By Kurt R. Karst –      

Within moments of FDA’s (Dr. Janet Woodcock) announcement during the February 9th House Energy and Commerce hearing on generic drug and biosimilar user fees that the Agency would issue draft guidance on biosimilar product development later in the day, Twitter was, well . . . . all atwitter with the news.  Release of the draft guidances, which perhaps have been overpromised as “coming soon” since last summer, was officially announced by FDA just a couple of hours later. 

FDA issued three draft guidances, which provide the Agency’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to FDA pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The BPCIA amended the Public Health Service Act (“PHS Act”) to, among other things, create an approval pathway for biosimilar and interchangeable versions of reference products (so-called § 351(k) applications) and establish a 12-year exclusivity period for reference products licensed under PHS Act § 351(a).  FDA’s three draft guidances are pretty dense and take into consideration comments the Agency received in response to a November 2010 public hearing on BPCIA implementation, as well as FDA’s experience thus far in meeting with sponsors of biosimilar products.  (It was recently reported that FDA has held 21 Pre-IND sponsor meetings, has received 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products, and has received 9 INDs.)

Draft Guidance No. 1 – Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009:  This draft guidance document is intended to provide answers to common questions from sponsors interested in developing proposed biosimilar products.  The Q&As are grouped into three categories: (1) Biosimilarity or Interchangeability; (2) Provisions Related to Requirement to Submit a BLA for a “Biological Product;” and (3) Exclusivity (presumably carefully worded to avoid another tussle over “market” versus “data” exclusivity – see our previous post here). 

Many of the questions are drafted to elicit an initial proposed answer of “yes” or “no,” which is then futher explained and modified.  For example, FDA answers "yes" to each of the following burning questions:

• Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
• Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
• Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?

Among other things, the draft guidance provides FDA’s interpretation of the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in PHS Act § 351(i)(1).  FDA defines the term “protein” to mean “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size,” and the term “chemically synthesized polypeptide” to mean “any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.”  FDA goes on to note that the Agency considers “any polymer composed of 40 or fewer amino acids to be a peptide and not a protein.”  Therefore, says FDA, “unless a peptide otherwise meets the statutory definition of a 'biological product'“, it will be regulated as a “drug” under the FDC Act.

Draft Guidance No. 2 – Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:  This draft guidance – the longest of the three draft guidances – is where FDA lays out the Agency’s approach to determining biosimilarity.  “FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity, and recommends that sponsors use a stepwise approach in their development of biosimilar products” (italics in original) says FDA.  Under the risk-based, “totality of the evidence” approach, FDA will consider “the totality of the data and information submitted in the application, including structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data.”  Under the stepwise approach, biosimilar sponsors should evaluate at each step “the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty,” and should start with an “extensive structural and functional characterization of both the proposed product and the reference product.” 

Draft Guidance No. 3 – Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:  The final draft guidance is intended to provide recommendations to biosimilar applicants on the scientific and technical information of the CMC section of a 351(k) application, and includes an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product.  FDA notes in the draft guidance that although it applies specifically to therapeutic protein products, “the general scientific principles may be informative for the development of other proteins, such as in vivo protein diagnostic products.” 

Under the PHS Act, as amended by the BPCIA, the terms “biosimilar” or “biosimilarity” mean that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (emphasis added).  FDA’s draft guidance provides a list and discussion of various factors to consider when assessing whether products are, in fact, highly similar.

We’re likely to see quite a bit of commentary submitted to FDA on the draft guidances in the coming weeks and months.  We’ve also heard that FDA might be scheduling a public hearing to elicit further comments on and discussion of the draft documents and the Agency’s approach to biosimilarity laid out therein.   

By Kurt R. Karst –      

In music, “coda” is a term used primarily to designate a passage that brings a piece (or a movement, which may be part of a symphony – an extended musical composition) to an end – the “fine.”  A coda can be as simple as a few measures, or as complex as an entire section.  These musical terms serve as a nice metaphor for The Medicines Company’s (“MDCO’s”) decade-long battle (multi-movement symphony) to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin). 

As most folks know by now, FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000 under NDA No. 020873, and MDCO submitted its PTE application to the U.S. Patent and Trademark Office (“PTO”) on February 14, 2001 – 62 days after NDA approval, including the December 15, 2000 date of approval.  Under 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use.”  (For additional background, see our previous post here.) 

In August 2010, Judge Hilton of the U.S. District Court for the Eastern District of Virginia (Alexandria Division) granted MDCO’s Motion for Summary Judgment and ordered the PTO to consider timely filed MDCO’s PTE application for the ‘404 patent under a next business day interpretation of the PTE statute, making December 18, 2000 the operative date for beginning the 60-day period instead of December 15, 2000.  The government decided not to appeal the decision, and the PTO proceeded to request that FDA determine the regulatory review period with respect to MDCO’s PTE application for the ‘404 patent.  FDA issued a notice in December 2010 with its determination. 

ANDA sponsor APP Pharmaceuticals, LLC (“APP”) attempted to intervene in the PTE litigation before Judge Hilton; however, APP’s Motion to Intervene was denied.  APP appealed the decision to the Federal Circuit challenging not only the district court’s intervention decision, but also the underlying merits decision.  

In the meantime, Congress passed the Leahy-Smith America Invents Act (“AIA”) (Pub. Law No. 112-029).  Section 37 of the AIA, titled “Calculation of 60-Day Period for Application of Patent Term Extension” and referred to by some as “The Dog Ate My Homework Act” or the “Medco fix,” amended the PTE statute at 35 U.S.C. § 156(d), and was intended to legislatively resolve MDCO’s PTE battle.  (There were several failed attempts in Congress to pass “The Dog Ate My Homework Act” going back to 2006.)  There was a post-AIA attempt in Congress to effectively nullify Section 37, but that effort failed – see here.

Shortly after the enactment of the AIA, MDCO sent a letter to the Federal Circuit notifying the Court of the enactment of Section 37 and asserting that it resolves the merits of the ongoing ‘404 patent PTE litigation with APP.  APP vigorously disagreed that Section 37 resolved the case, however, and argued that Section 37 cannot constitutionally be applied and that Section 37 does not take effect for one year after the AIA‘s enactment (i.e., September 16, 2012).  The parties brief the issues and oral argument was held on November 15, 2011 – see our previous post here. 

Before the Federal Circuit could issue its decision on AIA Section 37, MDCO and APP entered into a settlement agreement that includes APP’s agreement to dismiss its appeal of Judge Hilton’s August 2010 decision, as well as another Hatch-Waxman patent infringement lawsuit brought in the U.S. District Court for the District of Delaware over  two other Orange Book-listed patents for ANGIOMAX – see our previous post here.  The Federal Circuit dismissed the case on January 24, 2012.

Exiting the last movement of the ANGIOMAX Symphony and moving on to the coda, the PTO issued a Notice of Final Determination on January 31, 2012 saying that the ‘404 patent is entitled to a PTE of 1,728 days that expires on December 15, 2014 – 14 years to the clendar day that FDA approved NDA No. 020873, but three days earlier than the December 18, 2000 next business day date MDCO was determined to have received notification of the approval.  Although not necessary, MDCO promptly notified the PTO on February 3, 2012 of its acceptance of the 1,728-day PTE.  While the ‘404 PTE battle has taken numerous twists and turns throughout the years and has touched all three brances of government, we expect the coda here to be short.  All that seems to be left now is for the PTO to issue a Certificate of Extension (which will look something like this) and publish the information on the Official Gazette – fine!  Adieu ANGIOMAX PTE battle.

By Kurt R. Karst –      

It’s about that time of year again when we do some number crunching and take stock of the year that was in orphan drug designations and approvals.  And what a year it was!  FDA not only approved a record 26 marketing applications for products for orphan (i.e., rare) diseases and conditions, but FDA’s Office of Orphan Products Development (“OOPD”) granted a record 199 orphan drug designation requests.   OOPD also received 306 orphan drug designation requests in 2011, which is only second to the record of 323 designation requests set in 2010 (see our previous post here).  Of the 3,659 orphan drug designation requests submitted to FDA since the enactment of the Orphan Drug Act in 1983, OOPD has granted 2,507 of them, or about 68.5%. 

The tables below show OOPD’s designation and FDA’s orphan drug approval track record.  (Additional historical information on the year-by-year designation/approval numbers since the enactment of the Orphan Drug Act in 1983 is available here.) 

 
In addition to the record numbers of orphan drug designations and approvals, 2011 also saw a change in OOPD leadership with the installment of Gayatri Rao, M.D., J.D. as Acting Director (see our previous post here), and the first U.S. Conference on Rare Diseases and Orphan Products.  At the conference, Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski announced the release of a landmark report he authored on the flexibility in FDA’s review of potential treatments for patients with rare diseases (see our previous post here).  Shortly thereafter, FDA issued a proposed rule intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since the Agency promulgated its orphan drug regulations in December 1992 (see our previous post here).  FDA also issued a report to Congress with findings and recommendations to improve the current regulatory/scientific armamentarium to facilitate the development of products for rare and neglected diseases (see our previous post here). 

The 2011 orphan drug designation and approval numbers may be difficult marks to beat; however, FDA appears to be off to a decent start in 2012 with 8 designations and 2 approvals in January.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

On February 7, 2012, Judge Amy Berman Jackson of the U.S. District Court for the District of Columbia issued her decision in the long-running dispute concerning FDA’s July 23, 2010 approval of Sandoz Inc.’s (“Sandoz’s”) ANDA No. 077857 for a generic version of Sanofi-aventis U.S. L.L.C.’s (“Sanofi’s”) anti-coagulant drug LOVENOX (enoxaparin sodium injection).  Concluding that FDA’s (1) “request for immunogenicity data in Sandoz’s ANDA was both lawful and reasonable;” (2) “approval of the drug did not constitute an arbitrary departure from agency precedent;” and (3) “determination of active ingredient sameness was [reasonable],” Judge Jackson granted Motions for Summary Judgment filed by FDA and intervenor Sandoz (here and here) and denied Sanofi’s Cross-Motion for Summary Judgment.  The 33-page decision may have important implications on future lawsuits involving the approval of generic versions of complex drug products, and perhaps even biosimilars. 

As folks might recall, Sanofi initially filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction late on July 26, 2010 requesting that the  court issue a declaratory judgment that FDA acted unlawfully in approving ANDA No. 077857, as well as a temporary restraining order and preliminary injunction directing FDA to immediately suspend and withdraw approval of the Sandoz ANDA, and a permanent injunction under the same terms (see our previous post here).  On the same day that FDA approved Sandoz’s ANDA, the Agency responded to a February 2003 Sanofi citizen petition in which the Agency outlined five criteria (i.e., standards for identity) that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX (see our previous post here).  (FDA has subsequently indicated that the Agency might be considering applying similar criteria to another complex drug product, as well as biosimilars.) 

Judge Emmet G. Sullivan, who was originally assigned the case, denied Sanofi’s motion in an opinion handed down on August 25, 2010 (see our previous post here).  Several months later, Sanofi filed its Motion for Summary Judgment (see our previous post here) arguing three points:

(1) FDA exceeded its authority under the FDC Act (specifically FDC Act § 505(j)(2)(A)) by requiring Sandoz to submit studies beyond what is permitted for ANDAs (i.e., immunogenicity studies that, according to Sanofi, are studies intended “to demonstrate safety and effectiveness,” rather than, as FDA argued, chemistry, manufacturing, and control information);

(2) FDA departed from Agency precedent by approving ANDA No. 077857 when the product has not yet been fully characterized; and

(3) FDA approved ANDA No. 077857 without sufficient evidence that the drug product has the “same” active ingredient as LOVENOX (as required by FDC Act § 505(j)(2)(A)).

Judge Jackson ruled that each issue can be decided on summary judgment as a pure question of statutory interpretation or a pure question of law. 

Did FDA exceed its authority under the FDC Act by requiring Sandoz to submit immunogenicity data as part of its ANDA?  Analyzing this issue under the familiar two-step Chevron analysis, the court ultimately agreed with FDA that the Agency has the authority to interpret the “full description” requirement of FDC Act § 505(b)(1)(D) to encompass the information FDA requires to make the findings required by FDC Act § 505(j)(4)(A) specific to ANDAs, such as immunogenicity data, stating:

Through the ANDA pathway’s specific embrace of the NDA requirements, and the imposition of the clear demands in [FDC Act § 505(j)(4)(A)], Congress rendered the ANDA requirements to be ambiguous and open to agency interpretation, and not as restrictive as the plaintiffs describe them to be.  By specifically incorporating [FDC Act § 505(b)(1)(D)] into the ANDA requirements, Congress gave FDA the authority to utilize its expertise to determine what information it needs to make the assessment it is required to make under [FDC Act § 505(j)(4)(A)].

Citing D.C. Circuit precedent, Judge Jackson noted that the Court’s observations in Serono Labs., Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998), “express a clear view that [FDC Act § 505(j)(2)(A)] does not limit the agency’s freedom to determine what kinds of information will be needed to fulfill the listed ANDA requirements.”  Moreover, writes Judge Jackson, an analysis of the statutory text both in light of the entire statutory scheme and the statute’s purpose suggest that FDC Act § 505(b)(1)(D) applicable to NDAs and included by reference in FDC Act § 505(j)(2)(A) applicable to ANDAs is ambiguous, and therefore, cannot be decided at Chevron Step I.

Moving on to Chevron Step II, the court agreed with the determination Judge Sullivan made in connection with his August 25, 2010 decision that FDA’s interpretation of the statute to include immunogenicity testing was reasonable.

According FDA the deference required under Serono to make its own determination about the information it might need, the Court finds that FDA’s interpretation of the ANDA approval regime was reasonable, and that it was reasonable for the agency to conclude that immunogenicity studies are encompassed by the “full description” described in [FDC Act § 505(b)(1)(D)].  The potential for the generic drug to elicit a different adverse response than the parent could be the result of impurities, which in turn result from the methods, facilities, and controls used to manufacture, process, and pack a drug.  By revealing what impurities remain at the end of that process, the studies shed light on, or indirectly “describe,” those methods and controls.

Did FDA depart from Agency precedent by approving a generic drug that is not fully characterized?  Giving short schrift to this argument, Judge Jackson specifically incorporates Judge Sullivan’s analysis of this issue from his August 25, 2010 decision, and writes that “[i]n making its decision to approve Sandoz’s drug before it was fully characterized, FDA ‘provided ‘legitimate reason[s]’ for deciding that enoxaparin should be treated differently than the drugs cited by Sanofi’ [(i.e., Premarin, Hyaluronidase, and Omnitrope)] and therefore satisfied the minimal standard of rationality required.”  Judge Jackson also expresses some skepticism that the Premarin, Hyaluronidase, and Omnitrope precedents in which FDA would not accept an ANDA “rise to the sort of precedent from which a departure needs to be justified,” but she further notes that the court “does not reach that question since the decision and the manner in which [FDA] diverged from previous decisions were adequately explained in this instance.”

Did FDA sufficiently prove that Sandoz’s generic enoxaparin has the same active ingredient as Lovenox?  Here, arguments focused on the five criteria FDA laid out in the Agency’s citizen petition response that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX: (1) equivalence of physicochemical properties; (2) equivalence of heparin source material and mode of depolyierization; (3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) equivalence in biological and biochemical assays; and (5) equivalence of in vivo pharacodynamic profile. 

Instead of focusing on any one criterion, Judge Jackson focused on whether all five, overlapping criteria, when considered together, provided “a reasonable way for FDA to determine active ingredient sameness.”  “Not only did FDA support its approach in a thorough, well-reasoned response to Sanofi’s citizen petition, but it also carefully considered both sides of the argument internally – to settle the internal dispute over the validity of the five-pronged test – before doing so. . . .  While fully characterizing enoxaparin would have been another reasonable, or perhaps even more reasonable, way to determine active ingredient sameness, the Court is satisfied that the five-pronged approach FDA used was reasonable,” concludes Judge Jackson. 

By Jennifer D. Newberger –

On Thursday, February 2, Senators Bob Casey (D-PA) and John McCain (R-AZ) introduced S. 2067, titled the “Safe, Efficient, and Transparent Medical Device Approval Act” or the “SET Device Act.”  The bill would require FDA to reclassify preamendment Class III devices or require them to go through the premarket approval (“PMA”) process, and would streamline the de novo process.

In the Safe Medical Devices Act of 1990, Congress amended Section 515 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to require FDA to reclassify preamendment Class III devices to a lower class or require them to go through the PMA process.  The deadline to do so was December 1, 1995, but FDA still has over 20 preamendment Class III devices to reclassify.  The SET Act would require FDA to issue a final regulation for each device it determines should remain in Class III, or special controls for devices it reclassifies into Class II, within 18 months of enactment of the bill. 

This would not be the first time FDA has been encouraged to comply with the statutory requirements to classify the remaining Class III preamendment devices.  In January 2009, the Government Accountability Office (“GAO”) issued a report recommending that FDA “expeditiously take steps to issue regulations for class III device types currently allowed to enter the market via the 510(k) process by requiring PMAs or reclassifying them to a lower class.”  In response to the GAO report, FDA stated that it was committed to complete the classifications “as expeditiously as possible.”  In the three years since then, FDA has only issued final rules classifying four devices.  Given FDA’s disregard for the timeframe in the current statutory requirement, and its failure to follow through after the GAO report, there is no reason to believe that FDA will comply with the 18 month deadline put forth in this proposal.

Like two bills proposed in Congress in 2011 on which we previously commented (here and here), this bill also proposes to streamline the de novo process.  The current statutory language requires a sponsor to submit a 510(k) notification to FDA even if believes there is no appropriate predicate device.  The sponsor must then wait to receive a not substantially equivalent determination from FDA before it submits a de novo reclassification petition to reclassify the device into Class I or II.  Under the proposal in the SET Act, a sponsor may follow a process similar to that under current law, or may submit an initial petition for reclassification after determining that no predicate exists without the need to submit a 510(k) and wait for a not substantially equivalent determination. 

This proposed change will benefit both industry and FDA.  It will save FDA time and resources by consolidating the 510(k) review and de novo classification processes into one step.  It will also allow sponsors to more quickly bring new, innovative, low- to moderate-risk devices to market because they can submit a reclassification petition without having to wait for a not substantially equivalent decision.  Despite these positive procedural steps, the question remains whether FDA would be willing to review devices through the de novo process rather than requiring devices without a predicate go through the PMA process.  One of the reasons FDA may be hesitant to utilize the de novo process is the burden of creating special controls.  Perhaps if, in addition to remedying the procedural hurdles, creating special controls could be optional, FDA may be more likely to clear products through the de novo process.  Nevertheless, this bill is a step in the right direction.  As we stated in our prior blog posts on this topic, FDA and industry both would like to see improvements in the de novo process, and this bill should receive much support and little resistance.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Alan M. Kirschenbaum & Michelle L. Butler - 

A long anticipated proposed revision to CMS regulations governing the Medicaid Drug Rebate Program ("MDRP") appeared in the Federal Register on Thursday, February 2, 2012.  As expected, the proposal implements amendments to the MDRP that were enacted in the Patient Protection and Affordable Care Act ("ACA") (see our previous post here).  However, the regulation would also make a number of important changes to the MDRP and Medicaid drug payment that were not mandated by the ACA.  Among other notable provisions, the proposed regulation would:

• Require states to convert to an actual acquisition cost basis for Medicaid prescription drug payment 
• Expand the MDRP to the U.S. territories
• Apply a statutory alternative rebate for line extensions of oral solid dosage form innovator drugs, not only to new formulations, but new indications, combination products, and products marketed by companies independent of the company marketing the original drug
• Limit wholesaler sales included in AMP to those that can be documented as being subsequently sold to retail community pharmacies
• Require manufacturers of unapproved drugs to submit to CMS evidence that the product meets the definition of a covered outpatient drug
• Provide for penalties of $10,000 per day per drug for tardy AMP reports

Hyman, Phelps & McNamara, P.C. has prepared a memorandum summarizing the most important provisions of the proposed regulation.  The memorandum is available here.

By Kurt R. Karst –      
 
Earlier this week, Representatives John Carney (D-DE) and Larry Bucshon (R-IN) introduced H.R.3839, the “Drug Shortage Prevention Act,” which, according to its sponsors, is intended to bring “more efficiency to the manufacturing and distribution processes” and to require “FDA to take action to prevent drug shortage problems before they begin impacting patients.”  The bill is the latest action plan to address the increasing problem of drug shortages.  Last year saw the introduction of the “Preserving Access to Life-Saving Medications Act of 2011” (S. 296, H.R. 2245), an Executive Order from President Obama (see our previous post here), and an interim final rule from FDA to make better use of its existing shortage-related authority under the FDC Act among other things (see our previous post here).  The topic of drug shortages is expected to be raised next week at the House Energy and Commerce Committee hearing on generic drug and biosimilar user fees.

H.R.3839 would amend the FDC Act to add § 506D to require FDA to develop and make publicly available two lists of products: (1) a National Critical Drug List; and (2) a National Critical Drug Shortage List.  The bill does not actually define the terms “critical drug” or “critical drug shortage.”  Rather, FDA would be required to solicit stakeholder input through a public hearing or public docket to define the terms.  The bill does state what information should be included in each list, such as (for the shortage list) an indication of the severity of the shortage, the reason for the shortage, and identification of alternative therapies.

FDA would be required to expedite its review of NDAs and ANDAs seeking approval of a “critical drug” and any request by the sponsor of a critical drug to approve a change to the manufacturing process, manufacturing facility, or to add an alternate active pharmaceutical ingredient supplier.  “In expediting the review of applications and requests . . . [FDA] shall not unnecessarily delay the review of applications and requests for drugs and biological products that are not critical drugs.”  In addition, the bill would require the HHS Secretary to conduct a study on the feasibility of creating a national contingency plan to address critical drug shortages, including the possible creation of a Federal stockpile of critical drugs or the expansion of an existing Federal stockpile of drugs to include critical drugs for such purpose.

The Drug Shortage Prevention Act also requires FDA to notify the DEA of any critical drug on the critical drug shortage list that is a controlled substance, and permits the Attorney General to allow for the determination of whether or not it is appropriate to increase a controlled substance quota to address the shortage.

By Jennifer D. Newberger –

On January 31, 2012, Rep. Edward Markey (D-MA) introduced H.R. 3847, the “Safety of Untested and New Devices Act of 2012,” also known as the “SOUND Devices Act of 2012.”  The bill attempts to limit the body of devices that may be available for use as predicates.  The key provisions include:

• Submitters of 510(k) notifications would be required to include information about the history of corrections and removals of the predicate device and the predicates of that predicate; 
• FDA may reject a claim of substantial equivalence if the predicate device or its predicates were corrected or removed, or if FDA is in the process of taking regulatory action against the predicate or its predicates, due to an “intrinsic flaw in technology or design that adversely affects safety”;
• FDA may reject a claim of substantial equivalence if the predicate was corrected or removed and the manufacturer failed to report such correction or removal; and
• When a device is corrected or removed because of an intrinsic flaw in technology or design that adverse affects safety, FDA may order manufacturers of devices “in the same lineage” to submit a report stating whether their device shares the same intrinsic flaw, and if not, why not.

The underlying assumption reflected in the bill seems to be that sponsors are rampantly foisting badly designed devices on the public, that they refuse to improve their devices to correct known problems, and that FDA does not now have sufficient statutory authority to prevent the proliferation of badly designed devices. 

This assumption is not based in reality.  If one thinks back to the commonly used medical devices in use 20 years ago, or even 10 years ago, there has been continuous and sometimes dramatic improvement in quality of the design and technology of a wide range of devices.  Furthermore, FDA has ample authority to ensure the quality of the devices cleared through the 510(k) process, and it frequently exercises it.  Hence, the title of this blog post – this bill is truly a solution in search of a problem.

Turning to the provisions of the bill, certain of these proposals would be nearly impossible for sponsors to meet, while others would give FDA authority to prohibit a large number of devices from serving as predicate devices, limiting the use of the 510(k) program as a viable option for marketing devices.  As noted, all of this drama would be inflicted on the device industry for very little gain in patient health or safety.

Submission of Predicate Information.  The bill would require sponsors to provide information to FDA in a 510(k) submission on the “market status” of each predicate device and “each device in the full device lineage.”  The information to be provided includes information about whether the device has been corrected or removed from the market, the basis for such correction or removal, “including whether such correction or removal was because of an intrinsic flaw in technology or design that adversely affects safety,” and why the proposed device does not share “any such intrinsic flaw.”  Of course, all of these concepts are highly subjective and likely to engender years of disputes between FDA and industry. 

Also, the question of whether the device has been corrected or removed is not time-limited.  A strict reading of the bill language indicates that the question is whether the predicate (or its predicate) was ever corrected or removed.  Note also that this is not limited to reportable corrections or removals, e.g., Class I or Class II recalls, meaning that a sponsor would need to submit information related to Class III recalls, even though that information is generally not required to be reported to FDA.  It is not explained how the sponsor will be able to gather information that is not publicly available.

A “device in the full device lineage” is a “device for which a substantial equivalence determination was made leading to a substantial equivalence determination for a predicate device” used in a new submission.  So this means that a sponsor needs to provide market information not only on the predicate device, but on any device that served as a predicate to the predicate.  In the case of a device that cites multiple predicates, the sponsor presumably will need to provide a complete family tree for each of the predicates.

“Intrinsic flaw in technology or design that adversely affects safety.”  Currently, the Federal Food, Drug, and Cosmetic Act ("FDC Act") prohibits a finding of substantial equivalence to a predicate that was removed from the market at the initiative of FDA or was determined to be misbranded or adulterated by a judicial order.  (Both FDA-mandated recalls and judicial orders of this nature are exceedingly rare.)  In addition to these criteria, the bill would permit FDA to reject a claim of substantial equivalence to any predicate (or predicate’s predicate) corrected or removed from the market at the initiative of the sponsor and the correction or removal “is due, in whole or in part, to an intrinsic flaw in technology or design that adversely affects safety.”  The bill fails to address the obvious point that a correction or removal is typically conducted in order to modify a device to address a problem in design or manufacturing.  So, if the predicate device was, in fact, modified to address a design problem, what is the impact of the modification on the requirements of this bill?  If the modification was cleared through the 510(k) process, presumably the sponsor can simply claim substantial equivalence to the post recall 510(k) clearance and avoid this bill altogether.

FDA may also reject a claim of substantial equivalence to a predicate if FDA is undertaking any regulatory action (e.g., trying to rescind clearance, issuing a recall order) to remove the predicate, or the predicate’s predicate, from the market “because of an intrinsic flaw in technology or design that adversely affects safety.”  This means that, without considering whether the proposed device introduces modified technology or design that could remedy the problems associated with the predicate, FDA may reject a claim of substantial equivalence based solely on the safety issues of the predicate. 

Failure of predicate manufacturer to submit required report of correction or removal.  The most broad-reaching of the new authorities would permit FDA to reject a claim of substantial equivalence to a predicate “if the predicate device has been corrected or removed from the market and the manufacturer or importer of the predicate failed to submit” the required notice of such correction or removal.  Under this provision, the sins of the father would indeed be visited upon the sons.

Shared intrinsic flaw.  When a device is corrected or removed from the market because of an intrinsic flaw in technology or design that adversely affects safety, the bill would allow FDA to order a manufacturer or importer of a marketed “device in the same lineage” to submit a report stating whether the marketed device shared any intrinsic flaw, and, if not, to explain why the device does not share the flaw.

Congress, industry, and FDA should all consider how to best assure that marketed devices are as safe as they possibly can be.  This bill, however, does nothing to further that goal, and it should not be taken seriously.

By Kurt R. Karst –      

A new report released by the Government Accountability Office (“GAO”), titled “Antibiotics: FDA Needs to Do More to Ensure That Drug Labels Contain Up-to-Date Information,” says that since the September 27, 2007 enactment of the FDA Amendments Act (“FDAAA”) FDA has not taken sufficient steps to ensure that antibiotic labels contain up-to-date information, and that certain FDAAA provisions relating to antiobotic innovation have not resulted in the submission of marketing applications for antibiotics. 

The GAO report focuses on three FDAAA provisions:

(1) Section 1111, titled “Identification of clinically susceptible concentrations of antimicrobials,” which required FDA to identify “antibiotic breakpoints” “where such information is reasonably available,” to periodically update them, and to make these up-to-date breakpoints publicly available within 30 days of identifying or updating them.  (A “breakpoint” included on an antibiotic’s label reflects the concentrations at which bacteria are categorized as susceptible to treatment with a given antibiotic drug and can change over time.  An outdated breakpoint can result in the unknowing selecting ineffective treatments, which can also contribute to antibiotic resistance.);

(2) Section 1112, titled “Orphan antibiotic drugs,” which authorized funding for grants and contracts under the Orphan Drug Act and required FDA to convene a public meeting to discuss incentives, such as those included in the Orphan Drug Act, to develop or otherwise obtain marketing exclusivity for antibiotics that treat serious and life-threatening infectious diseases; and

(3) Section 1113, titled “Exclusivity of certain drugs containing single enantiomers,” which is not specific to antibiotic drug development, allows a sponsor of an enantiomer of a previously aproved racemate to elect to have its drug considered a New Chemical Entity (“NCE”) eligible for a period of 5-year NCE exclusivity (instead of 3-year exclusivity for enantiomers of previously approved racemates) provided certain statutory conditions are met.

Antibiotic Labeling Breakpoint Updates.  In 2008, FDA sent letters to application holders requesting that they inform the Agency as to whether or not their product included up-to-date breakpoints.  In June 2009, FDA issued final guidance on compliance with FDAAA § 1111 and discussing a sponsor’s responsibility to maintain up-to-date breakpoints on their antibiotics drug labels.  According to the GAO report, although FDA has taken these initial steps to update breakpoint information on antibiotic labels, the Agency “has not confirmed that the information is up to date for most reference-listed antibiotics.”  Indeed, as of November 2011:

over 3.5 years after FDA sent its letters, 146, or 70 percent, of the 210 antibiotics are still labeled with breakpoints that have not been updated or confirmed to be up to date. For 78 of the 146 antibiotics, FDA has not yet received a submission regarding the currency of the breakpoints; for 12 of the antibiotics, the sponsors’ submissions are pending FDA review; and for 56 of the antibiotics, FDA determined that the sponsors’ submission was inaccurate or incomplete and therefore requested a revision or additional information. Thus far, FDA has determined that 64, or 30 percent, of the 210 antibiotics have up-to-date breakpoints.

There are two reasons so many antibiotics still have breakpoints that FDA has not confirmed to be up to date, according to the GAO: (1) “many sponsors have not fulfilled the responsibilities outlined in FDA’s 2008 letters;” and (2) “FDA faced difficulty in keeping up with the workload that resulted from sponsors’ breakpoint submissions.”

The GAO recommends that FDA Commissioner Hamburg take several actions to help ensure the accurate labeling of antibiotics, including “expeditiously review sponsors’ submissions regarding the breakpoints on their antibiotics’ labels,” taking “steps to obtain breakpoint information from sponsors that have not yet submitted breakpoint information in response to the 2008 letters sent by the agency;” and establishing “a process to track sponsors’ submissions of breakpoint information included in their annual reports to ensure that such information is submitted to FDA and reviewed by the agency in a timely manner,”

Enhanced Incentives.  The two FDAAA provisions (Sections 1112 and 1113) applicable to antiobotic drug sponsors (although only generally in the case of FDAAA § 1113) that provide for enhanced incentives have apparently not encouraged the development or approval of new antibiotics.  According to the GAO:

To date, drug sponsors, including those we received comments from, have not submitted any NDAs for antibiotics as a result of the FDAAA provision granting additional market exclusivity for new drugs containing single enantiomers of previously approved racemic drugs.  According to FDA officials, they have received very few inquiries regarding this provision and as of November 2011, no NDAs for antibiotics have been submitted that would qualify for this exclusivity. . . .

The lack of NDAs for antibiotics submitted in response to this FDAAA provision is consistent with the overall trend in the approval of innovative antibiotic NDAs.  The number of annual approvals of antibiotic NMEs from 2001 through 2010 has not changed significantly since the passage of FDAAA. Specifically, the annual number of antibiotic NME approvals was two or less for the years prior to, and one or less for the years following, the enactment of FDAAA. 

FDAAA § 1113 amended the FDC Act to add § 505(u), which is scheduled to sunset this year unless reauthorized by Congress.  Although there are public reports of companies that have expressed interest in developing drug products that might qualify for the 5-year NCE exclusivity election, we are not aware of any NDA (antibiotic or otherwise) that has been approved and granted exclusivity under this provision.  Another exclusivity provision originally included in FDAAA, but removed and later enacted as part of the QI Act, that is targeted to so-called “old” antibiotics (i.e., FDC Act § 505(v)) is not discussed in the GAO’s report, presumably because of the limited scope of the GAO report.

On the orphan drug front (FDAAA § 1112), FDA held a public meeting on April 28, 2008 (Docket No. FDA-2008-N-0225) to, among other things, explore whether and how existing incentives and potential new incentives could be applied to promote the development of antibiotics as well as to discuss whether infectious diseases may qualify for grants or other incentives that may promote innovation.  While potential new incentives and tinkering with current ones were suggested at the public meeting, the GAO says that “many of these suggestions – such as tax incentives and extended market exclusivities – would require a statutory change.”

The GAO also examined orphan drug designation data and found that it is relatively uncommon for FDA’s Office of Orphan Products Development to designate an antibiotic an as orphan drug.  According to the GAO, its examination of odphan drug designations showed:

that the annual number of antibiotics that received an orphan drug designation from 2001 to 2007 – when FDAAA was enacted – was three drugs or fewer each year.  The number of antibiotics that received orphan drug designation following FDAAA’s enactment in 2007 has remained constant at this rate through 2010.  Additionally, not all antibiotics that have been awarded orphan drug designation have been or will apply to be approved for marketing.  Of the 15 antibiotics that received an orphan drug designation from 2001 through 2010, only 1 was approved for marketing as of November 2011.

To give you a sense of how small the figure 15 is, we tallied the number of orphan drug designation between 2001 and 2010 and came up with 1,262.  So, a mere 1.19% of those designations represent antibiotics.  

By Kurt R. Karst –      

The U.S. Patent and Trademark Office (“PTO”) has been sued once again after denying a Patent Term Extension (“PTE”) request.  The latest case in a long line of lawsuits concerns U.S. Patent No. 5,206,248 (“the ‘248 patent”), which is listed in FDA’s Orange Book as a method-of-use patent covering Avanir Pharmaceuticals Inc.’s (“Avanir’s”) NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) Capsules, and that is scheduled to expire on March 27, 2012.  The Complaint, filed last week by Avanir and the Center for Neurologic Study in the U.S. District Court for the Eastern District of Virginia (Alexandria Division), alleges that the PTO’s December 20, 2011 decision denying Plaintiffs’ PTE application for the ‘248 patent (Docket No. FDA-2011-E-0269) violated the Administrative Procedure Act (“APA”).  Plaintiffs request that the court vacate and set aside the PTO’s decision and order the PTO to extend the term of the ‘248 patent for the full period required under the PTE statute at 35 U.S.C. § 156. 

FDA approved NUEDEXTA on October 29, 2010 under NDA No. 021879 for the treatment of pseudobulbar affect (“PBA”).  NUEDEXTA is the first and only FDA-approved treatment for PBA.  PBA is a neurological condition sometimes referred to as “emotional incontinence” that is characterized by sudden outbursts of involuntary crying and/or laughing in patients with underlying neurological disease or injury.  In addition to the ‘248 patent, NUEDEXTA is listed in the Orange Book as covered by two additional patents – U.S. Patent Nos. 7,659,282, which expires on August 13, 2026, and RE 38,115 (“the ‘115 patent”), which expires on January 26, 2016 – and a period of 3-year exclusivity (new combination) that expires on October 29, 2013.  (Plaintiffs submitted a second PTE application to the PTO with respect to the ‘115 patent – Docket No. FDA-2011-E-0268.  The PTO also denied that PTE application on December 20, 2011; however, the ‘115 patent is not identified in the Complaint.)

Under the PTE statute at 35 U.S.C. § 156, the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”   While Plaintiffs acknowledge in their PTE application that “dextromethorphan-containing products have previously been sold in the United States,” they contend that “the approval of dextromethorphan hydrobromide in NUEDEXTA™” meets the “first permitted commercial marketing or use” prong of the PTE statute.  Specifically, according to the Plaintiffs in their PTE application:

The provision of law under which the dextromethorphan hydro bromide active ingredient in NUEDEXT A™ was subject to a regulatory review period is section 505 of the FFDCA as amended by the [1984 Hatch-Waxman Amendments].  To the best of Applicant's knowledge, dextromethorphan-containing products sold prior to 1962 were not subject to a “regulatory review period” as defined under section 156(g), and were permitted to be marketed under a provision of law different from the provision of law under which NUEDEXTA™ was studied, reviewed, and approved.  To the best of Applicant’s knowledge, dextromethorphan-containing products sold after 1962 have been marketed under the [FDA’s] Over-the-Counter Drug Review, and not under the provision of law under which NUEDEXTA ™ was studied, reviewed, and approved (35 U.S.C. § 156(a)(5)(A)).

Plaintiffs also proactively address in their PTE application the 1989 decision in Westwood v. Quigg, 13 U.S.P.Q.2d 2067 (D.D.C. 1989), which affirmed a PTE denial by the PTO for a drug that first came to market before 1962.  Plaintiffs maintain, however, “that Westwood was wrongly decided, is distinguishable, and would not withstand scrutiny today.  Among other reasons, the court erred in failing to apply the FFDCA as it existed at the time it was amended by the [1984 Hatch-Waxman Amendments].”

Not convinced by Plaintiffs’ arguments, the PTO denied the ‘248 patent PTE application after receiving notification from FDA that both the dextromethorphan hydrobromide and quinidine sulfate components in NUEDEXTA had each been approved for commercial marketing or use prior to the approval of NDA No. 021879.  Among other things, the PTO cites in its denial the Federal Circuit’s decision in Arnold P'ship v. Dudas, 362 F.3d 1338, 1341 (Fed. Cir. 2004), concerning a PTE denial for VICOPROFEN (ibuprofen and hydrocodone bitartrate), the Westwood decision, and a 2007 decision from FDA concerning PTE ineligibility for a patent concerning BiDil (isosorbide dinitrate and hydralazine hydrochloride) Tablets (a copy of which is attached to the PTO’s ‘248 patent PTE decision).  Referencing the BiDil case, the PTO states:

Applicant is mistaken in its reading of § 156(a)(5)(A).  As previously explained by FDA in a similar situation, FDA maintains that the phrase “provision of law” refers “to the statutory provision under which the regulatory review occurs for a particular class of products that is eligible for patent term restoration, regardless of whether that statutory provision is amended.”  The FDA stated there, and the USPTO concurs, that the phrase is unambiguous on its face.  However, as explained in the 2007 FDA letter, even if the phrase is ambiguous, this interpretation is permissible in light of legislative intent, public policy concerns, and applicable case law.  There is no suggestion in the legislative history that the phrase “first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” as used in § 156(a)(5)(A) is intended to treat amended versions of section 505 as different provisions of law.  Rather, as explained by the FDA at page 6 of the 2007 FDA letter, to treat each different amended version of section 505 as a different provision of law would contravene the legislative intent of Congress by allowing the term of more than one patent to be extended if a product received more than one approval as a member of a particular class of products.

(Interestingly, a somewhat similar dispute arose a few years ago after the enactment of the QI Act concerning so-called “old” antibiotics.  In that case, Citizen Petitions were submitted to FDA arguing, among other things, that the plain language of the QI Act directs FDA to apply the relevant statutory provisions of the Hatch-Waxman Amendments as they were enacted in 1984, not as subsequently amended by Congress.  FDA ruled otherwise.  See our previous post here.)

In their Complaint, Plaintiffs first argue that “the PTO erroneously defined the relevant ‘product’ for purposes of 35 U.S.C. § 156 as either dextromethorphan alone or quinidine alone.”  “Taken by themselves,” contend Plaintiffs, “dextromethorphan is a cough suppressant and quinidine treats heart arrhythmias and neither dextromethorphan nor quinidine alone has any effect on PBA.  However, together in Nuedexta®, the dextromethorphan/quinidine is a wholly new active ingredient that treats PBA.  The ‘248 patent covers this use of dextromethorphan/quinidine.”  Second, Plaintiffs argue that “the PTO erroneously determined that dextromethorphan has previously been the subject of a ‘regulatory review period’ under the same ‘provision of law’ under which Nuedexta® was approved.”  Not only is the conclusion misplaced based on the dextromethorphan/quinidine argument, contend Plaintiffs, but the PTO’s denial violates the APA “even if dextromethorphan alone is considered the active ingredient in Nuedexta®.”  According to the Plaintiffs:

[I]t is undisputed that Nuedexta® was approved for commercial marketing under the version of [FDC Act § 505] in effect on October 29. 2010, which requires proof of efficacy as well as safety. . . .  It is also undisputed that all other dextromethorphan products were approved by FDA under the pre-1962 version of [FDC Act § 505], which required no proof of efficacy, and no “regulatory review period.”  Despite these undisputed facts, FDA arbitrarily and capriciously found that the pre-1962 dextromethorphan products have been the subject of a “regulatory review period” and denied Avanir’s request for a PTE.

After all, write Plaintiffs, for NDAs submitted prior to the enactment of the 1962 Drug Efficacy Amendments, “FDA neither ‘reviewed’ nor ‘approved’ these NDAs before the products could be marketed. Instead, by operation of the statute, NDAs became automatically effective 60 days after they were filed, unless the FDA determined that it needed more time to ‘study and investigate the application’” (citing FDC Act § 505(c) (1938)).

Strap yourself in for another exciting ride on the PTE litigation train.

By Jennifer D. Newberger –

On Tuesday, January 24, FDA’s Center for Devices and Radiological Health (“CDRH”) released its strategic priorities for 2012:  (1) fully implement a total life cycle approach; (2) enhance communication and transparency; (3) strengthen the CDRH workforce and workplace; and (4) proactively facilitate innovation to address unmet public health needs.  Though the priorities have remained consistent over the last three years, the strategies and goals (sometimes) differ.  This blog post addresses some of the highlights.

Total life cycle approach.  This is the most comprehensive and aggressive of the four priorities.  Perhaps most ambitious is CDRH’s goal to finalize all guidance documents issued as part of the plan to improve premarket programs.  Given the number of draft guidance documents issued in 2011 for this purpose (approximately 11), it is unlikely CDRH will achieve this goal, nor, perhaps would it be advisable to do so.  While final guidance is helpful to industry, in this case, rapid finalization would likely mean that CDRH did not take the time necessary to consider and address all the comments submitted by stakeholders or consider the relationship between the various documents.  Rather than striving to finalize all guidances, CDRH should focus on those likely to have the biggest impact:  those regarding benefit-risk determinations, the 510(k) paradigm, appeals, and when to submit a 510(k) for modifications to currently marketed products.

This priority also proposes implementing a knowledge management strategic plan and a Center-wide quality assurance program.  It is not clear what role these proposals will play in day-to-day operations of the Center, or what issues they are intended to address.

A repeat goal is to enhance compliance capability by implementing its “business-case-for-quality” (in 2011 this was referred to as “Case for Quality”), though the sub-goals are different.  In 2011, this goal was to be completed by September 30, 2011.  In the 2012 priorities, CDRH will begin to implement the program by December 31, 2012.  Precisely what this initiative will entail is not clear from either the 2011 or 2012 language.

Enhance communication and transparency.  Given the importance of improving communication and transparency with industry, it is surprising that this priority has only two rather thin strategies and goals.  One goal (a repeat from 2011) is to continue taking “steps to strengthen information exchange and improve gathering feedback” from external constituencies.  It seems that industry’s concern is less about CDRH’s ability to gather feedback, and more its failure to adequately respond to the feedback it receives and its shortcomings in communicating with companies. 

Strengthen the workforce and workplace.  This priority emphasizes employee training and education, and enhancing effective leadership, all of great importance to industry.  Hopefully, training “to enhance premarket reviewer knowledge of how medical devices are designed, manufactured, and utilized” will allow for a better, more realistic understanding of devices by reviewers. 

The proposal “to provide CDRH managers and supervisors information and tools to assure effective leadership” has the potential to, for instance, encourage supervisors to work with reviewers to understand the boundaries of requests for additional information and to provide better guidance to staff.  Hopefully, it will also empower supervisors to overturn a subordinate’s decision when appropriate.

Proactively facilitate innovation to address unmet public health needs.  Innovation, and FDA’s role in its facilitation, is a “hot topic” in medical device regulation and reform.  Though the first strategy within this priority is the same as 2011—to foster the development of innovative medical devices—there are far fewer goals to implement this strategy in 2012 than there were in 2011.  The only goal in 2012 is to “create processes and tools that will improve the pipeline for innovative medical devices and transform the way CDRH works with medical device innovators.”  While this is a laudable goal, it lacks any specifics.  Until the review processes are more transparent and predictable, and review times are shortened, it is likely also an unrealistic one.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Riëtte van Laack –

On Monday, January 23, 2012, the U.S. Supreme Court ruled that a California state law prohibiting the slaughter, processing, and sale of any non-ambulatory animals is preempted by the Federal Meat Inspection Act (“FMIA”).

As we previously reported, under California's Downed Animal Law, section 599f of the California state penal code, prohibits the slaughter of any non-ambulatory livestock.  This law was adopted in 2008 as a reaction to the publication of an undercover video in 2008, showing workers at the California Westland/Hallmark Meat Co. cattle slaughterhouse dragging sick and disabled cows.  This video resulted in the largest beef recall in U.S. history, and federal regulations prohibiting slaughter of non-ambulatory cattle but not of other non-ambulatory livestock.  California’s law, section 599f, expanded the federal protections provided to non-ambulatory cattle to all non-ambulatory livestock, requiring that these animals must be returned to the farm or immediately euthanized, without examination by a veterinarian. 

Shortly after passing of the California law, the National Meat Association ("NMA") filed a request for an injunction on the grounds that the California law was preempted by the FMIA.  The U.S. District Court granted the injunction. However, the Court of Appeals of the Ninth Circuit upheld California’s right to prohibit slaughter of non-ambulatory pigs, reasoning that a non-ambulatory pig is a different kind of animal and that regulating what kind of animal may be slaughtered fell within the type of regulatory activity typically reserved for states.  According to the Ninth Circuit, just as California had the right to prohibit slaughter of horses, it had a right to prohibit slaughter of non-ambulatory pigs.  NMA petitioned the U.S. Supreme Court.

In the Supreme Court's unanimous decision (Docket No. 10-224), Justice Kagan writes that the FMIA regulates a broad range of activities to ensure the safety as well as human handling of animals.  The FMIA contains an express preemption provision in section 678 of the FMIA, which was added in 1967.  Section 678 provides, in relevant part, that “Requirements within the scope of this [Act]  . . . which are in addition to, or different than those made under this [Act] may not be imposed by any State.”  As Justice Kagan explained, this section “prevents a State from imposing any additional or different-even if non-conflicting-requirements that fall within . . . the scope [of the act] and concern slaughterhouse facilities or operations.”  According to the Court, the California law effectively tried to ban slaughterhouse activities that the FMIA and FSIS implementing regulations expressly allow.  As the Court explained, under federal law, non-ambulatory pigs can be slaughtered, processed and sold, subject to FSIS inspection and monitoring requirements.  Thus, the Court concluded, California’s section 599f is preempted by the FMIA. 

Although this case focused on pigs, the ruling applies equally to non-ambulatory sheep, goats and veal calves.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By John A. Gilbert, Jr. & Larry K. Houck –

The Government Accountability Office (“GAO”) has issued a report focusing on federal agency efforts to educate prescribers and the public about prescription pain reliever abuse and misuse.  The report’s title, “Prescription Pain Reliever Abuse: Agencies have Begun Coordinating Education Efforts, but Need to Assess Effectiveness” telegraphs the report’s conclusion.  The report evaluates the nine programs to educate current and future prescribers and nine programs to educate target groups within the general public about prescription pain reliever abuse and misuse, noting duplicative efforts and recommending coordination between the multiple agencies and measuring their effectiveness.

The GAO conducted the performance audit of federal efforts to educate prescribers and the public about prescription pain reliever abuse and misuse from December 2010 to December 2011.  The report notes at the outset that key measures of prescription pain reliever abuse and misuse increased from 2003 to 2009.  “Abuse” and “misuse” refer to using a prescription pain reliever to get high, using a prescription pain reliever for pain relief without a prescription or using a prescription pain reliever but in ways other than as prescribed.  

The report summarized the increased problem of prescription pain reliever abuse and misuse through several key measures.  The estimated number of emergency visits annually related to prescription pain reliever abuse and misuse increased by 288,000 visits, (142 percent), from 2004 to 2009; annual admissions to substance abuse treatment facilities for prescription pain reliever abuse and misuse increased by 133,000 admissions, (131 percent), from 2003 to 2009; and the annual number of deaths from unintentional overdoses of prescription pain relievers increased by more than 5,000, (83 percent), from 2003 to 2008.  Lastly, the estimated number of persons who abused or misused prescription pain relievers increased from an estimated 11.7 million in 2003 to 12.4 million in 2009, an increase of 6 percent.

The report notes that agency officials have suggested that the increase in adverse health consequences that are key measures of prescription pain reliever abuse and misuse are due to the increasing availability of prescription pain relievers, especially higher potency extended-release and long-acting pain relievers.  Another factor is the increase in high-risk behavior.  High-risk behaviors include combining the prescription pain relievers with other prescription drugs and alcohol as well as inhaling or injecting the pain relievers instead of taking them orally as prescribed.

The report notes that officials from each of the responsible federal agencies opined that more prescriber education about prescription pain reliever abuse and misuse is required.  The Food and Drug Administration (“FDA”), National Institutes of Health (“NIH”), and Substance Abuse and Mental Health Services Administration (“SAMHSA”) have implemented different voluntary CME programs to educate prescribers about issues related to prescription pain reliever abuse and misuse.  FDA requires manufacturers to develop a CME or CE course for prescribers as part of a Risk Evaluation and Mitigation Strategy (“REMS”) for extended-release and long-acting pain relievers.  NIH communicates with prescribers at medical conferences while SAMHSA developed a CME course on prescribing opioids for chronic pain, partnering with local organizations such medical organizations.  FDA requires prescribers of certain transmucosal immediate-release fentanyl products to be trained and certified, then re-certified every two years.  NIH and SAMHSA are pursuing funding to develop physician clinical support systems that provide educational resources and free mentoring services related to prescribing prescription pain relievers.  Lastly, NIH and SAMHSA are developing curricula for medical students.
 
The report further notes that the Office of National Drug Control Policy (“ONDCP”) with Drug Enforcement Administration (“DEA”), FDA and SAMHSA assistance, “are working to develop a legislative proposal to require all prescribers who request DEA registration to prescribe controlled substances be trained on the appropriate and safe use, proper storage, and disposal of prescription pain relievers as a precondition of registration.”  HPM will monitor and report on this legislative proposal.

The report also discusses the various efforts of DEA, FDA, NIH, ONDCP and SAMHSA to educate teenagers, parents, college students and the general public about prescription pain reliever abuse and misuse.  The report notes that several of the public education efforts are duplicative of those of other agencies though concedes that the agencies have different constituencies and approaches to the issue.
  
The report concludes that the agencies have established or plan to establish metrics to assess the impact of only two of the educational efforts, which leaves the agencies “with limited knowledge as to whether such efforts are effective.”  The GAO states the agencies should establish metrics to measure the effectiveness of their education efforts.  The GAO also believes that the agencies have missed opportunities to share feedback about their efforts, leveraging their resources and coordinating similar efforts.  The report concludes that “there is much to be gained from continued and robust coordination among similar education efforts” and that ONDCP occupies a unique position to coordinate similar agency efforts and ensure that agencies do not duplicate efforts.  While duplicative educational efforts can reinforce messages, given the limited resources available to government, it is reasonable for agencies to coordinate education efforts aimed at similar constituencies.   

The report’s appendices also contain several informative discussions relevant to the prescription pain reliever abuse and misuse issue in the appendices.  One section discusses the various abuse-deterrent formulations of prescription pain relievers.  A second summarizes DEA’s controlled substance aggregate production, bulk manufacturing and procurement quota system.  We would like to see GAO investigate and issue a full report on DEA’s quota process and its impact on these issues.       

By Kurt R. Karst –      

In a recent Hatch-Waxman decision from the U.S. District Court for the Northern District of Illinois (Eastern Division), the court denied Plaintiffs’ Seattle Children’s Hospital, Novartis Vaccines and Diagnostics, Inc., and Novartis Pharmaceuticals Corporation (collectively “Novartis”) Motion to Dismiss the lawsuit that they brought against Akorn, Inc. (“Akorn”) for lack of subject matter jurisdiction and granted Akorn’s Motion to Amend its Answer to include a claim for a declaratory judgment of noninfringement of U.S. Patent No. 5,508,269 (“the ‘269 patent”).  The ‘269 patent, which expires on October 19, 2014, is the only patent listed in the Orange Book for TOBI (tobramycin solution for inhalation), 300 mg/5 mL (NDA No. 050753).  The court’s decision sets up the possibility of a subsequent ANDA sponsor causing a 180-day exclusivity forfeiture event for a first applicant under the failure-to-market provisions at FDC Act § 505(j)(5)(D)(i)(I).

Akorn appears to have submitted ANDA No. 201422 to FDA back in 2010 seeking approval for a generic version of TOBI.  Akorn’s ANDA, which FDA has not yet tentatively approved, contains a Paragraph IV certification to the ‘269 patent; however, according to the court, non-party Teva Pharmaceuticals USA, Inc. (“Teva”) submitted the first ANDA containing a Paragraph IV certification to the ‘269 patent, making Teva a first applicant eligible for 180-day exclusivity.  (FDA’s Paragraph IV Certification List shows June 29, 2009 as the date of the first ANDA submission.)  In June 2011, Novartis granted Akorn a covenant not to sue with respect to infringement of the ‘269 patent, and subsequently argued that the court lost subject matter jurisdiction since the covenant not to sue moots the patent infringement lawsuit.  Although Akorn admitted that the covenant not to sue “resolves the infringement issue,” the company has maintained that the covenant does not resolve the “regulatory issue;” namely, approval of ANDA No. 201422.

Enter the now familiar Federal Circuit decisions in Caraco Pharm. Labs. v. Forest Labs., 527 F.3d 1278 (Fed. Cir. 2008) and Janssen Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353 (Fed. Cir. 2008) which analyzed whether an Article III controversy exists in a declaratory judgment action arising under the Hatch-Waxman Amendments.  As the Illinois District Court notes, “Caraco holds that the exclusion of non-infringing generic drugs from the market can be a judicially cognizable injury-in-fact,” and “Janssen reaffirms Caraco’s holding that the injury-in-fact must stem from the actions of the company that listed the patents in the Orange Book, not the inherent framework of the Hatch-Waxman Act.”

Holding that the TOBI case presents an actual controversy, and that as in Caraco, a favorable judgment for Akorn “would eliminate the potential for the [‘269 patent] to exclude [Akorn] from the drug market,” the court stated:

Notwithstanding Plaintiffs’ unilateral covenant not to sue, the case or controversy between the parties here endures because of the continued listing of the ‘269 Patent in the FDA’s Orange Book in connection with NDA No. 50-753 for Novartis’ TOBI drug product, which bears on Akorn’s efforts to obtain FDA approval to market a generic version of Novartis’ TOBI.  In these circumstances, guidance from the Federal Circuit, admittedly decided under the pre-2003 version of the Hatch-Waxman Act, suggests that Akorn may pursue a court judgment in order to advance the regulatory issues surrounding Akorn’s efforts to obtain FDA approval to market a generic version of Novartis’ TOBI in light of Akorn’s status as a subsequent filer.

Moreover, the court made its decision notwithstanding the fact that FDA had not yet tentatively approved Akorn’s ANDA No. 201422:

Notably, such a [civil action to obtain patent certainty] would have been authorized by statute even though Akorn had not received tentative approval for its ANDA at that time and even if Plaintiffs had not threatened suit.  The case law and the expression of congressional intent . . . , as well as the realities and time commitments associated with complex litigation, support Akorn’s attempt to pursue tentative approval of its ANDA with the FDA while simultaneously seeking “a favorable judgment in this action [to] eliminate the potential for the [listed] patent to exclude [Akorn] from the drug market.”  See Caraco, 527 F.3d at 1293; see also Pfizer, 726 F. Supp. 2d at 930 (denying motion to dismiss even though applicant’s ANDA had not yet been approved and its Paragraph III certification independently precluded approval at the time it filed its claims).

Undeterred by the district court’s decision, Novartis promptly filed a Renewed Motion to Dismiss the case and Akorn’s counterclaim for lack of subject matter jurisdction.  According to Novartis, since the court issued its decision “any possible remaining case or controversy has been mooted by the statutorily mandated forfeiture of any 180-day exclusivity” available with respect to Teva’s ANDA. 

Novartis points to the faiure to obtain tentative ANDA approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV) and alleges that Teva’s failure to obtain tentative approval by December 29, 2011 (“30 months after the June 29, 2009 submission of its ANDA”) means that exclusivity was forfeited and that there is no barrier to FDA approving Akorn’s ANDA No. 201422, and therefore, no Article III controversy supporting subject matter jurisdiction in the case.  (Novartis says in a footnote that this is the same issue recently raised in another Illinois District Court Hatch-Waxman case involving generic FOSRENOL (lanthanum carbonate) 500 mg, 750 mg, and 1000 mg Chewable Tablets – Shire Canada Inc. v. Alkem Laboratories, Ltd., Case No. 11-cv-00206 (N.D. Ill.).) 

Interestingly, Novartis asserts that the exception provision under the tentative approval forfeiture provision – that failure to obtain timely tentative approval results in forfeiture unless such failure “is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” – “is inapplicable here as there is no evidence that there was any change in the requirements for ANDA approval that resulted in Teva’s failure to obtain tentative approval by December 29, 2011.”  Of course, only FDA really knows the answer to the question of whether there has been a change in or review of ANDA approval requirements.  In our experience, it is a fact-intensive and case-specific analysis.  Whether the court will effectively step into FDA’s shoes on the matter remains to be seen. 

By Kurt R. Karst –      

It’s absolutely amazing how, after nearly 28 years, the 1984 Hatch-Waxman Amendments continue to provide surprises.  Consider the latest example we came upon recently (with a little help) involving PRISTIQ (desvenlafaxine) Extended-Release Tablets.

FDA approved PRISTIQ under NDA No. 021992 in a leap year, on February 29, 2008 at 3:15 PM Eastern Time (within business hours).  PRISTIQ is listed in the Orange Book with a single patent – U.S. Patent No. 6,673,838 (“the ‘838 patent”) expiring on February 11, 2022.  PRISTIQ is also identified in the Orange Book as a New Chemical Entity (“NCE”) with a period of 5-year exclusivity that expires in a non-leap year, on March 1, 2013.  The combination of an Orange Book patent listing and the 5-year NCE period granted to NDA No. 021992 sets up the possibility under the FDC Act that an ANDA (or a 505(b)(2) application) containing a Paragraph IV certification to the ‘838 patent could be submitted on the so-called “NCE-1 date.”  But is the correct 2012 (also a leap year) submission date March 1st or February 29th?

Let’s turn to the FDC Act’s ANDA provision at FDC Act § 505(j)(5)(F)(ii) under which 5-year NCE exclusivity is discussed.  (The provision applicable to 505(b)(2) applications – FDC Act § 505(c)(3)(E)(ii) – is substantially identical.)  FDC Act § 505(j)(5)(F)(ii) states, in relevant part (emphasis added):

If an application submitted under [FDC Act § 505(b)] for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under [FDC Act § 505(b)], is approved after September 24, 1984, no application may be submitted under [FDC § 505(j)] which refers to the drug for which the [FDC Act § 505(b)] application was submitted before the expiration of five years from the date of the approval of the application under [FDC Act § 505(b)], except that such an application may be submitted under this subsection after the expiration of four years from the date of the approval of the [FDC Act § 505(b)] application if it contains a [Paragraph IV] certification . . . .

In the case of PRISTIQ, “four years from the date of the approval” of NDA No. 021992 is February 29, 2012, not March 1, 2012.  If one were to use the often-referred-to “NCE-1 date” in this case, which calculates the submission date backwards beginning on the date of NCE exclusivity expiration, it would yield March 1, 2012, not February 29, 2012. 

So what’s the lesson here?  Beware of Hatch-Waxman shorthand and do the math under the statute.  After all, we all know how dates count and how counting can lead to controversy (and even changes in the law) – think ANGIOMAX (for which a settlement was just announced); also, see our previous post on counting here. 

UPDATE: A new note was added to the Orange Book stating: "Applications referencing NDA 021992 Pristiq (Desvenlafaxine Succinate) and challenging the listed patent may be received by the Agency beginning on Feb 29, 2012, four years from the NDA approval date."