By Ricardo Carvajal –

During a webinar on immunity claims sponsored by the Food and Drug Law Institute, Richard Cleland, Assistant Director of FTC's Division of Advertising Practices, confirmed that enforcement actions are in the works against probiotic products that make inadequately substantiated claims.  FTC is particularly concerned about any "immunity claim [that] conveys a general or specific health benefit beyond just maintaining one's immune system."  In FTC's view, such claims must be supported by "competent and reliable scientific evidence of a clinically significant enhancement of that benefit."  This is the second time in as many months that an FTC attorney has singled out probiotics for scrutiny in public remarks (see our prior post here).

During the webinar, Bruce Silverglade, Director for Legal Affairs at the Center for Science in the Public Interest (“CSPI”), presented that organization's objections to the use of structure/function claims that it regards as misleading.  In CSPI's view, any immunity claim is an implied disease claim, and CSPI is "encouraging" states and the private bar to act accordingly.  Several class actions have already been pursued against major food manufacturers for immunity and other claims on probiotic products, and San Francisco recently challenged the use of an immunity claim on a popular cereal.

By Susan J. Matthees –

A new preemption decision has just come down from a California appeals court (the sixth circuit appellate district).  In two consolidated cases,  McGuan v. Endovascular Technologies, Inc., et al. and Johnson v. Endovascular Technologies, Inc., the appeals court upheld a lower court’s ruling that the Medical Device Amendments Act of 1976 ("MDA") preempt these two personal injury and products liability actions.

Each case involved plaintiffs who suffered injuries after they were implanted with the Ancure Endograft System (Ancure Device).  They were consolidated on appeal.  The appeals court relied on the decision in Riegel v. Medtronic, but with an interesting new twist that may broaden the reach of that case.

The Ancure Device was designed, manufactured, and distributed by Endovascular Technologies ("EVT"), a subsidiary of Guidant.  FDA approved the device in September 1999, but a number of safety problems related to the device soon arose.  Guidant investigated and ultimately recalled the device in March 2001.  After the recall, Guidant allegedly “provided evasive, if not false, information to the FDA” in response to FDA’s request for an audit report.  FDA then approved a modified version device in August 2001.  EVT ultimately entered into a plea agreement in June 2003 for shipping misbranded medical devices between September 1999 and March 2001.  The device was off the market as of June 23, 2003.

Both plaintiffs had the Ancure Device implanted after 2001 and allegedly suffered severe injuries.  McGuan sued under the usual theories of strict product liability, negligence, breach of express and implied warranty, but also added a cause of action for fraudulent concealment.  Johnson likewise added to the usual theories a cause of action for fraud and misrepresentation.  The trial court granted defendants’ motion for summary judgment on the ground that plaintiffs’ claims were preempted by 21 U.S.C. § 360k(a).

Plaintiffs appealed, arguing that their causes of action were not preempted because of the fraudulent conduct by the defendants.  McGuan alleged that defendants “had the duty and obligation [to the plaintiff] to disclose . . . the true facts concerning the Ancure Device product” (i.e., that the device was dangerous and defective).  The court of appeals, however, stated that in order to prevail on this cause of action, a jury would have to find that the warnings were inaccurate.  FDA approved the warnings, so a verdict for the plaintiff would impose warnings that are “different from, or in addition to” those imposed by FDA and thus be preempted.  Thus, the court held that allegations that the defendant has defrauded the plaintiff are not sufficient to evade Riegel preemption. 

Johnson alleged a similar fraud cause of action, but added that the fraud was against “governmental agencies.”  Here, the appeals court concluded that this claim was preempted under Buckman Co. v. Plaintiffs’ Legal Comm, in which the U.S. Supreme Court held that state law fraud-on-the-FDA claims are preempted by federal law.  Johnson tried to distinguish her case from Buckman on the grounds that, unlike in the case against EVT and Guidant, the defendant in Buckman had not been investigated by FDA.  Johnson pointed out that in a concurring opinion in Buckman, Justice Stevens suggested that there might have been a different outcome if “the FDA had determined that petitioner had committed fraud during the § 510(k) process and had taken the necessary steps to remove the harm-causing product from the market.”  The court of appeals was not persuaded, explaining that although FDA investigated the defendants in this case, the agency did not take action and allowed the device to be marketed, so the situation Justice Stevens described did not apply.  In addition, because FDA found no violations of federal law after March 2001, a decision for plaintiff would “conflict with the FDA’s responsibility to police fraud consistently.”

By Kurt R. Karst –      

FDA’s recent announcement that the Agency approved IMPAX Laboratories, Inc.’s (“IMPAX”) ANDA No. 90-377 for the first generic version of Boehringer Ingelheim Pharmaceuticals, Inc.’s (“BI”) popular ($2.1 billion/year) treatment for benign prostatic hyperplasia, FLOMAX (tamsulosin hydrochloride) Capsules, has an interesting Hatch-Waxman backstory to it.  In the words of the A-Team's Hannibal Smith, the folks at IMPAX must have been saying “I love it when a plan comes together” when word came of the ANDA approval. 

FLOMAX is listed in the Orange Book with a single patent – U.S. Patent No. 4,703,063 (“the ‘063 patent”).  The ‘063 patent expired on October 27, 2009, but is subject to a period of pediatric exclusivity scheduled to expire on April 27, 2010.  Several companies, including IMPAX and Ranbaxy, submitted ANDAs for generic FLOMAX prior to expiration of the ‘063 patent.  The IMPAX and Ranbaxy ANDAs contained a Paragraph IV certification to the ‘063 patent.  (Other applicants presumably submitted a Paragraph III certification to the patent.)  Ranbaxy is reported to be a first applicant eligible for 180-day exclusivity.  BI filed patent infringement lawsuits in response to the Paragraph IV certifications: (1) Astellas Pharma Inc. et al. v. Ranbaxy, Inc., Civil Action No. 3:05-cv-02563 (filed May 13, 2005 in the District Court of New Jersey); and (2) Astellas Pharma Inc. et al. v. Impax Laboratories, Inc., Civil Action No. 5:08-cv-03466 (filed July 18, 2008 in the Northern District of California). 

In the patent infringement case against Ranbaxy, the district court ruled in February 2007 in favor of the plaintiffs (ruling that the ‘063 patent is not invalid on grounds of double-patenting).  Ranbaxy appealed the decision to the Federal Circuit.  During the appeal, however, the parties settled the case and entered into a joint stipulation of dismissal without prejudice.  Under the terms of the settlement agreement, Ranbaxy had the opportunity to launch its generic tamsulosin drug product on March 2, 2010, which is 8 weeks prior to the expiration of pediatric exclusivity applicable to the ‘063 patent.  FDA tentatively approved Ranbaxy’s ANDA in June 2007.

In the patent infringement case against IMPAX, IMPAX filed a motion for summary judgment of patent invalidity for double-patenting.  The plaintiffs and IMPAX settled the case in October 2009 before a district court decision, and after FDA tentatively approved ANDA No. 90-377.  The court entered a Consent Judgment acknowledging a negotiated settlement between the plaintiffs and IMPAX.  According to FDA’s ANDA approval letter and an IMPAX press release, the agreement is similar to the agreement reached with Ranbaxy insofar as an early launch date is concerned.  FDA’s approval letter provides additional details on the terms of the agreement: 

This settlement applies to [BI’s] selective and limited waiver of its pediatric exclusivity to IMPAX Laboratories, Inc. for the ‘063 patent as of March 2, 2010, with respect to this ANDA. Concurrent with the agency’s approval of this ANDA, the waiver effectively permits IMPAX Laboratories, Inc. to market Tamsulosin Hydrochloride Capsules, USP beginning on March 2, 2010, prior to the expiration of [BI’s] pediatric exclusivity for the ’063 patent on April 27, 2010.  The selective waiver also applies to [BI’s] exclusivity with respect to product labeling associated with the M-54 exclusivity code due to expire on June 22, 2013.

Interestingly, of the 7 ANDA applicants identified by FDA with tentative approval, IMPAX was the last applicant to obtain tentative approval (in October 2009), but the first company to obtain final ANDA approval.  Although Ranbaxy was eligible for 180-day exclusivity, that exclusivity was forfeited when the ‘063 patent expired, thereby opening the door to subsequent ANDA approvals. 

As we previously reported, Ranbaxy has had good manufacturing practice problems with FDA.  In early 2009, FDA announced that the Agency was taking the unusual step of invoking its Application Integrity Policy (“AIP”) against Ranbaxy’s Paonta Sahib manufacturing facility in India.  FDA takes such regulatory action under the Agency’s AIP procedures when FDA believes that a company’s actions raise significant questions about the integrity of data in marketing applications.  Importantly, FDA notes in the AIP letter with respect to pending ANDAs that:

In accordance with FDA policy, the Agency will assess the validity of the data and information in all of Ranbaxy’s affected applications which contain data developed at the Paonta Sahib site. . . .  This means that the Agency does not intend ordinarily to conduct or to continue its normal substantive scientific review (including review of data and labeling) of any such pending application or supplement, or of any new application or supplemental applications filed after the date of this letter, that contain data developed at the Paonta Sahib site, during a validity assessment of that application.

It is unclear whether Ranbaxy’s inability to obtain final ANDA approval for the company’s ANDA for its generic FLOMAX is due to FDA’s AIP and whether information supporting the ANDA file was generated from the company’s Paonta Sahib facility.  This is reportedly the case, but the basis for this report is not known.  Because 180-day exclusivity for generic FLOMAX was forfeited when the ‘063 patent expired, the issue of how FDA will handle Ranbaxy’s 180-day exclusivity eligibility for pending ANDAs implicated in the Agency’s AIP will apparently have to be saved for another day.

Although the Federal Trade Commission is generally opposed to generic drug settlement agreements, and has expressed support for legislation that would ban such agreements, FDA’s approval of ANDA No. 90-377 is a good example of the benefits of such agreements.  And it is also a good example of how a settlement agreement and a little bit of luck can take an ANDA applicant from last to first. 

By Nisha P. Shah and Ricardo Carvajal –

The title of a report issued by the U.S. Government Accountability Office (“GAO”) neatly sums up that agency’s perspective: “FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS).”  The report was requested by Tom Harkin, Chair of the Senate Health, Education, Labor, and Pensions Committee, and Rosa DeLauro, Chair of the House Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Entities of the Committee on Appropriations.

The Food, Drug, and Cosmetic Act exempts GRAS substances from the definition of “food additive” and the corresponding requirement that companies obtain FDA premarket approval.  This exemption permits companies to self-determine whether the intended use of a substance is GRAS.  Under a program established by FDA pursuant to a rule proposed in 1997, companies may voluntarily notify FDA of their GRAS self-determination.  FDA has yet to issue a final rule.

In part, the GAO report concludes:

• FDA lacks information about certain GRAS determinations because of the voluntary nature of the GRAS notification program;

• FDA does not systematically reconsider the safety of GRAS substances as new information or methods become available; 

• Because GRAS notification is voluntary and companies are not required to identify engineered nanomaterials in their GRAS substances, FDA has no way of knowing the extent to which these nanomaterials have entered the food supply.

In part, the GAO report recommends:

• FDA should “develop a strategy to require any company that conducts a GRAS determination to provide FDA with basic information … about this determination, such as the substance’s identity and intended uses, and to incorporate that information into relevant agency databases and its public Web site;” 

• FDA should “finalize the rule that governs the voluntary notification program, including taking into account the experience of the program to date, incorporating input from a new public comment period, and reporting to Congress and the public the agency’s timeline for making it final;”

• FDA should “develop a strategy that ensures the safety of engineered nanomaterials that companies market as GRAS substances without the agency’s knowledge, including taking steps such as issuing guidance recommended by the agency’s nanotechnology taskforce, developing an agency definition of engineered nanomaterials, and requiring companies to inform FDA if their GRAS determinations involve engineered nanomaterials.”

More broadly, the report recommends that, “[i]f FDA determines that it does not have the authority to implement one or more of these recommendations, the agency should seek the authority form Congress.”

In its response to the report, FDA generally agreed with GAO’s findings and recommendations.  Although FDA conceded that certain actions are beyond the scope of its current authority (e.g., collecting information about company reconsiderations of the safety of GRAS substances), FDA sidestepped GAO’s broader recommendation that the agency seek whatever additional authority is necessary to implement the report’s specific recommendations.  However, FDA’s response suggests that FDA is mulling all options:

FDA is actively considering steps it can take under current law to improve both premarket and post-market oversight of all added food substances, whether they enter the market based on a GRAS determination or through a formal FDA approval process.  In particular, FDA believes that its ability to oversee the safety of added food ingredients, including GRAS substances, would be enhanced if the manufacturer were required, prior to marketing any new substance or new use of an existing substance, to notify FDA and submit scientific evidence demonstrating the safety and legality of the intended use.  FDA also agrees with GAO that there is a need for enhancement of post-market oversight, including more effective tools for FDA to obtaining from sponsors new information related to the safety of marketed food ingredients sot that FDA is better able to identify substances meriting a substantive post-market review.  Implementation of these ideas would require additional resources, and some may require new legislation.

The current statutory regime for independent GRAS determinations has been in effect for over 50 years, since the enactment of the Food Additives Amendments of 1958.  Independent GRAS reviews have served as a useful tool to enable food products to enter the market with comprehensive safety reviews, without tying up limited government resources.  The GAO report does not identify a single actual safety problem that has been caused by this regime, but instead raises the specter of nanomaterials as an apparent basis for the conclusion that more regulations, and possibly amendments to the FDC Act, are necessary to protect the public.  At the same time, the GAO report fails to acknowledge the current regime’s important role in fostering innovation – not least in the area of biotechnology. 

For its part, FDA currently seems disinclined to recognize the effectiveness of post-market statutory tools in ensuring the safety of food ingredients.  Even so, the considerable benefits of the current regime are implicitly acknowledged in FDA’s response to GAO: “FDA believes that the GRAS concept has continuing utility as a practical tool for distinguishing between substances and new uses of substances that merit a full pre-market safety evaluation by FDA and those that do not.”  Query whether, in tightening its oversight of GRAS, the agency would only be making safe food more expensive. 

By Kurt R. Karst –      

FDA’s recent approval of Nycomed U.S., Inc.’s ANDA No. 78-548 for a generic version of ALDARA (imiquimod) Cream, 5%, appears to be the first instance in which FDA has determined that a first ANDA applicant is eligible for 180-day exclusivity on the basis that there was not a  forfeiture of such exclusivity because of a change in or review of ANDA approval requirements and no other forfeiture provision applied.

FDC Act § 505(j)(5)(D)(i)(IV) – “Failure to obtain tentative approval” – is one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the 2003 Medicare Modernization Act (“MMA”), and provides that 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarrified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).) 

As we previously reported, there has been one case in which tentative approval was not obtained within 30 months of ANDA submission and where FDA determined that exclusivity was not forfeited because of a change in or review of ANDA approval requirements – ANDA No. 77-532 (Acarbose Tablets, 25 mg, 50 mg, and 100 mg).  In that case, FDA ruled “that a change in bioequivalence requirements resulted in a delay in obtaining a tentative approval” and did not result in a forfeiture under FDC Act § 505(j)(5)(D)(i)(IV); however, FDA also determined that there was a forfeiture under its interpretation of the failure to market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) (which the D.C. Circuit recently struck down).  In the Acarbose case, although a citizen petition was submitted to FDA, because the petition was submitted to FDA after the date that was 30 months after ANDA submission, FDC Act § 505(q)(1)(G) was not implicated.

FDA’s approval letter for ANDA No. 78-548 explains that the Agency’s “ongoing review” of the requirements for ANDA approval excused the 30-month tentative approval date:

With respect to 180-day generic drug exclusivity, we note that Nycomed was the first ANDA applicant to submit a substantially complete ANDA with a paragraph IV certification to the '944 patent. Therefore, with this approval, Nycomed is eligible for 180 days of generic drug exclusivity for Imiquimod Cream, 5%. . . .  The agency notes that Nycomed failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed.  However, the agency has determined that the failure to obtain tentative approval within 30 months was caused by the agency’s ongoing review of the requirements for approval of Imiquimod Cream, 5%, and therefore Nycomed did not forfeit eligibility for 180-day generic drug exclusivity. See section 505(j)(5)(D)(i)(IV) of the Act.

Although FDA received and recently denied to two citizen petitions concerning generic ALDARA Cream (here and here), both petitions were submitted to FDA in July and August 2009.   The 30-month period for ANDA No. 78-548 expired in April 2009, so FDC Act § 505(q)(1)(G) was not implicated. 

UPDATE:

• On March 8th, the U.S. District Court for the District of New Jersey denied Graceway's motion for a temporary restraining order/preliminary injunction in a patent infringement lawsuit filed late last month concerning a newly issued patent that is not Orange Book-listed for ALDARA Cream.  The court noted that the late-filed lawsuit put at risk Nycomed's 180-day exclusivity, which has already been triggered. 

By Kurt R. Karst –      

The U.S. District Court for the Eastern District of Michigan (Southern Division) recently dismissed without prejudice a Complaint filed by Wyeth and granted a Motion to Dismiss filed by Sun Pharmaceutical Industries, Ltd. and Caraco Pharmaceutical Laboratories, Ltd. (“Sun”) in a Lanham Act case concerning the identification of a “polymorph” in the labeling of Sun’s generic PROTONIX (pantoprazole sodium) Delayed-Release Tablets.  PROTONIX contains pantoprazole sodium sesquihydrate as the active ingredient.  Wyeth alleged that “[d]espite expressly representing to the public that they are selling pantoprazole sodium sesquihydrate tablets, Sun and Caraco are actually selling tablets containing a different polymorphic form of pantoprazole sodium, pantoprazole sodium monohydrate,” and that “[b]y selling pantoprazole sodium monohydrate tablets labeled as containing pantoprazole sodium sesquihydrate as the active ingredient, Sun is making a literally false statement regarding the active ingredient of its pharmaceutical product, in violation of the Lanham Act” (emphasis in original), as well as in violation of the Michigan Consumer Protection Act (Mich. Comp. Law § 445.901).

By way of background, FDA has explained in guidance – “ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing, and Controls Information” – that polymorphs are different crystalline and amorphous forms as well as solvate and hydrate forms of the same chemical compound.  Polymorphs of a compound share the same chemical formula and molecular structure, but can have different properties, including melting point, stability, dissolution, and bioavailability.  It is FDA’s longstanding policy that active ingredient “sameness” for ANDA approval purposes is not affected by different polymorphs.  Indeed, the Orange Book Preface states that “[a]nhydrous and hydrated entities, as well as different polymorphs, are considered pharmaceutical equivalents and must meet the same standards and, where necessary . . . their equivalence is supported by appropriate bioavailability/bioequivalence studies.”  For example, FDA has approved generic versions of HYTRIN (terazosin HCL) in an anhydrous form, whereas the innovator product is in a dihydrate form.  FDA has also approved generic versions of ZITHROMAX (azithromycin) in a monohydrate form, whereas the innovator product is in a dihydrate form.  In that case, Pfizer submitted citizen petitions to FDA (here and here) challenging the accuracy of generic ZITHROMAX labeling related to polymorph identification. (FDA has not substantively responded to either petition.)

Sun argued that the complaint should be dismissed, primarily because FDA has the exclusive jurisdiction to determine the appropriate language in drug product labeling.  That argument is that Wyeth sought to inappropriately use the Lanham Act as a vehicle to privately enforce the FDC Act.  As we previously reported, many courts have ruled – including the Seventh Circuit’s recent decision in Schering-Plough Healthcare Products, Inc., v. Schwarz Pharma, Inc., 586 F.3d 500 (7th Cir., 2009) (Hyman, Phelps & McNamara, P.C. represented Schwarz Pharma, Inc. and Kremers Urban, LLC in that case) – that this is not a legitimate use of the Lanham Act.  Sun also argued that Wyeth failed to state a Lanham Act claim “because they fail to plead a necessary element of a false advertising claim – that the deception had a material effect on purchasing decisions because the allegedly false statements are in the package insert, which is not seen by the consumer until after purchase,” and that Wyeth failed to state an unfair competition claim under Michigan law. 

Explaining that “the Court finds that this is a matter that is better left to the FDA’s expertise,” the court ruled that for Wyeth to make a successful claim under the Lanham Act, the FDA must first make a finding under the FDC Act that the ingredient in Sun’s generic PROTONIX is not sesquihydrate.  Moreover, the court commented that:

Plaintiff has not identified, nor has the Court uncovered, a single instance in which a federal court has permitted the manufacturer of a pioneer drug to challenge generic-equivalency representations under the Lanham Act when the defending party markets a FDA-approved, Orange Book-listed generic version of the pioneer drug.

Although the court found that Wyeth “jumped the gun” by suing Sun before FDA addressed the polymorph labeling issue, the court, in dismissing the complaint without prejudice, commented that “[i]f the FDA confirms Plaintiff’s suspicions, however, Plaintiff may be able to sustain its Lanham Act claims.”  So, depending on the outcome of an FDA investigation, there might be more to come on this. 

By Kurt R. Karst –      

We’re food and drug attorneys, not patent attorneys.  So, when the Federal Circuit issued its decision in Forest Group, Inc. v. Bon Tool Co. in late December 2009 concerning the false marking of spring-loaded parallelogram stilts, we didn’t pay any attention to the decision.  (It’s not a Paragraph IV, Orange Book listing, or patent term extension case.)  We’re paying attention now, however!  The decision affects the FDA-regulated industry. 

Over the past several weeks, scores of qui tam actions have been filed against myriad companies – including several drug, device, and cosmetic companies – alleging so-called “false marking” in violation of 35 U.S.C. § 292.  (For a docket list, go to the Gray On Claims Blog.)  This statutory provision provides that:

(a) Whoever, without the consent of the patentee, marks upon, or affixes to, or uses in advertising in connection with anything made, used, offered for sale, or sold by such person within the United States, or imported by the person into the United States, the name or any imitation of the name of the patentee, the patent number, or the words "patent," "patentee," or the like, with the intent of counterfeiting or imitating the mark of the patentee, or of deceiving the public and inducing them to believe that the thing was made, offered for sale, sold, or imported into the United States by or with the consent of the patentee; or Whoever marks upon, or affixes to, or uses in advertising in connection with any unpatented article the word "patent" or any word or number importing the same is patented, for the purpose of deceiving the public; or Whoever marks upon, or affixes to, or uses in advertising in connection with any article the words "patent applied for," "patent pending," or any word importing that an application for patent has been made, when no application for patent has been made, or if made, is not pending, for the purpose of deceiving the public – Shall be fined not more than $500 for every such offense.

(b) Any person may sue for the penalty, in which event one-half shall go to the person suing and the other to the use of the United States.

In other words, it is a violation of 35 U.S.C. § 292 to intentionally mark an item in commerce with a patent number that has expired or that does not protect the item.  Although not a requirement, the FDA-regulated industry regularly places patent information on its product labels and labeling.

In Forest Group, Inc. v. Bon Tool Co., the Federal Circuit ruled that the $500 maximum penalty attaches to each individual article that is falsely marked; however, the Court noted that that “[t]his does not mean that a court must fine those guilty of false marking $500 per article marked. . . .  By allowing a range of penalties, the statute provides district courts the discretion to strike a balance between encouraging enforcement of an important public policy and imposing disproportionately large penalties for small, inexpensive items produced in large quantities.”  The Federal Circuit’s decision  overturned the U.S. District Court for the Southern District of Texas’ (Houston Division) decision that each “offense” is the single decision to falsely mark.  The Federal Circuit commented that:

[The] proposed statutory construction—that the statute imposes a single $500 fine for each decision to falsely mark—would render the statute completely ineffective. Penalizing those who falsely mark a mere $500 per continuous act of marking, which act could span years and countless articles, would be insufficient to deter in nearly all cases. Congress’ interest in preventing false marking was so great that it enacted a statute which sought to encourage third parties to bring qui tam suits to enforce the statute.

Enter the bounty hunters . . . . 

Complaints have been filed against the likes of Novartis, Merck, and L’Oreal for allegedly falsely marking HYPO-TEARS, CLARITIN, and mascara products with labels that bear an expired patent.  If each allegedly falsely marked item distributed is an “offense” subject to a maximum $500 fine, then the monetary damages could be astronomical. 

Although the Federal Circuit is set to hear oral argument soon in Pequignot v. Solo Cup, which concerns the question of intent to falsely mark under 35 U.S.C. § 292, and, as reported by our fellow bloggers over at Patent Docs, the U.S. Senate is considering an amendment to patent reform legislation that would appear to quash the qui tam lawsuits, at this point, the complaints will likely continue to pour in against the FDA-regulated industry.  Firms should review their product labels for expired patent information. 

By Ricardo Carvajal –

The ongoing recall of a widely used flavor enhancer known as hydrolyzed vegetable protein ("HVP") for possible contamination with Salmonella could mushroom to affect thousands of products.  Although no illnesses have been reported thus far and FDA judges the risk to consumers as “very low,” FDA is applying a zero tolerance approach with respect to potentially affected products that are marketed as ready-to-eat, meaning products that will not undergo a kill step such as cooking at the hands of the consumer.  With respect to potentially affected products that are intended to be cooked by the consumer, FDA is advising consumers to read and follow instructions on food preparation and cooking. For now, FDA is not asking for a recall of products that have a validated kill step.

According to senior agency officials, the HVP contamination incident came to FDA’s attention through the Reportable Food Registry ("RFR").  FDA is touting the importance of the RFR in bringing incidents such as this to FDA’s attention, but is also citing this incident as proof of the need for passage of food safety legislation.  In FDA’s eyes, that legislation is needed to help accomplish a shift from response to prevention, including the establishment of standards that would prevent similar incidents.  However, FDA has not as yet revealed any information about conditions of production in the facility implicated in the HVP recall, or explained how the imposition of additional requirements would have prevented the contamination of HVP with Salmonella.

Yep, it’s been three years since we started FDA Law Blog.  And that means it’s time again to take a minute from blogging on FDA issues to pat ourselves on the back.  It’s been a banner year for us.  We recently topped 800 posts (almost 350 this past year alone) , started a Twitter page, and our readership continues to grow – we are nearing 4,000 subscribers.  That’s a lot for a niche blog!  And, while we like any “major prize,” we are particularly proud that the American Bar Association named FDA Law Blog as one of the top legal “blawgs” in the blogosphere when the organization announced the ABA Blawg 100 last December.  We’re hoping for a repeat this year.
 
Thank you again to our loyal readers!  We appreciate your thoughtful comments, even though we do not always post them.  We also thank our Hyman, Phelps & McNamara, P.C. colleagues for their time and dedication to writing interesting and informative posts.

So here’s to three great years . . . . and hopefully many more to come!

By Kurt R. Karst –      

Earlier today, FDA sent a letter to Senator Charles Grassley (R-IA) indicating that the Agency may very well be poised to increase prosecution of company officials.  According to the letter, which includes several recommendations based on a committee the Agency formed (comprised of senior FDA leadership) to examine opportunities and develop recommendations to enhance coordination and strategic alignment between FDA’s Office of Criminal Investigations (“OCI”) and other Agency components, the committee recommended to “increase the appropriate use of misdemeanor prosecutions, a valuable enforcement tool, to hold responsible corporate officials accountable.”  In addition, FDA notes that “[c]riteria now have been developed for consideration in selection of misdemeanor prosecution cases and will be incorporated into the revised policies and procedures that cover appropriate use of misdemeanor prosecutions.” 

As we previously reported (here and here), the government believes that persons can be convicted under the FDC Act misdemeanor provisions without any showing that a person intended to violate the law or even knew about the violation.  Under this theory, which is often referred to as the “responsible corporate officer” principle and was derived from the 1975 U.S. Supreme Court case of United States v. Park, executives who do not prevent violations of the FDC Act may be held strictly liable for those violations.

Other committee recommendations described in the FDA letter include:

• “improve procedures for information-sharing between OCI and other Agency components with the goal of enhanced alignment of criminal/regulatory priorities and activities;”

• “that FDA strengthen the mechanisms that are used to ensure that senior leaders share information and coordinate strategic priorities to align criminal enforcement and regulatory activities;” and

• “that the Agency enhance its debarment and disqualification procedures.”

The latter recommendation was made consistent with the findings of a 2009 GAO report critical of FDAs oversight of clinical investigators – see our previous post here.

FDA issued the letter in response to a March 4, 2010 Government Accountability Office (“GAO”) report, titled “Food and Drug Administration: Improved Monitoring and Development of Performance Measures Needed to Strengthen Oversight of Criminal and Misconduct Investigations,” in which the GAO raised concerns about OCI oversight and the lack of performance measures to assess OCI’s success.  Sen. Grassley requested the report after concerns were raised about OCI, and an OCI component, the Office of Internal Affairs (“OIA”).  Specifically, concerns about OCI’s/OIA’s “procedures for conducting and coordinating investigations,” and that “these offices are operating without adequate oversight or accountability, and that OCI’s funding and staffing for criminal investigations have grown significantly despite limited federal resources to fund other FDA activities.”  FDA established OCI in 1991, after the generic drug scandal, to conduct and coordinate criminal investigations for the Agency.  OIA was established in 1995 after a congressional subcommittee recommended that FDA establish an internal affairs office. 

The GAO report concludes that:

Although OCI and OIA have policies that govern how they conduct investigations, FDA’s oversight of these investigations has been limited.  FDA has established a process to ensure compliance with OCI’s policies, but it does not routinely carry out this process as only about 30 percent of the OCI field office assessments have been completed.  OIA’s process to ensure compliance depends on its manager rather than an external reviewer, that is, someone who is not directly involved in ongoing investigations.  Without a review process and consistent implementation, FDA management cannot have reasonable assurance that OCI and OIA investigative policies and procedures are routinely followed and that deficiencies are promptly resolved when identified.  This is particularly important because OCI does work that is different from much of the rest of FDA.

FDA management cannot determine whether OCI’s criminal investigative program is achieving its goals—a key element of accountability—because OCI has not developed performance measures.  Because FDA managers have somewhat different perspectives on how best to assess the performance of OCI’s criminal investigative program, it is unclear how OCI and other FDA managers with oversight responsibility can strategically manage OCI’s criminal investigative program to ensure that it is operating successfully. Assessing program results is especially important given that OCI appears to operate more autonomously than other units within FDA’s regulatory office.

The GAO report also includes three recommendations:

• To ensure OCI’s compliance with investigative policies, instruct the Commissioner of FDA to have regular assessments of OCI’s field offices conducted in accordance with its existing policy.

• To ensure OIA’s compliance with investigative policies, instruct the Commissioner of FDA to establish a review procedure for the assessment of OIA’s compliance with its investigative policies.

• To assess whether OCI’s criminal investigative program is achieving its desired results, instruct the Commissioner of FDA to establish performance measures and assess program results against them.

By Kurt R. Karst –    

Citing FDA approval standards that “may deny the benefits of medical progress to seriously ill patients who face morbidity or death from their disease,” Representative Diane Watson (D-CA) introduced H.R. 4732, the Compassionate Access Act of 2010, earlier this week.  The bill would amend the FDC Act to create a new conditional approval system for drugs, biological products, and devices for seriously ill patients. 

Specifically, the bill would amend FDC Act § 561, titled “Expanded Access to Unapproved Therapies and Diagnostics,” and which was added in 1997 by the FDA Modernization Act, to create new subsection (d) – “Compassionate Investigational Access.”  Under this new subsection:

upon submission by a sponsor of an application intended to provide widespread access to an investigational drug, biological product, or device for eligible patients (referred to in this subsection as ‘Compassionate Investigational Access’), the Secretary shall permit such investigational drug, biological product, or device, to be made available for expanded access under a treatment investigational new drug application or treatment investigational device exemption if the Secretary determines that [certain] requirements . . . are met with respect to Compassionate Investigational Access.

In particular, a sponsor must submit to FDA an application for Compassionate Investigational Access containing:

• Data and information from completed Phase I clinical investigations and any other nonclinical or clinical investigations;

• Preliminary evidence (that may be based on uncontrolled data and on a small  number of patients or a subset of a patient population) that the product may be effective in humans against a serious or life-threatening condition or disease; and

• Evidence that the product is safe at the dose and duration proposed consistent with the level of information needed to initiate a Phase II clinical trial.

A sponsor must also state that it is actively pursuing marketing approval with due diligence.

FDA would then review the application and provide Compassionate Investigational Access approval, or refer the application to a new “Accelerated Approval Advisory Committee” for further review and recommendation.  In making an approval decision, FDA must “consider whether the totality of the information available to the Secretary regarding the safety and effectiveness of an investigational drug, biological product, or device, as compared to the risk of morbidity or death from a condition or disease, indicates that a patient (who may be representative of a small patient subpopulation) may obtain more benefit than risk if treated with the drug, biological product, or device.”  And “[i]f the potential risk to a patient of the condition or disease outweighs the potential risk of the product, and the product may possibly provide benefit to the patient, the Secretary shall provide Compassionate Investigational Access approval of the application.” 

The bill would also create FDC Act § 561A – “Accelerated Approval” – to permit the sponsor of a drug, device, or biologic application to submit an application containing:

data and information that the drug, biological product, or device has an effect on a clinical endpoint or on a surrogate endpoint or biomarker that is reasonably likely to predict clinical benefit to a patient (who may be representative of a small patient subpopulation) suffering from a serious or life-threatening condition or disease.

FDA would have 120 days to provide Accelerated Approval of the application or refer the application to the Accelerated Approval Advisory Committee.  If referred to the  Accelerated Approval Advisory Committee, the committee would have 90 days to make an approval recommendation, which FDA would need to act on within 30 days thereafter – either with an approval decision or an explanation as to why approval is not granted.  That non-approval decision could be appealed.

In addition, the bill would create FDC Act § 561B – “Expanded Access to Investigational Drugs and Devices” – requiring FDA to “establish a new program to expand access to investigational treatments for individuals with serious or life threatening conditions and diseases.”  Among other things, FDA would be required to “establish policies, regulations, and guidance designed to most directly benefit seriously ill patients,” implement training programs with respect to the expanded access programs, and “establish a program or expand upon an existing program to encourage the development of surrogate endpoints and biomarkers that are reasonably likely to predict clinical benefit for serious or life-threatening conditions for which there exist significant unmet patient needs.”  In a similar vein, the bill would amend the FDC Act to add § 568 – “Policies Related to Study Evaluation Information” – requiring FDA to “give consideration to clinical judgment and risks to the patient from the disease or condition involved in the evaluation of the safety and effectiveness of drugs, biological products, and devices that treat serious or life-threatening diseases or conditions” (i.e., non-statistical measures).

Rep. Watson’s bill comes several months after FDA issued its final rule on Expanded Access to Investigational Drugs for Treatment Use in August 2009.  As we previously reported, those regulatons clarified FDA’s existing expanded access regulations and added new types of expanded access for treatment use. 

Rep. Watson’s bill is not the first legislative attempt to create a new approval system for patients to access drugs for serious or life-threatening diseases or conditions.  In 2008, Senator Sam Brownback (R-KS) introduced S. 3046 – the “Access, Compassion, Care, and Ethics for Seriously Ill Patients Act” (the “ACCESS Act”).  That bill proposed to create a three-tiered approval system – “Compassionate Investigational Access,” “Accelerated Approval,” and “Final Approval” – for products for serious or life-threatening diseases or conditions (see our previous post here).  Sen. Brownback's bill was preceded by the U.S. Court of Appeals for the District of Columbia Circuit's August 7, 2007 8-2 opinion in Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach in which the court held “that there is no fundamental right ‘deeply rooted in this Nation’s history and tradition’ of access to experimental drugs for the terminally ill.” (see our previous post here) 

By Cassandra A. Soltis –

Think twice before putting that claim on your food label – or on your website.  Just last month, FDA issued 16 Warning Letters to food manufacturers regarding unauthorized nutrient content and health claims appearing in food labeling.  In addition, some companies were cited for making certain claims that caused their foods to be drugs. 

For example, Dreyer’s Grand Ice Cream, Inc. was told that some of their products were misbranded for including a “0 g trans fat” claim without an accompanying statement directing consumers to see the Nutrition Facts box for fat and saturated fat content.  FDA also informed Diamond Food, Inc. that its shelled walnuts were drugs because of claims that omega-3 fatty acids in walnuts may help lower cholesterol, protect against heart disease and stroke, and even fight depression and other mental illnesses. 

Why the focus on food claims?  In her open letter to industry, Dr. Margaret A. Hamburg, Commissioner of Food and Drugs, explained that “ready access to reliable information about the calorie and nutrient content of food” is important, particularly in light of the “prevalence of obesity and diet-related disease in the United States.”  She stated that further underscoring the need for accurate food labeling information is the First Lady’s campaign on childhood obesity.  Dr. Hamburg added that the agency intends to work with industry to design a front-of-package (FOP) labeling system that will be meaningful to consumers and help them use and understand the nutrition information provided.   

In that connection, FDA recently released the results of its 2008 U.S. Health and Diet Survey, which included questions about consumers’ use of food labels.  Among the results that caught our attention:

• 54% of consumers surveyed report that they often make use of the food label when purchasing a product for the first time.  66% of consumers who make at least rare use of the label do so to “see how high or low a food is in things like calories, salt, vitamins or fat.” 

• 72% of consumers surveyed report awareness of FOP health or nutrition-related symbols or icons.  Of those who are aware of such symbols, 77% report that they often or sometimes use those symbols when deciding to buy a food. 

• 56% of consumers question the accuracy of claims such as “low fat” or “high fiber.”

This latest evidence of the reliance of consumers on food labeling to make purchasing decisions is likely to stiffen FDA’s resolve to take a harder line on enforcement of labeling requirements.  As we discussed in a prior posting, FOP labeling is likely to garner especially close scrutiny.

By Kurt R. Karst –      

Earlier today, the U.S. Court of Appeals for the District of Columbia Circuit handed Teva Pharmaceuticals USA, Inc. (“Teva”) a significant victory in the company’s lawsuit against FDA concerning the availability of 180-day exclusivity for generic versions of Merck & Co., Inc.’s (“Merck’s”) blockbuster angiotensin II receptor antagonist drugs COZAAR (losartan potassium) Tablets and HYZAAR (hydrochlorothiazide; losartan potassium) Tablets.  Although FDA has made no determination with respect to generic COZAAR and HYZAAR 180-day exclusivity, Teva believes that FDA’s interpretation of the statute, as previously applied in the Agency’s adjudications concerning generic PRECOSE (acarbose) Tablets and generic COSOPT (dorzolamide hydrochloride; timolol maleate), will result in a forfeiture of 180-day exclusivity for both products.  The D.C. Circuit's decision is the culmination of several years of debate concerning the proper interpretation of the “failure to market” 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), beginning with FDA's so-called "bookend approach" described in the Agency's generic KYTRIL (granisetron HCl) Injection 180-day exclusivity decision.

As we previously reported (here, here, and here), Teva’s lawsuit challenged FDA’s interpretation of the “failure to market” 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), which were added to the FDC Act in December 2003 by the Medicare Modernization Act (“MMA”), and in particular FDA’s interpretation of the patent information withdrawal provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC).  That provisions states that one of the dates for calculating a forfeiture is the date that is 75 days after which “[t]he patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under [FDC Act § 505(b)].”  FDA has interpreted the provision such that a request to withdraw patent information from the Orange Book is a forfeiture event under FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC).  In discussing its interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), FDA determined that the U.S. Court of Appeals for the District of Columbia Circuit’s 2006 decision in Ranbaxy Labs. Ltd. v. Leavitt (a pre-MMA case) holding that FDA may not condition the delisting of a patent on the existence of patent litigation and deprive an ANDA applicant eligible for 180-day exclusivity of such exclusivity does not apply to the version of the FDC Act amended by the MMA. 

Teva argued in the D.C. District Court that it should not forfeit 180-day exclusivity because FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC) is unlawful.  Specifically, Teva argued that the mechanism added to the FDC Act by the MMA – i.e., FDC Act § 505(j)(5)(C)(ii)(I) – permitting a cause of action that allows a generic applicant to seek a court order compelling the brand manufacturer to delist a challenged patent must be read together with FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC):

Read together, as statutory provisions must be, it thus is clear that these twin Amendments – the delisting mechanism, on one hand, and the delisting trigger, on the other – were not remotely intended to open the proverbial floodgates to manipulative, exclusivity-divesting patent delistings by brand manufacturers, and thus sub silentio to abrogate the longstanding prohibition against such delistings that Ranbaxy recognized.

In July 2009, Judge Rosemary M. Collyer of the U.S. District Court for the District of Columbia ruled in a 27-page opinion that FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC) is not ambiguous and that FDA’s interpretation of the statute is reasonable.  The court, analyzing the arguments under the familiar Chevron standard, concluded that, “[a]t Chevron step one this Court must give effect to the clear intent of Congress as reflected in the statute because subsection (bb)(CC) is not ambiguous on its face.”  The court went on to state that “Teva is correct that the statute does not address when an Innovator may withdraw a patent, but what is important is that the statute does not limit the Innovator’s right to withdraw patent information.  The Court cannot take on the role of the legislature by creating such limitations when they were omitted by Congress.”  The court also dismissed the utility of the Ranbaxy decision in interpreting the 180-day exclusivity forfeiture provisions added by the MMA, noting that “Ranbaxy was decided under the Hatch-Waxman Amendments as they existed prior to the enactment of the MMA . . . .  The MMA now provides that the first generic manufacturer is entitled to exclusivity if it has not forfeited that exclusivity.” (emphasis in original)  Ultimately Judge Collyer concluded that “FDA’s interpretation of the MMA is a reasonable interpretation of the balance Congress struck between these competing goals.” 

(The court also denied FDA’s Motion to Dismiss the case on several grounds – that Teva is not challenging final agency action, Teva’s claims are not ripe, Teva has not suffered sufficient injury for Article III standing, and Teva has failed to exhaust administrative remedies – but primarily on the basis that Teva failed to state a claim pursuant to Federal Rule of Civil Procedure 12(b)(6), inasmuch as Teva was not challenging a final agency action.  FDA appealed only the ripeness and standing issues.)   

On appeal, Teva offered two primary arguments against FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC) – which the D.C. Circuit dubbed the “linguistic argument” and the “structural argument.”  Teva’s “linguistic argument”:

. . . takes the form of linguistic analysis focused almost entirely on the text of the “failure to market” forfeiture event and a related provision.  The [MMA], Teva explains, introduced a new procedure, a counterclaim in the brand manufacturer’s patent infringement suit, through which generic companies can force brand companies to delist an improperly asserted patent.  See 21 U.S.C. § 355(j)(5)(C)(ii)(I).  This counterclaim provision is the only portion of the statute that explicitly provides for the delisting of a patent after it has been challenged in an ANDA.  In the company’s view, that singular reference requires the conclusion that the counterclaim provision describes the only scenario in which the FDA may delist a challenged patent.

Under Teva's structural argument, Ranbaxy remains applicable post-MMA:

This brings us to Teva’s structural argument.  Ranbaxy, Teva notes, concerned an FDA policy with a virtually identical effect. See 469 F.3d at 125. This court condemned that rule, partly because it allowed a brand manufacturer,

by delisting its patent, to deprive the generic applicant of a period of marketing exclusivity. By thus reducing the certainty of receiving a period of marketing exclusivity, the FDA’s delisting policy diminishe[d] the incentive for a manufacturer of generic drugs to challenge a patent . . . in the hope of bringing to market a generic competitor for an approved drug without waiting for the patent to expire.  The FDA may not, however, change the incentive structure adopted by the Congress, for the agency is bound “not only by the ultimate purposes Congress has selected, but by the means it has deemed appropriate, and prescribed, for the pursuit of those purposes.”

Id. at 126 (emphasis added, citation omitted).  Nothing in the [MMA] altered that essential incentive structure, says Teva, so the preceding portion of Ranbaxy remains applicable even under the new regime.  Indeed, it is true that the 2003 amendments say nothing specific to undermine our prior understanding of the statute’s intended incentive structure.

The D.C. Circuit’s highly anticipated 31-page opinion, which also addressed the issues of ripeness and standing appealed by FDA, is a game-changer!   The Court ruled (Judges Williams and Griffith) that FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC) fails at Chevron step one.  Reviewing the district court’s decision de novo, the D.C. Circuit, although not convinced by Teva’s linguistic argument, found Teva’s structural argument to be persuasive: 

The real issue, then, is whether the FDA is right that the 2003 addition of the “failure to market” forfeiture provision, 21 U.S.C. § 355(j)(5)(D)(i)(I), altered the statute’s incentive structure to the point that Ranbaxy’s reasoning no longer controls the agency’s treatment of a delisting request in the wake of a paragraph-IV filing.

The terms of § 355(j)(5)(D)(i)(I) . . . create five possible dates on which a generic manufacturer otherwise entitled to exclusivity can forfeit it: (1) 75 days after the agency finally approves the relevant ANDA; (2) 30 months after the generic submits the relevant ANDA; (3) 75 days after a court judgment that the challenged patent is invalid or not infringed; (4) 75 days after a suit over the challenged patent is settled favorably to the ANDA filer; and (5) 75 days after the challenged patent is delisted. No forfeiture occurs, however, unless one of dates (1)-(2) and one of dates (3)-(5) have come to pass. . . .  Setting aside the subsection at issue in this case—listed as (5) above, and codified as (bb)(CC)—the “failure to market” forfeiture provision does not permit a brand manufacturer to vitiate a generic’s exclusivity without the generic manufacturer’s having had some say in the matter.  No forfeiture can take place unless the brand manufacturer brings an infringement suit against the generic and either loses on the merits or enters an unfavorable settlement agreement.  The latter necessarily entails some participation by the generic; the former invariably involves significant expense for the brand manufacturer, and affords the victorious generic the opportunity to ask the court to delay entering final judgment until a date that would not trigger forfeiture prematurely— before the agency grants final approval to the relevant ANDA.

The FDA’s view turns the last alternative among events (3)-(5) into a fundamentally different forfeiture trigger: it is satisfied when the patent targeted in a paragraph-IV filing “is withdrawn by the” brand manufacturer, full stop—meaning that Congress has now explicitly provided for a scenario in which the brand maker can unilaterally deprive the generic of its exclusivity.  The agency, however, offers not a single cogent reason why Congress might have permitted brand manufacturers to trigger subsection (CC) by withdrawing a challenged patent, outside the counterclaim scenario identified by Teva.

The argument that the plain language of the statute imposes no limit on the circumstances in which the agency may effectuate delisting requests fails. Precisely the same could have been said of the version of the statute that Ranbaxy addressed, and we nevertheless concluded that its structure precluded an FDA rule allowing the agency “to delist a patent upon the request of the [brand manufacturer]” when the delisting would rob the generic maker of earned exclusivity. . . .

As Congress deliberately created the 180-day exclusivity bonus, the FDA cannot justify its interpretation by proudly proclaiming that it has eviscerated that bonus.

We see nothing in the [MMA] that changes the structure of the statute such that brand companies should be newly able to delist challenged patents, thereby triggering a forfeiture event that deprives generic companies of the period of marketing exclusivity they otherwise deserve.  For that reason, the interpretation of the statute that the FDA has adopted in two recent adjudications, and that it regards itself as bound by law to apply to Teva’s ANDAs for losartan products, fails at Chevron step one. [(italics in original; bold emphasis added; citations omitted)]

So, under the D.C. Circuit's opinion, the patent delisting counterclaim provision at FDC Act § 505(j)(5)(C)(ii)(I) added by the MMA must be read together with the patent delisting forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC).

Judge Henderson filed a dissenting opinion in the case on the basis that Teva’s lawsuit is not ripe until FDA issues an exclusivity decision.  The case was remanded to the district court for further proceedings “as the court has yet to address the appropriateness of each form of relief that Teva has sought. . . .”  Teva's Complaint requested declaratory and injunctive relief.  

There could very well be a flurry of activity in this case until April 2010, when FDA is expected to approve generic losartan products, as interested parties decide whether or not to seek to overturn the D.C. Circuit’s decision.

By Kurt R. Karst –      

The Patent and Trademark Office’s (“PTO’s”) recent denial of a Patent Term Extension (“PTE”) for U.S. Patent No. 5,270,305, which was reissued as U.S. Patent No. RE40,045 (“the ‘045 patent”), covering Glaxo’s ADVAIR DISKUS (fluticasone propionate; salmeterol xinafoate) should be the last word from the PTO on the availability of PTEs for so-called “synergistic combinations” of previously aproved drugs.  Glaxo’s PTE application was initially submitted to the PTO in October 2000 and was last amended in August 2008 after the issuance of the reissue patent. 

As we previously reported, the PTO’s June 2008 decision, in which the Office denied a PTE for a patent covering SYMBICORT (budesonide; formoterol fumarate dihydrate) Inhalation Aerosol, clarified the PTO’s position that a PTE is not available for a drug product containing two previously approved active ingredients that purportedly act synergistically to create a new product.  Until then, companies – including Glaxo – relied on a statement in § 2751 of the PTO’s Manual of Patent Examining Procedure (“MPEP”) that seemed to raise the possibility that two previously approved active ingredients could synergistically interact to yield a new product eligible for a PTE.  MPEP § 2751 states, in relevant part, that “an approved product having two active ingredients, which are not shown to have a synergistic effect or have pharmacological interaction, will not be considered to have a single active ingredient made of the two active ingredients.”  

Companies relied on this statement notwithstanding a 1994 PTE decision concerning EMLA (lidocaine; prilocaine) Topical Cream, in which the PTO determined that, consistent with the legislative history of the PTE statute at 35 U.S.C. § 156, a patent claiming a combination of two previously and separately approved active ingredients is not eligible for a PTE, regardless of “any enhanced effect of the combination.”  In addition, in 2004, the U.S. Court of Appeals for the Federal Circuit stated in its decision in Arnold Partnership v. Dudas – a case concerning a PTE for VICOPROFEN (ibuprofen; hydrocodone bitartrate) – that “this court doubts that synergistic effects are an appropriate distinction for [PTE] policies, particularly where the statutory language does not distinguish between synergistic and nonsynergistic combinations.”

As with the previous SYMBICORT PTE denial, the PTO ruled that the ‘045 patent is not eligible for a PTE, and that Glaxo’s reliance on the MPEP statement above “is misplaced:”  

The synergistic effect of the active ingredients salmeterol xinafoate and fluticasone propionate has no relevance in determining "first permitted commercial marketing or use of the product" as required by 35 U.S.C. § 156(a)(5)(A).  The term "product" as used in 35 U.S.C. § 156 includes any new drug or antibiotic drug, "as a single entity or in combination with another active ingredient."  35 U.S.C. § 156 (f)(2).  Section 156(f)(2) says nothing about if a combination of active ingredient is synergistic, it is treated as a single entity.  See Arnold Partnership v. Dudas, 362 F.3d 1338, 1343 (Fed. Cir. 2004). . . .

The statement in the MPEP does not require that the USPTO treat an alleged synergistic combination drug product with two active ingredients as a single active ingredient made up of the two active ingredients for patent term extension purposes.  Rather, MPEP § 2751 merely explains that a product having two active ingredients, without synergy, will not be treated as a single active ingredient.  This does not imply that a showing of synergy in a product having two active ingredients, each of which was previously approved for commercial marketing or use, must be considered to be a single active ingredient for patent term extension purposes.  The USPTO construes 35 U.S.C. § 156(f)(2) by giving the plain meaning to each and every term of the provision.  A "drug product" exists as a single entity, i.e., a drug product having one active ingredient, or the drug product is a combination of two or more active ingredients.  No statutory language, regulation, court decision or legislative history account for synergy in the patent term extension context.  As such, Applicant cannot point to any precedent which would require finding that a drug product having two active ingredients, which exhibit a synergistic effect, is a single entity within the meaning of section 156.

So, absent another long-lingering PTE application (or a court challenge), the PTO’s latest decision shoud be the last we hear about this issue. 

By David B. Clissold & Carrie S. Martin –

Last Friday, FDA issued two new draft guidance documents regarding clinical trial designs: Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics (February 2010) and Guidance for Industry: Non-Inferiority Clinical Trials (March 2010).

These draft guidance documents are products of FDA’s Critical Path Initiative (“CPI”), FDA’s effort to modernize the scientific process through which a potential drug or device goes from “proof of concept” to a marketed medical product.  The CPI is an effort to optimize the scientific tests and tools used to determine whether a product is safe and effective.  One of the goals of the CPI is to streamline clinical trials, and the Adaptive Design and Non-Inferiority guidances are solid examples of FDA’s progress towards that objective.

Adaptive Design Guidance

The Adaptive Design draft guidance provides sponsors with information on those features of  adaptive designs that are valid, and discusses elements that may be problematic.  FDA defines an adaptive design clinical trial as one that “includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”  By allowing these modifications, a study may more efficiently provide information, increase the likelihood of successfully meeting a study objective, or improve the understanding of the drug’s treatment effect.  The guidance notes that such prospectively planned modifications can be submitted with the study protocol or in a statistical analysis plan (“SAP”).

Among the possible study design modifications, the guidance discusses study eligibility criteria, randomization procedure, total sample size, primary endpoints and secondary endpoints, and the methods used to analyze those endpoints.  The Agency explains that the adaptive design concept is best used in adequate and well-controlled studies and that study revisions should be based on blinded data.  A chief concern with adaptive design studies is the possibility of bias and false-positives.  To address these concerns, FDA recommends – among other things – that sponsors submit a written standard operating procedure (“SOP”), which defines who will conduct the interim analysis and implement the adaptation plan.  The Agency recommends using an independent entity for this purpose, such as a Data Monitoring Committee ("DMC"), to control access to unblinded data.

Because adaptive study designs may require more advanced planning by sponsors, the guidance document encourages sponsors to interact with the Agency during the planning stages of the clinical trials.  The timing and frequency of such meetings will vary based on the complexity of the study designs.

Non-Inferiority Clinical Trials Guidance 

The Non-Inferiority draft guidance explores FDA’s thinking on the use of non-inferiority study designs to provide evidence of a drug’s effectiveness.  This includes FDA’s thoughts on how best to choose an appropriate non-inferiority margin and how to analyze the results.  FDA explains that a non-inferiority trial seeks to demonstrate that “any difference between [ ] two treatments is small enough to allow a conclusion that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control.”  This is in contrast to the more common superiority trials, such as a placebo-controlled trial, which seek to prove a new drug is more effective than the control.  Non-inferiority trials are most often used when it would be unethical to use a placebo control. 

In addition to providing recommendations regarding study design and interpretation, the guidance provides answers to nine “commonly asked questions” regarding the estimation of margins, appropriate active control drugs, endpoints, and reliance on a single non-inferiority study to support effectiveness.  The guidance also discusses five examples derived from publicly available information that describe how to choose a non-inferiority margin, how to analyze the results, and other considerations relevant to the design and interpretation of non-inferiority studies.

Comments on both guidance documents are due June 1, 2010, and can be submitted to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, rm. 1060, Rockville, MD 20852 or electronically at http://www.regulations.gov.