standard, Malkin explained.

As FDA Lawyers Blog previously reported here, Jazz's latest Citizen Petition focuses on FDA's same labeling requirement for generic drugs and argues that risk management programs are included in that same labeling.

Jazz's Xyrem Citizen Petition

While Xyrem® has been designated by FDA as a product that has been deemed to have a Risk Evaluation and Mitigation Strategy ("REMS"), FDA does not list Xyrem® as a product with an approved REMS. To some extent, Xyrem® 's risk management program called the Xyrem® Success Program has been described on its website and in FDA's review package and public documents for Xyrem®.

Earlier this month, Jazz Pharmaceuticals ("Jazz") submitted a Citizen Petition requesting that the FDA rescind its acceptance of Roxane's abbreviated new drug application ("ANDA") referencing Xyrem®, an oral solution indicated for the treatment of patients with narcolepsy. In its petition, Jazz argues that Roxane's ANDA did not have the same labeling and conditions of use as Xyrem®, because it did not contain a risk management system when it was submitted. Jazz asks that the FDA require Roxane to file a new ANDA, which would result in a new thirty-month stay of the associated New Jersey Hatch-Waxman litigation.

Jazz's Xyrem Citizen Petition

Xyrem® is the sodium salt of gamma-hydoxybutyric acid ("GHB"), a notorious "date-rape" drug. In 2000, Congress passed the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act, defining GHB as a Schedule I controlled substance but creating an exception for FDA-approved drugs containing GHB. FDA approved Xyrem® in 2002, requiring extraordinary restrictions on the drug product's use under 21 C.F.R. § 314, Subpart H, including a restricted distribution program, an education program, restrictions on the distribution of prescriptions, and a registry system. To meet these demands, Jazz implemented and patented the "Xyrem® Success Program," and listed the patents claiming methods of using its program in FDA's Orange Book.

Jazz claims that Roxane's ANDA did not include a proposed risk management system when it was submitted. Instead, Jazz explains that Roxane submitted a six-page document describing a partial proposed risk management program for generic Xyrem® ten months after its initial ANDA submission and did not submit a full proposal until more than a year after the initial ANDA submission.

On Monday, July 16, FDA approved the first drug to be used for preventing Human Immunodeficiency Virus ("HIV") infection, in what reporters are calling "a milestone in the 30-year battle against the virus that causes AIDS," a "huge step toward controlling the spread of HIV," and a contributing factor to "the turning point in the AIDS epidemic." Truvada®, a pill owned by Gilead Sciences, is a drug used to treat HIV and Acquired Immunodeficiency Syndrome ("AIDS") since 2004. However, Monday's approval permits Gilead Sciences to market the drug for preventative use, potentially dramatically increasing the number of doctors prescribing the drug for that use. Using Truvada® as a preventative measure could help slow the spread of HIV, which currently infects about 50,000 new Americans per year.

Truvada® is a combination of two anti-HIV medications: Emtriva® (emtricitabine) and Viread® (tenofovir disoproxil fumarate). The two medications are combined into a single pill that is taken once a day with or without food. The drug works by lowering the amount of virus circulating in infected people's blood. Truvada® blocks the activity of the enzyme (HIV-1 reverse transcriptase) the virus needs to replicate and consequently slows down the progression of HIV by limiting its ability to take hold and start an infection.

The drug is approved for use by healthy, uninfected individuals who are at high risk of contracting HIV. Individuals considered "high-risk" include sex workers and people with HIV-positive partners. Additionally, people who engage in high-risk behaviors such as using intravenous drugs fall into the "high-risk" category. To prevent HIV infection, or at least reduce the risk of HIV infection, uninfected individuals at a high-risk of acquiring the virus must take the drug daily before and after exposure. Prevention, however, comes at a steep cost. A Truvada® prescription ranges from about $11,000 to $14,000 annually.

Off-Label Communications:
The Definitive Legal and Regulatory Forum on the Evolving Off-Label Landscape
Monday, June 25 to Tuesday, June 26, 2012
The Carlton on Madison, New York, NY

Attendees of ACI's Off Label Communications Conference will:

• Benchmark best practices against leading companies such as Endo Pharmaceuticals, Lundbeck Pharmaceuticals, Novo Nordisk, Pfi zer, Purdue Pharmaceuticals, Sandoz and many more
• Learn how to reposition your company's policies and protocols according to these shifting boundaries and determine what's fair and foul in off-label communications and promotion
• Master preparation skills for the new off-label framework based on the free speech defense
• Hear directly from the FDA and DOJ and several former federal prosecutors on how to guard proactively against impermissible off-label communications
• Over the years, previous attendees have demanded even more in-depth information on responding to government investigations so this year we are pleased to offer a 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.

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

For more information on how to register, please visit our website: www.americanconference.com/offlabel.

As of 2009, 46 percent of the drug products listed in the electronic Physician's Desk Reference ("ePDR") contained information for pediatric use. While this is a substantial increase from the mere 22 percent of labels that included this information in the 1970's, more than half of all drug labels still lack pediatric-use information. This scarcity of pediatric data in drug labels was recognized at least as early as 1968, when Dr. Harry Shirkey coined the term "therapeutic orphans."

In 1975, Dr. John Wilson performed a research study on the availability of medicines for children (and pregnant or breast-feeding women). Dr. Wilson studied the labeling of approximately 2000 drugs found in the 1973 print Physician's Desk Reference ("PDR") and found that only 22 percent of these drugs included adequate pediatric labeling. For the labeling to be deemed adequate, it had to contain effectiveness and safety data in children as well as dosage information for all pediatric age groups. Regarding the 78 percent of labels that were inadequate, 16 percent contained a disclaimer for the drug's use in children (a contraindication, a "use with caution" or a "use restricted by age"), while 62 percent either did not list a pediatric dose, or only included a dose for a single age group.

Dr. Wilson published an update in 1999 which demonstrated the continuous presence of the therapeutic orphan dilemma. Between 1973 and 1991, little had changed with the PDR -- while 22 percent of drugs in the 1973 PDR had adequate pediatric labeling, the 1991 PDR had only 19 percent (most having age disclaimers). As further validation for the dilemma, Dr. Wilson presented an analysis of off-label use of various drugs that had pediatric age restrictions. Drugs such as Albuterol, Ampicillin, Zoloft, and Prozac were frequently prescribed off-label to children despite the age-disclaimer present in the label.

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.

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.

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).

by Brian Malkin

On April 9, FDA simultaneously denied ViroPharma's Citizen Petition regarding bioequivalence and labeling requirements for generic Vancocin® capsules (vancomycin hydrochloride)
and approved three generic applications to Akorn, Strides Acrolabs Ltd. and Watson Pharmaceuticals. In an unprecedented 87-page response (with index), FDA responded to a myriad of arguments presented in ViroPharma's original Citizen Petition dated March 17, 2006, as well as its 20 additional supplements and 16 submissions to a public docket for FDA's Draft Vancomycin Bioequivalence Guidance.

FDA's response provides numerous insights into FDA's decision-making process for bioequivalence determinations in addition to FDA's affirmation of its draft generic Vancocin recommendation as "scientifically sound" and "the most accurate, sensitive, and reproducible approach for demonstrating bioequivalence for generic vancomycin capsules." For generic Vancocin® FDA will continue to permit in vitro dissolution data alone to demonstrate bioequivalence for generic Vancocin® capsule versions that contain the same active and inactive ingredients in the same amounts ("Q1/Q2"). Non-Q1/Q2 formulations must perform clinical endpoint studies in patients with Clostridium difficile Associated Diarrhea.

FDA's decision secondarily answered an issue raised in a later supplement regarding certain labeling changes to Vancocin® that was supported with clinical data, which FDA determined would not be eligible for 3 years of clinical data exclusivity because it is not a new indication. According to FDA, "old" antibiotics, such as vancomycin, may only obtain 3-year new data exclusivity for a significant new use or new indication, not for "refinements in labeling related to previously approved used for Old Antibiotics."

by Brian Malkin

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

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

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

by Kyle Deighan

On February 9, the Federal Circuit held that AstraZeneca failed to state a claim for patent infringement under 35 U.S.C. §271(e)(2) against generic pharmaceutical manufacturers that filed abbreviated new drug applications ("ANDAs") seeking approval for uses of Crestor® (rosuvastatin calcium) not covered by AstraZeneca's patents. The case is AstraZeneca Pharms. LP v. Apotex Corp..

AstraZeneca alleged that ANDA filings by various generics infringed or would infringe several of its patents covering methods of using rosuvastatin calcium. These patents covered methods of using rosuvastatin compounds to treat heterozygous familial hypercholesterolemia ("HeFH") and elevated C-reactive protein ("CRP"). As per the Hatch-Waxman Act, AstraZeneca filed a New Drug Application ("NDA") and obtained approval from FDA to market the drug. FDA approved several indications for using rosuvastatin calcium, including those uses claimed in AstraZeneca's patents. Additionally, FDA approved the drug for treating homozygous familial hypercholesterolemia ("HoFH") and hypertriglyceridemia, uses not covered by AstraZeneca's patents-in-suit.

Defendants filed ANDAs seeking to market generic versions of the drug, but submitted so-called Section viii Statements under the Federal Food, Drug, and Cosmetic Act ("FD&C Act") indicating they sought approval for uses not covered by the patents. In other words, the ANDA filers requested approval to treat only HoFH and hypertriglyceridemia while "carving out" the indications covered by AstraZeneca's listed patents. The ANDA filers moved to dismiss AstraZeneca's complaint for several reasons, including that the complaints failed to state a claim for patent infringement under Section 271(e)(2) because the ANDA filers were not seeking approval for uses of rosuvastatin calcium claimed in AstraZeneca's patents.

by Brian Malkin

On December 29, FDA announced that immediate -release transmucosal fentanyl products would have a shared Risk Evaluation and Mitigation Strategy ("REMS") that would replace the individual REMS presently in place for approved products in this category. In addition to other benefits, the single shared system would permit prescribers and pharmacies to enroll in one system rather than multiple, similar REMS programs. The shared REMS is called the Transmucosal Immediate-Release Fentanyl ("TIRF") REMS Access Program and will become effective in March 2012.

Presently, the list of affected brand-name drugs includes Abstral®, Actiq®. Fentora®, Lazanda®, and Onsolis®. which are all opioid drugs indicated to manage pain in cancer patients, who routinely take other opioid pain medications on a continual basis. Breakthrough pain is pain that comes on suddenly for short periods of time and cannot be reduced by a patient's normal pain management program. For TIRFs to be used safely, they must be used by patients who are already opioid tolerant based on their concurrent regular use of another opioid pain medication.

Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research ("CDER") said, "This TIRF REMS will ensure safe use and access to these drugs for patients who need them. We have worked with the sponsors of both the innovator and generic drugs to develop this single, shared system that will streamline the process and decrease the burden of the REMS on the health care system."