By Alexander J. Varond –

FDA announced earlier this week that it will hold a public hearing to obtain input on a potential new pathway to expedite the development of drugs and biological products for serious or life-threatening conditions that would address an unmet medical need.  The new pathway would be used to approve drugs studied in well-defined subpopulations of patients with more serious manifestations of a condition.  By focusing on patients with more serious manifestations of a condition, the pathway opens the door to the use of smaller and faster clinical trials.  This approach was recently outlined in FDA’s draft guidance entitled “Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products.”  We wrote about that draft guidance here.  FDA notes that by focusing on obtaining approval in well-defined, sicker subpopulations, the risk-benefit considerations may favor approval compared with trials that aim for approval in broader groups of patients with wide ranges of clinical manifestations. The potential new approval pathway could also help reduce the development of resistance to antibacterial drugs by limiting their use to certain patients.
 
The public hearing is a follow-up to a recommendation from the President’s Council of Advisors on Science and Technology’s (PCAST’s) September 2012 report entitled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation.”  We blogged on that report here.  Among the eight specific recommendations made in the report, PCAST recommended a new, optional pathway for initial approval of drugs shown to be safe and effective in a specific subgroup of patients.  The report also discussed a “Special Medical Use” designation which would strongly signal to prescribers and payors that the population that should be prescribed the drug is limited.

The issues to be addressed at the hearing include:

• The effectiveness of adding an additional pathway to expedite drug development (on top of accelerated approval and fast-track designation);
• Which serious or life-threatening conditions the new approval pathway might benefit;
• What approaches can be used to prevent, manage, and monitor use of a drug approved under this pathway in a broader population where safety and efficacy has not been demonstrated;
• Whether this pathway could be particularly useful in the development of antibacterial drugs;
• What benefit-risk considerations should to be taken into account regarding the smaller population of patients with more serious manifestations of a condition; and
• Would the use of a logo or formal designation that reflected approval under the new pathway be effective in limiting use to the indicated subpopulation?

FDA’s proposal for a special logo or formal designation reflects PCAST’s and the Enrichment guidance’s concerns that drugs approved under the new pathway would be used off-label in larger populations, effectively side-stepping the normal, more rigorous approval pathway FDA typically requires.  Importantly, FDA’s and PCAST’s proposals both note that a drug initially approved using the new pathway could be later approved for a broader population if long-term studies demonstrate safety and effectiveness for broader use.

The public hearing is scheduled for February 4 and 5, 2013.

By Kurt R. Karst –      

In a decision handed down last week by Judge Ellen Segal Huvelle of the U.S. District Court for the District of Columbia, the court may have finally put an end to ViroPharma Inc.’s (“ViroPharma’s”) litigation over FDA’s approval of generic versions of the company’s antibiotic drug VANCOCIN (vancomycin HCl) Capsules (approved under NDA No. 050606).  In denying ViroPharma’s Motion for Summary Judgment and granting FDA’s Cross-Motion for Summary Judgment as well as Intervenor-Defendants’ Cross Motion for Summary Judgment (one of which – Akorn, Inc. – was represented by Hyman, Phelps & McNamara P.C.) (reply briefs here, here, and here), Judge Huvelle upheld FDA’s decision not to grant a period of 3-year Hatch-Waxman exclusivity in connection with the Agency’s approval of a December 2011 supplemental NDA because of the limitation on such exclusivity for a so-called “old antibiotic” like vancomycin set forth in FDC Act § 505(v) as added by Section 4 of the 2008 QI Act.  Judge Huvelle also affirmed FDA’s decision to approve generic VANCOCIN based on in vitro dissolution data demonstrating bioequivalence.  Both issues were addressed by FDA in an April 9, 2012 response to a March 17, 2006 petition for stay of action submitted by ViroPharma (Docket No. FDA-2006-P-0007).

As we previously reported, ViroPharma sued FDA on April 13, 2012 after the Agency approved generic VANCOCIN.  (That lawsuit was preceded by other lawsuits related to VANCOCIN – see here and here.)  In an April 23, 2012 decision, Judge Huvelle denied ViroPharma’s Motion for a Preliminary Injunction after having determined that the company had not demonstrated a likelihood of success on the merits of either its exclusivity claim or its bioequivalence claim.  Nevertheless, ViroPharma pressed ahead for a decision on the merits of its claims against FDA and urged the court in its Motion for Summary Judgment to reconsider its arguments “with the benefit of the additional elaboration herein and additional time to consider the law and arguments.”  Judge Huvelle, despite the “additional elaboration” and “additional time,” refused to change her mind and stated:

[N]othing in the parties’ submissions convinces the Court to reach a different conclusion today.  ViroPharma all but admits that it has presented no substantially new arguments, but rather it relies on “additional elaboration,” none of which persuades the Court to reverse itself.  Moreover, no new facts have been presented that would dictate a different result.  Although the parties have submitted additional excerpts from the administrative record, which the Court has reviewed, these submissions do not alter the Court’s judgment.  To the extent that any portion of the supplemented record affects the Court’s opinion, it serves only to bolster it.  Therefore, the Court incorporates by reference the conclusions that it reached in its prior Memorandum Opinion, and will limit its discussion to the few additional points that are arguably being raised for the first time. [(Internal citations omitted)]

With respect to the December 2011 labeling changes that ViroPharma alleged supported an FDA decision to award 3-year exclusivity, FDA had ruled (in the Agency’s petition decision and in a memorandum prepared by FDA’s CDER Exclusivity Board) that the labeling changes merely “related to and refined the already-approved indication for treatment of [Clostridium difficile], and included a dosing regimen that was encompassed within, and at most refined, the prior regimen,” and therefore, precluded a grant of exclusivity pursuant to FDA Act § 505(v)(3)(B).  In addition to “rehashing the same arguments that the Court has already rejected,” ViroPharma suggested in the company’s Motion for Summary Judgment that “[i]f the labeling changes approved in the Vancocin sNDA constituted previously approved conditions of use, then the structure of innovator drug regulation under the FDCA would be seriously compromised,” because “manufacturers could make labeling changes without prior FDA approval because the changes would be considered ‘previously approved.’”   Judge Huvelle did not bite:

ViroPharma seriously misconstrues the FDA’s position.  The FDA does not claim that the labeling changes were “previously approved.”  Rather, “the conditions of use for the drug – how, to whom, and for what purpose the drug is administered – were previously approved.”  The FDA has been very clear, from its response to ViroPharma’s Citizen Petition through its briefing of the present motions, that it considered the new Vancocin labeling to have “merely refined and added new details to describe the previously approved conditions of use.”  The FDA has used the same definition of “condition of use” in applying subsection (v)(3)(B) that it has used in applying other subsections of the statute, such as subsection (j)(2)(A)(i), which requires ANDAs to have the same conditions of use as the innovator.

As the Court explained at length in its prior Memorandum Opinion, the agency acted within its discretion to determine that “the revision of the Vancocin label to incorporate clinical data that supports and refines labeling regarding already approved conditions of use, does not constitute approval for a condition of use that has not been ‘approved before the enactment’ within the meaning of section 505(v)(3)(B).”  The Court reaffirms this conclusion here, especially given the “high level of deference” accorded to the agency where the agency’s decision “involve[s] a subject matter [that] is technical, complex, and dynamic,” and “rests on the ‘agency’s evaluations of scientific data within its area of expertise.’” [(Internal citations omitted; italics in original)]

After reviewing certain portions of the administrative record, Judge Huvelle also noted that the studies supporting the approval of ViroPharma’s December 2011 Supplemental NDA approval – and the studies upon which ViroPharma staked its claim to 3-year exclusivity – were not essential to the approval of the Supplemental NDA.  The “essential to approval” criterion is one of the three criteria that must be met for FDA to grant 3-year exclusivity.

Similar to ViroPharma’s challenge to FDA’s exclusivity decision, Judge Huvelle found with respect to ViroPharma’s allegation that FDA violated its own regulations when the Agency approved generic VANCOCIN based on in vitro rather than in vivo bioequivalence testing data because FDA’s regulations establish an in vivo testing default requirement, that ViroPharma “[failed] to present any new arguments or facts to support its bioequivalence claim[, but rather,] has merely added two additional examples to support its previously articulated argument, neither of which compels a different result.”  Specifically, ViroPharma alleged that certain changes to FDA’s ANDA bioequivalence regulations at 21 C.F.R. Part 320 served to “expressly relinquish” the Agency’s authority under the FDC Act to determine on a case-by-case basis the appropriate method for demonstrating bioequivalence to a brand-name Reference Listed Drug.  Not so, wrote Judge Huvelle, who found no express relinquishment of statutory authority and stated her satisfaction that FDA did not abuse its authority in waiving a showing of in vivo bioequivalence to approve generic VANCOCIN. 

In sum, wrote Judge Huvelle, “[g]iven the absence of changed facts or new legal arguments or authority, the Court’s judgment remains the same: the FDA acted well within its discretion in denying three-year exclusivity to ViroPharma and in approving the ANDAs of intervenor-defendants.” 

For those Hatch-Waxman watchers, we note that the ViroPharma case is one of two recent cases involving 3-year exclusivity.  Currently on appeal to the U.S. Court of Appeals for the District of Columbia Circuit is the DC District Court’s July 2012 decision (see our previous post here) concerning the scope of 3-year exclusivity applicable to SEROQUEL (quetiapine fumarate).  One particularly enlightening document that has come out of that litigation is FDA’s March 27, 2012 letter decision, which lays out the Agency’s approach to 3-year exclusivity.  The letter decision discusses the scope of 3-year exclusivity as it relates to the scope of new clinical investigations conducted by the NDA sponsor.  According to FDA, the FDC Act sets up a “logical relationship between the change in the product for which the new clinical investigations were essential to approval of the supplement, and the scope of any resulting three-year exclusivity.”  Oral argument in the SEROQUEL case (Case No. 12-5227) is scheduled for March 21, 2013.  Copies of FDA’s Opening Brief and AstraZeneca’s Opening Brief and Reply Brief are available here, here, and here.

By Frank Sasinowski & William Koustas –

FDASIA/PDUFA V elevates the role of patients in developing orphan therapies.  It mandates that FDA implement ways to bring patients' views into drug development and FDA’s regulatory review.  This is appropriate as it is often these patients that push development of orphan drugs forward. 

While there are many, we highlight here one example that illustrates the growing power of patients.  The LAM Foundation is a patient organization chartered in 1995 by a mother of a LAM patient to raise awareness and fund research on this debilitating disease.  LAM (lymphangioleiomyomatosis) is a very rare, progressive, and frequently fatal systemic neoplasm that results in cystic destruction of the lungs and generally occurs in young women. 

The LAM Foundation helped arrange funding and subjects for a pivotal clinical trial to study sirolimus, a drug approved to prevent renal transplant rejection, for the treatment of LAM.  The results of this successful study were published in the New England Journal of Medicine and the Journal editors wrote an accompanying piece commending this patient organization for its sterling efforts.  See McCormack FX, et al. Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med 2011;364:1595-606.  The FDA granted orphan drug designation to The LAM Foundation for sirolimus for treating LAM on October 31, 2012. 

The efforts of The LAM Foundation are just one example of how the role of patients, particularly patients with rare diseases, is becoming even more crucial in developing new medicines.  Onward! 

By David B. Clissold –

FDA has released a Draft Guidance for Industry, titled “Abuse-Deterrent Opioids—Evaluation and Labeling.”  Since at least 2005, Congress has noted the need for FDA guidance governing the development and approval of abuse-deterrent drug products.  See e.g., H.R. Rep. No. 109-102 (2005) (here at page 81).  Most recently, in the Food and Drug Administration Safety and Innovation Act (“FDASIA”), Congress instructed FDA to promulgate guidance on the development of such products.  FDASIA, Pub. L. No. 112-144, 126 Stat. 993, § 1122(c) (2012) (see our FDASIA summary here).

FDA’s draft guidance notes that “[t]he science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving,” so the agency plans to “take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products.”  That said, the draft guidance identifies four categories of studies that should be addressed by applicants: Laboratory-based in vitro manipulation and extraction studies (Category 1), pharmacokinetic studies (Category 2), clinical abuse potential studies (Category 3), and postmarketing studies (Category 4).  As FDA explained, the first three categories of studies are designed to assess “the potentially abuse-deterrent properties of a product under controlled conditions” whereas the Category 4 postmarketing studies should be designed “to determine whether the marketing of the potentially abuse-deterrent formulation results in a significant decrease in population-based and use-based estimates of abuse compared to estimates of abuse if only formulations without abuse-deterrent properties are marketed.”  However, FDA acknowledged that since “data on the actual impact of an abuse-deterrent formulation on drug abuse are limited, the optimal design features of postmarketing epidemiologic studies capable of detecting a change in the occurrence of abuse and abuse-related clinical outcomes (addiction, overdoses, poisonings, and death) as a result of the drug product’s abuse-deterrent formulation have not yet been established.”

The amount of pre-clinical, clinical, and epidemiological data that FDA expects under this draft guidance sets a high bar.  However, in an important change with potentially far-reaching implications, the agency is now willing to permit abuse-deterrence information in labeling.  The draft guidance explains that four “tiers” of claims are possible: The Product is Formulated with Physicochemical Barriers to Abuse (Tier 1), The Product is Expected to Reduce or Block Effect of the Opioid When the Product is Manipulated (Tier 2), The Product is Expected to Result in a Meaningful Reduction in Abuse (Tier 3), or The Product has Demonstrated Reduced Abuse in the Community (Tier 4).  FDA noted that the tiers are generally correlated with the four categories of study data, but cautioned that “in order to provide as complete a picture as possible of a product’s abuse-deterrent properties, FDA generally expects sponsors to provide data from Categories 1, 2, and 3 in order to be eligible for Tier 1, Tier 2, or Tier 3 claims.”

Importantly, the draft guidance does not address the approvability or labeling of generic drugs with abuse-deterrent technology that may be submitted in an abbreviated new drug application (“ANDA”).  Must those generic companies have the same “tiered” labeling as the reference listed drug?  Must the generic use identical abuse-deterrent technology, or indeed, must the generic be abuse-deterrent at all? 

Some of these questions may be addressed in FDA’s pending response to a citizen petition filed on behalf of Purdue Pharma L.P (“Purdue”) (Docket No. FDA-2012-P-0939).  In that citizen petition, Purdue explains the development of an “abuse deterrent” reformulation of OxyContin.  Among other things, Purdue asks FDA to require any ANDA for reformulated OxyContin to contain comparability data using the in vitro tests performed by Purdue on OxyContin, an in vivo study “comparing the bioavailability of finely crushed generic product [to] finely crushed reformulated OxyContin” and possibly additional in vivo studies.  To date, FDA has not permitted Purdue to include abuse-deterrence claims in its labeling for this product, but the draft guidance document may further complicate FDA’s response to Purdue’s request, and have far-reaching implications for generic versions of other drugs with abuse-deterrent formulations.  Also pending at FDA are citizen petitions submitted by Endo Pharmaceuticals Inc. (Docket No. FDA-2012-P-0951) and Pfizer Inc. (Docket No. FDA-2012-P-1009) that raise questions about abuse-deterrent versions of OPANA ER (oxymorphone HCI) Extended-release Tablets and Oxecta (oxycodone HCl) Tablets, respectively, vis-à-vis generic competition.

Congress has also entered the fray with the July 2012 introduction of H.R. 6160, the Stop Tampering of Prescription Pills Act of 2012 (“STOPP Act”).  The STOPP Act, which is expected to be reintroduced in the 113th Congress, would amend the FDC Act to, among other things, establish new requirements for the approval of brand-name and generic drugs that are otherwise available in a tamper-resistant formulation (see our previous post here).  Several Members of Congress have also teamed up to form the Congressional Caucus on Prescription Drug Abuse.

The draft guidance document concludes by highlighting again the “rapidly evolving” technologies involved in this field and the way in which FDA intends to evaluate those technologies.  The draft guidance document noted four areas that should be the subject of additional research:  (1) Characterization of the quantitative link between changes in the pharmacokinetics of opioids in different formulations and results of a clinical abuse potential study with those same formulations; (2) Characterization of the best assessment methods to employ when analyzing a clinical study of abuse potential; (3) Characterization of the quantitative link between the outcomes from a clinical study of abuse potential comparing formulations and the effect on those same formulations on abuse in the community; and (4) Further understanding of the best study methods to employ to assess the effect of an abuse-deterrent formulation on the rates of abuse in the community.

Hyman, Phelps & McNamara, P.C. will hold a complimentary webinar on Thursday, January 31, 2013, from 12:00 – 2:00 PM (Eastern) on the Second Circuit's recent and long-awaited decision in United States v. Caronia.  This webinar is not just another summary of the Second Circuit's decision. Nor is it merely high-level positing about the future of off-label promotion prosecutions, such as here and here. This webinar will provide practical tips to address the real-world implications to companies from this significant decision. The impacts go beyond just the pharmaceutical marketing industry – the marketing of devices, dietary supplements, and tobacco products likely will be affected.  Hear from experts who evaluate and advise FDA-regulated industries about relevant business considerations that are impacted by Caronia. Participants will gain an understanding of:

• The Caronia decision and other First Amendment court rulings involving FDA and what the government is likely to do as a result of the Caronia decision;
• Views from people familiar with how the FDA Centers (including CDER, CDRH, CFSAN, and CTP) will modify enforcement and other decisions as a result of Caronia;
• Strategies for promotional review committees to use; and
• Defenses to current and future off-label marketing and government reimbursement cases.

There will be an opportunity to submit questions during the webinar. Responses to any questions that are not addressed will be available on the HP&M firm website after the webinar.

You can register for the conference here.  Please contact Lisa Harrington at lharrington@hpm.com with any registration questions. 

By Kurt R. Karst –      

Every once in a while we receive a series of similar questions from various quarters such that a critical mass has been reached justifying a blog post on the topic.  This is one of those posts.  And it has to do with the always hot – and particularly hot as of late (see our previous post here) – topic of 5-year New Chemical Entity (“NCE”) exclusivity.  The question is: can 5-year NCE exclusivity be cut short, such that FDA can approve an ANDA or a 505(b)(2) application prior to the expiration of such period?  The answer under one interpretation of the law, surprising to some, appears to be “Yes.”

NCE exclusivity is explained in the FDC Act vis-à-vis the submission and approval of an ANDA (at FDC Act § 505(j)(5)(F)(ii)) or a 505(b)(2) application (at FDC Act § 505(c)(3)(E)(ii)) for a drug product containing an active moiety protected by NCE exclusivity.  For example, FDC Act § 505(j)(5)(F)(ii) states:

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 [ANDA] may be submitted under [FDC Act § 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 [an ANDA] may be submitted under [FDC Act § 505(j)] 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].  The approval of such [ANDA] shall be made effective in accordance with [FDC Act § 505(j)(5)(B)] except that, if an action for patent infringement is commenced during the one-year period beginning forty-eight months after the date of the approval of the [NCE NDA], the thirty-month period referred to in [FDC Act § 505(j)(5)(B)(iii)] shall be extended by such amount of time (if any) which is required for seven and one-half years to have elapsed from the date of approval of the [NCE NDA].

For our purposes here, the important part of the statutory quote above is the reference to FDC Act § 505(j)(5)(B) and the effective date of ANDA approval when there is not a timely filed patent infringement lawsuit made in response to the notice of a Paragraph IV certification contained in an ANDA submitted beginning at year 4 of the 5-year NCE exclusivity period.  Section 505(j)(5)(B) governs the effective date of ANDA approval depending on the type of certification to patent information listed in the Orange Book for the Reference Listed Drug (“RLD”) that forms the basis of submission of an ANDA.  With respect to an ANDA containing a Paragraph IV certification, the statute, at FDC Act § 505(j)(5)(B)(iii), states: 

If the applicant made a [Paragraph IV certification], the approval shall be made effective immediately unless, before the expiration of 45 days after the date on which the notice described in [FDC Act § 505(j)(2)(B)] is received, an action is brought for infringement of the patent that is the subject of the certification and for which information was submitted to the Secretary under [FDC Act §§ 505(b)(1) or (c)(2)] before the date on which the application (excluding an amendment or supplement to the application), which the Secretary later determines to be substantially complete, was submitted.  If such an action is brought before the expiration of such days, the approval shall be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the [Paragraph IV certification] notice . . . or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action, [with certain exceptions . . . . .] [(Emphasis added)]

Bam!  There you have it!  The statute says ANDA approval is made effective “immediately” if there is not a timely filed patent infrongement lawsuit made in response to notice of a Paragraph IV certification.  Thus, in a hypothetical scenario where the 5-year NCE exclusivity period for a drug expires on January 2, 2014, an ANDA containing a Paragraph IV certification to an Orange Book-listed patent can be submitted on January 2, 2013.  Let’s say that our hypothetical ANDA is received after a 60-day review period by FDA’s Office of Generic Drugs.  There is then a 20-day period to send notice of the Paragraph IV certification to the NDA holder and patent owner.  If notice is promptly sent and 45 days pass without the filing of a patent infringement lawsuit, our hypothetical ANDA could be approved with about 8 months of the 5-year NCE exclusivity period remaining on the RLD. 

How often does it happen that the 5-year NCE exclusivity period is cut short?  Not often.  In fact, we cannot immediately think of a case.  And with median ANDA approval times still hovering around 33 to 34 months, it seems more of a theoretical possibility now than a real possibility that FDA could turn around an ANDA within a few months.  Perhaps a 505(b)(2) application containing verly little data and that is granted priority review could be turned around in short order.  With the enactment of the Generic Drug User Fee Amendments and the expectation of significantly reduced ANDA review timelines, however, it might be possible for FDA’s Office of Generic Drugs to promptly act on an ANDA.  Only time will tell.

The possibility that NCE exclusivity might be cut short might be one explanation as to why an NDA sponsor with a single Orange Book patent with a questionable basis for listing might request that FDA delist the patent prior to the expiration of 4 years after the NCE NDA approval.  For example, see our previous post here concerning INVEGA (paliperidone) Extended-release Tablets.  If there is not a resonable basis to assert a patent against the sponsor of an ANDA, then the listing of that patent could actually trigger ANDA approval much earlier than expected.  Alternatively, if there is not a patent, then the ANDA cannot even be submitted until the 5-year NCE exclusivity period expires.

By Kurt R. Karst –

Although the number of cases involving 180-day exclusivity under the version of the FDC Act in effect before the December 8, 2003 enactment of the Medicare Modernization Act (“MMA”) is nearing an end, the pre-MMA statute, and the handling of it by FDA and the courts, never fails to surprise us.  Take, for example, the December 28, 2012 approval of ANDA No. 202608 for Mallinckrodt Inc.’s (“Mallinckrodt”) generic version of Janssen Pharmaceuticals, Inc.’s CONCERTA (methylphenidate HCl) Extended-Release Tablets, 27 mg, 36 mg, and 54 mg.  Mallinckrodt’s December 31, 2012 press release on the approval, and, in particular, the announcement that “Mallinckrodt believes it holds a separate 180-day exclusivity period for each of the 27, 36 and 54 mg dosage strengths” (emphasis added), left a lot of jaws on the floor and a lot of people scratching their heads.  First, nobody really expected Mallinckrodt to be a player for 180-day exclusivity.  How did they do it?  Second, why would a company only believe it has 180-day exclusivity?  Wouldn’t the ANDA approval letter remove any doubt?  Some answers were provided when FDA finally posted the approval letter for ANDA No. 202608.  But before we get into that, a quick refresher on some pre-MMA 180-day exclusivity issues . . . .

Under the pre-MMA version of the statute, 180-day exclusivity is patent-based, such that an ANDA applicant (or different applicants) may be eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the Reference Listed Drug (“RLD”) if the applicant submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered by either first commercial marketing (for all relevant patents), or by a court decision favorable to an ANDA applicant (with respect to a particular patent), whichever is earlier.  The marketing of an authorized generic by a first filer eligible for 180-day exclusivity is commercial marketing that triggers exclusivity.  

When the first ANDA containing a certification to any Orange Book-listed patent was submitted to FDA before December 8, 2003, but the first Paragraph IV certification is submitted post-MMA, then, as FDA explained in the Agency’s April 2009 “pre-MMA/post-MMA Straddle” Letter Decision (see our previous post here), exclusivity for that drug is governed by the pre-MMA statute.  Also, as a result of the pre-MMA’s patent-by-patent approach to 180-day exclusivity, there is the possibility of shared exclusivity, which FDA clarified in 2010 (see here) applies only where “two applicants have submitted paragraph IV certifications to two different patents, and one applicant was first to file a paragraph IV certification on one patent and the other was first to file on a different patent” (i.e., an “exclusivity stand-off”).  Finally, for our purposes here, it is important to note that the pre-MMA patent-by-patent approach to 180-day exclusivity means that a new Orange Book patent listing can significantly complicate and alter the 180-day exclusivity calculus.  On-the-ball companies that submit so-called “serial Paragraph IV certifications” to FDA for newly issued patents in anticipation of Orange Book listing may qualify for 180-day exclusivity based on their certification.  

CONCERTA, which is approved under NDA No. 021121, is currently listed in the Orange Book with three patents – U.S. Patent Nos. 6,919,373 (“the ‘373 patent”), 6,930,129 (“the ‘129 patent”), and 8,163,798 (“the ‘798 patent”).  All three patents are scheduled to expire on July 31, 2017, but are subject to a period of pediatric exclusivity that expires on January 31, 2018.  According to FDA’s Paragraph IV Patent Certifications List, the first ANDA containing a Paragraph IV certification for all four approved strengths of CONCERTA (18 mg, 27 mg, 36 mg, and 54 mg) was submitted to the Agency post-MMA on July 19, 2005.  Nevertheless, the first ANDA containing a certification to an Orange Book-listed patent for CONCERTA was made pre-MMA, thereby making generic CONCERTA a pre-MMA/post-MMA straddle drug governed by the pre-MMA rules on 180-day exclusivity.  Although the ‘373 patent, the ‘129 patent, and the ‘798 patent were all issued and listed in the Orange Book post-MMA (the ‘373 and ‘129 patents were issued in 2005, and the ‘798 patent was issued in 2012), CONCERTA was initially listed in the Orange Book with patents that expired in 2002 and 2003.  Presumably the first ANDA submitted to FDA contained Paragraph III certifications to those patents.

In 2005, pending ANDAs for generic CONCERTA were amended to include Paragraph IV certifications to the ‘373 and ‘129 patents – although questions about who was first (Andrx or Impax) remained.  Patent infringement litigation was brought against ANDA sponsors with respect to these patents in the U.S. District Court for the District of Delaware, resulting in a decision of non-infringement and invalidity of the ‘373 patent, which the U.S. Court of Appeals for the Federal Circuit affirmed in an April 26, 2010 decision and mandated on June 2, 2010, thereby triggering 180-day exclusivity with respect to that patent.  Infringement claims and defendant counterclaims concerning the ‘129 patent were dismissed with and without prejudice, respectively.  The door was apparently left open on litigation over the ‘129 patent depending on 180-day exclusivity associated with that patent.  Meanwhile, in May 2011, Watson, which had acquired Andrx in 2006, announced that the company had launched an authorized generic version of all strengths of CONCERTA.  And in July 2012, FDA affirmed in a response to a citizen petition (Docket No. FDA-2004-P-0151) what many had already suspected – that the Agency would depart from conventional bioequivalence metrics and set partial AUC parameters for generic CONCERTA.  FDA’s decision may have led to some reformulation efforts on the part of ANDA sponsors.

The ‘798 patent, which issued on April 24, 2012, was listed in the Orange Book on May 18, 2012.  And in what might be a case of serial certifications, FDA states in a footnote to the approval letter for ANDA No. 202608 that “Mallinckrodt’s paragraph IV certification to the ‘798 patent was submitted in an amendment to its ANDA on May 18, 2012, the same day on which this patent was submitted for listing in the Orange Book.”  This certification made Mallinckrodt eligible for 180-day exclusivity with respect to the ‘798 patent.  ANDA No. 202608 also contains Paragraph IV certifications to the ‘373 and ‘129 patents, thereby raising the prospect of shared exclusivity with respect to the ‘129 patent, if there is any exclusivity remaining on that patent.  FDA’s ANDA approval letter does not delve into the issue.  But what the ANDA approval letter does say with respect to 180-day exclusivity associated with the ‘798 patent is quite interesting:

With respect to 180-day generic drug exclusivity, we note that Mallinckrodt was the first ANDA applicant for Methylphenidate Hydrochloride Extended-Release Tablets USP, 27 mg, 36 mg, and 54 mg, to submit a substantially complete ANDA with a paragraph IV certification to the ‘798 patent.  Therefore, with this approval, Mallinckrodt may be eligible for 180 days of generic drug exclusivity for Methylphenidate Hydrochloride Extended-Release Tablets USP, 27 mg, 36 mg, and 54 mg.  This exclusivity would begin to run from the earlier of the commercial marketing or court decision dates identified in section 505(j)(5)(B)(iv).  The agency is not, however, making a formal determination at this time of Mallinckrodt’s eligibility for 180-day generic drug exclusivity.  It will do so only if another paragraph IV applicant becomes eligible for full approval (a) within 180 days of the earlier of the commercial marketing or court decision dates identified in section 505(j)(5)(B)(iv), or (b) at any time prior to the expiration of the ‘798 patent if neither the commercial marketing nor court decision events identified in section 505(j)(5)(B)(iv) has occurred. [(Emphasis added)]

Similar language punting on 180-day exclusivity has appeared in ANDA approval letters for years, dating back to FDA’s July 31, 2006 approval of ANDA No. 076969 for Metoprolol Succinate Extended-Release Tablets (see our previous posts here, here, and here).  All of FDA’s 180-day exclusivity punts, however, have involved post-MMA 180-day exclusivity.  The approval of ANDA No. 202608 marks the first instance in which FDA has punted on pre-MMA 180-day exclusivity.

Naturally, the question is why FDA would have punted on exclusivity in this case.  Certainly, 180-day exclusivity for generic CONCERTA is complicated.  Lingering dispute concerning exclusivity associated with the ‘129 patent may be to blame, perhaps in part.  But we think the primary reason FDA punted in this case is because of the recent decision by Judge Amy Berman Jackson of the U.S. District Court for the District of Columbia in a pre-MMA 180-day exclusivity case concerning generic ACTOS (pioglitazone HCl) Tablets.  In that case, which is on appeal to the U.S. Court of Appeals for the District of Columbia Circuit (see the opening briefs of FDA and Mylan here and here), Judge Jackson ruled against FDA and ordered the approval of Watson’s ANDA No. 076798.  (Motions to expedite the appeal – here and here – were denied.)  As we previously discussed, Judge Jackson’s decision could potentially be interpreted to say that what is in an amendment to an ANDA does not count for 180-day exclusivity purposes.  Rather, it is the original ANDA submission that counts.  In the case of generic CONCERTA, the prospect for Mallinckrodt to become eligible for 180-day exclusivity was the result of an ANDA amendment (as was the case for all of the ANDA first filers here).  So, from FDA’s perspective, it would seem a punt in any pre-MMA case in which exclusivity depends on a Paragraph IV certification contained in an ANDA amendment is warranted until the generic ACTOS case is resolved on appeal.  Reasonable minds may differ, however.

By Jeffrey K. Shapiro –

FDA has enhanced authority over the sale, distribution and use of devices that the agency designates as “restricted.”  21 U.S.C. § 360j(e).  FDA almost always designates Class III devices as “restricted devices” in premarket application (“PMA”) approval orders.  21 U.S.C. § 360e(d)(1)(B)(ii).  Some Class III devices perform elective procedures that tend to be advertised to consumers by surgical centers and other user facilities.  As a practical matter, FDA has seldom issued warning letters to user facilities in connection with such advertising.

That may be changing.  In 2011 and 2012, FDA issued a spate of warning letters directed to advertising of the LapBand gastric banding system (“LapBand”) for weight loss (see, e.g., here).  The LapBand is manufactured by Allergan, but the letters were directed to surgical centers and other facilities advertising the procedure to consumers. 

In each case, FDA asserted that the device has been misbranded while in commerce because the advertisements failed to disclose information describing the risks associated with this surgery, patient eligibility requirements, and the need for ongoing modification of eating habits – all of which are in the approved LapBand labeling.  The asserted legal theory is that the failure to disclose risk information renders the advertisements misleading (21 U.S.C. § 321(n)), and also violates an affirmative statutory requirement to disclose such risk information (21 U.S.C. § 352(r)).

On December 18, 2012, FDA issued four warning letters to surgical centers offering laser-assisted in-situ keratomileusis (“LASIK”) with WaveLight and VISX lasers (see here, here, here, and here). Again, the gravamen of each warning letter is that the advertisements fail to disclose key risk information found in the approved labeling for this laser vision correction device.  The asserted legal theory is the same as with the LapBand letters.

Clearly, FDA wants to see more risk information in consumer advertising for surgical procedures.  The agency also has obviously gotten comfortable with the legal basis for issuing these warning letters.  Therefore, it would not be surprising to see more of them.  Devices used for cosmetic surgery could become another target, since they are also heavily advertised to consumers. 

Bottom line — manufacturers of restricted devices may wish to do more to educate user facilities and contractually require them to comply with these requirements.  This step will help ensure that the manufacturer itself does not receive a warning letter.  It also may be helpful in avoiding the potential to damage the brand image that multiple warning letters may bring, even if directed at user facilities rather than the manufacturer directly.

By Ricardo Carvajal –

FDA released two long-awaited proposed rules to implement key provisions of the Food Safety Modernization Act ("FSMA"): Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Human Food and Standards for the Growing, Harvesting, Packing, and Holding of Produce for Human Consumption.

New 21 CFR Part 117 would implement FSMA § 418, which addresses preventive controls, and would modernize the cGMP regulation at Part 110.  In developing Part 117, FDA applied the framework of HACCP, such that the structure and provisions of the proposed rule will feel familiar to those with HACCP experience in other regulatory contexts (e.g., seafood and juice).  Note, however, that FDA is requesting comment on a number of important issues that are not addressed in the text of the regulation itself.  For example, FDA did not include provisions that require product testing, environmental monitoring, or supplier approval and verification.  However, these “elements of a preventive controls system” are extensively discussed in an appendix to the proposed rule, and it is clear that they could yet be integrated into the final rule pending further evaluation.  As an additional example, FDA requests comment on the scope of certain exemptions, such as that granted to dietary supplement manufacturers in compliance with Part 111 and serious adverse event reporting requirements.  Interested parties are therefore urged to read the preamble in its entirety.

New 21 CFR Part 112 would implement FSMA § 419, which addresses produce safety.  As expected, the proposed rule focuses on the four major pathways for the introduction of microbiological hazards – water, employee hygiene, soil amendments, and incursion by animals.  The rule would target commodities and practices where FDA believes intervention can significantly reduce risks, and would provide a number of exemptions (e.g., for certain commodities that are rarely consumed raw, and for produce that receives a kill step). 

Comments on both rules are due May 16, 2013.  It is highly unlikely that final rules would publish prior to the end of the year.  In any event, both final rules would have staggered compliance dates, such that larger business would not be expected to comply until 2014, at the earliest. 

By Jennifer D. Newberger –

On December 31, 2012, CDRH released three final guidance documents, the drafts of which were issued in the summer and fall of 2012.  The quick finalization of these guidance documents is likely due to their fairly uncontroversial nature, since they are more about process than substance.  Each guidance is discussed below.

eCopy Program for Medical Device Submissions.  The Food and Drug Administration Safety and Innovation Act (“FDASIA”) requires CDRH to issue a guidance document describing the processes for submitting an “eCopy” of medical device submissions.  Finalization of the guidance document is intended to meet this FDASIA requirement. 

An eCopy is required for nearly all medical device submissions, including  510(k)s, de novo petitions, PMAs, IDEs, HDEs, and pre-submissions.  Though an eCopy is not required for a 513(g) submission, FDA “strongly encourages” companies to submit an eCopy for that type of submission. 

It is important to note that an eCopy is not considered to be an electronic submission.  Rather, it is “an exact duplicate of the paper submission, created and submitted on a compact disc (CD), digital video disc (DVD), or a flash drive.  An eCopy is accompanied by a paper copy of the signed cover letter and the complete paper submission.”  There may be exceptions to the “exact duplicate” requirement, such as when “a paper copy is not practical or appropriate for analysis purposes (e.g., raw data and statistical analysis programs, data line listings to facilitate  bioresearch monitoring review) or is not feasible (e.g., videos, x-rays).”  In these limited circumstances, “the eCopy must include all of the required information for FDA review, whereas the paper copy can include a placeholder cross-referencing the location of certain information in the eCopy.”  The cover letter should describe any differences in the paper and eCopy versions.

FDA has established a free eSubmitter-eCopies tool, available on its website, which FDA “strongly encourage[s]” submitters to use.  That tool meets the standards that FDA lays out in Attachment 1 of this guidance document, so use of the tool should ensure consistency with FDA’s requirements.  Review of a submission will not begin until FDA receives a valid eCopy, so compliance with FDA’s requirements is critical.

PDF files are the primary format used for an eCopy, and failure to follow the PDF file requirements described in the guidance will result in the eCopy failing the loading process.  The requirements include: (1) Adobe Acrobat PDF Version 10.0 or below.  If the submitter uses a more recent version, it must “save the PDF as a reduced size PDF or the eCopy will fail the loading process;” (2) eCopies may not include attachments to PDF files; (3) PDF files may not have security settings; (4) PDFs must conform to an FDA-specified naming convention; and (5) PDF file size must be 50MB or smaller, though there is no limitation on the total size of a submission.

Acceptance and Filing Reviews for Premarket Approval Applications.  As discussed in our earlier post on the draft guidance, this guidance separates the criteria for PMA filing into: (1) acceptance criteria; and (2) filing criteria.  The guidance document contains a checklist to help clarify the necessary elements and contents of a complete PMA submission.

To be accepted, the submission should include all organization and administrative elements, or a rationale for those determined by the applicant to be not applicable.  The acceptance review should be completed within 15 days of receipt of the submission, and FDA should provide a written response to the submitter within that time frame identifying any missing elements, or informing the submitter that the PMA is “Accepted.”  If the submitter does not hear from FDA within 15 days, the PMA should be considered accepted.  If FDA identifies missing information, the submitter may submit this information under the originally assigned PMA number.  FDA will then again conduct the acceptance review to determine the completeness of the submission.  The review clock will not begin until FDA has both “accepted” and “filed” an application, and the start date will be determined by the date on which FDA received the submission or amendment that made the PMA complete.

As stated in the draft guidance and repeated in the final version, in determining whether a PMA should be accepted and filed, FDA should not evaluate the submitted information to determine whether it is sufficient to demonstrate reasonable assurance of safety and effectiveness.

Submitters should refer to the “Checklists for Accepting and Filing PMAs” contained in the final guidance document to help ensure their submissions are complete and will be accepted and filed in a timely fashion.

Refuse to Accept Policy for 510(k)s.  This guidance document adopts a procedure for 510(k)s similar to that described above for PMAs.  The guidance modifies FDA’s prior Refuse to Accept (“RTA”) policy “to include an early review against specific acceptance criteria and to inform the submitter within the first 15 calendar days after receipt of the submission if the submission is administratively complete, or if not, to identify the missing element(s).”  The guidance and the checklists in the appendix are intended to “clarify the necessary elements and contents of a complete 510(k) submission.”  During acceptance review, FDA should not consider whether the information provided is sufficient to demonstrate substantial equivalence to a legally marketed predicate device, but only administrative completeness.

For FDA to accept the 510(k), all administrative elements identified in the guidance document and checklists should be included, or the submitter should provide a rationale explaining why certain missing elements are not applicable.  As with PMAs, the acceptance review will be conducted and completed within 15 calendar days of FDA receipt of the 510(k) notification.  FDA will use the appropriate checklist (traditional, special, or abbreviated) depending on the type of 510(k) submitted. 

If FDA accepts a submission, it should notify the submitter in writing that the 510(k) has been accepted and substantive review will commence.  If FDA does not complete the acceptance review within 15 days, “the submitter should be notified in writing that the acceptance review was not completed and the submission is under substantive review.”  FDA can request any information that may have resulted in an RTA during the substantive review, even if FDA provided notice to the submitter that the 510(k) was accepted.  The review clock starts on the date of receipt of the submission or of the amendment to the submission that enables FDA to accept the 510(k).  If acceptance review was not complete within 15 calendar days, “the submission will be considered to be under substantive review, and the FDA review clock start date will be the . . . receipt date of the most recently received information for the submission.  Once the submission is under substantive review the calendar days used to conduct the acceptance review (i.e., up to 15 days) are included within the 60 calendar days to reach the Substantive Interaction goal” described in the commitment letter for MDUFA III.

As with PMAs, submitters should review the checklists provided as appendices to this guidance to help ensure their 510(k)s are complete upon submission.

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By Kurt R. Karst –      

Last week in a post-Christmas decision, Judge John D. Bates of the U.S. District Court for the District of Columbia granted both FDA’s and Intervenor-Defendant Ranbaxy Laboratories Limited’s (“Ranbaxy’s”) Motions for Summary Judgment and denied Mylan Laboratories Limited’s and Mylan Pharmaceuticals Inc.’s (collectively, “Mylan’s”) Motion for Preliminary Injunction in a case stemming from an October 2, 2012 Complaint challenging FDA’s September 28, 2012 decision that Ranbaxy is eligible for 180-day exclusivity for its generic version of DIOVAN (valsartan) Tablets despite Ranbaxy not having obtained tentative approval of its ANDA No. 077492 within 30 months of ANDA submission.  Unfortunately, many of the documents in the case remain sealed – including FDA’s September 28, 2012 letter decision on the non-forfeiture of 180-day exclusivity eligibility – so we don’t have much to go on except the 25-page decision from Judge Bates.

As we previously reported, Mylan’s lawsuit is the first involving 180-day generic drug exclusivity and the so-called “failure to obtain timely tentative approval” forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV) added by the 2003 Medicare Modernization Act (“MMA”).  Under FDC Act § 505(j)(5)(D)(i)(IV), 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

FDA has explained that under FDC Act § 505(j)(5)(D)(i)(IV),

it is not sufficient to show that FDA changed or reviewed the requirements for approval while the application was under review.  The applicant must also show that its failure to obtain tentative approval at the 30 month date is caused by this change in or review of approval requirements – that is, the issues holding up approval at the 30 month date must be causally connected to the approval requirements that FDA reviewed or changed. [(Emphasis added)]

On December 28, 2004, Ranbaxy submitted the first ANDA to FDA containing a Paragraph IV certification to an Orange Book-listed patent for DIOVAN Tablets; specifically a Paragraph IV certification to U.S. Patent No. 6,294,197 (“the ‘197 patent”), the pediatric exclusivity for which expires on December 18, 2017.  Ranbaxy’s ANDA also contained a Paragraph III certification to now-expired U.S. Patent No. 5,399,578 (“the ‘578 patent”), and a “section viii” statement to U.S. Patent No. 5,972,990, a method-of-use patent the pediatric exclusivity for which expires on April 26, 2017.   FDA tentatively approved ANDA No. 077492; however, that tentative approval came on October 25, 2007, which is well after the 30-month anniversary date of the submission of ANDA No. 077492 (i.e., June 28, 2007 by FDA’s calculation).  Mylan’s ANDA No. 090866 was submitted to FDA on September 15, 2008 and also contains a Paragraph IV certification to the ‘197 patent.  FDA tentatively approved the ANDA on September 28, 2012.  Final approval of ANDA No. 090866 (as well as the ANDAs of subsequent applicants) depends on the disposition of Ranbaxy’s 180-day exclusivity.

Although there was no patent or exclusivity block preventing FDA from granting final approval to Ranbaxy’s ANDA No. 077492 once the ‘578 patent expired on September 21, 2012, the application remains unapproved.  This may be due to a January 2012 Consent Decree Ranbaxy entered into with the United States after FDA invoked the Agency’s Application Integrity Policy against Ranbaxy.  The Consent Decree identifies several Ranbaxy ANDAs by a non-descriptive label that may be subject to forfeiture if certain conditions detailed in the Consent Decree are not met within certain timeframes.  It is possible that ANDA No. 077492 is one of those affected applications.  Nevertheless, at this time, Ranbaxy remains eligible for 180-day exclusivity. 

Why does Ranbaxy remain eligible for 180-day exclusivity despite having failed to obtain timely tentative approval?  According to FDA’s September 28, 2012 letter decision discussed in Judge Bates’ decision, “there had been changes to the approval requirements for both labeling and chemistry” affecting Ranbaxy’s ANDA.  Specifically, “[f]irst, on November 22, 2006, FDA approved a labeling supplement for Diovan that consisted of changes to three sections of the drug’s labeling, [and second], on May 1, 2007 (about two months before the 30- month forfeiture date), a new USP monograph for valsartan became official.”  Indeed, FDA’s October 25, 2007 tentative approval letter noted that for purposes of FDC Act § 505(j)(5)(D)(i)(IV), “the agency regards the change in the USP monograph for Valsartan, published on May 1, 2007, . . . to be a change in the requirements for approval imposed after the date on which your ANDA was filed.”  According to FDA’s letter decision as conveyed by the court, “Ranbaxy had not forfeited its eligibility for 180-day exclusivity because its efforts to comply with the USP monograph, and FDA’s review thereof, ‘were a cause of’ Ranbaxy’s failure to obtain tentative approval within 30 months.”  As a result, FDA apparently “found it unnecessary to determine whether the November 22, 2006 labeling change was also a cause of the failure to obtain tentative approval.”

FDA’s determination as to whether Ranbaxy’s failure to obtain timely tentative approval of ANDA No. 077492 was “caused by” a change in USP requirements was based on a 7-factor test:

(1) “whether the monograph change is in a proposed or final monograph,” (2) “the timing of any publication of or change in a monograph in relation to a particular 30-month forfeiture date,” (3) “whether FDA requires compliance with the new/changed compendial standard [i.e., the USP],” (4) “whether the [FDC Act] requires compliance with the new/changed compendial standard,” (5) “the consistency of the new/changed monograph with pre-existing approval requirements,” (6) “the nature and timing of the sponsor’s efforts to comply with USP monographs,” and (7) “[the nature and timing] of FDA’s review of such efforts.”  [(Quoting FDA’s September 28, 2012 letter decision)]

After considering each of these factors, “FDA determined that (1) the May 1, 2007 publication of the USP monograph for valsartan constituted a change in the requirements for approval of Ranbaxy’s ANDA, and (2) this change was a cause of Ranbaxy's failure to obtain tentative approval by the 30-month forfeiture date.”

In evaluating the likelihood of success of Mylan’s Administrative Procedure Act (“APA”) challenge, Judge Bates considered three sets of arguments raised by Mylan in the company’s Motion for a Preliminary Injunction: (1) whether there was a lack of reasoned FDA decisionmaking; (2) whether FDA’s decision is contrary to congressional intent; and (3) whether Ranbaxy failed to actively pursue ANDA approval.  In each instance, Judge Bates rejected Mylan’s arguments.

Mylan’s primary argument was that FDA’s September 28, 2012 letter decision lacks a reasoned explanation and states only a bare conclusion that Ranbaxy did not forfeit 180-day exclusivity eligibility, and, in particular, with respect to factor number 5 of the 7-factor test – i.e., “the consistency of the new/changed monograph with pre-existing approval requirements.”  Although the court agreed with Mylan that this factor should be considered in the causation analysis, because “[c]ausation in this context requires a showing of something more than just the fact and timing of a USP monograph publication,” Judge Bates ultimately found that FDA’s decision was based on something more than merely the fact and timing of publication of the USP monograph: 

The Forfeiture Memo discusses Ranbaxy’s efforts to comply with the monograph, listing the specific changes to drug substance specifications and test methods proposed by Ranbaxy. . . .  The consistency of the monograph with pre-existing approval requirements mattered to FDA’s decision because (1) the monograph was new and set USP-specific requirements, and (2) the time that it took Ranbaxy to both make responsive changes and show that some of its existing methods met the new requirements, and for FDA to review these efforts, spanned a period of more than three months.  It does not take guesswork to see that, regardless of any case-by-case standards that existed before the USP monograph became official, the imposition of USP standards for the first time, and the specific sequence of events that took place thereafter, led FDA to conclude that the publication of the monograph was a cause of the delay in tentative approval.

Mylan also argued that FDA’s September 28, 2012 letter decision violates the APA  because it frustrates the congressional policy underlying the Hatch-Waxman Amendments, and, in particular, the intent of the MMA’s forfeiture provision – to “ensure that the 180–day exclusivity period enjoyed by the first generic to challenge a patent cannot be used as a bottleneck to prevent additional generic competition.”  Not so, said Judge Bates:

Stripping Ranbaxy of exclusivity where, as FDA has determined, its failure to obtain tentative approval was caused by a change in approval requirements would contravene congressional intent as expressly stated in the exception.  It also would deprive Ranbaxy of its anticipated reward for “stick[ing] out [its] neck[] (at the potential cost of a patent infringement suit)” by challenging Novartis’s patent and, at least in theory, decrease the expected returns from future generic challenges to patents claiming brand drugs. . . .  Considering the purposes of not only the forfeiture provision, . . . but also the exception and the exclusivity incentive created by Congress, the Court will not set aside FDA’s decision on the ground that it frustrates the congressional policy underlying Hatch-Waxman.

Finally, Judge Bates refused to consider Mylan’s argument that immediate approval of Mylan’s ANDA is warranted because Ranbaxy is not actively pursuing approval of ANDA No. 077492.  FDA’s regulation at 21 C.F.R. § 1314.107(c)(3), which was raised in litigation in 2012 concerning generic PROVIGIL (modafinil) Tablets (see here) states, in relevant part, that “if FDA concludes that the applicant submitting the first application is not actively pursuing approval of its abbreviated application, FDA will make the approval of subsequent abbreviated applications immediately effective if they are otherwise eligible for an immediately effective approval.”  FDA has never enforced this regulation.  Judge Bates concluded that Mylan raised this argument to late (i.e., in the company’s Reply Memorandum in support of its Motion for a Preliminary Injunction) and waived it. 

It is unclear at this time whether Mylan will appeal the decision.  The generic DIOVAN decision is the last Hatch-Waxman 180-day exclusivity court decision in a year that saw its share of litigation, both on the pre-MMA and post-MMA exclusivity fronts.  With less than a handful of pre-MMA drugs remaining, 2013 may be the last hurrah for pre-MMA cases (i.e., the generic ACTOS 180-Day exclusivity decision – see here – is still on appeal), but with a vast majority of FDA’s post-MMA 180-day exclusivity forfeiture decisions involving the “failure to obtain timely tentative approval” forfeiture provision, it seems likely that more litigation over this provision remains on the horizon.

By John R. Fleder –

We have extensively written about the “Park Doctrine” (see, e.g., here and here)  In United States v. Park, 421 U.S. 658 (1975), the Supreme Court authorized the government to criminally prosecute individuals for violations of the FDCA even if a corporate official is unaware of the violation, if the individual was in a position of authority to prevent or correct the violation and did not do so.

The Park Doctrine is also referred to as the Responsible Corporate Officer Doctrine.  It has resulted in hundreds of criminal misdemeanor prosecutions of corporate officers, without allegations by the government that the defendant intended to violate the FDCA or even knew about the alleged violations.  However, these prosecutions largely disappeared many years ago when the Justice Department focused its resources on prosecuting individuals under the felony provision of the FDCA, which requires that the government prove that the defendant violated the FDCA with the intent to defraud or mislead.  Beginning in early 2010, FDA and DOJ made public statements indicating that the government intended to resurrect the Park Doctrine.

There have been some criminal prosecutions in recent years in which the government charged individuals with misdemeanor violations of the FDCA.  It seemed clear from the public record in those cases that the government believed that the companies which employed the individuals had engaged in felony conduct.  In contrast, we saw very few, if any, misdemeanor cases where the public record did not reflect that the government believed that at least one person at a company had engaged in felonious conduct.  However, a 2012 prosecution that has largely flown under the public radar screen suggests that the government may have indeed prosecuted someone even though there was no evidence that anyone involved in the case had committed a felony.

On February 10, 2012, the United States Attorney for the Northern District of Texas filed a two count criminal Information against Gary D. Osborn and his company, Apothécure, Inc.  United States v. Osborn, No. 3:12-cr-00047.  Apothécure was a compounding pharmacy and Mr. Osborn was its owner, president, pharmacist-in-charge, and sole director.  The Information alleged that Mr. Osborn was the person responsible for the business activities of Apothécure, including the oversight of employee training and the quality control of the drugs that were compounded.

The Information alleged that Apothécure sold vials of injectable colchicine to a medical center in Portland, Oregon, which provided the product to three patients who died in March 2007, after being administered the drug.  The government alleged that drugs from the shipment to Portland were in some instances super-potent and in other instances were sub-potent.

The Information alleged that Mr. Osborn by reason of his position at the company, had the responsibility to prevent the FDCA violations.  It also alleged that Mr. Osborn instructed employees as to how to perform their duties, including ensuring that pharmacists and pharmacy technicians were properly trained and supervised.  However, the Information contained no allegation that Mr. Osborn played any direct role in the shipments that the government alleged were illegal.  Nor did the Information contain any suggestion that FDA had ever provided a prior warning to either Apothécure or Mr. Osborn that they were violating the FDCA.

On April 24, 2012, the government filed a Factual Resume and a Plea Agreement.  The government alleged that Mr. Osborn was a responsible corporate officer of Apothécure.  It also alleged that he had the responsibility and authority to prevent the FDCA violations.  Yet again, the government did not allege that Mr. Osborn was directly involved in the FDCA violations or the death of the patients, or that he even knew about the violations before they occurred.  The parties agreed that the proper offense level under the U.S. Sentencing Guidelines was 4.  An offense level of 4 normally results in probation for a defendant with no prior convictions but the sentencing judge is authorized to impose a term of incarceration.  On October 3, 2012, the Court imposed a $100,000 fine on Mr. Osborn and placed him on probation.  He was not sentenced to serve any jail time.

The public record does not reflect all the pleadings and papers that the parties submitted to the court.  For example, the record does not include the presentence report applicable to Mr. Osborn.  Nor does it include the government’s actual sentencing recommendation.  These documents presumably would provide a more complete factual picture than one can glean from the public record.

It is impossible to determine from the public record if the government investigated Mr. Osborn for possible felony violations of the FDCA.  There is no indication that the government had any evidence that Mr. Osborn engaged in felonious conduct.  Nor is there any indication that Apothécure or anyone affiliated with the company engaged in felonious conduct or had ever received any prior warning from FDA before the shipment that allegedly caused the death of patients.

This public record suggests that Mr. Osborn was prosecuted under the Park Doctrine in the manner that the government brought criminal cases twenty to thirty years ago, but not often after that time.  The government believed that Mr. Osborn was “responsible” for patient deaths, although there is no indication that he personally had any involvement in those deaths.  Although most old school Park cases involved situations where FDA had previously warned individuals about violative conditions, there were a number of old cases where individuals were prosecuted where FDA believed that the defendant had caused deaths or serious injury even without a prior FDA warning.

The Osborn case certainly demonstrates the discretion that is afforded to the government in deciding the people to be prosecuted under the Park Doctrine.  For that reason, company executives in industries regulated by FDA are presented every day with decisions and actions that could result in the government choosing to criminally prosecute a person based on wholly undefined standards.  One can only hope that the government will exercise that discretion wisely and carefully to avoid situations where some individuals are prosecuted for doing the very same things as others who are not prosecuted.

By Larry K. Houck –

The Drug Enforcement Administration (“DEA”) published its long awaited notice of proposed rulemaking to implement the Secure and Responsible Drug Disposal Act of 2010 (“Disposal Act”).  77 Fed. Reg. 75,784 (Dec. 21, 2012).  Interested persons should submit electronic comments on or before February 19, 2013.  Written comments must be postmarked on or before that date.

Congress enacted the Disposal Act on October 12, 2010.  Prior to enactment, the Controlled Substances Act  (“CSA”) and DEA regulations provided few options to ultimate users (e.g., patients) who wanted to dispose of unused, unwanted, or expired controlled substances.  Individuals were limited to destroying the substances themselves, surrendering the drugs to law enforcement agencies or seeking assistance from the local DEA office.  These restrictions invariably led to increased potential diversion or misuse from drugs being thrown away in trash receptacles or accumulating in household medicine cabinets.

The Disposal Act and DEA’s proposed regulations seek to establish controlled substance diversion prevention parameters that will encourage public and private entities to develop methods for collecting and destroying controlled substances that are secure, convenient, and responsible.  A second goal is to decrease the amount of controlled substances released into the environment, especially into water and sewage systems.  DEA believes that the new regulations will reduce the supply of unused controlled substances in households thereby reducing the risk of diversion or harm.

The proposed regulations contain sweeping changes that reorganize and consolidate existing requirements for disposal of controlled substances, including the role of reverse distributors.   The proposed regulations also expand the entities to whom ultimate users may deliver unused, unwanted, or expired controlled substances for disposal, and the methods by which the controlled substances may be collected.  Authorized entities may voluntarily administer any of the authorized collection methods but are not required to do so.

Disposal by Ultimate Users.  DEA is proposing three voluntary disposal options for ultimate users: take-back events, mail-back programs and collection receptacles.  Individuals entitled to dispose of deceased patients’ property will also be authorized to dispose of the controlled substances by utilizing the three options.

DEA is proposing to continue to authorize federal, state, tribal, and local law enforcement agencies, independently or in partnership with private entities or community groups, to hold take-back events and administer mail-back programs.  DEA also proposes to permit manufacturers, distributors, reverse distributors, and retail pharmacies to obtain DEA authorization to receive controlled substances from ultimate users or long term care facilities for the purpose of destruction.  DEA registrant may become “collectors” and would be authorized to conduct mail-back programs.  However, mail-back programs must provide specific mail-back packages to the public at no cost or for a fee, and collectors conducting mail-back programs must utilize an on-site method of destruction.  Collectors must also comply with specific security and recordkeeping requirements. (new § 1317.50) 

The proposed regulations would authorize law enforcement agencies to maintain collection receptacles at that their physical location and would authorize collectors to maintain collection receptacles at their registered locations.  Retail pharmacies that are authorized collectors may maintain collection receptacles at long term care facilities (“LTCFs”).  LTCFs are permitted to dispose of controlled substances on behalf of ultimate users who reside or have resided at that LTCF only through a collection receptacle maintained by a retail pharmacy at that LTCF.

DEA also proposes to allow all controlled substances collected through take-back events, mail-back programs, and collection receptacles to be comingled with non-controlled substances. Collectors would be restricted from individually counting or inventorying controlled substances that they collect. 

Disposal by Registrants and Reverse Distributors.  DEA is proposing to delete 21 C.F.R. § 1307.21, the existing regulation on registrant disposal, and incorporate requirements on disposal procedures, recordkeeping and security in a new part 1317.  DEA proposes to modify existing DEA Form 41, “Registrants Inventory of Drugs Surrendered”,  for documenting the destruction of controlled substances among registrants and to account for registrant destruction of controlled substances collected from ultimate users and other non-registrants.

DEA is also proposing to revise regulations for reverse distributors.  Reverse distributors acquire controlled substances from other registrants and may also be authorized as collectors, so they accumulate greater quantities of controlled substances for destruction than other registrants.  DEA proposes to revise definitions related to reverse distribution and add new acquisition procedures, recordkeeping and security requirements.

DEA is proposing to delete the existing regulation on return and recall (21 C.F.R. § 1307.12) and incorporate requirements into a new part 1317.10.  The new regulations would clarify which registrants are authorized to handle returns and recalls and enhance recordkeeping and ordering requirements. 

Methods of Destruction.  DEA is proposing a “non-retrievable” standard of destruction for persons who destroy controlled substances.  DEA will not require a particular method of destruction, so long as the controlled substance is rendered “non-retrievable.”  This standard will allow public and private entities to develop a variety of destruction methods that are “secure, convenient, and responsible, consistent with preventing the diversion of such substances.”

We anticipate focusing on specific elements of DEA’s proposed rulemaking in future blog posts.

By Ricardo Carvajal –

Signaling potential movement on an issue that has bedeviled industry, FDA published a notice requesting comments “relevant to conducting a risk assessment to establish regulatory thresholds for major food allergens.”  Undeclared major food allergens continue to be one of the two principal causes of reportable food incidents, typically leading to Class I recalls.  As acknowledged in the notice, the “establishment of regulatory thresholds or action levels for major food allergens would help [FDA] determine whether, or what type of, enforcement action is appropriate when specific problems are identified.”

FDA’s notice suggests other ways that establishment of thresholds could be helpful (i.e., by helping to “establish a clear standard for evaluating claims in FALCPA petitions” for exemption from allergen declaration, and by helping industry “conduct allergen hazard analyses and develop standards for evaluating the effectiveness of allergen preventive controls” – actions that will be required under FSMA).  However, the most immediate and tangible benefits could be realized in the context of enforcement.  This point is more clearly recognized in FDA’s accompanying release (“If safe thresholds can be established, the FDA could more effectively determine the appropriate corrective action to unintentional allergen contamination issues…[and] better respond to situations where undeclared allergens are found in foods”).  The release also recognizes that the absence of thresholds might be unnecessarily constraining consumer choice. 

FDA’s notice hints at the “significant advances in both scientific tools and data resource related to food allergens” that have taken place in the six years since the agency’s Threshold Working Group issued a report summarizing its evaluation of approaches for establishing thresholds.  The agency evidently felt the time was ripe to ask for data that will support its conduct of a quantitative risk assessment.  The notice asks for comments (including data) on the following issues:

1. How should we define “an allergic response that poses a risk to human health?”
2. Which major food allergens are of greatest public health concern and what is the size of the at-risk population?
3. How should clinical dose distribution data be used when establishing regulatory thresholds for the major food allergens?
4. What approaches exist for using biological markers or other factors related to the severity of allergic responses in a threshold risk assessment?
5. What data and information exist on dietary exposure patterns for individuals on allergen avoidance diets?
6. What data or other information exist on current levels of exposure associated with the consumption of undeclared major food allergens in packaged foods?
7. What other information or data should we consider in establishing regulatory thresholds for major food allergens?

The scope of the above issues and the history of other risk assessments suggests that any risk assessment for establishing regulatory thresholds will take considerable time and effort to complete.  Given the high stakes, this initiative appears worthy of strong industry support.  Comments are due February 12.

By Jennifer D. Newberger & Jeffrey N. Gibbs –

A quick Google search of “dog trained to identify medical conditions” indicates that, around the world, dogs are already working with people to help sniff out certain medical conditions.  For example, in the United Kingdom an organization called “Medical Detection Dogs” works “to train specialist dogs to detect the odour of human disease.”  Those dogs have been trained to identify the odor associated with low blood sugar in diabetics, as well as to assist in conditions such as Addison’s disease, pain seizures, and narcolepsy.

On December 13, 2012, BMJ published an article titled “Using a dog’s superior olfactory sensitivity to identify Clostridium difficile in stools and patients: proof of principle study.”  This study took place in two hospitals in the Netherlands.  A two-year old beagle, Cliff, was trained to identify the smell of C difficile and tested on 300 patients (30 with C diff infection and 270 controls).  The dog, trained to sit or lie down when C diff was detected, was guided along the wards by its trainer, who was blinded to the participants’ infection status.  Cliff was able to correctly identify 25 of the 30 cases (sensitivity 83%,) and 265 of the 270 controls (specificity 98%).  This compares favorably with the diagnostic performance of some diagnostic kits.

Cliff’s success at detecting a highly transmissible and dangerous infection, and use of dogs to assist in caring for individuals with chronic conditions, potentially offers great promise for the management of many diseases.  The question arises, however, whether FDA would appreciate the potential of man’s best friend, and let dogs be dogs, or if it could, and would, stretch its authority to actually attempt to regulate dogs as medical devices when they are “intended” for such medical purposes.

The question is not necessarily as far-fetched as it may seem at first glance.  Keep in mind that FDA currently regulates maggots and leeches as medical devices. If they fit under the statutory definition of a device, why couldn’t a dog that is trained and promoted for its ability to sniff out C diff?  While this might seem like a shaggy dog joke, it is both a potentially vexing FDA issue, and a great law school exam question. 

Let’s hope we never have to engage with FDA on this issue and, as they say, let sleeping dogs lie.