By Cassandra A. Soltis –

That’s what the Food and Drug Administration (“FDA”) is hoping anyway.  In a notice expected to be published in the Federal Register on Thursday, April 29, 2010, FDA will announce that it is requesting data and information from “all interested parties,” including the food industry, graphic and package designers, marketing experts, and the nutrition community, both domestic and foreign, on the use of front-of-pack (“FOP”) nutrition symbols on food packages or shelf tags.   This request for information follows FDA Commissioner Margaret Hamburg’s letter to industry last month, in which she urged companies to review their food labels and remove false or misleading claims that prevent consumers from “mak[ing] informed and healthy food choices.”  The notice also follows First Lady Michelle Obama’s recent announcement of her Let’s Move initiative, which has the goal to reduce the prevalence of childhood obesity, in part, by having parents and children choose healthier foods.

Citing to “[t]he prevalence of diet-related diseases in the U.S. population and the need to accommodate Americans’ increasingly busy lifestyles,” FDA stated that nutrition information needs to be tailored to help consumers make better food choices.  To that end, FDA indicated that voluntary FOP labeling should be “[b]ased on standardized nutrition criteria that are grounded in the Dietary Guidelines for Americans,” “[w]idely adopted by food retailers and manufacturers,” and appear in a standardized format that consumers of varying literacy and educational levels can comprehend and notice.

FDA and the U.S. Department of Agriculture are already working with stakeholders in the public and private sectors to develop a “voluntary” FOP label.  Although it appears that a manufacturer’s use of any FOP label scheme agreed to by FDA would be voluntary, FDA’s stated goal of having a standardized format suggests that manufacturers might not be able to use an alternate FOP label scheme of their own choosing.  Depending on the underlying rationale, such a restriction could invite a First Amendment challenge.   An additional impact on industry could result from the imperative to reformulate products so that there is no loss of market share to competing products that an FOP labeling scheme designates as being more nutritious.

FDA stated that it is currently conducting studies on consumer understanding of nutrition symbols.  However, the Agency is interested in data and information that has not been published, particularly those studies on a wide range of nutrition symbol schemes and on consumer responses to different symbol schemes.  Other data and information requested include:

• whether FOP labeling may cause manufacturers to reformulate their products;
• design considerations, such as color, location, shape, and amount of information; and
• consumer attitudes toward, and use of, such symbols, including whether FOP labeling affects purchasing decisions.

The Agency is also considering issuing a draft guidance on voluntary calorie declarations and a draft guidance or proposed rule on dietary guidance statements. 

Comments on this FOP labeling notice will be due 90 days after publication in the Federal Register.

By Cassandra A. Soltis –

In an advertising challenge brought by the Perrigo Company (“Perrigo”), the National Advertising Division (“NAD”) of the Better Business Bureau recommended that Pharmavite, LLC (Pharmavite) refrain from making several claims for its Nature Made® Prenatal + DHA Liquid Softgel Vitamins until the company completes competent and reliable testing that establishes the bioavailability of the folic acid in the product.  Advertising for the Prenatal Vitamin included FDA’s authorized folic acid/neural tube defects health claim and a statement that the product was formulated for “easy absorption.” 

Perrigo alleged that Pharmavite could not substantiate the claims because the product does not adhere to the U.S. Pharmacopeia (“USP”) standard titled “Disintegration and Dissolution of Dietary Supplements, 2040,” which determines whether a dietary ingredient is bioavailable.  Dietary supplements bearing the folic acid/neural tube defects health claim must meet this standard in order to bear the health claim, unless the standard is not applicable, in which case “the folate in the dietary supplement [must] be shown to be bioavailable under the conditions of use stated on the product label.”  21 C.F.R. § 101.79(c)(2)(ii)(B).

According to Perrigo, it tested Pharmavite’s Prenatal Vitamin using the pertinent USP standard and found less than 12.5% of the labeled amount of folic acid had dissolved after six hours.  (The USP’s standard requires that at least 75% of the labeled amount dissolve within one hour under the intended conditions of use.)  Perrigo explained that fat or oil-based components, such as DHA, are expected to inhibit the absorption of water soluble vitamins, such as folic acid.  Accordingly, Perrigo asserted, it is unlikely that Pharmavite’s product can pass a dissolution test of any kind.

Pharmavite responded that its Prenatal Vitamin product did meet the pertinent USP Standard for softgel dietary supplements, which is the rupture test.  Pharmavite explained that, because its product passed the rupture test, the product was bioavailable and the claims were substantiated.  Even so, Pharmavite conducted more testing by incorporating an additional dissolution step, which used a surfactant to determine the availability of the contents of the softgel.  Pharmavite stated that the results from this testing further supported the bioavailability of the product.

The NAD disagreed with Pharmavite, essentially finding that neither USP standard could show that the product was bioavailable.  NAD based its decision on an article that appeared in the Pharmacopeial Forum, which explained that the rupture test may be inadequate on its own when the contents of a softgel are dispersed as a suspension or emulsion (i.e., an oil).  The article suggested that dissolution conditions that mimic the in vivo environment may be helpful in these circumstances.  Because Pharmavite’s additional testing did not mimic the in vivo environment, NAD concluded that Pharmavite did not show that the folic acid in its softgel Prenatal Vitamin was bioavailable. 

Pharmavite agreed to discontinue the challenged claims until it conducts testing that recreates the in vivo setting.  This case may have repercussion for similar products that combine water soluble vitamins with oil-based components.

By Kurt R. Karst –   

Last Friday, at the American Bar Association’s Section of Antitrust Law Spring Meeting in Washington, D.C., Federal Trade Commission (“FTC”) Chairman Jon Leibowitz issued the FTC’s 2010 Annual Report.  Among other things, including allegedly false or unsupported claims concerning dietary supplements, the 96-page report highlights the Commission’s efforts to stop allegedly anticompetitive “pay-for-delay” patent settlement agreements.

According to the FTC, “[o]ne of the Commission’s top priorities is putting an end to anticompetitive pay-for-delay patent settlement agreements.”  Indeed, the Commission commented in its January 2010 report, titled “Pay-for-Delay: How Drug Company Pay-Offs Cost Consumers Billions,” that there are “multiple investigations underway.”  President Obama’s proposed version of the Patient Protection Affordable Care Act (“PPACA”) included provisions that would have made patent settlement agreements, if challenged, presumptively anticompetitive and unlawful (although some groups wanted more); however, the provisions did not make it into the law.  The FTC expressed its deep disappointment and vowed to press ahead. 

The FTC’s Annual Report focuses on three cases the Commission has been involved in concerning patent settlement agreements:

• King Drug Co. of Florence, Inc. v. Cephalon, Inc. –  In this consolidated case concerning Cephalon, Inc.’s PROVIGIL (modafinil) that is pending in the U.S. District Court for the Eastern District of Pennsylvania, the FTC alleged that Cephalon engaged in anticompetitive conduct when the company paid four firms to refrain from selling generic versions of PROVIGIL until 2012.  In March 2010, the court denied various defendants’ motions to dismiss the case (except for selected counts brought under several state statutes), finding that the agreements may violate antitrust laws.

• In re: AndroGel Antitrust Litigation (No. II) – This case stems from a February 2009 challenge by the FTC and the California Attorney General concerning  Solvay Pharmaceuticals, Inc.’s ANDROGEL (testosterone gel) 1%, in which the FTC alleged that Solvay and generic companies violated various federal antitrust laws when they agreed to dismiss patent infringement litigation in exchange for a profit-sharing arrangement and provided the generic competitors would not launch their generic versions of ANDROGEL until 2015.  As we previously reported, in February 2010, in a setback to the Commission’s battle against patent settlement, the U.S. District Court for the Northern District of Georgia (Atlanta Division) largely dismissed the case.

• Federal Trade Commission v. Bristol-Myers Squibb Co. – In this first action involving § 1115 of the 2003 Medicare Modernization Act, and which stems from a 2003 FTC Order involving Bristol-Myers Squibb Company (“BMS”) and the reporting of patent settlement agreements, the FTC obtained a $2.1 million fine from BMS for failing to inform the FTC of agreements reached with Apotex, Inc., regarding potential generic competition to PLAVIX (clopidogrel bisulfate).  MMA § 1112(c) requires each party to a settlement of patent litigation to file such settlements with the FTC and the Department of Justice, and MMA § 1115 provides “a civil penalty of not more that $11,000, for each day” a company fails to comply with the submission requirement.  The FTC charged that, among other things, BMS failed to disclose (as part of a patent settlement with Apotex) that the company orally promised that it would not compete with Apotex during the first 180-days that Apotex marketed its generic version of PLAVIX.

Although not among the cases discussed in the FTC’s Annual Report, the U.S. District Court for the District of New Jersey’s recent order in In re K-Dur Antitrust Litigation to adopt a Special Master’s Report and Recommendation in the long-running patent settlement dispute concerning K-DUR (potassium chloride) is also noteworthy.  In that case, direct purchasers of K-DUR alleged that Merck & Co., Inc. (“Merck”) (formerly Schering-Plough Corporation) restricted competition in violation of the Sherman Act by settling patent infringement lawsuits against potential generic K-DUR entrants.  Merck filed a motion for summary judgment and the Special Master appointed to preside over the case recommended that the motion be granted.  The direct purchasers promptly appealed the decision.  The In re K-Dur Antitrust Litigation followed an FTC action against Schering challenging the same settlements.  In 2005, in Schering-Plough Corp. v. FTC, 402 F.3d 1056 (11th Cir. 2005), the U.S. Court of Appeals for the Eleventh Circuit upheld a district court dismissal of that case.

By Nisha P. Shah –

FDA recently issued a white paper revealing that the Agency intends to strengthen its review of medical devices for home use, such as hemodialysis equipment, wound therapy care, intravenous therapy devices, and ventilators, as more hospital patients are being discharged to continue treatment at home.

FDA claims that about “7.6 million individuals in the United States currently receive home healthcare from roughly 17,000 paid providers” with annual U.S. expenditures for home care estimated as high as $57.6 billion in 2007.  Jeffrey Shuren, M.D., J.D., director of the Center for Devices and Radiological Health, stated that “[u]sing complex medical devices at home carries unique challenges … Caregivers may lack sufficient training, product instructions may be inadequate or overly technical, and the home environment itself may pose environmental or safety hazards that can affect the product’s functioning.”

Currently, there is no clear regulatory pathway for devices intended for home use that describes what manufacturers should consider when designing, testing, and labeling such products.  FDA’s Medical Device Home Use Initiative attempts to fill this gap.  Under the Initiative, the Agency will develop guidance for home medical device manufacturers on the premarket approval or 510(k) clearance of these devices, including device testing with at-home caregivers and patients, identify instances under which FDA may exercise its authority to require that certain devices contain a statement in its label that it has not been cleared for home use, and develop educational materials on home use of devices.

The Initiative also contains measures for enhanced post-market oversight through HomeNet, a “subnetwork of the FDA’s Medical Device Surveillance Network” which is an adverse event reporting program that includes more than 350 health care facilities nationwide.  Additionally, beginning this summer, FDA plans to launch a 10-month pilot program in which home medical device manufacturers may voluntarily submit labeling to the Agency for posting on a central website repository to help patients and caregivers access important information about the safe use of the devices. The pilot program will support FDA’s goal of eventually creating an online labeling repository for devices cleared or approved for home use.

A public workshop on May 24, 2010 has been scheduled to discuss measures manufacturers can take to design and test medical devices used at home, and to develop instructions for home care patients and caregivers.

By Kurt R. Karst –   

Last Friday, several days after FDA held a meeting on the public’s assessment of the overall performance of the fourth iteration of the Prescription Drug User Fee Act (“PDUFA”), which was reauthorized as Title I of the 2007 FDA Amendments Act (“FDAAA”), and what aspects of the program should be retained, changed, or discontinued in the next iteration of the program – PDUFA V – when it comes up for reauthorization (PDUFA IV expires at the end of September 2012), FDA quietly made public the Agency’s FY 2008 PDUFA Performance Report.  There was no FDA press release, no notice on FDA’s “What’s New (Drugs)” website – and, in fact, there is not yet any mention of the report on FDA’s PDUFA website (as of publication of this post).  BioCentury (subscription required) reported on the report over the weekend, but other than that, no one else has mentioned the report in print. 

So why has FDA been radio silent on the FY 2008 PDUFA Performance Report, which marks the 16th year of PDUFA and the beginning of PDUFA IV?  After all, industry knew some of what to expect after Office of New Drugs (“OND”) Director Dr. John Jenkins presented some figures at Windhover’s December 2009 FDA/CMS Summit.  Well, there is not much in the FY 2008 Performance Report that FDA can tout as a success – many of the performance goals FDA agreed to under PDUFA IV have not been met.  As FDA Commissioner Dr. Margaret Hamburg states in a preface to the report, “performance in many traditionally strong PDUFA goal areas decreased in FY 2008; and, therefore, this report presents a picture of mixed success.” 

According to FDA, much of the “mixed success” is due to FDAAA, which, among other things, gave FDA increased responsibilities and authorities regarding the post-market safety of drugs (e.g., Risk Evaluation and Mitigation Strategies).  “[T]he changes and challenges that FDA faces in PDUFA IV as a result of the expansion of FDA’s responsibilities under FDAAA place unprecedented demands on FDA reviewer workloads.  These added responsibilities can also have unintended and unexpected impacts on FDA’s short-term abilities to meet PDUFA IV goals,” according to the FY 2008 Performance Report.  Given these increased responsibilities, in November 2007, Dr.  Jenkins granted permission for OND managers to exercise greater flexibility regarding PDUFA goals.  That permission was later documented in a communication to FDAers.  In October 2009, Dr. Jenkins withdrew that permission and instructed OND managers to begin moving back to the “prior posture of meeting PDUFA goals whenever possible.”

Below are some of the facts and figures of note from the FY 2008 Performance Report.  FDA agreed to a “90% on time” goal under PDUFA IV for each item.  Also, in each case, a “highest potential performance” statistic is provided.  This statistic assumes that FDA will meet a pending and not overdue item.  

Original Applications (FY 2008 Submissions)

Resubmitted Applications (FY 2008 Resubmissions)

Efficacy Supplements (FY 2008 Submissions)

Resubmitted Efficacy Supplements (FY 2008 Resubmissions)

 
Manufacturing Supplements (FY 2008 Submissions)

Meeting Management (FY 2008 Performance)

Special Protocol Assessments (FY 2008 Performance)

Responses to Clinical Holds (FY 2008 Performance)

 
Major Dispute Resolution (FY 2008 Performance)

First Cycle Filing Review Notification (FY 2008 Submissions)

By Kurt R. Karst –   

In recent weeks, two advocacy groups have sent letters to FDA requesting that the Agency enhance and accelerate its enforcement activities with respect to marketed unapproved drugs.  FDA began its current Unapproved Drugs Initiative in June 2006 when the Agency published a compliance policy guide explaining the Agency’s risk-based enforcement policy.  Under this approach, FDA gives higher priority to enforcement action against unapproved drugs in the following categories:

• drugs with potential safety risks;
• drugs that lack evidence of effectiveness;
• drugs that present a “health fraud”;
• drugs that present direct challenges to the new drug approval and OTC drug monograph systems;
• unapproved new drugs that are also violative of the FDC Act in other ways (e.g., Current Good Manufacturing Practice regulation violations); and
• drugs that are reformulated to evade an FDA enforcement action (e.g., when a firm, in anticipation of FDA enforcement action, changes its unapproved drug product by, for example, adding an active ingredient, in an attempt to evade such enforcement action).

Since June 2006, FDA has taken scores of enforcement actions affecting hundreds of drug products.  And, as we previously reported, along the way, FDA has begun using new mechanisms, such as drug listing information, to guide enforcement activity.

The National Minority Quality Forum (“NMQF”), a “research and educational organization dedicated to ensuring that high-risk racial and ethnic populations and communities receive optimal health care,” recently announced that the organization sent a letter to FDA expressing concern that marketed unapproved drugs “may compromise the health of patients, and create increased liability for the physicians who prescribe them” and requesting that FDA enhance its enforcement of the Agency’s Unapproved Drugs Initiative.  To support FDA’s enhanced enforcement, NMQF also announced that it is launching a public information campaign called “Did You Know?”  The campaign is intended to “serve as an educational resource to consumers, physicians and policymakers who want to learn more about risks associated with unapproved drugs in the marketplace.”

Another advocacy group, MANA, a self-described national Latina organization, has also joined the fray and has asked FDA to accelerate its efforts to remove unapproved drugs from the marketplace.  According to MANA’s letter, “removal of all unapproved drugs from the marketplace is an important and commendable goal that must be achieved as soon as possible.  Doing so will not only encourage other companies to pursue the proper measures necessary to win FDA approval for their own products, but more importantly, will assure that no more unnecessary harm is brought to the unknowing purchasers of unapproved drugs in this country.”  MANA is also concerned that “even well-meaning physicians continue to write scripts for unapproved drugs falsely characterizing these drugs as ‘generics’ and leaving the patients they care for at risk.”  MANA offers its assistance to FDA to accelerate the removal of marketed unapproved drugs, but the organization’s letter offers no details on what assistance MANA could provide to FDA to achieve this goal. 

By Kurt R. Karst –   

The U.S. District Court for the District of Delaware’s recent decision in Millennium Pharmaceuticals, Inc. v. Teva Parenteral Medicines, Inc., denying a stay of patent infringement proceedings concerning generic versions of Schering’s INTEGRILIN (eptifibatide) Injection is (to our knowledge) the latest case in which a court has been asked to “toll” the 30-month stay of ANDA approval provided under FDC Act § 505(j)(5)(B)(iii) in an effort to preserve 180-day exclusivity eligibility.  As we previously reported, last year the U.S. District Court for the Northern District of Illinois (Eastern Division) in Abbott Labs. v. Matrix Labs., Inc., No. 09-cv-1586 (N.D. Ill. Nov. 5, 2009) ordered the tolling of the 30-month stay in the context of patent infringement litigation over generic KALETRA (lopinavir; ritonavir) Tablets. 

Under FDC Act § 505(j)(5)(B)(iii), the 30-month stay may be “for such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action . . . .”  FDA commented in the preamble to the Agency’s 1994 final regulations implementing the Hatch-Waxman Amendments that “[t]he statute leaves the issue of extending the 30-month period (based on a lack of cooperation between the parties in patent litigation) to the discretion of the trial court.  The agency believes that the trial court should make determinations of cooperation on a case-by-case basis.”  FDA also commented, without qualification, that “[u]nder the statute, the reduction or enlargement of the 30-month period is left to the trial court’s discretion.” 

In the latest case, Teva filed a Motion to Stay requesting an order from the court “(1) staying the present actions until May 11, 2012 (subject to a showing of good cause by any party that the stay should be lifted earlier), and (2) tolling the [FDA] thirty-month stays of approval of Teva's [ANDAs] for the drug at issue here, eptifibatide.” 

INTEGRILIN is covered by five Orange Book-listed patents.  Two of the patents, to which one of Teva’s ANDAs reportedly contains Paragraph III certifications, are scheduled to expire in 2014.  The three other patents, to which one of Teva’s ANDAs reportedly contains Paragraph IV certifications, are scheduled to expire in 2015.  As we previously discussed, this sets up a scenario whereby an early court decision on the Paragraph IV certification patents – that is, a decision well before the Paragraph III certification patents expire – could trigger the 75-day period under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA), such that, if Teva is a first applicant eligible for 180-day exclusivity, that eligibility could be forfeited under the “failure-to-market” forfeiture provisions.  Those provisions provide that 180-day exclusivity is forfeited based on the “later of” two events – (aa) the earlier of “75 days after the date on which the approval of the application of the first applicant is made effective under [FDC Act § 505(j)(5)(B)(iii)]” or “30 months after the date of submission of the application of the first applicant,” and (bb) 75 days after a final court decision finding certain patents invalid or not infringed with respect to a “first applicant or any other applicant (which other applicant has received tentative approval)” or patent delisting.   

Citing the court’s three-factor stay standard articulated in In re Brimonidine Patent Litig., No. 07-md-1866 (D. Del. Oct. 31, 2008), in which an NDA sponsor requested (and was denied) a stay and tolling of the 30-month stay, Teva argued that: (1) the company would be “greatly prejudiced if the requested stay is not granted;” (2) a “stay could simplify the issues or render litigation unnecessary;” and (3) although the INTEGRILIN patent infringement litigation is in its infancy, case law supports granting a stay at this early stage of litigation.  

Schering and Millennium opposed Teva’s motion arguing that the three factors in In re Brimonidine Patent Litig. are not met.  Most significantly, they argued that:

Teva’s motion is grounded in the incorrect assertion that this Court has complete discretion to extend the FDA’s thirty-month stay.  Although a district court often has broad discretion to stay litigation to control its own docket, there is no such discretion here because Teva is asking this Court to extend the FDA’s statutory thirty-month stay. [(italics in original)]

. . . Congress has expressly provided that the thirty-month stay can not be altered unless a “party to the action failed to reasonably cooperate in expediting the action.” 21 U.S.C. § 355(j)(5)(B)(iii).  The Federal Circuit has made it clear [in Eli Lilly & Co. v. Teva Pharm. USA, Inc., 557 F.3d 1346 (Fed. Cir. 2009) and Andrx Pharm., Inc. v. Biovail Corp., 276 F.3d 1368, 1376 (Fed. Cir. 2002)] that failure to reasonably cooperate in expediting litigation is the sole ground for which a court may extend the thirty-month stay in an ANDA litigation.

And with respect to the decision in Abbott Labs. v. Matrix Labs., Inc., Schering and Millennium commented that:

Even apart from the fact that a decision from a district court in Illinois is not binding in the District of Delaware, Abbott Labs does not justify Teva’s proposed stay. Most critically, the Abbott Labs court improperly did not recognize that the “failed to reasonably cooperate” restriction in section 355(j)(5)(B)(iii) limits the court’s discretion to enlarge the thirty-month period. . . .  As such, the Abbott Labs decision plainly runs afoul of the Federal Circuit’s holdings in Eli Lilly and Andrx and Chief Judge Sleet’s decision in Brimonidine.

Teva replied that the court does, in fact, have the authority to toll the 30-month stay, and that the patent infringement actions “should be stayed regardless of whether the Court also tolls the stays at the FDA.  Tolling at the FDA is not a prerequisite to a stay here” (italics in original).  

Finding, among other things, that “Plaintiffs would be prejudiced in not being able to timely ‘clear the cloud’ that has been cast over the validity of their patents,” Judge Joyner ruled in his brief opinion that:

Although it would be permissible to grant a stay at this stage of the proceedings, given the balancing of the other factors discussed above, we do not believe that it would be appropriate to exercise our discretion to do so at this time.  Granting a stay would cause a hardship to Plaintiffs and any hardship caused to Defendants was the foreseeable result of Defendants’ choice to file their ANDAs when they did.

With respect to the court’s ability to toll the 30-month stay of ANDA approval, Judge Joyner decided to sidestep the issue, commenting that “we do not find it necessary to address these arguments as we have decided against staying the present action, and, therefore, there is no reason to extend the FDA’s stay.”

The March/April 2010 issue of FDLI Update contains an article by Hyman, Phelps & McNamara, P.C.’s Peter M. Jaensch and John R. Fleder that addresses the increasing number of cases brought under the federal Lanham Act law where plaintiffs have arguably sought to privately enforce the FDC Act.  In particular, the article analyzes Schering-Plough Healthcare Products, Inc., v. Schwarz Pharma, Inc. et al., 586 F.3d 500 (7th Cir. 2009).  The Court of Appeals ruled that the plaintiff was improperly seeking to enforce the FDC Act, and was treading on FDA’s primary jurisdiction over drug labeling issues.

Just after this article was published, the Ninth Circuit issued a similar ruling on April 14, 2010, in PhotoMedex, Inc. v. Irwin. The plaintiff commenced a Lanham Act case based on allegations of misrepresentations made by defendants regarding: (1) clearance by FDA to market their laser device, (2) the anticipated date their laser would be available for purchase, and (3) Irwin’s role as inventor of the device. 

The Court ruled that the first alleged misrepresentation would have required the Court to address whether a medical device manufacturer which is not permitted to bring a private action to enforce the FDC Act may nevertheless maintain a suit under the Lanham Act based on a claim that a competitor misrepresented that its product had received FDA clearance, when the FDA had declined to make such a finding or bring an enforcement action. The Court concluded that because the FDA permits Defendants to determine in the first instance whether their laser device was covered by an FDA clearance previously given to a similar device and to market their device without an affirmative statement of approval by the FDA, the Lanham Act claim could not proceed.  The Court did, however, allow the other two alleged misrepresentations.

The Court of Appeals cautioned that it was not suggesting that the Lanham Act can never support a claim involving FDA approval or clearance of drugs or medical devices.  It stated that if a company makes “an affirmative statement of approval by the FDA was required before a given product could be marketed and that no such FDA approval had been granted,” a Lanham Act claim could be pursued.

By Kurt R. Karst –   

Earlier this week, the U.S. Court of Appeals for the Federal Circuit issued its decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd., No. 2010-1001, interpreting the patent delisting counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act (“MMA”) – and specifically addressing whether the counterclaim provisions may be used to correct or delete an Orange Book-listed patent use code.  As we previously reported, last year the U.S. District Court for the Eastern District of Michigan (Southern Division) ruled and issued an Order and Injunction requiring Novo Nordisk, Inc. (“Novo”) to change an Orange Book-listed patent use code for a patent (U.S. Patent No. 6,677,358 (“the ’358 patent”)) on its drug product, PRANDIN (repaglinide) Tablets.  Novo appealed and the Federal Circuit reversed and vacated the district court’s judgment in a 2-1 decision. 

As we noted in our previous post, this case stems from a patent infringement action Novo brought against Caraco Pharmaceutical Laboratories, Ltd. (“Caraco”) and Sun Pharmaceutical Laboratories, Ltd with respect to the ’358 patent, and two related citizen petitions Novo and Caraco initially submitted to FDA in 2008 concerning generic drug labeling carve-out and split patent certification issues.  Novo submitted a  petition to FDA after the Agency required the company to amend PRANDIN’s labeling to reflect a new Indications and Usage statement.  Specifically, FDA required a unitary indication statement stating: “PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.”  (Previously, the PRANDIN Indications and Usage labeling statement discussed both monotherapy and combination therapy.)  Novo ultimately amended its Orange Book patent listing for the ’358 patent with a new use code: “U-968,” which is defined as “A METHOD FOR IMPROVING GLYCEMIC CONTROL IN ADULTS WITH TYPE 2 DIABETES MELLITUS.”   (Previously, the ’358 patent was listed in the Orange Book with a “U-546” code, which is defined as “USE OF REPAGLINIDE IN COMBINATION WITH METFORMIN TO LOWER BLOOD GLUCOSE.”)

The district court deciding the patent infringement action stated that “[a]s a result of the revised use code, the FDA will no longer permit Caraco to file a ‘section viii statement’ carving out the patented repaglinide-metformin combination therapy as a predicate for securing approval of Caraco’s ANDA to market its generic repaglinide for non-infringing uses.”  That is, FDA is apparently requiring a “full” Paragraph IV Certification from Caraco as to the ‘358 patent as a result of the use code change.

Caraco challenged Novo’s use code change in an FDC Act §505(j)(5)(C)(ii)(I)  counterclaim seeking an order from the court requiring Novo to amend the ‘358 Orange Book patent listing to revert back to the U-546 use code.  FDC Act §505(j)(5)(C)(ii)(I) states:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under [FDC Act § 505(b)] or (c) on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

Under FDC Act §§ 505(b) and (c), an NDA holder must submit with its application and after NDA approval “the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture use, or sale of the drug.”

The district court issued an Order and Injunction requiring Novo to submit to FDA a revised Form FDA 3542 reinstating the former U-546 listing for PRANDIN within twenty days from the date of the Order and Injunction.  Novo promptly appealed the decision to the Federal Circuit, which stayed the district court’s Order and Injunction.

In (soon-to-be Chief) Judge Rader’s April 14th majority opinion, the Court ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to replace Novo’s U-968 patent use with the former U-546 use code.  First, “the Hatch-Waxman Act authorizes a counterclaim only if the listed patent does not claim any approved methods of using the listed drug” (emphasis added).  Second, “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative.” 

Judge Rader sets up the dispute in the case as follows:

Novo and Caraco agree that the ’358 patent claims only one of the three approved methods of using PRANDIN (i.e., repaglinide in combination with metformin).  Novo asserts that the counterclaim is available only if the ’358 patent does not claim any approved methods.  Caraco argues that it is entitled to the counterclaim because the ’358 patent does not claim two of the approved methods of PRANDIN use.  In other words, Novo reads “an approved method” in the counterclaim statute as “any approved method” while Caraco reads it as “all approved methods.”

Detecting “no ambiguity in the statutory language,” Judge Rader notes that “when an indefinite article is preceded and qualified by a negative, standard grammar generally provides that ‘a’ means ‘any.’”  As such, for a counterclaim to be available, the Orange Book-listed patent cannot claim any approved methods of using the drug.  Judge Rader goes on to note that:

a broad use code covering all uses of a pharmaceutical could require generic manufacturers to prove specifically that their use will not overlap with and infringe the patented use.  This proof, under Hatch-Waxman procedures, will take the form of a Paragraph IV lawsuit.  In that context, the generic may provide proof that their use will not cause infringement of the patented use.  This court perceives that the Hatch-Waxman Act will thus ensure that a generic drug for non-patented purposes will not be used for patented purposes via a simple section viii certification.  Instead, the generic manufacturer will need to alleviate the risk of infringement or induced infringement in a proceeding that fully tests for infringement and its implications, including potential health and safety risks.  Thus, the Act again facilitates efficient resolution of disputes concerning potential overlapping of protected and unprotected uses.  The Act seeks to strike a balance of the pioneering and generic manufacturers’ interests.

To be sure, Judge Rader states that “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative.”  The counterclaim provision refers to “patent information” submitted by the NDA holder under FDC Act § 505(b) or § 505(c).  And both of these provisions refer only to “the patent number and the expiration date of any patent . . . which claims a method of using such drug” (emphasis added).  Thus, “the counterclaim provision only authorizes suits to correct or delete an erroneous patent number or expiration date.  The authorization does not extend to the use code narrative.”  This “careful use of language” suggests to Judge Rader that the Hatch-Waxman Act “facilitates efficient resolution of disputes over the potential overlap of patented and unpatented uses in the form of a Paragraph IV suit.”

Judge Clevenger, who agreed with Judge Rader’s analysis, filed a concurring opinion expressing skepticism that “the ongoing Paragraph IV litigation will cleanly resolve the dispute between the parties.”  He also fingered FDA as the culprit for for complicating the PRANDIN patent infringement litigation:

If not for FDA’s request that Novo change its labeling to the present broad indication, everything would have worked properly under the relevant statutes. . . .  Caraco was [] set to get FDA approval to bring its generic drug to market and to defend itself in Novo's Paragraph IV suit.

But FDA, acting independently, gummed up the works.  By requiring a single broad indication for repaglinide as part of the approved labeling, FDA created a situation where Caraco can no longer assert that its proposed labeling does not infringe the '358 patent.  It remains to be seen what impact FDA's action will have on Caraco's ability to defend itself in the ongoing Paragraph IV litigation, but FDA's regulatory action threatens to impair Caraco's ability to disprove infringement.  FDA thus may have inadvertently upset the careful balance of interests represented by the efficient dispute resolution mechanism Congress created in the Hatch-Waxman Act.

According to Judge Dyk, who lodged a 28-page dissent, “the majority’s crabbed view of the statute sanctions an unjustified manipulation of the Orange Book.” 

The statute does not require the listing of patent numbers and expiration dates in the abstract.  It contemplates the description of the scope of the patent and of the relationship between the patent and the drug or the method of use; the description of that scope and relationship is itself “patent information” . . . .  Other provisions of the statute also contemplate that the ANDA filer will be able to understand the scope of the patent and to relate the patent information to the drug or drugs being claimed and the method or methods of use being claimed. [(emphasis in original)]

The statute thus must allow correction of a misdescription of patent scope that includes a drug not covered by the patent and erroneous information about the relationship between the patent and the drug, even if the patent is properly listed elsewhere in the Orange Book.  In other words the scope of the patent and its relationship to the drug must be “patent information” . . . .

There is no basis in the statutory language or statutory purpose for distinguishing between drug information and method of use information. Either both must be “patent information,” or neither must be patent information.  In my view, all Orange Book information is “patent information.”

Judge Dyk’s dissent harkens back to the recent decision in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), in which the D.C. Circuit was convinced by Teva’s structural argument that the patent delisting counterclaim provision at FDC Act § 505(j)(5)(C)(ii)(I) must be read together with the patent delisting 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC).  In Teva, the Court stated that FDA was unable to offer “a single cogent reason why Congress might have permitted brand manufacturers to trigger [FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC)] by withdrawing a challenged patent, outside the counterclaim scenario identified by Teva,” and ruled that there is “no reason to conclude that the 2003 addition of forfeiture provisions meant to give the brand manufacturer a right to unilaterally vitiate a generic’s exclusivity.” 

The import of the Teva decision is no lost on Judge Dyk:

In holding that the counterclaim provision is unavailable, the majority’s approach is notably inconsistent with the approach adopted by our sister circuit in another recent Hatch-Waxman Act case, [Teva]. . . .  Here the majority reaches a result that is unsupported by any cogent reason for leaving an ANDA applicant without a remedy to correct an erroneous Orange Book listing with respect to a method of use patent, and is directly contrary to the congressional purpose.

It is unclear whether Caraco will seek a review of the decision.  In the meantime, it will be interesting to see what effects the Federal Circuit’s decision might have on other related litigation – namely, in another patent infringement action concerning PRANDIN, and with respect to a patent delisting counterclaim recently filed in patent infringement litigation concerning ACTOS (pioglitazone) (here and here), but that does not concern patent use codes – and whether Congress will take interest in the issue and further amend the Hatch-Waxman Amendments. 

By Kurt R. Karst –

It seems to be a popular headline these days: “FDA Sued Over [take your pick].”  Following the frenetic losartan 180-day litigation – which is still not over, as FDA has filed a petition for panel rehearing and rehearing en banc of the D.C. Circuit's March 2, 2010 decision in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), and Roxane Laboratories, Inc. has appealed to the D.C. Circuit the D.C. District Court’s April 2, 2010 ruling denying Roxane’s preliminary injunction motion – FDA has been hit with two new lawsuits. 

First, on April 6, 2010, a coalition of animal rights advocates filed a complaint in the U.S. District Court for the District of Columbia seeking declaratory and injunctive relief to require FDA to substantively respond to a November 2007 citizen petition.  That petition posits that “FDA has the authority to mandate the use of nonanimal alternatives and to restrict the use of animal test methods for purposes of FDA approval,” and “requests that the FDA exercise this authority to promulgate a regulation mandating that investigators and testing facilities use scientifically satisfactory non-animal replacements for animal-based methods when meeting the requirements of the Federal Food, Drug and Cosmetic Act.” 

According to the petitioners, the requested regulation is needed to eliminate or greatly reduce the use of “ineffective and costly animal testing methods that fail to identify the dangerous and lethal effects of drugs and devices on humans, and yet needlessly inflict pain and suffering on millions of animals each year.”  Although FDA has stated in letters related to the petition (here and here) that “FDA suggests and encourages the development, validations, and utilization of alternatives to animal testing,” the Agency has not formally responded to the citizen petition.  The animal right advocates who have sued FDA allege that the Agency has failed to comply with the Administrative Procedure Act (5 U.S.C. § 555(b) and the Agency’s citizen petition regulations (21 C.F.R. § 10.30(e)) by failing to substantively respond to the November 2007 petition within “a reasonable time,” and request the court to compel FDA to provide a timely substantive response.  Historically, courts have been hesitant to grant such relief (see e.g., here).

Second, earlier this week, a group of ear candle advocates sued FDA after the Agency issued about 15 Warning Letters to companies marketing the products.  According to FDA, ear candles are “hollow cones that are about 10 inches long and made from a fabric tube soaked in beeswax, paraffin, or a mixture of the two” that are being marketed as treatments for a variety of conditions, including “ear wax buildup, sinus infections, hearing loss, headaches, colds, flu, and sore throats.”  Ear candling, also known as “ear coning” or “thermal-auricular therapy,” is an alternative medicine practice that advocates claim improves general health and well-being.  

FDA’s Warning Letters (see e.g., here) state that the products are unapproved medical devices and requests that the companies cease marketing and distributing their products:

Specifically, the ear candle is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g)of the Act, 21 U.S.C. 360j(g).  Your device is also misbranded under section 502(o) of the Act, 21 U.S.C. 352(o), because you did not notify the agency of your intent to introduce the device into commercial distribution for the intended uses discussed above, as required by section 510(k) of the Act, 21 U.S.C. 360(k).

This is not the first time FDA has taken enforcement action against companies marketing ear candles.  FDA issued similar Warning Letters in 1998 – here and here.

The ear candle advocates (they refer to the products as “Holistic Candles”) allege in their complaint that “Holistic Candle is a generic product that is exempt from defendant FDA’s regulation requirements.”  According to the Plaintiffs:

Holistic Candles are not medical devices.  Properly made Holistic Candles are a natural holistic modality are used for and intended to be used for relaxation, comfort, reduction of stress and for the natural furtherance of the well-being of the user.  The relaxation process, from the viewpoint of any alternative health modality, is for the fostering of and the support for the human body’s own propensity to spontaneously seek natural homeostasis, via relaxed and stress-reducing circumstances, catalysts, or environments.

Such traditional and intended use, usually in a family or private association context does not “treat or cure” any condition of illness, and does not specifically affect any body function.  Alternative modalities simply allow the body to do what the human body does naturally, and that is to find a proper and necessary balance between the integrated components of the mind-body-spirit. This, in essence, is what homeostasis is.

The ear candle advocates seek “that proper Disclosure and Disclaimers be given with regard to Holistic Candles, to save them from being considered Medical Devices,” and contend that Holistic Candles are not medical devices, or if they are, that “they are exempt from registration as Class I Devices,” and if “Holistic Candles are not exempt Class I Devices,” then they are grandfathered “as having been in use prior to 1974.”  (The reference to 1974 should be 1976.  Under the FDC Act, certain devices that were legally marketed prior to the May 28, 1976 enactment of the Medical Device Amendments, and which have not been significantly changed or modified since that time – so-called “preamendment” or “grandfathered” devices – do not require submission of a premarket approval application (“PMA”) (or a 510(k) premarket notification) until after FDA issues a final rule requiring a PMA for that device.)  

By Susan J. Matthees –

By letter of March 26, 2010, FDA denied a 2003 Citizen Petition from CTFA (now PCPC) and The Soap and Detergent Association which had requested FDA to include antiviral indications, labeling, and test methods in the Tentative Final Monograph ("TFM") for OTC Healthcare Antiseptic Drug Products (59 Fed. Reg. 31,402).  The industry had long chafed under FDA’s restriction of OTC topical antimicrobials only to antibacterial use. 

In denying the Citizen Petition, more than 7 years later, FDA concluded that: (1) the data submitted did not “clearly demonstrate” antiviral effectiveness; (2) the proposal to use surrogate viruses to test antiviral effectiveness was unacceptable because of the variability of viruses in their susceptibility to antiseptics; (3) the proposed effectiveness criterion of a 2-log10 reduction was unsupported; (4) the proposed ASTM test methods were inadequate; (5) the proposed antiviral labeling is unsupported by evidence of effectiveness, and may be misleading; and (6) some of the active ingredients are not eligible for inclusion in the OTC healthcare antiseptics review because they did not include antiviral claims in their pre-1972 labeling.

Despite the agency’s across-the-board rejection of the Citizen Petition, the letter asserts:  “we believe that the availability of products with demonstrated antiviral activity would be of benefit to healthcare professionals, consumers, and foodhandlers, and we encourage you to submit additional data on this issue.”  At present, however, the agency does not intend to add antiviral claims to the OTC healthcare antiseptic TFM. 

But in an apparently contradictory statement, FDA was “able to document the pre-1972 marketing of healthcare personnel hand-washes containing benzalkonium chloride, providone-iodine, and triclosan for an antiviral indication.”  Therefore, these products may be eligible for consideration of antiviral claims in the OTC healthcare antiseptic review.  Moreover, these products could be marketed now with antiviral claims while the review is pending, pursuant to FDA’s enforcement policies.  See Compliance Policy Guide (CPG) 7132b.15, CPG Manual 450.200; see also 21 C.F.R. § 330.13.  The agency may have created at least a short-lived marketing opportunity for some products.  

By Jennifer B. Davis –

(1) Regenerative Sciences, Inc. v. FDA.  On March 26, 2010, Chief Judge Wiley Y. Daniel of the United States District Court for the District of Colorado dismissed on “ripeness” grounds a February 22, 2009 action brought by Colorado-based Regenerative Sciences, Inc. (“RSI”).  The lawsuit  – filed after RSI’s receipt and response to an FDA Untitled Letter, and in the midst of a subsequent FDA inspection of its laboratory – sought declaratory and injective relief from FDA jurisdiction and regulation under the Federal Food, Drug, and Cosmetic Act (“FDC Act”), Public Health Service Act (“PHS Act”), and the 21 C.F.R. Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products regulations (“HCT/P regulations”) of RSI’s autologous, mesenchymal stem cell (“MSC”) Regenexx™ Procedure for treatment of musculoskeletal and spinal injuries.  To our knowledge, the case represents the first attempt to challenge in federal court the FDA’s claimed legal authority for portions of the HCT/P regulations.  The decision is also notable for its precedent-confirming pronouncement that FDA Warning Letters are not “final agency action.”

In the Regenexx™ Procedure, MSCs isolated from a patient’s bone marrow undergo a 1-2 week expansion in the laboratory using natural growth factors from the same patient’s blood.  The expanded MSCs are then returned to the patient at a site of injury with the goal of regenerating bone and cartilage to repair the degenerated area. 

FDA’s July 25, 2008 letter to RSI advised that based on the review of RSI’s website, the agency determined RSI was promoting “use of [MSCs] under conditions that cause these cells to be ‘drugs’ under section 201(g) of the [FDC Act] (21 U.S.C. §321(g)), and biological products, as defined in section 351(i) of the [PHS Act] (42 U.S.C. §262).”  FDA further asserted that the Regenexx MSCs were HCT/Ps as defined by section 1271.3(d) of the HCT/P regulations, but, that they did not satisfy all of the section 1271.10 criteria establishing when a cellular HCT/P is not subject to the requirements for an approved biologics license application (“BLA”) or investigational new drug application (“IND”).  FDA’s letter advised the company that “implantation of the mesenchymal stem cells for which a valid license or IND is not in effect appears to violate the [FDC] Act and the PHS Act and may result in FDA seeking relief as provided by law.”

RSI argued in response that its MSCs were not “drugs” or “biological products,” and that they should not be regulated by the agency.  Six months later, FDA initiated an inspection of RSI’s facilities under its authority in the FDC and PHS Acts.  RSI then filed its lawsuit claiming that: (1) the Regenexx Procedure constitutes the practice of medicine and is beyond the scope of FDA’s regulatory authority and jurisdiction under the FDC And PHS Acts; (2) FDA’s decision that the manipulation of MSCs renders the cells a “drug” and a “biological product” requiring an IND or BLA was arbitrary and capricious; and (3) FDA’s regulatory definition of “HCT/P,” which fails to distinguish between allogenic or autologous transfers to a “human recipient,” was ultra vires FDA’s authority because Congress did not intend to give FDA authority over the autologous, “practice of medicine” use of HCT/Ps.

Judge Daniel found that RSI’s claim challenging the validity of FDA’s HCT/P regulatory definition was a “purely legal” question “fit” for judicial review, but nevertheless concluded that the claim was not ripe because RSI “ha[d] not shown any specific concrete action taken by the FDA that has harmed it or any specific losses it has suffered as a result of FDA action.”  Adhering to prior precedent, Judge Daniel explained that “the July 25, 2008, FDA warning letter is not a ‘final agency action’ as defined under the APA,” but “a ‘tentative or interlocutory action.’”

Addressing RSI’s other claims – that the Regenexx Procedure constitutes the Practice of Medicine, over which FDA has no authority under the FDC Act or PHS Act, and that FDA’s decision that the MSCs were “drugs” or “biological products” requiring an investigational new drug application (“IND”) or biologics license application (“BLA”) was arbitrary and capricious – Judge Daniel concluded that they, too, were not ripe because such claims would “require a factual inquiry into whether FDA can regulate autologous use of [HCT/Ps] and their functions” and  “do not involve a final FDA action interpreting and applying Part 1271 ‘to a specific set of circumstances as required for the action to be ripe and fit for review.’”   Further explaining his decision, Judge Daniel wrote:

[RSI] asks this Court to find, as a matter of law, that Congress intended to foreclose the possibility that FDA would regulate any autologous use of HCT/Ps – regardless of the type of HCT/Ps, the intended use of the HCT/Ps, the degree to and circumstances under which the HCT/Ps are manipulated prior to implantation, and regardless of how these factors may contribute to the transmission of diseases. . . .  [S]uch a task would be unduly complex and speculative.  The Court would have to assess the likelihood of the transmission of a wide range of diseases, under diverse methods for processing numerous types of HCT/Ps with various autologous uses, to determine at this stage whether FDA’s regulation defining HCT/Ps . . . is “ultra vires” in all possible circumstances.  Only a final FDA action interpreting and applying Part 1271 (including its exceptions) to a specific set of circumstances would reduce this amorphous inquiry to a controversy of ‘more manageable proportions.’

In promulgating the Part 1271 HCT/P regulations, FDA has consistently claimed that its authority comes from section 361 of the PHS Act (42 U.S.C. §264), which allows the agency to make and enforce regulations necessary to prevent the introduction, transmission, or spread of communicable diseases.  As RSI contended in its lawsuit, however, and as other stakeholders have argued in comments on various HCT/P rulemakings and guidance documents, it is not clear that all of FDA’s promulgated HCT/P requirements are actually (or reasonably) related to the prevention, introduction, transmission or spread of communicable disease, or whether – especially in cases of autologous use –  FDA’s HCT/P requirements impermissibly infringe on the congressionally recognized “practice of medicine.”

(2) Independent Turtle Farmers of Louisiana, Inc. v. FDA.  In a coincidental twist of timing, three days after Judge Daniel dismissed the RSI lawsuit, on March 29, 2010, Judge Dee D. Drell of the United States District Court for the Western District of Louisiana, Alexandria Division, ruled in favor of the agency in another case challenging FDA’s authority under section 361 of the PHS Act – to continue its enforcement of a thirty-five-year-old ban on pet turtles.

In 1975, FDA issued a regulation banning the sale of turtles and turtle eggs (21 C.F.R. §1240.62) based on studies showing that fourteen percent of all Salmonella-induced illnesses were “turtle-related.”  (FDA’s determination of its jurisdiction to issue the ban was challenged and upheld in State of La. v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).)  In promulgating the regulation, FDA said it would consider lifting or changing the restrictions based on “future evidence . . . demonstrat[ing] that Salmonella-  . . . free turtles can be produced and that sufficient safeguards exist to prevent a public health hazard through recontamination of turtles after shipment.”  40 Fed. Reg. at 2544.  In 2006, citing improvements in turtle rearing technology, and other scientific Salmonella-reducing advancements such as liquid antibacterial soap, the Independent Turtle Farmers of Louisiana, Inc. (“ITFL”) petitioned FDA to lift the ban. 

FDA denied the ITFL’s request, concluding that its petition “[did] not demonstrate that Salmonella-free turtles can be consistently produced and that, if Salmonella-free turtles are produced, they will not be recontaminated with Salmonella after shipment.”  The agency also rejected the ITFL’s argument that the ban was unfair in light of FDA’s less stringent guidelines for control of Salmonella in food sources.  The ITFL sued the agency in May 2007 claiming, in part, that the turtle ban exceeded FDA’s authority under section 361 of the PHS Act.

Upholding FDA’s decision to retain the turtle ban, Judge Drell concluded that “FDA’s interpretation of [§361] is entitled to wide deference” and that section 361’s enumeration of the actions that could be taken by the agency (i.e., “inspection, fumigation, disinfection, sanitation, pest extermination, destruction of animals or articles found to be so infected or contaminated”) “does not act as a limitation upon the types of regulations that may be enacted under Section 361.”  Moreover, observed Judge Drell, “the Court is obligated to defer to an agency’s interpretation of its own regulations” and “[j]udging from the evidence presently before the Court, and under the FDA’s interpretation of the Turtle ban, the FDA’s decision to deny the ITFL’s petition was not arbitrary or capricious.” 

Despite their coincidental timing, and although both decisions involved challenges to the scope of FDA’s authority under section 361 of the PHS Act, the merits of these two cases have little to do with one another.  We would not expect the outcome of the ITFL case, which implicates the core concern of § 361 to prevent disease transmission, to have any relevant impact on the merits of the RSI case, which questions the extent of FDA's § 361 authority when a regulation’s relationship to preventing disease transmission is more tenuous, and whether the regulation of autologous stem cells infringes the practice of medicine.

By Kurt R. Karst –   

Since 2008, FDA’s annual guidance document agendas (here, here, and here) have noted FDA’s plans to issue guidance on the Agency’s so-called Pre-Launch Activities Importation Request (“PLAIR”) program.  Although FDA officials have discussed PLAIRs in presentations, the Agency has not yet provided any formal guidance, and the PLAIR program remains largely shrouded in mystery.  Despite the lack of guidance to industry, FDA has been implementing its PLAIR program and simultaneously refining its policies.  As such, we think it’s high time to pull back the shroud and demystify FDA’s PLAIR program.

FDC Act § 505(a) prohibits the introduction or delivery for introduction into interstate commerce of a new drug “unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.”  While there are several regulations that permit the transport of unfinished bulk product for further manufacture in anticipation of marketing (see e.g., 21 C.F.R. § 314.410(a)(2) and § 201.122(c)), there is no regulation excepting the domestic transport of finished product in anticipation of marketing approval.  Instead, FDA has historically exercised enforcement discretion to permit these shipments, and has traditionally cited to its authority under FDC Act § 309 as the legal basis for its use of enforcement discretion when the belief is that the public health is best served. 

FDA developed the PLAIR program with an eye towards the increasing globalization of the drug industry, and presumably as a means to both formalize the Agency’s historical use of enforcement discretion and to extend to finished products manufactured overseas the same courtesy FDA extends to unfinished bulk product.  FDA’s PLAIR program allows, on a case-by-case basis, the importation and warehousing of finished drugs where an application for drug approval (i.e., an NDA or ANDA) is pending and where the import and warehousing will expedite the commercial launch of the drug once FDA approves an application.  Specifically, FDA’s Center for Drug Evaluation and Research (“CDER”) and the Division of Import Operations and Policy (“DIOP”) exercise enforcement discretion to permit certain interstate shipments of unapproved products in finished dosage form by the domestic drug industry to prepare these products for market launch in anticipation of approval.  Such shipments are allowed under certain controls and restrictions.  For example, the drug products may only be shipped to facilities identified in a pending NDA or ANDA or to facilities owned and controlled by the applicant.

When pressed, FDA has provided informal guidance on PLAIRs.  In the interest of transparency, that guidance is provided below:

Please provide us with the following information on an electronic compatible file by email. If you have more than one application, please submit these separately.

a. Drug product name (trade and established) and complete product description (color, shape, etc);

b. Name of CDER Project Manager assigned to pending application;

c. Finished bulk drug NDC #, if assigned;

d. Name & address of foreign manufacturer (includes building # and street name) of finished drug product;

e. Name & address of U.S. consignee;

f. Pending application number (and supplement number, if appropriate) and date applicant expects its approval;

g. The name and address of the warehouse or distribution warehouse controlled by or under contract by the applicant where finished dosage form product in final packaged form will be stored pending approval;

h. When finished dosage form drug product in bulk is imported for further processing, the name and address of the facility where further processing activities will occur;

Include description of further processing activities;

If processed product will be transferred, provide information on the location where the product will be stored until the application is approved and effective; and,

i. Letter signed by senior management stating that neither they nor their consignee or distributor in the U.S. will sell, offer for sale, or distribute in domestic commerce this drug product until FDA approval is effective.

After receipt of this information, we will decide on a case-by-case basis, whether to exercise enforcement discretion to permit entry of the unapproved, finished dosage form drugs and notify you if the importation request is acceptable (normally within two weeks or less).  Please that the firm must register and the drugs must be listed once the application is approved.  Although drug listing is not required until the drug product is ready for commercial distribution, it is recommended to list your drug product electronically as this will expedite the listing process once the application is approved.  If changes need to be made, the information can later be updated.  We will also provide an email confirmation to the Division of Import Operations and Policy (DIOP) in the Office of Regulatory Affairs (ORA) that the importation request is acceptable.  You should then provide to DIOP (contacts: Steven Branch and Stella Notzon) the Customs Entry number in advance (at least one month before the expected arrival) your company is importing under the PLAIR enforcement discretion letter.  Also, please note that one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching.  Keep in mind that the amount of product imported into the US must match with what you stated in the PLAIR.  Otherwise, an amended PLAIR must be submitted to CDER-OC-PLAIR@fda.hhs.gov for approval.  You can make the changes on the existing PLAIR request, however, identify your request as an “amendment.”

FDA is reportedly still working through some of the kinks in the implementation of its PLAIR program, and policy changes are expected as the Agency gains greater experience with PLAIRs.  Our experience with FDA’s current PLAIR program, however, has revealed one problem in particular that should be fixed.

The informal PLAIR guidance provided by FDA notes that “one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching.”  Thus, regardless of the amount of drug product FDA authorizes under a PLAIR, if a company’s carrier is unable to ship that full amount because of space limitations and the shipment must be broken up into multiple shipments, we understand that the Agency’s current policy is not to allow a second shipment, absent a public health issue or a shortage.  A similar problem could arise if, for example, there are changed circumstances, such as a decision from FDA concerning 180-day exclusivity eligibility.  If a company has already used up its PLAIR and circumstances change such that additional product will be needed in anticipation of approval, we understand that FDA does not currently allow a company to amend its PLAIR or to obtain a second PLAIR to account for the changed circumstance. 

These limitations to FDA’s current PLAIR program are likely related the Agency’s funding and personnel limitations and concern about losing control of product imported into the U.S.  Hopefully, with time and experience, FDA will be better able to address them, if not universally, then on a case-by-case basis.  (For example, perhaps FDA can integrate an initial PLAIR approval into the Agency’s new PREDICT system for imports, thereby allowing for automated approvals of subsequent shipments.)

By Ricardo Carvajal –

The Office of Inspector General ("OIG") of the U.S. Department of Health and Human Services released a report that finds fault with FDA’s inspection activities for food facilities and recommends several changes, including an expansion of FDA’s statutory authority.  OIG reviewed FDA's food facility inspection activities between FY 2004 and FY 2008.  Among OIG’s findings:

• “On average, FDA inspected less than 25% of food facilities each year, and the total number of inspected facilities declined over time.”
• “56% of food facilities went 5 or more years without an FDA inspection.”
• In FY 2007, “FDA took regulatory action against 46 percent of the facilities with initial OAI classifications [an OAI or 'Official Action Indicated' classification means that objectionable conditions were found that might warrant regulatory action]; for the remainder, FDA either lowered the classification or took no regulatory action.”
• “For 36 % of the facilities with OAI classifications in FY 2007, FDA took no additional steps to ensure that the violations were corrected. For the remaining facilities, FDA took additional steps to ensure that the violations had been corrected. Specifically, FDA reinspected 35 percent of the facilities within a year of the initial inspection. For an additional 30 percent of facilities, FDA reported that it reviewed some type of evidence from the facility that demonstrated that the facility had corrected violations.”

For FY 2008, OIG also found that most of the facilities that received OAI classification had “a history of violations.”  Further, 2% of the facilities that received OAI classification refused FDA requests for access to records. 

Based on these findings, OIG recommended that FDA:

• “Increase the frequency of food facility inspections, with particular emphasis on high-risk facilities.”
• “Provide additional guidance about when it is appropriate to lower OAI classifications.”
• “Take appropriate actions against facilities with OAI classifications, particularly those that have histories of violations.”
• “Ensure that violations are corrected for all facilities that receive OAI classifications.”
• “Consider seeking statutory authority to impose civil penalties through administrative proceedings against facilities that do not voluntarily comply with statutory and regulatory requirements.”
• “Seek statutory authority to allow FDA access to facilities’ records during the inspection process.”

In its response, FDA noted that food safety legislation pending in Congress and supported by FDA would expand civil penalties for food-related violations and would expand FDA’s authority to access records, among other things.  As for its inspection activities, FDA has added nearly 700 field staff to its Foods Program since 2007, and the agency expects a corresponding increase in the number of food inspections; however, FDA noted that calls for increased inspections need to be backed by “a reliable, consistent funding source.”  FDA is also taking additional measures to enhance its inspections, most notably by conducting “intensive environmental sampling” intended to detect “unsuitable manufacturing conditions.” 

With respect to following up on findings of violation, FDA restated its commitment to the enforcement strategies outlined by Commissioner Hamburg in August 2009, including (1) establishing a timeframe for firms to submit responses to FDA findings, (2) streamlining Office of Chief Counsel review of warning and untitled letters, (3) prioritizing follow-up activities on warning letters and recalls with significant health implications, and (4) taking “swift, aggressive and immediate enforcement action in cases where significant health concerns or egregious violations are identified.”

By Susan J. Matthees –

FDA's Center for Veterinary Medicine ("CVM") recently announced an advanced notice of proposed rulemaking (“ANPRM”) to solicit comments on possible changes to the current regulation for veterinary feed directive (“VFD”) drugs.
 
The VFD drug category was established in 1996 as part of the Animal Drug Availability Act (“ADAA”).  A VFD drug is defined as “new animal drug approved under” FDC Act § 512(b) or “listed in the index under section 572 of the act for use in or on animal feed.”  21 C.F.R. § 558.3(b)(6).   In 2000, CVM issued final regulations implementing the VFD drug provisions of the ADAA.  VFD drugs must be used under the professional supervision of a licensed veterinarian. 

Congress intended the VFD drug category to help make more drugs available for animals, but over the past 9 years CVM “has received a number of informal general comments that characterize the current VFD process as being overly burdensome.”  CVM also expressed concern that the program would “become particularly problematic to administer in the future as the number of approved VFD animal drugs increases.”  With these concerns in mind, CVM seeks comments on whether, and if so, how, to improve current regulations and promote efficiency.  CVM asks submitters to organize their comments into 7 distinct categories:

• Conditions that must be met by veterinarians issuing a VFD;
• What veterinarians must do with a VFD (e.g., disposition of original VFD and copies);
• Records that must be kept related to the VFDs;
• Notification requirements for distributors of animal feeds containing a VFD drug;
• Additional recordkeeping requirements that apply too distributors;
• Cautionary statements required for VFD drugs and animal feeds containing VFD drugs; and
• Other.

Comments are due by June 28, 2010.