In June, the U.S. Patent and Trademark Office (“PTO”) determined that AstraZeneca’s U.S. Patent No. 5,674,860 (“the ‘860 patent”), which covers the drug product SYMBICORT (budesonide; formoterol fumarate dihydrate) Inhalation Aerosol, is ineligible for a Patent Term Extension (“PTE”).  The PTO’s decision is important in that it clarifies the Office’s position that a PTE is not available for a drug product containing two previously approved active ingredients that purportedly act synergistically to create a new product.

Under the PTE statute at 35 U.S.C. § 156, the term of a patent claiming a drug shall be extended from the original expiration date of the patent if: (1) the term of the patent has not expired; (2) the patent has not been previously extended; (3) the PTE application is submitted to the PTO by the owner of record within 60 days of New Drug Application (“NDA”) approval; (4) the product, use, or method of manufacturing claimed has been subject to a “regulatory review period” before it is commercially marketed; and (5) the NDA is the first permitted commercial use of the drug product.  In this case, the PTO denied AstraZeneca’s PTE request because the SYMBICORT NDA was not the first permitted commercial use of budesonide or formoterol fumarate dihydrate, and also because the PTE application was not submitted within the 60-day statutory period.  (Spoiler Alert: While this post deals solely with the first basis for the PTO’s denial, the second basis – i.e., not meeting the 60-day period criterion – is another issue simmering at the PTO that we will post on in the near future.)

FDA approved SYMBICORT on July 21, 2006 for the long-term maintenance treatment of asthma in patients 12 years of age and older.  SYMBICORT contains two previously approved active ingredients.  On September 19, 2006, AstraZeneca submitted a PTE application to the PTO.  AstraZeneca takes the position in its application that the ‘860 patent is eligible for a PTE because “the combination of budesonide and formoterol fumarate dihydrate as a new active ingredient required full scientific review by the FDA.”  AstraZeneca apparently relies on the PTO’s Manual of Patent Examining Procedure (“MPEP”), which states, in relevant part, that “an approved product having two active ingredients, which are not shown to have a synergistic effect or have pharmacological interaction, will not be considered to have a single active ingredient made of the two active ingredients.”  This statement seems to raise the possibility that two previously approved active ingredients could synergistically interact to yield a new product eligible for a PTE. 

The PTO first addressed (to our knowledge) the issue of PTEs for combination drug products containing previously approved active ingredients in a 1994 decision concerning EMLA (lidocaine; prilocaine) Topical Cream.  In that case, the PTO determined that, consistent with the legislative history of 35 U.S.C. § 156, a patent claiming a combination of two previously and separately approved active ingredients is not eligible for a PTE, “notwithstanding any enhanced effect of the combination.”  More recently, in 2004, the U.S. Court of Appeals for the Federal Circuit stated in Arnold Partnership v. Dudas that “this court doubts that synergistic effects are an appropriate distinction for [PTE] policies, particularly where the statutory language does not distinguish between synergistic and nonsynergistic combinations.”  Notwithstanding these decisions, patent owners have continued to raise the possibility of a PTE for a patent covering a combination drug product containing two previously approved active ingredients, presumably because of the ambiguity of the MPEP passage quoted above.

In June 2007, the PTO issued a preliminary analysis in which the Office determined that SYMBICORT “is nothing more than a combination of previously approved active ingredients” and therefore fails to meet the statutory PTE criterion that the NDA approval represents the first permitted commercial use of the drug product.  “Whether the product is a synergistic or nonsynergistic combination of active ingredients is of no consequence to a determination of compliance with [this statutory criterion],” states the PTO in reliance on the dicta in Arnold Partnership.  In a December 2007 letter to the PTO, FDA agreed that the ‘860 patent is ineligible for a PTE because the SYMBICORT NDA “does not represent the first permitted commercial marketing or use of either of the active ingredients in this ‘product.’”  FDA also states that the SYMBICORT NDA “was approved on July 21, 2006, which makes the submission of the [PTE] application on September 19, 2006, NOT timely . . . .” (i.e., the PTE application was submitted on the 61st day after the date of NDA approval).

On June 13, 2008, the PTO issued a final decision that the ‘860 patent is ineligible for a PTE.  The decision goes to great lengths to clarify the MPEP statement on synergistic effect:

The synersistic effect of the active ingredients formoterol fumarate dehydrate and budesonide has no relevance in determining “first permitted commercial marketing or use of the product” . . . .  Applicant’s reliance on MPEP § 2751 is misplaced.  The statement in the MPEP does not require that the USPTO treat an alleged synergistic combination drug product with two active ingredients as a single active ingredient made up of the two active ingredients for [PTE] purposes.  Rather, MPEP § 2751 merely explains that a product having two active ingredients, without synergy, will not be treated as a single active ingredient.  This does not imply that a showing of synergy in a product having two active ingredients, each of which was previously approved for commercial marketing or use, must be considered to be a single active ingredient for [PTE] purposes.

It is unclear whether AstraZeneca will submit a request for reconsideration of the PTO’s June 2008 decision.  The company has until later this summer to do so. 

By Kurt R. Karst    

On June 26, 2008, ranking Republican of the U.S. House of Representatives Energy and Commerce Committee, Representative Joe Barton (R-TX), along with several co-sponsors, introduced the “Strengthening of FDA Integrity Act of 2008” (H.R. 6378).  According to an Energy and Commerce Committee Republicans press release, the bill:

• Gives FDA the authority to debar any company or individual who is convicted of crimes relating to any drug or device.

• Gives FDA the authority to debar companies for any misconduct relating to the drug or device, not just over misconduct that takes place during a drug or device’s development or approval.

• Provides great accountability by requiring the FDA to bring debarment actions within one year of the date of conviction.

• Requires the FDA to report to Congress on the number of debarment proceedings initiated and imposed each year.

H.R. 6378 follows a February 2008 report prepared for Rep. Barton by the Energy and Commerce Committee Minority Staff highlighting what is characterized as a “record of weaknesses in FDA’s ability and authority to carry out its duties and to protect its own integrity.”  According to Rep. Barton, H.R. 6378 “fixes the problem by giving FDA the authority it currently lacks.”

The Federal Food, Drug, and Cosmetic Act (“FDC Act”) was amended in 1992 by the Generic Drug Enforcement Act (“GDEA”).  Specifically, the GDEA, which was enacted in response to the discovery in 1989 of widespread corruption in the generic drug approval process, amended the FDC Act to authorize debarment and other penalties for illegal acts involving the approval of Abbreviated New Drug Applications.  According to the Energy and Commerce Committee Minority Staff report, however:

Since the passage of the [GDEA], FDA has not debarred a single corporation. After more than 15 years with the Act, FDA has debarred 71 individuals (five of the permanent debarments were later terminated and one was withdrawn), but almost half of these debarments (32) occurred in about the first 2 years of the Act and involved convicted felons who figured in the generic drug scandal of the late 1980s. . . .

FDA’s ad hoc approach to carrying out its debarment authority is partly to blame for its paltry enforcement record. At FDA, responsibility for handling debarments is not centralized; rather the manner in which it is handled is left to each FDA center. Although it was signed into law over 15 years ago, FDA has never issued regulations implementing the debarment provisions in the [GDEA].

The report notes that although “Congress granted debarment authority to FDA to serve a remedial purpose, ” the Agency’s ability to carry out this intent has been hampered in two ways:

First, FDA lacks adequate authority.  Under the statute, the agency cannot debar companies other than those that submit generic drug applications. The FDA also lacks authority to debar companies for post-approval criminal conduct. Second, FDA lacks focus in its debarment actions. A review of some cases involving debarred and non-debarred individuals convicted of FDA-related crimes demonstrates FDA’s uneven application of its debarment authority.

To address these issues, the report recommends that Congress consider, among other things, extending the GDEA’s debarment provisions to innovator drug and medical device companies, as well as whether a company’s misconduct post-approval should be a basis for debarment.  (Interestingly, during debate of GDEA legislation in 1990, the limitation to generic drugs was critized as too narrow by Rep. Henry Waxman and by Acting FDA Commissioner James Benson.)

H.R. 6378 incorporates many of the changes recommended in the report.  The bill was referred to the Energy and Commerce Committee for further consideration.  A companion bill has not yet been introduced in the U.S. Senate. 

By Kurt R. Karst 

ADDITIONAL READING: 

• John R. Fleder, The History, Provisions, and Implementation of the Generic Drug Enforcement Act of 1992, 49 Food & Drug LJ 89 (1994) – available here.

On June 27, 2008, the U.S. Drug Enforcement Administration (“DEA”) published a much anticipated Notice of Proposed Rulemaking Regarding Electronic Prescriptions for Controlled Substances.  The proposed regulations are in addition to existing prescribing requirements for controlled substances and are expected to work in tandem with standards developed by the U.S. Department of Health and Human Services on transmitting electronic prescriptions.

The proposed regulations are voluntary and provide practitioners with the option of issuing prescriptions for controlled substances electronically.  However, the practitioner must follow strict controls to deter the diversion of controlled substances.  Such controls include implementing a physically secure information management system and monthly review by the practitioner of a system-generated controlled substance prescription log.  There is a corresponding duty to notify DEA of anything found to be “unusual” within a certain time period.  There are also strict guidelines imposed upon a practitioner on transmitting electronic prescriptions, such as authenticating the system just before signing and not printing or faxing an electronically transmitted prescription.  The burden in on the practitioner to ensure compliance with the proposed regulations and to prevent the diversion of controlled substances.  Among other things, practitioners will be held liable for knowingly permitting another individual to issue electronic prescriptions in the practitioner’s name and for failing to maintain adequate security measures in the handling of electronically transmitted prescriptions.

The proposed regulations also permit pharmacies to receive, dispense, and archive electronic prescriptions.  Again, this is voluntary.  Upon receipt of an electronic prescription, a pharmacy must check the validity of the prescriber’s DEA registration.  “A pharmacy that fails to check the validity of a controlled substance prescription before dispensing is legally responsible if the prescription is invalid.”  The proposal also places strict controls on the participating pharmacy to guard against diversion, such as an enhanced pharmacy information management system, internal audits and back-up systems.  For example, the pharmacy must establish and implement a list of auditable events, and the pharmacy’s system must analyze the audit logs at least once every 24 hours and generate an incident report that identifies each auditable event.  The pharmacy must then decide whether any auditable event poses a security incident that would have to be reported to DEA.

The DEA’s proposal has been long awaited to complement existing initiatives  to promote electronic prescribing, such as those under Medicare and the Health Insurance Portability and Accountability Act.  However, the cumbersome and strict framework proposed by DEA could be an obstacle to widespread adoption of electronic prescribing.  The ability to integrate these requirements into existing technology could be important to how extensively electronic prescribing is used, particularly by doctors.  The fear of DEA enforcement actions for failure to comply with these requirements will also play a role in whether a practitioner decides to adopt these procedures.  DEA should consider these issues in refining the proposed rule before issuing final regulations.  Comments on the proposed regulations must be submitted by September 25, 2008.

By John A. Gilbert & Serafina E. Lobsenz

On June 11, 2008, the Accreditation Council for Continuing Medical Education (“ACCME”) issued for comment a proposal “that the commercial support of continuing medical education end.”  The proposal is intended to provoke debate on whether unbiased CME is possible when funded by individual pharmaceutical or device companies.  The ACCME notice cautioned that comments on the proposal should discuss alternatives, “as nothing would be worse than the deconstruction of a system without the identification of alternatives.” 

As an alternative to a complete ban on commercial funding, the ACCME outlined a restrictive new paradigm under which commercial support would be permissible if all of the following conditions were met:

• Needs assessments are performed by organizations that do not receive commercial support and are free from financial relationships with industry (e.g. government agencies);
• The CME addresses a practice gap of a particular group of learners that is corroborated by bona fide performance measurements (e.g. National Quality Forum) of the learners’ own practice;
• CME content comes from a continuing education curriculum specified by a bona fide organization (e.g. American Medical Association, Agency for Healthcare Research and Quality, American Board of Medical Specialties); and
• The CME is verified as free of commercial bias.

The ACCME is requesting that members of the profession, public and CME community submit comments on the new proposal by August 11, 2008. 

This proposal responds to increasing scrutiny of commercially supported CME on the part of Congress and the medical community.  In April 2007, Senate Finance Committee Chair Max Baucus and ranking member Charles Grassley publically criticized the ACCME for not doing enough to prevent industry influence over commercially supported CME.  The American Medical Association ("AMA") recently considered a report by its Council on Ethical and Judicial Affairs ("CEJA") recommending that individual physicians, medical institutions, and professional organizations cease accepting industry funding to support professional education activities, with the exception of technical training when new diagnostic or therapeutic devices and techniques are introduced.  After hearing testimony largely opposing the CEJA recommendation at AMA’s annual House of Delegates Meeting on June 15, the AMA’s Reference Committee declined to adopt CEJA’s recommendation, concluding that broader discussion was needed before adopting an ethics policy on commercial support of CME. 

Concern over the appearance of bias in commercially supported CME led one drug company, Pfizer Inc., to announce today that it will discontinue all direct funding for CME provided by medical education and communication companies.  Pfizer will continue to fund CME provided by medical institutions, medical societies and associations.

By Noelle C. Sitthikul & Alan M. Kirschenbaum

On June 27, 2008, the District of Columbia Department of Health proposed regulations to implement Title 1 of the SafeRx Amendment Act of 2008 (“SafeRx Act”), which FDA Law Blog previously reported on in January 2008.  Under the proposed regulations, pharmaceutical detailers in the District would need to be licensed by the Board of Pharmacy by April 1, 2009.  The Board would begin accepting applications for licensure on October 1, 2008.

The proposed regulations outline:

• A pharmaceutical detailer code of ethics, including mandatory compliance with the PhRMA Code on Interactions with Healthcare Professionals to the extent that the PhRMA Code does not conflict with the SafeRx Act or its implementing regulations;
• The license application process and fees;
• Education requirements for licensure and the educational requirement waiver process;
• Continuing education requirements and approval of continuing education programs;
• The authority of the Board of Pharmacy to collect information from licensed detailers; and
• Detailer record retention requirements.

Comments on the Proposed Rule are due by July 27, 2008.

An article that appeared in the June 2008 issue of RAPS Focus describes the relevant provisions of the SafeRx Act.

By Bryon F. Powell

Are state law personal injury suits against drug and device manufacturers preempted by federal regulation of these products?

This question has been the subject of much litigation since the early 1990s.  The U.S. Supreme Court has issued a string of decisions in this area, with one case pending.  But the preemption waters are likely to remain roiled for some time to come.  A new twist involves combination device-drug or device-biologic products.

For the complete post, including an overview of preemption law as applied to drugs and medical devices, click here.

By Jeffrey K. Shapiro

On June 5, 2008, a citizen petition was submitted to FDA requesting that the Agency “initiate rulemaking proceedings addressing the authoritative statement nutrient content claim provisions” of the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  The petition takes issue with FDA’s November 27, 2007 proposal to prohibit nutrient content claims for Eicosapentaenoic acid (“EPA”) and Docosahexaenoic acid (“DHA”).

A nutrient content claim characterizes the level of a nutrient in a food, e.g., “high,” “more,” or “good source.”  Until the FDA Modernization Act of 1997 (“FDAMA”), foods could carry only nutrient content claims that were authorized by FDA.  Moreover, only nutrients of the type required to be in nutrition labeling were eligible for nutrient content claims.  FDAMA amended the FDC Act to authorize nutrient content claims based on an “authoritative statement” published by “a scientific body of the United States with responsibility for public health protection or research directly relating to human nutrition,” or by the National Academy of Sciences (“NAS”) which “identifies the nutrient level to which the claim refers.”  Notice of the claim must be submitted at least 120 days before its use.  The notified nutrient content claim may be made until FDA issues a regulation prohibiting the claim. 

Between 2004 and 2006, FDA received three nutrient content claim notifications for the omega-3-fatty acids Alpha-linolenic acid, EPA, and DHA.  All three notifications stated that the claims were based on authoritative statements in a prepublication copy of a report by the NAS Institute of Medicine (“IOM”).   In November 2007, FDA proposed to prohibit the notified nutrient content claims for EPA and DHA.  The Agency concluded that the IOM publication did not identify a “nutrient level” for EPA and DHA within the meaning of the FDCA, and thus the statements cited as authoritative in the notifications did not meet the statutory requirements.

The newly filed petition challenges FDA’s view that a notified nutrient content claim must be based on an established reference value such as a Dietary Reference Intake or Daily Value.  According to Petitioners, Congress “intended the phrase ‘nutrient level’ to apply in situations when a Daily Value had not been established and to be broad enough to include any appropriate references to nutrient levels.” 

The petition also argues that FDA’s narrow interpretation of “nutrient level” conflicts with the First Amendment, and that before prohibiting a notified nutrient content claim, FDA must consider the use of disclaimers “to appropriately qualify authoritative statement nutrient content claims.” 

Considering its limited resources and the fact that notified nutrient content claims have not been a high priority for FDA, a prompt response to this petition does not appear likely.  However, FDA faces a number of the same issues in comments submitted in response to its proposed prohibition of EPA and DHA nutrient content claims.

By Riëtte van Laack & Ricardo Carvajal

On June 23, 2008, Representative William Delahunt (D-MA) introduced, and the U.S. House of Representatives quickly passed by voice vote, H.R. 6344 – the Responsive Government Act of 2008.  The 12-page bill includes several provisions, including the latest iteration of the so-called “Dog Ate My Homework Act,” which is legislation that would permit the U.S. Patent and Trademark Office (“PTO”) to exercise discretion to accept untimely filed Patent Term Extension (“PTE”) applications.  As we previously reported, a similar provision was added to the Patent Reform Act of 2007 (S.1145) by Senator Edward Kennedy (D-MA) in July 2007; however, efforts to get that bill passed have stalled.

The impetus for the “Dog Ate My Homework Act” is the PTO’s decision to deny an application submitted by Massachusetts-based The Medicines Company for a PTE for U.S. Patent #5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin), an anticoagulant drug product FDA first approved on December 15, 2000 for use in conjunction with aspirin in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.  The Medicines Company submitted a PTE application to the PTO 62 days after FDA approved the company’s ANGIOMAX New Drug Application (“NDA”).  The patent term extension law at 35 U.S.C. § 156(d)(1), requires the submission of a PTE application “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (i.e., within 60-days of the date of NDA approval). 

Section 4 of the Responsive Government Act of 2008 would amend 35 U.S.C. § 156 to add new subsection (i), which states that the PTO Director “may accept an application under this section that is filed not later than three business days after the expiration of the 60-day period provided in subsection (d)(1) if the applicant files a petition, not later than five business days after the expiration of that 60-day period, showing, to the satisfaction of the Director, that the delay in filing the application was unintentional.”  (The 5-day petition period for a PTE application pending before the PTO would begin on the date of enactment of the Responsive Government Act.)  However, there is a cost for unintentional delay.  “In order to effect a [PTE] under section 156(i) of title 35, United States Code, the patent holder shall pay a fee to the United States Treasury . . . .” 

The fee for The Medicines Company is $65,000,000.  For other patent owners, the fee is determined based on a complex calculation.  Specifically, the bill states that a patent holder shall pay a fee equal to “(i) $65,000,000 with respect to any original application for a [PTE], filed with the [PTO] before the date of the enactment of this Act, for a drug intended for use in humans that is in the anticoagulant class of drugs” (i.e., ANGIOMAX), or “(ii) the amount estimated under subparagraph (B) with respect to any other original application for a [PTE].”  Under proposed subparagraph (B), the PTO and the Under Secretary of Commerce for Intellectual Property must consider a host of factors to calculate a late-filing fee, including “any net increase in direct spending arising from the extension of the patent term,” “any net decrease in revenues arising from such [PTE],” and “any indirect reduction in revenues associated with payment of the fee under this subsection.”  If enacted, proposed § 156(i) would apply to any application – (A) that is made on or after the date of the enactment of this Act; or (B) that, on such date of enactment, is pending before the Director or as to which a decision of the Director is eligible for judicial review.”

According to the sponsor and co-sponsors of H.R. 6344 (and as evidenced by its quick passage in the House by voice vote), the PTE provisions in the bill have bi-partisan support and are intended to correct “an anomaly in the patent law.”  In discussing the PTE provisions in H.R. 6344, co-sponsor Rep. Donna Christensen (D-VI) stated that the provisions “will make a minor but important amendment to the landmark Hatch-Waxman Act patent act of 1984.  The act of 1984 has done much to make medicine available and more affordable for countless people in this country.  Inadvertently though, in patent term restoration, there is an inflexible deadline provision which has the potential to limit the good that the act can do.”  A copy of the House floor discussion of H.R. 6344 is available here.

After passage in the House, H.R. 6344 was referred to the Senate Judiciary Committee for consideration. 

By Kurt R. Karst    

On June 2, 2008, First DataBank, a private publisher of prescription drug prices in the United States, announced a new proposed settlement in a class action suit alleging that the company conspired with a wholesaler to inflate the Average Wholesale Price (“AWP”) for certain prescription drugs. Among other prices, First Data Bank publishes Blue Book AWPs, which are widely used by Medicaid and private health insurers as a benchmark for reimbursement of prescription drugs. Under the terms of the new agreement, First DataBank will be required to adjust its reporting of Blue Book AWP for approximately 1400 National Drug Codes (“NDCs”) to 1.20 times the Wholesale Acquisition Cost (“WAC”) or Direct Price for those NDCs that are on a mark-up basis, and establish a centralized data repository to facilitate reasonable access to First DataBank material describing its drug price reporting practices. In addition, First DataBank agrees to pay $1 million and certain settlement-related expenses and fees.

On January 23, 2008, the Court issued an order denying approval of a previous proposed settlement, which would have required that First Databank cease publishing AWP data within two years after the Court’s approval of the settlement, as long as no competitor continues publishing similar AWP data. Because AWP is widely used by third-party payers as a drug reimbursement benchmark, the court was concerned that the original settlement had the potential to affect many providers that were not parties in the lawsuit.

Although the requirement that First DataBank cease publishing AWP was dropped in the new proposed settlement, First DataBank has announced, independent of the litigation, that it will discontinue publishing the Blue Book AWP data field for all drugs no later than two years after the changes noted above are implemented. First Databank also announced that it will apply the same 1.20 mark-up factor to all other NDCs whose Blue Book AWP is set based upon a markup to WAC or Direct Price in excess of 1.20. First DataBank will continue to publish other drug pricing information including WAC, Direct Price, Suggested Wholesale Price, Federal Upper Limits, as well as other clinical drug information.

The changes to the Blue Book AWP will become effective on or about 90 days after final court approval of the proposed settlement agreement. The proposed settlement agreement will require preliminary approval by the court, notification to the class members, and final approval by the court. Although the settlement does not require the termination of AWP, First DataBank’s decision to do so could result in significant changes in current reimbursement methodologies.

By Noelle C. Sitthikul

On April 3, 2008, Representatives Frank Pallone, Jr., (D-NJ), Chairman of the House Energy and Commerce Committee Subcommittee on Health, and Nathan Deal (R-GA), ranking Republican of the Subcommittee on Health, sent a letter to a diverse group of 35 stakeholders, such as AARP, PhRMA, GPhA, and General Motors, soliciting feedback on how to establish a pathway to allow FDA to approve so-called biogenerics.  According to the letter:

Members of the Subcommittee on Health are committed to [creating a biogenerics pathway] and several have introduced legislation to establish an abbreviated approval process.  We have found it challenging, however, to reach consensus on a single bill that would accomplish this goal.  In order for the Subcommittee to better evaluate the merits, benefits, and costs of a biosimilars bill, we wish to understand more fully the range of perspectives, concerns, and objectives that might be addressed in such a legislative proposal.  We are also interested as to where consensus exists within the biotechnology community and among other stakeholders.

Earlier this year, Rep. Anna Eshoo (D-CA), who is a member of the Subcommittee on Health, introduced the Pathway for Biosimilars Act (H.R. 5629).  In February 2007, Rep. Henry Waxman (D-CA), who is also a member of the subcommittee, introduced the Access to Life-Saving Medicine Act (H.R. 1038).  Energy and Commerce Committee member Jay Inslee (D-WA) also introduced a bill in April 2007 – the Patient Protection and Innovative Biologic Medicines Act of 2007 (H.R. 1956).  None of these bills have moved very far along in the legislative process.  Although there was speculation earlier this year that Congress might pass legislation before the conclusion of the 110th Congress, that now seems highly unlikely.  Instead, this issue will probably be taken up by the 111th Congress when it convenes in January 2009.  Nevertheless, stakeholder feedback on the Subcommittee on Health letter could help Congress craft a consensus bill.

The April 2008 Subcommittee on Health letter includes 6 pages of questions divided among several general areas, including science/safety, regulatory/administrative, interchangeability, patents, incentives/exclusivity/investment, and economic impact.  Earlier this week, the Subcommittee on Health announced the availability of the stakeholder responses.  The stakeholder responses provide a wide range of views on the topic of biosimilars.  For example, the Association of American Universities suggests that “the proposed legislation should avoid the unintended consequence of encouraging patent challenges that unnecessarily involve our researchers in patent litigation, diverting institutional resources away from scientific research,” and that “[t]he longer the data exclusivity period, the more likely it is that a university’s patent will expire before FDA approval of the biosimilar, and thus the less reason for [a biogeneric] applicant to challenge the university’s licensed patents.”  Conversely, GPhA “believes that five-year market exclusivity, along with intellectual property and the patent restoration provisions included in the Hatch-Waxman amendments, provides a reasonable balance between innovation and access and should be used for biogenerics.”  Clearly, as Congress moves forward on biogenerics there will be no dearth of debate on the various issues they raise. 

By Kurt R. Karst

On June 6, 2008, Wyeth Holdings Corporation and its Fort Dodge Animal Health Division (collectively “Wyeth”) filed a complaint in the U.S. District Court for the District of Columbia against FDA and the U.S. Patent and Trademark Office (“PTO”) requesting declaratory and injunctive relief with respect to Wyeth’s request for a Patent Term Extension (“PTE”) for U.S. Patent #4,916,154 (“the ‘154 patent”), which covers the company’s new animal drug CYDECTIN (moxidectin) Pour-On.  FDA first approved CYDECTIN on January 28, 1998 under New Animal Drug Application (“NADA”) #141-099 for the treatment and control of certain internal and external parasites of cattle.  Although Wyeth’s complaint is in the context of a PTE for an animal drug, a court decision could further clarify the PTE regulatory review period timeframes applicable to FDA-regulated products eligible for an extension.  In addition, this appears to be the first instance in which a company has challenged a PTE for a so-called Administrative NADA, a type of application discussed further below. 

Under 35 U.S.C. § 156(g)(4), as amended by the Generic Animal Drug Patent Term Restoration Act of 1988, certain patents covering animal drugs are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review. As with other FDA-regulated products, such as human drugs and medical devices, the “regulatory review period” is composed of a “testing phase” and a “review phase.”  For animal drugs approved under FDC Act § 512, the “testing phase” begins on the earlier of the effective date of an Investigational New Animal Drug (“INAD”) exemption or the date a major health or environmental effects test on the drug was initiated, and ends on the date a NADA is “initially submitted” to FDA under FDC Act § 512(b).  The “review phase” is the period between the initial submission and approval of the NADA.  FDA’s PTE regulations at 21 C.F.R. § 60.22(f) clarify that a marketing application “is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application.” 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 issuance or during which the applicant did not act with due diligence to obtain approval).   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 NADA.  The current case concerns when NADA #141-099 was “initially submitted” to FDA. 

Wyeth submitted a marketing application to FDA for CYDECTIN under the Agency’s Phased Data Review Policy and Administrative NADA process.  An Administrative NADA “is a new animal drug application that is submitted after all of the technical sections that fulfill the requirements for the approval of the new animal drug . . . have been reviewed by [the Center for Veterinary Medicine (‘CVM’)] and CVM has issued a technical section complete letter for each of those technical sections.”  In this respect, an Administrative NADA is similar to the statutory “Fast Track” process for human drugs and biologicals and the Modular Premarket Approval Application process for medical devices.  Both of these processes permit a type of rolling submission and review of marketing application sections.  As we previously reported, FDA and the PTO have addressed both processes with respect to PTE issues.  For example, under current FDA “Fast Track” policy and precedent, the Agency has determined that the date a final reviewable unit is submitted to the Agency is the date the PTE review phase begins.  Wyeth reportedly submitted the first technical section to the company’s INAD on August 8, 1995.  On January 13, 1998, after the submission and acceptance of the last technical section, and pursuant to Wyeth’s submission of an Administrative NADA for CYDECTIN, FDA issued an acknowledgement letter for the application.  Sixteen days later, on January 28, 1998, FDA approved NADA #141-099. 

In March 1998, Wyeth timely submitted an application to the PTO requesting a PTE with respect to the ‘154 patent.  In that application, Wyeth calculated a PTE based on the date the company submitted the first technical section to its INAD (i.e., August 8, 1995).  Using this date, Wyeth calculated a new expiration date of the ‘154 patent of January 28, 2012. (The original expiration date of the ‘154 patent was April 10, 2007.) 

In September 2006, FDA issued a Federal Register notice stating the Agency’s determination that the date NADA #141-099 was initially submitted to FDA was on January 13, 1998.  In the notice, the Agency also stated that “[i]t is FDA’s position that the approval phase begins when the marketing application is complete.”  In November 2006, Wyeth submitted a request for reconsideration and revision of the regulatory review period, in which the company argued that August 8, 1995 is the controlling date for PTE purposes.  On May 7, 2008, FDA denied Wyeth’s request.  FDA’s letter provides two bases for the Agency’s decision:

First, for phased review applications, it is FDA’s position that the approval phase for purposes of [PTE] begins when the marketing application is complete, including all technical sections and the CVM complete letters.  This correlates to the “fast track” and “rolling review” of human drug applications in that applications submitted under those programs are not considered initially submitted until all required technical information is addressed and available for FDA decision making to commence. . . . 

Second, the technical sections of the administrative NADA are submitted for FDA review not to the NADA, but to the INAD.  Regulatory review of the components is conducted under the first investigational phase of the regulatory review period allowing for review of the data at the time most appropriate and productive in the drug development process. . . .

A few weeks after FDA’s decision, Wyeth filed its complaint.  The complaint alleges that using the August 8, 1995 for purposes of calculating the regulatory review period is consistent with Congress’ intent in passing the PTE provisions at 35 U.S.C. § 156 and with FDA’s PTE regulations at 21 C.F.R. 60.22(f), and that a mere 16-day approval period “is unreasonable.”

Wyeth’s complaint asks for a declaratory judgment that FDA’s determination of the regulatory review period for CYDECTIN violated the FDC Act and the Agency’s implementing regulations, as well as injunctive relief directing FDA to recalculate the CYDECTIN regulatory review period and directing the PTO to refrain from issuing a certificate of extension for the ‘154 patent until FDA has recalculated the PTE period consistent with the law.

By Kurt R. Karst    

Hyman, Phelps & McNamara, P.C., the nation’s largest dedicated food and drug practice, seeks a mid-level associate experienced in drug/biologics development and approval for our D.C. office.  The ideal candidate will have a scientific or medical background and prior regulatory experience in drug/biologics development issues at a law firm, pharma/biotech company, or FDA.  J.D. and strong writing skills are required.  Must be a member of D.C. Bar (or eligible to waive into D.C. Bar).  Compensation commensurate with experience.  Excellent benefits package.

Email resume to jwasserstein@hpm.com.  For more information about the firm, see www.hpm.com.  HP&M is an equal opportunity employer.

The German Federal Institute for Risk Assessment (“BfR”) has issued a report that discusses recent human data on potential health risks arising from consumption of energy drinks.  According to the report, the safety concerns expressed by BfR in a prior expert opinion are “substantiated by more recent human data.”  BfR reiterates its recommendation that the packaging of energy drinks should state that “adverse effects cannot be ruled out when larger amounts of these beverages are consumed in conjunction with intensive physical activity or with intake of alcoholic beverages,” and that “beverages of this kind, particularly when consumed in larger amounts, are not recommended for children, pregnant women, lactating women or individuals who are sensitive to caffeine."  Citing risks of spontaneous abortion, premature delivery, and intrauterine growth retardation, BfR advises a reduction in the daily intake of caffeine for pregnant women (from 300 to 200 mg/day).  With respect to children, BfR cites findings indicating that increased excitability, nervousness, or anxiety are observed at a dose of 5 mg/kg of body weight, and that there is little information on the long term effects of caffeine consumption.  Finally, BfR also raises the question of whether individuals with existing health disorders are at increased risk of adverse effects from consumption of energy drinks, and recommends that patients with high blood pressure or heart disease who consume energy drinks do so in moderation.

As noted by BfR, a number of European and non-European countries have imposed requirements on, or acted to curtail the sale of, energy drinks.  Given the recent transatlantic furor over reports of potential health risks to children reportedly associated with consumption of certain colors, it would not be surprising to see an increased focus in the U.S. on potential health risks to certain subpopulations that may be presented by consumption of energy drinks.  In fact, New Jersey assemblyman Ralph Caputo was reported to be contemplating introducing legislation that would have prohibited the sale to minors of energy drinks containing large doses of caffeine.  For now, Mr. Caputo appears to have opted to tackle fruit hanging a bit closer the ground – marketing to minors of merchandise, including foods and beverages, that links a product to any “controlled dangerous substance or analog” – a clear strike at energy drinks such as Cocaine^TM and Blow^TM.  For the text of the bill, click here.

By Ricardo Carvajal

In a case involving a highly unusual set of facts for FDA-regulated companies, Leiner Health Products, Inc. (Leiner) is seeking to have a plea agreement approved by a Bankruptcy court.  The case involves violations of Current Good Manufacturing Practices (cGMPs) for over-the-counter drugs.  What also makes this case unusual is that the violation alleged in the case is not an FDC Act violation for selling adulterated or misbranded drugs.  Instead, the government is apparently seeking a plea from Leiner to violations of the Mail Fraud Act under 18 U.S.C. § 1341.  Also unusual is that under the proposed agreement Leiner would not have to pay any criminal fine.  Instead, it would pay a ten million dollar forfeiture. 

The Motion, proposed Information and Plea Agreement are available here.

FDA has filed an amicus curiae brief with the Second Circuit Court of Appeals that supports a New York City (“NYC”) law requiring all menu boards and menus in chain restaurants with 15 or more establishments nationally to bear calorie content information for each menu item.  The case is New York State Restaurant Association v. New York City Board of Health, Docket No. 08-1892-cv.  Oral argument in the case is scheduled for mid-June.  The NYC law is one of several similar local laws or proposals in various stages of consideration across the country.  FDA’s support for the NYC law could lend a boost to similar measures elsewhere.

In its brief, FDA takes the position that the NYC law is not expressly preempted by the Nutrition Labeling and Education Act of 1990 (“NLEA”) because it compels the disclosure of “information that is properly included in required nutrition labeling” and does not constitute a nutrient content claim.  FDA also takes the position that the NYC law does not violate the First Amendment because it compels “an accurate, purely factual disclosure… and addresses a legitimate state interest in preventing or reducing obesity among its citizens by making accurate calorie information available to consumers.” 

The possibility of having to adapt to a patchwork quilt of local menu labeling requirements may yet prompt support by industry for federal menu labeling legislation. The Menu Education and Labeling (“MEAL”) Act, introduced by Representative Rosa DeLauro in October 2007, would require that menus disclose next to the name of the food the number of calories, grams of saturated fat plus trans fat, and milligrams of sodium contained in a standard serving of the food.  Menu boards would have to disclose the number of calories per serving.  However, the MEAL act, as proposed, would not preempt state or local requirements mandating disclosure of additional nutrition information.

By Ricardo Carvajal and Diane McColl