Earlier this month, FDA announced the release of the Agency’s draft Prescription Drug User Fee Act (“PDUFA”) IV Drug Safety Five-Year Plan.  The draft plan is one of the goals FDA agreed to under PDUFA IV, which is the latest reauthorization of PDUFA that was enacted as part of the FDA Amendments Act (“FDAAA”) in September 2007.  Specifically, FDA agreed to prepare and implement “a 5-year plan to modernize drug safety, including improving communication and coordination between the post-market and pre-market review staff.” 

FDAAA Title I reauthorized PDUFA through Fiscal Year 2012 and made several changes to the law, including the broader use of user fee revenue to fund FDA’s drug risk management activities.  Since the enactment of PDUFA in 1992, FDA has only been authorized to use user fee revenues “for the process for the review of human drug applications.”  PDUFA III, enacted in 2002, first expanded the definition of “process for the review of human drug applications” in FDC Act § 735(6) to include “collecting, developing, and reviewing safety information on [drugs approved after October 1, 2002], including adverse event reports, during a period of time after approval of such applications or supplements, not to exceed three years.”  PDUFA IV further expands the range of postmarket activities (without any temporal limitation) for which user fees revenues can be expended by adding the development and use of “improved adverse-event data-collection systems,” “improved analytical tools to assess potential safety problems,” and enforcement of new provisions of the FDC Act added by FDAAA into the definition of “process for the review of human drug applications.”   

Under PDUFA IV, $29.29 million (plus an annual inflation factor) in user fee revenue is to be used by FDA for drug safety activities – specifically the negotiated drug safety commitments identified in the goals letter accompanying PDUFA IV.  FDA refers to this funding stream as “PDUFA IV drug safety enhancement resources.”  In addition to the $29.29 million, FDAAA authorized FDA to collect additional user fees ($25 million in Fiscal Year 2008, increasing annually to $65 million in Fiscal Year 2012) to broaden the focus of drug safety.  FDA refers to this funding stream as “FDAAA authorized resources.”  FDA believes that “Congress intended these additional resources to increase the Agency’s capacity for handling new authorities and requirements of FDAA, including (as examples) efforts associated with implementing Risk Evaluation and Mitigation Strategies (REMS), Post-Market Study/Trial Requirements, Safety Labeling Changes, Active Postmarket Risk Identification, and other provisions.”  At this time, FDA’s draft safety plan focuses only on “PDUFA IV drug safety enhancement resources.”  However, FDA intends to update the draft plan periodically (not less than annually), and a future plan will reportedly include the Agency’s strategies for spending the additional “FDAAA authorized resources.”

FDA’s PDUFA IV drug safety commitments identify several goals, including: (1) strengthening management and operations; (2) improving collection and analysis of adverse event data; (3) implementing epidemiology best practices; (4) expanding database acquisition and use for targeted post-marketing surveillance and epidemiology; (5) strengthening risk management and communication tools; (6) improving post-market information technology systems; and (7) increasing timely, consistent review of new drug trade names to prevent confusion. 

FDA’s draft safety plan discusses the Agency’s strategies for meeting each of these commitments. For example, to strengthen FDA’s management and operations, the Agency will significantly expand the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research by hiring additional staff.  FDA notes, however, that the effects of a staff increase might not be immediately felt, because “[t]ypically, it takes at least two to three years of intense training to prepare new staff to be seasoned in drug regulation.”  Some of FDA’s strategies are not new, but rather, expand on previous proposals.  For example, while FDA notes in the draft plan that the Agency will be holding a public workshop in May 2008 on developing guidance on conducting scientifically sound pharmacoepidemiologic safety studies, FDA floated the idea of developing and issuing guidance on epidemiology best practices in the Agency’s January 2007 report responding to the to the Institute of Medicine’s September 2006 report September, titled The Future of Drug Safety: Promoting and Protecting the Health of the Public.

By Kurt R. Karst    

Earlier today, Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia issued a 2-page order in Teva Pharmaceuticals USA, Inc. v. Leavitt siding with Teva.  This case concerns the relisting of U.S. Patent #5,158,952 (“the ‘952 patent”) in the Orange Book covering Janssen Phaemaceutica’s RISPERDAL (risperidone) Tablets.  As we previously reported (here and here), Teva sued FDA in March 2008 after the Agency denied a citizen petition Teva submitted in August 2007 requesting that the Agency relist the ‘952 patent and confirm Teva’s eligibility for 180-day exclusivity.  Judge Lamberth’s order declares that the delisting of the ‘952 patent was unlawful, orders FDA to relist the patent in the Orange Book and restore Teva’s Paragraph IV patent certification, and enjoins FDA from approving any generic RISPERDAL Tablets ANDAs until Teva’s 180-day exclusivity expires.

According to Teva’s citizen petition, Teva submitted ANDA #76-228 to FDA on August 28, 2001.  The ANDA contained a Paragraph III certification to U.S. Patent #4,804,663 (which expired in December 2007, but is covered by a period of pediatric exclusivity scheduled to expire in June 2008), and a Paragraph IV certification to the ‘952 patent.  In October 2001, FDA notified Teva that the ‘952 had been delisted from the Orange Book, and required the company to amend its patent certification to reflect that the ‘952 patent was no longer listed in the Orange Book as claiming RISPERDAL Tablets.  Teva complied and submitted the ANDA amendment.  After the U.S. Court of Appeals for the District of Columbia Circuit decided in Ranbaxy Laboratories Ltd. v. Leavitt in November 2006 that FDA may not delist a patent from the Orange Book following the submission of an ANDA with a Paragraph IV certification to that patent, however, Teva reportedly reviewed its ANDA portfolio for any potential unlawful patent delistings that could affect the company’s eligibility for 180-day exclusivity.  This review led to the company’s August 2007 citizen petition.

Teva argues 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 ANDA #76-228, “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.”  As such, according to Teva, given the decision in Ranbaxy, FDA could not have lawfully delisted the ‘952 patent because of the company’s Paragraph IV certification to that patent, and the company remains eligible for 180-day exclusivity.  Teva also contends that because FDA “failed to provide official notice of the ‘delisting’ for several months following the submission of Teva’s ANDA,” the delisting does not affect Teva’s “entitlement” to 180-day exclusivity. 

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.  Specifically, FDA states that the “delisting of the ‘952 patent was reflected in the publicly available, electronic Orange Book shortly after June 29, 2001, and no later than July 20, 2001, the date of the next database update.”  As such, “at the time Teva submitted its ANDA, the electronic Orange Book contained the most current information regarding patents listed for Risperdal tablets . . . [and Teva’s] assertion that the delisting of the ‘952 patent did not become effective until publication of the 2002 annual edition of the Orange Book is without merit.” 

Teva’s complaint requests that the court enter an injunction compelling FDA to relist the ‘952 patent and restore the company’s paragraph IV patent certification, and declare that Teva is entitled to 180-day exclusivity.  Teva also requests that the court enjoin FDA from granting final approval to other ANDAs for generic RISPERDAL during Teva’s 180-day exclusivity period.  Both Mylan, which subsequently entered the case, and Pliva have tentatively approved ANDAs, the final approval of which would be delayed if the District Court’s ruling stands.  Teva argues that “FDA’s refusal to relist the ‘952 patent and award Teva 180-day exclusivity period violates the plain language of the Hatch-Waxman Act and flounts the D.C. Circuit’s binding decision in [Ranbaxy] . . . .  In addition, FDA’s refusal to restore the ‘952 patent to the Orange Book and award Teva 180-day exclusivity conflicts with the Agency’s own regulations and the Orange Book itself.  As such, FDA’s actions here contravene the Administrative Procedure Act (‘APA’), because they fail to embody principles of reasoned agency decision-making and are contrary to settled agency practice, arbitrary, capricious, and otherwise contrary to law.” 

As Teva states in a recent court submission, “Teva’s complaint raises the purely legal question of whether FDA violated the APA when it denied Teva’s citizen petition  . . . .  [T]he validity of that decision rises or falls on the Agency’s purely legal rationale: that its ‘electronic Orange Book Query’ feature – but not the Orange Book and then-current Cumulative Supplement – provided the legally operative patent listings at the time Teva submitted its risperidone ANDA.  If the Query feature controlled, Teva’s certification was improper and it is not entitled to exclusivity – regardless of what the Cumulative Supplement indicated.  And if the current Cumulative Supplement controlled, then Teva’s certification was not only appropriate but legally required, and Teva is entitled to exclusivity – regardless of what the Query feature would have shown . . . .”  In support of its position that the printed version instead of the electronic version of the Orange Book was controlling in 2001, Teva notes, among other things, that both the Orange Book and monthly Cumulative Supplements at that time “explicitly confirmed that those publications (but not the electronic Orange Book Query feature) provided the ‘drug patent . . . information required of the Agency by [Hatch-Waxman],’ and instructed applicants that the annual Orange Book ‘must be used in conjunction with the most current Cumulative Supplement . . . [b]ecause all parts of the publication are subject to changes, additions, or deletions’” (citing the August 2001 Orange Book Supplement at iii).

Judge Lamberth apparently agreed with Teva’s rationale that the printed version of the Orange Book controlled in 2001 in granting Teva’s requested relief.  It seems likely that FDA and Mylan will appeal the decision to the U.S. Court of Appeals for the District of Columbia Circuit.

By Kurt R. Karst    

On April 2, 2008, upon FDA’s request, federal agents seized more than $1.3 million in dietary supplements from LG Sciences, LLC of Brighton, Michigan.  According to FDA’s news release, the seized products contained “unapproved food additives and/or new dietary ingredients for which there [was] inadequate information to provide reasonable assurance that the ingredients do not present a significant or unreasonable risk of illness or injury.”  This may be the first instance of a seizure for failure to comply with requirements applicable to new dietary ingredients.

FDA’s news release references a warning letter to Legal Gear (now LG Sciences) from March 2006.  According to that warning letter, Legal Gear’s Methyl-1-P was determined to be an unapproved drug because the product contained synthetic steroids that did not qualify as dietary ingredients as defined in 21 U.S.C.§ 321(ff).  LG Sciences no longer markets Methyl-1-P.

The seizure is a reminder that FDA has an array of enforcement options at its disposal that go beyond the issuance of warning letters. The manufacture and interstate shipment of adulterated or misbranded dietary supplements can lead to product seizures, injunctions and even criminal prosecution.  This seizure and the February 28, 2008 indictment of five individuals and three companies for fraudulent marketing of dietary supplements with illegal claims suggest an upswing in enforcement activity.

By Riëtte van Laack

UPDATE:

• Earlier today FDA announced yet another seizure action.

Earlier today, the U.S. Court of Appeals for the Third Circuit issued its much anticipated opinion in Colacicco v. Apotex, Inc.  (Several parties, including FDA, entered and argued the case as amici for the appellee.)  The case concerns whether actions taken by FDA pursuant to the FDC Act and the Agency’s implementing regulations preempt plaintiffs’ state law failure-to-warn claims against two drug manufacturers (Apotex and Pfizer) with respect to two selective serotonin reuptake inhibitors – paroxetine HCl (PAXIL) and sertraline HCl (ZOLOFT).  The plaintiffs alleged that the companies had violated state common law by selling their products with labeling that failed to warn consumers of the increased risk of suicidality and worsening depression in adults taking the drug products. 

The case was on appeal from two district court decisions.  First, in Colacicco v. Apotex, the U.S. District Court for the Eastern District of Pennsylvania dismissed a complaint in May 2006 on the basis of preemption.  Second, in McNellis ex rel. DeAngelis v. Pfizer, Inc., 2006 WL 2819046 (D.N.J. Sept. 29, 2006), the U.S. District Court for the District of New Jersey, after denying Pfizer’s motion for summary judgment that McNellis’s claim was preempted by federal law, denied in September 2006 (after to the district court’s decision in Colacicco) Pfizer’s motion to vacate the court’s denial of the summary judgment motion.  The New Jersey court framed the question for appeal as whether:

[FDA’s] requirements for the form and content of the labeling for the prescription antidepressant Zoloft preempted New Jersey’s failure-to-warn law, under the doctrine of conflict preemption, where the FDA’s regulations at 21 C.F.R. 201.57(e) [(2003)] and 314.70(c)(6)(iii) [(2007)] permit a manufacturer to unilaterally enhance its warning when the manufacturer has reasonable evidence of an association of a serious hazard with a drug. 

In affirming the Pennsylvania District Court’s decision dismissing Colacicco’s complaint, the Third Circuit held that “based on our own review of the FDCA, the FDA’s regulations, and the FDA’s actions taken pursuant to its statutory authority, we conclude that the failure-to-warn claims brought by Colacicco and McNellis conflict with, and are therefore preempted by, the FDA’s regulatory actions.”  This decision will likely loom large as the U.S. Supreme Court gears up to consider Wyeth v. Levine, which also concerns whether prescription drug labeling preempts state law product liability claims. 

By Kurt R. Karst    

Last month, the U.S. Court of Appeals for the Fourth Circuit held that the whistleblower protection provisions of the Sarbanes-Oxley Act, 18 U.S.C. § 1514A, did not protect a former employee of Wyeth who alleged that he was fired for complaining to Wyeth management about insufficient training.  The Court affirmed a summary judgment decision by the U.S. District Court for the Middle District of North Carolina, which held that Mr. Livingston’s complaints were not protected “because Livingston could not reasonably have believed that Wyeth was violating the securities laws.”      

The case, Livingston v. Wyeth, presents an interesting fact pattern based on the following allegations.  Mark Livingtson, Wyeth’s former Associate Director of Training and Continuous Improvement, claimed to be fired in December 2002 after an altercation with Wyeth’s Human Resources Director, David McCuaig.  Mr. Livingston threw a holiday party at Wyeth did not invite Mr. McCuaig.  When Mr. McCuaig appeared at the party (allegedly to wish everyone a happy holiday), Mr. Livingston became very angry (allegedly in part because Mr. McCuaig had not brought a gift for the gift exchange), and threatened to call the police.  This was not the first time Mr. Livingston had been cited for hostile behavior, and shortly after the incident, Mr. Livingston was fired. 

Mr. Livingston claimed he was fired because he complained that Wyeth was making insufficient progress in teaching employees good manufacturing practices.  Under the FDC Act, pharmaceutical products produced in a facility that does not adhere to good manufacturing practices, including training, are considered adulterated.  In 2000, FDA cited Wyeth for failure to observe good manufacturing practices.  Wyeth, as part of a Consent Decree advised FDA that the company would implement a new training program.  Although FDA has not publically suggested that Wyeth failed to implement the program and an internal audit found that the program was on track, Mr. Livingston complained that the training program was not on track.  Two months later, in September 2002, Wyeth met the compliance target date set by the Consent Decree. 

The district court found sufficient evidence to support Wyeth’s contention that it had fired Mr. Livingston for his hostile behavior.  The court further concluded that there was no “objectively reasonable basis . . . for Livingston to equate the perceived training deficiencies with imminent wrongdoing” and that even if the wrongdoing Mr. Livingston had hypothesized had been true, it would not have resulted in a material loss to Wyeth.  The Fourth Circuit affirmed this decision, concluding “not one link in Livingston’s imaginary chain of horribles was real or was in the process of becoming real.”

The United States Chamber of Commerce filed an amicus brief for this case.    

By Susan J. Matthees

On March 31, 2008, FDA published a Federal Register notice announcing the availability of Compliance Policy Guide (“CPG”) § 500.500, which sets “guidance levels” for 3-MCPD in acid-hydrolyzed protein (“acid-HP”) and Asian-style sauces. 3-MCPD is a chloropropanol, and chloropropanols have been identified as carcinogens.  Under certain conditions, 3-MCPD may be formed during production of acid-HP, which is then used as an ingredient in some Asian-style sauces.

A guidance level is not binding on FDA or on industry, and can not serve as the direct legal basis for an enforcement action.  Thus, FDA states that the purpose of CPG § 500.500 is “to provide guidance to help FDA personnel determine whether to take enforcement action based on the presence of 3-MCPD,” and that FDA “will determine whether to take enforcement action . . . on a case-by-case basis, considering the totality of the circumstances. In any given case, FDA may decide to initiate an enforcement action against [products] with concentrations of 3-MCPD below 1 ppm or decide not to initiate an enforcement action against [products] with concentrations of 3-MCPD at or above 1 ppm.” Notably, CPG § 500.500 is silent as to factors that could lead the agency to take enforcement action against products that contain 3-MCPD below the guidance level, or to refrain from taking enforcement action against products that contain 3-MCPD above the guidance level. Thus, it remains to be seen just how FDA will make use of the guidance levels in determining whether to take enforcement action.

FDA previously set guidance levels for radionuclides in food. FDA interprets those guidance levels as indicative of the presence of a poisonous or deleterious substance, or of insanitary conditions, that may render a food injurious to health. But in CPG § 500.500, FDA interprets guidance levels as indicative of the presence of an unsafe food additive. Whatever the underlying legal theory, the nonbinding nature of guidance levels means that FDA will need to rely on a wholly separate evidentiary basis to pursue enforcement actions relating to 3-MCPD and other substances that are the subject of guidance levels. Notwithstanding this important limitation, we expect that FDA will continue to set guidance levels as a means of conserving scarce resources and avoiding the rigidity that setting action levels though rulemaking would impose.

Comments on CPG § 500.500 can be submitted at any time to the FDA Division of Dockets Management (Docket No. FDA-2008-D-0143).

Ricardo Carvajal & John R. Fleder

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