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  • FDA Solicits Public Comment on Yet Another 180-Day Generic Drug Exclusivity Issue

    For the third time in as many weeks, FDA has requested public comment to help resolve 180-day exclusivity issues.  This time FDA’s request concerns the antinauseant and antiemetic drug granisetron HCl, which is marketed by Roche under the tradename KYTRIL.  In late September, FDA solicited comment on acarbose (PRECOSE) (9/26/2007 FDA Law Blog post) generic exclusivity issues, and earlier this week the Orange Book Blog reported that FDA requested comment on ramipril (ALTACE) 180-day exclusivity issues.  These requests follow others from earlier this year on a variety of exclusivity issues concerning amlodipine besylate and midodrine HCl.

    FDA’s latest solicitation is the result of a letter submitted by Teva Parenteral Medicines (“Teva”) and involves the “failure to market” 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I).  Under these provisions, a generic applicant whose ANDA contains a paragraph IV patent certification and who is a “first applicant” eligible for 180-day exclusivity forfeits eligibility for such exclusivity if the firm fails to market the drug by the later of:

    (aa) the earlier of the date that is —

    (AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

    (BB) 30 months after the date of submission of the application of the first applicant; or

    (bb) . . . the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:

    (AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

    (BB) In an infringement action or a declaratory judgment action described in subitem (AA), a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

    (CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under [FDC Act § 505(b)].

    These forfeiture provisions, which were added to the FDC Act by the Medicare Modernization Act (“MMA”) in December 2003, have been controversial.  Indeed, Senator Orrin Hatch (R-UT) expressed concern about how to interpret them within 24 hours of the MMA’s enactment.  Teva’s letter to FDA illustrates a current example of the complexity of the statutory forfeiture provisions. 

    In May 2004, Teva submitted the first ANDA to FDA containing a paragraph IV certification for a generic version of KYTRIL.  The application also contained a paragraph III certification (date of patent expiration) and a section viii statement to a method-of-use patent.  Roche did not sue Teva (or any subsequent ANDA applicant) for patent infringement, and FDA tentatively approved Teva’s ANDA in August 2005.  To date, FDA has not approved Teva’s ANDA, and cannot do so until the patent subject to the paragraph III certification expires in December 2007.  Nevertheless, the 30-month period described in FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB) above expired in November 2006. 

    Teva argues that despite the expiration of the 30-month period, the firm remains eligible for 180-day exclusivity, which would be triggered by Teva’s commercial marketing of the drug.  Specifically, Teva’s letter states:

    [T]he plain language and structure of the [FDC Act] compel the conclusion that Teva is entitled to 180-day exclusivity because Teva is the first applicant that submitted a substantially complete paragraph IV ANDA . . . .  Teva’s exclusivity has not been forfeited . . . because there is a continuing possibility of ANDA-based patent litigation that could result in a “later” forfeiture event under [FDC Act § 505(j)(5)(D)(i)(I)]. . . .

    [The FDC Act] requires FDA to determine which is “the later of” (1) a determinate forfeiture trigger . . . “or” (2) a contingent forfeiture trigger . . . .  But there is no conceivable way for FDA to determine which of those 2 potential triggers occurs “later” until (a) one of the contingencies that could give rise to a forfeiture trigger [under FDC Act § FDC Act § 505(j)(5)(D)(i)(I)(bb)] has occurred, or (b) none of the contingencies can occur.  After all, it is impossible to know whether a contingent event has occurred before it does occur — and twice as hard to determine that such an event will not occur until it no longer can occur.

    FDA’s increasing trend to attempt to resolve post-MMA 180-day exclusivity issues on a case-by-case basis, instead of the Agency proactively addressing such issues more broadly in proposed and final regulations, may very well mean that the courts will end up setting the ground rules for interpreting the FDC Act’s exclusivity provisions, even more so than under the pre-MMA exclusivity provisions. 

    Categories: Hatch-Waxman

    HPM Issues Detailed FDAAA Summary and Analysis

    Earlier today, Hyman, Phelps & McNamara, P.C. issued its detailed summary and analysis of the recently-enacted FDA Amendments Act (“FDAAA”).  A copy of the summary and analysis is available here. 

    FDAAA reauthorizes several user fee and pediatric-related laws, and includes a host of new provisions, the longest reaching of which concern drug safety.  FDAAA also creates a new Direct-To-Consumer (“DTC”) television ad user fee system.  Last week, FDA’s Division of Drug Marketing, Advertising, and Communications established a website dedicated to DTC user fee issues.  In addition, FDA issued its PDUFA IV Performance Goals.  A copy of the transmittal letter to Congress is available here, and the Performance Goals document is available here.  Information on medical device user fees is available here.  FDA’s drug and device user fee rates for Fiscal Year 2008 will be published in the Federal Register tomorrow.  Pre-publication versions of those notices are available here (drug) and here (devices).

    OIG Report Critical of FDA’s Clinical Trial Oversight

    The U.S. Department of Health and Human Services’ Office of Inspector General (“OIG”) recently issued a report critical of FDA’s clinical trial oversight along with recommendations to improve such oversight.  Congress requested the OIG report after a series of news articles published in 2005 highlighted various clinical trial vulnerabilities.  The objective of the report is two-fold: (1) to determine the extent to which FDA conducted inspections of clinical trials between Fiscal Years 2000 and 2005; and (2) to assess the Agency’s process for inspecting clinical trials.

    OIG found that FDA had no method in place to identify all clinical trials or Institutional Review Boards (“IRBs”), which are responsible for approving and monitoring research involving human subjects within their institution.  This lack of information reportedly impeded FDA’s ability to both inspect clinical trials and to ensure that IRBs are providing appropriate oversight.  The report also notes that FDA only inspected an estimated 1% of clinical trials, and that these inspections were spread across a number of different divisions within the Agency.  Further, nearly 75% of the inspections that did take place occurred only after the trial concluded, and were designed to assess the quality of the data rather than the safety of the human subjects involved.

    To remedy this problem OIG recommends that FDA take five steps to improve its clinical trial oversight:

    1. Develop a database that includes information on all clinical trials;
    2. Create an IRB registry;
    3. Create a database to allow inspection tracking between FDA components;
    4. Seek legal authority for clinical trial oversight; and
    5. Establish an institutional procedure to provide feedback to local FDA inspectors on their reports and findings.

    FDA concurred in all of the recommendations, except establishing a feedback mechanism (on which the Agency did not comment).

    The recently-enacted FDA Amendments Act includes new provisions intended to improve the availability of clinical trial information, including expanding the current clinical trial registry database and creating a new results database. The clinical trial database recommended in the OIG report would be a separate database for internal FDA use only. 

    Categories: Drug Development

    FDA Will Meet to Address Possible Behind-The-Counter Drug Availability

    On October 4, 2007, FDA issued a Federal Register notice announcing that the Agency will hold a public meeting to address the possible creation of a third category of drugs for the U.S. market – so-called Behind-the-Counter (“BTC”) drugs.  Such drugs would be available without a prescription, but only after intervention by a pharmacist.  Currently, the law only recognizes two categories of drugs – prescription and Over-the-Counter (“OTC”).  FDA states in the notice that the Agency would like to “explor[e] the public health benefit of certain drugs being available BTC that were previously prescription medications,” and that “BTC [drugs] could be comprised of certain medications available behind the counter at the pharmacy without a prescription and require the intervention of a pharmacist before dispensing.”  FDA seeks written comments on the BTC category by November 28, 2007.  The public meeting is scheduled for November 14, 2007.  Because seating is limited, people wishing to attend the meeting must register with FDA by November 5, 2007.

    Several other countries, including Australia, Canada, France, New Zealand, United Kingdom, Denmark, Germany, Italy, Netherlands, Sweden, and Switzerland, already recognize BTC drug status.  These countries generally use the following criteria to determine whether a drug’s switch from prescription to BTC class is warranted:  “(1) [i]ndications suitable for self-medication, including self-diagnosis, with the intervention of a pharmacist and (2) the medicine has a low potential for side effects or overdose, and intervention by a pharmacist could minimize these risks.” 

    FDA’s notice lists several issues that the Agency would like feedback on, including: (1) which drugs should be made available BTC and why; (2) whether BTC status should be used as a temporary or transitional status for drugs that move from prescription to OTC; (3) whether BTC availability will be cost-effective to patients; and (4) what impact BTC drugs will have on the practice of pharmacy.  Given the complex issues that a new BTC drug category raises, FDA will likely receive significant public input with widely varying points of view.  Indeed, there was considerable discussion and differing points of view expressed about BTC status in 2005 and 2006 when FDA considered various issues related to the prescription-to-OTC switch of the contraceptive drug PLAN B (levonorgestrel) Tablets.

    Moreover, FDA has previously considered and declined to create BTC drug status.  Specifically, in 2003, Pharmacists Planning Service, Inc., a non-profit organization that promotes consumer public health education and pharmaceutical information, submitted a citizen petition to FDA (that was later amended) requesting that the Agency “switch Nicotrol Inhaler (Nicotine Inhalation System) from prescription only to [OTC] status TO BE SOLD ONLY UNDER A PHARMACIST’S SUPERVISION as a third class of drugs.”  FDA denied the petition in April 2004 in a 3-page response without substantively discussing BTC status.

    By Cassandra A. Soltis

    Categories: Drug Development

    Congress Set to Consider Multiple Food-Related Bills

    In response to recent scares over tainted food imports and E.coli outbreaks in produce, several members of the U.S. House of Representatives and Senate have introduced (and plan to introduce) a variety of bills aimed at improving food safety and security.  In late September alone, three new bills were introduced.  In addition, two food safety-related amendments to the 2007 “Farm Bill” (H.R. 2419) are expected in the Senate.  Specifically, Representative John Dingell (D-MI) introduced a food safety import bill in the House, and in the Senate, Senators Sherrod Brown (D-OH) and Robert Casey (D-PA) introduced a food safety bill and Senator Tom Harkin (D-IA) introduced a produce safety bill.  Senator Richard Durbin (D-IL) announced plans for an amendment to the 2007 Farm Bill that would force Congress to reauthorize all food safety agencies in 2010, and Senator Harkin announced plans to propose an amendment to the Farm Bill to create a Food Safety Commission.  In addition, the recently-enacted FDA Amendments Act includes various food-related provisions (in Titles IX [Section 912] and X of the new law).

    As we previously reported, Rep. Dingell’s bill, the “Food and Drug Import Safety Act of 2007” (H.R. 3610), establishes user fees of up to $50 per line item of imported food and up to $1,000 per line item on imported drugs.  Not less than 90% of the fees would be used to fund inspections, and no more than 10% of the fees could be used for research.  The bill would also restrict food importation to specific points of entry, require food to be labeled with its country of origin, create a voluntary program for import companies to abide by specific food safety guidelines, enhance civil monetary penalties, prevent the U.S. Department of Health and Human Services (“DHHS”) from terminating or consolidating any FDA field laboratories or FDA district offices, increase food and drug inspections, and create labeling requirements for food containing carbon monoxide.  Rep. Dingell’s bill has already raised concerns over mounting user fees, and two House members, Rep. Gene Green (D-TX) and Rep. Janice Schakowsky (D-IL), question limiting imports to ports with an FDA lab, which could result in ports without an FDA lab losing a significant amount of business, including Houston and Chicago, and logjams at others. 

    Sen. Harkin’s bill, the “Fresh Produce Safety Act of 2007” (S. 2077), is much more narrow in scope and is specifically directed at improving the safety of fruits and vegetables.  The bill would require the inspection of facilities that process produce, and would require DHHS to establish standards for agricultural production, including standards for manure application management, exclusion of domestic animals during harvesting and growing season, water standards, and ground water monitoring.  The bill would also create a public education program related to food safety for fresh produce and require DHHS, in consultation with the U.S. Department of Agriculture (“USDA”), to promulgate regulations for equivalency with foreign nations that export produce to the U.S.

    Sens. Brown and Casey’s bill, the “Food and Product Responsibility Act of 2007” (S. 2081), is a lengthy bill that covers nearly all types of food and many consumer goods.  The bill would give greater authority to FDA and USDA to recall the products they regulate, and would require manufacturers to demonstrate the means to cover the cost of potential recalls before they can place their products into the stream of commerce.  Products covered in the bill include food, drugs, devices and cosmetics, biological products, consumer products, and meat, meat products, poultry, and poultry products, eggs and egg products.

    The 2007 Farm Bill, which the House passed earlier this year and the Senate Agriculture Committee is currently considering, has also become vehicle for food safety legislation.  Sen. Durbin, in an effort to force Congress to reform the current food safety system and place all food safety responsibilities in a single federal agency, announced on September 28th that he would propose an amendment to sunset all food safety agencies by 2010.  Sen. Harkin, who chairs the Senate Agriculture Committee, has voiced support for the proposed Durbin amendment, and has also announced plans for his own amendment to the Farm Bill.  The Harkin amendment would create a domestic food safety panel to work with President Bush’s import panel to recommend ways to improve food safety.  Sen. Harkin’s panel would be modeled after the 2002 Food Safety Commission, which never received the appropriations it needed to begin work. 

    At this point, with no fewer than 20 FDA-related bills circulating in Congress, the greatest barrier to passing meaningful legislation may be weeding through the sea of bills to decide which to pass and which to scrap. 

    By Susan J. Matthees

    Categories: Foods

    Bristol-Myers Squibb Achieves Global Resolution on Array of Historical Drug Pricing and Marketing Allegations

    On September 28, 2007, the U.S. Department of Justice announced that Bristol-Myers Squibb (“BMS”) agreed to pay more than $515 Million Dollars to settle off-label promotion, anti-kickback, Average Wholesale Price (“AWP”), and Best Price (“BP”) allegations, and related False Claims Act claims.  The enforcement action comes just three months after BMS earned praise from a federal monitor as a company “that today is governed by the highest standards of integrity, ethics and accountability, and one that reflects its commitment to those principles in both words and deeds,” and correspondingly, having a U.S. Attorney dismiss a two year old a criminal complaint and terminate a deferred prosecution agreement (“DPA”).  Despite the seeming inconsistency between glowing praise followed by new allegations and a large settlement, the settlement documents suggest that while this is not “old news,” the “covered conduct” stopped relatively shortly after the company entered into the DPA in June 2005.  Specifically, according to the government’s allegations, the covered conduct ceased in December 2001 (anti-kickback), December 2000 (AWP), December 2003 (anti-kickback again), December 2005 (off-label promotion), and 1997 (BP).

    The $515M includes a $328M federal share, $25M of which comes as disgorgement of profits under the FDC Act.  The states will share in $187M.  False Claims Act relators in seven actions will share $50M.

    As is usual in these types of resolutions, BMS also entered into a Corporate Integrity Agreement with the Office of the Inspector General for the U.S. Department of Health and Human Services.


    By James P. Ellison

    Categories: Enforcement

    FDA Announces New Generic Drug Initiative

    Earlier today, FDA announced a new initiative, called the Generic Initiative for Value and Efficiency (“GIVE”), which is intended to increase the number and variety of generic drug products.  According to Gary Buehler, R.Ph., Director of FDA’s Office of Generic Drugs (“OGD”):

    GIVE is an initiative aimed at optimizing OGD’s generic drug review process to increase efficiency. The goals of GIVE are to approve higher numbers of applications for generic products and expedite review of applications for which there are few generics available.

    Over the last three to four years, the number of [ANDAs] submitted to [OGD] has increased. This has led to a growing list of pending applications. We’ve made a number of successful process improvements during this time. In fact, the office approved a record number of applications during the past two years. We approved 510 products in 2006, and approved more than 650 in the fiscal year that just ended.

    But the advancement of medical science and the related increasing cost of health care and disease prevention have caused the role of OGD and its review staff to grow. The number of firms producing generic products and the number of products each firm proposes are growing at an unforeseen pace. The improvements we have made serve to unify and enhance the review process to address the growing workload, and to increase the efficiency of our office’s review efforts.

    As part of GIVE, FDA will revise the review order for certain ANDAs. “For example, first generic products, for which there are no blocking patents or exclusivity protections on the reference listed drug, are identified at the time of submission for expedited review. This will mean that these products, for which there are currently no generic products on the market, may reach the consumer much faster.”  Although there are about 215 full-time FDA staff working on ANDA reviews, under GIVE, FDA will also “hire and train new generic drug reviewers and focus on enhanced use of electronic programs for handling drug submissions and internal documents,” and, when possible, engage the efforts of other FDA components.  A diagram of how OGD will make more drugs available under GIVE is available here.

    OGD’s GIVE program is the latest of several initiatives intended to accelerate the generic drug development and approval processes.  Last year, OGD announced changes to its “First-In, First-Reviewed” policy to provide for exceptions under certain circumstances (see Orange Book Blog post).  In May 2007, FDA issued its “Critical Path Opportunities for Generic Drugs,” which identifies what FDA believes are challenges in the generic drug development process and outlines some actions intended to address those challenges (see FDA Law Blog post).  Also in May, FDA announced the availability of a draft guidance document and database providing recommendations on how to design product-specific bioequivalence studies to support ANDAs (see FDA Law Blog post).

    It is unclear the extent to which OGD’s GIVE initiative might or might not affect the Agency’s push for generic drug user fees.  Earlier this year, FDA proposed creating generic drug user fees as part of the Agency’s Fiscal Year 2008 budget.  The recently-enacted FDA Amendments Act does not include such a user fee program.

    House Committee Passes Dextromethorphan Distribution Act; DEA Reviewing for Possible Control

    On September 27, 2007, the U.S. House of Representatives Committee on Energy and Commerce passed H.R. 970, the Dextromethorphan Distribution Act of 2007, after a legislative “mark-up” session.  Similar legislation was introduced in the U.S. Senate in May 2007 (S. 1378) and was referred to the Health, Education, Labor, and Pensions Committee, where it has remained dormant.  Now that the House Energy and Commerce has passed the bill, it will be scheduled for a vote by the full House.

    H.R. 970, if enacted, would restrict the distribution and possession of raw dextromethorphan, an antitussive (i.e., cough-suppressant) drug found in many over-the-counter cold/cough drug products.  Specifically, the bill would restrict the distribution of unfinished dextromethorphan to anyone but FDA-registered drug manufacturers and the possession of unfinished dextromethorphan by anyone but registered drug manufacturers.  The bill defines the term “unfinished dextromethorphan” to mean “dextromethorphan that is not contained in a drug that is in finished dosage form.”

    Dextromethorphan is not a federally-controlled substance, but the Drug Enforcement Administration (“DEA”) recently noted that the Agency is reviewing the drug for possible control (that is, “scheduling”) under the Controlled Substances Act (“CSA”).  DEA observes that the 2006 “Monitoring the Future Study” showed that in 2005, 4% to 7% of 8th, 10th, and 12th graders reported using dextromethorphan for non-medical use.  DEA further reports that a California Poison Control System study showed a 10-fold increase of dextromethorphan abuse by all age groups from 1999 to 2004, and a 15-fold increase of abuse by adolescents during the period.

    Should DEA decide to schedule dextromethorphan as a controlled substance under the CSA, the Agency would most likely propose placement of the drug in Schedule IV or V (i.e., substances with a low potential for abuse and with a currently accepted medical use).

    By Larry K. Houck

    DOJ Settles with Five Hip and Knee Replacement Companies

    On September 27, 2007, the U.S. Attorney’s Office for the District of New Jersey announced settlements with five companies (Biomet, Inc., Depuy Orthopaedics, Smith & Nephew, Inc., Zimmer, Inc., and Stryker Orthopedics, Inc.) resolving anti-kickback allegations.

    The allegation common to all five cases is that each of the companies entered into consulting agreements with orthopedic surgeons under which the companies paid to induce the surgeons to use that company’s hip and knee replacement products.

    Resolution for the first four companies listed above was through a deferred prosecution agreement (“DPA”), civil settlement, and corporate integrity agreement (“CIA”).  Stryker Orthopedics, Inc., which according to the press release “cooperated with the U.S. Attorney’s Office before any other company,” entered into a non-prosecution agreement (“NPA”), but did not enter into any civil settlement agreement or CIA, and therefore, did not get a release from civil or administrative liability.

    All five companies have agreed to the appointment of federal monitors, who include former Attorney General John Ashcroft, and Debra Yang, the former U.S. Attorney for the Central District of California, whose investigation of Representative Jerry Lewis (R-CA), and somewhat abrupt departure from Gibson, Dunn & Crutcher LLP (the law firm representing Rep. Lewis), made headlines in connection with the U.S. Attorney firings earlier this spring.

    The criminal complaints, filed in connection with each of the four cases in which there is a DPA, allege conspiracy to violate the criminal anti-kickback statute, 42 U.S.C. § 1320a-7b(b)(2), in violation of the general criminal conspiracy statute, 18 U.S.C. § 371.  It appears that the alleged conspiracy was between each company and surgeons as co-conspirators.  There does not seem to be any allegation of inter-company conspiracy.

    The press release states that the civil releases resolve "claims under the anti-kickback statute and civil federal False Claims Act."  The settlement agreement summarily states that the "United States contends that certain of these financial arrangements were improper, that the remuneration paid thereunder was improper and/or unlawful, and that these arrangements caused hospitals and physicians to submit false and fraudulent claims. . . ."  Thus, it appears that the False Claims Act theory behind these settlements follows those cases in which the government has alleged that anti-kickback allegations necessarily give rise to false claims, a theory that is not tested in a settlement. 

    In a post-McNulty Memorandum footnote on the controversy over the U.S. department of Justice requesting waivers of the attorney-client privilege, each of the DPAs and the NPA is clear that the companies are not waiving attorney-client privilege or attorney work-product protection, which contrasts with a pre-McNulty Memorandum DPA from that Office.

    If last week’s activity from Senator Charles Grassley (R-IA), Ranking Member of the U.S. Senate Finance Committee, and False Claims Act champion, are any indication, resolution with the N.J. U.S. Attorney’s office may not put this matter behind these companies.  Senator Grassley sent a letter to Medtronic, which settled similar allegations in July of last year for $40M.  Senator Grassley nevertheless appears to want additional information from the company.


    By James P. Ellison

    Categories: Enforcement

    CDER Launches Drug Safety Newsletter

    On September 18, 2007, FDA’s Center for Drug Evaluation and Research (“CDER”) launched its latest publication, the “Drug Safety Newsletter”.  This quarterly electronic publication is intended as an additional source of drug safety information for healthcare professionals and complements existing communications targeted at healthcare professionals (i.e., prescription drug labeling, Healthcare Professional Sheets, FDA Alerts, and other information available on FDA’s website).

    With its new Drug Safety Newsletter, CDER hopes to “enhance communication of new drug safety information, raise awareness of reported adverse events, and stimulate additional adverse event reporting.”  Each newsletter will include postmarketing safety information obtained from the Agency’s review of adverse event reports, and from clinical trials and epidemiological studies, postmarketing safety information for “recently approved new molecular [entities]” and “recent advisories on drug safety that have been posted on FDA’s Web site.”  In addition to these recurring items, FDA plans to include “topics of special interest.”

    The first issue of the Drug Safety Newsletter includes postmarketing reviews of Rituximab, Modafinal, and Temozolamied, early safety findings of the new molecular entity Deferasirox, and FDA’s advisories on drug safety from January 1, 2007 through June 1, 2007.

    The electronic newsletter is free.  Anyone interested in receiving a copy can subscribe here.

    By Riëtte van Laack

    Categories: FDA News

    DEA Proposes to Expand Definition of Dronabinol Drugs Classified in Schedule III

    On September 24, 2007, the Drug Enforcement Administration (“DEA”) published a notice of proposed rulemaking that would expand the classification of dronabinol, commonly known as delta-9-tetrahyrdocannabinol (“THC”), as a Schedule III controlled substance under the Controlled Substances Act. 

    THC is a federally-controlled Schedule I controlled substance.  Currently, only MARINOL (dronabinol), an FDA-approved synthetic formulation of dronabinol in sesame oil and encapsulated in a soft gelatin capsule, is regulated as a Schedule III controlled substance.  DEA created the schedule classification for MARINOL based on the fact that the formulation greatly diminishes the potential for THC abuse.  DEA states that the Agency has received information that several companies are pursuing approval of ANDAs for generic versions of MARINOL based on the fact that the formulations would meet the statutory approval requirements because they have the same active ingredient, strength, dosage form and route of administration as MARINOL, and are bioequivalent.  DEA notes that neither FDC Act § 505(j) (ANDA approval) nor FDA’s regulations requires solid oral dosage forms such as capsules proposed for approval in ANDAs to contain the same inactive ingredient as the listed drug.  DEA notes that FDA recognizes that an ANDA sponsor referencing MARINOL could propose a capsule for approval with an inactive ingredient other than sesame oil, even though the “Marinol” referenced is not the product defined in the DEA regulation.

    DEA’s proposed rule would expand the classification of dronabinol products in Schedule III to include tablets and capsules, not just soft gel capsules.  The rule would also allow for classification of both synthetic and natural (derived from the cannabis plant) dronabinol products in Schedule III.  DEA reasons that for the purposes of the proposed rule, generic dronabinol can be substituted for MARINOL “with the full expectation that the generic drug will produce the same clinical effect and safety profile as the innovator drug.” DEA also notes that the Agency expects that the “eight-factor analysis,” which is used to determine a drug’s potential for abuse, would examine the same medical, scientific, and abuse data for the innovator and the generic drug.   DEA is indicating that the abuse liability of a tablet or capsule as well as naturally-derived THC is likely to be the same as MARINOL.  Note, however, that under the proposed rule DEA will still have to make scheduling decisions on non-oral dronabinol dosage forms. 

    Procedurally, DEA’s proposed rule will preempt the need for the Agency to conduct a separate scheduling action for each ANDA dronabinol product approved by FDA.  DEA notes that this will save Agency resources.

    Written comments on the proposed rule must be postmarked, and electronic comments sent, on or before November 23, 2007.

    By John A. Gilbert

    WLF Asks Supreme Court to Hear Abigail Alliance Case on Access to Experimental Drugs

    On September 28, 2007, the Washington Legal Foundation (“WLF”) asked the Supreme Court to review the U.S. Court of Appeals for the District of Columbia Circuit’s recent ruling in Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach concerning access to experimental therapies.  As we previously reported, the full D.C. Court of Appeals ruled on August 7, 2007 that “there is no fundamental right ‘deeply rooted in this Nation’s history and tradition’ of access to experimental drugs for the terminally ill.”  The decision reversed a May 2006 D.C. Court of Appeals panel decision.

    WLF’s petition to the Supreme Court caps off an effort that began in 2003 when the organization filed suit on behalf of itself and the Abigail Alliance for Better Access to Developmental Drugs to establish a right for terminally ill patients to gain access to investigational drugs.  The organization is asking the Supreme Court to reinstate the May 2006 D.C. Court of Appeals panel decision that where there are no other FDA-approved treatment options, a terminally ill patient’s access to investigational new drugs is a “fundamental right” protected under the Due Process Clause of the U.S. Constitution.

    WLF requests the Supreme Court’s consideration of the following question:

    Whether the Due Process Clause protects the right of a terminally ill patient with no remaining approved treatment options to attempt to save her own life by deciding, in consultation with her own doctor, whether to seek access to investigational medications that the Food and Drug Administration concedes are safe and promising enough for substantial human testing.

    The organization contends in its petition that:

    The D.C. Circuit [] held that FDA regulations interfering with the medical judgment of terminally ill patients and their doctors do not implicate fundamental rights, and should be subjected to nothing but rational basis review.  That is a profound and important error.  This Court has rightly urged caution in substantive due process cases, but as the dissent below noted “[t]o deny the constitutional importance of the right to life and to attempt to preserve life is to move from judicial modesty to judicial abdication.”  The D.C. Circuit’s decision abandons the textual commitment to “life” in the Due Process Clause, creates bizarre inconsistencies with this Court’s cases, and denies thousands of Americans their most important rights. [(citation omitted)]

    The Supreme Court will likely decide whether or not to hear the case by January 2008.

    Categories: Drug Development

    FDA Announces Enforcement Plans for Marketed Unapproved Hydrocodone Drug Products; The Specter of Legislation Looms

    Earlier today, FDA announced that the Agency plans to take enforcement action with respect to marketed unapproved drugs containing hydrocodone.  Hydrocodone is an opioid derived from codeine that is recognized both for its analgesic and antitussive effects, and is an active ingredient in several FDA-approved drug products.  The announced enforcement action is the first since May 2007 when FDA announced enforcement action on marketed unapproved timed-release guaifenesin drug products. 

    FDA’s latest enforcement action, a notice of which will be published in the Federal Register on October 1, 2007 (a pre-publication version is available here), wraps up the Agency’s previous conclusions made under the Drug Efficacy Study Implementation (“DESI”) program for certain pre-1962 FDA-approved hydrocodone drug products, which were last addressed in 1982 Federal Register notices.  According to FDA, since 1969, when FDA first implemented an adverse event reporting system, and as of 2005, the Agency “has received more than 400 spontaneous reports of serious adverse events associated with all antitussive hydrocodone-containing products” that involve the central nervous system, the gastrointestinal tract, the cardiopulmonary system, and hypersensitivity and intentional and unintentional overdose.  In addition, “some of these [hydrocodone] products omit important labeling warnings and information or are inappropriately labeled for use in young children.”  FDA also notes additional risks, such as medication errors because of “confusion based on similarity between the proprietary names of unapproved hydrocodone-containing antitussive products and other drug products.”  

    According to the FDA announcement and notice:

    Anyone marketing unapproved hydrocodone products that are currently labeled for use in children younger than 6 years of age must end further manufacturing and distribution of the products on or before October 31, 2007. Those marketing any other unapproved hydrocodone drug products must stop manufacturing such products on or before December 31, 2007 and must cease further shipment in interstate commerce on or before March 31, 2008.

    FDA does not expect to issue Warning Letters or any other further warnings to firms marketing unapproved hydrocodone drug products prior to taking enforcement action. 

    FDA’s actions are consistent with the Agency’s June 2006 Compliance Policy Guide, in which FDA announced its enforcement priorities for marketed unapproved drugs.  These enforcement priorities include taking action on drugs with potential safety risks. 

    FDA’s action comes on the heels of an article on CNN.com and an editorial in the Wall Street Journal critical of the Agency’s handling of marketed unapproved drugs.  In addition, the Wall Street Journal article notes that “Congressional legislation [creating a special regulatory pathway for marketed unapproved drugs] will be introduced shortly.”  Indeed, earlier this year the Branded Pharmaceutical Association (“BPA”) announced that the organization submitted draft legislation to Congress to create a special approval pathway for what the organization terms “legacy drugs.”  The BPA has reportedly been working with certain members of Congress to get the bill introduced.  In July 2007, 11 members of the House of Representatives sent a letter to FDA Commissioner Andrew von Eschenbach asking for FDA’s “assurance that ‘Legacy Drugs’ will not be unfairly targeted before Congress has the opportunity to afford due process.”


    Categories: Enforcement

    President Bush Signs FDA Amendments Act

    Earlier today, the White House announced that President Bush signed H.R. 3580, the FDA Amendments Act of 2007, into law.  The U.S. Department of Health and Human Services subsequently issued an announcement praising the new law as "an important step forward in ensuring the safety of drugs and medical devices."  A copy of the enrolled bill sent to the President is available here.  A copy of the public law, as well as FDA’s PDUFA IV "goals documents" (and perhaps the Fiscal Year 2008 user fee rates), should be available shortly.  Any signing statement that might accompany the new law will be available in the Weekly Compilation of Presidential Documents.

    Categories: FDA News

    FDA Solicits Comments on 180-Day Exclusivity Forfeiture & Orange Book Patent “Delisting” Issues

    Earlier today, FDA’s Office of Generic Drugs posted a letter on its website requesting comment on certain 180-day exclusivity forfeiture and Orange Book patent “delisting” issues concerning at least one ANDA submitted to the Agency containing a paragraph IV patent certification requesting FDA approval for a generic version of Bayer Pharmaceuticals’ PRECOSE (acarbose) Tablets.

    Under changes made to the 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.  180-day exclusivity eligibility may be forfeited if, among other reasons, a “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” (FDC Act § 505(j)(5)(D)(i)(IV)), or if such applicant fails to market the drug “30 months after the date of submission of the application” (FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB)).  Although FDA was previously confronted by a potential forfeiture case involving a company’s failure to obtain tentative approval within 30 months of ANDA submission, the Agency ultimately did not have to resolve the situation. 

    With respect to Orange Book patent “delisting,” the U.S. Court of Appeals for the District of Columbia Circuit ruled in November 2006 on the question of “whether the FDA may delist a patent upon the request of the NDA holder after a generic manufaturer has filed an ANDA containing a paragraph IV certification so that the effect of delisting is to deprive the applicant of a period of marketing exclusivity.”  In striking down FDA’s policy decision on the matter, the court reasoned:

    Not only does the statute not require litigation to preserve a generic applicant’s eligibility for exclusivity . . . such a requirement is inconsistent with the structure of the statute because, if the patent is delisted before a pending ANDA is approved, then the generic manufacturer may not initiate a period of marketing exclusivity.

    By thus reducing the certainty of receiving a period of marketing exclusivity, the FDA’s delisting policy diminishes the incentive for a manufacturer of generic drugs to challenge a patent listed in the Orange Book in the hope of bringing to market a generic competitor for an approved drug without waiting for the patent to expire.  The FDA may not, however, change the incentive structure adopted by the Congress.

    In the matter currently before FDA concerning Acarbose Tablets, there is one patent listed in the Orange Book for PRECOSE (NDA #20-482), U.S. Patent No. 4,904,769 (“the ‘769 patent”), which expires on September 6, 2009.  At least one generic applicant submitted an ANDA to FDA on March 22, 2005 containing a paragraph IV certification to the ‘769 patent.  According to FDA’s September 26, 2007 letter:

    As of the date of this letter, which is more than 30 months from March 22, 2005, no first applicant’s ANDA has been approved. Also, on April 16, 2007, Bayer requested that 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.

    FDA’s letter requests that comments be submitted to the Agency by October 10, 2007.  FDA’s decision to request comment on Acarbose Tablets exclusivity issues is part of an increasing trend at FDA to ask for input to help resolve complicated exclusivity issues.  In March 2007, FDA requested comment on amlodipine besylate 180-day and pediatric exclusivity issues, and in August 2007, FDA requested comment on midodrine HCl three-year exclusivity issues.  Presumably FDA will continue this trend as new issues crop up, particularly post-MMA 180-day exclusivity issues.  

    Categories: Hatch-Waxman