In mid-April, GlaxoSmithKline Consumer Healthcare (“GSK”) and a trio of research and advocacy organizations submitted a citizen petition to FDA that asks the Agency to prohibit structure/function claims for dietary supplements that expressly or impliedly reference weight loss. In addition to claims that expressly reference weight loss, the petition contends that the following categories of claims should be prohibited: energy expenditure, modulation of carbohydrate metabolism, increased satiety or suppression of appetite, increased fat oxidation or reduced fat synthesis, and blockage of fat absorption.  The petition acknowledges FDA’s longstanding position that weight loss claims are permissible structure/function claims.  However, the petition urges FDA to change its position on the ground that: (1) recent evidence establishes that overweight is a risk factor for disease; (2) consumers believe that there is a relationship between weight loss and a reduction of risk of disease; (3) claims that a product will reduce a risk factor for disease are disease claims; (4) the use of ineffective therapies can divert consumers from safe and effective therapies such as GSK’s weight loss drug AlliÒ; and (5) manufacturers of weight loss supplements should be forced to substantiate their claims through health claim petitions before going to market. Although the petition targets dietary supplements, the action it requests also would affect conventional foods.

The potential marketing value of the weight loss market and the food and dietary supplement industries’ major investment in weight loss products ensures that the petition will receive strong drug industry supported and vigorous food and dietary supplement industry opposition.  Although the petition contends that the requested action will not require rulemaking, there are arguments that would support the need for rulemaking given FDA’s longstanding position that weight loss claims, as opposed to claims to treat obesity, do not imply disease treatment or prevention.

By Ricardo Carvajal

On April 17, 2008, U.S. Representatives Steve Buyer (R-IN) and Jim Matheson (D-UT) introduced H.R. 5839, the “Safeguarding America’s Pharmaceuticals Act,” which would substantially expand federal drug pedigree requirements.  Among other things, the legislation would authorize destruction of counterfeit drugs at ports-of-entry, revise federal drug pedigree standards and preempt State requirements, require standardized numerical identifiers on each package, require an electronic identification and tracking system to follow drugs through the supply chain, provide grants for community pharmacies to assist them in acquiring hardware and software to comply with the new tracking system, and provide enforcement incentives for States.

If enacted, H.R. 5839 would require pedigrees, in either electronic or paper form, on all prescription drugs sold in the U.S. within 6 months. Longer term, the legislation will require that  manufacturers, distributors and pharmacies put in place systems to electronically track and trace individual prescription drugs through the supply chain.

The bill calls for a risk-based approach to application of unique standardized numerical identifiers for prescription drugs.  Under the FDA Amendments Act § 913, which created FDC Act § 505D(b)(2), FDA must develop a “standardized numerical identifier” that is to be applied to a prescription drug “at the point of manufacturing and repackaging . . . at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug.” H.R. 5839 would require that FDA develop, not later than March 27, 2010, a list of drugs at high risk for counterfeiting and diversion.  Within 18 months later, manufacturers of these high-risk drugs would be required to place standardized numerical identifiers on their products.  Manufacturers of other drugs would be required to comply according to a timetable to be established by regulation. 

The regulations are to include a process by which a manufacturer or repackager may request an exemption from the standardized numerical identifier requirement, but only if it can demonstrate that:  “the requirement would adversely affect the safety, effectiveness, purity, or potency of the drug product or would not be technologically feasible”; and “the concerns underlying the request [for exemption] could not reasonably be addressed by measures such as package redesign . . .”

The bill also calls for the development through rulemaking of an electronic drug identification and tracking system through which drug manufacturers, re-packagers, wholesale distributors, and dispensers will be able to authenticate the wholesale distribution history of any drug by authenticating its standardized numerical identifier against an interpretable electronic database.  Regulations proposing such a system are to be published by March 31, 2010, with final regulations issued not later than one year after the date of the proposed regulations.  The regulation must take into account the technical feasibility of compliance by manufacturers, repackagers, wholesale distributors, and dispensers, for different types of drugs.  Once effective, the rules would preempt any inconsistent state requirements.  (So far, the only state to enact an electronic pedigree requirement is California.  The requirement will take effect on January 1, 2011.)

The federal bill provides for grants to pharmacies to facilitate the purchase and use of a drug identification and tracking system.  To be eligible for such grants, the pharmacy must apply to the Secretary of Health and Human Services and agree to match funds.  The bill also provides for reports to Congress for delays in issuing proposed or final regulations; civil penalties for violations; and incentives for State enforcement of federal requirements.    

The Healthcare Distribution Management Association, a national association of healthcare distributors, supports the bipartisan legislation.

By Anne Marie Murphy

As we previously reported (see post here and article here), FDA has been seeking stiffer sentences under the U.S. Sentencing Guidelines for at least the past five years.  For the preceding four years, the FDA’s pleas seemed to fall on deaf ears, but in this past year the Commission included FDC Act offenses in its priorities, held a public hearing, and received public comments with regard to some amendments the FDA asked the Commission to consider.  At the end of the process, FDA got some, but certainly not all or even most, of what it was seeking.

In the amendments to the Guidelines forwarded by the Commission to Congress on May 1, 2008, the Commission made two changes to the applicable Guideline, § 2N2.1.  First, the base offense level for a second FDC Act offense would be ten (10) , up from the current base offense level of six (6).  Under the Guidelines, a base offense level and various other factors determine the sentence imposed.  Under the FDC Act, first offense regulatory (non-fraud) offenses are misdemeanors with a maximum jail sentence of one (1) year.  In contrast, second offenses are felonies with a three (3) year maximum jail sentence.  The proposed amendment reflects this difference in the FDC Act in the Guidelines. 

Second, the proposed amendment expands the scope of conduct that the Guidelines suggest may warrant an upward departure.  Under the Guidelines, there are certain instances in which the Guidelines indicate to the sentencing court that it may be appropriate to depart upwards or downwards from the sentence otherwise calculated by the Guidelines.  To date, the Guideline applicable to FDC Act non-fraud offenses has limited consideration of such an upward departure based upon death or injury to cases in which death or bodily injury actually resulted.  In the proposed amendment, a sentencing court would be instructed to consider an upward departure in any case in which the offense created a “substantial risk of bodily injury or death” (emphasis added).  Unlike an actual death or bodily injury, which either did or did not occur, the proposed amendment would support an upward departure in any case in which the government could convince the sentencing judge that the offense created a “substantial risk” of such harm.  Based on the government’s historical position in FDC Act regulatory offense cases, one can reasonably assume that the government will routinely invoke the “substantial risk” upward departure.

The Commission declined to adopt the following FDA recommendations:

1.  to amend the Guidelines to explicitly cover human growth hormone (hGH) offenses;

2.  to amend the Guidelines to increase the sentences for Prescription Drug Marketing Act offenses; 

3.  to amend the Guidelines so that the value of any FDC Act regulated product (drug, device, food) would be zero if that product were deemed adulterated or misbranded under the FDC Act.

Absent congressional action, these proposed amendments will become effective on November 1, 2008.

By John R. Fleder, Douglas B. Farquhar, and J.P. Ellison

On May 7, 2008, the U.S. Court of Appeals for the Federal Circuit is scheduled to hear oral argument in Lupin Ltd. v. Abbott Labs.  This is a patent infringement action concerning U.S. Patent #4,935,507 (“the ‘507 patent”) with respect to Abbott’s antibiotic drug product OMNICEF (cefdinir) Oral Suspension, approved under New Drug Application (“NDA”) #50-749, and Lupin’s Abbreviated NDA (“ANDA”) for a generic version of the drug product.  The case is on appeal from the U.S. District Court for the Eastern District of Virginia, which in June 2007 granted Lupin’s motion for summary judgment with respect to certain ‘507 patent claims. The case is interesting not because of the particular drug product at issue, but rather because of the effects a decision in favor of Abbott could have on the U.S. Patent and Trademark Office’s (“PTO’s”) policy of permitting multiple patent term extensions. 

Under 35 U.S.C. § 156, certain patents covering products regulated by FDA are eligible for a Patent Term Extension (“PTE”) if patent life was lost during a period when the product was undergoing regulatory review. The “regulatory review period” is composed of a “testing phase” and a “review phase.”  For drugs approved under the FDC Act, the “testing phase” begins on the effective date of an Investigational New Drug Application (“IND”), and ends on the date an NDA is submitted to FDA.  The “review phase” is the period between the submission and approval of the NDA.  A patent term may be extended for a period of time that is the sum of one-half of the time in the “testing phase,” plus all the time in the “review phase” (minus any of the “regulatory review period” that occurs prior to the patent grant).   The “regulatory review period” must be reduced by any time that the applicant “did not act with due diligence.”  The total (calculated) regulatory review period may not exceed 5 years, and the extended patent term may not exceed 14 years after the date of approval of the marketing application.  The PTE statute also states (at 35 U.S.C. § 156(c)(4)) that “in no event shall more than one patent be extended . . . for the same regulatory review period for any product.” 

PTO interprets 35 U.S.C. § 156(c)(4) to permit multiple PTEs under certain circumstances.  Specifically, for a drug product covered by several patents PTO may extend a different patent for each NDA approved on the same first day (even when multiple NDAs share common “testing phase” and a “review phase” dates). That is, PTO considers each NDA “regulatory review period” to be distinct and for which a PTE is available.  Of course, the difficulty in such cases is to obtain FDA approval for each NDA on the same first day, because the PTE statute states under 35 U.S.C. § 156(a)(5) that for the PTO to extend the term of a patent claiming a drug (or a use of the drug or a method of manufacturing a drug) from the original expiration date of the patent, the NDA must be for the first permitted commercial use of the drug. 

The difficulty of obtaining FDA approval for multiple NDAs for the same drug on the same first day making a company eligible for multiple PTEs is borne out in the dearth of such precedents.  Indeed, we are aware of only 3 such cases.  This post concerns two of those cases.  One case involves OMNICEF (the subject of the patent infringement litigation noted above), and the other case concerns MYCAMINE (micafungin sodium).

On December 4, 1997, FDA approved two NDAs for OMNICEF: NDA #50-739 for OMNICEF Tablets, and NDA #50-749 for OMNICEF Oral Suspension.  Abbott applied for and was granted two PTEs based on these approvals – one for U.S. Patent #4,559,334 with respect to NDA #50-739, and one for the ‘507 patent with respect to NDA #50-749.  The PTO’s decision to grant a PTE for the ‘507 patent extended the term of the patent by 1,213 days until December 4, 2011. The ‘507 patent was originally scheduled to expire on August 8, 2008.

On March 16, 2005, FDA approved two NDAs for Astellas’s MYCAMINE: NDA #21-506 for MYCAMINE for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation, and NDA #21-754 for MYCAMINE for the treatment of esophageal candidiasis.  Astellas (which licensed the product from Abbott) applied for two PTEs based on these approvals – one for either U.S. Patent #5,376,634 (“the ‘634 patent”), #6,265,536 (“the ‘536 patent”), or #6,107,458 (“the ‘458 patent”) for NDA #21-506, and one for either of these same patents for NDA #21-754.  In December 2007, the PTO issued final determinations on the PTE applications, which state that “two patents are eligible for extension based on the regulatory review periods for Mycamine (micafungin sodium) in NDA 21-506 and 21-754.”  In January 2008, Astellas received a PTE for the ‘458 patent with respect to NDA #21-506.  Although Astellas was also eligible for a PTE with respect to NDA #21-754 for either the ‘634 patent or the ‘536 patent, the company decided not to elect a PTE for the second NDA and withdrew its PTE applications for these patents. 

So why would a company turn down a PTE?  We think such a decision might be related to the ongoing litigation in Lupin Ltd. v. Abbott Labs. concerning OMNICEF.

In October 2006, Lupin filed a complaint against Abbott in the U.S. District Court for the Eastern District of Virginia alleging that the ‘507 patent is invalid or not infringed by the company’s generic OMNICEF drug product.  Count III of Lupin’s First Amended Complaint for Declaratory Judgment seeks a declaratory judgment of invalidity of the PTE for the ‘507 patent.  Lupin argues that “[t]he issuance of two PTEs for regulatory review periods involving cefdinir as the active ingredient was not authorized under 35 U.S.C. § 156,” and requests that the court declare the ‘507 patent PTE invalid. 

In early June 2007, Abbott and Lupin entered into an agreement concerning the ‘507 patent after the district court ruled in Lupin’s favor with respect to certain ‘507 patent claims.  As part of a Stipulated Order of Dismissal, which incorporates the terms of the Abbott/Lupin agreement, Count III of Lupin’s First Amended Complaint for Declaratory Judgment concerning the PTE for the ‘507 patent was dismissed without prejudice.  However, the Stipulated Order of Dismissal also states that Lupin “may re-assert Count III in accordance with the parties’ Agreement in the event that the Final Judgment based on the Court’s May 21, 2007 Order on claims 2-5 or on claim 1 with regard to the doctrine of equivalents is not affirmed, and is remanded, on appeal.”  On June 14, 2007, the court granted Lupin’s motion for summary judgment with respect to the literal infringement of claims 2-5 of the ‘507 patent.  Abbott appealed the case to the U.S. Court of Appeals for the Federal Circuit where it is pending. 

If Abbott prevails in the Federal Circuit, then Lupin might once again challenge the validity of the PTE for the ‘507 patent.  It seems reasonable to conclude that in order to avoid a future decision that could invalidate the PTO’s multiple PTE policy, Astellas and Abbott decided on a conservative approach with respect to MYCAMINE.  That is, the companies apparently adopted the “a bird in the hand is worth two in the bush” approach and decided to take only one PTE instead of the two that were available.

By Kurt R. Karst    

Medicure Pharma submitted a citizen petition to FDA that asserts that all dietary supplements containing pyridoxal 5’-phosphate (“P5P supplements”) are adulterated under FDC Act § 402(f). The petition asserts that P5P (a form of vitamin B6) is a new dietary ingredient which has neither been present in the food supply as an article used for food in a form in which the food has not been chemically altered, nor has it been the subject of a new dietary ingredient notification. The petition further asserts that those supplements were therefore not lawfully marketed prior to the date on which the investigation of P5P as a drug triggered the dietary supplement exclusionary clause in FDC Act § 201(ff)(3)(B)(ii). The petition asks FDA to remove all P5P supplements from the market, or in the alternative, to initiate rulemaking under FDC Act § 201(ff)(3)(A) to exclude them from the statutory definition of a dietary supplement. Medicure Pharma is investigating a drug product under an Investigational New Drug Application that contains P5P as its active ingredient, and the company contends that marketing of P5P supplements undermines the company’s incentive to continue developing its drug product.

The success or failure of the petition will turn on a few issues. First, the petition contends that P5P is a new dietary ingredient because it was not marketed before October 15, 1994. This is certain to prompt a thorough search on the part of P5P supplement manufacturers for evidence of marketing prior to that date. Second, the petition contends that P5P has not been “present in the food supply as an article used for food” within the meaning of FDC Act § 413(a)(1) because the presence of P5P in foods is “incidental.” However, the Institute of Medicine recognizes that P5P is one of the major forms of vitamin B6 in animal tissues, and that animal tissues are a source of vitamin B6. Third, the petition contends that even extensive marketing of a dietary supplement does not forestall application of the dietary supplement exclusionary clause if the supplement was marketed unlawfully. Although the petition acknowledges that a plain reading of the exclusionary clause does not support this view, the petition asks FDA to read the term “lawfully” (as in “lawfully marketed”) into the exclusionary clause on the ground that not doing so would yield absurd results. Finally, the petition contends that, even if P5P is lawfully marketed as a dietary supplement, FDA can prohibit any further marketing under section 201(ff)(3)(A) to help preserve incentives for new drug development. In doing so, the petition fails to acknowledge that FDA’s rulemaking authority under FDC Act § 201(ff)(3)(A) is tied to a finding of adulteration under § 402(f), a finding that could be difficult to support in the case of a form of vitamin B6.

To view the petition and file comments, click here.

By Ricardo Carvajal and Diane B. McColl

Under Title II of the Hatch-Waxman Act, certain patents related to products regulated by FDA are eligible for extension by the U.S. Patent and Trademark Office (“PTO”) if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase.”  The Patent Term Extension (“PTE”) statute at 35 U.S.C. § 156 defines the testing and review phases depending on the type of product subject to regulatory review (e.g., a drug, a biological products, or a medical device). 

For a medical device subject to a Premarket Approval Application (“PMA”), the “testing phase” begins on “the date a clinical investigation on humans involving the device was begun and [ends] on the date [a PMA] was initially submitted with respect to the device.”  The “review phase” is the period between PMA submission and approval.  For a drug or a biological product, the “testing phase” begins on the effective date of an Investigational New Drug Application (“IND”), and ends on the date a New Drug Application (“NDA”) or a Biologic License Application (“BLA”) is initially submitted to FDA.  The “review phase” is the period between NDA/BLA submission and approval. 

Under certain circumstances a company may obtain an interim PTE prior to product approval.  There are two types of interim patent extensions available: (1) interim patent extensions available during the “review phase” (35 U.S.C. § 156(d)(5)); and (2) interim patent extensions available during PTO’s review of a PTE application (35 U.S.C. § 156(e)(2)).  Under 35 U.S.C. § 156(d)(5), the PTO may grant an interim patent extension while a PMA (or an NDA or a BLA) is undergoing FDA review if the patent owner (or his agent) “reasonably expects that the applicable regulatory review period . . . that began for a product that is the subject of such patent may extend beyond the expiration date of the patent term in effect. . . .” (emphasis added).   The patent owner (or his agent) must submit to PTO an application “during the period beginning 6 months, and ending 15 days, before such [patent] term is due to expire.”  If PTO determines that, except for receipt of FDA’s permission to market or use a product commercially, the patent would be eligible for a statutory extension of the patent term under 35 U.S.C. § 156, then PTO publishes a notice in the Federal Register announcing the interim patent extension for the particular product, and issues to the applicant a certificate of interim patent extension for a period of not more than one year.  The applicant may apply for additional interim patent extensions under 35 U.S.C. § 156(d)(5), however, PTO generally limits subsequent applications for a particular patent to four one-year interim patent extensions (thus, a total of five years). 

In early February 2008, Jarvik Heart, Inc. (“Jarvik”) requested an interim PTE for U.S. Patent #4,994,078 (“the ‘078 patent”) covering the company’s Jarvik 2000 Heart Assist System.  (A copy of the PTE application is available via PTO’s Patent Application Information Retrieval service.)  The request was made pursuant to 35 U.S.C. § 156(d)(5) on the basis that Jarvik submitted a PMA Shell to FDA in November 2007, and on January 14, 2008, after FDA acceptance of the PMA Shell, the company submitted Module 1 of the PMA to FDA.  (A PMA Shell is an outline of those PMA sections that will be necessary to complete a PMA, and includes all modules needed -submitted as PMA Modular Submissions- to support the filing and approval of a specific medical device.  Additional information on FDA’s modular approach to PMA submission and review is available here.)  Jarvik contended that the submission of the PMA Shell and Module 1 began the “review phase” period for PTE purposes.  The PTO disagreed and the ‘078 patent expired on February 19, 2008. 

In the PTO’s final decision denying Jarvik’s interim PTE request, the Office notes that one of the requirements under 35 U.S.C. § 156(d)(5) for an interim PTE is that the “review phase” for a medical device “which must have begun for a product would continue beyond the original expiration of the patent term” (emphasis in original).  “Neither the PMA Shell nor the Module 1 constitutes ‘an application . . . initially submitted with respect to the device under [FDC Act § 515].’  Therefore, the applicable regulatory review period . . . has not begun,” states the PTO in its decision letter.  The PTO also goes on to note that “the FDA does not consider the submission of a PMA shell or a first PMA module to trigger the beginning of the [‘review phase’],” and cites FDA’s previous decision with respect to a PTE request from Advanced Neuromodulation Systems for the company’s Genesis Neurostimulation System. 

FDA’s policy with respect to the initiation of the “review phase” for PTE purposes for medical devices subject to the PMA Shell/Module approach mirrors FDA policy for NDAs and BLAs submissions made pursuant to the Agency’s “Fast Track” approach under FDC Act § 506.  The Fast Track program was created in 1997 by the FDA Modernization Act to help facilitate the development and expedite the review of drugs and biologics for serious or life-threatening conditions that demonstrate a potential to address unmet medical needs.  Under FDC Act § 506, companies may request Fast Track designation for their product at the time they submit an IND to FDA or at any time thereafter.  The benefits of Fast Track designation include the option of submitting an NDA or a BLA for “rolling review” (i.e., submission in sections rather than all components simultaneously). 

Under current FDA guidance on Fast Track products, FDA’s review clock for the application “will not begin until the applicant informs the Agency that a complete BLA or NDA has been submitted.”  For PTE “review phase” determinations on Fast Track products, FDA has determined that the date a final reviewable unit is submitted to the Agency is the date the “review phase” begins.  FDA recently noted this policy in a Federal Register notice concerning a PTE request for the Fast Track-designated biological product KEPIVANCE (palifermin).

By Kurt R. Karst    

On April 11, 2008, we reported that Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia issued a 2-page order in Teva Pharmaceuticals USA, Inc. v. Leavitt siding with Teva over the reslisting of U.S. Patent #5,158,952 (“the ‘952 patent”) in the Orange Book covering Janssen Phaemaceutica’s RISPERDAL (risperidone) Tablets.  Teva sued FDA in March 2008 after the Agency denied a citizen petition Teva submitted to FDA in August 2007 requesting that the Agency relist the ‘952 patent in the Orange Book and confirm Teva’s eligibility for 180-day exclusivity. Judge Lamberth’s order declared that the delisting of the ‘952 patent was unlawful, ordered FDA to relist the patent in the Orange Book and restore Teva’s Paragraph IV patent certification, and enjoined FDA from approving any generic RISPERDAL Tablets ANDAs until Teva’s 180-day exclusivity expires. 

Absent the relisting of the ‘952 patent in the Orange Book and any 180-day exclusivity available to Teva, the only obstacle for generic applicants to obtain full approval of their ANDAs is U.S. Patent #4,804,663 (“the ‘663 patent”).  This patent expired in December 2007, but is covered by a period of pediatric exclusivity scheduled to expire on June 29, 2008.  Since the April 11, 2008 order, companies with a stake in the outcome of this litigation have been patiently waiting to learn whether FDA or Mylan Pharmaceuticals, Inc., which entered the case as an intervenor-defendant, would appeal the decision to the U.S. Court of Appeals for the District of Columbia Circuit.  At least one company does not want to wait any longer.

On April 22, 2008, Apotex, Inc. filed a motion to intervene in the case “to safeguard its substantial interests in the outcome of this litigation.”  According to Apotex’s motion, the company “expected to receive approval of its ANDA in time to launch its generic risperidone tablets by June 29, 2008 and to begin commercial marketing immediately.”  Apotex’s ANDA is not yet tentatively approved.  (Only Mylan and Pliva have tentative ANDA approvals.)  If Judge Lamberth grants Apotex’s motion, then the company “intends to file a notice of appeal and immediately pursue the appropriate appellate remedies to obtain a stay of the District Court’s ruling pending appeal, and/or review of the ruling on an emergency or expedited basis prior to the June 29, 2008 launch date.” 

So why has Apotex only now decided to attempt to intervene in the litigation?  According to the company’s motion, “Apotex’s grounds to intervene arose post-judgment, when it became apparent that neither the Federal Defendants nor Mylan would immediately appeal this Court’s decision, and that even if they appeal, may not prosecute the appeal timely so as to try to dissolve or stay the injunction prior to June 29, 2008” when the period of pediatric exclusivity applicable to the ‘663 patent expires.

Teva quickly filed its opposition to Apotex’s motion to intervene.  According to Teva’s filing, “Litigants who wait to intervene until an adverse judgment has been entered face an especially heavy burden – and Apotex has not come close [to] discharging that burden here . . . .  No court has ever granted a post-judgment motion to intervene on such a thin demonstration of need, and this Court should not wield its substantial discretion to become the first.”  Teva’s opposition also goes on to argue that any speculative risks to Apotex were well known at the outset of the case when Apotex decided not to intervene, and cites industry periodicals and “widely read blogs,” including FDA Law Blog.

By Kurt R. Karst 

Earlier this year, we reported on a provision in Title VIII of the FDA Amendments Act (“FDAAA”) requiring the responsible party of an “applicable clinical trial” (for both drugs and devices) to certify that the new requirements of Public Health Service Act (“PHS Act”) § 402(j) have been met.  Under PHS Act § 402(j), the responsible party of an “applicable clinical trial” must submit to the National Institutes of Health certain required information for inclusion in the clinical trial data bank at ClinicalTrials.gov.  Currently, only descriptive information about the trial design and enrollment is required to be registered at ClinicalTrials.gov, however certain results of those studies will also be required to be posted within the next few years.

New PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial” to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .”  An “applicable device clinical trial” is defined to mean “a prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the [FDC Act] against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and a pediatric postmarket surveillance as required under [FDC Act § 522].”  Pursuant to new PHS Act § 402(j)(5)(B), drug and device sponsors must include a certification with their regulatory submissions that they have complied with new PHS Act § 402(j).  In December 2007, FDA announced the availability of a new form (Form FDA 3674) to accompany certain applications to meet the certification requirement.

Since the new certification requirement went into effect in December 2007, there has been significant debate within the drug and device industries as to the applicability of PHS Act § 402(j) to certain submissions.  For example, with respect to drugs, it has been unclear whether a company submitting an Abbreviated New Drug Application (“ANDA”) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new PHS Act § 402(j) applies and that the studies have been registered at ClinicalTrials.gov.  That is, it has been unclear to some companies whether an in vivo bioequivalence study is an “applicable drug clinical trial” subject to the PHS Act § 402(j) databank registration requirements and whether a generic applicant must certify on Form FDA 3674 that the PHS Act § 402(j) requirements have been met.  Under FDC Act § 301(jj), as amended by FDAAA, the failure to submit a certification, knowingly submitting a false certification, failing to submit required clinical trial information to ClinicalTrials.gov, and submitting false or misleading information to ClinicalTrials.gov is a prohibited act subject to a new civil monetary penalties provision, as well as to other enforcement sanctions under the FDC Act.   

On April 18, 2008, FDA announced the availability of a draft guidance document providing the Agency’s current thinking regarding whether some types of information and documents submitted to FDA must be accompanied by Form FDA 3674.  The draft guidance document lists several submissions to FDA that typically do not require a Form FDA 3674, including CMC amendments and supplements, meeting requests, safety reports, promotional materials for review, and “ANDA amendments and supplements that contain no in vivo bioequivalence information,” leaving open the possibility that ANDA submissions that do contain in vivo bioequivalence determinations also need to have a Form FDA 3674.  FDA notes in the Federal Register notice accompanying the draft guidance document that “[w]hile we intend the draft guidance to assist submitters in determining whether to submit a certification based on the type of document being submitted to FDA, this guidance does not address, nor does it make a recommendation on, all possible information and documents that may be submitted to FDA. . . . We will continue to review the types of information and documents that a certification typically does not need to accompany.” 

Because of the limited nature of FDA’s draft guidance document, it is still unclear to many in the drug and device industries whether new PHS Act § 402(j) applies to certain submissions – such as an initial IND submission containing a clinical trial protocol.  By regulation (21 C.F.R. § 312.40), the sponsor must wait 30 days before beginning such trials, but the study does not need to be registered under the law until 21 days after the first patient is enrolled.  FDA frequently requires modifications to protocols, or even places them on clinical hold.  If protocols were required to be registered upon initial submission to FDA, it would force the sponsor and NIH to edit the information in ClinicalTrials.gov whenever FDA made such modifications.  Would the sponsor then need to re-certify to FDA?  It would seem that all of the statutory objectives would be met if the Form FDA 3674 certification was required when the results of a study were submitted to the IND. In addition, it is unclear whether new PHS Act § 402(j) applies to ANDAs containing the results of in vivo bioequivalence studies.  This is a critical issue because many ANDA companies deem the existence of bioequivalence studies (which ordinarily do not require an IND) as trade secret or confidential commercial information, particularly from the NDA holder.  Moreover, bioequivalence studies are simply not large enough to discover previously unknown safety information and few companies or medical journals, for that matter, are interested in publishing the results of such studies.  Finally, if ANDAs applicants are also forced (ultimately) to post their bioequivalence results so that they can submit Form FDA 3674, will that open FDA to second-guessing by the NDA holder? 

Help might be on the way, however.  We have learned that FDA is in the process of drafting another draft guidance document that will provide the Agency’s interpretation of the scope of the terms “applicable drug clinical trial” and “applicable device clinical trial.”  That draft guidance, once issued, should provide greater clarity to industry on the types of studies to which PHS Act § 402(j) applies.   

By Kurt R. Karst & David B. Clissold

Earlier this month, we reported on the status of litigation in the U.S. Court of Appeals for the District of Columbia Circuit concerning Nu-Pharm Inc.’s efforts to get FDA to approve the company’s ANDA for a generic version of Abbott Laboratories’ DEPAKOTE (divalproex sodium) Delayed-Release Tablets, 500 mg.  In January 2008, the U.S. District Court for the District of Columbia dismissed Nu-Pharm’s complaint against FDA.  Nu-Pharm sought both a judicial declaration that FDA’s decision not to approve ANDA #77-615 for Divalproex Sodium Delayed-Release Tablets, 500 mg, after the 30-month stay of approval reportedly expired without a court decision violated the Administrative Procedure Act, and preliminary and permanent injunctive relief requiring FDA to approve ANDA #77-615.  The district court dismissed the complaint, declining to exercise jurisdiction for “prudential reasons,” reportedly on the ground that the injunctive relief sought by Nu-Pharm would “conflict irreconcilably” with a previous order entered in a contempt proceeding.

Nu-Pharm appealed the district court decision to the U.S. Court of Appeals for the District of Columbia Circuit, and argued, among other things, that “the district court improperly refused to exercise jurisdiction over Nu-Pharm’s complaint” when it declined to exercise subject matter jurisdiction over Nu-Pharm’s complaint, and that FDA’s decision not to approve ANDA #77-615 is contrary to the language of FDC Act § 505(j)(5)(B)(iii), which states that ANDA approval “shall be made effective” after the expiration of the 30-month stay.  In February, FDA submitted a Motion for Summary Affirmance arguing that Nu-Pham’s case is “baseless” and that the district court properly declined jurisdiction.

On April 17, 2008, a 3-judge panel from the U.S. Court of Appeals for the District of Columbia Circuit issued a 1-page order granting FDA’s Motion for Summary Affirmance.  It is unclear whether Nu-Pharm will petition the court for rehearing or rehearing en banc. 

By Kurt R. Karst    

Yesterday, the U.S. House of Representatives Committee on Energy and Commerce released a Discussion Draft of the "Food and Drug Administration Globalization Act of 2008."  The “Discussion Draft is meant to stimulate discussion about how to provide adequate funding and authority for FDA to ensure safety of . . . food, drug, medical device, and cosmetic” products, according to a memorandum accompanying the draft legislation.  The Energy and Commerce committee intends to hold hearings and to markup the draft in the next few weeks. 

The Discussion Draft contains comprehensive language that addresses the safety of food, drugs, devices, and cosmetics as well as a number of general provisions relating to the agency.  Although the draft may undergo significant change during hearings and markup, there are several noteworthy provisions.  The draft proposes an annual registration fee of $2,000 for food facilities operating in the U.S. or exporting food to the U.S., would require labeling to identify the country-of-origin of foods and whether certain foods have been treated with carbon monoxide, and would provide FDA with mandatory recall authority.  With regard to drugs and devices, the draft proposes a registration fee to cover the cost of drug and device inspections, and would require country-of-origin labeling.  The draft also would require cosmetic facilities to register with the FDA at a cost of $2,000 per facility and require adverse-event reporting for cosmetics.  Finally, the draft proposes to increase the capacity of FDA to monitor foreign facilities. 

Of particular interest in the Discussion Draft is the number of fees proposed. There are fees for registration, reregistration, reinspection, certification, certifying agent accreditation, laboratory accreditation, export certification, and importer registration.  The Energy and Commerce Committee predicts that the food registration fees alone will generate approximately $600 million for food safety activities at FDA.  In addition, the bill provides for the levying of substantial fines for violations of the new requirements.  The proposed fees in this bill mirror the efforts seen in FDAAA to increase user fees as a means of generating revenue for FDA.  We will continue to monitor this trend and report any new developments in the "Food and Drug Administration Globalization Act of 2008." 

Susan J. Matthees & Ricardo Carvajal

Recently, calls have been mounting for FDA to require manufacturers of cosmetics to highlight the presence in their products of what are variously referred to as “nanomaterials,” “nanoingredients,” and “nanoscale materials,” among other descriptors. The objective of this requirement would be to enable consumers to avoid any potential risks posed by “nanomaterials.” Whatever its merits from a policy standpoint, such a requirement would have little grounding in science or law.

As FDA noted in its 2007 Nanotechnology Task Force Report, there is no scientific basis on which to conclude that “nanoscale materials” as a class are inherently more hazardous than “non-nanoscale” materials. In fact, FDA declined to even attempt to define “nanoscale material” or any similar term for regulatory purposes, in recognition of the fact that currently there exists no scientific rationale for drawing any particular definitional lines. Without a supporting scientific rationale, a regulatory definition of “nanoscale material” for purposes of imposing label declaration requirements could not be grounded in the misbranding provisions of the act, and would be vulnerable to a First Amendment challenge.

Similarly, calls for FDA to more vigorously exercise its regulatory authority to require substantiation of ingredient safety fail to acknowledge the limits of FDA’s statutory authority. It is true that the FDCA prohibits the introduction into interstate commerce of a cosmetic that is adulterated because it bears or contains a poisonous or deleterious substance which may render it injurious to users, and thus places the burden on cosmetic manufacturers to ensure that the ingredients they use are safe. However, the FDCA does not authorize FDA to require proof from a cosmetics manufacturer that any particular ingredient (other than a color additive) is safe. To the contrary, in the context of a judicial proceeding, FDA would bear the burden of demonstrating that a particular ingredient is unsafe (i.e., is a poisonous or deleterious substance that may render the cosmetic injurious to users).

One is reminded of calls for FDA to require label declaration of the presence of bioengineered ingredients in foods. In the absence of demonstrable risk posed by those ingredients, FDA demurred, noting that the agency lacks authority to require labeling statements for the purpose of satisfying consumer interest. This view is likely to guide FDA’s position on “nanotech” labeling, at least until there is a change in the law or the underlying science.

By Ricardo Carvajal

In a previous post we opined that § 912 of the FDA Amendments Act (“FDAAA”) could represent a fundamental shift in the dividing line between foods and drugs.  For our most recent thoughts on that subject, we refer you to the column we recently published in FDLI Insighter.  There, we examine the potential of § 912 not only to reduce the historic flexibility by which an article may be deemed a food or a drug, but more importantly to deter innovation in the research and development of new food ingredients.

By Diane B. McColl & Ricardo Carvajal

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

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

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

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

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

By Kurt R. Karst    

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

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

Teva argues in its petition that because the “official Orange Book” (that is, the printed edition of the Orange Book) listed the ‘952 patent when the company submitted ANDA #76-228, “FDA’s putative delisting of the ‘952 patent did not become effective until January 2002, when the official Orange Book reflected the delisting of that patent.”  As such, according to Teva, given the decision in Ranbaxy, FDA could not have lawfully delisted the ‘952 patent because of the company’s Paragraph IV certification to that patent, and the company remains eligible for 180-day exclusivity.  Teva also contends that because FDA “failed to provide official notice of the ‘delisting’ for several months following the submission of Teva’s ANDA,” the delisting does not affect Teva’s “entitlement” to 180-day exclusivity. 

FDA states in its petition response that according to the Agency’s records, the ‘952 patent was delisted before Teva submitted ANDA #76-228 to FDA in August 2001, and that as a result, the delisting was proper and Teva is not eligible for 180-day exclusivity.  Specifically, FDA states that the “delisting of the ‘952 patent was reflected in the publicly available, electronic Orange Book shortly after June 29, 2001, and no later than July 20, 2001, the date of the next database update.”  As such, “at the time Teva submitted its ANDA, the electronic Orange Book contained the most current information regarding patents listed for Risperdal tablets . . . [and Teva’s] assertion that the delisting of the ‘952 patent did not become effective until publication of the 2002 annual edition of the Orange Book is without merit.” 

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

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

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

By Kurt R. Karst    

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

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

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

By Riëtte van Laack

UPDATE:

• Earlier today FDA announced yet another seizure action.