By Ricardo Carvajal & JP Ellison –

The Vermont Public Interest Research Group ("VPIRG") and Center for Food Safety ("CFS") filed a motion to intervene in the lawsuit challenging Vermont’s new law requiring labeling for foods produced with genetic engineering (see our prior posting here).  VPIRG and CFS (collectively Applicants) contend that the lawsuit “threatens to upend” the new law, thereby “negating Applicants’ extensive efforts and severely injuring their core organizational missions as well as the personal interests of thousands of their members.” 

The memorandum in support of the motion details VPIRG’s grassroots campaign and other efforts mounted in support of the bill – including the provision of supporting materials and testimony regarding the law’s constitutionality.  It also references CFS’s “work with dozens of states on GE labeling legislation.”  Applicants thereby claim a “clear interest in the continuing constitutional viability” of the law.  Applicants also claim their members have “strong interests” that support intervention, including their “need to know whether foods they eat and feed their families are genetically engineered for health, environmental, economic, and other reasons.”

Applicants further argue that Vermont’s representation of their interests might not be adequate because of the state’s “serious financial concerns regarding the cost of [the] litigation” – reportedly estimated to cost between $1 million and $5 million.  As noted in the memorandum, the law created a fund to collect donations in part to pay for the law’s defense.  The balance of that fund has risen from $15,000 on June 9 (according to Applicants) to over $100,000 on July 11 (according to the fund’s Facebook page).

 By Jay W. Cormier & David B. Clissold —

Although an apple a day idiomatically keeps the doctor away, it appears true to one federal judge that one bad apple (or in this case three) really does spoil the bunch. 

As we previously reported here, in 2011, Lorillard, Inc., Lorillard Tobacco Company, and R.J. Reynolds Tobacco Company sued the FDA, DHHS, Kathleen Sebelius, Margaret Hamburg, and Lawrence Deyton seeking declaratory and injunctive relief to bring the membership of the Tobacco Products Scientific Advisory Committee (“TPSAC”) and the membership of the Constituents Subcommittee of the TPSAC into compliance with applicable laws, and to prevent the defendants from taking any action based on any report or advice provided by the TPSAC or the Constituents Subcommittee.  Among the reports issued by TPSAC, perhaps none has the potential for spurring more effect and controversy than the 2011 “Menthol Report,” which concluded in part that “removal of menthol cigarettes from the marketplace would benefit public health in the United States.”

Monday, in a scathing rebuke to FDA, the United States District Court for the District of Columbia issued its summary judgment ruling, stating that FDA violated the Administrative Procedure Act and the Federal Advisory Committee Act when it appointed three members because they were consultants to pharmaceutical companies developing nicotine replacement therapies and were involved in tobacco-related litigation. 

Congress enacted a specific conflict of interest provision applicable to members of the TPSAC. 21 U.S.C. § 387q(b)(1)(C).  The court initially noted that even the plaintiffs did not allege that the three members violated that conflict provision “because this provision only contemplates conflicts arising from one perspective: it bars voting members from receiving any remuneration from tobacco industry businesses.”

Nevertheless, the court felt compelled to examine whether other laws applicable to special government employees ("SGEs") precluded these three members from serving on the TPSAC due to financial conflicts of interest.  Under the circumstances presented in this case, the court agreed with plaintiffs that the three members’ participation in certain TPSAC activities had a “direct and predictable effect” on their financial interests.  FDA claimed that it had conducted extensive screenings of each TPSAC member and had determined that there was no conflict of interest presented by members’ consulting work.  Discussing FDA’s assertion that these members had no competing financial interest due to their consulting work, Judge Richard J. Leon’s reaction was simple:  “Please!”   He ruled that such a “conclusion defies common sense” and that FDA exhibited a “clear error in judgment.”  With respect to the three members’ participation in tobacco litigation, the Court concluded that when individuals have “repeatedly” testified in litigation against tobacco industry and had commitments to do so in the future, FDA acted arbitrarily and capriciously when it nonetheless appointed such individuals to the TPSAC.  The court noted that “numerous commentators and media outlets” had publicly questioned the impartiality of these appointments.  Expanding upon the conflicts provisions of the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), which expressly disqualifies any member who received “any salary, grants, or other payment or support” from any tobacco company in the 18 months before serving on the TPSAC, Judge Leon wrote that “it stands to reason that past remuneration from direct competitors of those companies, such as manufacturers of smoking-cessation drugs, would also constitute a conflict of interest.”

As a result, the Court concluded that appointment of those members to the TPSAC “fatally” and “irrevocably tainted its composition and its work product.”  The court found that the TPSAC findings and recommendations, including the Menthol Report, “are, at a minimum, suspect, and, at worst, untrustworthy.”  Accordingly, the Court instructed FDA to appoint an entirely new TPSAC constituted of interest-free members and barred FDA from using the TPSAC’s Menthol Report.

FDA is not obligated to follow the recommendations of its advisory committees, including TPSAC.  Indeed, in April 2014 FDA announced that it is conducting its own review of all the information regarding menthol, including the Menthol Report.

Nevertheless, potentially the biggest winner here, at least in the short term, may be Reynolds, which earlier this month offered to purchase its fellow-plaintiff, Lorillard, for $25 billion in cash, a move that, if approved by anti-trust regulators, will dramatically increase Reynolds’ portfolio of menthol-containing tobacco products. 

FDA and the other defendants have 60 days to file a notice of appeal.  Given the significance and breadth of the ruling, we expect that a notice of appeal will be filed.

By Michelle L. Butler –

On July 21, 2014, the Department of Health and Human Services (“HHS”)/Health Resources and Services Administration (“HRSA”) announced the availability of an interpretive rule titled “Implementation of the Exclusion of Orphan Drugs for Certain Covered Entities Under the 340B Program,” which is scheduled to be published in the Federal Register on July 23, 2014. 

In its Notice announcing the availability of the interpretive rule, HHS stated that, as the court “decision did not invalidate HHS’s interpretation of the orphan drug exclusion,” “there still is a need for HHS to clarify its interpretation of how the orphan drug exclusion in the 340B Program should be implemented to be consistent with [the statute].”  Consequently, HHS issued an interpretive rule, which states that HHS

interprets section 340B(e) of the Public Health Service Act as excluding drugs with an orphan designation only when those drugs are transferred, prescribed, sold, or otherwise used for the rare condition or disease for which the drug was designated under section 526 of the Federal Food, Drug, and Cosmetic Act (FFDCA) Section 340B(e) does not exclude drugs that are transferred, prescribed, sold, or otherwise used for conditions or diseases other than for which the drug was designated under section 526 of the FFDCA.

Interpretive Rule, at 6.

In articulating the reasons for its interpretation, HHS discussed the purpose and effect of the Orphan Drug Act and the orphan drug exclusion in the Public Health Service Act.  HHS stated that “it is appropriate to construe the orphan drug exclusion consistent with FDA’s longstanding interpretation of the orphan drug provisions of the FFDCA – distinguishing the use of a drug for an orphan indication from its use for other (non-orphan) indications.”  Id. at 4.  Moreover, HHS stated that ‘[i]nterpreting the statutory language to exclude all uses of drugs with an orphan designation, including indications for other (non-orphan) diseases and conditions would nullify the benefits of the expansion of the 340B Program” for newly-eligible entities.  Id. at 5.  Accordingly, HHS “concluded that interpreting the statutory language to exclude all indications for a drug that has an orphan drug designation would be contrary to the Congressional intent of section 4340B(e) to balance the interests of orphan drug development and the expansion of the 340B Program to new entities.”  Id. 

According to the Notice, the effective date for the interpretive rule will be the date of publication in the Federal Register.  HRSA’s website contains information pertaining to implementation of the orphan drug exclusion, including orphan drug lists to be used to “assist all stakeholders in complying with HRSA’s policy.” 

HHS/HRSA’s decision to implement its interpretation of the statute as an interpretive rule appears to set the stage for another round of judicial review.  As previously described, in May, in a suit brought by the Pharmaceutical Researchers and Manufacturers of America (“PhRMA”), the United States District Court for the District of Columbia vacated HHS’s substantive rule on the orphan drug exclusion on the ground that HHS did not have the authority to promulgate its rule as a substantive rule.  Having reached its decision on this ground, the court did not come to a final decision on whether the rule could be upheld as interpretive, but seemed skeptical of the argument and invited further briefing on the subject.  PhRMA subsequently filed a motion requesting briefing on the matter of an interpretive rule, which HHS opposed as moot in light of its decision to issue “new, separate interpretive guidance.”  HHS argued in its opposition that any challenge to HHS’s interpretive guidance would be a challenge to “new agency action,” which would require a new suit or amendment of the complaint to include such a new claim.  Last week, PhRMA filed a reply brief to its request for briefing on whether the rule “(however packaged) can survive as an interpretive rule,” particularly in light of HRSA statements that PhRMA argues demonstrate the binding effect HRSA appears to intend for the interpretive rule to have.  We will continue to monitor the developments in this case as HHS/HRSA and PhRMA continue their battle over the orphan drug exclusion.

By Alexander J. Varond —

FDA recently released its report entitled “Complex Issues in Developing Drugs and Biological Products for Rare Diseases and Accelerating the Development of Therapies for Pediatric Rare Diseases Including Strategic Plan: Accelerating the Development of Therapies for Pediatric Rare Diseases.”  The report fulfills the requirements set out in PDUFA V and in Section 510 of FDASIA, which require FDA to hold a public meeting to discuss ways to encourage and accelerate the development of new therapies for pediatric rare diseases (“PRDs”), and to issue a report that includes a strategic plan for encouraging and accelerating such therapies See our previous posts here and here).

FDA’s 86-page report summarizes the difficulties facing sponsors of drugs for PRDs, outlines legislation and approaches to expedite and accelerate rare disease medical product development, provides an overview of the three-day workshop held on January 6-8, and sets forth FDA’s strategic plan.  The first two days of the workshop focused on “complex issues in developing drug and biological products for rare diseases,” while the third day focused on “complex issues in developing medical devices for pediatric patients affected by rare diseases.”

FDA noted that its strategic plan is not a legislative wish list, but is instead an outline of what FDA can reasonably achieve under its existing authority to encourage and accelerate the development of new therapies for PRD.  The report includes a helpful summary of FDA’s strategic plan that we include here:

Objective 1:  Enhance foundational and translation science for PRD

• Drugs/biologics strategies
• Facilitate the conduct of natural history studies for PRD
• Publish draft guidance on common issues in rare disease drug development
• Device strategies
  • Identify unmet PRD needs in medical device development
  • Refine and expand the use of computational modeling
  • Explore the use of registry data for use in both premarket and postmarket evaluation of medical devices intended for pediatric populations

Objective 2:  Strengthen communication, collaboration and partnering for PRD within and outside FDA

• Drugs/biologics and devices strategies
• Continue to foster interagency (public-public) and public-private partnerships
• Continue to foster international collaborations
• Continue to foster Intra-Agency collaborations

Objective 3:  Advance the use of regulatory science to aid clinical trial design and performance for PRD

• Drugs/biologics strategies
• Develop additional FDA guidance relevant to PRD
• Increase engagement of the Study Endpoints and Labeling Development (SEALD) Staff early in instrument development to navigate COA process
• Facilitate increasing the knowledge of biomarkers and COAs useful for PRD, including engaging with investigators and organizations in biomarker and clinical outcome qualification programs to advise during their development
• Develop training programs for pediatric clinical investigators
• Explore modeling and simulation approaches  (e.g., physiologically-based pharmacokinetic [PBPK] models) to provide preliminary data for drugs used in PRD to inform the design and conduct of PK/PD studies and other clinical trials for investigational drugs in PRD population
• Device strategies
• Develop expedited approval pathway for certain devices intended to treat unmet medical needs
• Evaluate the results of an analysis of approved medical devices to explore the feasibility of shifting some premarket data requirements to the postmarket setting for future medical devices
• Support the development of Medical Device Development Tools to improve clinical trial performance
• Develop curriculum for undergraduate/graduate studies to increase understanding of regulatory approval process for device development
• General strategies
• Use FDA web-based resources to update and expand awareness of PRD product development issues
• Increase awareness in pediatric rare disease researchers, product developers, and patient community of funding opportunities through OPD grant program

Objective 4:  Enhance FDA’s review process for PRO products

• Drugs/biologics strategies
• Foster FDA’s efforts to obtain patients’ and caregivers’ perspectives for incorporation in drug development
• Further develop and implement a structured approach to benefit-risk assessment in the drug review process
• Issue Rare Pediatric Disease PRV draft guidance document
• Continue reviewer training for rare and PRD
• Explore potential for innovation in data analysis
• Device strategies
• Further develop methods to implement the incorporation of patient preferences into assessments of premarket approval and de novo classifications of devices
• Establish a patient engagement panel as part of CDRH’s Medical Advisory Committee
• Analyze the HDE process for medical devices that diagnosis and treat PRD
• Set standards for whole genome sequencing that can he used as a comparator
• General strategies
• Continue to enhance FDA’s expertise to review innovative products

By Kurt R. Karst —       

Beginning in 1999, around the time FDA issued a (still) draft guidance document on 505(b)(2) applications, and lasting until about 2009, this blogger taught an introduction to drug law course at FDA to FDAers.  The focus of my talk was – surprise, surprise – Hatch-Waxman.  Each time I arrived at the section of the talk on 505(b)(2) applications I would take a poll of participants: “How many of you have heard of the 505(b)(2) NDA?”  In 1999, 15 years after the enactment of the Hatch-Waxman Amendments, which created the 505(b)(2) NDA, and 8 years after two of my colleagues wrote what might be the first analysis of the statutory provision (see Sasinowski FJ, Scarlett T. Reliance on Phantom ANDAs to Access NDA data. Reg Affairs. 1991;3: 467-482), only a few hands in an audience of about 50 participants would be raised.  By 2009, almost every participant raised a hand.  That significant change in the familiarity with the 505(b)(2) NDA tracks industry’s use of the approval route – and which increase continues today.  Ahh, but with greater use comes greater controversy. . .  (just as as Uncle Ben would say to Peter Parker) with great power comes great responsibility.  And that’s where we begin our story today.    

In a recent response to a March 2014 citizen petition (Docket No. FDA-2014-P-0318) submitted by Antares Pharma, Inc. (“Antares”), and the subtext of which might be “make sure you get your publicly available facts straight when petitioning FDA,” FDA denied Antares’s request that the Agency refrain from approving (and withdraw) any 505(b)(2) application submitted by Medac Pharma, Inc. (“Medac”) directed to a methotrexate drug product for subcutaneous injection if such application does not reference Antares’ single-dose auto-injector OTREXUP (methotrexate) Injection, 10 mg/0.4 mL, 15 mg/0.4 mL, 20 mg/ 0.4 mL and 25 mg/0.4 mL, and that FDA order Medac to submit a new application citing OTREXUP as a listed drug (that would, of course, include certifications to any patents listed in the Orange Book for OTREXUP). 

FDA approved OTREXUP on October 11, 2013 under NDA No. 204824 for severe rheumatoid arthritis including polyarticular juvenile idiopathic arthritis, and for symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy.  That 505(b)(2) NDA, which was submitted to FDA on December 14, 2012, is identified in the Orange Book as the Reference Listed Drug (“RLD”) for an injectable methotrexate solution with a subcutaneous route of administration. 

Meanwhile, Medac was developing its own methotrexate injection drug product – a prefilled pen available in 10 strengths called RASUVO (methotrexate) Injection – for the same uses as OTREXUP.  Medac submitted its 505(b)(2) NDA No. 205776 for RASUVO to FDA just a few weeks before FDA approved OTREXUP – on September 10, 2013.  And notwithstanding Antares’ petition to stop the approval of RASUVO, FDA approved NDA No. 205776 on July 10, 2014.  Enter FDA’s intervening NDA approval policy. . . .

FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.”  21 C.F.R. § 314.101(d)(9).  FDA explained how the Agency interprets this regulation in a June 2004 response to a citizen petition (Docket No. FDA-2003-P-0338).  In that case, which concerned a then-pending 505(b)(2) application for Loratadine Tablets, 10 mg, FDA determined that an intervening NDA approval for the same drug product does not bar the Agency from approving a pending 505(b)(2) application.  Specifically, FDA ruled that 21 C.F.R. § 314.101(d)(9) “bars 505(b)(2) applications for products eligible for approval under section 505(j) of the Act only if the product described in a 505(b)(2) application may be approved via section 505(j) at the time of the application’s submission” (emphasis added).  A 505(b)(2) application submitted to FDA before the approval of another NDA – an intervening NDA – that would otherwise render the 505(b)(2) application drug product a duplicate of an approved drug is, according to FDA, unaffected by the intervening NDA approval.

More recently, FDA discussed the Agency’s intervening NDA approval policy as part of a May 17, 2012 decision granting a citizen petition to designate VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% (NDA No. 050803) as a second RLD in the Orange Book.  A comment submitted to FDA contended, among other things, that VELTIN could have been submitted via an ANDA given the intervening approval of NDA No. 050802 for ZIANA (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%.  According to FDA, however:

Because there were no pharmaceutically equivalent products approved at the time that Veltin was submitted, it would not have been appropriate for the Veltin application to be submitted as a 505(j) application.  Although we approved the Ziana NDA while the Veltin application was under review, our policy is that we do not require applicants to withdraw and resubmit applications if another pharmaceutically equivalent drug product is subsequently approved.  Therefore, the 505(b)(2) NDA was an appropriate pathway for Veltin’s application.

Under othercircumstances, FDA has decided (Docket No. FDA-2008-P-0329) that the intervening approval of an NDA after the submission of an ANDA made pursuant to an approved suitability petition, and where the NDA approval renders the pending ANDA a duplicate of an approved drug, requires the generic applicant to submit a new ANDA citing the newly approved NDA drug product as the RLD.

Given the longstanding FDA policy on intervening NDA approvals as a result of the Agency’s interpretation of 21 C.F.R. § 314.101(d)(9), why would Antares petition FDA?  Antares’ petition requests may have been triggered by a January 27, 2014 Medac press release announcing FDA’s acceptance of the RASUVO 505(b)(2) NDA.  That press release did not mention FDA’s PDUFA goal date for acting on the NDA.  Ok, so without a PDUFA date, one might speculate that FDA slipped up and accepted the RASUVO 505(b)(2) NDA after the October 11, 2013 approval of OTREXUP.  But not long after Antares submitted its petition to FDA, Medac made known in a  the PDUFA date for the application: “the PDUFA date for Rasuvo is July 10, 2014.”  Based on a standard 10-month review, that meant the RASUVO 505(b)(2) NDA was submitted to FDA on September 10, 2013.  But the petition was not withdrawn.

Although Antares raised in its petition, among other things, choice of listed drug and pharmaceutical equivalence issues, all FDA needed to deny the petition was to answer one very simple question: “Is September 10, 2013 before October 11, 2013.”  According to FDA:

Antares’ claims are based on a number of erroneous assumptions, the first and foremost of which is the date of submission of Medac’s NDA.  Contrary to what Antares asserts, Medac submitted its application not after Otrexup was approved on October 11, 2013, but before Otrexup’s approval, that is, on September 10, 2013.  FDA’s policy is that when reviewing 505(b)(2) applications, FDA will not require sponsors to withdraw and resubmit applications if pharmaceutically equivalent product is approved after the application is submitted but before it is approved. That is precisely the factual situation here. . . .

Therefore, regardless of whether Otrexup is pharmaceutically equivalent to Medac’s product, Medac was under no obligation to resubmit its application and reference Otrexup.  Since it did not rely for approval on Otrexup in its application, Medac also had no obligation to certify any patents listed for Otrexup.  The date of submission of a complete 505(b)(2) NDA is the only controlling factor in this instance.  Thus, for the purposes of responding to this Petition, the Agency does not need to reach the issue of whether Otrexup is pharmaceutically equivalent to Medac’s product. [(Emphasis in original)]

By James E. Valentine* —

On July 15, 2014, FDA announced the availability of a draft guidance, titled “Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors” (“FDA Draft Information Sheet”).  When final, it will replace the Agency’s informed consent  1998 Information Sheet, “A Guide to Informed Consent,” and the related informed consent sections of “Frequently Asked Questions”. 

The proposed FDA Draft Information Sheet, builds upon its previous guidance, assisting parties involved in clinical investigations of FDA-regulated products in carrying out their responsibilities related to informed consent under 21 CFR part 50.  FDA’s recommendations cover the informed consent process, the elements of informed consent, and the documentation of informed consent.  

The basics remain unchanged, but FDA explained that it is issuing these proposed recommendations as a draft guidance because of revisions to the previous Information Sheets that respond to changes in regulation and regulatory policy, as well as to questions from external stakeholders. 

The FDA Draft Information Sheet emphasizes unique considerations for informed consent of certain vulnerable populations, including:

• Careful consideration of ethical ramifications of enrolling or excluding potential subjects when there is a language barrier between investigator and potential subjects, and ensuring the information presented is understandable to subjects who do not understand English;
• Modifications to the consent form and process when enrolling subjects with impaired consent capacity, and additional considerations to address challenges and provide safeguards for subjects who lack consent capacity;
• Safeguards for inclusion of children as subjects, explaining the framework that is based upon receiving parental permission and child assent; and
• Approaches to modification of informed consent for subjects with low literacy or numeracy.

The FDA Draft Information Sheet also provides new recommendations in other areas, including:

• Addressing the new element of informed consent for “applicable clinical trials,” the requirement to include a statement that clinical trial information and results have been or will be submitted for inclusion on www.ClinincalTrials.gov (see our previous posts on this requirement here and here);
• Determining whether review of patient records is considered part of the clinical investigations and requires informed consent;
• Discouraging subject participation in more than one clinical trial; and
• Notifying and providing study information to subjects in the events of study suspension or termination.

The FDA Draft Information Sheet comes at a time when HHS and the Office of Human Subjects Research are reviewing various ways to enhance regulations overseeing research on human subjects (see our previous post on the Advanced Notice for Proposed Rulemaking for revision to the Common Rule here).  FDA assured stakeholders that it is actively working with HHS to harmonize the Agencies’ regulatory requirements, and that the FDA Draft Information Sheet was developed as part of these efforts.

Comments on the FDA Draft Information Sheet can be submitted to FDA until September 15, 2014 here. 

* Not admitted in the District of Columbia

By Kurt R. Karst –      

Our FDA Citizen Petition Tracker is littered with petitions and petitions for reconsideration submitted to FDA over the past 18 months requesting that the Agency recognize a period of 5-year New Chemical Entity (“NCE”) exclusivity for certain Fixed-Dose Combination Drugs (“FDCs”) the Agency approved before announcing in February 2014 in a draft guidance document (and in a consolidated citizen petition decision) that FDA planned to change (but only prospectively for FDCs approved after the guidance is finalized) its interpretation of the FDC Act’s NCE exclusivity provisions to award 5-year exclusivity for a newly approved FDC containing an NCE and a previously approved drug (see our previous posts here, here, and here).  The period to comment on the draft guidance expired months ago, and there has been no indication as to when it might be finalized.  This, of course, raises the possibility that more companies will petition FDA as NDAs for FDCs are approved in the interim period.

The latest entrant to the “NCE for FDC Club” is Pfizer Inc. (“Pfizer”).  In a May 30, 2014 petition (Docket No. FDA-2014-P-0737) that was only recently made public on the federal government’s docketing system website (www.regulations.gov), Pfizer says FDA erred in not granting NCE exclusivity with respect to Pfizer subsidiary Wyeth Pharmaceuticals, Inc.’s DUAVEE (conjugated estrogens/bazedoxifene) Tablets on the basis that FDA never before approved a drug product under FDC Act § 505 containing bazedoxifene as an active moiety.  FDA approved DUAVEE on October 3, 2013 under NDA No. 022247 for use in women with a uterus for treatment of moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis, for the treatment of moderate to severe vulvar and vaginal atrophy associated with menopause, for the treatment of moderate to severe vasomotor symptoms associated with menopause, and for prevention of postmenopausal osteoporosis.  Six months later, in the March 2014 Orange Book Cumulative Supplement (published in mid-April), FDA finally made public the Agency’s decision to – not unexpectedly – award a period of 3-year new clinical investigation exclusivity.  But that doesn’t mean the decision is correct, says Pfizer. 

Similar to other “NCE for FDC Club” petitioners who have challenged FDA’s basis for denying NCE exclusivity, Pfizer argues that none of the reasons FDA articulated in the February 2014 Consolitated Petition Decision apply in this case.  Briefly, FDA said that the Agency would not immediately or retroactively apply its new interpretation of the statute’s NCE exclusivity provisions for several reasons:

First, although the relevant statutory and regulatory provisions are ambiguous, our existing interpretation of these provisions is longstanding and has been consistently applied in many prior cases presenting similar facts.  Second, the new interpretation we are proposing represents a departure from our past interpretation, and we wish to avoid any unnecessary disruption to regulated industry.  Third, if the new interpretation were to be applied to products for which ANDAs already have been filed, it could impose a burden on the ANDA sponsors, who relied on our existing interpretation in filing their applications.

In addition, we do not believe that applying our new interpretation to the Petitioners’ products would advance the goals of the Hatch-Waxman Amendments. . . . Recognizing additional exclusivity in this case is not necessary to encourage the development of novel drugs.  We believe that changing our interpretation going forward will foster Congress’s goal of encouraging the development and approval of novel drugs.  (Emphasis in original.)  

According to Pfizer:

None of the concerns articulated by FDA support denial of 5-year exclusivity for bazedoxifene.  The general presumption is that an agency will apply a new statutory interpretation adopted in the course of an administrative adjudication in that proceeding, and all subsequent adjudications.  There is no reason to depart from that general practice here.  Furthermore, none of the concerns about “retroactive” regulatory changes that might call for a different effective date are apposite here.  Certainly, FDA’s concerns about disrupting industry and burdening ANDA sponsors do not apply in the case of bazedoxifene.  Indeed, those concerns do not apply to any FDC drug products containing at least one new active moiety for which no ANDA was filed prior to the date of issuance of the Consolidated Response.  And, even as to ANDAs filed before the Consolidated Response, there is no impermissible retroactive effect on the ANDA applicants of FDA immediately applying its new policy to all cases adjudicated from that date forward, such as bazedoxifene.

There is no indication that an ANDA has been submitted to FDA for a generic version of DUAVEE.  In fact, FDA has not approved an ANDA for conjugated estrogens.  Way back in May 1997, FDA ruled in the context of PREMARIN (conjugated estrogens) Tablets, that because PREMARIN “is not adequately characterized at this time, the active ingredients of Premarin cannot now be definitively identified,” and that “[u]ntil the active ingredients are sufficiently defined, a synthetic generic version of Premarin cannot be approved.”  Instead, companies have generally pursued approval of 505(b)(2) NDAs – e.g., CENESTIN (synthetic conjugated estrogens, A) Tablets. 

Whether today, 17 years after FDA’s PREMARIN decision, FDA is willing to entertain approval of an ANDA for conjugated estrogens remains to be seen.  FDA has accepted ANDAs for conjugated estrogen drugs, as the Agency’s ANDA Paragraph IV List indicates that an ANDA was submitted for generic PREMARIN prior to March 2, 2004, and that ANDAs for generic CENESTIN were submitted in November 2008 and March 2009.  But years after these ANDA acceptances, there’s still not an approval. 

That raises the question of why NCE exclusivity for DUAVEE – and specifically for the bazedoxifene moiety – is so important to Pfizer.  An ANDA for a generic version of a drug product containing conjugated estrogens will likely be very difficult to push through FDA’s Office of Generic Drugs.  A 505(b)(2) NDA for the combination is perhaps more likely, though there is no mention of that approval route in the DUAVEE petition.  So that leaves us with bazedoxifene.  That moiety is currently under investigation for other uses according to ClinicalTrials.gov and other reports.  A grant of 5-year NCE exclusivity with respect to bazedoxifene would help extend the lifecycle of that drug if there are follow-on NDA approvals in the coming years. 

By James E. Valentine* & Sara A. Khan** –

On July 11, 2014, the House Energy and Commerce’s Subcommittee on Health held its fourth hearing, as part of its 21st Century Cures Initiative, to seek input regarding the incorporation of patient perspectives in drug development and review.  (See our coverage of two previous 21st Century Cures hearings here and here.)  The Subcommittee leadership set the tone early that the most important aspect of the 21st Century Cures Initiative is what medical innovation and faster cures mean for patients.  They also emphasized that there is a need to understand the patient perspective in order to focus on results for patients who lack adequate medical treatment options. 

The witnesses (representatives from patient groups, healthcare professional organizations, industry, and FDA) described the current state of patient input in drug development and review and highlighted models and frameworks to further integrate the patient perspective.  Recommendations for elevating the patient voice emerged as two distinct categories of “input:” (a) increasing the use of patient-reported outcomes (“PROs”) in clinical research and (b) incorporating the patient perspective, either directly or indirectly, in the drug development enterprise and throughout FDA review.

Patients as Participants in Clinical Research.  Historically, the role of patients in drug development has been limited to their role as research subjects, and measures of patient symptoms, overall mental state, or the effects of a disease on how a patient functions were captured by clinician observations or tests.  Recently, however, the medical community has begun to recognize that there is value in measuring the status of a patient’s health directly from the patient, rather than through the lens of a clinician. As such, various parties in the drug development process have begun to show an interest in incorporating PROs into clinical trials. 

As the FDA panelist at the hearing, Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research (“CDER”), discussed how CDER is working to advance development and improve the use of PROs under the Prescription Drug User Fee Act V (“PDUFA V”).  Previously, FDA did not have a rigorous process for qualifying PROs, but, now relying on the science of measurement, consortia can come to FDA to propose a PRO endpoint, if qualified (see here).  Qualified PROs, which are published on FDA’s website, are considered by FDA to be valid outcome measures that could be used to support drug labeling claims.  (We previously reported on FDA’s 2009 Guidance on review and evaluation of PROs here).  Dr. Woodcock noted that FDA is currently engaged in 79 PRO qualification projects.

Noting that in cancer drug development, certain self-reported symptoms that are measured qualitatively, such as nausea and pain, are often reported differently by physicians than by their patients, Dr. Leonard Lichtenfeld, the Deputy Chief Medical Officer of the American Cancer Society, advocated the use of PROs in all clinical trials.

Many panelists cited the lack of established and consistent methods to assess PROs as a barrier to their widespread acceptance and use.  Richard Pops, the Chairman and CEO of Alkermes, a pharmaceutical company that specializes in therapies for chronic central nervous system diseases, called for standardized methods for industry to follow when using patient-reported data.  Both Dr. Woodcock and Dr. Robert Beall, President and CEO of the Cystic Fibrosis Foundation, recommended that Congress provide federal agencies with increased resources for regulatory science, which could support efforts in this area.

The Patient Perspective in Drug Development & Review.  Of much greater interest to Subcommittee members and witnesses alike were models for incorporating the patient perspective in both industry and FDA decision-making throughout the drug development lifecycle.  As patients ultimately experience the risks and benefits of approved medical treatments, witnesses offered suggestions for increasing the patient voice in various aspects of drug development and review. 

Prior to the enactment of the Food and Drug Safety and Innovation Act (“FDASIA”), patient input in drug approval decisions was generally limited to patient representatives serving on FDA Advisory Committee meetings, which are mainly focused on approval decisions upon submission of a marketing application.  The FDA Office of Health and Constituent Affairs, in concert with the Agency’s medical product centers, recruits and trains patients to serve as Special Government Employees.  Recognizing the need to include patient input earlier in the FDA review process, Section 1137, which calls for FDA to develop and implement strategies to include the patient representatives earlier in drug review, at appropriate FDA-sponsor meetings, was included in FDASIA.  Dr. Lichtenfeld, from ACS, advocated that the FDA Patient Representative Program be expanded to include patient representatives in the review process, so that patients can provide input on risk tolerance and contribute to discussions of clinical trial design.  As Dr. Lichtenfeld pointed out, FDA Patient Representative Program would need additional resources in order to realize this goal.  The time burden for FDA to conduct conflict-of-interest screening of patient representatives is a barrier to their inclusion in FDA-sponsor meetings (i.e., pre-IND, end of Phase 2), which are scheduled under tight PDUFA-directed timeframes.  Although this barrier was not discussed at the hearing, it is important for the Subcommittee to recognize it when considering approaches to implement Dr. Lichtenfeld’s recommendation.

Dr. Woodcock described a more recent program for incorporating the patient perspective in FDA’s regulatory decision-making.  FDA committed under PDUFA V to hold at least twenty patient meetings over five years, each focused on a particular disease area, in an effort to obtain and utilize patient input in clinical trial design. This Patient-Focused Drug Development (“PFDD”) program provides an opportunity to more systematically obtain patient perspectives on how their disease impacts their daily lives, gauge the types of treatment benefits that matter most to patients, and assess the adequacy of available therapies for the disease with respect to the treatment benefits that patients desire.  Dr. Woodcock highlighted that the first meeting, which was held for patients with chronic fatigue syndrome (“CFS”) and myalgic encephalomyelitis (“ME”), resulted in a draft guidance for industry on CFS/ME drug development. 

Pat Furlong, Founder and CEO of Parent Project Muscular Dystrophy (“PPMD”), described her recent experience conducting a survey of on risk and benefit preferences in the Duchenne Muscular Dystrophy (“DMD”) community and suggested that other patient groups consider conducting similar surveys.  With FDA’s encouragement, PPMD developed and conducted the survey with the help of researchers at Johns Hopkins University.  PPMD shared the results of this study with FDA, showing that this population (parents of children with Duchenne Muscular Dystrophy, a condition that is 100% fatal at a young age) had a particularly high risk tolerance for treatment options. 

Dr. Marshall Summar, Director and Chair of the Scientific Advisory Committee for the National Organization for Rare Diseases (NORD), suggested that FDA develop guidance for patient groups to hold independent drug development meetings and present their findings to the Agency.  In the absence of such guidance, Ms. Furlong discussed PPMD’s six month effort, in collaboration with medical experts, industry, and their patient community to draft a guidance document to FDA on DMD clinical trial design and other drug development issues.  She described that their model was successful because of the structure the put in place with a multi-stakeholder Steering Committee, seven Working Groups to focus on various sections of the guidance, and an overarching Community Advisory Board, made up of DMD patient groups and patient advocates.  There was consensus among the witnesses that PPMD’s guidance development could serve as a model for other patient groups to effectively engage with FDA and industry and ultimately influence key issues in drug development. 

A final, and probably most dramatic, model for incorporating the patient perspective in drug development is for patients to provide resources that situate them as partners in drug development programs.  Dr. Robert Beall, President and CEO of the Cystic Fybrosis Foundation (“CFF”), discussed a series of investments his group made that led to the first approval of a drug for CF, as well as a second promising therapy in Phase 3 that targets a larger segment of the CF patient population.  First, in 1965, CFF created the first patient registry in the U.S., which enabled the group to collect the data that was needed to understand the natural history of the disease.  CFF also accredits health care centers, which treat 90% of all CF patients. The CFF accreditation program improves access to potential clinical research participants.  To further this goal, CFF created a CF clinical trial network, the first clinical trial network developed by a patient group, in 1998.  Finally, CFF raised funds and provided the initial investment in the biotech company developing the two drugs mentioned previously.  All of CFF’s efforts allowed for advancement in the research and development of product candidates for CF and ultimately de-risked the transition into clinical research.  CFF continues to engage with FDA on substantive regulatory and scientific issues, seen as an active partner in ongoing drug development programs.    

Piecing Together a Patient Engagement Framework.  Overall, there was consensus that patient engagement is not new, but the wide range of emerging models that further incorporate the patient perspective are advantageous to the drug development and review process.  There was also agreement that, to better incorporate patient perspectives, it is necessary to do so in a data-driven, systematic, and efficient manner.  Mr. Pops added, from the industry perspective, that the framework for patient input should not add new steps to the already complex drug development program.  Additionally, Dr. Woodcock stated that CDER believes it has the statutory authority it needs to meet the needs of expanded patient input into regulatory decision-making (although there are concerns regarding conflict-of-interest rules that are barriers to including FDA Patient Representatives in appropriate FDA-sponsor meetings).

For more information on FDA’s framework for patient engagement, Hyman, Phelps & McNamara, P.C.’s James E. Valentine presented an overview of FDA’s framework for patient engagement at the 2014 Drug Information Association Annual Meeting.  Best practices for effective engagement by industry and academia with patient groups around clinical trials will be emerging from the Clinical Trials Transformation Initiative, an FDA public-private partnership (see here).

* Not admitted in the District of Columbia
** Summer Associate

By Kurt R. Karst –      

We watched the World Cup final between Germany and Argentina this past weekend and were pleased with the outcome (well, at least this blogger was).  Things got pretty intense as the minutes in extra time ticked away, edging the match ever closer to a possible penalty shootout round to determine the winner.  Thankfully, Germany’s (Super) Mario Götze scored a goal in the 113th minute, giving Germany a fourth World Cup.  Zogenix, Inc. (“Zogenix”), the sponsor of ZOHYDRO ER (hydrocodone bitartrate) Extended-release Capsules, which FDA approved on October 25, 2013 under NDA No. 202880 for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, was not so lucky in its latest match against Massachusetts Governor Deval Patrick.  Last week, the U.S. District Court for the District of Massachusetts issued a decision allowing in part and denying in part the company’s Motion for a Preliminary Injunction, while denying the Commonwealth’s Motion to Dismiss (opposition briefs are available here and here).  Zogenix had hoped to score a total victory against the Commonwealth, but the court’s ruling means that we are likely far off from naming a winner in this match.

As we previously reported (here and here), Zogenix first sued Massachusetts Governor Deval Patrick and other Commonwealth officials after the Massachusetts Department of Public Health (“DPH”) and its Commissioner, Cheryl Bartlett, RN, took actions to combat opioid overdose, including granting DPH “emergency powers” to, among other things, ban the prescribing and dispensing of ZOHYDRO ER.  Zogenix filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction alleging that the Commonwealth’s ban on ZOHYDRO ER is unconstitutional because the ban violates the Supremacy Clause, the dormant Commerce Clause, and the federal Contracts Clause of the U.S. Constitution.  Shortly thereafter, the district court found that Governor Patrick’s March 27, 2014 Declaration of Emergency and the March 27th order of the Commissioner of the Department of Public Health banning the sale and distribution of ZOHYDRO ER obstructed FDA’s Congressionally-given charge.  The court allowed Zogenix’s motion for preliminary injunctive relief and enjoined, until April 22, 2014, the Commonwealth from taking any action to implement or enforce the declaration and order.

Though down, the Commonwealth was not out.  Commonwealth officials went right to work after the district court’s decision to come up with emergency regulations that might pass muster under a preemption analysis.  The result was the announcement of an April 22, 2014 emergency order from DPH Commissioner Bartlett and an emergency regulation promulgated by the Board of Registration in Medicine (“BORIM”) requiring an individually licensed prescriber to do the following before prescribing “a hydrocodone-only extended release medication that is not in an abuse deterrent form” (i.e., ZOHYDRO ER):

(a) Thoroughly assess the patient, including an evaluation of the patient’s risk factors, substance abuse history, presenting conditions(s), current medication(s), and a check of the online Prescription Monitoring Program;

(b) Discuss the risks and benefits of the medication with the patient;

(c) Enter into a Pain Management Treatment Agreement with the patient that shall appropriately address drug screening, pill counts, safe storage and disposal and other requirements based on the patient’s diagnoses, treatment plan, and risk assessment;

(d) Supply a Letter of Medical Necessity as required by the Board of Registration in Pharmacy that includes the patient’s diagnoses and treatment plan, verifies that other pain management treatments have failed, indicates that a risk assessment was performed and that the licensee and the patient have entered into a Pain Management Treatment Agreement; and

(e) Document 243 CMR 2.07(25)(a)-(d) in the patient’s medical record.

Other ZOHYDRO ER regulations followed in the coming weeks.  First, On May 6, 2014, the Board of Registration in Pharmacy (“BORIP”) promulgated two regulations (here and here) saying that “[a] certified pharmacy technician, pharmacy technician, pharmacy technician trainee, or pharmacy intern may not handle [ZOHYDRO ER],” and that before dispensing ZOHYDRO ER a pharmacist must satisfy a bevy of prerequisites,  including: (1) storing Zohydro in a locked cabinet; (2) dispensing Zohydro in a container with a child-proof safety cap; (3) reviewing the Letter of Medical Necessity; (4) including a warning about Zohydro’s dangers; (5) providing counseling on various issues; and (6) checking the patient’s history on the Prescription Monitoring Program.  Second, on May 8, 2014, the Board of Registration of Physicians Assistants (“BOROPA”) promulgated a set of regulations identical to the ones BORIM passed two days before.  These and the previous April 2014 regulations are referred to generally in court papers as the “Letter of Medical Necessity (‘LMN’) regulation” and the “pharmacist-only regulation.”

Zogenix filed a Motion for Preliminary Injunction on May 23, 2014 arguing that the new slate of regulations have the cumulative effect of creating an implicit ban on ZOHYDRO ER (i.e., obstacle preemption) and therefore “suffer[] from the same preemption problem as the first ban the Court already enjoined.”  Zogenix also alleged that the regulations violate the Contract Clause and the Commerce Clause of the U.S. Constitution, as well as the Equal Protection Clause “by singling out Zohydro™ ER for draconian restrictions not applicable to any other extended-release opioid products.”  (Nearly a doppelgängerof the counts Zogenix lodged in the company’s initial court papers filed in April.)

The Commonwealth shot back with a Motion to Dismiss. 

The Boards’ emergency regulations are not preempted by the [FDC Act] because, as the FDA itself has repeatedly acknowledged, States retain their traditional authority to regulate the medical and pharmacy professions, including the prescribing and dispensing of medications.  Nor do these emergency regulations begin to constitute an “effective ban” on Zohydro.  As the FDA Commissioner has indicated, they are instead reasonable requirements consistent with both best medical practices and longstanding parallel federal and state responsibilities in the field of drug regulation.  And Zogenix’s class-of-one equal protection claim is equally unavailing, because (1) the claim is not available in the circumstances present here, (2) critical elements of the claim are not (and cannot be) alleged, and (3) clear rational basis exists for the Board’s emergency regulations.

The Commonwealth also argued that Zogenix lacked standing to bring the suit and that the case should be dismissed for lack of subject matter jurisdiction.

In her July 8th decision, Judge Rya W. Zobel zeroed in on the essence of the case: obstacle preemption.  (Judge Zobel gave short schrift – the German spelling – to Zogenix’s Equal Protection Clause argument, saying “[t]hat argument is misplaced.”  Similarly, Judge Zobel did not consider Zogenix’s Contract Clause and the Commerce Clause arguments, saying that they were “undeveloped.”)  But to make such a preemption analysis, Judge Zobel she must do what the U.S. Supreme Court instructed in Savage v. Jones, 225 U.S. 501 (1912): “assess whether the regulations prevent the accomplishment of the FDCA’s objective that safe and effective drugs be available to the public.”  Her assessment: the LMN regulation is ambiguous and unclear, and the pharmacist-only regulation is uncertain. 

By any reckoning, the text of the “LMN regulation” is ambiguous.  Exactly what “pain management treatments” must fail before a doctor may prescribe Zohydro?  Plaintiff believes other opioids must fail.  Defendants do not believe a physician must prescribe other opioids before she may prescribe Zohydro. . . .  [I]f the Commonwealth interprets its regulation to make Zohydro a last-resort opioid, it undeniably makes Zohydro less available.  That presents a constitutional problem.

The “LMN regulation” is unclear in another way.  How long ago must the “other pain management treatments” have failed? . . .  If the Commonwealth interpreted its regulation to require a fresh failure as a precondition to each 30-day Zohydro prescription, it would severely frustrate Zohydro’s availability and pose significant constitutional concerns.

As for the “pharmacist-only regulation,” the parties rely on competing affidavits.  In a sealed declaration, Zogenix co-founder and Chief Executive Officer Roger L. Hawley discloses that unspecified major retail pharmacy chains do not plan to stock Zohydro because the “pharmacist-only regulation” is “fundamentally incompatible with personnel infrastructure and established policies for dispensing ER/LA opioids.”  Defendants present the affidavit of Michael Reppucci, R. Ph., owner of and pharmacist at Inman Pharmacy in Cambridge, Massachusetts.  Reppucci states that because BORIP already regulates pharmacy technicians, “prohibiting any pharmacy technicians from transporting and handling Zohydro does not add any substantial administrative burden or present substantial logistical problems.”  Neither party directs the court to any pharmacy’s announcement that it will or will not carry Zohydro.

Given the uncertainty as to how the Commonwealth might interpret and enforce the regulations, and a lack of an enforcement record on which to assess whether there is a case for obstacle preemption, Judge Zobel allowed Zogenix’s motion to preliminarily enjoin the LMN regulation, but with the caveat that “[i]f defendants provide adequate and constitutional guidance to physicians regarding the prerequisites for prescribing Zohydro in compliance with the regulation, then they may thereafter move to lift the injunction.”  On the other hand, with respect to the pharmacist-only regulation, Judge Zobel concluded that “[b]ecause its sealed declaration does not provide sufficient detail that pharmacies will not carry Zohydro, plaintiff has not met its burden of proof on the “pharmacist-only regulation,” and that Zogenix’s Motion for a Preliminary Injunction “is denied without prejudice to renewal upon a more detailed submission.”

So it’s not quite “goodbye” to this controversy, but rather – and quite literally – “auf Wiedersehen” (until we meet again).

By Ricardo Carvajal –

FDA released data for its Total Diet Study (TDS) covering the period from 2006 to 2011.  Under the TDS, FDA collects data on levels of pesticide residues, industrial chemicals, toxins, and nutrients present in foods to monitor changes in the levels of those substances and help the agency evaluate potential risks to public health.  Because the TDS is intended to monitor levels of those substances in foods as consumed, FDA collects samples for the study by shopping at grocery stores and restaurants around the U.S.

FDA cautions that “[i]ndividuals who intend to use either the data summaries or individual analytical results are urged to review all the information” on the study design and data collection “to ensure a good understanding of the study and the data” – perhaps an effort to discourage armchair analysts from casually perusing the data and jumping to erroneous conclusions.  FDA’s bottom line advice: consumers should “eat a varied, well-balanced diet, consistent with the Dietary Guidelines for Americans.”  Nonetheless, the updated data could reveal trends of interest.  One such result is pointed out by FDA in its news release: “the agency found statistically significant declines in sodium contents of several processed foods.” 

It’s July, and that means the American Bar Association (“ABA”) has initiated the annual process for selecting the top legal blogs (or “blawgs”) in the blogosphere.  The 8th iteration of the list will be revelaed later this year when the ABA announces the “Blawg 100” in the print and electronic versions of the ABA Journal.  The ABA’s initiation of the selection process also means that we at the FDA Law Blog once again need to go to the well and ask our loyal readers to nominate us for the Blawg 100.  With your help, we’ve made the top 100 list three times before.  We would like nothing more than to make the 2014 list so that we can add another badge to the “Awards and Honors” collection posted on our blog webpage.  So here’s our best Arnold Horshack “Ohh, Ohh, Ohh . . . Choose me” plea for nominations. 

To nominate the FDA Law Blog for the 2014 Blawg 100, readers should use the Amici Form – available here – supplied by the ABA and submit a friend-of-the-blawg brief.  Although it’s called a brief, it’s not legal in nature.  In fact, you only have 500 characters to say why you’re a fan of the blog.  Remember, when you complete the nomination form, our URL is www.fdalawblog.net.  Friend-of-the-blawg briefs are due no later than than 5 PM ET on Friday, August 8, 2014.  (That’s the same day one of your Blogmeisters is scheduled to be at Uhuru Peak of Mt. Kilimanjaro; so while he’s literally on top of the world – or at least the roof of Africa – you can figuratively keep the Blogmeisters flying high and on top of the world by timely submitting your nomination.)  ABA editors make the final decisions about what blogs to include in the Blawg 100.  We hope they’ll be impressed with what our readers have to say about us.  Thank you!

By Kurt R. Karst –      

Earlier this week, and just a day after the second anniversary of the 2012 FDA Safety and Innovation Act that, among other things, includes the Generic Drug User Fee Amendments (“GDUFA” ), FDA announced the release of two draft guidance documents that explain how the Agency (and the Office of Generic Drugs in particular) intends to implement the rather complex ANDA amendment and Prior Approval Supplement (“PAS”) provisions and performance metric goals contained in the Program Performance Goals and Procedures (“Commitment Letter”) accompanying GDUFA.  The draft guidances, along with pre-recorded webinars (here and here) and slides (here and here), come less than three months before the October 1, 2014 date when GDUFA goes into full effect, and when the generic drug industry will be forever changed.

The amendment and PAS provisions of the Commitment Letter – and the amendment provisions in particular – are not for the faint of heart.  You’re left scratching your head after the first readthrough of the Commitment Letter wondering how this system is going to work, but by the tenth readthrough things begin to start sinking in.  And the two new draft guidances – ANDA Submissions – Prior Approval Supplements Under GDUFA and ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA – go a long way to elucidate how the submission system will work under GDUFA, and provide several very helpful real-world examples.

Let’s start with a few basics from GDUFA and the Commitment Letter, and some concepts shared among both draft guidances before moving on to some specifics from each draft guidance:

• ANDAs are now categorized according to cohort year (i.e., FY 2015, FY 2016, FY 2017).  PASs are also identified by the fiscal year of submission, but the term “cohort year” is not specifically used to refer to a particular submission year.
• Once an original ANDA is in a particular cohort year based on the original submission date made through FDA’s electronic gateway (see our previous post here), dates of submission of an amendment to that original ANDA do not change the cohort year.   In other words, if you submit your original ANDA in FY 2015, that application will forever be a cohort year 3 ANDA.  The same holds true for a PAS fiscal year submission. 
• FDA agreed to review and act on 60% of original ANDA submissions within 15 months from the date of submission for the year 3 cohort (FY 2015); 75% of original ANDA submissions within 15 months from the date of submission for the year 4 cohort (FY 2016); and 90% of original ANDA submissions within 10 months from the date of submission for the year 5 cohort (FY 2017). 
• FDA agreed to review and act on 60% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2015; 75% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2016; and 90% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2017. 
• Acting on an original ANDA and PAS includes issuance of a Complete Response (“CR”) letter, an approval letter, a tentative approval letter, or a refuse-to-receive action.
• The date of submission of an original ANDA or PAS is calculated in months beginning on the receipt date of arrival of the submission in the electronic submission gateway.  For example, if a complete PAS (not requiring an inspection) is submitted on November 3, 2014, the 6-month GDUFA goal date for FDA review and action is May 2, 2015.  Note that this calculation differs from the goal date calculation under the Prescription Drug User Fee Act.
• The 15-month and 10-month base period action dates for cohort year 3-5 ANDAs can change (i.e., are incremental and can be recalculated to a longer period/date) based on the type and number of amendments submitted to FDA and how they are tiered (i.e., Tier 1, Tier 2, and Tier 3).  Similarly, the 6-month and 10-month base period action dates for PASs can be recalculated.  GDUFA established certain review goals for the various types and tiers of amendments that are fully explained (with examples) in the draft guidances.

ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA:  The draft guidance delves into the details of the various categories of amendments to an original ANDA or PAS.  The number, classification, and tier group of amendments can affect FDA’s goal date for acting on an original ANDA or PAS, as well as the need for an inspection.  Amendments to an original ANDA or PAS are classified as solicited, unsolicited, or administrative.  Solicited amendments are identified as major, minor, or as an Easily Correctable Deficiency (“ECD”).  Unsolicited amendments are identified as delaying and non-delaying.  In addition, amendments are grouped as Tier 1, Tier 2, or Tier 3.  Together, they result in the matrix below from the draft guidance.

A solicited amendment is a submission made by an applicant in response to a CR letter.  The classification of such an amendment as major or minor (or as an ECD) is largely a matter of FDA discretion.  Nevertheless, FDA applies the following general principles, which are further explained with examples in appendices to the draft guidance:

• “Major amendments contain a substantial amount of new data or new information not previously submitted to or reviewed by FDA, requiring, in FDA’s judgment, a substantial expenditure of FDA resources.  In general, the type, quantity, or complexity of data contained in a major amendment requires a lengthy review by FDA, and consults from other divisions or offices may be required to complete the review.”
• “FDA review of a minor amendment requires, in FDA’s judgment, fewer FDA resources than are necessary to review a major amendment, but more than are necessary to review the information submitted in response to an ECD.”
• “FDA review of information submitted in response to an ECD requires, in FDA’s judgment, a modest expenditure of FDA resources.  An applicant should be able to respond to an ECD quickly as the applicant should already possess or be able to quickly retrieve the information needed for an adequate response to an ECD.”

Unsolicited amendments, which are either delaying (Tier 1) or non-delaying (Tier 2), are submitted on an applicant’s own initiative and not in response to a CR letter.  As FDA explains, “[d]elaying amendments address actions by a third party that would cause delay or impede application review or approval timing and that were not a factor at the time of submission. ”  Thus, for example, “if a [citizen petition] requests certain [bioequivalence] data be submitted to support an ANDA for a particular drug product and FDA grants that petition, an ANDA applicant may submit the [bioequivalence] data reflected in the [citizen petition] response prior to FDA’s request of the data from the ANDA applicant.”  In contrast, non-delaying amendments “are unsolicited amendments that contain information that is not requested by FDA and is not the result of changes to the RLD or USP monograph, changes to the RLD labeling, a REMS and REMS modification, or generic approval requirements reflected in citizen petition responses issued by FDA.”  Finally, administrative amendments “are routine in nature and do not require scientific review.”  They do not fall within the tier matrix, and therefore do not affect GDUFA action dates.

The draft guidance also provides instructions for applicants that want to challenge FDA’s classification of an amendment by requesting reconsideration:

• “If an applicant is requesting reconsideration of a CR amendment, the applicant will submit a written request for a post-CR-letter meeting within 10 business days from issuance of the CR letter. . . .  The division will issue a decision about the request for reconsideration and notify the applicant of the decision within 10 business days from the date of the meeting.”
• “If an applicant wishes to request reconsideration of a change in classification that occurred after submission of the applicant’s CR amendment, the applicant should submit a request for reconsideration within 10 business days from issuance of the goal letter. . . .  The division will notify the applicant of the decision within 10 business days from the date the request for reconsideration was received.”

ANDA Submissions – Prior Approval Supplements Under GDUFA:  This draft guidance, which should be read in conjunction with the first draft guidance, addresses various topics in relation to PASs to approved ANDAs, including how the GDUFA performance metric goals apply to a PAS subject to the refuse-to-receive standards, a PAS that requires (or does not require) an inspection, and PAS amendments.  (It bears noting that the statutory and regulatory criteria for submitting information to an ANDA as a PAS – or as a changes being effected supplement, or as an annual reportable change – based on a major, moderate, or minor change were not altered by GDUFA.  These reporting criteria should not be confused with FDA’s categorization of amendments as major or minor.) 

Most ANDA sponsors have experienced at some point in time a delay in the approval of a submissions to FDA because of an “expired” inspection.  But FDA explains in the draft guidance that in some cases the Agency will cut sponsors some slack:

FDA intends to continue the practice of using a risk-based assessment in determining the need for an inspection, guided by a 2-year cycle for finished dosage product sites and a 3-year cycle for API sites and consideration of the type of finished product or API in the application.  Practically, this means that in making decisions about pending supplemental applications for which FDA does not have current inspection information within the time period indicated, FDA may use previous FDA inspection information and/or use inspection information from another regulatory authority as appropriate.  If FDA determines that an actual inspection is not required, the goal date would be revised from 10 months to 6 months.

The draft guidance also explains FDA’s approach to so-called “grouped supplements” – i.e., “multiple supplements (typically five or more) submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application.”  FDA says that each supplement in the group is considered an indivdual submission assessed a separate PAS user fee (with generally the same GDUFA goal date).  Alternatively, an ANDA sponsor may want to consider submitting a PAS with a comparability protocol outlining the change and the support for it.  “Once the PAS is approved, the agreed-upon reporting category could be used.  Thus, at the time the PAS containing the comparability protocol is approved, FDA can designate, where appropriate, a reduced reporting category for future reporting of changes covered by the approved comparability protocol (e.g., from a PAS to a CBE-30 supplement).”  This means that while the GDUFA performance metric goals and applicable user fees would apply to the initial PAS, they would not apply to future supplements submitted under the reduced reporting category.  What a deal (or not), depending on what’s more important to you – time or money.  (Though time is money, no?)

By Kurt R. Karst –   

Earlier this year we posted on two pending lawsuits brought by potential biosimilar applicants challenging the the so-called “patent dance” patent resolution provisions added to the PHS Act by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The BPCIA created a pathway for the submission and approval of biosimilar (both “highly similar” and interchangeable) versions of brand-name reference products under a Section 351(k) application.  The first case was brought by Sandoz Inc. (“Sandoz”), which has appealed to the U.S. Court of Appeals for the Federal Circuit (Docket No. 14-1693) a November 2013 decision from the U.S. District Court for the Northern District of California granting Amgen Inc.’s (“Amgen’s”) and Hoffmann-La Roche Inc.’s (“Roche’s”) Motion to Dismiss a June 2013 Complaint for Declaratory Judgment and Patent Invalidity and Non-infringement concerning two patents Roche licensed to Amgen that purportedly cover Amgen’s biological product ENBREL (etanercept) (see our previous post here).  The second case was brought by Celltrion Healthcare Co., Ltd. and Celltrion, Inc. (collectively “Celltrion”), which filed a Complaint for Declaratory Judgment in the U.S. District Court for the District of Massachusetts seeking a judgment with respect to certain patents allegedly covering Janssen Biotech, Inc.’s (“Janssen’s”) biological product REMICADE (infliximab) (see our previous post here).  Both cases are moving steadily towards resolution, though an appeal is likely in both no matter how the courts rule.  (A third case – also involving  infliximab and a Celltrion Complaint for Declaratory Judgment – was filed in the U.S. District Court for the Southern District of New York against The Kennedy Trust for Rheumatology Research, which holds third-party patents – here, here, and here – that allegedly cover infliximab.)  

When we last left off with the Sandoz case, the company had filed its opening brief with the Federal Circuit, saying, among other thinge, that the district court’s decision undermines the BPCIA’s purpose of advancing competition for biologic products because that decision “completely deprives federal courts of jurisdiction over any declaratory judgment action implicating a biosimilar product until after the FDA had already approved the product.”  The district court dismissed the case after ruling that Sandoz was subject to, but had not satisfied, any of the BPCIA’s limitations on declaratory judgment, and that Sandoz had not presented a case or controversy.

A couple of months later, Amgen and Roche shot back with a 95-page filing arguing, among other things, that it is Sandoz’s interpretation of the law would eviscerate the statutory biosimilars patent dance framework:

Sandoz argues that the BPCIA’s patent provisions limit declaratory judgment actions only after (1) a biosimilar applicant has submitted a subsection (k) application to the FDA, (2) the FDA has accepted that application for review, and 20 days thereafter (3) the applicant “fails to provide” the application and additional manufacturing information to the RPS.  Until such “failure” has occurred, Sandoz argues, the patent provisions of the BPCIA do not limit the prospective biosimilar applicant’s ability to bring biosimilar-related declaratory judgment patent actions that would otherwise be restricted under the BPCIA.  Sandoz’s construction, however, eviscerates the statutory framework, is inconsistent with the BPCIA’s cross-referencing within the PHSA and between it and the DJ Act, furthers no logical public policy, undermines orderly access to the courts, and invites gamesmanship. [(Emphasis in original.)]

Most recently, Sandoz filed its reply brief hammering home the company’s points that the BPCIA is not the exclusive mechanism for resolving patent disputes involving biological products, and that the BPCIA in no way bars the company’s Complaint for Declaratory Judgment:

[T]he BPCIA creates one potential mechanism to resolve patent disputes, by amending 35 U.S.C. § 271(e) to create a new infringement action based on the “artificial” activity of parties exchanging patent contentions.  However, nothing in the BPCIA says that a § 271(e) action is the only way to resolving biologic patent disputes.  The BPCIA does not purport to deprive federal courts of jurisdiction where it would otherwise exist under the Patent Laws, such as for declaratory judgments filed under §§ 271(a)-(c).

By their express terms, the BPCIA’s sole limitations on a declaratory judgment remedy apply after a subsection (k) application is filed, and then, only “if” a subsection (k) applicant first “fails” to cooperate in prescribed informational exchanges, 42 U.S.C. §§ 262(l)(9)(B)-(C), or does not identify particular patents on a final list, § (l)(9)(A).  Sandoz is not a “subsection (k)” applicant; it has not “failed” to comply with any obligations; and thus, no provision of the BPCIA bars Sandoz’s Complaint. [(Emphasis in original.)]

To our knowledge, a date for Oral Argument as not yet been set in the case, though Sandoz has pressed the Federal Circuit to schedule Oral Argument as soon as possible.

Moving on to the Celltrion case and Celltrion’s REMSIMA biosimilar version of REMICADE, Janssen not surprisingly filed a Motion to Dismiss Celltrion’s Declaratory Judgment Complaint for lack of subject matter jurisdiction.  Alternatively, Janssen asks the district court to decline to exercise declaratory judgment jurisdiction on the basis that to proceed would be inconsistent with the BPCIA.  Mirroring some of the arguments in the Sandoz case, Janssen says:

Under the law, if Celltrion had already filed its biosimilar application it would be statutorily barred from bringing the instant declaratory judgment action.  Instead, Celltrion filed this suit prematurely – before filing its biosimilar application – in an attempt to avoid the patent resolution procedures of the BPCIA.  There is no justification for permitting Celltrion to avail itself of the biosimilar approval pathway in the BPCIA while at the same time skirting the patent resolution procedures.

Celltrion, in the company’s opposition brief filed earlier this week, vigorously defends its position, saying that the case is ripe based on the U.S. Supreme Court’s decision in MedImmune, Inc. v. Genentech, Inc., 549 U.S. 118 (2007), and the “totality of the circumstances:”  “In this case, all the circumstances weigh in favor of jurisdiction.  They include Celltrion’s substantial preparation to market Remsima; the fact that Remsima’s formula is fixed and will not change in any way relevant to the three disputed patents; Janssen’s aggressive efforts to defend its patents and oppose Remsima; and Janssen’s repeated refusal to grant licenses to Celltrion.”

As to whether or not the district court should exercise declaratory judgment jurisdiction, Celltrion says that doing so would be an abuse of discretion:

First, Janssen’s proposal proceeds from a false premise.  The BPCIA’s information- exchange process is not an alternative to litigation or a “dispute resolution” process Celltrion is trying to end-run. . . . It is a dispute preparation process designed to facilitate and culminate in litigation.  Dismissing this case because Celltrion and Janssen have not yet engaged in that process will not keep the dispute out of court; it will only delay the time when a court resolves it.

Second, forcing Celltrion and Janssen to engage in the information-exchange process before adjudicating their patent dispute would serve no purpose.  Celltrion already has identified the three disputed patents, and if Janssen thinks there are more, it can file counterclaims alleging infringement of them.  The only consequence of dismissal would be to extend Janssen’s exclusivity for Remicade by the time it would take to complete the information-exchange process.  That would turn the process on its head.  Congress designed it to provide certainty and to ripen unripe disputes so that a court can adjudicate them in a timely fashion without practically extend-ing the 12-year exclusivity term.  Here, Celltrion’s dispute is already ripe, and Janssen’s 12-year term has already expired. The Court should reject Janssen’s effort to mis-use a tool for promoting competition as a weapon to delay it.

Third, Janssen’s argument rests on an invalid policy premise.  In drafting the BPCIA, Congress addressed declaratory-judgment actions between biologics manufacturers and decided to bar only a subset—those filed after the information-exchange process begins but before it ends.  Dissatisfied with Congress’s policy choice, Janssen asks the Court to bar declaratory-judgment actions between biologics manufacturers filed before the information-exchange process even begins. T his Court cannot use its discretion under the Declaratory Judgment Act in a way that rejects Congress’s deliberate policy choice. [(Emphasis in original; citations omitted.)]

Regardless of how the district court rules in the Celltrion case, it seems destined to go up to the Federal Circuit.  But timing will be everything.  If the Federal Circuit rules first in the Sandoz case, then we might have different appellants and appellees.

By Wes Siegner –

Just in time for the windup to ad campaigns for the fall/winter cold/flu season, FDA has sent Zarbee’s, Inc. a Warning Letter alerting the company that its dietary supplement products are in fact illegal drugs, some prescription drugs, given the claims that the company is making on the web, Facebook, and Twitter.  FDA also notified Zarbee’s that it is responsible for the content of testimonials on the company’s Facebook page.  Zarbee’s has 15 days from June 27 to notify FDA of the specific steps that the company intends to take to correct the violations noted in the Warning Letter.

By Kurt R. Karst –      

The years-long, knock-down, drag-out fight between the K-V Pharmaceutical Company (“KV”) – now known as Lumara Health Inc. – and FDA (and the Department of Health and Human Services) involving KV’s pre-term birth orphan drug MAKENA (hydroxyprogesterone caproate) Injection, 250 mg/mL, has ended.  But that ending is more akin to the final scene from the hit HBO series “The Sopranos” than the final scene from ABC’s “Lost.”  In the former, viewers were treated to a “cut to black” final scene leaving some to feel cheated.  In the latter, there was at least some final resolution of what happened to the “survivors” of Oceanic Airlines Flight 815. 

Last week, just before the Independence Day holiday, KV and FDA filed a Joint Stipulation of Dismissal With Prejudice with the U.S. District Court for the District of Columbia to dismiss the litigation.   The case is now over and we’ll never know what might have been had the court issued a merits decision.  We’re also left hanging as to what (if anything) KV got out of a deal to settle the case. 

As we previously reported (here, here, and here), KV sued FDA on July 5, 2012 alleging that the Agency violated myriad provisions of the FDC Act, the Administrative Procedure Act Section 706(2), and the Due Process Clause of the Fifth Amendment to the U.S. Constitution by failing to take sufficient enforcement action to stop the unlawful competition with MAKENA by pharmacies that were compounding 17P during KV’s period of orphan drug exclusivity.  The DC District Court ruled for FDA in September 2012, and KV appealed to the U.S. Court of Appeals for the District of Columbia Circuit. 

Earlier this year, in an interesting turn of events, the DC Circuit issued an unpublished judgment ordering and adjudging that the DC District Court’s September 6, 2012 order dismissing KV’s claims be vacated and that the case be remanded to the district court for reconsideration in light of the DC Circuit’s July 23, 2013 decision in Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013), and the November 27, 2013 enactment of the Drug Quality and Security Act (“DQSA”), Pub. L. No. 113-54, 127 Stat. 587 (2013) (see our previous post here).  As we previously noted, in Cook, the DC Circuit largely affirmed a March 2012 decision from the DC District Court permanently enjoining FDA from permitting the entry of (or releasing any future shipments of) foreign manufactured thiopental into interstate commerce.  Title I of the DQSA, the Compounding Quality Act, concerns state and federal oversight of compounding of human drugs. (FDA recently issued several notices concerning the DQSA’s compounding provisions – see here and here).

Perhaps the writing was on the wall that a settlement might be forthcoming.  In several recent court filings, the parties requested (and were granted) extensions to file supplemental briefs “because the parties were engaged in active settlement discussions.”  Most recently, a filing indicated that settlement discussions “have continued, and the parties have reached agreement in principle to resolve this litigation.”  It’s unclear to us what the settlement between KV and FDA might entail. . . . and we might never have a clear picture of that.