FDA recently announced that on June 5 and 6, 2008, the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research will hold a public meeting to discuss the Agency’s plans to launch a pilot program on the testing and review of proprietary names and the issuance of a concept paper that will describe the logistics of the pilot program, recommendations for implementing a proprietary name review, and the proposed review of submissions made under the pilot program.  The pilot program will allow participating companies to submit data generated from their own testing and evaluation of proposed proprietary product names.  FDA expects to issue the concept paper by the end of Fiscal Year (“FY”) 2008 and begin enrollment in the pilot program in FY 2009.

The pilot program and concept paper are intended to increase the transparency of FDA’s review process of proprietary names and to decrease the risk of medication errors. Currently, FDA reviews proprietary names to determine any promotional or safety issues.  For example, FDA considers whether a proposed name overstates the efficacy of the drug product, minimizes the drug product’s risks, or broadens its indications.  FDA also considers whether the name is spelled similarly or sounds similar to another marketed product or could otherwise cause confusion, such as having similar abbreviations.  The current safety review expands the entire medication process, taking into consideration, for example, errors that could arise during the procurement, prescribing, ordering, dispensing, and administration of a drug.

Under the performance goals FDA agreed to as part of the recent reauthorization of the Prescription Drug User Fee Act (i.e., PDUFA IV), the Agency committed to implement various measures with respect to proprietary name review in an attempt to reduce medication errors.  These measures include meeting certain proprietary name review performance goals (beginning in FY 2009) during the IND and NDA/BLA review phases, publishing guidance and policy procedures on proprietary name review and best practices, developing and implementing a pilot program “to enable pharmaceutical firms participating in the pilot to evaluate proposed proprietary names and submit the data generated from those evaluations to the FDA for review,” and “exploring the possibility of ‘reserving’ proprietary names for companies once the names have been tentatively accepted by the Agency.”  FDA’s June 2008 meeting is part of the Agency’s efforts to meet these goals.  FDA’s efforts also respond to calls for more industry involvement in the proprietary name testing process, including requests made in reports by the Institute of Medicine in 2006 and 1999 and recommendations made by the Health and Human Services Advisory Committee on Regulatory Reform in November 2002. 

During the meeting, FDA plans to discuss the following key issues: (1) best practices in safety and promotional testing of proprietary names; (2) testing procedures that should be used and data that should be submitted by those participating in the pilot; (3) standardization of testing; (4) criteria to consider in evaluating the testing and data submitted; (5) the structure and evaluation of the pilot program; and (6) any public health concerns raised by the pilot program.  FDA will use the information gathered from the meeting and from comments submitted to the docket to develop the concept paper and the pilot program.

The meeting will be held from 8:30 a.m. to 5:00 p.m. each day at the Crowne Plaza Hotel in Silver Spring, Maryland.  Information on meeting attendance and registration is provided in FDA’s Federal Register notice announcing the meeting.  Written comments regarding the concept paper and pilot program must be submitted by July 6, 2008 to the Division of Dockets Management or electronically at www.regulations.gov.

By Carrie S. Martin

Dextromethorphan is an important ingredient in many cough/cold medications.  The World Health Organization (“WHO”) is considering whether to schedule dextromethorphan as a controlled substance under the international conventions of the United Nations system.  If that occurs, then the U.S. government will be obligated to schedule dextromethorphan under the Controlled Substances Act, an action that could dramatically affect the manufacturing, distribution, and availability of medicines containing the substance.

At the next meeting of WHO’s Expert Committee on Drug Dependence, dextromethorphan is scheduled to be given a “pre-review.”  That meeting will occur in April, 2009.  If, following this “pre-review,” the drug is recommended for “critical review,” the committee will at the meeting thereafter determine whether to recommend scheduling.

Space does not permit a full description of the WHO scheduling process.  If this issue is of interest, please call Jim Phelps or John Gilbert at Hyman, Phelps & McNamara, P.C.   Also, please see our previous post, which, among other things, provides some background information on the WHO scheduling process.

On May 1, 2008, a federal judge in the Middle District of Florida brought some measure of closure to FDA’s more than six years of attempts to regulate a self-identified custom device manufacturer.  In his May 1st order, Judge G. Kendall Sharp mostly sided with Endotec, Inc., and the two individual defendants, Michael J. Pappas, Endotec’s co-owner and president, and Dr. Frederick F. Buechel, Endotec’s other co-owner and medical director. 

Since at least its March 15, 2002 Warning Letter to Endotec, FDA has maintained that Endotec’s devices were not custom devices under FDC Act § 520(b).  While the Judge agreed with FDA with respect to the knee devices manufactured by Endotec, he refused to grant FDA’s request for disgorgement of profits even with respect to these devices.  Judge Sharp found, as a conclusion of law, that Endotec’s ankle and TMJ devices were custom devices, and thus not adulterated or misbranded.

The court, without the deference to agency expertise and regulations that one often sees in challenges to FDA decisions, stated that an FDA witness’ “interpretation of ‘custom device’ is so narrow as to make the definition useless.”

FDA typically takes the position that a device being studied under an investigational device exemption (“IDE”) cannot also qualify as a custom device, because it is capable of being studied.  The court concluded, however, that even though Endotec had an approved IDE for the Buechel-Pappas Ankle (“B-P Ankle”), the ankle devices at issue were custom devices.  The court so held based on testimony from Endotec that the “surgeon specials” although “similar to the standardized B-P Ankle that was being studied under the IDE,” were custom devices and not “‘merely a variation’ within a range.”

While not strictly relevant to its analysis, the court’s decision notes as several points that there is no allegation that these devices are unsafe or ineffective.  Additionally, while recognizing that it is up to Congress to improve the law, the court suggested that FDA’s premarket approval (“PMA”) and 510(k) processes were unduly burdensome and time-consuming and were preventing technological advances from reaching patients. 

The case was not a total loss for FDA.  As noted above, the court did find that Endotec’s knee devices were adulterated and enjoined their manufacture and distribution.  In addition, with respect to the ankle devices that the court found to be custom devices, the defendants are enjoined “from advertising the B-P Ankle or any custom ankle device through websites, in professional journals, at professional conferences, or by any other means, thereby essentially incorporating the statutory and regulatory restrictions into a court order.   

FDA has 60 days to appeal from the court’s order to the Eleventh Circuit.  Aside from an appeal, it is uncertain how this case may affect FDA’s regulation of custom devices.  The court did not hold or suggest that FDA’s definition of custom device is invalid.  Nevertheless, the decision demonstrates that for device manufacturers who may disagree with FDA’s application of the custom device exemption, FDA’s enforcement position is not necessarily the final word.

By J.P. Ellison

We previously reported (here and here) on FDA’s efforts to resolve 180-day exclusivity forfeiture issues concerning generic versions of Bayer Pharmaceuticals’ (“Bayer’s”) diabetes drug PRECOSE (acarbose) Tablets by establishing a public docket.  (FDA has also taken similar actions to resolve 180-day exclusivity issues concerning ramipril and granisetron.)  Under changes made to the Federal Food, Drug, and Cosmetic Act (“FDC Act”) by the 2003 Medicare Modernization Act (“MMA”), generic applicants that are “first applicants” are eligible for 180-day exclusivity, unless such eligibility is forfeited.  A “first applicant” eligible for 180-day exclusivity is defined in FDC Act § 505(j)(5)(B)(iv)(II)(bb) to mean “an applicant that, on the first day on which a substantially complete [ANDA] containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete [ANDA] that contains and lawfully maintains a [Paragraph IV certification].”  Forfeiture of 180-day exclusivity eligibility can occur under several statutory provisions.   

In September 2007, FDA issued a letter soliciting public comment on whether the “first applicant” to submit an ANDA for generic PRECOSE Tablets was eligible for 180-day exclusivity, or whether such eligibility was forfeited.  Specifically, FDA’s September 2007 letter identifies the following facts and requested comment on the following forfeiture issues:

As of the date of this letter, which is more than 30 months from March 22, 2005 [when the first ANDA was submitted], no first applicant’s ANDA has been approved.  Also, on April 16, 2007, Bayer requested that [U.S. patent #4,904,769 (“the ‘769 patent”] be “delisted” as to Precose, i.e., they withdrew the patent information.  On September 26, 2007, FDA indicated in [the Orange Book] that the request to delist this patent had been submitted on April 16, 2007.

To determine whether any ANDA referencing Precose is eligible for final approval, the agency must consider how the 180-day generic drug exclusivity forfeiture provisions at section 505(j)(5)(D) of the [FDC Act] apply to this set of facts.  As part of the process for making such a determination, we are seeking your views regarding the applicability of sections 505(j)(5)(D)(i)(IV) — failure to obtain tentative approval within 30 months — and 505(j)(5)(D)(i)(I)(aa)(BB) — failure to market by 30 months. We also are interested in your views regarding the applicability of section 505(j)(5)(D)(i)(I)(bb)(CC) — relating to the delisting of a patent.

The “first applicant” eligible for 180-day exclusivity was later revealed to be Cobalt Pharmaceuticals, Inc. (“Cobalt”) when the company submitted an Emergency Petition for Stay of Action to FDA on October 24, 2007 requesting that the Agency stay the approval of all subsequent acarbose tablets ANDAs until Cobalt’s 180-day exclusivity period expires.  Sixteen days later, Cobalt submitted a Citizen Petition and another Emergency Petition for Stay of Action to FDA challenging the Agency’s bioequivalence recommendations for generic PRECOSE Tablets. 

Cobalt submitted ANDA #77-532 to FDA in January 2005 containing a Paragraph IV certification to the ‘769 patent; however, after initially reviewing the application, FDA refused to receive the ANDA.  FDA later received the application on March 22, 2005, and Cobalt provided the required notice of the Paragraph IV certification to Bayer.  Bayer did not sue Cobalt.  In October 2007, Cobalt filed an action for declaratory judgment of non-infringement and invalidity of the ‘769 patent.  The case was later voluntarily dismissed without prejudice. 

On May 7, 2008, FDA issued a Letter Decision in which the Agency determined that Cobalt forfeited 180-day exclusivity eligibility on September 22, 2007 under the “failure to market” forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) because the company did not begin to market its drug product by that date.  (FDA also simultaneously denied Cobalt’s October 2007 Emergency Petition for Stay of Action.) According to FDA’s calculations, September 22, 2007 is the “earlier of” date between March 22, 2005 (i.e., the date that is 30 months from the date on which Cobalt submitted a substantially complete ANDA #77-532 containing a Paragraph IV certification to the ‘769 patent) and July 21, 2008 (i.e., the date that is 75 days after FDA approved ANDA #77-532 on May 7, 2008).  September 22, 2007 is also the “later of” date that is 75 days after April 16, 2007, when Bayer withdrew the ‘769 patent from the Orange Book (i.e., June 30, 2007). 

In what will likely be a surprise to those following 180-day exclusivity issues (and could have significant implications on some currently pending ANDAs otherwise eligible for 180-day exclusivity), FDA notes that the U.S. Court of Appeals for the District of Columbia Circuit’s 2006 decision in Ranbaxy Labs. Ltd. v. Leavitt holding that FDA may not condition the delisting of a patent on the existence of patent litigation and deprive an ANDA applicant eligible for 180-day exclusivity of such exclusivity does not apply to the version of the FDC Act amended by the MMA.  FDA’s Decision Letter states:

[T]he Ranbaxy court noted that the decisions rendered by the FDA and the district court had been made pursuant to the Act “as it stood before the MMA and, because the MMA was not made retroactive . . . this decision is also geared to the Act pre-MMA” (469 F.3d at 122). Therefore, the court did not purport to render a decision on patent delisting and exclusivity under the MMA. The effect of patent delisting on eligibility for 180-day exclusivity is expressly addressed by the plain language of section 505(j)(5)(D)(i)(I) of the Act. . . .  FDA reads the plain language of 505(j)(5)(D)(i)(I)(bb)(CC) to apply whenever a patent is withdrawn (or requested to be “delisted”) by the NDA holder.

FDA’s Decision Letter also addresses the forfeiture of exclusivity under FDC Act § 505(j)(5)(D)(i)(IV), which states that 180-day exclusivity eligibility is forfeited when “[t]he first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.”  (FDA has previously made determinations under this forfeiture provision – see FDA Law Blog post here – but has not, until now, substantively discussed the provision.) FDA states that “[t]o calculate the start of the 30-month period under this forfeiture provision, it is reasonable to use the date that qualifies the applicant as a first applicant for 180-day exclusivity purposes: the date the ANDA is sufficiently complete to permit a substantive review,” and further notes that:

[I]n contrast, the failure to market provision at section 505(j)(5)(D)(i)(I)(aa)(BB) of the Act calculates the 30-month period from the date of “submission,” rather than the date the application is “filed.”  The exclusivity provisions appear to use the terms “submit” and “file” interchangeably; there is no evidence that Congress intended a difference in meaning between these latter two terms.  Because both terms are used in the context of “first applicant” status, we will interpret the terms to refer to the time that the agency has determined [an] ANDA to be sufficiently complete to permit substantive review.  If we interpreted the term “submission” in this context to mean the date the ANDA is date-stamped by FDA, regardless of whether the application is found to have been reviewable, an applicant whose ANDA cannot be reviewed without the submission of additional information would find its failure to market period under section 505(j)(5)(D)(i)(I)(aa)(BB) to have begun to run even before the agency could begin a substantive review of the application.

In the context of Cobalt’s ANDA #77-532, FDA notes that the application “was sufficiently complete to permit review and was received on March 22, 2005, and that the 30-month period beginning on this date ended on September 22, 2007.  As of that date FDA had not granted tentative or final approval.  However, because FDA’s May 7, 2008 decision with respect to Cobalt’s November 2007 Citizen Petition and Emergency Petition for Stay of Action changed certain bioequivalence requirements, and as a result of a new provision added to the FDC Act at § 505(q)(1)(G) by the FDA Amendments Act permitting the extension of this 30-month period if “approval of the application was delayed because of a petition,” FDA determined that Cobalt did not forfeit exclusivity for failing to obtain tentative approval by September 22, 2007.   

FDA’s May 2008 Letter Decision also addresses the Agency’s interpretation of the beginning of the two 30-month periods described in the “failure to market” and “failure to obtain tentative approval” forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) and § 505(j)(5)(D)(IV), respectively.  Cobalt had argued that “FDA must interpret the two 30-month periods described in the MMA forfeiture provisions as beginning not from the date the application is submitted or filed, but rather from the date the NDA holder and patent owner receive the first applicant’s notice of paragraph IV certification.”  FDA disagreed, and referring back to a passage quoted above, states that “although there is some ambiguity created by the use of the term ‘submission’ in section 505(j)(5)(D)(i)(I)(aa)(BB) and ‘filed’ in section 505(j)(5)(D)(i)(IV) to identify what appears to have been intended to be the same event, that ambiguity can be easily resolved in a manner that is both consistent with the agency’s use of these terms in the review of ANDAs and with the statutory scheme.”

Dissatisfied with FDA’s decision, Cobalt sued FDA in the U.S. District Court for the District of Columbia on May 8, 2008 seeking declaratory and injunctive relief.  A copy of Cobalt’s Complaint, Cobalt’s Motion for Temporary Restraining Order, FDA’s Opposition Memorandum, and Cobalt’s Supplemental Memorandum are available via the hyperlinked text.  We understand that on May 9th the court denied Cobalt’s motion for a temporary restraining order.  Roxane Laboratories has also filed a Motion to Intervene in the case.  We understand that the court granted Roxane’s motion.  The lawsuit is the latest in a recent spat of cases concerning Hatch-Waxman issues, including controversies over generic PLAVIX (clopidogrel bilsulfate), generic DEPAKOTE (divalproex sodium), and generic RISPERDAL (risperidone) Tablets. 

By Kurt R. Karst   

The Committee on Energy and Commerce of the U.S. House of Representatives sent a letter of inquiry to 49 major food firms that requests extensive information on the firms’ handling of food recalls and food contamination events.  The letter was signed by both John Dingell, Chairman of the Committee on Energy and Commerce, and Bart Stupak, Chairman of the Subcommittee on Oversight and Investigations. The Congressional press release states that FDA has failed to maintain the integrity of the food supply, and that “it is time to determine if the owners of the largest brand names on supermarket shelves have been forthcoming with the American people about the safety of their products.”  The press release provides a link to a list of 313 food recalls that are asserted to have occurred in the past 16 months, based on notices released by FDA and the affected companies.

For the time period dating back to January 1, 2000, the letter of inquiry requests: 1) a list of all food recalls and safety alerts issued and the corresponding contaminant, if any; 2) all instances of positive internal test results for certain bacteria and viruses in excess of limits acceptable to FDA or state regulatory authorities; 3) all instances of positive internal test results for chemical contaminants in excess of limits acceptable to FDA or state regulatory authorities; 4) for imported products, all instances of positive internal or external test results for chemical or microbiological contaminants in excess of FDA or State regulatory limits; 5) for each of the preceding items, information as to whether FDA was notified, and if not, why not; and 6) a list of all instances where FDA or a state regulatory authority was denied entrance to any foreign or domestic facility or denied access to records regarding microbiological or chemical testing.  The Committee requests domestic facilities’ information by May 22, 2008 and foreign facilities’ information by June 5, 2008.

Issuance of the letters of inquiry follows closely on the heels of the release of a discussion draft of the FDA Globalization Act of 2008, which would overhaul the nation’s food safety system. The issuance of the letters is further evidence, as if any were needed, that food safety is likely to remain at the top of the Congressional agenda and that additional hearings are likely.

By Diane B. McColl & Ricardo Carvajal

“The Constant Gardener,” a 2001 novel and 2005 movie, revolves in part around an ethically questionable drug trial a foreign drug company conducts in Africa.  Real life events have also occurred where a company was accused of ethical violations during the conduct of foreign clinical studies.  In 2001, “The Washington Post” ran a series of articles titled “The Body Hunters” describing the news organization’s investigation into corporate drug tests around the world. 

Since 1975, FDA has required any clinical study used to support the approval of a drug application to meet certain ethical and data management criteria, including meeting the standards of the 1989 version of the Declaration of Helsinki or the local laws of the country, whichever provided greater protection for the research subjects.  Although the Declaration of Helsinki has been amended several times since 1989 (most recently in 2004) FDA did not adopt the later versions due to various factors, including, recent changes that FDA portrayed as an attack on the use of placebos in clinical studies and that could make it more difficult to assess the safety and efficacy of proposed drug products.

On April 28, 2008, FDA promulgated final regulations revising the standards foreign clinical trials that are not conducted under an Investigational New Drug application (“IND”) must meet to support an IND or New Drug Application submission.  The regulation (at 21 C.F.R. § 312.120) only applies to a minority of studies, as FDA estimates that only about 15% of all foreign trials for drugs intended to eventually be submitted to the Agency are not conducted under an IND.  The new regulation lays out specific requirements these studies must meet.  Studies failing to meet these requirements must still be identified in regulatory submissions, but FDA will only consider them for safety issues and they will not contribute to the Agency’s efficacy evaluation unless a waiver is sought.

The specific requirements identified by FDA in § 312.120 include following Good Clinical Practices (“CGPs”), and allowing the Agency the option to validate foreign clinical data through an onsite inspection.  Major GCP components include the prior approval and continued oversight of an Independent Ethics Committee (“IEC”), and obtaining documented informed consent from every clinical study subject.  The new regulation defines an IEC to mean “a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection.”  An Institutional Review Board is a type of IEC.  The new regulation also details what must be submitted to show compliance with GCPs. 

By Gwendolyn M. McKee

In response to a February 2006 citizen petition by Quaker Oats Co. (“Quaker”), FDA amended  21 C.F.R. § 101.81 concerning health claims on the relationship between soluble fiber from certain foods and a reduced risk of coronary heart disease.  Before the amendment, food eligible for the health claim had to meet the nutrient content requirements for low saturated fat, low cholesterol and low fat.  Quaker’s “flavored reduced sugar instant oatmeal products were ineligible” for the health claim because the substitution of sugar with more whole oats caused the products to exceed the low fat criterion.  Effective May 1, 2008, the final rule allows qualifying foods bearing the health claim to exceed the nutrient content requirement for low fat, provided that the fats in the foods are from whole oat sources.

In response to a comment stating that the new exemption “would be the same as saying that full fat whole oatmeal cookies could reduce the risk of heart disease,” FDA emphasized that “[u]nder the new exemption, a food must meet the low fat requirement unless the food exceeds this requirement due to fat content derived from whole oat sources . . . .  The products eligible to bear the claim would not contain any fat from sources other than the fat inherent in the whole oat sources.  Food products that are typically made with other fat sources, such as cookies, would likely be ineligible for the claim.”

By Cassandra A. Soltis

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