By Karla L. Palmer –

A very busy House Energy and Commerce’s Subcommittee on Health (chaired by Joe Pitts (R-PA)) held a hearing earlier this week to review six bi-partisan bills intended to benefit veterans, address the prescription drug abuse crisis, secure access to medical care, and improve certain provisions of the Controlled Substances Act.  Several witnesses testified in support of the bills.  A link to the bill summaries, witness list and testimony is available here. Two of the bills should seem familiar and of particular interest to those following DEA matters.

The first, H.R. 4299, titled “Improving Regulatory Transparency for New Medical Therapies Act,” was first introduced in March 2014 (see our previous post here).  The current version would amend 21 U.S.C. § 811(a); specifically, any request by the Secretary of HHS to control a drug or substance not previously scheduled, “shall be commenced not less than 120 days after receipt of written recommendations by the Secretary.”  The bill continues, “the final rule [scheduling the drug] shall be issued not later than 60 days after the date on which both the public comment period has closed and the substance is the subject of an approved new drug application.” Recall that DEA’s delay in scheduling new drugs made headlines (as reported here and here), when Eisai (maker of seizure treatment medication FYCOMPA) sued DEA after a delay in excess of a year in scheduling FYCOMPA.  Eisai later sued FDA over a related issue involving the start of new chemical entity exclusivity (see our previous poet here).  Dr. Nathan Fountain, on behalf of the Epilepsy Foundation of America, yesterday testified that DEA’s scheduling of new molecular entities lacks transparency and timeliness. He noted that the time period between drug approval and scheduling has increased over the years almost five times (from an average of 49.3 days to an average of 237.6 days).  Dr. Fountain urged that passage of the bill would permit innovative treatments to reach the market and provide a clear timeline for availability. 

Seeking to ensure timely manufacturing of study drugs, H.R. 4299 would permit drug manufacturers to more quickly obtain a DEA registration when using controlled substances in only clinical trials.  The DEA would be required – in accordance with to-be-enacted regulations — to grant a manufacturer registration or serve an order to show cause on the applicant not later than 180 days after receipt of an application (and all other information the Attorney General deems necessary to make a determination).  One question remaining is what exactly is “all other information the Attorney General deems necessary to make a determination,” and, whether a claim that DEA has not received such information — whatever that information may be — could significantly delay the circumvent the 180-day deadline. 

The second DEA-related bill addresses the definition of “imminent danger” in the context of immediate suspension orders, and would provide for greater oversight of DEA’s activities.  Note that Immediate Suspension Orders permit DEA to bypass the typical Show Cause process and suspend a DEA registration without notice or a hearing.  H.R. 471, titled “Ensuring Patient Access and Effective Drug Enforcement Act of 2015,” is purportedly based on former H.R. 4079, which passed the House last year.  The new bill is similar to S. 2862 (see our previous post here).

New H.R. 471 would modify the definition of “imminent danger to the public health and safety” to mean that, “in the absence of an immediate suspension order, controlled substances: (1) will continue to be intentionally distributed or dispensed (a) outside the usual course of professional practice or (b) in a manner that poses a present or foreseeable risk of serious adverse health consequences or death; or, (2) will continue to be intentionally diverted outside of legitimate distribution channels. 

S. 2862 differs from from H.R. 471 in at least two material respects: First, it tied imminent danger to dispensing and distribution by a registrant “who knows or should have known through fulfilling the obligations of the registrant under the Act, or has reason to believe that” dispensing is outside the usual course of professional practice….”  In other words, the suspension would be tied to the registrant with knowledge of the wrongful activity.

Second, the new bill does not seem to tie “imminent danger” to a “registrant’s” knowledge.  And, it defines “imminent danger” as those situations when controlled substances will “intentionally be distributed or dispensed …” or will “continue to be intentionally diverted outside legitimate distribution channels.” The bill is unclear about whose “intent” counts for the purpose of the “imminent danger” determination – is it a registrant, a downstream user, an upstream supplier?    

Like proposed legislation introduced last year (see our previous post here), the bill also proposes to amend 21 U.S.C. § 824 to provide a registrant facing revocation or suspension of a DEA registration the opportunity to submit a corrective action plan within 30 days after receipt of an order to show cause.  The new provision would require DEA to review a corrective action plan to determine whether to dissolve, modify or continue with show cause.  The bill states that the corrective action provisions do not apply to immediate suspension orders. 

Lastly, the bill contains reporting requirements concerning the effect of DEA enforcement activities on patient access to controlled substances and diversion.  The report must be prepared in consultation with patient groups, pharmacies, manufactures and other entities throughout the pharmaceutical manufacturing and distribution chain. 

By Jennifer D. Newberger –

The question of what constitutes an accessory has never been well answered.  In a December 1996 guidance document, Medical Device Quality Systems Manual: A Small Entity Compliance Guide, FDA said that accessory devices are devices “packaged, labeled, and distributed separately to a hospital, physician, etc., for health-related purposes.”  Apart from this, no definition of this statutory term was ever provided.   Despite the lack of a definition for accessories, FDA historically classified accessories either by classifying the accessory in the same class as the parent device, or by issuing a separate classification regulation. 

On January 20, 2015, FDA issued a draft guidance document putting forth a definition for accessory, and proposing a new way of classifying accessories.  The draft guidance defines an accessory as a “device that is intended to support, supplement, and/or augment the performance of one or more parent devices.”  This definition is further parsed as follows:

• “A device supports the performance of a parent device by enabling or facilitating that device to perform according to its intended use.”
• “A device supplements the performance of a parent device if it adds a new function or a new way of using the parent device, without changing the intended use of the parent device.”
• “A device augments the performance of a parent device by enabling the device to perform its intended use more safely or effectively.”

These distinctions are likely to be difficult to apply in practice.  To provide more clarity, FDA gave some examples, some of which seem questionable.  For example, FDA states that a rechargeable battery intended to operate when paired with an automated external defibrillator (AED) is an accessory to the AED because it is intended to support the AED by enabling it to defibrillate.  It would not seem that a battery that is required for the operation and function of the parent device would be considered an accessory, but rather part of the parent device itself.

As an example of an accessory that “supplements” the parent, FDA cited a pulse oximeter that allows a multi-parameter monitor to display oxygen saturation but does not change its intended use:  to record and display multiple physiological parameters.  While multi-parameter monitors are cleared to display specific parameters, including oxygen saturation, they are rarely cleared for use with specific devices.  Additionally, a pulse oximeter is a finished device with its own regulatory classification that requires 510(k) clearance.  It is therefore not evident that a pulse oximeter would appropriately be considered an “accessory” to a multi-parameter monitor.  In light of the examples provided, the definition of an accessory would seem to include a larger number of devices than previously believed to be accessories, and could presumably include any device that, for any purpose, is intended to be used with another device.

In addition to questionable examples of accessories, the draft guidance proposes that manufacturers consider submitting de novo classification petitions for device accessories.  The intent behind the proposal may be well-founded:  some accessories may have a lower risk profile than their parent, and therefore may warrant being regulated in a lower class.  The application, however, seems flawed.  First, as noted above with respect to the AED battery, some “accessories” are key to the functionality of the device, and it is debatable whether FDA would clear or approve a submission that did not include a key part of the product. Second, the utility of the de novo process for accessories would be limited because it would apply only to accessories “of a new type.”  Finally, it is not clear in what circumstances use of de novo for an accessory would be appropriate or practical.  FDA proposes this approach in very high-level, theoretical terms, but provides no examples of when de novo classification for an accessory may actually be suitable.

While it is welcome to, at long last, have FDA provide a definition of an accessory, the examples provided do not seem to fit the traditional understanding of an accessory.  Furthermore, the proposal to utilize the de novo pathway is likely to be beneficial only in limited circumstances that are not entirely evident.  Thus, while the draft guidance does provide a definition, it will not likely alter the way in which accessories are cleared. 

By Kurt R. Karst –      

For months we have been waiting with bated breath for the promised January 2015 release of a discussion draft of legislation to implement the 21st Century Cures Initiative, which was launched in April 2014 by now-Chairman of the House Energy and Commerce Committee Representative Fred Upton (R-MI) and Committee Member Representative Diana DeGette (D-CO).  That wait came to an end on January 27, 2015 when an announcement was posted on the Committee website stating: “21st Century Cures Legislative Phase Now Underway.”  The Committee released a nearly 400-page discussion draft of the 21st Century Cures Act, a 13-page section-by-section summary of the draft bill, a 7-page white paper, and a 1-page discussion document.   

The release of the discussion draft was immediatly acknowledged by several organizations, including the Advanced Medical Technology Association, the National Health Council, United for Medical Research, Research!America, the Biotechnology Industry Organization, and the Pharmaceutical Research and Manufacturers of America, and by some Members of Congress (here and here).  Most folks still need time to digest the discussion draft, but don’t seem to be dissatisfied with the first draft; however, there is a growing opposition to the draft bill.  The Generic Pharmaceutical Association issued a press release stating that the organization “is deeply disappointed in [the] discussion draft” and that “in its current form, the bill would upset the important balance between creating competition and encouraging innovation in the pharmaceutical marketplace, putting savings at risk and limiting access to affordable medicines for millions of American patients.”  In addition, Representative DeGette and Representative Frank Pallone (D-NJ), Ranking Member of the Energy and Commerce Committee, expressed their disappointment with the draft.  In a press release, Representative DeGette said: “While I don’t endorse the draft document, I know that with continued engagement, we can reach a bipartisan consensus to help advance biomedical research and cures.”  Meanwhile, Representative Pallone said in a press release that he is “disappointed that the discussion document released today by Chairman Upton does not reflect true bipartisan collaboration,” and that “[i]n its current form, I am concerned that the nearly 400 page draft could create more problems for our health care system than it solves.”

Like many others, we’re still poring over the draft bill, some sections of which include a placeholder for draft text that will be added in the coming weeks, but we found some time to put together a post on the draft legislation.  We’re certain to have additional posts on the bill – or on specific sections of the bill – in the weeks and months ahead as we learn more and as the 21st Century Cures Act takes greater shape while it moves through the legislative process.     

The 21st Century Cures Act is chock-full of proposals, some of which are new and some of which are old (i.e., based on or inspired by previously introduced legislation), from various stakeholders.  As noted in the Energy and Commerce Committee’s discussion document:

Over the course of the last year, patients, providers, innovators, regulators, and researchers from around the country have provided a wide range of specific ideas on how Congress can help accelerate the discovery, development, and delivery of promising new treatments and cures for patients and maintain our nation’s standing as the biomedical innovation capital of the world.  While it remains a work in progress, the legislative language included in the discussion document is based on such ideas, including proposals authored by both Republicans and Democrats.

The 21st Century Cures Act discussion draft has 5 titles.  Each title includes a series of proposals covering a wide range of drug, biologic, and medical device topics – from various “push” and “pull” incentives (see here and here), to orphan drugs, to clincial trial requirements, to social media, to controlled substances, to reimbursement, to . . .  well, you get the idea: there’s a lot in the draft bill!   Here’s the title framework from the discussion draft:

TITLE I – PUTTING PATIENTS FIRST BY INCORPORATING THEIR PERSPECTIVES INTO THE REGULATORY PROCESS AND ADDRESSING UNMET MEDICAL NEEDS

TITLE II – BUILDING THE FOUNDATION FOR 21ST CENTURY MEDICINE, INCLUDING HELPING YOUNG SCIENTISTS

TITLE III – MODERNIZING CLINICAL TRIALS

TITLE IV – ACCELERATING THE DISCOVERY, DEVELOPMENT, AND DELIVERY CYCLE AND CONTINUING 21ST CENTURY INNOVATION AT NIH, FDA, CDC, AND CMS

TITLE V – MODERNIZING MEDICAL PRODUCT REGULATION

Some of the interesting items this blogger tagged while going through the draft legislation are identified below (with subtitle or section and page number references to the discussion draft); but note that because of this blogger’s penchant for all things related to drug regulation (and especially the Hatch-Waxman Amendments, the Orange Book, and the Biosimilars Act), the items tagged below reflect my interest in those topics over other topics (though that doesn’t mean other topics aren‘t interesting . . . just that they’re probably more interesting to others with different predilections and expertise in those matters).

Title I of the draft bill includes an array of proposals intended to incorporate patient perspectives into the regulatory process and to help address their unmet medical needs.  This goal would be accomplished in part by requiring that a “structured risk-benefit assessment framework” be built into the new drug approval process that includes the development and use of patient experience data to facilitate a balanced risk-benefit consideration, and the development and implementation of “a consistent and systematic approach to the discussion of, regulatory decisionmaking with respect to, and the communication of, the benefits and risks of new drugs” (Section 1001; pages 8-15). 

Other sections of Title I further provide for surrogate endpoint qualification and use, and the qualification of other biomarkers (Subtitle B 1021; pages 15-28); modify the breakthrough therapy evidentiary standard and other provisions in FDC Act § 506 (Subtitle C; pages 29-34); foster the development of new antibiotics along the lines of the Antibiotic Development to Advance Patient Treatment Act (“ADAPT Act”) (see our previous post here) and the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act (“DISARM Act”) (Sections 1061-1064; pages 34-72); require greater transparency for expanded access programs (Subtitle G; pages 82-91); and allow for streamlined data review so that the sponsor of an approved prescription drug can submit “qualified data summaries” in a supplemental application for approval of a “qualified indication” (i.e., “an indication for the detection, diagnosis, prevention, treatment, or cure of cancer,” or other types of indications identified by FDA) (Subtitle J; pages 94-98).  The bill's provisions on antibiotic development may be considered in tandem with a proposal that will be included in the President’s 2016 Budget.  The White House laid out that multi-pronged proposal to combat antibiotic resistance in a fact sheet released on January 27th.   

As expected (see our previous post here), several provisions in the draft bill (Title I) would also create new patent and non-patent exclusivity opportunities.  Continuing a trend of “exclusivity stacking” started in 1997 with the creation of 6-month pediatric exclusivity, the draft Cures Act would extend a period of 3-year new clinical investigation exclusivity by 2 years if the NDA sponsor provides documentation to FDA demonstrating that:

(I) the new clinical investigations essential to the approval of the application or supplement and conducted or sponsored by the person submitting the application or supplement support the approval of a new indication or use for the drug that is the subject of the application or supplement; or

(II) the drug that is the subject of the application or supplement has been reformulated or redesigned so that the drug can reasonably (as determined by the Secretary in consultation with the person submitting such application or supplement) be expected—

(aa) to promote greater patient adherence to an approved treatment regime relative to the previously approved formulation or design of the drug;

(bb) to reduce the public-health risks associated with the drug relative to the previously approved formulation or design of the drug;

(cc) to reduce the manner or extent of side effects or adverse events associated with the previously approved formulation or design of the drug;

(dd) to provide systemic benefits to the health care system relative to the previously approved formulation or design of the drug; or

(ee) to provide other patient benefits that are comparable to the benefits described in items (aa) through (dd).

We can envision several instances in which this provision (Subtitle M; pages 118-122), if enacted, might come into play, including with the development of abuse-deterrent formulations of opioids. 

Another exclusivity stacking provision would provide a 6-month extension to the 5-year new chemical entity, 3-year new clinical investigation, and 7-year orphan drug exclusivity periods available to drug products approved under the FDC Act (and to patents listed in the Orange Book for a drug), and to the 4-year and 12-year reference product exclusivity and 7-year orphan drug exclusivity periods available to biological products licensed under the PHS Act if a sponsor obtains approval of a drug or biological product for a “new indication for use of the drug to prevent, diagnose, or treat [a designated] rare disease or condition.”  This provision (Subtitle N; pages 123-131) appears to be intended to address the situation where a product shows potential to prevent or treat both a prevalent and an orphan disease, but it is developed first (and perhaps only) for the prevalent disease.  As a result, many patients with orphan diseases don’t have viable access to potentially beneficial drugs because the drugs are approved only for the prevalent disease.  Indeed, there are numerous examples of drugs approved for a prevalent indication that are also used as an effective off-label treatment for patients with orphan diseases.  Clonidine is one such example.  It is approved for the treatment of high blood pressure, a prevalent disease, but clonidine can also be used to treat Tourette’s Syndrome, an orphan disease.  Clonidine, however, has never been developed for that orphan use.  The 6-month incentive provided by this provision in the draft bill would target a situation like that. 

The draft Cures Act also includes provisions (Subtitle L; pages 101-118) modeled after the Dormant Therapies Act of 2014 (S. 3004), which Senator Orrin Hatch (R-UT) introduced last December.  The Dormant Therapies Act is a redo of the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures Act (“MODDERN Cures Act”), which was introduced in 2013 (H.R. 3116) and 2011 (H.R. 3497).  Among other things, the draft Cures Act would create a new guaranteed 15-year “protection period” for certain drug and biological products designated and approved as dormant therapies.  As part of the deal, however, companies must agree to waive patent rights. 

In what is a rather innovative way to approach the concept of “wildcard exclusivity” (see our previous post here) the draft Cures Act would amend the Generating Antibiotic Incentives Now Act (“GAIN Act”) (FDC Act § 505E), which amended the law to include a 5-year marketing exclusivity add-on for a drug product designated and approved by FDA as a Qualified Infectious Disease Product, to allow a sponsor to convey a portion of its exclusivity (currently pegged at 12 months) to apply with respect to one or more other drugs (Section 1063; pages 59-68).  Such conveyance – which could include the sale of exclusivity from one company to another company – would also apply to Orange Book-listed patents.  But there’s a catch!  In addition to certain cutoff periods for conveyance, the sponsor of an application to which exclusivity has been conveyed must make donations to the National Institutes of Health and to a “bona fide, independent patient assistance program.”  The amounts of the donations are still being ironed out, but donation amounts would not exceed 5% of sales of the recipient drug in the United States for a defined period and for a yet-to-be-determined total donation. 

Other topics of interest in other titles of the discussion draft include:

• Provisions concerning genetically targeted platform technologies for rare diseases under which accelerated approval is available based on the extrapolation of evidence that is reasonably likely to predict clinical benefit of a product (Section 2051; pages 150-153); 
• Revisions to human subject research regulations (Section 3001; pages 223-231); 
• The requirement that FDA “establish and implement a framework through which sponsors of drugs, biological products, or devices may submit to the Secretary a proposal for the incorporation of adaptive trial designs, Bayesian methods, or other alternative statistical methods into proposed clinical protocols and marketing applications for drugs, biological products, or devices” (Section 3021; pages 232-235);
• Changes to the Tropical Disease Priority Review Voucher provisions of FDC Act § 524 that broaden the voucher program to infectious diseases (Section 4045; pages 267-271); 
• In what seems likely be a nod to President Obama’s announcement at the 2015 State of the Union Address of the creation of a new precision medicine initiative, the Cures Act includes a placeholder for text on “Precision Medicine” (Section 2301; page 223);
• FDA succession planning (Section 4121-4122; pages 280-282); and
• A lot, lot more . . . . 

We’ll end this post with one more exclusivity provision included in the draft Cures Act.  Unlike all of the other exclusivity provisions in the draft bill, this last provision applies to generic drugs and biosimilars.  Tucked away in Title V of the draft legislation (Section 5001; pages 347-349), it gives FDA the authority to designate a drug or biological product as an “American-manufactured drug.”  Such a designation means, with certain limitations, that 180-day exclusivity applicable to generic drugs and the 1-year, 18-month, or 42-month period granted (as applicable) to an interchangeable biosimilar biological product will be extended.  The amount of that extension is still being debated, however.

As Porky Pig would say at the conclusion of a Looney Tunes cartoon, “That’s All Folks!” 

By Kurt R. Karst – 

Earlier today (January 26, 2015), FDA announced the first approval of an ANDA for a generic version of AstraZeneca Pharmaceuticals LP's (“AstraZeneca's”) NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg.  But it wasn’t Ranbaxy Laboratories, Ltd./Ranbaxy, Inc. (“Ranbaxy”) that scored the approval for its long-pending application (ANDA 077830); it was Teva Pharmaceuticals USA subsidiary Ivax Pharmaceuticals, Inc. that scored the approval of its application (ANDA 078003).  Generic NEXIUM is expected by some folks to be one of the most lucrative generic launches in years.

The fact that purported first-filer Ranbaxy was not the recipient of the ANDA approval could mean only one thing for the company: that FDA determined that Ranbaxy forfeited eligibility for 180-day exclusivity.  (FDA's approval of ANDA 078003 also appears to indicate that before approving the application, AstraZeneca waived successive and overlapping periods of pediatric exclusivity expiring on May 25, 2015 and August 3, 2015 and associated with U.S. Patent Nos. 5,690,960 and 5,714,504, respectively, that would otherwise have prevented ANDA approval until later this year.)  Indeed, in a Notice of Administrative Action filed in the U.S. District Court for the District of Columbia in pending litigation concerning the stripped tentative approvals for both generic NEXIUM and VALCYTE (valganciclovir) Tablets, 450 mg, FDA states:

Defendants . . . hereby withdraw their argument that Ranbaxy’s claims in this matter regarding generic esomeprazole are unripe and lack final agency action.

Today, FDA determined that Ranbaxy had forfeited its eligibility for 180-day exclusivity for esomeprazole because it failed to obtain tentative approval of its ANDA within 30 months after the date on which the ANDA was submitted and that failure was not caused by a change in or a review of the requirements for approval, and notified Ranbaxy of this determination.

The failure-to-obtain-timely-tentative approval basis for generic NEXIUM is the same basis FDA used to determine that Ranbaxy forfeited eligilbity for 180-day exclusivity for generic VALCYTE (see our previous post here), and that led Ranbaxy to sue FDA over the decision and the stripped tentative approvals (see our previous post here).  Both Dr. Reddy’s (represented by Hyman, Phelps & McNamara, P.C.) and Endo intervened in the case.  A merits decision in the case has been pending since Judge Beryl A. Howell issued a Minute Order earlier this month vacating a hearing scheduled for January 9, 2015.  Late on January 26th, Ranbaxy filed a Motion for Expedited Ruling on Pending Motions.

FDA also states in the court filing that the Agency responded to and denied a 2012 Citizen Petition (Docket No. FDA-2012-P-0661) related to generic esomeprazole.  In that petition, Sandoz Inc. (“Sandoz”) asked FDA to determine whether Ranbaxy forfeited 180-day exclusivity eligibility for generic NEXIUM as a result of FDA’s February 5, 2008 tentative approval of the application (which was later stripped).  The ANDA was received as of August 5, 2005, so February 5, 2008 was the 30-month anniversary date of submission.  Although FDA has previously indicated through at least one approval precedent (see our previous post here) that a tentative approval on the 30-month anniversary date is timely tentative approval for 180-day exclusivity forfeiture purposes, FDA’s denial of the Sandoz petition appears to be the first instance in which the Agency has publicly described its rationale.  

By Kurt R. Karst –      

It’s been a little more than 2.5 years since Section 505(w) was added to the FDC Act by Section 1134 of the 2012 FDA Safety and Innovation Act (“FDASIA”).  Section 505(w), titled “Deadline For Determination on Certain Petitions,” requires FDA to issue a final, substantive determination on a petition submitted pursuant to 21 C.F.R. § 314.161(b) – a so-called  “discontinuation petition” – “no later than 270 days after the date the petition is submitted.”  The provision, which many believe was included in FDASIA to make the bill compliant with the Statutory Pay-As-You-Go Act of 2010 (see our FDASIA Summary here), applies to any discontinuation petition submitted to FDA on or after July 9, 2012.  Unlike Section 505(q) petitions, which FDA must respond to within 150 days of receipt, FDA is not required to report to Congress on the Agency’s track record in responding to discontinuation petitions.  (Last December, we reported on FDA’s most recent Report to Congress on 505(q) petitions.)  So we took it upon ourselves to assess – and grade – FDA on the Agency’s efforts to meet the statutory deadline.  After all, when FDA is not subject to any oversight, the Agency has been known to slip on meeting statutory deadlines.  Just consider FDA’s 30-plus-year track record in meeting (or not) the 90-day statutory deadline for ruling on ANDA suitability petitions.  This blogger analyzed that record in an article for the William Mitchell Law Review’s Hatch-Waxman 30th anniversary edition, titled “Letting the Devil Ride: Thirty Years of ANDA Suitability Petitions Under the Hatch-Waxman Act.”

As we noted when the provision that would become FDC Act § 505(w) was initially proposed under FDC Act § 505(j)(4)(I), FDA may refuse to approve an ANDA if the Agency determines that the Reference Listed Drug (“RLD”) was withdrawn from sale for reasons of safety or effectiveness.  In addition, FDA can withdraw (or suspend) approval of an ANDA if the RLD is withdrawn from sale for reasons of safety or effectiveness (FDC Act § 505(j)(6)).  In that case, the RLD is removed from the Orange Book (FDC Act § 505(j)(7)(C)).

The Hatch-Waxman Amendments didn’t specify any procedure for FDA to follow in determining whether a drug that is withdrawn from sale by its manufacturer is withdrawn for safety or effectiveness reasons.  So FDA took it upon itself to create such a procedure, which is laid out at 21 C.F.R. § 314.161.  Prior to FDASIA’s enactment, FDA’s timeframe for responding to withdrawal petitions was all over the map; however, that’s probably because the Agency generally responded to discontinuation petitions only when it was necessary to do so (i.e., when FDA was nearing an ANDA approval decision).

By our tally, 41 discontinuation petitions were submitted to FDA since the July 2012 enactment of FDASIA and the end of 2014.  (As a side note, the first such petition, from August 2012, was the topic of a lawsuit against FDA – see our previous posts here and here.)  Of those 41 petitions, 3 (7.32%) were withdrawn before an FDA decision was published, and 3 (7.32%) are pending and within the 270-day deadline.  That leaves 35 petitions for which there is either a timely or untimely FDA decision.  So how did the Agency do?  As shown in the table below, FDA has timely responded to nearly 86% of Section 505(w) petitions.  That puts FDA in solid  “B” grade territory.

As you can calculate from the docket-specific information below that we compiled, most of the missed deadlines were not too far off the 270-day mark.  So, if we’re grading on a curve (vis-à-vis other statutory deadlines for FDA action), then perhaps FDA’s B” grade can be bumped up to a “B+” or “A-”.  

By Anne K. Walsh –

This post relates to the all-important package insert, which provides health care professionals with the latest information about the approved uses of a prescription drug or biological product, as well as information necessary for the safe and effective use of the product.  Last month, FDA proposed getting rid of the well-known, but little-used, paper form of the package insert, and instead requiring manufacturers to distribute this information electronically via FDA’s electronic database, http://labels.fda.gov/.  No change was proposed to the substantive content of the package insert.  The Drug and Device Law Blog aptly evaluated the product liability implications of this change; this post considers the regulatory impact of this proposal. 

To be clear, patients receiving a prescription drug will continue to receive a paper copy of the warning, risk information, or special instructions related to the drug.  FDA’s proposal only relates to the prescribing information intended for health professionals. 

FDA has been considering electronic distribution for a long time.  In 2007, FDA held a public hearing to solicit views on the feasibility of an electronic-based system, and the benefits associated with it.  In the intervening eight years, the health industry has only increased its reliance on electronic-based systems, including the labeling information supplied on DailyMed, a public database maintained by the National Library of Medicine, a sister agency of FDA.  In fact, FDA has been coordinating with the National Library of Medicine to ensure DailyMed provides the current package insert information for drugs.  The website states: 

DailyMed provides trustworthy information about marketed drugs. DailyMed is the official provider of FDA label information (package inserts). This Web site provides a standard, comprehensive, up-to-date, look-up and download resource of medication content and labeling found in medication package inserts.

The National Library of Medicine (NLM) provides this as a public service and does not accept advertisements. The drug labeling information on this Web site is the most recent submitted to the Food and Drug Administration (FDA) and currently in use; it may include, for example, strengthened warnings undergoing FDA review or minor editorial changes. These labels have been reformatted to make them easier to read.

In contrast, the language on FDA’s labeling website states:

The drug labels and other drug-specific information on this Web site represent the most recent drug listing information companies have submitted to the Food and Drug Administration (FDA). (See 21 CFR part 207.)  The drug labeling and other information has been reformatted to make it easier to read but its content has neither been altered nor verified by FDA.  The drug labeling on this Web site may not be the labeling on currently distributed products or identical to the labeling that is approved. 

Obviously this disclaimer language will need to be removed if the proposed rule is accepted.  It is unclear why FDA proposes to populate its currently unreliable database, rather than rely on the already existing and well-regarded DailyMed database. 

As a side note, FDA’s labeling website also includes information on OTC drugs, homeopathic drugs, unapproved drugs, and medical devices, with similar disclaimers that this information may not be current or even accurate.  It is unclear whether FDA will impose similar electronic and verification requirements on those product manufacturers in the future. 

According to FDA, and the study it commissioned, prescribing physicians and nurses typically do not receive the paper version of the package insert because they do not dispense drugs.  They already use a variety of electronic databases (like DailyMed) to access prescribing information.  Pharmacists, who do dispense drugs and do receive the package insert from manufacturers, complain the package insert is difficult to read due to the small font size, thin paper, and multiple folds.  FDA also found a long delay (up to 39 months) after a change is made to a drug’s prescribing information before the change actually appears in the printed prescribing information attached to a drug product.  FDA claims these delays raise concerns about use of outdated information in clinical decision-making. 

Under the proposal, manufacturers would be required to submit to FDA’s website (www.labels.fda.gov) the updated labeling every time there is a change in the labeling.  This must be done within 2 days after approval of a Prior Approval Supplement, and simultaneously with a Changes Being Effected submission.  The rule also would require manufacturers to verify that the information on the website is accurate, complete and up-to-date, and to notify FDA if this is not true, even if it is FDA’s fault for not promptly posting the information. 

The proposal also would require manufacturers to revise the product’s immediate container label and outside package to identify the FDA labeling website and a toll-free telephone number to process requests for prescribing information if the Internet is unavailable.  The manufacturer would be responsible for establishing the toll-free number, and staffing it 24 hours a day, 7 days a week, so that the prescribing information can be sent to a requestor by e-mail, fax, or paper.  Therefore manufacturers still would need to print and have on hand paper copies of the latest package insert, even though the proposal is intended to eliminate confusion from paper versions.

FDA references the July 2013 Government Accountability Office Report titled “Electronic Drug Labeling: No Consensus on the Advantages and Disadvantages of its Exclusive Use.”  Recognizing some of the challenges for electronic access, FDA proposes to exempt companies in circumstances when compliance with the rule could adversely affect the safety, effectiveness, purity, or potency of the drug; is not technologically feasible; or is otherwise inappropriate.  Examples of such circumstances include a product which requires multiple steps for reconstitution, a product that is intended for use in an emergency room, a product that may be stockpiled for use during an emergency, and cell therapy products that require proper handling and multiple steps. 

FDA proposes an effective date of 6 months from publication of the final rule, and a compliance date 2 years subsequent, to give manufacturers time to make preparations to comply with the rule.  FDA also proposes a staggered compliance date to allow blood and blood components more time for compliance.  Comments on the proposal are due by March 18, 2015.

By Kurt R. Karst –      

When Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia noted in a January 12, 2015 Minute Order that the Court filed under seal a “lengthy opinion” on January 9, 2015 denying Motions for Summary Judgment from Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”), the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, and Elliott Associates, L.P., Elliott International, L.P., and Knollwood Investments, L.P. (collectively “Elliott”), entities with investment interests in COLCRYS, in a dispute stemming from FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its partner, West-Ward Pharmaceutical Corp. (“West-Ward”), for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares, she wasn’t kidding.  Judge Jackson’s decision, which was unsealed earlier this week, comes in at 80 pages long, including a table of contents.  It’s one of those must-read opinions for Hatch-Waxman practitioners.  Not only is the decision well written, but it’s the first ever court decision to attempt to untangle some of the knotty issues involving 505(b)(2) applications, including FDA statements concerning the “choice of listed drug” for 505(b)(2) applicants.  And Judge Jackson’s opinion is unlikely to be the last word on the issue.  On January 20, 2015, Takeda and Elliott each filed a Notice of Appeal (here and here) to the U.S. Court of Appeals for the District of Columbia Circuit.

We previously discussed the colchicine dispute in a post last October when Takeda first filed suit (), and again earlier this month () when Judge Jackson issued her January 9th Order denying Motions for Summary Judgment from Takeda and Elliott and granting Cross-Motions for Summary Judgment from FDA and Hikma/West-Ward.  This post focuses on Judge Jackson’s Memorandum Opinion, which is summed up as follows (pages 31-32):

[T]his Court concludes that Plaintiffs are wrong to characterize FDA’s actions with respect to Mitigare as unauthorized, unsafe, or unreasoned; to the contrary, it is clear on the record presented that FDA’s approval of Mitigare was consistent with the FDCA, the regulations the agency has promulgated pursuant to the FDCA, the Citizen Petition Responses FDA has issued, and the policies and practices under which the agency operates.  Furthermore, the record clearly reveals the reasonableness of FDA’s expert determination that Mitigare is safe and effective as labeled, and it supports the agency’s conclusion that Mitigare’s labeling best reflects current scientific information regarding the risks and benefits of Mitigare—a conclusion that, in any event, is entitled to a high degree of deference.  Consequently, Plaintiffs have failed to establish that summary judgment should be entered in their favor on their [Administrative Procedure Act] (APA)] claims, and this Court finds that Defendants are entitled to summary judgment as a matter of law.

The Issues 

Both Takeda and Elliott make myriad arguments challenging the propriety of FDA’s approval of the MITIGARE 505(b)(2) application.  Here’s how Judge Jackson characterizes those issues in her Opinion: 

First, both Takeda and Elliott steadfastly maintain that FDA should not have approved Mitigare without requiring West-Ward to certify to the Colcrys patents that cover the use of colchicine for the prophylaxis of gout flares, with Takeda asserting that the agency relied on Colcrys’s data to approve Mitigare and thus FDA’s failure to require West-Ward to reference Colcrys and certify to the Colcrys patents violated the agency’s own procedural rules, and Elliott arguing additionally that the agency’s failure to require West-Ward to certify to the Colcrys patents without regard to any reliance on Colcrys contravened both the agency’s longstanding policies and the FDCA itself.  In addition, Takeda takes issue with Mitigare’s label, arguing that “[t]he Mitigare label contains neither the FDA-approved low-dose-treatment notation for acute gout nor the drug-drug interaction dosing adjustments, both of which FDA expressly required in light of the severe safety concerns it identified during the Colcrys review process.”  Consequently, Takeda contends that Mitigare is unsafe as labeled, and also that FDA’s approval of Mitigare constitutes an unreasoned change in the agency’s position regarding the requirements for the labeling of single-ingredient oral colchicine products.  Takeda also argues that “FDA’s failure to enforce its own labeling requirements allowed [West-Ward] to circumvent the statutory directive that it file a Paragraph IV certification to Takeda’s patents[.]” [(Internal citations omitted)]

Judge Jackson’s handling of each of these issues is discussed separately below.

Do FDA’s procedural rules require West-Ward to reference COLCRYS even though the West-Ward did not rely on COLCRYS data?

As an initial matter, Takeda’s assertion that FDA should have required West-Ward to cite COLCRYS as a listed drug and certify to relevant Orange Book patents is generally the same argument that Takeda’s predecessor in the COLCRYS NDA, Mutual Pharmaceutical Company, Inc. (“Mutual”), made to FDA in a 2010 Citizen Petition (Docket No. FDA-2010-P-0614).  There, Mutual asked FDA to refrain from approving any future 505(b)(2) application for a single-ingredient oral colchicine drug product that does not reference COLCRYS. 

FDA largely denied Mutual’s petition in a May 2011 response.  In doing so, FDA stated that a 505(b)(2) application for a single-ingredient oral colchicine product might not need to cite COLCRYS as its listed drug, regardless of similarities in strength, pharmacokinetic profile, or other characteristics (such as dosage form or conditions of use).  FDA also emphasized in the petition response that “[w]hether another 505(b)(2) application for a single-ingredient colchicine product that does not cite Colcrys as a listed drug could ever be appropriate will depend on the facts and circumstances of the particular application. . . .”

“Plaintiffs argue now that the facts and circumstances of Mitigare’s approval are such that the agency should have required a Colcrys reference and patent certifications, and that FDA arbitrarily and capriciously failed to do so,” wrote Judge Jackson.  Specifically:

Takeda asserts that FDA’s refusal to make West-Ward reference Colcrys and certify to the Colcrys patents violated two of the agency’s “procedural requirements”: (1) the requirement that a Section 505(b)(2) applicant reference another product if the agency itself relies on studies or data relating to that other product in approving the applicant’s application, and (2) the requirement that a Section 505(b)(2) applicant choose the “most appropriate” listed drug to be its reference drug.  Elliott makes the slightly different argument that FDA not only violated the agency’s own policies, its actions also breached the FDCA itself, which, according to Elliott, requires a Section 505(b)(2) applicant to certify to all method-of-use patents that claim a use for the drug substance for which the applicant is seeking approval.  [(Internal citations omitted)]

But Judge Jackson was unconvinced, and refused to accept Plaintiffs' argument that FDA arbitrarily and capriciously violated any requirements when the Agency approved the MITIGARE 505(b)(2) application.  “[T]his Court discerns no basis in law or fact for Plaintiffs’ insistence that FDA was legally required to force West-Ward to reference Colcrys and to certify to the Colcrys patents under the circumstances presented here,” wrote Judge Jackson.

Turning to the alleged procedural requirement that a 505(b)(2) applicant cite in its application as a listed drug relied on for approval an approved drug if FDA (but not the 505(b)(2) sponsor) relies on data or information from that approved drug in approving the 505(b)(2) application, Judge Jackson boiled Takeda’s reliance argument down to major corollaries:

(1) that, under FDA’s rules, “[t]he ultimate reference and certification obligations depend on whether FDA relies on other drug studies or data” regardless of whether the Section 505(b)(2) applicant does so, and

(2) that the instant administrative record shows that “FDA explicitly referenced and relied on the Colcrys data—over and over and over again—in approving Mitigare.”  [(Internal citation omitted; emphasis in original)]

Judge Jackson found Takeda wrong on both counts.  With respect to whether or not FDA reliance counts for 505(b)(2) listed drug purposes, Judge Jackson wrote:

[T]he contention that, under established agency policy, the patent certification requirement is triggered by the agency’s reliance on the investigations underlying another drug product is entirely unsupported. . . .  The key to understanding why Takeda’s agency-reliance argument fails is recognizing its linchpin: the proposition that, without “a right of reference or use,” FDA lacks the authority to review or access third-party data from a previously approved new drug application when it is evaluating a Section 505(b)(2) new drug application.

Her opinion goes on to note that Congress used the phrase “right of reference or use” in passing FDC Act § 505(b)(2) to “expressly appl[y] only to the Section 505(b)(2) applicant,” and that it “pertains only to what application materials such sponsor is required to submit.”  “And just as the statute says nothing about the circumstances under which FDA can, or cannot, consult third-party data when it makes a scientific determination regarding whether or not to approve a Section 505(b)(2) application, the ‘right of reference’ definition that the agency provides in 21 C.F.R. § 314.3 is similarly silent on the issue of whether the agency itself needs such a ‘right’ before it can” reference data in a previously approved NDA when acting on another applicant’s 505(b)(2) application. 

Moreover, wrote Judge Jackson:

Surely the prior applicant’s voluntary submission of its proprietary data to FDA waived any right that applicant may have had to prohibit FDA from “open[ing] th[e] locked file drawer” to access the applicant’s data in the future.  And to extent that a drug sponsor’s proprietary data contributes to the general body of scientific knowledge about what a particular pharmacological agent is or does, it is not at all clear that it would even be feasible to prevent FDA’s scientists from applying that knowledge when other new drug applications are considered in the future.  [(Internal citation omitted; emphasis in original)]

That first sentence might raise some eyebrows among those in the brand-name industry, particularly given previous FDA statements on the matter (see, e.g., here).

In any case, and notwithstanding Judge Jackson’s conclusions about FDA versus 505(b)(2) applicant reliance, she says that “[e]ven if one were to accept Takeda’s legal argument that the agency’s reliance on third-party studies and data gives rise to an obligation on the part of the agency to require the applicant to reference the relied-upon drug product and certify to its patents, this Court concludes that the record here does not demonstrate FDA ‘reliance’ on Colcrys” in the Agency’s approval of the MITIGARE 505(b)(2) application “in the relevant sense.”

Does a 505(b)(2) applicant have a right to choose which approved drug is (or is not) most appropriate or most similar to cite (or not) as a listed drug relied on for approval?

Turning to Plaintiffs’ next alleged “procedural requirement” argument – that FDA violated a “choice of listed drug” requirement in approving MITIGARE without requiring a reference (and patent certifications) to COLCRYS because it is most similar to MITIGARE – Judge Jackson analyzes various FDA responses to relevant Citizen Petitions and uses them to pick apart Plaintiffs’ argument:

[T]heir argument hinges on the existence of an FDA drug reference policy that does not exist. . . .  When all of the agency’s statements are read in context, [] it is clear that FDA’s policy is to view the “most appropriate” drug to be whatever drug fills in the gaps in the data the drug sponsor submits to support the sponsor’s contention that the drug is safe and effective, and not whatever listed drug is most similar in nature to the one the applicant proffers. . . . 

The bottom line is this: FDA’s prior statements confirm that, other than where duplicate drug products are involved, a Section 505(b)(2) applicant has the discretion to select a reference drug, and to make that selection in relation to the scope of the materials the applicant desires to submit.  Thus, to the extent that the agency has any “policy” about what drug should be referenced in a Section 505(b)(2) application, FDA has decided to leave it up to the drug sponsor to determine whether the sponsor would like to do less work and rely on a very similar drug, or do more work and rely on a dissimilar drug.  [(Internal citations omitted; emphasis in original)]

FDA’s “choice of listed drug” policy is one that we’ve commented on before in our post “FDA’s House Rules on 505(b)(2) NDA Choice of Listed Drug; How Does it Affect Dealer’s Choice?”  As noted there, we think there’s room in the 505(b)(2) space for an applicant to argue that even where there is an approved pharmaceutical equivalent, such drug does not necessarly have to be cited by a 505(b)(2) applicant as a listed drug relied on for approval.  The policy is also at issue in a recent Citizen Petition (Docket No. FDA-2014-P-2188) concerning abuse-deterrent immediate-release oxycodone tablets.

Does the FDC Act unambiguously require a 505(b)(2) applicant to certify only to patents associated with the RLD?

“Yes,” says Judge Jackson in response to Elliott’s argument that the text of the FDC Act required West-Ward to certify to the various patents listed in the Orange Book for COLCRYS regardless of whether or not West-Ward did relied on COLCRYS for the MITIGARE approval.  In revisiting the debate as to whether the word “drug” in the statute means a particular drug product, or, more generally, a drug substance, Judge Jackson sets up the issue as follows:

The statutory question that Elliott raises here is, in essence, whether 21 U.S.C. § 355(b)(2)(A) requires not only certification to those patents that claim the drug product on whose investigations the 505(b)(2) applicant relied (i.e., the reference listed drug), but also certification to all patents that claim a method of using the drug substance (i.e., the active ingredient) in the new drug product that the applicant has proffered for approval.  [(Emphasis in original)]

Her Chevron analysis ends at Step One:

[T]his Court finds that Congress’ intent regarding the scope of a Section 505(b)(2) applicant’s patent certification obligation is clear on the face of the statute: such applicant need only certify to the product patents or the method-of-use patents that are associated with the reference listed drug (i.e., the drug product on whose investigations the 505(b)(2) applicant relies).

We’ll leave it to you to go through the sepcifics of Judge Jackson’s analysis on pages 52-65 of the opinion. 

Is the MITIGARE approval an unreasoned change of FDA policy concerning single-ingredient oral colchicine drug products, and do certain safety-related labeling differences call into question FDA”s approval of MITIGARE?

In the final two sections of her decision, Judge Jackson moves out of the listed drug/patent certification space and into the drug labeling space.  First, Takeda questioned FDA’s approval of MITIGARE with labeling that differs from COLCRYS with respect to certain drug-drug interactions, and in light of certain FDA statements in the Agency May 2011 Citizen Petition response.  Judge Jackson didn’t bite:

Given that FDA never promised in the Colchicine Citizen Petition Response to require that Colcrys’s drug-drug interaction table appear on all future products, and also that the agency did engage in precisely the kind of individualized assessment of Mitigare’s label that the Colchicine Citizen Petition Response said would be required regarding single-ingredient oral colchicine products in the future, FDA’s conclusion that Mitigare did not need to include the same low-dose requirements as appear on Colcrys’s label was hardly a change of FDA’s position, much less an “arbitrary” or “capricious” deviation from its prior policy.

Although a closer question was presented in the context of certin FDA statements and “the extent to which the labels of future single-ingredient oral colchicine products approved for the prophylaxis of gout flares must provide information about the use of the product for the treatment of acute gout flares,” Judge Jackson concluded that “[t]o the extent that FDA’s decision to approve Mitigare without a label that included Colcrys’s AGREE trial regimen can be viewed as a departure from the agency’s prior position, this Court concludes that it was not an unreasoned change in position in violation of the APA, because the record clearly reflects the agency’s well-reasoned and well-supported rationale for reaching this conclusion.”  (Internal citation omitted.) 

Second, Takeda argued that the MITIGARE approval was arbitrary and capricious because the drug product is not safe in light of certain labeling deficiencies.  Judge Jackson quickly dispensed with this matter by deferring to FDA’s scientific judgment:

[FDA’s] scientific determination that Mitigare is safe and effective as labeled is entitled to the highest degree of deference, meaning that, even if this Court had the expertise to reevaluate FDA’s safety and efficacy decision, it could not freely supplant the agency’s scientific judgments about what a drug product’s label must include in order to ensure safe use of that product, any more than it could roll up its sleeves and dig into the data or run its own clinical experiments in order to determine whether FDA was wrong to conclude that such drug product was, in fact, safe.

We anticipate a lively debate as this case moves on to the D.C. Circuit.  And we’ll be keeping a close eye on it. 

By Jennifer D. Newberger –

FDA has historically taken the position that products intended to benefit a user’s overall health and wellness, and that did not make claims about disease prevention, treatment, mitigation, or cure, would not be regulated as medical devices.  For example, in 1995, FDA issued Guidance Document for the Preparation of Premarket Notification [510(k)] Applications for Exercise Equipment.  In that guidance, FDA stated:

Note that FDA regulates exercise equipment only if the equipment is intended to be used for medical purposes, such as to redevelop muscles or restore motion to joints or for use as an adjunct treatment for obesity. FDA does not regulate exercise equipment intended only for general physical conditioning and/or for the development of athletic abilities in individuals who lack physical impairment. Therefore, it is not necessary to notify FDA of an intent to market a device if it will not be labeled or promoted for medical uses. However, FDA will regulate the equipment and may require premarket notification if any promotional material appears which makes medical claims after marketing begins.

When FDA issued the Mobile Medical Applications guidance in September 2013, it again repeated its position that it did not intend to regulate apps intended for general health and wellness. 

Given this historical view on general wellness devices, FDA’s issuance of a draft guidance, General Wellness: Policy for Low Risk Devices, on January 16, 2015, would not, on its face, appear to present a major change to these types of products.  There are, however, a few points in the guidance worth noting.  First, FDA, for the first time, defines a “general wellness product” as a product that has:

1. an intended use that relates to maintaining or encouraging a general state of health or a healthy activity, or
2. an intended use claim that associates the role of healthy lifestyle with helping to reduce the risk or impact of certain chronic diseases or conditions and where it is well understood and accepted that healthy lifestyle choices may play an important role in health outcomes for the disease or condition.

Draft Guidance, at 3.

The second of these is particularly interesting, and appears to expand the category of general wellness products excluded from FDA’s jurisdiction.  FDA states that this second category includes two subcategories:

1. intended uses to promote, track, and/or encourage choice(s), which, as part of a healthy lifestyle, may help to reduce the risk of certain chronic disease or conditions; and
2. intended uses to promote, track, and/or encourage choice(s) which, as part of a healthy lifestyle,  may help living well with certain chronic diseases or conditions.

Draft Guidance, at 4 (emphasis in original).

The draft guidance includes examples of claims falling within this subcategory, including the product promotes physical activity, which, as part of a healthy lifestyle may help reduce the risk of high blood pressure. Another example would be a product that tracks caloric intake and helps manage a healthy eating plan to maintain a healthy weight and balanced diet, which in turn may help living well with high blood pressure and type 2 diabetes.

The significance of this is that the manufacturer may say more about the product than that it merely helps achieve a healthy lifestyle or may help aid in weight loss.  It can then link those outcomes to potential benefits with specific disease states, implying that the product itself may, to a certain extent, help mitigate or reduce the risk of those disease states.  FDA has included the caveat that it must be well known that healthy lifestyle choices are associated with improved outcomes for those diseases or conditions.  This seems like a reasonable requirement, and still permits health outcomes claims that, prior to the guidance, may not have been permissible or were at least questionable.

This draft guidance is another welcome sign that FDA is attempting to focus its resources on high(er) risk products, and will not actively regulate products that present a low risk to the user.  We hope to see this trend continue when FDA issues its draft guidance on regulation of clinical decision support software, on the “A-list” for development in FY2015. 

By Riëtte van Laack –

As we previously reported, the Farm Bill of 2014 tasked the Agricultural Marketing Service (AMS) with the preparation of a report regarding the need for a federal standard of identity for honey. Without much fanfare, AMS recently published its report to FDA.

Not surprisingly, the majority of the 85 comments to AMS support the development of a standard. However, there is no consensus as to the specific content of the standard. Among other things, the comments differ in whether filtration should be permitted in honey, the maximum hydroxymethylfurfural (HMF) (a measure of heat treatment of honey) level for honey, and a requirement for pollen count to identity floral sources, growing region and filtration. Thus, other than confirming that stakeholders see a need for a federal standard of identity, the report provides little direction for FDA.  It therefore appears unlikely that FDA will develop a federal standard for honey in the near future.

By Kurt R. Karst –       

The news came down on Thursday that FDA’s Center for Drug Evaluation and Research Director Janet Woodcock, M.D., named Kathleen “Cook” Uhl, M.D., as the permanent director of the Office of Generic Drugs (“OGD”).  Although Dr. Uhl has manned the helm at OGD since March 2013 (see here), she has only done so in an acting capacity.  She was tapped as Acting Director after the departure of Gregory P. Geba, M.D., who was OGD Director for only about nine months (see here).  OGD has done without a longstanding permament Director since Gary J. Buehler, RPh., left OGD in March 2010. (He then left FDA several months later for an industry position.)  Keith Webber, Ph.D., who has also  since left FDA for a position in industry, filled in as Acting Director after Mr. Buehler’s departure.  A copy of Dr. Woodcock’s announcment of Dr. Uhl’s permanent position follows:

Dear Office of Generic Drugs Staff:

I am pleased to share with you the following news.  An announcement will be issued to all CDER staff today.

Kathleen “Cook” Uhl, M.D., has been named the permanent director of the Office of Generic Drugs (OGD). She brings to the position more than 30 years of regulatory and medical policy, scientific, and government leadership experience. 

I am confident in Cook’s continued exceptional leadership of OGD and its support of our Center’s mission.  She brings extensive knowledge and skills in developing and implementing standards for the safety and effectiviness of generic drugs. 

I would like to extend my sincere thanks to Cook for her outstanding work and service as acting director.  I would also like to thank all of you in OGD for your continued hard work and dedication to CDER’s mission during not only this leadership transition, but also the transition of OGD into a super-office.

Please join me in welcoming Cook to her permanent role.  Keep up the great work in OGD! 

Janet Woodcock

During her tenure as Acting Director, Dr. Uhl has overseen dramatic change within OGD, primarily as a result of FDA’s implementation of the Generic Drug User Fee Amendments of 2012.  This includes significant changes in OGD operations and personnel (see here and here) – including recent changes to the Office of Pharmaceutical Quality (see here) – as well as policy changes (not all of which have been welcomed by the generic drug industry) (see here). 

Dr. Uhl’s accession to permanent OGD Director signals Dr. Woodcock’s confidence in Dr. Uhl’s ability to man the OGD ship through the sometimes turbulent waters of GDUFA and generic drug approvals.  To many in the generic drug inductry, Uhl’s transition from acting to permanent OGD Director was also a foregone conclusion, though the position was advertised for a short time last year on USAJobs.gov. 

By John R. Fleder –

Lawyers are often asked if a client can be sued if the client does something.  Almost without exception, the answer is yes.  It does not take much for a person to file a lawsuit in court without much or any evidence, and without a viable legal theory.  As shown below, a lawsuit filed in court hardly translates in many instances to a viable cause of action.   Nevertheless, these suits are being filed in great numbers.

These days, enforcement of the FDC Act in court stems largely from civil cases filed under seal under the federal False Claims Act, 31 U.S.C. § 3029 et. seq. (“FCA”).  The cases are typically brought by one or more individuals who previously worked for the defendant or defendants and are generally referred to as whistleblowers.  In the FDA arena, more often than not, the cases are filed against a drug or medical device manufacturer.  However, we have also seen FCA suits filed against individuals, state and local governments, and even FDA consultants.

We have previously discussed (see, e.g., here, here, here, and here) other cases where plaintiffs have filed FCA cases against companies regulated by FDA, using a theory that purported regulatory violations, such as those relating to good manufacturing practices, could form a legal basis for an FCA case.  Just last week a judge in California issued a thorough and well-written decision that may put to rest plaintiffs’ efforts to use FDC Act matters to support an FCA case.

In U.S. ex rel. Campie v. Gilead Sciences, Inc., No. 11-0941 (N.D. Cal. Jan. 7, 2015) a judge dismissed an FCA case.  Plaintiffs had alleged that Gilead and others had violated FDA cGMP regulations, and thus were liable under the FCA.  The court methodically went through each of plaintiffs’ theories and rejected all of them.  These theories included: (1) using an unregistered manufacturing facility; (2) distributing adulterated drugs; (3) making false statements in NDAs, in that impurities in the drugs were not identified in the NDAs; (4) submitting false certificates of analysis that an API was in compliance with cGMPs; and (5) using adulterated drugs in clinical trial products.

The court ruled that plaintiffs had failed to state a claim for relief under the FCA.  In particular, the court concluded that plaintiffs had failed to allege that defendants had engaged in any fraudulent conduct or made any false statement to CMS (Centers for Medicare and Medicaid Services).

Instead, plaintiffs had alleged that defendants falsely certified to FDA that they would comply with FDA’s cGMP regulations, and withheld information in various submissions to FDA.  However, the court’s thorough analysis of this issue resulted in yet another court ruling that alleged false certificates, statements and other allegedly fraudulent conduct directed at FDA during the approval process does not state a valid FCA cause of action, even though there are subsequent reimbursement requests made to CMS.

The court also said that even when companies make a purported false certification to a regulatory agency such as FDA, asserting that the company is in compliance with provisions of the FDC Act, that certification cannot in and of itself serve as a basis for an FCA cause of action.  Rather there must be a direct link between the alleged false statement and the resulting request for payment, namely that the payment must be conditioned on the falsity.  Here, the court concluded that reimbursement by CMS was conditioned only on the drugs having been approved by FDA, not whether Defendants were in compliance with FDA rules.

In a discussion that is relevant to many types of cases in suits filed against drug and medical device companies, the court also noted the difficulty of second guessing FDA’s decision to approve a drug.  The court refused to delve into what it called “the complexities, subtleties and variabilities of the FDA approval process,” because the court would have had to determine whether a falsity submitted to FDA would have caused the agency to make a different approval decision than the agency made.  “Violations of for example cGMPs would seem better addressed by the FDA regulatory process than by the blunt tool of FCA litigation.”

The answer to the question “can I be sued” is thus all too often yes.  The answer to “can I be sued for doing xxx” is also too often yes.  The better question to ask is “if I am sued for xxx, what is the likelihood that the suit will be successful?”  This court ruling should give comfort to many FDA-regulated companies that although they will continue to face a serious threat of so-called whistleblower suits under the FCA, the cases may well not make their way past a Motion to Dismiss.

By Riëtte van Laack –

According to an FTC Complaint, filed in the United States District Court for the Northern District of Illinois, the advertising practices of NourishLife, an Illinois Company, and its owner, Mark Nottili, (“Defendants”) violated the FTC Act.  The FTC alleges that Defendants falsely advertised its “speech” supplements with claims that the products would help children with speech problems and develop normal speech and language capacity, without having clinical evidence to support such claims.  The FTC asserts that from at least 2008 through 2013, Defendants sold the supplements on the company’s website and through a network of distributors.  Among other things, the FTC alleged that:

• Defendants claimed that the speech products were clinically proven to work whereas they had no clinical data;
• Defendants claimed that a website, which discussed evidence regarding the effectiveness of various ingredients included in Defendants’ speech products, was independent, whereas Defendants controlled the website; and
• Defendants used “dramatic testimonials from parents” but failed to disclose a material connection between the parents (who received free supplies) and Defendants.

Under a proposed stipulated settlement Defendants will be enjoined from making advertising claims for Defendants’ speech products unless they possess competent and reliable scientific evidence to support the claims.  For the speech products,  “competent and reliable scientific evidence” is “evidence [on the covered or an essentially equivalent  product] that is sufficient in quality and quantity, based on standards generally accepted by experts [in the field] when considered in light of the entire body of relevant and reliable scientific evidence, to substantiate” the speech product’s claim.  The clinical testing must

(1)  “be randomized, double-blind, and placebo-controlled” (“RCT”) and
(2)  “be conducted by researchers qualified by training and experience to conduct such testing.”

Notably, the settlement does not specify the number of RCTs required for claims for the speech products.  The provision regarding substantiation of claims for non-speech products does not include a specific requirement for RCTs.

The proposed settlement also addresses Defendants’ future use of endorsements and testimonials.  Any material connections must be disclosed “clearly and conspicuously, and in “close proximity” to the endorsement, testimonial, or other representation.  The terms “clearly and conspicuously” and close proximity” are defined (e.g., “close proximity” means “on the same print page, webpage, or other electronic page, and not accessed or displayed through hyperlinks, pop-ups, [etc.]”). 

The settlement includes a monetary judgment of $3.68 million.  However, due to the Defendants’ alleged inability to pay, all but $200,000 of this amount is suspended.  

By Kurt R. Karst –      

A little over three months ago, we on a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction Takeda Pharmaceuticals U.S.A., Inc.’s (“Takeda”) filed against FDA in the U.S. District Court for the District of Columbia challenging the Agency’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares.  Takeda is the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, which FDA approved back in 2009 to prevent gout, treat gout flares, and treat Familial Mediterranean Fever.  The Orange Book currently list a single period of unexpired non-patent exclusivity for COLCRYS, as well as information on several patents that expire in 2028 and 2029.  The MITIGARE NDA does not cite COLCRYS as a listed drug relied on for approval, but rather a different drug: COLBENEMID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) FDA approved under NDA 012383 on July 27, 1961, that is no longer marketed, and for which no patents are listed in the Orange Book.  That choice of listed drug for the MITIGARE 505(b)(2) NDA is at the heart of Takeda’s early October 2014 lawsuit against FDA. 
 
Briefly, Takeda alleges that FDA’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act in several respects:

First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products.  Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.  And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process. 

A lot has happened since early October.  Here are some highlights . . . .

• On November 4, 2014, three related entities – Elliott Associates, L.P.,  Elliott International, L.P., and Knollwood Investments, L.P. (collectively “Elliott”) – with investment interests in COLCRYS filed a separate Complaint against FDA in the D.C. District Court challenging the Agency’s approval of MITIGARE along the same lines as Takeda.  Elliott also filed a Motion for Summary Judgment in its case.  D.C. District Court Judge Ketanji Brown Jackson subsequently determined that the two cases should be considered in tandem.
• On November 5, 2014, Judge Jackson converted Takeda’s Motion for a Preliminary Injunction into a Motion for Summary Judgment by consolidating Takeda’s Motion for a Preliminary Injunction with the merits of Takeda’s case against FDA.  Also, Judge Jackson subsequently permitted Hikma and West-Ward to intervene in the case.
• Cross-Motions for Summary Judgment were subsequently filed by FDA (here) and Hikma/West-Ward (here) in the Elliott case.  (Additional briefs filed in the cases along the way are available here, here, here, here, here, and here.)
• Meanwhile, in a patent infringement action Takeda filed against Hikma and West-Ward in early October in the U.S. District Court for the District of Delaware, see Takeda Pharmaceuticals U.S.A., Inc. v. West-Ward Pharmaceutical Corporation et al, Case No. 1:14-cv-01268-SLR, that district court issued a Temporary Restraining Order (on October 9, 2014) preventing Hikma from marketing MITIGARE.  Later, the district court denied Takeda’s request for a Preliminary Injunction, which Takeda appealed to the U.S. Court of Appeals for the Federal Circuit, but granted an injunction pending appeal.  On January 9, 2015, the Federal Circuit issued an Order (Memorandum Opinion to follow) affirming the Delaware District Court’s Order denying Takeda’s Motion for Preliminary Injunction, and vacating the injunction pending appeal ordered by the Delaware District Court.

That brings us to Judge Jackson’s January 9, 2015 Order.  In it, Judge Jackson denied Takeda’s Motion for Summary Judgment, denied Elliott’s Motion for Summary Judgment in the separately filed action, and granted FDA’s and Hikma’s/West-Ward’s Cross-Motions for Summary Judgment in the Elliott action.  Those decisions led Judge Jackson to order the dismissal of the Elliott action, and also to order that Takeda show cause (on or before January 23, 2015) as to why the D.C. District Court should not dismiss Takeda’s lawsuit sua sponte. 

Unfortunately, Judge Jackson's Memorandum Opinion providing the basis for her decisions is not yet public.  It was issued under seal on January 12, 2015 is is reportedly "quite lengthy."  (A response to the court's Order to Show Cause as to why the Memorandum Opinion should not be made public is due by January 23, 2015.)  So consider this post as a setup to a further discussion of the issues in the case once the decision is unsealed. 

Regardless of when Judge Jackson’s Memorandum Opinion will issue, it appears that the parties will fight on.  Shortly after Judge Jackson’s Order was handed down last Friday, Takeda and Elliott separately filed an Emergency Motion for Injunction Pending Appeal (here and here).  FDA and Hikma/West-Ward promptly opposed the motions (here and here).

The battle over FDA’s approval of MITIGARE is not the only battle over a 505(b)(2) application we’re keeping a close eye on these days.  As we previously reported, FDA was sued in December after the Agency granted only a tentative approval to Veloxis Pharmaceuticals, Inc.’s 505(b)(2) NDA 206406 for ENVARSUS XR (tacrolimus extended-release tablets), 0.75 mg, 1 mg, and 4 mg, for prophylaxis of organ rejection in kidney transplant patients.  That battle, which concerns the scope of 3-year non-patent exclusivity, has been on hold until FDA issues a decision on the underlying merits in the matter.  FDA was supossed to have issued a decision on January 12, 2015.  The parties were ordered to appear before the court for a status hearing on January 14, 2015. 

UPDATE:

• The following Minute Order was entered late on January 12, 2015: "MINUTE ORDER denying Takeda's Emergency Mot. for Inj.  Relief Pending Appeal and Elliott's Mot. for Inj. Pending Appeal and Joinder in Takeda's Mot. for Same.  This Court issued an order denying Plaintiffs' motions for summary judgment on January 9, 2015, and filed a lengthy opinion stating the reasons for that order today. (See Order, ECF No. 68; see also Mem. Op., ECF No. 74.)  Plaintiffs have now moved for a stay of this Court's order pending appeal.  "A party who moves for a stay or injunction pending appeal bears the burden of showing [that] the balance of four factors weigh[s] in favor of the stay/injunction: (1) the likelihood that the party will prevail on the merits of the appeal; (2) the likelihood that the party will be irreparably harmed absent a stay; (3) the prospect that others will be harmed if the court grants the stay; and (4) the public interest in granting a stay."  McCammon v. United States, 584 F. Supp. 2d 193, 197 (D.D.C. 2008) (citing United States v. Philip Morris USA, Inc., 449 F. Supp. 2d 988, 990 (D.D.C. 2006)).  In considering such a motion, the Court must be mindful of the fact that "a stay pending appeal is 'always an extraordinary remedy,' and that the moving party carries a heavy burden to demonstrate that the stay is warranted."  Philip Morris, 449 F. Supp. at 990 (quoting Brotherhood of Railway and Steamship Clerks, Freight Handlers and Station Employees v. National Mediation Board, 374 F.2d 269, 275 (D.C. Cir. 1966)).  With that standard in mind, this Court has considered the applicable factors and concludes that the balance of these factors weighs against entering the injunction that Plaintiffs seek.  Plaintiffs are unlikely to prevail on the merits of their appeal for the reasons stated in this Court's opinion denying their motions for summary judgment, and whatever economic harm that Plaintiffs may suffer in the absence of a stay is outweighed by the harms that the Defendant-Intervenors and the public at large will suffer as a result of a stay. Consequently, Plaintiffs' Motions for Stay Pending Appeal are DENIED."

By James C. Shehan –

FDA’s Oncologic Drugs Advisory Committee unanimously voted in favor of approval of EP2006, Novartis’s biosimilar version of Amgen’s Neupogen® (filgrastim) for all five of the indications for which Neupogen is approved. This ground-breaking event manages to both move the US a little closer to the long-awaited first approval of a BPCIA biosimilar and to highlight the challenges biosimilars have overcome and the open issues they still face before winning FDA approval, launching and gaining market acceptance. Among those issues are what the generic names will be, the standard for interchangeability and the applicability of the patent dance provisions.

Novartis announced in July that EP2006 was the first 351(k) application accepted for review by FDA, an event that occurred almost 4 12 years after passage of the BPCIA. Neupogen was first approved in February 1991 and is a relatively simple biologic, checking in at 175 amino acids. Amgen sold about $1.2B of Neupogen last year. Novartis, which claims world leadership in the biosimilar market, currently sells biosimilar filgrastim (as Zarzio) in over 40 countries. It is one of 19 approved biosimilars in Europe, where it was approved in February 2009 (EMA Public summary).

In advance of the advisory committee meeting, Novartis announced in December the results from Pioneer, its Phase 3 study of 218 patients. According to Novartis, Pioneer demonstrated EP2006’s similarity to Neupogen in the prevention of severe neutropenia in breast cancer patients. Novartis also said that the study showed that repeated switching at each cycle between the biosimilar and reference filgrastim showed no impact on efficacy, safety or immunogenicity.

As is customary, the Advisory Committee meeting was preceded by FDA’s release of a briefing document. The briefing document states that the analytical data show that both clinical and commercial lots of the Novartis product are “highly similar” to Neupogen notwithstanding “minor differences in clinically active components.” FDA also stated that the clinical development program showed that "there are no clinically meaningful differences” between EP2006 (Novartis’s internal name for its product) and Neupogen in terms of safety, purity and potency.” FDA specifically cited five PK and PD studies in healthy subjects and the Pioneer study. Of particular note, FDA discussed in the briefing document that commercial lots of EP2006 had a lower protein content than Neupogen, an issue that did not occur with the EP2006 clinical study lots. FDA also referenced Novartis’s use of EU-approved Neupogen in some clinical studies and the comparability studies submitted by the company to support the use of non-US product.

FDA added eight temporary members to the roster of the Oncologic Drugs Advisory Committee for this meeting, including the chief of the cell processing section of NIH’s Clinical Center, a biochemical engineer, a pharmaceutical sciences expert and a pharmacology expert. Given the reliance on analytical as well as clinical data to support biosimilar approval, this is not surprising.

As reflected in the unanimous votes on the questions raised by FDA, the Advisory Committee ultimately had relatively few concerns about the safety and efficacy of EP2006. The issue of pricing was, however, raised by several committee members, and questioning of one Novartis employee led to an assurance that the product would cost less than Neupogen (see New York Times article here).

The issues that were not raised in the briefing document and at the meeting are worth noting. One prominent one is of course whether the Novartis product will have the generic name filgrastim or some variant. Another issue for Novartis is that its proposed brand name, Zarxio, has apparently not yet been accepted by FDA. Without either a settled generic or brand name, the internal reference EP2006 was used throughout the meeting and in the briefing document. There was also no mention at all of interchangeability, governed by a higher standard than simple biosimilarity.

Assuming that FDA accepts its advisory committee’s recommendation and moves on to approval, EP2006 faces another big challenge before it gets to the market. Novartis and Amgen are locked in patent litigation that has raised the issue of whether and how the complicated patent dance provisions of the BPCIA applies (see our previous posts here, here, here and here).  Amgen recently fled a Motion for Partial Summary Judgment in the case. The issue that has spilled over into an FDA citizen petition (see our previous post here).  And patent dance applicability reared its head on another front last week as Momenta supplemented its 2012 comments to an Amgen citizen petition that requests FDA to declare that the patent dance provisions are mandatory (see comments here).

One other event last week illustrates the less than smooth road ahead for biosimilars. FDA announced that it plans to issue four more biosimilar guidances in 2015, covering interchangeability, labeling, statistical issues, and additional general questions and answers.

By Ricardo Carvajal –

A California federal district court granted summary judgment in favor of the government in a lawsuit brought by animal rights organizations that focused on treatment of egg-laying hens.  Plaintiffs initially filed petitions with several federal agencies asking them to issue regulations that would have required egg producers to identify their egg production methods (e.g., cage-free vs. battery cage) on the label of their eggs.  When the petitions were denied, plaintiffs filed suit, alleging that the denials were arbitrary and capricious in violation of the APA.

As expected given their varying statutory authorities, each of the agencies in question cited somewhat different grounds for denying the petitions.  In part, FDA claimed that it lacked authority “to regulate egg labeling based only upon consumer interest in animal welfare (as opposed to reasons relating to safety or nutrition).”  FTC “found that the plaintiffs' petition provided insufficient evidence by which [FTC] could conclude that consumers are deceived by egg producers' current labeling practices.”  USDA/AMS concluded that it could not require the labeling desired by plaintiffs under its voluntary marketing programs, and USDA/FSIS concluded that its labeling authority over shell eggs was too limited to accommodate the plaintiffs’ request. 

The court held that none of the agency responses were arbitrary or capricious.  A common thread running through the court’s analysis of FDA and FTC’s responses was the high level of deference accorded to an agency’s refusal to promulgate a rule, particularly where rulemaking is left to agency discretion (as opposed to being mandated by Congress).