By Kurt R. Karst –      

The hope is that years from now (but hopefully not too many years), once the review and performance metrics FDA agreed to as part of the Generic Drug User Fee Amendments are in full effect and 10-month ANDA reviews (resulting in timely tentative and final approvals) are the norm, we’ll look back at posts like this one just to refresh our recollection as to how FDA, in the “dark ages,” went about determining that a sponsor forfeited eligibility for a period of 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(IV).  We’re already in a period of relative calm when it comes to forfeiture, with only a dozen or so FDA decisions so far this year.  But that calm is probably a bit misleading, as forfeiture decisions that would have come up at 30 months after ANDA submission have been delayed to 40 months as a result of the enactment of Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) (see our previous post here).  

It’s been a while since we last posted on an FDA forfeiture decision.  But that’s the topic of today’s post . . . a recent and interesting case concerning generic ACTONEL (risedronate sodium) Tablets approved under NDA No. 020835.  And the case serves as a gentle reminder of FDA’s “our failure is your failure position” when it comes to the failure-to-obtain-timely-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  First things first, however . . . a little statutory background.

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.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final Agency action on the petition (inclusive of such beginning and ending dates) . . . .” FDC Act § 505(q)(1)(G).  Forfeiture decisions involving this provision have been invariably linked to a change in or review of decision under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has yet to make a stand-alone decision under FDC Act § 505(q), adding a specific number of days to the 30-month forfeiture date. 

FDASIA made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs.  In particular (though not relevant to the case at hand), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months.

FDA’s application of the exception (i.e., the “unless”) provision at FDC Act § 505(j)(5)(D)(i)(IV) was, at first, very narrow and draconian (and it still is to some extent).  For example, FDA explained in an October 2008 Letter Decision that “[t]his express description of the circumstances in which exclusivity will not be forfeited for failure to obtain tentative approval makes it clear that, under other circumstances in which an applicant has failed to obtain tentative approval, regardless of what party might be responsible for that failure, the first applicant will forfeit exclusivity” (emphasis added).  Although FDA still sticks to a “our failure is your failure position,” as we explained in a post back in June 2013, the Agency has shown some willingness to allow a little wiggle room under FDC Act § 505(j)(5)(D)(i)(IV).  In particular, FDA has rejected as too draconian “but for” causation in its application of the statutory forfeiture provision.  As we explained back then:

FDA has determined that even if one of the causes of failure to get tentative approval by the 30-month forfeiture date was a change in or a review of the requirements for approval imposed after the application was submitted, a first applicant will not forfeit eligibility notwithstanding that there may have been other causes for failure to obtain tentative approval by the 30-month forfeiture date that were not caused by a change in or review of the requirements for approval.  That is, to avoid forfeiture, an applicant need only show that acceptability of one aspect of its ANDA (e.g., chemistry, labeling, or bioequivalence) was delayed due, at least in part, to a change in or review of the requirements for approval, irrespective of what other elements may also have been outstanding at the 30-month date.  In other words, “but-for” causation is not required in order to qualify for the exception under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has apparently determined that this interpretation best effectuates the policy embodied in the exception, insofar as it does not penalize first applicants for reviews of or changes in approval requirements imposed after their ANDAs are submitted that cause the failure to obtain approvals or tentative approvals within 30 months, and continues to incentivize applicants to challenge patents by preserving (in many instances) the opportunity to obtain 180-day exclusivity.

In the case of forfeiture of 180-day exclusivity eligibility for generic ACTONEL Tablets, 150 mg, FDA builds on to and hammers home the Agency’s “our failure is your failure position.” 

Teva Pharmaceuticals USA (“Teva”) submitted the first ANDA to FDA – ANDA No. 079215 – containing a Paragraph IV certification for two strengths of generic ACTONEL Tablets: 75 mg and 150 mg.  The first Paragraph IV for the 75 mg strength was submitted on September 10, 2007 as part of the company’s original ANDA submission, and a second Paragraph IV for the 150 mg strength was submitted on August 12, 2008 as part of an amendment to ANDA No. 079215.  Teva’s eligibility for 180-day exclusivity for the 75 mg strength was forfeited pursuant to FDC Act § 505(j)(5)(D)(i)(II) when the company withdrew the strength from ANDA No. 079215 on December 98, 2009, but Teva continued to pursue approval of the remaining 150 mg tablet strength. 

Years passed, and it was not until August 17, 2011 that FDA finally tentatively approved ANDA No. 079215.  This is, of course, more than six months past the date that is 30 months from the August 12, 2008 submission of the 150 mg strength amendment to the ANDA (i.e., February 12, 2011).  (Final ANDA approval was granted on June 13, 2014.) 

Although FDA has not yet posted on the Agency’s Drugs@FDA website a copy of the approval letter for ANDA No. 079215, we were able to get our hands on a copy of FDA’s internal 180-Day Exclusivity Forfeiture Memorandum.  In that memorandum, FDA’s Office of Generic Drugs (“OGD”) details the basis for the Office’s conclusion that Teva forfeited 180-day exclusivity eligibility pursuant to FDC Act § 505(j)(5)(D)(i)(IV), even though as of February 11, 2011, one day prior to the 30-month forfeiture date, all OGD review disciplines had completed review of the ANDA:

We note that although no individual disciplines were outstanding at the 30-month forfeiture date, FDA had not completed its final review of the ANDA by that date.  The decision to approve (or tentatively approve) an ANDA involves not only the disciplines’ evaluations of their respective portions of the ANDA, but final review by [OGD] management.  That final step did not take place by the 30-month forfeiture date, and was complete on August 17, 2011.  We also note that any claim that a company should not forfeit because of the possibility that FDA’s delays caused the company’s failure to obtain tentative approval by the 30-month forfeiture date is unavailing.  Under section 505(j)(D)(1)(IV) of the FD&C Act, exclusivity is forfeited “unless” there is a review of or change in the requirements that has delayed approval or tentative approval of the ANDA.  The statute does not permit, let alone require, either FDA or an ANDA applicant to comb through the ANDA review records and decide whether, had the review been conducted more quickly, the application could have received tentative approval before the 30-month forfeiture date.  Notably, section 1133 of FDASIA . . . , which, among other things, extended the 30-month forfeiture period to 40 months for certain ANDAs, reflects Congress’s understanding both that the length of time that it takes FDA to review an ANDA might contribute to a sponsor’s failure to obtain tentative approval by the 30-month forfeiture date, and that in such instances forfeiture nonetheless may occur.

We’ve always found FDA’s “our failure is your failure position” problematic from a fairness standpoint; however, no company has yet taken FDA to task in a lawsuit challenging the Agency’s interpretation and application of this position.  That’s probably because finding the perfect case is very difficult.  After all, what ANDA file is clean enough from a response timeframe to make such a challenge? 

By Ricardo Carvajal & Diane B. McColl –

The Grocery Manufacturers Association ("GMA") announced an initiative designed to “improve the process and increase transparency for making Generally Recognized As Safe ("GRAS") determinations of ingredients added to food.”  The initiative includes the following five elements:

1. Development by independent technical experts of a publicly available standard to provide guidance on the conduct of ingredient safety assessments.  The standard is intended to be “suitable for accreditation using an independent official accreditation body.”
2. Establishment of a database listing information on GRAS assessments conducted pursuant to the aforementioned standard.  Information in the database will be made available to FDA and other stakeholders.
3. Expansion of GMA’s curriculum of GRAS education and training programs, both with respect to regulatory requirements and the scientific procedures used in safety assessments.  The expertise of the recently established Center for Research and Ingredient Safety (CRIS) will be made available to stakeholders.
4. Adoption of a Code of Practice that addresses the conduct of assessments, maintenance of the GRAS assessment database, and training of employees on GRAS procedures.
5. Outreach to inform stakeholders and consumers of the above-described measures.

The initiative implicitly recognizes that, at least when it comes to food ingredient safety, we live in a “show me” era.  The increased flow of information on safety assessments to FDA and others, coupled with greater clarity about the conduct of such assessments, should help address the principal concerns that have been raised about the current system.

Of course, we also live in a “my way” (or the highway) era.  As we’ve noted in prior postings (here and here), some critics of the current system have pursued a no-holds-barred approach to seeking change, and would prefer nothing less than mandatory premarket approval – a solution that is both unworkable and unattainable.  The GMA initiative effectively calls their bluff.

By Alan M. Kirschenbaum –

We have reported previously (here and here) on PhRMA’s lawsuit challenging a HRSA regulation implementing the orphan drug exclusion that applies to certain types of covered entities under the 340B Drug Discount Program. To recap briefly, the rule had provided that the orphan drug exclusion is applicable only to orphan drugs when used for the rare condition or disease for which that orphan drug was designated, so that covered entities are entitled to 340B discounts when a drug designated as an orphan drug for one indication is used for a different, non-orphan indication. In May, the D.C. District Court vacated the rule on the ground that HRSA did not have statutory authority to promulgate a legislative rule on this subject. Last month, HRSA responded by issuing a substantially identical rule, but characterizing it as an interpretive rule. PhRMA then asked the Court to either order additional briefing on whether the now-interpretive rule is valid, or to vacate the rule.

Today, the Court denied PhRMA’s request, ruling that the new interpretive rule is not the subject of PhRMA’s lawsuit. Accordingly, PhRMA “is free to challenge that interpretive rule, but such a challenge is beyond the scope of the instant action.”

To be continued . . . .

By Jennifer D. Newberger –

On August 20, 2014, CDRH issued a guidance document, “Unique Device Identifier System: Frequently Asked Questions, Vol. 1.”  The purpose, according to the guidance, is to “provide[] clarification of key provisions of the UDI Rule.”  We previously posted on the UDI rule here.

Clarification, in this instance, appears to be little more than a regurgitation of information contained in the rule itself, the preamble to the rule, the UDI website, and the Global Unique Device Identification (GUDID) guidance document.  It is not clear what new insights FDA intended this guidance to impart.  There are parts of the rule that do deserve further clarification, but those issues are not addressed. 

For example, the definition of an implantable device is one that “is intended to remain implanted continuously for a period of 30 days or more.”  21 C.F.R. § 801.3.  By this definition, extended wear contact lenses are considered implantable devices, since they are intended to remain in the eye for 30 days.  Nevertheless, we assume that FDA did not intend to include extended wear contact lenses in the definition of an implantable device.  It would be helpful for FDA to clarify this point, but failed to do so in the FAQ.

Additionally, we have been made aware that many retailers may not be able to read automatic identification and data capture (AIDC) codes for a number of years.  All labels are required to contain a UDI in plain text and AIDC format.  For devices available over-the-counter at retail stores, it is not clear how the presence of a code in AIDC format will benefit the public health (e.g., by facilitating a recall) if the retailer is unable to read the code.  Even though FDA rejected an overall exception to UDI requirements for devices available at retail establishments, it would be helpful to industry for FDA to discuss situations in which a UPC code may suffice as a UDI until retail technology catches up to the AIDC requirement.  Until then, requiring companies to place AIDC codes on retail devices with UPC codes is burdensome with no countervailing public health benefit.

The title of this guidance document states that it is “Vol. 1,” implying that there will at least be a “Vol. 2.”  Hopefully, future UDI guidance documents will do more than repeat information that is already available.

By Kurt R. Karst –      

This blogger’s oldest child started middle school this past week.  Naturally, I was excited to get his impressions of the first day of school.  “Good” was his initial comment – a now all too familiar one-word tween response with which I am still coming to grips.  So I pressed further: “Tell me more.”  “It’s all so different from elementary school,” he said.  “I got 8 pages of homework on the first day!”  While I expressed surprise, what I was really thinking was: “If only life could be that simple again.”  That thought is similar to this blogger’s first reaction after reviewing FDA’s latest draft guidance document issued in preparation for the October 1, 2014 implementation of the review and performance goals agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”): “Controlled Correspondence Related to Generic Drug Development.”  When did every little aspect of generic drug development – even simple correspondence to FDA – become so complicated?  Of course, we know the answer to that question: when GDUFA was enacted.  But just as we get used to new responsibilities as we move through the education process, the generic drug industry will step up to the task of evolving with GDUFA no matter how complicated things get.

So-called “controlled correspondence” has been a mainstay of the generic drug development and approval process for many years now.  It’s how many companies have been able to get answers from FDA’s Office of Generic Drugs (“OGD”) to questions like “What are the bioequivalence requirements for drug X?” and “How close is my formulation to that of the brand-name reference listed drug?”  OGD gets a ton of controlled correspondence each year.  Although the volume of controlled correspondence was reduced with OGD’s decision – after some internal FDA legal wranglings – to publish product-specific bioequivalence recommendations (see our previous post here), OGD continues to receive hundreds (if not thousands) of controlled correspondence requests each year.  Not surprisingly, there’s been a backlog of controlled correspondence awaiting a response from OGD.

For a long time there was no guidance (informal or formal) on how to submit controlled correspondence to FDA – or even what controlled correspondence encompassed.  Eventually, FDA posted some recommendations on the Agency’s website.  And then GDUFA came along . . . .

Early on in GDUFA negotiations it was suggested that timeframes be established for  controlled correspondence between FDA and industry to support application review targets.  Those suggestions were ultimately captured in the GDUFA review and performance goals letter where controlled correspondence was described (below) and where FDA agreed to response metrics.  The following is from the review and performance goals letter:

Controlled correspondence – FDA’s Office of Generic Drugs provides assistance to pharmaceutical firms and related industry regarding a variety of questions posed as “controlled documents.” . . . Controlled correspondence does not include citizen petitions, petitions for reconsideration or requests for stay.

Controlled Correspondence Metrics

• Controlled Correspondence
• FDA will respond to 70 percent of controlled correspondence in 4 months from date of submission in FY 2015.
• FDA will respond to 70 percent of controlled correspondence in 2 months from date of submission in FY 2016.
• FDA will respond 90 percent of controlled correspondence in 2 months from date of submission in FY 2017.
• If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.
• In the case of controlled correspondence which raises an issue or question that is the same as or related to the issue or question that is the subject of one or more pending citizen petitions, or petitions for stay or reconsideration, the above goals will apply from the date FDA issues responses to the pending petitions.

FDA’s draft controlled correspondence guidance, which is announced in an August 27, 2014 Federal Register notice and is the topic of a pre-recorded webinar, puts some meat on the bones of the review and performance goals letter.  We knew the draft guidance would be issued soon.  After all, FDA identified the guidance as a topic for discussion at a public hearing on GDUFA implementation scheduled for September 17, 2014 (see our previous post here). 

The draft controlled correspondence guidance provides, for the first time, a definition of “controlled correspondence” (at least for the purposes of GDUFA): “A correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development.”  It also limits controlled correspondence to inquiries and requests from generic drug manufacturers and related industry.  “Inquiries related to generic drugs submitted by other parties (for example, private citizens, financial firms, or public advocacy groups that are not directly involved in developing generic drug products) should be directed to CDER’s Division of Drug Information,” says FDA in the draft guidance.  From there, FDA puts some controls on what types of controlled correspondence are subject to the GDUFA metrics and when responses may be issued.  For example, FDA says that the goal dates for responding to controlled correspondence concerning issues raised in a pending citizen petition (including a petition for reconsideration or a request for stay) depend on when a petition response is issued:

If a controlled correspondence is submitted that raises an issue that is the same as or related to an issue or question that is the subject of one or more pending citizen petitions, petitions for reconsideration, or requests for a stay, the goal dates set forth in the GDUFA Commitment Letter for controlled correspondence will apply from the date FDA issues responses to the pending petitions.  Likewise, if a citizen petition, petition for reconsideration, or request for stay is submitted that raises an issue that is the same as or related to an issue or question in a pending controlled correspondence, the goal date for that controlled correspondence will apply from the date FDA issues a response to the related citizen petition, petition for reconsideration, or stay request.  For example, if a controlled correspondence is submitted in FY 2015 that relates to an issue in a pending petition, and the Agency responds in FY 2016 to that petition, the 4-month goal date for FY 2015, the year in which the controlled correspondence was submitted, will apply to the controlled correspondence from the 2016 date that the petition is answered.

For controlled correspondence related to matters still under consideration by FDA (e.g., requests for specific approval requirements for an ANDA for a complex drug product for which FDA is still considering the scientific standards for approval), parties may get a non-response response that will close the matter.  According to FDA:

For such questions that call for developing a new policy, FDA will respond to the controlled correspondence to notify the requestor that such a policy is under development, but that the Agency cannot provide information at that time because the matter is still under consideration.  The Agency will consider this response to close the controlled correspondence, and it will not provide additional direct communications to an inquirer on the matter.

Although FDA’s draft guidance does provide some specific examples of what inquiries and topics are appropriate for controlled correspondence (e.g., requests related to inactive ingredients, formulation assessments, and labeling standards for certain container/closure systems), along with general guidance that controlled correspondence should involve “inquiries on a specific element of generic drug development, and not general questions related to product planning,” FDA spends quite a bit of time explaining what topics fall outside the scope of controlled correspondence, as well as what controlled correspondence is excepted from GDUFA goals.  “First, the Agency considers any question related to a pending ANDA a review issue,” says FDA. “Such inquiries will not be treated as controlled correspondence and should be submitted only to the ANDA so they can be included as part of the full administrative record for that application.”  “Second, inquiries that are submitted to FDA that are not directly related to generic drug development will not be considered controlled correspondence for the purposes of GDUFA.” Finally, “general, open-ended, or insufficiently detailed questions related to product development are not the appropriate subject of [controlled correspondence].”

Excepted from the GDUFA goals are three types of inquiries that fall within the definition of controlled correspondence, but that FDA has historically treated differently than other inquiries on generic drug development: (1) requests for bioequivalence study recommendations for a specific drug produc; (2) requests for review of bioequivalence clinical protocols; and (3) requests for pre-ANDA meetings to discuss generic drug development.  “FDA will continue to respond to these inquiries consistent with its current practices, and to exclude these inquiries from the goal dates in the GDUFA Commitment Letter,” writes FDA.

Finally, the draft guidance provides detailed information on how generic drug manufacturers or related industry should go about submitting controlled correspondence, the specific components FDA expects to see in controlled correspondence, and what OGD disciplines might review and respond to controlled correspondence. 

The draft guidance is a lot to digest, but it’s also welcomed detail of an information request process that is intended to result in quicker ANDA approval.  Nevertheless, some questions still remain.  For example, how will FDA’s focus on addressing controlled correspondence submitted in Fiscal Years 2015-2017 affect controlled correspondence submitted during the first two years of GDUFA (and before)?  Will those pending requests be put on a backburner? 

By David C. Gibbons –

It is rare that we urge our readers to keep a copy of a court ruling or brief.  A Brief that FDA filed on August 21, 2014 is an exception.  Companies and others should read this brief and keep it close at hand. When someone wants to question FDA’s legal authority to compel a recall, this brief provides the clearest statement of FDA’s limited authority to compel a recall.

We previously described (here and here) the litigation commenced by Hospira, Inc. (“Hospira”) wherein the company filed suit against FDA following the Agency’s approval of generic PRECEDEX (see FDA Dear Dexmedetomidine Hydrochloride Injection NDA Holder/ANDA Applicant Letter (Aug. 18, 2014) (hereinafter “FDA Letter Decision”)).  In summary, Hospira sought, and was granted, a Temporary Restraining Order (“TRO”) that included a stay of FDA’s Letter Decision, rescission of any ANDA approvals predicated upon that Letter Decision, an order that FDA recall any product sold or distributed under such an ANDA approval, and an injunction prohibiting FDA from granting any further or additional approvals predicated upon the Letter Decision.  The court order directing FDA to recall a drug product based on a Hatch-Waxman dispute was unprecedented.

Generally speaking, FDA cannot compel a mandatory recall, except in very limited circumstances as authorized by statute, none of which apply to drugs (see here at § 7-5-3).  FDA can order a recall when the Agency:

• finds there exists a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death (21 U.S.C. § 360h(e)(1)); 
• determines that a batch, lot, or other quantity of a biological product presents an imminent or substantial hazard to the public health (42 U.S.C. § 262(d)(1)); 
• determines that an adulterated or misbranded infant formula presents a risk to human health (21 U.S.C. § 350a(e); see also 21 C.F.R. § 107.200);
• finds there is a reasonable probability that a tobacco product contains a manufacturing or other defect not ordinarily contained in tobacco products on the market that would cause serious, adverse health consequences or death (21 U.S.C. § 387h(c)(1)); or
• determines there is a reasonable probability that an article of food (other than infant formula) is adulterated or misbranded and the use of or exposure to such article will cause serious adverse health consequences or death to humans or animals (21 U.S.C. § 350l(a));

Finally, FDA has the discretion to compel a mandatory recall when it finds that a human cell, tissue, or cellular and tissue-based product is a source of dangerous infection to humans, or does not provide adequate protections against the risks of communicable disease transmission.

Recalls, in situations other than those described above, are voluntary actions by a company expected to conform to FDA policy set forth in its regulations. 

Thus, as we circle back to the Hospira litigation, we arrive at a threshold question: can a court order FDA to order a recall?  The answer from the Defendant-Intervenors as well as FDA in this case is no.  FDA states clearly and succinctly in its Brief: “FDA cannot order recalls.”  The Agency goes on to argue that the recall ordered in the Hospira TRO could not even be requested by FDA because the basis for the recall was a patent dispute and not a matter of product safety or efficacy.  FDA says: “consumers should believe that recalled products present a risk to health or are grossly deceptive. That is decidedly not the case here.”  The Agency admitted that “[i]f a company chooses not to comply with an FDA request to recall, FDA has no mechanism to enforce its request because it does not have statutory authority to order drug recalls.” FDA also argued that the court-ordered recall was not in the public interest because the recall “threaten[ed] to disrupt the consistent regulatory standards for recalls.” Finally, the Agency makes the argument that a recall based, such as this, on a patent issue and not on a product safety or efficacy issue will undermine the perception of future recalls.  To this point, FDA says: “When other future products are recalled, consumers may question whether the recall is related to a legitimate public health concern, or whether it is merely another patent dispute in which safety or efficacy is not at issue. The public interest weighs strongly against” ordering a recall.

The district court held a hearing on August 26, 2014 to decide on a Motion for Reconsideration of the TRO entered on August 19th.  In the end, the court granted the Motion for Reconsideration in part and vacated that part of the TRO that ordered FDA to compel a recall of generic PRECEDEX.

By Riëtte van Laack –

As previously discussed, since at least 2006, the U.S. honey bee industry has been trying to get FDA to adopt a standard of identity for honey.   In 2006, the American Beekeeping Federation and honey industry groups petitioned FDA for a standard (Docket No. FDA-2006-P-0207).  More than five years later, in 2011 and despite continued prodding by different parties, FDA denied this petition.  FDA concluded that no standard of identity was needed.  As evidenced by the draft guidance issued in April 2014, FDA has maintained its position.  In this 2014 draft guidance, the Agency repeated its position that honey is “a thick, sweet, syrupy substance that bees make as food from the nectar of flowers and store in honeycombs.” According to FDA, this definition accurately reflects the common usage of the term honey. 

In the absence of a federal standard of identity, a number of states (including Wisconsin and Florida) have adopted, or proposed to adopt, their own state standards of identity or a definition for honey.  According to comments to the draft guidance, no two state standards or definitions are identical.  Apparently concerned about the potential effect of these state standards and definitions, and FDA’s continued refusal to adopt a federal standard, Congress, in the 2014 Farm Bill, tasked USDA’s Agricultural Marketing Service (“AMS”) with the preparation of a report on the need for a standard of identity for honey (Section 10012 of Public Law No. 113-79).  In its report, AMS is to address whether a federal standard of identity for honey would be in the interest of consumers, the U.S. honey industry, and U.S. agriculture.

As directed by the 2014 Farm Bill, AMS issued a notice seeking comments on the 2006 petition.  Specifically, AMS seeks comments regarding the adoption of deviations from the Codex Standard for Honey, CODEX standard 12–1981, Rev. 2 (2001), as defined in the petitioner’s request and on how a federal standard of identity for honey would benefit consumers, the honey industry, and U.S. agriculture.

At best, the AMS report might persuade FDA to reconsider its position.  Ultimately, it remains for FDA to decide on the adoption of a standard.  Comments are due Sept. 19, 2014.

By Karla L. Palmer –

The U.S. Drug Enforcement Administration (“DEA”) published last Friday a Final Rule rescheduling hydrocodone combination products (“HCPs”) from Schedule III to Schedule II.  We posted about the proposed rescheduling here (NPRM published February 27, 2014).  There was little doubt that DEA would up-schedule HCP’s, especially in light of HHS’s recommendation to do so.  It is disappointing, however, that DEA did not heed the request of industry and provide for more time for the implementation of the heightened security and other requirements.  

The Final Rule comes on the heels of more than a decade of review of the rescheduling issue for HCPs by both the Department of Health and Human Services (“HHS”) and DEA.  Back in 2004, in response to a petition, DEA first submitted a request to HHS for a scientific and medical evaluation, and scheduling recommendation for HCPs pursuant to 21 U.S.C. § 811(b).  In 2008, HHS recommended that HCPs remain controlled in schedule III of the CSA.  In 2009, DEA requested HHS re-evaluate their data and provide another scientific and medical evaluation and scheduling recommendation based on additional data and analysis. 

The 2012 FDA Safety and Innovation Act (“FDASIA”) (summarized here) included a provision requiring review, including public meetings, on rescheduling of HCPs. That statutorily mandated review included the creation of an FDA advisory committee (Drug Safety and Risk Management Advisory Committee), which after two days of public meetings in 2013, and review of 768 comments submitted by patients, patient groups, advocacy groups, and professional societies, voted in favor of rescheduling.  After review of scientific and medical evidence, and other considerations mandated by FDASIA, HHS completed its required eight-factor analysis under 21 C.F.R. § 811(b) and recommended in late 2013 that HCPs be placed in Schedule II.  DEA published its notice of proposed rulemaking in late February 2014.

DEA received 573 comments on the proposed rule; it reports that 52% (or 298 comments) supported (or supported with qualification) rescheduling, and 41% (235 comments) opposed rescheduling (many opposition comments were from pharmacists).  Seven percent of the comments did not take a definitive position.  The lengthy preamble addresses comments received, and the 45-day period for implementation of necessary changes by registrants as a result of the up-scheduling.  Although DEA received comments seeking a longer implementation window, those comments did not deter DEA from sticking with what is perceived by many to be a woefully short transition period.  Specifically, in order to prevent “continued misuse, abuse and diversion,” DEA deems it “necessary to set an effective date for this scheduling action, including security and labeling requirements, with all reasonable haste.  After careful consideration of the risk to the U.S. public health and safety related to the diversion and abuse of HCPs, the DEA believes the 45-day effective date is reasonable.”  Final Rule at 61.  DEA also stated that it may not refuse to reschedule a drug or other substance based on alleged “economic impacts” of the rescheduling.  Furthermore, as to retail pharmacies, DEA noted that they are “not required by the CSA or DEA regulations to place schedule II controlled substances in a vault or safe.”  Specifically, in accordance with 21 CFR § 1301.75(b), pharmacies “may disperse schedule II controlled substances throughout their stock of noncontrolled substances in such a manner as to obstruct the theft or diversion of the controlled substances.”

DEA clarified that the Final Rule affects hydrocodone combination products, which are those substances described in 21 C.F.R. § 1308.13(e)(1)(iii) and (iv).  DEA noted that all other products containing hydrocodone are already controlled under Schedule II.  It specifically pointed out that Zohydro™ ER does not meet the cited definition; it is currently controlled under 21 C.F.R. § 1308.12(b)(1)(vi).  However, excluding Zohydro™, all “pharmaceuticals containing hydrocodone currently on the market in the United States are HCPs and are subject to this rulemaking,” including cough suppressants containing HCPs.   DEA noted that HCPs are the “most frequently prescribed opioid in the United States with nearly 137 million prescriptions” for HCPs dispensed in 2013.  Final Rule at 13.  

As we previously posted, rescheduling HCPs from Schedule III to Schedule II affects the entire drug supply chain – every handler of controlled substances.  (The effects of rescheduling are included in that post).  Rescheduling imposes significantly more stringent regulatory requirements on manufacturers, distributors, pharmacies, physicians, importers and exporters. 

The preamble addresses a multitude of issues raised by the rescheduling, including but not limited to the following:

1.   Authority to Prescribe HCPs as Schedule IIs

Commenters were concerned that prescribing authority differed in states, and now mid-level practitioners and others with no CII prescribing authority in certain states would not be able to prescribe HCPs.  DEA responded that it is outside its authority to decide who has prescribing authority within any particular state.

2.  Transmission Methods of HCP Prescriptions as Schedule IIs

Commenters were concerned about the inability for prescribers to transmit oral and faxed prescriptions for Schedule II HCPs. DEA responded that rescheduling does not hinder legitimate access to HCPs, and that contrary to the concerns of commenters, in the event of an emergency situation as defined in DEA regulations, a practitioner would be able to prescribe, and a pharmacy would be able to dispense, HCPs in accordance with 21 C.F.R. § 1306.11(d).  It noted however, in particular, that a practitioner may not delegate to a nurse, pharmacist, or anyone else, authority to make a medical determination whether to prescribe a particular controlled substances.  Final Rule at 49.  

3.  Quantity and Frequency of Refills

DEA noted that many commenters expressed concern about the limitation on refills on CII prescriptions, that this would required more frequent physician visits, and cause doctors to prescribe large quantities of HCPs per prescription.  DEA responded that, while courts have recognized that prescribing “inordinate” amounts of controlled medications may be a violation of the CSA, neither DEA nor the CSA generally imposes a quantitative minimum or maximum on the amount of medication.  Nevertheless, DEA recognizes that limitations on quantities by states or benefit providers exist, and that registrants must comply with such limitations.  Although the CSA prevents refills of CII prescriptions, DEA stated that practitioners may issue multiple prescriptions covering up to a 90-day period, and that DEA regulations do not require patients to be seen on a monthly basis.  DEA’s regulations, however, should not be construed “as mandating or encouraging” individual practitioners to issue multiple prescriptions or see their physicians only once every 90 days. 

4.   Patient Access

DEA received many comments voicing concerns related to access to HCPs, including fear of criminal prosecution, and impact on availability.  DEA stated that rescheduling should not hinder access to legitimate use of the medication, and that increased criminal sanctions for wrongful use, or use of the CSOS or Form 222 ordering process, should not result in limited availability.   DEA noted it takes approximately 1 hour to complete an order using a Form 222, and approximately 3 minutes to complete an order for CIIs using CSOS.

5.   Impact on Long-Term Care Facilities (“LTCFs”)

Although several comments addressed the detrimental effect that rescheduling will have on access to HCPs for patients in LTCFs, DEA responded that regulations already in place, such as permitting transmission of a prescription through the practitioner’s agent under 21 C.F.R. § 1306.11(f), and permission for partial fills under section 1306.13(b) already accommodate the unique needs of LTCFs.  DEA denied any request for a LTCF exemption based on lack of likelihood of diversion in LTCF settings, instead citing data demonstrating high incidents of diversion and abuse in such settings. 

6.   Impact on Manufacturers and Distributors
 
The most notable issue for the Final Rule for manufacturers and distributors is likely the 45-day implementation window for various HCP security and handling requirements.  For example, manufacturers and distributors must secure schedule II substances in a safe, steel cabinet or vault while schedule III substances may be stored in a less secure controlled substance cage or other enclosure.   DEA stated that, in accordance with the Administrative Procedure Act, most scheduling actions have a 30-day implementation period.  Final Rule at 55.  DEA deems the 45-day period to be a reasonable amount of time for registrants to comply with the requirements, and “was established upon a full consideration of the totality of the circumstances specific to HCPs” — discussed at pages 55- 62 of the Final Rule.

7.   Distribution of C-III Labeled HCPs Post Implementation of the Final Rule

DEA states that manufacturers are required to print on the labeling of each “commercial container of HCPs they distribute the designation of HCPs as “C-II”.  Final Rule at 63.  Furthermore, “it shall be unlawful for commercial containers of HCPs to be distributed without bearing the label properly identifying them ….as C-IIs,” and all labels must comply with the labeling requirements “on or before the effective date established in the final order for the transfer or addition.”  Thus, DEA is specifically requiring that commercial containers of HCPs distributed 45 days from date of publication be labeled as “C-II” and be packaged in accordance with 21C.F.R. part 1302. 

Further, DEA states that a “distribution” after the effective date of the Final Rule requires the use of a DEA Form 222 to transfer the substance.  A registrant may transfer upstream commercial containers of HCPs labeled as “C-III”, with utilization of a Form 222 in accordance with 21 C.F.R. § 1305.03.  DEA notes that, as discussed in the Economic Impact section of the Rule, manufacturers and distributors can make “minor adjustments” during the implementation period to meet the effective date requirement.  And, distributors have the option of returning stock labeled “C-III” to the manufacturer.  DEA declined to exempt manufacturers and distributors from physical security requirements for C-IIs given, among other things, their high potential for diversion and abuse, and recommends that registrants work closely with local DEA offices regarding submission of materials necessary for compliance with DEA security requirements.  Final Rule at 65.

DEA also clarified that regulations pertaining to labeling of commercial containers applies to distributions by distributors and manufacturers.  The DEA does “not regulate the labeling and packaging of commercial containers of controlled substances downstream of distributors.”  Final Rule at 64. 

Despite the fact that HCPs have been prescribed and handled as Schedule III drugs for decades, are the most prescribed narcotic in the United States, and there are significant differences in the regulatory requirements between Schedule II and Schedule III drugs, DEA’s unwillingness to provide more than a 45-day compliance window is both surprising, and disappointing, especially because fighting the prescription drug abuse problem requires a cooperative effort between the medical community, industry and the government.

We understand that this blogpost is just a short synopsis of the entire publication of the Final Rule.  We will publish additional posts in the coming days and weeks to address specific issues that arise as the registrants grapple with the effects – and the tight implementation timeframe – of DEA’s rescheduling decision. 

By Alan M. Kirschenbaum –

Beginning with CY 2011, Section 9008 of the Patient Protection and Affordable Care Act (“ACA”) has imposed an annual fee on manufacturers and importers of “branded prescription drugs.”  The global 2014 fee for all manufacturers and importers is $3 billion, to be shared by covered manufacturers and importers in proportion to their relative sales of branded prescription drugs to government purchasers and payors.  You’ll find a summary of this provision of the ACA here.

On July 28, the IRS issued a final regulation to implement the Section 9008 industry fee.  The definition of “branded prescription drugs,” on which the fee is imposed, is straightforward and tracks the statute:  the term means a prescription drug approved under an NDA, or a prescription biological approved under a BLA.  See 26 C.F.R. § 51.2(c).  Accordingly, generic drugs approved under ANDAs are not subject to the fee.

However, interestingly, the IRS acknowledges in the preamble that certain generic drugs were approved under NDAs prior to the enactment of the Drug Price Competition and Patent Restoration Act of 1984 (Hatch-Waxman Amendments), when the ANDA provisions were added to the statute.  IRS is referring to FDA’s “Paper NDA” policy, described in a July 31, 1978 FDA staff memorandum (and eventually published in the Federal Register at 46 Fed. Reg. 27,396 (May 19, 1981)), under which FDA allowed approval of duplicate versions of brand name drugs that were approved after 1962.  Under this policy, a manufacturer could submit, among other things, published reports of studies as the main supporting documentation of safety and effectiveness.  In other words, Paper NDAs were the functional equivalent of ANDAs before the ANDA provisions were added to the Federal Food, Drug, and Cosmetic Act.  FDA revoked the “paper NDA” policy in 1989 when the Agency proposed regulations implementing the Hatch-Waxman Amendments (54 Fed. Reg. at 28, 890 (July 10, 1989)). 

The IRS is requesting comments on “whether a special rule is appropriate regarding the treatment of generic drugs for which applications were submitted under [NDAs] prior to the 1984 [Hatch-Waxman Amendments],” including comments on how to distinguish such generic products from other drugs approved under pre-1984 NDAs.  The preamble explains that any special rule would be prospective only.  Therefore, at least for 2014, drugs approved under pre-1984 Paper NDAs will be included in the industry fee.

Manufacturers marketing drugs that were approved under pre-Hatch-Waxman Paper NDAs should consider submitting comments advocating a special rule to exclude these drugs from the definition of “branded prescription drug.”  Although the preamble does not specify a deadline for comments, we have been informed by the IRS that comments must be received within 120 days after publication in the Federal Register – i.e., by November 25, 2014.

The Food and Drug Law Institute is sponsoring a conference titled "Food Safety: Latest FSMA Developments & Enforcement Actions in a Changing Business Climate," scheduled for September 9.  The conference will feature a regulatory update by Michael Landa (Director of FDA/CFSAN), an exploration of the seven proposed rules that have been issued to implement FSMA, a case study on recalls that includes Roberta Wagner (Deputy Director for Regulatory Affairs at CFSAN), and a discussion of FDA’s enhanced enforcement authorities that includes Jeffrey Steger (Assistant Director of the Consumer Protection Branch in DOJ’s Civil Division).  To close out the conference, HP&M’s Ricardo Carvajal will moderate a session on the business aspects of food safety.  More information on the agenda and registration is available here.

By Kurt R. Karst –    

The pace of litigation concerning FDA’s approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials, has been anything but sedate.  On the morning of August 18, 2014, there was no sign of the controversy that would erupt later that day after FDA issued its long-awaited Letter Decision addressing issues raised in the Agency’s January 15, 2014 “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic PRECEDEX. 

As we reported earlier this week, FDA ruled that ANDA sponsors could omit (i.e., carve out) from their generic drug labeling information protected by U.S. Patent No. 6,716,867 (“the ‘867 patent”).  The ‘867 patent is currently listed in the Orange Book for PRECEDEX with a “U-1472” patent use code defined as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”  (The ‘867 patent was previously listed in the Orange Book with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”)  

Hospira – and ANDA sponsor Sandoz, Inc. (“Sandoz”), which is eligible for a period of 180-day exclusivity based on a Paragraph IV certification to the ‘867 patent – contended that FDA was prohibited from omitting any labeling information related to the ‘867 patent, because the patent, as reflected by the U-1472 patent use code narrative, covers both approved uses for PRECEDEX – i.e., (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures – thereby leaving ANDA sponsors with carved-out labeling without an approved use.  Specifically, Hospira, citing the U.S. Supreme Court’s decision in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)), where the Court noted in dicta that “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code,” argued in comments to FDA that because the patent use code for the ‘867 patent fully covers the first indication and may overlap with the second indication, an ANDA sponsor whose application contains a “section viii” statement to omit patent-protected information must carve out both the first and the second indications in their entirety, thereby precluding approval of any ANDAs with carved out labeling.  FDA, however, concluded otherwise:

Both the original and the revised use codes are limited to “intensive care unit sedation.”  Although the revised use code includes additional language specifying some of the types of patients that Hospira claims are encompassed within the “intensive care unit sedation” use, i.e., non-intubated ICU patients prior to and/or during surgical and other procedures, it does not broaden the claimed method of use beyond “intensive care unit sedation.” . . .  Nor does the clarified use code and its explicit inclusion of a subset of patients that may undergo procedural sedation somehow expand the patented use to encompass and prevent approval for all patients who seek to use the drug for the separately delineated procedural sedation indication. . . .  FDA previously has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.  The procedural indication and related information in the labeling do not impermissibly disclose the use of Precedex for procedures in the ICU (i.e., for the use covered by the use code).  ANDAs therefore may be approved for the second indication, consistent with how FDA has implemented use codes and allowed carve outs in other circumstances.

FDA also approved two ANDAs: (1) ANDA No. 202881 from Mylan Institutional LLC (“Mylan”), which began selling drug product; and (2) ANDA No. 203972 from Par Sterile Products.

In the wee hours of August 19, 2014, Hospira took action against FDA.  The company filed a Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction in the U.S. District Court for the District of Maryland seeking from the court a stay of FDA’s Letter Decision, rescission of any ANDA approvals predicated upon that Letter Decision, an order FDA to recall any product sold or distributed under such an ANDA approval, and an injunction prohibiting FDA from granting any further or additional approvals predicated upon the Letter Decision.  According to Hospira, FDA’s Letter Decision that led to the ANDA approvals violates Section 505(j)(2)(A)(viii) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) concerning ANDA labeling carv-outs, as well as the rulemaking requirements of the Administrative Procedure Act (“APA”):

Instead of complying with statutory and regulatory requirements, FDA adopted an unauthorized procedure (the opening of Docket No. FDA-2014-N-0087) and then relied upon that unauthorized procedure to make a decision which is contrary to law.  Absent injunctive relief, FDA’s unauthorized approach will allow generic versions of Precedex on the market without those generics’ first establishing, as the law requires, that they do not infringe Hospira’s rights under its method-of-use patent, and FDA will have applied a “rule” within the meaning of the [APA] which rule FDA adopted without complying with any of the rulemaking requirements of the Act. . . .

Here, in the face of demonstrable and FDA admitted overlap between the indications included in the generic’s labeling and Hospira’s patent use code, FDA has acted unlawfully in issuing a decision which allows approval of generic versions of Precedex.

In addition, FDA has not adopted a regulation, pursuant to the notice and comment rulemaking requirements of the APA, to modify its prior rule and authorize the agency to approve a generic version in an “overlap case” such as this (assuming, without conceding, that FDA would have statutory authority to adopt such a rule).  In its review and approval of applications for generic versions of Precedex, FDA has unlawfully applied a new substantive rule without FDA’s complying with the rulemaking requirements of the APA.  Because FDA’s past or imminent approvals of generic versions of Precedex rests entirely on this unauthorized, unlawfully adopted new rule, any resulting generic drug approval decisions are invalid.

The Maryland District Court (Judge George Jarros Hazel) scheduled an emergency hearing on Hospira’s Motion for Temporary Restraining Order for Tuesday, August 19, 2014 at 3PM.  Both Mylan and Sandoz entered the case as intervenors, and Sandoz filed a brief in support of Hospira’s Motion for Temporary Restraining Order and/or Preliminary Injunction saying, among other things that FDA’s Letter Decision and ANDA approvals deprives Sandoz of 180-day exclusivity. 

Then came Judge Hazel’s late-night Memorandum Opinion and Order on August 19th.  In granting Hospira’s Motion for Temporary Restraining Order, Judge Hazel ruled that Hospira demonstrated that it is likely to succeed on the merits regarding its contention that FDA violated FDC Act § 505(j)(2)(A)(viii), and with respect to Hospira’s APA claim:

Here, the first indication for Precedex is entirely covered by Plaintiff’s use-code.  As to the second indication, there is, at the very least, some overlap.  Because its use-code statement asserts that its method-of-use patent overlaps with all approved indications, Plaintiff further contends the FDA must reject any ANDA application based upon a section viii statement.  FDA, on the other hand, contends that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling. Notably, however, Plaintiff’s interpretation has been endorsed by the United States Supreme Court in its recent decision of [Caraco], in which the Court stated (albeit as dicta) that “the FDA will not approve such an ANDA if the generic’s proposed carve-out label overlaps at all with the brand’s use code.”  At this juncture, the Court therefore finds that FDA’s decision was at odds with relevant authority.

Furthermore, to now permit FDA to approve generic versions of Precedex on the basis that it can approve ANDAs for broad, general indications that overlap with a protected method of use would be tantamount to a change of the rules.  Such a change would require FDA to employ the formal rulemaking procedures of the [APA], which it indisputably did not do.  Moreover, even if the Court were to assume for argument’s sake that the governing statute is ambiguous under Chevron U.S.A., Inc. v. Nat. Res. Def. Council, 467 U.S.837 (1984), given the prior understanding of the law by the Supreme Court, the Court cannot find, at this current juncture, FDA’s interpretation to be reasonable.

But Judge Hazel did not stop there.  In his Order, which will continue in full force and effect until September 2, 2014, Judge Hazel not only stayed FDA’s Letter Decision and any future FDA actions under it, as well rescinding ab initio any FDA actions already taken pursuant to that Letter Decision, but he took the highly unusual – and perhaps unprecedented – move in a Hatch-Waxman case of ordering FDA to recall any product sold or distributed under the two ANDA’s approved for generic PRECEDEX.  

If it stands, the court’s decision could have significant implications on Hatch-Waxman law.  For some, it could be the long sought-after (and thus far illusive) Northwest Passage route to avoid some generic drug labeling carve-outs.  Companies may seek to clarify Orange Book method-of-use patent listings – and may petition FDA regarding the same – in efforts to prevent generic drug labeling omissions and to force Paragraph IV patent certification submissions. 

UPDATES:

• On August 20, 2014, the Court issued a paperless Order denying Mylan's Motion to File Response to TRO by 5 pm August 20 2014.  According to the Court, “Mylan and Sandoz have each been permitted to intervene in this matter and the Court gave consideration to their arguments at the motion hearing on the TRO. The Court did not request post-hearing briefing and did not consider the brief filed by Intervenor Sandoz prior to issuing its ruling. Both Mylan and Sandoz will be permitted to submit memoranda pursuant to the scheduling order to be set during today's scheduling call for future motions.”
• On August 20, 2014, Mylan filed a Motion to Stay Paragraph 3 (product recall) & Paragraph 4 (rescission of actions made pursuant to FDA's Letter Decision) of the Court's August 19th Order. 
• On August 20, 2014, the Court issued a paperless Order granting Mylan's Motion to Stay.  According to the Court, “Paragraphs 3 and 4 of the Court's August 19, 2014 [Order] are stayed pending Defendant Mylan's Motion for Reconsideration.”
• Par Sterile Products joins the party after the Court grants the company's Motion to Intervene.
• On August 22, 2014, the Court issued a paperless Notice of Hearing on Mylan's Motion to Reconsider for Tuesday, August 26, 2014 at 9:30 am.
• On August 26, 2014, the Court granted in part and denied in part Mylan's Motion for Reconsideration.  Paragraphs 3 and 4 of the August 19th TRO Order are vacated, and Paragraphs 1 and 2 are amended. 
• On August 29, 2014, Motions for Summary Judgment were filed by FDA (here), Hospira (here), Sandoz, (here), Mylan (here), and Par (here).

By Jennifer D. Newberger –

On August 14, 2014, FDA issued a draft guidance titled, “De Novo Classification Process (Evaluation of Automatic Class III Designation)” (draft guidance). 

The de novo review process, formally known as Evaluation of Automatic Class III Designation, is established by section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act (FDC Act), as amended.  This process was added to the FDC Act by the Food and Drug Administration Modernization Act of 1997 (FDAMA) to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill suited to the PMA process. 

Under FDAMA, before a device could utilize the de novo process, a device first had to be found not substantially equivalent (NSE) to a predicate device through the 510(k) process, even if the submitter and FDA agreed no appropriate predicate existed.  Due to the burdensome, time consuming nature of the de novo process, it was under utilized.

In September 2011, FDA issued a draft guidance document attempting to streamline the de novo process.  We discussed this draft guidance here.  Under that draft guidance, a person could submit a 510(k) and de novo petition simultaneously, and FDA could begin review of the de novo petition immediately upon issuance of the NSE letter. 

In July 2012, Congress amended section 513(f)(2) through passage of the Food and Drug Administration Safety and Innovation Act (FDASIA).  Under section 607 of FDASIA, a finding of NSE is not required before submitting a de novo petition.  Instead, if a person believes the device is low to moderate risk but no appropriate predicate exists, the person may submit a de novo without previously submitting a 510(k).  With the passage of FDASIA, the draft guidance issued in September 2011 was essentially mooted. 

The latest draft guidance describes the process of submitting a de novo petition under FDASIA, focusing primarily on the information to include in a de novo petition or a request for a Pre-Submission meeting prior to submitting a de novo request.  The information to include in a de novo petition includes the following: 

• a recommendation whether the device should be regulated as Class I or Class II;
• whether the device should be subject to 510(k) requirements;
• if a Class II device subject to 510(k), the petition should include a proposed special controls document, describing the intended use, risks, and risk mitigation strategy for the device;
• supporting protocols and data;
• a summary of benefits and known and potential risks; and 
• risk and mitigation information. 

In addition, the submission must include a “classification summary” demonstrating that the submitter has thoroughly researched legally marketed devices and concluded that no appropriate predicate exists.  To demonstrate that the submitter conducted such a search, the de novo submission should include:

• a description of the databases searched and terms used to establish no predicate exists; 
• regulations, PMAs, and/or product codes that may relate to or are potentially similar to the subject device; and 
• a rationale for why the subject device does not fit within or is different from the identified regulations, PMAs, and/or product codes. 

The draft guidance states that if a submission fails to include this information, it will be put on hold.

While it seems appropriate for a submitter to demonstrate that it has conducted a reasonable search and concluded that no appropriate predicate exists, there is a potential for overly burdensome implementation of these search requirements by FDA.  If FDA places a de novo submission on hold after concluding that insufficient information has been provided, FDA should help guide the submitter in searching for or identifying information FDA believes may be relevant.

The de novo process has long been in need of remediation.  FDASIA provided the basis for that remediation, and the guidance should help industry take advantage of this process.  Hopefully this more streamlined process will allow innovative, moderate risk devices to more easily enter the marketplace.

By Kurt R. Karst –       

We were beginning to wonder whether FDA would ever issue a letter decision addressing the novel issues raised in the Agency’s January 15, 2014 “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials.  The days turned into weeks, and the weeks into months.  But earlier today, FDA finally issued the highly anticipated decision. [UPDATE – Subsequent to posting we learned of a lawsuit filed early on August 19, 2014 challenging the FDA Letter Descision.  Links to the papers in that case are provided below.]  And the decision was probably surprising to many.  Instead of addressing head-on the novel generic drug labeling “carve-in” and patent use code issues FDA initially raised in the Agency’s “Dear NDA/ANDA Applicant” letter – and that were the subject of numerous comments – FDA instead ruled that generic dexmedetomidine is a straight-on labeling carve-out case, similar to that faced by the Agency when it initially considered approving generic versions of PRANDIN (repaglinide) Tablets (prior to the change in patent use code issue that was ultimately ruled on by the U.S. Supreme Court in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)).  That treatment of the case is immediately apparent in the second paragraph of FDA’s August 18, 2014 Letter Decision:

Today’s letter reflects FDA’s determinations with respect to permissibility of labeling carve outs for ANDAs referencing Precedex.  For the reasons set forth below, FDA concludes that regardless of whether the original use code or the revised use code applies, the agency can approve an ANDA that submits a “section viii” statement and omits labeling that discloses the protected use (as identified by Hospira).  FDA further concludes that such omissions do not render the drug less safe or effective for the remaining non-protected conditions of use.

For much of the backgound on this case, we refer you to our previous post; however, here are a few key facts to keep in mind:

• PRECEDEX is currently approved in three strengths and for two indications: (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting; and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures. 
• FDA’s Orange Book currently lists one unexpired patent for the 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials strength at issue: U.S. Patent No. 6,716,867 (“the ‘867 patent”), which expires on March 31, 2019, but is subject to a period of pediatric exclusivity that expires on October 1, 2019. 
• The ‘867 patent is listed in the Orange Book as a method-of-use patent with a “U-1472” patent use code, which is defined in an Orange Book addendum as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”
• The ‘867 patent was previously listed with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”

The general question FDA initially had to address was whether FDA could, in light of the the original and clarified patent use code narratives, approve an ANDA for a generic version of PRECEDEX containing a “section viii” statement to omit information protected by the ‘867 patent, or whether the omission of such information would preclude a carve-out and ANDA approval.  Or, as FDA explains it in the Agency’s Letter Decision:

Hospira asserts that both its original and its revised use code overlap not only with the first indication for Precedex but also with the second indication for that drug because there is a subset of non-intubated patients that may receive Precedex for procedural sedation (the second indication) in the ICU setting.  Hospira argues that because its use code(s) for the ‘867 patent fully cover the first indication and may overlap with the second indication, an applicant with a section viii statement to the ‘867 patent must carve out both the first and the second indications in their entirety, thereby precluding approval of any ANDAs with carved out labeling.

Among other things, Hospira cited the Caraco decision in which the Court stated: “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code.”

After affirming FDA’s authority to determine permissible labeling carve-outs, the Agency, pointing to precedent labeling carve-out decisions involving generic repaglinide (Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411), tramadol HCl (FDA Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003), and oxandrolone (Docket No. FDA-2005-P-0368) rejected Hospira’s arguments.  According to FDA:

Both the original and the revised use codes are limited to “intensive care unit sedation.”  Although the revised use code includes additional language specifying some of the types of patients that Hospira claims are encompassed within the “intensive care unit sedation” use, i.e., non-intubated ICU patients prior to and/or during surgical and other procedures, it does not broaden the claimed method of use beyond “intensive care unit sedation.” . . .  Nor does the clarified use code and its explicit inclusion of a subset of patients that may undergo procedural sedation somehow expand the patented use to encompass and prevent approval for all patients who seek to use the drug for the separately delineated procedural sedation indication. . . .  FDA previously has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.  The procedural indication and related information in the labeling do not impermissibly disclose the use of Precedex for procedures in the ICU (i.e., for the use covered by the use code).  ANDAs therefore may be approved for the second indication, consistent with how FDA has implemented use codes and allowed carve outs in other circumstances.

And:

Just as FDA concluded that a labeling carve out was proper for repaglinide before Novo broadened its use code to duplicate in its entirety the single approved indication, so, too, here ANDAs for Precedex may carve out the protected information (related to use for ICU sedation), and be approved for procedural sedation despite the fact that use for procedural sedation may at times occur in an intensive care setting.  Use in an intensive care setting is not expressly disclosed in any proposed ANDA labeling.  Hospira’s reliance on a single sentence about a different type of “overlap” at issue in Caraco does not control the outcome here.

From there it was relatively easy for FDA to conclude that “permitting ANDA sponsors to omit information from the labeling related to use for ICU sedation does not render the product less safe or effective for the remaining use of sedation of non-intubated patients prior to and/or during surgical and other procedures,” which is a finding that must be made in labeling carve-out cases pursuant to 21 C.F.R. § 314.127(a)(7).

Whether FDA’s side-stepping of several of the issues the Agency initially raised last January was a deliberate attempt to avoid having to address those thorny issues, or the result of an epiphany that this is, to the Agency at least, a “straight 8 case” is unclear.  Certainly one thing was clear all along: at least one party involved in the dispute would be disappointed with FDA’s result.  Now the question is: how disappointed?

UPDATES:

• Early on August 19, 2014, Hospira filed a Complaint and Motion for Temporary Restraining Order and/or Preliminary Injunction in the U.S. District Court for the District of Maryland to stay FDA's Letter Decision, rescind any ANDA approvals predicated upon that Letter Decision, order FDA to recall any product sold or distributed under such an ANDA approval, and enjoin FDA from granting any further or additional approvals predicated upon the Letter Decision.
• PAPERLESS ORDER (Entered: 08/19/2014)) scheduling an emergency hearing on the Motion for Temporary Restraining Order for Tuesday, August 19, 2014 at 3pm in Courtroom 2C. 
• ORDER directing that the decision of Defendant Food and Drug Administration (FDA), in Docket No. FDA-2014-N-0087 is STAYED; directing that this order is to remain in effect until September 2, 2014.  Temporary Restraining Order Granted.

By Kurt R. Karst –      

The folks in FDA’s Office of Generic Drugs (“OGD”) have been especially busy as of late preparing for the October 1, 2014 implementation of the review and performance metrics agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”).  The Office continues to make personnel changes in preparation for the big event (see here), and has been pumping out policy and guidance documents faster than we can keep up with them.

Earlier this month, OGD issued two important Manual of Policy and Procedures (“MAPPs”) documents for managing the ANDA review queue: (1) MAPP 5200.4, Criteria and Procedures for Managing the Review of Original ANDAs, Amendments and Supplements; and (2) MAPP 5240.3 (Rev. 1), Prioritization of the Review of Original ANDAs, Amendments, and Supplements.  The documents convey OGD’s reworked prioritization schedule for ANDAs in light of GDUFA.  Under the revised policy, ANDAs will be prioritized and considered for expedited review if they meet the specifics of one or more various categories:

1. Submissions containing patent certifications pursuant to 21 CFR 314.94(a)(12), including the following circumstances in which priority review may be granted:
• Potential first generic products for which there are no blocking patents or exclusivities on the reference listed drug may receive expedited review; 
• Submissions that contain a Paragraph IV certification, but become eligible for approval during the review period as a result of no blocking patents or exclusivities (including 180-day exclusivity) and no applicable stays; and 
• Submissions that contain a Paragraph IV certification, that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted, and that are received as substantially complete.
2. Submissions related to drug shortages
3. Submissions that are subject to special review programs such as the President’s Emergency Plan for AIDS Relief
4. Submissions related to public health emergencies
5. Submissions related to certain government purchasing programs
6. Submissions subject to statutory mandates or other legal requirements
7. Supplements for which expedited review is requested under 21 CFR 314.70(b)(4)

OGD has also been – and will continue to be – busy issuing new guidance documents explaining current policies and procedures in the post-GDUFA world of ANDA review and approval.  In a notice that will be published in the Federal Register later this week, OGD announced a public hearing on GDUFA implementation that will be held on September 17, 2014, from 9 AM to 5 PM.  In the notice, FDA is soliciting comment on five guidance documents, some of which have yet to see the light of day:

• ANDA Submissions – Content and Format of ANDAs
• ANDA Submissions – Refuse to Receive for Lack of Proper Justification of Impurity
  Limits
• ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA (see our previous post here) 
• ANDA Submissions – Prior Approval Supplements Under GDUFA (see our previous post here)
• Controlled Correspondence Related to Generic Drug Development 

The notice follows a January 2014 notice (see our previous post here) in which FDA announced the establishment of a public docket (Docket No. FDA-2014-N-0032) to receive input and suggestions on ways to improve the quality of ANDAs (original, amendments, and supplements) submitted to OGD and on how to best communicate those suggestions to the generic drug industry.  Thus far, FDA has received only a handful of comments in response to the solicitation.

In addition to canvassing for comments on OGD GDUFA guidances and future policy priorities, the September public hearing will tackle “GDUFA Implementation Related to Generic Drug Exclusivity” and “GDUFA Implementation and Potential First Generics.”  The second topic relates to the two MAPPs discussed above.  According to FDA:

Subsequent to GDUFA’s enactment, FDA has received numerous individual stakeholder comments on what should qualify as a first generic ANDA for the purposes of expedited review.  These comments reflect a range of options, for example, from a broad definition that would prioritize review of all ANDAs for each strength of a Reference Listed Drug submitted for which there is not already an approved ANDA at the time of submission, to a more narrow definition under which only ANDAs that contain a paragraph IV certification and qualify as a “first applicant” under section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act would be designated as a first generic eligible for expedited review.  In addition, several stakeholders have indicated that depending on the criteria FDA applies, first generic status could or should change over time based on other external factors, for example, withdrawal or rescission of approval of another applicant’s ANDA, or shifts in the patent or exclusivity landscape (for example, an unsuccessful patent challenge).

As such, FDA wants to hear from industry as to what specific criteria should FDA apply to identify an ANDA as a first generic eligible for expedited ANDA review, and whether there are there other topics related to first generics eligible for expedited review that require further consideration.

Moving on to “GDUFA Implementation Related to Generic Drug Exclusivity,” FDA is seeking to get a better handle on the topic that generates the most controversy under Hatch-Waxman and in the generic drug industry: 180-day exclusivity.  The current system FDA follows, under which 180-day exclusivity decisions are typically made at the last possible moment (and that sometimes result in a non-decision decision – e.g., 180-day exclusivity “punts” under the failure-to-obtain-timely-tentative-approval forfieture provision), is not optimal.  It is a drain on industry and FDA resources, and can lead to court fire drills.  So, FDA is considering building a better model, and wants to hear industry input on various questions:

1. Should FDA’s consideration of eligibility for 180-day exclusivity for a specific drug product be a public process, including consideration of whether a first applicant has forfeited its eligibility for exclusivity under section 505(j)(5)(D) of the FD&C Act? If a public process is advisable, would it be so in all instances, or is there a subset of circumstances in which the process should be public?  Also, what administrative mechanisms would best facilitate such a process?
2. Legal challenges to FDA’s decisions on 180-day exclusivity often must be resolved on an expedited basis which can be inconvenient for the parties and the court. What legal or regulatory mechanisms, if any, are available to better facilitate FDA’s determination of and orderly resolution of sponsors’ challenges to 180-day exclusivity determinations?
3. Are there other topics related to 180-day exclusivity on which you would like to comment?
4. Are there topics related to 180-day exclusivity that would benefit from FDA guidance?

Elsewhere, and in the more informal context of FDA’s “From a Clinical Perspective” pubication, the Agency is seeking comment on the five generic drug regulatory science priorities for Fiscal Year  2014: (1) post-market evaluation of generic drugs; (2) equivalence of complex products; (3) equivalence of locally acting products; (4) therapeutic equivalence evaluation and standards; and (5) computational and analytical tools.  Those topics were laid out last year consistent with the GDUFA goals document. 

By Kurt R. Karst –      

For several years now we’ve closely tracked the changes in user fees rates FDA sets each fiscal year under the Prescription Drug User Fee Act (“PDUFA”).  Last year, we added rates set pursuant to the Generic Drug User Fee Amendments of 2012 (“GDUFA”) and the Biosimilar User Fee Act of 2012 (“BsUFA”) (see our previous post here).  This year we’re a little late reporting on the Fiscal Year 2015 (“FY 2015”) rates established by FDA earlier this month . . . but with good cause.  While FDA was busy ascending on some user fee rates and descending on other user fee rates, this blogger was busy doing his own ascending and descending – up to and down from the summit of Mt. Kilimanjaro in Tanzania, Africa.  And while we were at the summit (Uhuru Peak, at 19,341 feet), we staked a claim for Hyman, Phelps & McNamara, P.C.  Here’s proof if you need it:

The FY 2015 PDUFA application user fee rate is set at $2,335,200 for an application requiring “clinical data” (defined here in an FDA guidance document), and one-half of a full application fee ($1,167,600) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  FDA’s Federal Register notice announcing the new rates is available here.  These figures reflect FDA’s estimate of 115.042 fee-paying full application equivalents – an average of the number of full applications that paid fees over the lateset 3 years.  This figure is slightly lower than last year’s estimate of 116.333 fee-paying full application equivalents and explains somewhat the increase in the application fee rate.  Annual establishment and product fees have been set at $569,200 and $110,370, respectively, and are based on estimates of 472 establishments (an increase of 17 compared to FY 2014) and 2,434 products (an increase of 9 compared to FY 2014).    

The FY 2015 PDUFA user fee rates become effective on October 1, 2014 and generally represent a modest change vis-à-vis the FY 2014 user fee rates.  All BsUFA user fees – i.e., the initial and annual biosimilar Biological Product Development (“BPD”) fees, the reactivation fee, and the biosimilar biological product application, establishment, and product fees – are keyed to PDUFA user fees.  The FY 2015 rates have thus been set at $233,520 (initial and annual PBD), $467,040 (reactivation), $2,335,200 (application), $569,200 (establishment), and $110,370 (product).  FDA’s Federal Register notice announcing the new rates is available here. 

The table below shows the changes in PDUFA user fee rates for the latest iteration of the law – PDUFA V.  Hisorical tables for user fee rates changes since the enactment of PDUFA are avilable here. 

GDUFA establishes several types of user fees that together generated $299 million in funding for FDA in FY 2013 (including $50 million from the one-time ANDA backlog fee).  That $299 million base amount is adjusted annually, and in FY 2015 has been set at $312,224,000. (The FY 2014 adjusted base figure was $305,659,000.)  Several of the FY 2015 GDUFA user fee rates FDA announced earlier this month, and which go into effect this October, are peddled back vis-à-vis the FY 2014 user fee rates; however, the Active Pharmaceitical Ingredient (“API”) and Finished Dosage Form (“FDF”) facility fee rates did take a hike up vis-à-vis the FY 2014 user fee rates. 

The original ANDA and PAS fees, which make up 24% of the $312,224,000 (or $74,934,000 rounded to the nearest thousand dollars), are based on a total number of 1,276 fee-paying full application equivalents expected to be received in FY 2015.  Dividing $74,934,000 by the total number of fee-paying full application expedted to be received results in an original ANDA fee of $58,730 and a PAS fee of $29,370 for FY 2015.  The 1,276 fee-paying full application equivalents figure FDA identifies is significantly higher than the 1,148.8 figure used in FY 2014, and therefore, largely explains a drop in the original ANDA and PAS fees.  Interestingly, that figure is an estimate of ANDAs that excludes the massive bolus of applications submitted in June 2014, before FDA’s enhanced ANDA stability requirements went into effect.  That bolus – any any bolus of applications submitted when the GDUFA performance goals go into effect in October 2014 – will be reflected in future user fee figures, and could lead to user fee rate decreases over the following years.

The Drug Master File (“DMF”) fee, which makes up 6% of the $312,224,000 ($18,734,000 rounded to the nearest thousand dollars), is based on an estimate of 701  fee-paying DMFs in FY 2015 – a significant increase over the 583 fee-paying DMFs estimated for FY 2014.  The resulting fee is $26,720 for FY 2015, which is a drop from the $31,460 user fee rate set for FY 2014.

The API and FDF facility fees are based on data submitted by generic drug facilities through the self-identification process.  The FDF facility fee revenue makes up 56% of $312,224,000 ($174,845,000 rounded to the nearest thousand dollars), and the API facility fee makes up 14% of $312,224,000 ($43,711,000 rounded to the nearest thousand dollars).  According to FDA, the total number of FDF facilities identified through self-identification was 681 (271 domestic and 410 foreign), and the total number of API facilities identified through self-identification was 795 (103 domestic and 692 foreign).  These numbers translate into FY 2015 FDF facility fee rates of $247,717 for a domestic facility and $262,717 for a foreign facility, and API facility rates of $41,926 for a domestic facility and $56,926 for a foreign facility.  These are pretty hefty increases compared to the FY 2014 FDF and API facility user fee rates, and are likely explained by the significant decrease in self-identified facilities.  In FY 2014, the number of self-identified facilities used to calculated the facility fee rates was 748 (315 domestic and 433 foreign) FDF facilities, and 903 (128 domestic and 775 foreign) API facilities. 

The table below shows the changes in GDUFA user fee rates for the first iteration of the law.