By Ricardo Carvajal –

The Government Accountability Office ("GAO") issued a report recommending in part that FDA “identify and request from Congress the authorities needed to access evidence from food companies regarding potentially false or misleading structure/function or other claims on food that would allow the agency to establish whether there is scientific support for the claims.”  As acknowledged by FDA, the agency currently lacks “express legal authority to compel” a company to provide such evidence.  In its response to the report, FDA indicated that it will consider “whether additional statutory authorities are needed."

In recommending that FDA seek additional authority, GAO noted that the Federal Trade Commission ("FTC") already has authority to compel production of evidentiary documents during its investigations, and that FTC could not have taken its recent actions on certain claims in food advertising without that authority.  GAO also noted that the European Union has adopted premarket review of similar claims, and that 85% of such claims have been rejected due to a lack of scientific support.  Similarly, Canada has initiated review of structure/function claims, most of which have been rejected – including some claims used in labels of food marketed in the U.S.

In preparing and issuing its report, GAO was responding to a Congressional directive to study FDA’s implementation of qualified health claims.  The report provides no recommendations with respect to FDA’s oversight of those claims.

On January 23rd, BioCentury This Week TV will broadcast a program concerning the latest thinking about how to create a sustainable economic model for both orphan drug developers and payers.  The program, titled “The Economics of Orphan Drugs – Why Successful Cures Bring Challenges for Patients and Payment,” will be posted on the internet here, and featues Peter Saltonstall, President & CEO of the National Organization for Rare Disorders, Frank Sasinowski, Chairman of the Board at NORD (and Hyman, Phelps & McNamara, P.C. Director), and Lauren Barnes of Avalere Health, former director of U.S. payment and coverage at Amgen.  Eight of the 22 new chemical entities FDA approved in 2010 were for rare (orphan) diseases; however, the successes in the orphan drug arena are bringing new challenges, including assuring patient access as Orphan Drug prices are prompting insurance companies to consider impose prior authorization requirements, higher co-pays, and scrutinize off-label use.  BioCentury This Week will explore these important issues.

By Kurt R. Karst –     

Following the submission of two letters to FDA from both members of the U.S. House of Representatives and the U.S. Senate (see our previous posts here and here) critical of the Agency’s recent characterization of the 12-year reference product exclusivity period provided by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) as “marketing exclusivity” rather than “data exclusivity,” several generic drug manufacturers (Hospira, Momenta Pharmaceuticals, Hospira, Mylan Labs, Teva Pharmaceuticals, and Watson Pharmaceuticals) and other companies and organizations (AARP, Aetna, CVS Caremark, Express Scripts, GPhA, Humana, Medco, and the Pharmaceutical Care Management Association) have added their voice to the debate. 

Under the BPCIA (PHS Act § 351(k)(7)(A)-(B)), FDA cannot approve a biosimilar or interchangeable product that references a brand biologic product until 12 years after the first licensure of the reference (brand) product; however, a biosimilar or interchangeable applicant can submit an application to FDA 4 years after the date on which the reference product was first licensed.  This is somewhat similar to the FDC Act, which provides a 5-year period of new chemical entity exclusivity during which time an ANDA or a 505(b)(2) application containing the protected active moiety cannot be submitted to FDA, except that the application can be submitted beginning at year 4 of the exclusivity period if the ANDA or 505(b)(2) application contains a Paragraph IV certification to an Orange Book-listed patent to the reference listed drug containing the protexted moiety.

In a January 20, 2011 letter to FDA Commissioner Dr. Margaret Hamburg, the generic supporters say that PHS Act § 351(k)(7)(A)-(B) creates periods of both data and market exclusivity:

[D]uring the initial four years of the 12-year period, effectively a reference brand product has both data exclusivity for its application and market exclusivity in relation to biosimilar applicants under the Section 351(k) pathway.  After the initial four years, the data exclusivity expires (meaning that a biosimilar application that benefits from a reference brand biologic showing of safety and efficacy can be filed), and the market exclusivity continues for the remaining eight years. Congress wisely recognized the confusion that the terms “data” and “market” exclusivity caused during the legislative debate and chose to define clearly the process to avoid confusion.

Furthermore, the generic supporters allege that any interpretation of the BPCIA’s reference product exclusivity provisions to prevent the submission of biosimilar or interchangeable product applications for 12 years could have serious consequences.  “If the legislation is interpreted to prevent biosimilar filings for 12 years, consumers will have to endure an unknown period of delay of FDA review and approval that could stretch far beyond the 12-year total that was set in the legislation,” says the letter.  “We concur with the FDA’s initial understanding of the provision and ask that FDA implement the law as passed.”

By Jeffrey K. Shapiro –

Yesterday FDA announced that the Center for Devices and Radiological Health (“CDRH”) intends to take 25 actions to improve the 510(k) program in 2011.  The full action plan and remarks from CDRH Center Director Jeffrey Shuren, M.D., J.D. can be accessed here.  Our brief summary of the plan is laid out below.

Guidance Documents

FDA says it will issue several guidance documents in 2011.  Our list of the most important:

• “Clarification” of when a device modification requires a new 510(k) submission, and which device modifications are eligible for a Special 510(k) (expected June 15, 2011).  Depending upon how this is implemented it could increase the burdens on industry.
• Streamlining of the “de novo” process (expected September 30, 2011).  This process is needed for lower risk devices that lack a predicate device but do not need the rigor of the PMA process.  In recent years, the timelines to de novo classification have ballooned.  Any steps to shorten the process will be welcome.
• Clarification on how to appeal CDRH decisions, including decisions to rescind a 510(k) (October 31, 2011).  Better information will be helpful, since the menu of available appeals processes and their associated requirements has created confusion.  However, right now there are no deadlines for the agency in the most commonly used appeals processes (e.g., supervisory appeal), and appeals can languish for months.  CDRH needs to improve the appeals process and adopt firm deadlines for their own decision making.
• Clarification of the 510(k) Paradigm, to provide greater clarity regarding when clinical data should be submitted for a 510(k), the appropriate use of multiple predicates, resolving discrepancies between the 510(k) flowchart and the Federal Food, Drug, and Cosmetic Act, and development of 510(k) summaries to ensure their accuracy (September 30, 2011).  All of this clarity could be helpful, or it could be a means of introducing greater regulatory burdens.  Time will tell.

Internal, Administrative, and Regulatory Matters

FDA is considering establishing a Center Science Council, enhancing staff/reviewer training, and developing a network of external experts, among other matters.  CDRH is also considering establishing a “Notice to Industry Letters” as a standard practice to clarify to manufacturers those changes in CDRH’s regulatory expectations, and it is also considering the implementation of a unique device identification system.  Most of these reforms are promising, but the implementation will tell the tale.

CDRH says it will issue a regulation by the end of this year to track transfers of 510(k) ownership.  This reform is long overdue.  Unlike PMA approvals, CDRH has never tracked ownership of 510(k) clearances.  The result has been uncertainty as to ownership, creating difficulties for industry, especially in contractual agreements.  A 510(k) clearance is an asset.  As with real estate assets, it is appropriate to have a system that accurately tracks ownership.

Referrals to IOM

The agency has postponed decision making on many of the more controversial issues, deferring to the review that the Institute of Medicine (“IOM”) will conduct later this year.  These include the agency’s rescission authority, post-market surveillance authority, establishment of a Class IIb, clarification on when a device should no longer be available as a predicate, consolidation of the terms “intended use” and “indications for use,” and the possibility of pursuing a statutory amendment that would provide the agency with authority to consider an off-label use when determining a device’s intended use.  It is possible that this is a “good cop, bad cop” situation, in which the IOM will recommend the most controversial and unpleasant changes.  Again, time will tell.

By Kurt R. Karst –

In an unpublished, and subsequently sealed, decision handed down earlier this week by Chief Judge Garrett Brown, Jr. of the U.S. District Court for the District of New Jersey, the court dismissed without prejudice an Amended Complaint filed by Paddock Laboratories, Inc. ("Paddock") seeking a declaratory judgment of noninfringement and invalidity of Orange Book-listed U.S. Patent No. 7,101,574 ("the ‘574 patent") covering ANTARA (fenofibrate) Capsules, which is approved under NDA No. 21-695, and granted a Motion to Dismiss filed by defendants Ethypharm S.A., Lupin Limited, and Lupin Pharmaceuticals, Inc. (collectively "Ethypharm/Lupin") arguing that the court lacks subject matter jurisdiction over the action. The decision is the first that we are aware of in which a court has exercised its discretion to decline jurisdiction under the Declaratory Judgment Act based on FDA’s requirement that an ANDA sponsor make a Paragraph IV recertification.

Paddock, which is reportedly not a first applicant eligible for 180-day exclusivity, submitted ANDA No. 91-362 to FDA in February 2009 seeking approval to market generic fenofibrate capsules, 43 mg and 130 mg. Paddock’s ANDA contained a Paragraph IV certification to the ‘574 patent. After FDA received the ANDA, Paddock reportedly provided timely notice if its Paragraph IV certification to Ethypharm/Lupin, but was not sued for patent infringement within the statutory 45-day period (or thereafter), which would have triggered a 30-month stay of approval of ANDA No. 91-362. As such, in July 2009, and consistent with the FDC Act’s declaratory judgment provisions at §　505(j)(5)(C) as added by the December 2003 Medicare Modernization Act, Paddock filed a complaint seeking a declaratory judgment that the company’s proposed fenofibrate capsules drug product does not infringe the ‘574 patent.

Just one month after Paddock filed its initial Complaint (later amended), FDA apparently informed the company that the Agency’s review of ANDA No. 91-362 was suspended because the proposed drug product did not meet the definition of a "capsule," and recommended that the company reformulate its drug product. Paddock has described its initial proposed drug product as having the active ingredient coated on the outside of the capsule. (Interestingly, in August 2010, FDA denied without comment a Lupin citizen petition (Docket No. FDA-2010-P-0092) requesting that FDA refuse to approve Paddock’s ANDA because it is "not in capsule dosage form and, therefore, is not in the same dosage form as Antara capsules.") Paddock apparently followed FDA’s recommendation and submitted an amendment to the company’s pending application, making the drug product a capsule by placing the previous formulation inside a larger, enveloping capsule, but the company reportedly did not submit a new Paragraph IV certification (i.e., a recertification to the ‘574 patent). We understand that FDA subsequently contacted Paddock and conveyed the news that a new certification to the ‘574 patent is required, and Paddock presumably complied. Last fall, Lupin filed a second citizen petition (Docket No. FDA-2010-P-0561) to FDA requesting, among other things, that FDA enforce the FDC Act’s patent certification requirements against Paddock.

In October 2010, Ethypharm/Lupin filed a Motion to Dismiss the case arguing that as a result of FDA’s requirement that Paddock recertify to the ‘574 patent, the court no longer has subject matter jurisdiction. The court agreed in its January 18, 2011 decision, granting Ethypharm’s/Lupin’s Motion to Dismiss, and therefore giving the companies another chance to sue for infringement in response to a new Paragraph IV certification.

Patent recertification issues seem to be a hot topic these days. As we previously reported, in October 2010, FDA granted a citizen petition requesting a second, superseding 30-month stay for one sponsor’s ANDA for a generic version of HECTOROL (doxercalciferol) Injection after the ANDA sponsor reformulated and recertified to certain Orange Book-listed patents. Although the case involving generic ANTARA does not involve a second, superseding 30-month stay (as Ethypharm/Lupin did not sue for infringement in response to Paddock’s initial Paragraph IV certification triggering an initial 30-month stay), it seems likely that, consistent with FDA’s HECTOROL decision, Ethypharm/Lupin will argue for a stay if there is a timely filed patent infringement lawsuit.

By William T. Koustas –

We previously reported on the struggle between FDA and Regenerative Sciences, Inc. (“Regenerative”) in which Regenerative challenged FDA’s claim that the company’s stem cell procedure is subject to FDA jurisdiction and regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and/or the Public Health Service Act (“PHSA”) as the manufacture and sale of an unapproved drug and/or biologic.  (See our previous posts here, here, and here.)  Regenerative has developed a procedure in which stem cells are isolated from a patient’s bone marrow, undergo an expansion in a laboratory and are then returned to the patient’s site of injury to treat musculoskeletal and spinal injuries (“Regenexx Procedure”). 

Regenerative filed a lawsuit against FDA in February 2009 in response to an FDA letter and inspection of its laboratory seeking declaratory and injunctive relief from FDA’s regulation of the Regenexx Procedure, arguing that the stem cells used in that procedure are not drugs or biologics and the Regenexx Procedure is the practice of medicine which is outside of FDA’s jurisdiction.  Regenerative’s February 2009 lawsuit was dismissed on ripeness grounds, but Regenerative filed another complaint in June 2010 after FDA conducted an inspection on Regenerative’s facility in February and March 2009, which culminated in FDA issuing a Form 483.  In response, FDA filed a complaint in August 2010 seeking to permanently enjoin Regenerative from using stem cells to treat patients without approval.  The Court eventually issued an order denying Regenerative’s motion for a temporary restraining order in its June 2010 complaint as moot because Regenerative agreed to voluntarily discontinue the use of the Regenexx Procedure while the August 2010 case is pending.  The Court also entered a stay while the related August 2010 case is litigated.

Now, the U.S. Justice Department, on behalf of FDA (“the Government”), has filed a motion for summary judgment and a motion to dismiss Regenerative’s counterclaims. 

The Government’s January 7, 2011, motion for summary judgment claims that there is no issue of material fact in the case as Regenerative is manufacturing a “drug” (the cultured stem cells) that is being held for sale “after one or more of its components have been shipped in interstate commerce,” and that such a drug is adulterated since Regenerative is not complying with current Good Manufacturing Practices.  The Government further argues that, as a drug, Regenerative’s stem cells are misbranded as they do not bear the symbol “Rx only” and do not have adequate directions for use.  In response to Regenerative’s argument that the Regenexx Procedure is the practice of medicine outside of FDA’s jurisdiction, the Government asserts that while FDA may not “interfere with a physician prescribing lawfully marketed products for uses other than those for which they are approved, licensed, or cleared by FDA, the agency’s role in determining the availability of therapeutic products inevitably affects the options available to practitioners seeking to use or prescribe those products.”  Thus, the Government appears to claim that FDA may not directly interfere with a physician’s prescribing habits, but it may limit what drugs are available to physicians to prescribe in the U.S. market.  Accordingly, the Government argues that FDA is not impinging on Regenerative’s ability to practice medicine as it is only requiring a drug product to be approved for sale in the U.S.

In addition to the motion for summary judgment, the Government also filed a motion to dismiss Regenerative’s counterclaims.  Regenerative claims that FDA’s attempt to regulate stem cells as used in the Regenexx Procedure constitutes the regulation of the practice of medicine and that FDA’s human cell, tissue or cellular or tissue-based product (“HCT/P”) rule’s definition of “minimal manipulation” is arbitrary and capricious and should have been issued through notice-and-comment rulemaking.  As with its motion for summary judgment, the Government asserts that Regenerative’s counterclaims alleging that the Regenexx Procedure is the practice of medicine should be dismissed under similar reasoning as described above while also noting that the FDCA applies to drugs manufactured by physicians.  The motion to dismiss also takes issue with Regenerative’s counterclaims regarding FDA’s HCT/P rule.  Regenerative argues that preamble statements regarding “minimal manipulation” in the HCT/P rule “imposed a per se rule which provides that any expansion of stem cells constitutes more than minimal manipulation” without explaining how such expansion alters biological characteristics of the cells.  The Government argues that such statements in the preamble are not part of the rule requiring notice-and-comment rulemaking as that statement was just a policy statement clarifying the rule.   

The Government further claims that Regenerative’s challenge to the HCT/P rule, which was issued in 2001, is time barred as the chalenge was not filed within six years of the rule being issued as required by 28 U.S.C. § 2401.  The Government asserts that Administrative Procedure Act claims are governed by a “catch-all” statute of limitations of six years after the right of action accrues as described in 28 U.S.C. § 2401(a) unless a different statute requires a different timeframe.  The Government argues that a cause of action accrues when the regulation is applied to the claimant (if the challenge to the rule is based on substantive grounds) or when the regulation is issued (if the challenge to the rule is based on procedural grounds).  Since it is clear that the rule has been applied to Regenerative within the last six years, the Government argues that Regenerative’s counterclaims relating to the HCT/P rule are procedural in nature, and are therefore time barred.

By Kurt R. Karst –      

On January 18th, the U.S. Supreme Court denied Apotex Inc.’s Petition for Writ of Certiorari asking for a review of the U.S. Court of Appeals for the District of Columbia Circuit’s decision involving Teva’s 180-day exclusivity for generic versions of Merck’s COZAAR and HYZAAR (i.e., losartan).  Teva’s 180-day exclusivity for losartan expired on October 3, 2010, the day before Apotex filed its petition with the Supreme Court.  Justice Kagan took no part in the consideration or decision of Apotex’s petition.

The Supreme Court’s decision leaves intact the D.C. Circuit’s March 2, 2010 decision in Teva Pharms USA, Inc. v. Sebelius, in which a 3-judge panel of the D.C. Circuit ruled in a 2-1 decision that there is “no reason to conclude that the 2003 addition of forfeiture provisions meant to give the brand manufacturer a right to unilaterally vitiate a generic’s [180-day] exclusivity.”  Both FDA (Federal Respondents) and Teva opposed (here and here) the Supreme Court’s review, while AARP and the Consumer Federation of America urged review.  According to FDA, although the “court of appeals’ methodology, reasoning, and holding are incorrect,” the Supreme Court “should defer review of the question presented.”  “FDA has applied the MMA’s forfeiture provisions on only a few occasions, and the D.C. Circuit is the only court of appeals to have construed those provisions.  If future controversies materialize, they are likely to be heard by another court of appeals, giving the Court greater assurance that the question presented is of recurring significance and the legal issues have fully percolated in lower courts,” says Acting Solicitor General Neal Katyal in the government’s brief.  According to Apotex’s Reply Brief, however, “[a] [circuit] split is exceedingly unlikely to develop.”

By Kurt R. Karst –      

In a Complaint for Declaratory Judgment filed in the U.S. District Court for the Eastern District of Michigan (Southern Division) last week by Apotex Inc., the company is trying to trigger 180-day exclusivity for generic LEXAPRO Tablets.  Apotex heavily relies on the U.S. Court of Appeals for the Federal Circuit’s October 2010 decision in Teva Pharms. USA, Inc. v. Eisai Co., 620 F.3d 1341 (Fed. Cir. 2010), for establishing jurisdiction.

LEXAPRO Tablets is currently listed in FDA’s Orange Book with three patents:  U.S. Patent Nos. 6,916,941 ("the '941 patent") and 7,420,069 ("the '069 patent"), both of which expire on August 12, 2022, but are subject to pediatric exclusivity that expires on February 12, 2023, and RE34712 (“the ‘712 patent”), which expires on September 14, 2011, but is subject to pediatric exclusivity that expires on March 14, 2012.  FDA’s Paragraph IV Certification List does not identify the first date on which an ANDA containing a Paragraph IV certification was submitted to FDA, because the ANDA was submitted to FDA before the Agency began listing such a date in March 2004.  Nevertheless, we understand that at least one ANDA containing a Paragraph IV certification to the ‘712 patent was submitted to FDA prior to December 8, 2003, when the Medicare Modernization Act (“MMA”) was enacted.  As such, 180-day exclusivity is governed by the pre-MMA version of the FDC Act, where exclusivity is patent-by-patent.

Apotex submitted ANDA No. 78-777 to FDA in 2007 containing a Paragraph IV certification to the ‘941 patent, and later amended the ANDA to contain a Paragraph IV certification to the ‘069 patent.  (There is no indication that Apotex submitted a Paragraph IV certification to the ‘712 patent, and we assume such certification is a Paragraph III.)  Apotex believes that the company is a subsequent Paragraph IV applicant with respect to the ‘941 and ‘069 patent, and is therefore blocked by another company’s 180-day exclusivity on each patent.  Neither the NDA holder nor patent owner sued Apotex for infringement of the ‘941 or ‘069 patents within the statutory 45-day period (or thereafter), leaving Apotex unable to obtain a court decision through the normal channels to trigger the first applicant’s 180-day exclusivity.  Instead, Apotex, through its January 2011 Complaint, seeks to use the MMA’s declaratory judgment provisions to obtain a court decision to trigger 180-day exclusivity

The MMA amended the FDC Act to affirmatively permit a generic applicant with an application containing a Paragraph IV certification to bring an action for declaratory judgment of patent invalidity or noninfringement (referred to in the law as a “civil action to obtain patent certainty”), provided: (1) the NDA holder or patent owner has allowed the 45-day period in which to file a suit for patent infringement to expire without bringing an action for patent infringement or invalidity; and (2) if the generic applicant’s notice to the NDA holder or patent owner relates to patent noninfringement, the notice includes an offer of confidential access to the generic applicant’s application for purposes of determining whether the NDA holder or patent owner should bring an action for patent infringement.  (Apotex apparently met both requirements.)  The MMA also amended the patent statute to provide that “courts of the United States shall, to the extent consistent with the Constitution, have subject matter jurisdiction in any action brought  . . . under [28 U.S.C. § 2201] for a declaratory judgment” of invalidity or noninfringement.

In the last few of years, the Federal Circuit has addressed the proper jurisdictional scope of the “case or controversy” requirement under Article III of the U.S. Constitution for a court to have jurisdiction in ANDA Hatch-Waxman declaratory judgment actions where a patent covering the Reference Listed Drug is listed in the Orange Book.  Most recently, in Teva Pharms. USA, Inc. v. Eisai Co., the Federal Circuit ruled that “[w]hen an Orange Book listing creates an ‘independent barrier’ to entering the marketplace that cannot be overcome without a court judgment that the listed patent is invalid or not infringed – as for Paragraph IV filers – the company manufacturing the generic drug has been deprived of an economic opportunity to compete.  A declaratory judgment redresses this alleged injury because it eliminates the potential for the corresponding listed patent to exclude the generic drug from the market.” (Internal citations omitted.)

Given the Federal Circuit’s recent ruling, Apotex argues:

By listing the ‘941 patent and the ‘069 patent in the Orange Book and not suing Apotex on those patents, Defendants have created patent and legal uncertainty that impairs Apotex’s right to market a non-infringing generic product without the risk of catastrophic infringement damages.  By virtue of Defendants’ actions, Apotex is also suffering an “FDA-approval-blocking-injury” or “the harm of being unable to launch . . . generic products covered by the [Apotex] ANDA” because of another applicant’s so-called 180-day exclusivity.  This patent and legal uncertainty and impairment of Apotex’s rights are, alone or in combination, sufficiently concrete and cognizable injuries-in-fact that are fairly traceable to the Defendants and that can be redressed only by a declaratory judgment from this Court.

Apotex’s recent Complaint concerning generic LEXAPRO is not the only case in which the company is arguing that the Federal Circuit’s ruling in Teva Pharms. USA, Inc. v. Eisai Co. creates declaratory judgment jurisdiction to obtain a court decision to trigger a first-filer’s 180-day exclusivity.  In Pfizer Inc. v. Apotex Inc., Case No. 1:08-07231, which is pending in the U.S. District Court for the Northern District of Illinois (Eastern Division), Apotex is seeking a declaratory judgment to create a court decision to trigger 180-day exclusivity for generic LIPITOR (arotvastatin calcium) Tablets, which is reportedly held by Ranbaxy.  Both of the pending Apotex cases, which were brought following what appears to be an increasing trend with some companies in deciding not to sue within the statutory 45-day period (and obtain a 30-month stay on ANDA approval) but rather following a wait-and-see approach, should add some helpful interpretation on the scope and effect of the Federal Circuit’s October 2010 decision.

By Susan J. Matthees –

FDA is announcing that it is taking steps to reduce the maximum dosage strength of acetaminophen in prescription combination products to 325 mg in a single dosage unit.  The Agency will also require safety labeling changes, including a boxed warning, for products that contain acetaminophen.  The changes will apply only to prescription drug combination products, not OTC products.  FDA has established a website to keep people informed about the changes. 

In a Federal Register notice, which is being published on January 14, 2011, FDA states that the changes were precipitated by the safety risks associated with acetaminophen.  Although FDA acknowledges that the recommended doses of acetaminophen do not, unlike other pain drugs, cause gastro-intestinal discomfort or bleeding, and that most people’s glutathione levels are sufficient to prevent liver damage, FDA states that the fact that some people are at increased risk for liver injury from acetaminophen is sufficient reason to warrant limiting the dosage strength of the drug.  FDA also notes that “there is a high incidence of cases of unintentional acetaminophen overdose” due to a variety of factors, including consumers taking more than their prescribed dose of pills unaware that they are taking too much acetaminophen and patients who are unaware that their prescription drugs contain acetaminophen because the ingredient is often identified as “APAP” or “ACET.” 

FDA will send sponsors of NDA and ANDA prescription acetaminophen products a letter notifying them of the required labeling changes.  FDA cites section 505(o) of the Federal Food, Drug, and Cosmetic Act (which was part of the 2007 Food and Drug Administration Amendments Act) as its authority to require safety-related labeling changes based on new safety information.  Pursuant to section 505(o), sponsors will have 30 days from the date of the letter to submit to FDA a new label or a statement detailing the reasons why the change is not warranted.  Sponsors will have until January 14, 2014, to request that FDA withdrawal approval of products containing more than 325 mg of acetaminophen.  FDA states that sponsors with approved products with more than one dosage strength, such as a dosage strength above 325 mg and below 325 mg, need only request withdrawal of approval for the higher dosage strength product and will not have to submit an application for approval of the lower strength product.  However, sponsors without a lower dosage strength will need to develop a new product strength and submit an application for approval.  FDA believes that these products will likely be approved through the ANDA process.  FDA also intimates that if companies do not voluntarily withdraw combination products that contain more than 325 mg of acetaminophen in a single dose that FDA will use the NDA withdrawal authority under section 505(e) to remove these products from the market.

By Ricardo Carvajal & Wes Siegner –

As we would wager is true of all major pieces of legislation, the Food Safety Modernization Act (“FSMA”) can be expected to have significant unanticipated consequences.  By way of background, the FSMA requires all food facilities subject to registration under FDC Act § 415 to implement a HACCP-type system (or in the terms of the FSMA, Hazard Analysis and Risk-Based Preventive Controls – but that yields an ugly acronym).  There are exceptions, one of which applies to “any facility with regard to the manufacturing, processing, packing, or holding of a dietary supplement that is in compliance with the requirements of sections 402(g)(2) and 761” of the FDC Act.  Section 402(g)(2) authorizes FDA to prescribe good manufacturing practices (GMP) for dietary supplements, and § 761 requires serious adverse event reporting for dietary supplements. 

Generally, dietary ingredient suppliers aren’t subject to FDA’s dietary supplement GMP regulation (but they can be under certain circumstances, as discussed in FDA’s recent guidance for small businesses).  Further, the reporting requirement under § 761 applies only to the manufacturer, packer, or distributor of a dietary supplement whose name appears on the label.  Given these circumstances, it appears that the FSMA’s exemption from HACCP for dietary supplement facilities could be interpreted to not apply to dietary ingredient facilities, thereby making these facilities subject to the mandatory HACCP requirement.  This result would seem to make little sense in light of FDA’s conclusion when it issued the final dietary supplement GMP rule that the quality of dietary supplements could be achieved without subjecting all dietary ingredient suppliers to the GMP rule.  Given that the HACCP requirement takes effect 18 months after FSMA’s enactment, and that operation of a facility that doesn’t comply with the HACCP requirement is a prohibited act, affected entities will want a seat at the table when FDA drafts the implementing regulation. 

By Riëtte van Laack –

As previously reported here, on Dec. 8, 2010, FDA issued a proposed rule to amend the interim final rule (“IFR”) for the phytosterol health claim.  In the preamble to that proposal, the agency stated its intent to discontinue its policy of enforcement discretion that has been in effect since 2003, by February 22, 2011, and instead exercise enforcement discretion with respect to claims that comply with the proposed rule.  This change in exercise of enforcement discretion would cause dietary supplements containing unesterified phytosterols to no longer be eligible for the health claim.  Moreover, as a result of the stated change, many conventional foods would no longer be eligible for the health claim because the level of phytosterols in many of those foods is below 500 mg per serving, or because the phytosterol used has not been the subject of a GRAS notification to FDA. 

Not surprisingly, this announcement of a dramatic shift in enforcement discretion policy, which has been in effect for seven years, has created a stir in the industry.  On December 22, 2010, the Council for Responsible Nutrition (“CRN”) requested an extension of 18 months to allow dietary supplement companies to reformulate products or modify their labeling.  According to CRN, 18 months will be sufficient to complete reformulation and exhaust current inventory of dietary supplements containing free phytosterols.  An 18-month extension also would be consistent with FDA precedent providing food and dietary supplement companies with at least two years to come into compliance with labeling changes. 

More recently, Cargill, Inc. (“Cargill”) submitted a petition requesting a stay of the change in enforcement discretion until a final rule is issued.  According to Cargill, the sudden change in enforcement discretion would cause many phytosterol products (conventional foods as well as dietary supplements) to no longer be eligible for the phytosterol health claim.  Relabeling or reformulating these products by February 22, 2011, is not feasible.  Thus, a large number of conventional foods and the majority of phytosterol-containing dietary supplements would need to be pulled from the market.  Cargill estimates that relabeling or reformulating these products will take 16 to 34 months. 

As pointed out by Cargill, the change in enforcement discretion policy appears premature.  After all, the proposed rule is just that, a proposal.  It is likely that FDA will revise the proposed rule based on comments and information submitted in response to the notice of proposed rulemaking.  As a result, a company may find itself in the position of having to reformulate and relabel its products twice; first to come into compliance with the proposed rule, and then to come into compliance with the final rule.  Thus, rather than requesting an extension of time to bring its products into compliance with the proposed rule, Cargill requests a stay until the rule is final.

By Kurt R. Karst –      

In a Complaint lodged against the U.S. Patent and Trademark Office (“PTO”) in the U.S. District Court for the Eastern District of Virginia last September, but only recently served, the Genetics & IVF Institute (“GIVF”) is challenging the PTO’s August 2010 denial of a Patent Term Extension (“PTE”) for U.S. Patent No. 5,135,759 (“the ‘759 patent”), which covers a method to preselect the sex of offspring.  The patent is for a medical device for sperm sorting apparatus that is the subject of a Premarket Approval application (“PMA”) undergoing FDA review.  The ‘759 patent is owned by the U.S. Department of Agriculture (“USDA”) and is exclusively licensed to GIVF.

Under the PTE statute at 35 U.S.C. § 156(d)(5)(A), the PTO may grant an interim patent extension while a PMA 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 of the patent term in effect.”  To request an initial interim PTE, the owner (or his agent) submits an application to the PTO “during the period beginning 6 months, and ending 15 days before such term is due to expire.”  The statute provides that a total of 5 interim PTEs may be granted.  After the initial interim PTE is granted, 35 U.S.C. § 156(d)(5)(C) provides that “[e]ach such subsequent application shall be made during the period beginning 60 days before, and ending 30 days before, the expiration of the preceding interim extension” (emphasis added).

The 17-year term of the ‘759 patent was set to expire on August 4, 2009; however, the USDA requested, and the PTO granted, an interim PTE for a period of one year, through August 4, 2010.  Just days before the interim PTE was going to expire, the USDA, on July 27, 2010 petitioned the PTO under 37 C.F.R. §§ 1.182 and 1.183 for an extension of time to file a second interim PTE and also a request for a second subsequent interim PTE.  Sections 1.182 and 1.183 relate to mechanisms for persons to file petitions to seek waiver of a rule or relief from the enforcement of a rule.  The USDA argues in its petition, among other things, that the language, structure, and purpose of the PTE statute give the PTO discretion to grant a second subsequent interim PTE outside of the timing window of 35 U.S.C. § 156(d)(5)(C).  In particular, the USDA argues that the PTE statute at 35 U.S.C. § 156(a) states that a PTE “shall” be granted provided certain conditions are met, and the USPTO’s implementing regulation at 37 C.F.R. § 1.720(a) uses the word “may.”  Thus, according to the USDA, if the word “shall” means “may” to the PTO for purposes of 35 U.S.C. § 156(a), then the word “shall” in 35 U.S.C. § 156(d)(5)(C) should also mean “may,” and the PTO has discretion to grant the USDA’s untimely request for a second subsequent interim PTE for the ‘759 patent.

The PTO was unconvinced and on August 2, 2010 denied both the USDA’s petition and request for a second subsequent interim PTE. 

As an initial matter, the PTO ruled that 37 C.F.R. §§ 1.182 and 1.183 do not permit an extension of the time period to request a second subsequent interim PTE.  “Because the relief that petitioner seeks is from a statute, the USPTO, without any statutory authority to grant such relief, cannot excuse failure to comply with the statutory timing requirement of § 156(d)(5)(C), and thus must deny the petition under 37 C.F.R. § 1.182,” states the PTO in its ruling.  Similarly, with respect to the USDA’s petition under 37 C.F.R. § 1.183, the PTO ruled that “Petitioner’s situation is controlled by statute, thus, there is no rule which can be waived which would provide sufficient relief.”

With respect to the meaning of the word “shall” in the PTE statute, the PTO states that as a general matter “the best definition of ‘shall’ as used throughout section 156 indicates an imperative duty based upon the text, structure, and purpose of the statute.”  Moreover, the USDA’s “shall/may” argument is misplaced, according to the PTO:

Petitioner’s argument fails to appreciate the “if” at the end of the introduction to 37 C.F.R. § 1.720(a).  Specifically, the rule states, “[t]he term of a patent may be extended if.”  The use of “if” in the rule language serves to require certain information in order for the Director to have authority to issue an extension.  Thus, the “may” to which petitioner refers, when read in conjunction with the “if” of the phrase, actually means “may only.”  In essence, the USPTO may only grant a patent term extension if certain conditions are met.  Because the USPTO may only grant a patent term extension is certain conditions are met, the “may . . . if” of 37 C.F.R. § 1.720 has the effect of requiring a timely filing, i.e. “shall.”  The USPTO’s use of “may . . . if” does not mean that the USPTO is departing from “shall.” [(Emphasis in original)]

GIVF, as the exclusive licensee of the now-expired ‘759 patent, sued the PTO under the Administrative Procedure Act, and asks the court to, among other things, vacate and set aside the PTO’s August 2nd decision and to declare that the PTO has the discretion to extend the term of the ‘759 patent for the full period required under 35 U.S.C. § 156.  The arguments in GIVF’s Complaint echo some of those made by the USDA in its petition and request for a second subsequent interim PTE.  In particular, GIVF argues that:

The language, structure, and purpose of § 156 give the USPTO discretion to authorize a second interim [PTE] sought outside the statutory window.  Though § 156 states that “[t]he term of a patent . . . shall be extended” as long as certain criteria are met, .the regulations promulgated pursuant to this statute do not use the word “shall.”  Instead, they list the same statutory criteria, and state that the [sic] “[t]he term of a patent may be extended.” [(Internal citations omitted)] 

And pulling the U.S. District Court for the Eastern District of Virginia’s March 2010 decision (and later August 2010 decision) concerning a late-filed PTE application for ANGIOMAX out of it’s back pocked, GIVF notes that:

Indeed, this Court recently recognized in a similar matter that “[t]here is a strong presumption that when Congress repeats the same word in the same statute, it intends for that word to be given the same meaning.”  If the word “shall” in § 156(a) means “may” as the USPTO seems to indicate in its own regulations, then that word should have the same meaning in § 156(d)(5)(C) as well.  Given the permissive, discretionary nature of the word “shall” in § 156, it stands to reason that the USPTO has the discretion to approve USDA’s petition for a second interim [PTE]. [(Internal citation omitted)]

GIVF also takes issue with the PTO’s decision that 37 C.F.R. §§ 1.182 and 1.183 do not permit an extension of the time period to request a second subsequent interim PTE.  According to GIVF, both sections provide the PTO with ample discretion to remedy the USDA’s “mild tardiness” in untimely requesting a second subsequent interim PTE.

Hyman, Phelps & McNamara, P.C.'s Jeff Shapiro published an article in this month's MD&DI magazine -  What Happens to Medical Device Reports Once They Reach FDA?  In the article, he summarizes a Office of Inspector General Report finding that FDA has not used medical device reporting ("MDR") data to improve medical device safety.  He suggests that eliminating malfunction MDRs would significantly reduce the burden on industry and FDA, and would allow FDA to better focus on device problems that cause actual serious injuries or deaths.

By Ricardo Carvajal –

The American Bar Association’s Section of Ligation (specifically the Food and Supplements Subcommittee of the Products Liability Committee) is presenting its First Annual Workshop on Food and Supplements on February 17 in Atlanta.  Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal will be co-moderator for a session on the impact of the Food Safety Modernization Act and other reforms on the food industry.  The program will also address state consumer laws and class actions related to packaging, labeling, and marketing; the evolving science of food safety and technology; ethical considerations in the labeling of biologically active foods; and predictions for the future of food labeling and regulation.  A brochure with additional information is available here and on-line registration is available here.

By Kurt R. Karst –      

In a January 7th letter sent to FDA Commissioner Margaret Hamburg, a group of four U.S. Senators take exception to FDA’s recent characterization of the 12-year exclusivity period provided by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) as a period of “market exclusivity” instead of “data exclusivity.”  The Senators also take the opportunity to remind FDA that the BPCIA allows for a separate period of exclusivity for new biological products. 

The letter, signed by Senators Kay Hagan (D-NC), Orrin Hatch (R-UT), Michael Enzi (R-WY), and John Kerry (D-MA), raises the same two issues some House members – the principal authors of the BPCIA – raised in a December 2010 letter to FDA.  As we previously reported, the House letter notes “significant and critical differences between the two types of exclusivity” (i.e., data and market exclusivity) and says that while so-called “evergreening” is not permitted under the BPCIA, “if a ‘next generation’ product is approved by the FDA as a new product (significant changes in safety, purity, or potency) then that new biologic will receive its own 12-year period of data exclusivity.” 

The January 7th Senate letter, which similarly seeks to clarify the exclusivity vernacular and to lay an early foundation for what are certain to be future battles over the availability and scope of the exclusivity period created by the BPCIA, states:

The [BPCIA] does not provide market exclusivity for innovator products.  It provides data exclusivity, which prohibits FDA from allowing another manufacturer of a highly similar biologic to rely on the Agency's prior finding of safety, purity and potency for the innovator product for a limited period of time.  It does not prohibit or prevent another manufacturer from developing its own data to justify FDA approval of a full biologics license application rather than an abbreviated application that relies on the prior approval of a reference product. . . . 

At the same time, the Act provides incentives for innovators to research and develop new treatments for patients.  If a manufacturer modifies an approved product to produce a change in safety, purity or potency, the modified product is rightly considered a new product.  It will be protected by the data exclusivity provisions afforded new products. Exclusivity on the first generation product will expire as scheduled.

For those of you who are interested in a further discussion of data versus market exclusivity, which folks have tussled over for years, our friend Steve Grossman over at FDA Matters had a nice post on the topic last year in the context of the BPCIA.

The BPCIA’s 12-year exclusivity period (which can be extended to 12.5 years with pediatric exclusivity) has been criticized from several quarters.  Late in 2010, Senator Bernie Sanders (I-VT) even said that the BPCIA’s 12-year exclusivity provisions create an ethical “defect” and should be changed.  (See our previous post here.) 

Taking a somewhat different position than Sen. Sanders on the topic of exclusivity are the authors of a recent article published in Health Affairs, titled “The Benefits From Giving Makers of Conventional ‘Small Molecule’ Drugs Longer Exclusivity Over Clinical Trial Data.”  The article details the results of a study (apparently the first of its kind, and funded by INTERPAT, “an association of research-based pharmaceutical companies,” and by the National Institute on Aging) intended to calculate the financial and social costs of limiting access to trial data.  The article focuses on small molecule drugs, which are subject to the Hatch-Waxman Amendment’s 5-year new chemical entity and 3-year new clinical investigation exclusivities, but asks whether a longer period of exclusivity, like the BPCIA’s 12-year period, would benefit innovation, population longevity, and social welfare.  Guess what?  According to the authors, extending data exclusivity to 12 years would (1) “increase lifetime drug revenues by 5 percent, on average;” (2) “result in 228 extra drug approvals between 2020 and 2060, relative to the number of approvals that we project under the current Hatch-Waxman data exclusivity provisions;” and (3) for people turning 55 in 2060, they “can expect increased life expectancy of 1.44 years as opposed to 1.30 years under the status quo.”