By Susan J. Matthees –

FDA is withdrawing its draft guidance titled “Draft Guidance for Industry:  Questions and Answers Regarding Implementation of the Menu Labeling Provisions of Section 4205 of the Patient Protection and Affordable Care Act of 2010,” which was published in August 2010.  As we blogged in August, the draft guidance consisted of commonly asked questions and answers about implementation of PPACA § 4205, which requires disclosure of calories and additional nutrition information on the menus of chain restaurants. 

The draft guidance was intended to help industry comply with the provisions of the PPACA § 4205 that became effective upon enactment, and in it FDA stated it would delay enforcement of those provisions until it published a final guidance document, which it anticipated would be in December 2010.  FDA did not meet that anticipated date.  In announcing the withdrawal of the draft guidance, FDA states that it received “extensive comments” on the draft guidance, and it now intends to finalize notice and comment rulemaking of the regulations implementing PPACA § 4205 before initiating enforcement actions.  FDA states it intends to publish the proposed regulations by March 23 and will consider the comments to the draft guidance in publishing its proposed regulations.  FDA states it hopes this approach will “minimize uncertainty and confusion” and lead to consistent disclosure of nutrition information.
 
Note that FDA is not withdrawing its guidance document on the effect of PPACA § 4205 on state and local menu and vending machine labeling laws, which was published at the same time as the withdrawn draft guidance.

By Kurt R. Karst –      

Yesterday, we posted on FDA’s report to Congress on encouraging the early submission of citizen petitions covered by FDC Act § 505(q).  Today, we take a look at the two annual reports FDA has submitted to Congress detailing the Agency’s experience with implementing FDC Act § 505(q).

Both the Fiscal Year 2008 report and the Fiscal Year 2009 report, sent to Congress on April 28, 2009, and July 29, 2010, respectively, are required by FDC Act § 505(q)(3).  According to that provision, each annual report to Congress must specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  The stats for each of these categories, by fiscal year (although the Fiscal Year 2008 report covers the period of September 27, 2007 through September 30, 2008), are as follows:

The number of ANDAs and 505(b)(2) applications that were approved during the preceding 12-month period.

Fiscal Year 2008 – 476 ANDAs and 31 505(b)(2) applications approved

Fiscal Year 2009 – 489 ANDAs and 35 505(b)(2) applications approved

The number of such ANDAs and 505(b)(2) applications whose effective dates were delayed by a 505(q) petition during the preceding 12-month period.

Fiscal Year 2008 – The effective dates of 2 ANDAs were delayed by the same petitions (submitted by another ANDA sponsor);

Fiscal Year 2009 – The effective date of one ANDA was delayed by a petition

The number of days by which such ANDAs and 505(b)(2) applications were so delayed.

Fiscal Year 2008 – Each of the 2 delayed ANDAs was delayed by 138 days 

Fiscal Year 2009 – The one delayed ANDA was delayed by 27 days

The number of 505(q) petitions that were submitted during the preceding 12-month period.

Fiscal Year 2008 – 21 505(q) petitions

Fiscal Year 2009 – 31 505(q) petitions

And what about FDA’s ability to meet the statutory 180-day timeframe to respond to 505(q) petitions?  FDA does not provide that information for the Agency’s Fiscal Year 2008 report, but according to the Fiscal Year 2009 report, “FDA responded to 23 petitions subject to section 505(q) within the 180-day statutory timeframe.”  That would appear to mean that FDA failed to meet the timeframe for 8 of the covered petitions.  FDA’s pursuit to timely respond to 505(q) petition is apparently causing a drain on Agency resources.  According to the Fiscal Year 2009 report, “FDA has met the 180-day timeframes for these petitions by redirecting efforts previously directed to other work.” 

After two year of experience in implementing section 505(q), FDA “believes it may still be too early to make a determination as to whether section 505(q) is effectively discouraging petitions submitted with the primary purpose of delaying approval of an ANDA or 505(b)(2) application,” but the Agency notes that “the number of 505(q) petitions submitted during fiscal year 2009 increased by more than 47 percent over the number submitted during the first reporting period.”  By our count, the number of 505(q) petitions submitted in Fiscal Year 2010 is roughly the same as the number of petitions submitted in Fiscal Year 2009. 

FDA wraps up the Fiscal Year 2009 report by noting some “areas of concern.”  Specifically:

FDA continues to receive 505(q) petitions from ANDA and 505(b)(2) applicants and not solely from innovator companies;

FDA is seeing an increase in petitions for reconsideration pursuant to 21 CFR 10.33, requiring the agency to readdress issues that have already been decided; and

FDA has also received serial 505(q) petitions frequently from the same petitioner about a specific drug product or class of drug products, sometimes resulting in several petition responses about different aspects of the same product.

A couple of these concerns are carryovers from FDA’s Fiscal Year 2008 report and from the Agency’s initial report to Congress on encouraging the early submission of citizen petitions covered by FDC Act § 505(q), but could, according to FDA, become trends that  upset the primary purpose of FDC Act § 505(q).  “If these areas of concern become trends,” FDA says in the 2009 report, “they may undermine the goal of discouraging the submission of petitions that do not raise valid scientific issues and have the effect of improperly delaying approval of ANDAs or 505(b)(2) applications.”

FDC Act § 505(q) is not one of those statutory provisions, like the Prescription Drug User Fee Act or the Best Pharmaceuticals for Children Act, that is up for reauthorization at the end of Fiscal Year 2012.  Nevertheless, we would not be surprised if there is an effort to amend FDC Act § 505(q) to address some of FDA’s and industry’s concerns with the provisions and to make them more effective.  Despite the apparent drain on FDA resources, we think FDC Act § 505(q) has, if nothing else, provided more timely advice and greater transparency into FDA’s thinking on important Hatch-Waxman issues. 

By Kurt R. Karst –      

On January 24th, the U.S. Court of Appeals for the Ninth Circuit issued its decision in Gaeta v. Perrigo, reversing a decision from the U.S. District Court for the Northern District of California (San Jose Division) that Plaintiff-Appellant Gaeta’s state law causes of action were preempted by the FDC Act to the extent that they allowed for liability based on a lack of adequate warning on Perrigo’s Over-the-Counter (“OTC”) ibuprofen drug product.  With its decision, the Ninth Circuit joins the Fifth and Eighth Circuits, which ruled in Demahy v. Actavis, Inc., 593 F.3d 428 (5th Cir. 2010) and Mensing v. Wyeth, Inc., 588 F.3d 603 (8th Cir. 2009), that the U.S. Supreme Court’s March 2009 decision in Wyeth v. Levine “extends with equal force to claims against generic manufacturers.”  In Levine, the U.S. Supreme Court ruled, in the context of a brand-name prescription drug, that FDA labeling approval does not preempt state laws.  In December 2010, the U.S. Supreme Court decided to hear appeals in both the Mensing and Demahy cases.  

By way of background, the decision in Gaeta stems from an alleged injury from consuming OTC ibuprofen that led to a liver transplant and other complications.  The Gaetas allege that Perrigo and several other generic ibuprofen manufacturers failed to warn physicians and consumers of an increased risk of acute liver injury and renal failure when ibuprofen is taken with other drug products.  As we previously reported, the district court found that Gaeta’s state law causes of action were preempted to the extent that they allowed for liability based on a lack of adequate warning on Perrigo’s drug product.  Gaeta had argued that “although the specific facts of Levine involved a brand-name drug, the Court’s holding was broad enough to also encompass the interaction between FDA regulations and state tort law with regard to generic drugs.”  The court disagreed, however, ruling that “Levine does not govern whether the Court may grant summary judgment on Plaintiff’s state tort claims,” because “Levine did not address a dispositive issue in this case, namely, whether a generic drug manufacturer may use the [Changes Being Effected (‘CBE’)] process to make warning-label changes without prior FDA approval.”

In reversing the district court’s decision, the Ninth Circuit rejected both of Perrigo’s conflict preemption arguments – that the Gaetas’ claims are conflict preempted because (1) “it is impossible for Perrigo to comply with both the state-law duties to warn and the federal regulatory regime governing generic drugs,” and, alternatively, (2) “they obstruct the full accomplishment of the purposes and objectives of Congress in enacting the Hatch-Waxman Amendments.”

The Ninth Circuit’s decision that there is no impossibility of compliance in this case (as in Demahy and Mensing) is based on the Court’s determination that the FDC Act provides generic drug manufacturers “with at least three separate mechanisms by which they can discharge their state-law duty to warn of additional risks associated with their products: (a) the CBE process approved by the Supreme Court in Levine; (b) the ‘prior approval’ process; and (c) by asking the FDA to send ‘Dear Doctor’ warning letters to health care professionals.”  Interestingly, however, both the U.S. Solicitor General and FDA have recently stated in amicus briefs (here and here) that although FDA may coordinate appropriate Dear Health Care Professional letters or take other action with respect to labeling, the CBE and prior approval supplement processes are not available to generic drug sponsors. 

The Ninth Circuit also joined the Fifth and Eighth Circuits in ruling that there is no obstruction of purpose of the Hatch-Waxman Amendments in exposing generic drug manufacturers to liability.  “We join those two circuits in concluding that while the Hatch-Waxman Amendments were meant to provide an inexpensive and easy way for generic drugs to enter the market, they were not intended as a relief from the fundamental requirement of the FDCA that all marketed drugs remain safe,” says the Circuit Court.  Moreover, according to the Court, “Perrigo’s argument that consumers will lose confidence in generic drugs if they contain warnings different from those of the brand name drugs also fails” for three reasons. “First, it is purely speculative that consumers will opt for a more expensive brand name product . . . if the less expensive generic product contains additional warnings.”  Second, “there is no indication Congress intended consumers to have access to low cost drugs at the expense of safety.”  Third, “by using the ‘prior approval’ process,” which we note once again FDA has said is not available to generic drug sponsors, “a generic manufacturer can avoid consumer confusion because, if the FDA accepts the proposed change, that change would be imposed uniformly on both generic and brand name manufacturers.”

By Ricardo Carvajal –

When FDA issued a report on the Reportable Food Registry ("RFR") 7 months after the RFR’s implementation, the agency cautioned that it was “too early to draw inferences concerning patterns of food and feed adulteration.”  Not so in the agency’s first annual report on the RFR, which is claimed to contain data that “represent an important tool for targeting [FDA’s] inspection resources, bringing high risk commodities into focus, and driving positive change in industry practices – all of which will better protect the public health.”  The annual report confirms what was becoming apparent at the 7-month mark – foodborne pathogens (especially Salmonella) and undeclared allergens/intolerances are the principal culprits, together accounting for more than 85% of RFR reports. 

The report describes numerous agency initiatives associated with the RFR, including import alerts and bulletins, field assignments, and guidance and other publications.  The report also describes RFR-associated industry initiatives, such incorporation of RFR requirements into audit standards, industry guidance for spices and baked goods, and incorporation of RFR-related provisions into supply agreements.  Manufacturers and distributors of commodities that feature prominently in the RFR can expect to continue to receive FDA’s attention as the agency begins to implement the Food Safety Modernization Act, which dictates risk-based allocation of FDA resources. 

Notably, FDA expresses concern over the relatively small number of RFR reports from foreign facilities, which handily outnumber domestic facilities.  FDA intends to build awareness of RFR requirements in the international arena in 2011.

By Kurt R. Karst –      

Reports FDA submitted to Congress on the Agency’s implementation of FDC Act § 505(q) recently became available and show that only a few applications have been delayed by certain citizen petitions covered by the law, and that the Agency is timely responding, one way or another, to many of the covered citizen petitions.  The reports also show, however, that FDA is wrestling with implementing some of the statutory provisions and is concerned about some unintended consequences.  This is Part I of a two-part post on those reports. 

FDC Act § 505(q) was added to the law by § 914 of Title IX of the FDA Amendments Act of 2007 (“FDAAA”), Pub. L. No. 110-85 (2007), as amended by § 301 of Pub. L. No. 110-316 (2008), and is intended to prevent the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) applications.  Briefly, FDC Act § 505(q) provides that FDA shall not delay approval of a pending ANDA or 505(b)(2) application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under FDC Act § 505(q), which FDA has interpreted to apply only to certain petitions submitted to the Agency after September 27, 2007, “[FDA] shall take final agency action on a petition not later than 180 days after the date on which the petition is submitted.”  FDA may not extend the 180-day period “for any reason,” including consent of the petitioner, and may summarily deny a petition submitted with the primary purpose of delaying ANDA or 505(b)(2) application approval. 

FDC Act § 505(q) does not apply to all citizen petitions.  Excluded from the new law are petitions that relate “solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv)” (i.e., 180-day exclusivity), and petitions that are made by an ANDA or 505(b)(2) sponsor “that seeks only to have [FDA] take or refrain from taking any form of action with respect to that application.”  Petitions subject to FDC Act § 505(q) must include a specific certification identified in the new law, and petition supplements and comments must include a specific verification statement.  FDA Law Blog vigilantly follows 505(q) petitions and our FDC Act § 505(q) Citizen Petition Tracker has been a big hit.  (It beats wading through Regulations.gov to find a particular citizen petition or FDA petition response.)

In January 2009, FDA published a draft guidance document titled “Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act.”  (See our previous post here.)  The draft guidance describes FDA’s interpretation of FDC Act § 505(q), including how FDA determines if § 505(q) applies to a particular petition, and whether such a petition would delay approval of a pending ANDA or 505(b)(2) application.  According to a December 2010 Federal Register notice, FDA is in the process of finalizing the guidance.

Both FDAAA and FDC Act § 505(q) include separate provisions requiring FDA to report on how to encourage early citizen petition submission and on the Agency’s experience with implementing the law.  Specifically, FDAAA § 914(b) states that “[n]ot later than 1 year after the date of the enactment of this Act [(i.e., September 27, 2008)], the Secretary of Health and Human Services shall submit a report to the Congress on ways to encourage the early submission of petitions under section 505(q). . . .”  FDC Act § 505(q)(3) requires FDA to submit an annual report to Congress that specifies, “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”

FDA’s February 9, 2009 report, which is the focus of today’s post, is titled “Encouraging Early Submission of Citizen Petitions and Petitions for Stay of Agency Action,” and fulfills the requirement under FDAAA § 914(b).  The report describes several FDA initiatives to encourage early submission of certain petitions so that the petitions can be received in time to avoid a delay in ANDA or 505(b)(2) application approval.  Although FDA has already implemented some of these initiatives, such as the establishment of the Agency’s Individual Product Bioequivalence Recommendations database and the Paragraph IV Certifications list (both of which are specific to ANDAs), other initiatives are still under consideration.  In particular, FDA is still considering whether it is appropriate to answer a 505(q) petition raising bioequivalence issues for a particular drug product with a very brief response when a draft bioequivalence guidance has already been published or when a petition is submitted to FDA more than a certain number of days after the Agency publishes a final bioequivalence guidance.  According to FDA:

The rationale for such an approach is that the petitioner already had an opportunity to raise these issues in the context of a proposed product specific guidance.  Whether or not anyone raises an issue in the context of a bioequivalence guidance, where someone disagrees with FDA's bioequivalence recommendations issued in a final guidance and chooses to raise those issues in a petition, the objections can be raised shortly after the publication of a final guidance because the petitioner should have been aware of both the draft and the final guidance.  An exception to this could be if the petition contains material new information not previously considered by the agency.

Another brief response option FDA is considering concerns 505(q) petitions involving ANDAs containing Paragraph IV certifications.  According to FDA:

Another possible means to encourage the early submission of 505(q) petitions that involve ANDAs with paragraph IV certifications – or more precisely, discourage their late submission – is to establish a policy under which FDA may, if appropriate, issue only a brief response to a petition that raises any issues pertaining to the approval of an ANDA if the petition is submitted more than a certain number of days after the filing of the first substantially complete ANDA using a particular listed drug as the basis of its submission and containing a paragraph IV certification.  Again, a possible exception that FDA could invoke would be situations where the agency determines that a petition contains material new information not previously considered.

Implementing both brief response options FDA discusses in the report or issuing a summary denial of a petition pursuant to FDC Act § 505(q)(1)(E) could be difficult because of some “potential statutory impediments.” 

Under FDC Act § 505(q)(1)(E), FDA can summarily deny a petition if: (1) the Agency determines the petition was submitted with the primary purpose of delaying the approval of a pending ANDA or 505(b)(2) application; and (2) the petition does not obviously raise valid scientific or regulatory issues.  The provision also states that FDA “may issue guidance to describe the factors that will be used to determine . . . whether a petition is submitted with the primary purpose of delaying the approval of an application.”

Because both of the preconditions stated above must be met for FDA to summarily deny a 505(q) petition, the Agency believes the statutory standard “would be extremely difficult to meet.  In fact, we are not aware of a single case since the enactment of FDC Act § 505(q) in which FDA has invoked FDC Act § 505(q)(1)(E) to deny a citizen petition.  “Although a petition may not raise persuasive scientific or regulatory issues when those issues have been reviewed by FDA, a petition can easily raise valid scientific or regulatory issues,” says FDA in the report, making it nearly impossible for the Agency  to divine intent to delay.  FDA acknowledges that the Agency “could issue guidances describing petitions filed under certain circumstances that would give rise to the presumption that a petition was filed with the primary purpose to delay approval of an ANDA or 505(b)(2) application,” but “given the statutory standard in 505(q)(1)(E) for summary denial of petitions, the agency does not believe issuing a guidance on delay would allow the summary denial of petitions under this provision.  Without any significant impediment to filing a late petition, such as summary denial, it may be difficult to encourage the early submission of petitions under 505(q).”  Moreover, “if FDA was able to issue a summary denial or brief response to a petition, the agency would still want to have an adequate internal record that the merits of any relevant substantive issues had been addressed in the consideration of affected applications.”

FDA concludes the 2009 report by noting that with only one year of experience with § 505(q) under the Agency’s belt, it is premature to determine the impact of FDC Act § 505(q), and “particularly whether petitions that may delay approval of an application are being discouraged overall.”  (This is a question that a subsequent annual report appears to answer.)  The Agency also notes some potential “unintended consequences” (a couple of which are deemed “areas of concern” in a later annual report):

• Many 505(q) petitions have been filed by companies that hold ANDA applications or have applications pending before FDA, rather than by innovator companies that hold the NDA referenced by an ANDA or 505(b)(2) applicant.  These petitions raise issues about the standards for approval for applications that, if approved, might compete with the petitioner's approved or pending application.

• Petitions that are filed early may not be subject to 505(q) and its 180-day response deadline because, when the petition is submitted, an ANDA or 505(b)(2) application may not be pending.

• Early response to one petition may give rise to a new petition raising additional issues or a petition for reconsideration. These new petitions could cause additional work and delay approval of ANDAs or 505(b)(2) applications. 

In Part II of this post, which will be posted tomorrow, we’ll take a look at the two annual reports FDA has submitted to Congress detailing the Agency’s experience with 505(q) citizen petitions.

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.