On March 24, 2008, FDA asked the U.S. District Court for the District of Connecticut to dismiss a January 22, 2008 Amended Complaint alleging that the Agency improperly denied HiFi DNA Tech, LLC’s petition for reclassification of an HPV nested DNA polymerase chain reaction (PCR) detection device to Class II.  As stated in HiFi’s Amended Complaint, the company’s device is intended to be used for preparation of sample materials for accurate HPV genotyping by direct automated DNA sequencing.  HiFi asked the Court to review and reverse the denial of its reclassification petition, or to declare the denial invalid and to order FDA to conduct an unbiased review of the reclassification petition. 

HiFi submitted a 510(k) premarket notification to FDA on December 7, 2006, requesting that the Agency deem the new device substantially equivalent to Digene’s Hybrid Capture 2(hc2) High-Risk HPV DNA test.  Digene’s test was approved by FDA as a Class III device under the premarket approval process.  Consequently, on January 9, 2007, FDA rejected HiFi’s premarket notification and determined the device to be a Class III device.  FDA states in its Motion to Dismiss that HiFi could not demonstrate that its device was substantially equivalent to a predicate device that did not require premarket approval.  HiFi then submitted a request for de novo review.  FDA deemed the device ineligible for de novo review because it was of the same type as Class III devices; two other HPV detection devices have been approved as Class III devices. 

On March 7, 2007, HiFi submitted to FDA a petition to reclassify its device as Class II.  FDA denied the petition on December 14, 2007.  In its Amended Complaint, HiFi alleges that FDA’s review of the petition did not “follow established FDA procedures” in that the Agency did not forward the petition to the FDA Commissioner or to a classification panel for review.  However, FDA has discretion as to whether to refer a reclassification petition to a panel; as FDA points out in its Motion to Dismiss, 21 U.S.C. § 360c(f)(3) says the “Secretary may for good cause shown refer the petition to an appropriate panel.”  The legislative history of this section confirms that Congress wanted FDA to have such discretion.  HiFi alleges that FDA improperly compared its device to Digene’s test, as that test (which HiFi used as the predicate device in its premarket notification) uses a different scientific basis to determine the presence and type of HPV in a sample.  HiFi further alleges that FDA’s denial of its reclassification petition results in “FDA’s over-regulation of the device as a cancer test rather than as a test for a common virus . . . in violation of the least burdensome [standard] . . . and at the expense of public interest.”  According to HiFi, the denial was inappropriate and applied an incorrect scientific standard to the device.  The company challenges FDA’s assertion that the device is intended for use in evaluating cancer risk.  FDA maintains that many cancers of the cervix are associated with HPV infection and that if used as intended, HiFi’s device will guide patient management decisions to refer a woman for further cervical cancer screening.  Further, FDA reveals in its Motion to Dismiss that HiFi’s own submissions to the Agency referenced professional Guidelines for cervical cancer screening. 

FDA states that it evaluated all of the scientific evidence to determine that HiFi’s device does not meet the statutory criteria for Class II.  FDA’s Motion to Dismiss cites inadequacies in HiFi’s data including that performance characteristics, clinical sensitivity and specificity, cross-reactivity, and the rate of false negatives could not be assessed.  Moreover, HiFi described its device as being used in conjunction with HPV genotyping to confirm positive HPV DMA results, but FDA’s Motion to Dismiss asserts that the company did not submit any evidence to establish that HPV genotyping has been clinically validated for diagnostic use in relation to cervical cancer.  According to FDA, HiFi failed to provide the Agency with sufficient evidence to establish special controls to assure the safety and effectiveness of the device for its intended use.  FDA’s Motion to Dismiss argues that the administrative record of its review of HiFi’s submissions supports its decisions, and that the Agency acted within its authority.  HiFi faces an uphill battle in this litigation.

By Christine P. Bump

Earlier this year, we reported on the U.S. District Court for the District of Columbia’s January 24, 2008 order dismissing Nu-Pharm Inc.’s complaint against FDA seeking declaratory and emergency injunctive relief with respect to Nu-Pharm’s ANDA #77-615 for a generic version of Abbott Laboratories’ DEPAKOTE (divalproex sodium) Delayed-Release Tablets, 500 mg.  Specifically, Nu-Pharm sought both a judicial declaration that FDA’s decision not to approve ANDA #77-615 violated the Administrative Procedure Act (“APA”), and preliminary and permanent injunctive relief requiring FDA to approve ANDA #77-615.  The district court dismissed the complaint, declining to exercise jurisdiction for “prudential reasons,” reportedly on the ground that the injunctive relief sought by Nu-Pharm would “conflict irreconcilably” with a previous order entered in a contempt proceeding (see below).  As we anticipated, on January 29, 2008, Nu-Pharm appealed the decision to the U.S. Court of Appeals for the District of Columbia Circuit. 

Nu-Pharm submitted ANDA #77-615 to FDA in March 2005 with paragraph IV certifications to two Orange Book-listed patents covering DEPAKOTE: U.S. Patent #4,988,731 (“the ‘731 patent”) and #5,212,326 (“the ‘326 patent”).  These patents expired on January 29, 2008; however, in December 2007, FDA granted Abbott pediatric exclusivity for the drug, thereby delaying generic approval under certain circumstances until July 29, 2008.  Abbott sued for patent infringement within the statutory 45-day period, and the 30-month stay triggered by the suit reportedly expired on November 13, 2007.  Nu-Pharm argued that FDA must approve ANDA #77-615 because the company satisfied all requirements for final ANDA approval and the 30-month stay of approval triggered by the submission of Nu-Pharm’s ANDA with a paragraph IV patent certification expired without a substantive ruling on patent validity or infringement.  FDA nevertheless refused to approve ANDA #77-615 based on an order entered in a contempt proceeding by the U.S. District Court for the Northern District of Illinois (Eastern Division) (Judge Richard Posner sitting by designation) involving an ANDA with a paragraph IV patent certification for generic DEPAKOTE submitted by Apotex Inc. (which formerly owned Nu-Pharm) that also extended to Nu-Pharm’s product.  In October 2007, the U.S. Court of Appeals for the Federal Circuit held in Abbott Labs. V. TorPharm, Inc. that the contempt procedure used by the Illinois court was proper, that Nu-Pharm’s divalproex sodium drug product was not colorably different from Apotex’s divalproex sodium drug product, and that Nu-Pharm’s product would infringe patents covering DEPAKOTE.  On January 7, 2008, Apotex petitioned the U.S. Supreme Court for review (Case #07-912).  A response from the Supreme Court as to whether or not the Court will hear the case is anticipated later this month.

After appealing the January 24, 2008 district Court order, Nu-Pharm submitted a motion to expedite consideration of the company’s appeal.  Nu-Pharm argues that “the district court improperly refused to exercise jurisdiction over Nu-Pharm’s complaint” when it declined to exercise subject matter jurisdiction over Nu-Pharm’s complaint for “prudential reasons” given the order entered in the contempt proceeding.  “The court’s decision conflicts with the well-accepted principle that the federal courts have a virtually unflagging obligation . . . to exercise the jurisdiction given them” (internal quotations omitted), states Nu-Pharm.  Further, Nu-Pharm argues that FDA’s decision not to approve ANDA #77-615 is contrary to the language of FDC Act § 505(j)(5)(B)(iii), which states that ANDA approval “shall be made effective” after the expiration of the 30-month stay, and that FDA’s decision conflicts with past Agency policies and practices.  “To Nu-Pharm’s knowledge, FDA has never delayed one ANDA applicant’s approval based on an unfavorable decision in another, unrelated action that did not arise out of that applicant’s paragraph IV certification,” states Nu-Pharm.  Nu-Pharm also argues that “FDA’s ruling [with respect to ANDA #77-615] turns the entire Hatch-Waxman system on its head and can not stand,” as it “impermissibly rewards the NDA-holder for attempting to escape a finding of non-infringement in the patent infringement action it filed against a particular ANDA applicant by running to an entirely different district court to extend an injunction order over and entirely different ANDA product.” 

FDA’s Combined Motion for Summary Affirmance and Response to Nu-Pharm’s Motion to Expedite Appeal Consideration was filed on February 13, 2008.  “The baseless nature of this case makes it unnecessary for this Court even to reach the question of expedited briefing; Judge Roberts’ decision should be affirmed summarily.  The weakness of this case also means that the case does not present a ‘substantial challenge,’ which is one of the Circuit’s requirements for expedited consideration,” states FDA.  The Agency goes on in its brief to argue that the district court properly declined jurisdiction, that under the D.C. Circuit’s recent opinion in Taylor v. Blakey, res judicata bars Nu-Pharm’s complaint, and that Nu-Pharm’s complaint fails to state a claim that is plausible on its face.

Abbott, which joined the case as an intervenor-defendant-appellee, takes issue with Nu-Pharm’s lack of expedition in attending to the appeal in its response to Nu-Pharm’s motion to expedite: “Nu-Pharm has not been acting with the sort of dispatch one might expect from a party claiming to be irreparably harmed and thus requiring immediate relief and expedited treatment from this Court.”  Abbott cites several examples, including the fact that Nu-Pharm took 5 days to notice its appeal of the district court’s order.  Abbott also argues that “the fact that Nu-Pharm would prefer not to compete with other manufacturers does not mean it will suffer ‘irreparable harm’ absent relief in this case; it simply means that Nu-Pharm will have to play by the same rules as everyone else.”  In response, Nu-Pharm argues that “[w]hat Abbott and FDA continue to ignore is the fact that Nu-Pharm is not in the same position ‘as everyone else.’  Unlike other divalproex sodium paragraph IV ANDA-filers, Nu-Pharm, to its knowledge, was the only applicant entitled to final approval prior to the natural expiration of Abbott’s patents . . . .  [W]hile ‘everyone else’ may have been rightfully denied access to the market during Abbott’s pediatric exclusivity period, by virtue of FDA’s refusal to approve Nu-Pharm’s ANDA after the 30-month stay had expired, Nu-Pharm was unlawfully denied the opportunity to take advantage of limited generic competition during this six-month period.”

Nu-Pharm’s February 29, 2008 brief in opposition to FDA’s motion to summarily affirm the district court’s dismissal argues that the motion should be denied because dismissal “would deprive Nu-Pharm from ever having its APA case heard on the merits,” and because “additional briefing and argument would benefit the disposition of this appeal.”  With respect to FDA’s argument that res judicata bars Nu-Pharm’s complaint, the company counters that “the issues raised in Nu-Pharm’s APA complaint were not, and could not have been, raised [in previous patent infringement litigation] . . . .  Further, these cases involve not only different parties, but also different rights, different injuries, and different requests for relief . . . and a different nucleus of facts.” 

In response to FDA’s argument that Nu-Pharm’s complaint fails to state a claim, the company argues that “[t]he truth is that FDA simply is unwilling to take-on the straight-forward statutory arguments raised in Nu-Pharm’s complaint, as demonstrated by the Agency’s refusal to address these arguments anywhere below or in its motion to this Court.”  FDA’s March 7, 2008 reply brief ups the ante in this war of words and states that Nu-Pharm’s argument “is based on a contrived and convoluted view of exactly what constitutes Nu-Pharm’s ‘claim.’  Nu-Pharm attempts to define its claim narrowly so that it would pertain only to APA allegations against FDA, and then argue that that particular claim was not addressed by the Illinois court because FDA was not a party there . . . .  This is too clever by half. . . .  Nu-Pharm is attempting to litigate here the issue resolved by Judge Posner, i.e., the timing of FDA approval of its ANDA . . . .  [T]his attempt should be rejected and the district court should be summarily affirmed.” 

By Kurt R. Karst    

In our October 2007 summary and analysis of the FDA Amendments Act (“FDAAA”), Hyman, Phelps & McNamara, P.C. noted that FDAAA § 912, concerning a new prohibition against foods to which drugs or biological products are added, is “of potential significance to the development of functional food ingredients.”  Further analysis convinces us that FDAAA § 912 could represent a fundamental shift in the dividing line between foods and drugs.  This makes it all the more important for both food and drug manufacturers to more closely examine FDAAA § 912 and consider its likely effect on their existing portfolios and product development strategies.

The first line of inquiry is whether a given substance falls within the scope of the § 912 prohibition. Section 912 prohibits the addition to food of an approved drug or a licensed biologic. It also prohibits the addition of “a drug for which substantial clinical investigations have been instituted and for which the existence of those investigations has been made public” (emphasis added).  The reference to “drug,” with its attendant uncertainties regarding the manifestation of intent, is not so bright a line as that provided by the FDC Act § 201(ff) dietary supplement exclusionary clause, which excludes articles for which an IND has been authorized. Contributing to the blurred distinction is the vague threshold of “substantial clinical investigations.” 

If a given substance falls within the scope of § 912, applicability of the exceptions to the prohibition must then be considered. Unfortunately, several of the exceptions are not straightforward. The grandfather exception hinges on the “drug” having been first “marketed” in food. The meaning of the term “marketed,” also present in the dietary supplement exclusionary clause, has never been resolved, although at least one court – the U.S. District Court for District of Utah (Central Division) – commented on it in dictum.  See Pharmanex, Inc. v. Shalala, 2001 WL 741419 (D.Utah). Another exception applies when FDA has issued a regulation, after notice and comment, approving the use of the “drug” in the food. This exception begs the question of whether an existing regulation, such as one approving a health claim for the “drug,” would suffice. Yet another exception requires that use of the “drug” in food be to “enhance safety,” and not to have an independent “biological” or therapeutic effect. One can readily imagine different ways that a substance could “enhance safety,” but it is more difficult to conjure up examples of substances that can be ingested without having a “biological” effect.

These are just a few of the difficult interpretive issues presented by FDAAA § 912.  FDA has made clear that it already has begun to grapple with those issues.  Members of the food and pharmaceutical industries would be well advised to do the same.

By Diane B. McColl and Ricardo Carvajal

The latest FDLI Update article by Hyman, Phelps & McNamara, P.C.’s Riëtte van Laack and John R. Fleder discusses a recent court ruling showing the potential perils faced by a company and its officers who aggressively defend their position.   In United States v. Kaminski, the U.S. Court of Appeals for the Sixth Circuit affirmed in part and reversed in part a ruling by the U.S. District Court for the Southern District of Ohio concerning Ovimmune, Inc., its owner, Marilyn Coleman, and her business partner, Mitchell Kaminski, and the appropriate enhanced criminal sentences to be imposed after the defendants allegedly obstructed justice by complaining about FDA’s allegedly poor treatment of them during an investigation of claims about defendants’ hyperimmunized eggs product.  According to the article, “Ovimmune was a small corporation and the sale of the hyperimmunized eggs, although found to be adulterated and misbranded, did not apparently cause any physical harm.  Nevertheless, the hostilities that developed during the government’s investigation may well have caused the prosecution to be initiated, and surely increased the sentences that were imposed after conviction.”

Welcome to the wonderful world of blogging, Dr. von Eschenbach!  Yep, just like his boss, Department of Health and Human Services Secretary Michael Leavitt, who started “Secretary Mike Leavitt’s Blog” last year, FDA Commissioner, Dr. Andrew von Eschenbach, has started a blog as well – aptly titled “Andy’s Take.”  As The Washington Post noted, however, “Andy’s Take,” unlike “Secretary Mike Leavitt’s Blog,” “is not a give-and-take blog.  It’s a weekly posting, sort of an electronic newsletter.”  In his first posting (also available in an MP3 format), Dr. von Eschenbach states:

As Commissioner, I want to give you my take on some of the events about food and medical products that you have been hearing about in the news. 

I want to give you the inside story on some of the things that will soon be announced at the FDA so that you have my insights about why these initiatives are of such great importance to protecting and promoting your health. 

I want to give you my take on the changes at the FDA and what we need to do to improve and be responsive to the rapidly changing world around us.

In this brief column I will alert you to upcoming issues and events, and give you my inside view of events or news items of current interest, and tell you about our plans and our progress in better protecting and promoting your health.

We are all ears, Dr. von Eschenbach! 

Dr. von Eschenbach’s second post from March 28, 2008 focuses on FDA’s recent troubles with the blood-thinning drug heparin and the Agency’s “Beyond our Borders” initiative.  “Through the Beyond our Borders initiative, the FDA can expand our capacity for regulation of food, drugs, and medical devices.  We will do this primarily by nurturing cooperation for information sharing, improving procedures for expanded inspections, and working with private and government agencies to assure standards for quality,” according to Dr. von Eschenbach.

On March 21, 2008, the California EPA Office of Environmental Health Hazard Assessment (“OEHHA”) announced a workshop scheduled for April 18, 2008 to seek public input on the potential regulation of nutrients, such as vitamins and minerals, under Proposition 65 (the Safe Drinking Water and Toxic Enforcement Act of 1986, Health and Safety Code § 25249.5, et. seq.). Proposition 65 requires that the state publish and maintain a list of chemicals known to cause cancer or birth defects or other reproductive harm. The list now includes approximately 775 chemicals. If a chemical is on the list, then a product that contains that chemical must carry a specified warning statement unless the exposure poses no significant risk of cancer or is significantly below levels observed to cause birth defects or other reproductive harm. If exposure falls below OEHHA’s “safe harbor number” for that chemical, then no warning is required.

OEHHA’s workshop announcement states that “certain chemicals or compounds such as vitamins and minerals are necessary to promote human health or to ensure the healthy growth of food crops,” but that “[e]xcessive exposures to these same chemicals or compounds can cause cancer or adverse reproductive effects.”  OEHHA asserts that it is “seeking a way to balance the need for these nutrients with the necessity for providing Proposition 65 warnings for exposures to listed chemicals in foods.”

OEHHA has drafted language for a possible regulation. That language would exempt from the definition of “exposure” the consumption of a listed chemical in food if the person “causing the exposure” can show that the chemical is a nutrient that is “beneficial to human health,” and that the total amount of the chemical consumed in a food does not exceed the Recommended Daily Allowance (“RDA”) established by the Food and Nutrition Board of the Institute of Medicine (“IOM”).  If no RDA is established, then the total amount cannot exceed 20% of the Tolerable Upper Intake established by the IOM. A chemical would be considered “beneficial to human health” only if a daily value or allowance has been established by the IOM.

At least three points are notable about OEHHA’s proposal. First is the use of RDA’s as thresholds for determining whether an “exposure” has occurred. This is, to say the least, a novel use of RDA’s. Second is the notion that a nutrient is “beneficial to human health” only if a daily value or allowance has been established by the IOM. What of nutrients that have clearly established health benefits but have yet to make it into IOM’s Dietary Reference Intake Tables? Finally, there is the prospect that dietary supplements and conventional foods that comply with the applicable safety standards and labeling requirements in the Federal Food, Drug, and Cosmetic Act will nonetheless be made to bear a warning label in the state of California.

In a limited sense, California is not breaking new ground. Vitamin A already is included in the Proposition 65 list of chemicals. But the potential breadth of OEHHA’s proposal is such that it is impossible to not recall the long and painful history of FDA’s attempts to regulate the sale of articles containing “excessive” levels of vitamins and minerals. Decades of aborted rulemakings, protracted litigation, and legislative activity resulted in FDA’s virtual retreat from a playing field that proved formidably hostile. It’s hard to imagine that OEHHA has any interest in a reprisal of that experience – the state agency is prudently “requesting input from stakeholders in the enforcement and business communities, as well as other members of the public, concerning issues that may arise if OEHHA proceeds with such a regulatory proposal.” No doubt, OEHHA will get an earful. 

By Ricardo Carvajal, A. Wes Siegner, and Brian J. Donato

Earlier today, FDA issued a Federal Register notice notifying holders of applications for certain prescription drug products approved under FDC Act § 505(b) (NDA) or § 505(j) (ANDA) and biological products licensed under § 351 of the Public Health Service Act that they will be deemed to have in effect an approved Risk Evaluation and Mitigation Strategy (“REMS”) under the recently-enacted FDA Amendments Act (“FDAAA”).  FDA also made available a “Questions and Answers” document explaining the Federal Register notice and discussing, among other things, when a decision will be made for a specific application that a REMS is needed. 

FDAAA was signed into law on September 27, 2007.  Title IX, Subtitle A of FDAAA created new FDC Act § 505-1, which authorizes FDA to require applicants submitting a marketing application for a prescription drug or biological product to submit and implement a REMS if the Agency determines that such a mechanism is necessary to ensure that the benefits of the product outweigh its risks.  Certain products approved prior to the effective date of FDAAA are, under FDAAA § 909(b)(1), deemed to have a REMS in effect “if there are in effect on the effective date of this Act elements to assure safe use — (A) required under [FDA’s accelerated approval restricted distribution regulations at 21 C.F.R. § 314.520 or § 601.42]; or (B) otherwise agreed to by the applicant and the Secretary [of Health and Human Services] for such drug.”  New FDC Act § 505-1(f)(3) states that “elements to ensure safe use” include the following:

(A) health care providers who prescribe the drug have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the drug shall be available to any willing provider from a frontier area in a widely available training or certification method (including an on-line course or via mail) as approved by the Secretary at reasonable cost to the provider);

(B) pharmacies, practitioners, or health care settings that dispense the drug are specially certified (the opportunity to obtain such certification shall be available to any willing provider from a frontier area);

(C) the drug be dispensed to patients only in certain health care settings, such as hospitals;

(D) the drug be dispensed to patients with evidence or other documentation of safe-use conditions, such as laboratory test results;

(E) each patient using the drug be subject to certain monitoring; or

(F) each patient using the drug be enrolled in a registry.

FDAAA § 909 took effect earlier this week, on March 25, 2008.  Under FDAAA § 909(b)(3) and today’s Federal Register notice, sponsors of products with “deemed REMS” applications must submit a proposed REMS to FDA by September 21, 2008.  “Such proposed strategy is subject to [FDC Act § 505-1] as if included in such application at the time of submission of the application to the Secretary.”

FDA’s Federal Register notice identifies 16 products (subject to 28 approved or licensed applications) approved prior to the effective date of FDAAA Title IX with “elements to assure safe use.”  According to FDA’s notice, “[a] drug will not be deemed to have a REMS if it has only a Medication Guide, patient package insert, and/or communication plan.” However, the Agency also states in its “Questions and Answers” document that “[i]n the future, a product with only a new or revised Medication Guide (without elements to assure safe use) will be under a REMS that will include a timetable for assessment of the REMS.”  The Agency requests that members of the public notify FDA if they are aware of products that should have a “deemed REMS” in effect, and also requests that application holders who do not believe their product should be on the list submit a letter to the Agency with justification as to why its product was improperly listed.

FDA is reportedly working on an interim guidance document that will describe the content and format of a proposed REMS and provide a template and a model REMS.  Violations of REMS are subject to stiff civil monetary penalties.  Under FDAAA, the penalties may not exceed $250,000 per violation, or $1 million for all violations adjudicated in a single proceeding.

Also earlier today, Dr. Douglas C. Throckmorton, Deputy Director of FDA’s Center for Drug Evaluation and Research, commented during a presentation concerning FDAAA implementation at the Food and Drug Law Institute’s Annual Conference here in Washington, D.C. that FDA will use its REMS authority “judiciously,” as there is a “targeted use” per FDAAA.  “Too many [REMS] would increase confusion in the system, [and] could increase errors and decrease [product] availability,” according to Dr. Throckmorton.

By Kurt R. Karst    

FDA and the University of Rhode Island College of Pharmacy will co-sponsor an interactive forum from June 30 through July 1, 2008 at the Hyatt Regency in Bethesda, Maryland on how and how not to communicate with FDA’s Office of Generic Drugs (“OGD”).  Forum presenters will also address how the legal landscape for generic drug companies has changed over the past few years following the enactment of the Medicare Modernization Act (“MMA”) in December 2003. A copy of the forum brochure is available here.  Forum presenters include an all-star cast from FDA, including OGD Director Gary J. Buehler and FDA’s Associate Chief Counsel for Drugs, Elizabeth H. Dickinson.  Hyman, Phelps & McNamara, P.C.’s Robert A. Dormer will present on post-MMA FDA decisions and related communications concerning 180-day generic drug exclusivity and other issues.

Last week, the Pennsylvania Court of Common Pleas of Philadelphia County (the lowest court of general jurisdiction in Pennsylvania) ruled in Clark v. Pfizer, Inc., Case No. 1819 (June Term 2004) – a class action lawsuit in which the plaintiffs allege that Parke-Davis (then a Warner-Lambert and now a Pfizer subsidiary) fraudulently promoted the anticonvulsant drug product NEURONTIN (gabapentin) for “off-label” uses (i.e., uses not approved by FDA) – that drug companies may have a legal obligation to class members for the money spent on generic versions of the drug product.  The class action lawsuit, brought on behalf of a certified class of persons “who purchased Neurontin, or its generic equivalent, gabapentin, in the Commonwealth of Pennsylvania” for unapproved uses, stems from a May 2004 agreement in which Warner-Lambert pled guilty to charges of illegally marketing NEURONTIN for off-label uses and paid $430 million to resolve federal charges.  NEURONTIN is approved in capsule, tablet, and oral solution dosage forms for the treatment of partial seizures associated with epilepsy and for the management of post-herpetic neuralgia.

The complaint (amended) in the lawsuit alleges that Gregory Clark and other plaintiffs were prescribed NEURONTIN for off-label uses (e.g., knee pain and bipolar disorder) “as a direct result of defendant’s active marketing and promotion of Neurontin for unapproved uses,” and that “plaintiffs and the class members sustained injuries, including ascertainable economic losses, by purchasing Neurontin” “as a direct and proximate result of [such] marketing and promotional schemes.”  The complaint includes several counts, including misrepresentation, negligence, negligence per se, breach of express warranty, and violations of the Pennsylvania unfair trade practices and consumer protection law. 

Judge Mark I. Bernstein’s March 14, 2008 ruling on Pfizer’s Motion for Partial Summary Judgment let stand the class action claims of negligent misrepresentation, negligence, and intentional misrepresentation regarding generic NEURONTIN manufactured by third-party drug companies.  “The legal question presented by this Motion for Partial Summary Judgment is whether under Pennsylvania Law, a drug company which negligently or intentionally perpetrates a fraud upon the medical community may be held responsible for sums paid to other drug manufacturers because of their misrepresentations,” Judge Bernstein states in his opinion. Assuming that the plaintiffs can prove their allegations at trial, “[u]nder Pennsylvania law, a defendant may be liable for misrepresentation to foreseeable plaintiffs even without any direct relations between the parties.”  According to the opinion:

Given the presumption that plaintiffs will be able to factually prove their allegations, the question presented becomes whether under Pennsylvania law, defendants owed any duty for which they can be held liable to purchasers of the drug because defendants had reason to anticipate those individuals would be induced to act.  The sale of generic Gabapentin for non-approved uses was not only foreseeable and predictable, but in fact predicted.  A heavily and successfully marketed drug will, at the time exclusive rights to the formulation have passed, be copied and sold by competitors as a generic equivalent.  The medical literature which plaintiffs claim was manipulated by defendants’, often referred to the generic chemical name rather than the defendants’ brand name.  When generic drugs become available they are often required by law or insurance companies to be prescribed as a substitute unless a physician specifically designates a brand name drug. . . . Defendants themselves estimated that Neurontin would lose between 65 and 95 percent of its market once its patents had expired.  Accordingly, defendant Pfizer proposed manufacturing its own “authorized” generic, to keep a portion of that market.  The significant increased sale of generic Gabapentin was a foreseeable result of defendants actions in marketing Neurontin for “off-label” use. 

The Pennsylvania court’s decision is contrary to other court decisions, which have found that the manufacturer of a brand name (i.e., innovator) drug product does not have a duty to those persons who purchase generic versions of the drug.  For example, the U.S. Court of Appeals for the Fourth Circuit held in 1994 in Foster v. American Home Products Corp., 29 F.3d 165 (4th Cir. 1994), that an innovator drug manufacturer does not owe a legal duty to a consumer of a generic drug.  Indeed, the U.S. District Court for the Eastern District of Pennsylvania stated in dicta in its May 2006 opinion in Colacicco v. Apotex, Inc., 432 F. Supp. 2d 514 (E.D.P.A. 2006) (which is on appeal to the U.S. Court of Appeals for the Third Circuit), that “name brand drug manufacturer does not owe a legal duty to consumers of a generic equivalent of its drug . . . .”  Nevertheless Judge Bernstein, citing the Pennsylvania Supreme Court’s 5-part test in Althaus v. Cohen, 756 A.2d 1166 (Pa. 2000), for determining whether a duty exists as discussed, determined that a duty existed for Pfizer. 

Judge Bernstein’s opinion also opines on the Colacicco case with respect to preemption of state law and takes a stab at FDA’s current pro-preemption policy on drug labeling.

Giving excessive deference to [FDA’s] reinterpretation of the Statute and the Regulations it administers as to preemption, the Colacicco Court found state claims preempted.  While taking the opposite position for many years, in 2006 the FDA promulgated a “preemption preamble” [(see pages 3933-36)] which for the first time stated that FDA labeling requirements did not represent a minimal safety standard, but did in fact “establish both ‘floor’ and ‘ceiling’.”  Although it might be said that this preamble was a politically motivated legal opinion about statutory construction and not one of “agency expertise,” in the field of Pharmaceuticals, the Colacicco Court found that the “FDA has acted within its authority and this Court must respect its expert judgment that an October 2003 warning label other than approved by the FDA would have been in direct actual conflict with Federal law.”  In contradiction, it is plaintiff herein who supports the FDA in the proposition that in violation of Federal law, defendants unlawfully manipulated scientific “truth” to convince by misrepresentation the entire medical community of the proposition that Gabapentin could be therapeutically used for indications never approved by the FDA.

While State Courts respect the reasoning of Federal Courts particularly when interpreting Federal law issues of nationwide import which impact upon Federal-State relations, the right of each sovereign State to protect its citizens is a matter of State law interpretation protected by the 10th Amendment to the United States Constitution.  As a Pennsylvania Trial Court, this Court is obligated to enforce state law until such time as the Supreme Court of the United States having actual authority determines that state law has been preempted.

Additional information on Clark v. Pfizer, Inc. is available from The Legal Intelligencer.

By Kurt R. Karst    

Earlier this month, we reported on a lawsuit filed by Teva Pharmaceuticals USA against FDA in the U.S. District Court for the District of Columbia concerning the relisting of U.S. Patent #5,158,952 (“the ‘952 patent”) in the Orange Book covering Janssen Phaemaceutica’s RISPERDAL (risperidone) Tablets.  The lawsuit was filed after FDA denied Teva’s citizen petition requesting that FDA relist the ‘952 patent and confirm the company’s eligibility for 180-day exclusivity based on its Paragraph IV certification to the patent. 

FDA states in its petition response that according to the Agency’s records, the ‘952 patent was delisted before Teva submitted ANDA #76-228 to FDA in August 2001, and that as a result, the delisting was proper and Teva is not eligible for 180-day exclusivity.  Teva had argued in its petition that because the “official Orange Book” (that is, the printed edition of the Orange Book) listed the ‘952 patent when the company submitted its ANDA to FDA, “FDA’s putative delisting of the ‘952 patent did not become effective until January 2002 when the official Orange Book reflected the delisting of that patent.”  Teva’s complaint and motion for preliminary injunction requests that the court enter an injunction compelling FDA to relist the ‘952 patent and restore the company’s Paragraph IV certification, declare that Teva is entitled to 180-day exclusivity, and enjoin FDA from granting final approval to other ANDAs for generic RISPERDAL during Teva’s 180-day exclusivity period.  The Orange Book currently lists one patent covering RISPERDAL, U.S. Patent #4,804,663, which expired on December 29, 2007, but that is covered by a period of pediatric exclusivity expiring on June 29, 2008. 

On March 14, 2008, FDA submitted its memorandum opposing Teva’s motion for a preliminary injunction.  According to FDA, “[t]here are numerous reasons to deny Teva’s request.”  In response to Teva’s argument that the printed version of the Orange Book is the official version of the publication and that the delisting of the ‘952 patent did not become effective until the official Orange Book reflected the delisting of the ‘952 patent in January 2002, FDA argues that “Teva’s contention is meritless.  Contrary to Teva’s arguments, neither the FDCA nor FDA regulation limit FDA’s publication of patent information to a paper version or preclude FDA from listing that information on its web site.”  FDA’s brief also opposes Teva’s request based on arguments that the company cannot show irreparable harm in the event Teva is denied injunctive relief, and that Teva has not shown that an injunction would serve the public interest.  FDA also takes issue with Teva’s “years-long delay” in raising the issue with FDA and states that “Teva’s lengthy delay . . . severely undermines its request for equitable relief, especially its allegations of irreparable harm.” 

On March 11, 2008, Mylan Pharmaceuticals Inc., which has a pending ANDA for Risperidone Tablets, submitted a motion to enter the case as an intervenor-defendant and a proposed answer.  According to Mylan’s motion, the company’s “final approval and market entry are at risk of being substantially delayed” because of Teva’s lawsuit, and as such, the court should permit Mylan to intervene “to ensure that its interests are protected.”  On March 20, 2008, the court granted Mylan’s motion to intervene.  Mylan is expected to file its brief in intervention later this week (by March 26th).  Teva’s reply brief is due by April 1, 2008.  Oral argument is scheduled for April 4, 2008. 

We will continue to update you on this interesting case as we learn more information. 

By Kurt R. Karst    

Last year, in our post titled “180-Day Exclusivity Forfeiture – A Zen Moment,” we reported on a case in which FDA took a stance with respect to the forfeiture of 180-day exclusivity eligibility that is reminiscent of the old “if a tree falls in the woods and nobody is there” enigma.  That case concerned Sandoz’s ANDA #76-969 for Metoprolol Succinate Extended-Release Tablets, 25mg, which was submitted to FDA in December 2003.  Sandoz was a “first applicant” eligible for 180-day exclusivity based on its Paragraph IV certification to a patent listed in the Orange Book covering the Reference Listed Drug (“RLD”), TOPROL-XL. 

In July 2006, FDA granted full approval for the 25mg drug product, but noted that Sandoz failed to obtain tentative approval within 30 months after the date on which the ANDA was filed, and might therefore not be eligible for 180-day exclusivity.  Under FDC Act § 505(j)(D)(5)(i)(IV), as amended by the Medicare Modernization Act:

The first applicant [forfeits 180-day exclusivity eligibility if the 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.

Ultimately, FDA punted on the issue, and stated in the ANDA approval letter that “the agency is not making a formal determination at this time of Sandoz’s eligibility for 180-day generic drug exclusivity.  It will do so only if another applicant becomes eligible for approval within 180 days after Sandoz begins commercial marketing Metoprolol Succinate Extended-Release Tablets USP, 25 mg.” 

Over the past several weeks, FDA has been faced with two similar situations concerning FDC Act § 505(j)(D)(5)(i)(IV).  In one case FDA used language similar to that stated in the Sandoz ANDA approval letter.  In another case FDA made clear its determination that 180-day exclusivity eligibility was forfeited.

In the case of Perrigo R&D Co.’s ANDA #77-355 for a generic version of PEPCID COMPLETE (famotidine, 10mg; calcium carbonate, 800mg; magnesium hydroxide, 165 mg) Chewable Tablets, Perrigo was a “first applicant” based on the company’s Paragraph IV certification to 3 Orange Book-listed patents.  The ANDA was submitted to FDA in October 2004.  According to FDA’s February 2008 approval letter, “Perrigo failed to obtain tentative approval of this ANDA within 30 months of the date on which the ANDA was filed . . . .  However, the agency is not making a formal determination at this time of Perrigo’s eligibility for 180-day generic drug exclusivity.  It will so only if another applicant becomes eligible for approval within 180-days after Perrigo begins commercial marketing” of the drug product approved under ANDA #77-355. 

In the case of Watson Laboratories, Inc’s ANDA #77-219 for a generic version of CAMPTOSAR (irinotecan HCl) Injection, 20mg/mL, Watson was the first applicant to submit a submit a substantially complete ANDA with a Paragraph IV certification to an Orange Book-listed patent covering CAMPTOSAR.  As such, the company was eligible for 180-day exclusivity.  Watson submitted ANDA #77-219 to FDA in July 2004, and FDA tentatively approved the application in May 2007 – about 34 months after the date on which the application was filed.  In contrast to the two previous cases cited above, FDA’s February 20, 2008 approval letter to Watson states:

The ANDA filing date plus 30 months was January 26, 2007; therefore, this ANDA was not granted tentative approval within the 30-month period described in section 505(j)(D)(5)(i)(IV).  We also have determined that the requirements for approval of this ANDA were not changed or reviewed after your ANDA was filed . . . .  We therefore conclude that the 180-day exclusivity period . . . for Irinotecan Hydrochloride Injection, 20 mg/mL, was forfeited by Watson. 

FDA’s decision that Watson forfeited 180-day exclusivity eligibility was almost certainly prompted by the fact that several generic applicants that would have been subject to Watson’s 180-day exclusivity were pending and ready for approval.  Indeed, on February 27, 2008, just a few days after approving Watson’s ANDA, FDA approved 7 ANDAs for generic Irinotecan HCl Injection drug products.

FDA’s decision in the Watson case should put to rest any speculation based on the Agency’s previous letters that FDA will determine that a “first applicant” has not forfeited 180-day exclusivity eligibility if tentative approval was not granted within 30 months of the date on which the ANDA was filed and there are other ANDAs in the approval queue. 

By Kurt R. Karst    

Hyman, Phelps & McNamara, P.C. (“HPM”) is pleased to announce that Ricardo Carvajal has joined the firm as Of Counsel.  From 2002 to 2007, Mr. Carvajal served as Associate Chief Counsel in FDA’s Office of Chief Counsel, where he handled issues concerning foods (including conventional foods, bioengineered foods, dietary supplements, functional foods, and food additives), labeling compliance (such as the use of health, nutrient content, structure/function, and disease claims), Good Manufacturing Practices, and the Hazard Analysis and Critical Control Point regulations.  Mr. Carvajal has particular expertise in the regulation of products derived through biotechnology and nanotechnology, and in the regulation of allergens.  Mr. Carvajal has also worked on matters involving drugs, devices, and other products regulated by the FDA.  Mr. Carvajal received an M.S. in Biology from the University of Michigan, and his law degree from Northwestern University School of Law.  He is an active member of the Food and Drug Law Institute, the Institute of Food Technologists, and the American Bar Association.

Last month, we reported on the U.S. Supreme Court’s 8-1 decision in Riegel v. Medtronic, in which the Court provided a definitive decision preempting state tort law claims for medical devices subject to an approved Premarket Approval Application.  Immediately after the decision was issued, some members of Congress threatened to introduce legislation that would have the effect of overturning the Riegel decision.  Representative Henry Waxman (D-CA) vowed that Congress will “pass legislation as quickly as possible to fix this nonsensical situation,” and House Energy and Commerce Health Subcommittee Chair Rep. Frank Pallone (D-NJ) stated that the Riegel decision “shows why it is more necessary than ever for Congress to step in and restore the protections that patients are entitled to if they are the victim of a life-altering accident caused by a medical device.” 

A 2-page draft bill, styled as the “Medical Device Safety Act of 2008,” is being circulated on Capitol Hill.  The bill (apparently originating from Rep. Pallone) would amend § 521 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to add a new subsection, titled “No Effect on Liability Under State Law,” which states: “Nothing in this section shall be construed to modify or otherwise affect any action for damages or the liability of any person under the law of any State.” If enacted, the amendment would apply to any civil action pending or filed on the date of the enactment of the Medical Device Safety Act of 2008.  Furthermore, the bill, if enacted, would be retroactive to the enactment of the Medical Device Amendments of 1976, which added FDC Act § 521.

By Kurt R. Karst    

Last Friday, Representatives Anna Eshoo (D-CA) and Joe Barton (R-TX) announced the introduction of H.R. 5629, the “Pathway for Biosimilars Act.”  We previously reported on a draft version of the bill circulated on Capitol Hill in February 2008.  H.R. 5629 will be referred to the House Energy and Commerce Committee where it will presumably be scheduled for a hearing or mark-up session later this year.

Much of H.R. 5629 is similar to the draft version.  The bill would amend § 351 of the Public Health Service Act (“PHS Act”) to permit the submission of an application for licensure of a biogeneric that includes, among other things, information demonstrating that the biogeneric is biosimilar to a reference product based on analytical studies, animal studies, and a clinical study or studies sufficient to demonstrate the safety and efficacy of the biosimilar product.  While the draft version would have permitted the Department of Health and Human Services Secretary (“Secretary”) to waive only analytical and animal studies (if determined to be unnecessary), H.R. 5629 also permits the Secretary to waive clinical studies (again, if determined to be unnecessary).

As with the draft version, H.R. 5629 provides the sponsor of the first biogeneric determined to be interchangeable with a reference product with a 24-month period of market exclusivity.  Innovator companies would get a period of 12-year exclusivity after initial licensure that may be increased to 14 years if during the 8-year period following licensure of the reference product, the Secretary approves a supplement for a “medically significant new indication” that would be a “significant improvement” compared to marketed products.  The 12-year or 14-year exclusivity periods may be extended by 6 months by pediatric exclusivity.  As is currently the law for pediatric exclusivity applicable to drugs under § 505A of the Federal Food, Drug, and Cosmetic Act (“FDC Act”), H.R. 5629 states that pediatric exclusivity would not apply to a biological product unless FDA determines no later than 9 months prior to the expiration of market exclusivity that pediatric studies submitted to the Agency in response to a Pediatric Written Request meet the terms of the request.  Other provisions in FDC Act § 505A would also apply to biologics under H.R. 5629.

New to H.R. 5629 is a provision stating that an application for a biological product must be submitted under PHS Act § 351, except that “an application for a biological product may be submitted under [FDC Act § 505] if  – (A) such biological product is in a product class for which a biological product in such product class is the subject of an application approved under [FDC Act § 505] not later than the enactment of [the Pathway for Biosimilars Act]; and (B) such application” was submitted to FDA before the enactment of the Pathway for Biosimilars Act or is submitted to FDA not later than 10 years after enactment.  This exception provision is limited so that “if there is another biological product approved under [PHS Act § 351(a)] that could be a reference product with respect to such application” (that is, if such application were submitted under new PHS Act § 351(k) for a biosimilar), then the application may not be submitted under FDC Act § 505.  If enacted, H.R. 5629 would also deem an application for a biological product approved under FDC Act § 505 to be a license under PHS Act § 351 on the date that is 10 years after the enactment of the Pathway for Biosimilars Act.

FDA Law Blog will continue to follow H.R. 5629 as it makes its way through the legislative gauntlet. 

By Kurt R. Karst    

There is a rather memorable (and hilarious) scene from the movie “Good Morning, Vietnam” in which Robin Williams (playing the role of Airman First Class and disc jockey Adrian Cronauer) questions an Army lieutenant about a 1965 press conference to be given by former Vice President Richard Nixon: “Excuse me, sir.  Seeing as how the VP is such a VIP, shouldn’t we keep the PC on the QT?  ‘Cause if it leaks to the VC he could end up MIA, and then we’d all be put out in KP.”

Although the use of acronyms in the military is ubiquitous and probably not matched in any other sector, the healthcare sector probably comes in a close second.  It not uncommon to read legal memoranda, court documents, or agreements in which a single sentence contains 5 or more acronyms.  Consider the following:  “FDA’s ANDA regulations implementing the FDCA provide that a PE drug product must be shown to be BE to the RLD covered under an approved NDA in order to obtain an AB rating in the OB.”  Translated: “The Food and Drug Administration’s Abbreviated New Drug Application regulations implementing the Federal Food, Drug, and Cosmetic Act provide that a pharmaceutically equivalent drug product must be shown to be bioequivalent to the Reference Listed Drug covered under an approved New Drug Application in order to obtain a substitutable rating in the Orange Book.” 

For those of us who need a guide to wade through the various FDA-related acronyms, FDA has created an Acronyms and Abbreviations Database, beginning with “A-V” (arteriovenous) and ending with “YTD” (year to date).  The database is not complete; however, visitors to FDA’s website may suggest new entries.  (How about “AAD” – Acronyms and Abbreviations Database?)

Click here for previous FDA Law Blog “Lighter Side” posts.

By Kurt R. Karst