By Kurt R. Karst –      

There’s no rest for the weary!  There certainly hasn’t been much rest for FDA’s litigation team this past week . . . . and it’s not getting any better.  The week started off quiet (though clearly anxiety was in the air), as folks awaited FDA’s decision on whether or not to approve generic versions of Otsuka Pharmaceutical Co.’s  blockbuster drug ABILIFY (aripiprazole) with labeling that omits certain information protected by orphan drug exclusivity.  But that was the end of the quiet.

Late Monday, the first lawsuit dropped.  Spectrum Pharmaceuticals, Inc. (“Spectrum”) filed a Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction challenging FDA’s February 24, 2015 denial of a Citizen Petition (Docket No. FDA-2014-P-1649) and March 9, 2015 approval of an ANDA for a a generic version of FUSILEV (levoleucovorin) for Injection with labeling that omits certain information protected by orphan drug exclusivity. 

On Tuesday, FDA handed down its Aripiprazole Letter Decision and announced (around 1:30 PM) that the Agency had approved ANDAs.  That reignited a legal battle that had been brewing for the past month (see our previous post here), as well as Otsuka’s Motion for Temporary Restraining Order and/or Preliminary Injunction.  Later that afternoon, the parties convened in the U.S. District Court for the District of Maryland before Judge George J. Hazel, who indicated he would rule promptly on Otsuka’s Motion for Temporary Restraining Order and/or Preliminary Injunction.

On Wednesday morning, the U.S. District Court for the District of Columbia heard Oral Argument on Spectrum’s challenge to generic FUSILEV approval.  Judge Royce C. Lamberth quickly denied Spectrum’s request for a Temporary Restraining Order, and scheduled a Preliminary Injunction Hearing for May 18, 2015.  On Wednesday evening, Judge Hazel denied Otsuka’s Motion for Temporary Restraining Order and/or Preliminary Injunction. 

We were hopeful that Thursday would be a day of rest.  Fat chance!  The “rule of three” came into play. . . .

On Thursday morning, we learned that late on Wednesday, Boehringer Ingelheim Pharma GmbH & Co. KG and Boehringer Ingelheim Pharmaceuticals, Inc. (collectively “Boehringer”) filed a Complaint in the U.S. District Court for the District of Columbia alleging that FDA and the U.S. Patent and Trademark Office (“PTO”) shorted by about two months a Patent Term Extension (“PTE”) for a patent – U.S. Patent No. 6,087,380 (“the ‘380 patent) – covering Boehringer’s PRADAXA (dabigatran etexilate) Capsules approved under NDA 022512. 

In February 2015, we posted on FDA’s PTE regulatory review period decision.  In short, as explaind in the operative Federal Register notice:

[Boehringer] claims December 15, 2009, as the date the new drug application (NDA) for PRADAXA (NDA 22–512) was initially submitted.  However, FDA records indicate that NDA 22–512, received December 15, 2009, was incomplete.  FDA refused to file this application and notified the applicant of this fact by letter dated February 12, 2010.  The completed NDA was then submitted on April 19, 2010, which is considered to be the NDA initially submitted date.

Boehringer alleges in its Complaint that FDA violated the Administrative Procedure Act when the Agency unlawfully relied on the NDA “filing” standard instead of an “initially submitted” standard in the Agency’s calculation of PTE for the ‘380 patent.  Specifically, Boehringer says that:

The PTE statute unambiguously states that the approval phase begins when a marketing application is “initially submitted” to FDA. An application is “initially submitted” when it “contains sufficient information to allow FDA to commence review.”  21 C.F.R. § 60.22(f).  The PRADAXA® application was “initially submitted” to FDA no later than December 15, 2009, when BIPI submitted the final elements of the application.  At this point, all of the required elements of the PRADAXA® application were submitted, and the application contained sufficient information for FDA to commence review.  FDA was actively reviewing the application, and it continued to do so thereafter, even after FDA issued the RTF Letter.

In addition, Boehringer alleges that FDA’s action cannot be squared with past Agency practice, saying that “[t]he agency previously has explained that once review has commenced, the approval phase is triggered; FDA cannot thereafter revert back to the testing phase.”   Boehringer cites a 1985 notice (50 Fed. Reg. 19,809 (May 10, 1985)) providing FDA’s PTE regulatory review determination for Tonocard Tablets to support that contention. 

What will next week bring (or Friday, May 1st for that matter)?  Who knows, but it will be difficult to top this week.

By David B. Clissold –

A bill, H.R. 2058, introduced into the House of Representatives is short in length, but potentially long on effect for many tobacco product manufacturers.  The Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) established February 15, 2007 as the date on which tobacco products are deemed to be “new tobacco products.”  New tobacco products are subject to the premarket review requirements in the Tobacco Control Act — notably either a report under § 905(j) of the Federal Food, Drug, and Cosmetic Act (FDC Act) demonstrating substantial equivalence to a product that was commercially marketed in the U.S. as of February 15, 2007, or a premarket tobacco product application (PMTA) under § 910(b) of the FDC Act.  Thus, tobacco products that were commercially marketed in the U.S. as of February 15, 2007, are not “new tobacco products,” and FDA refers to these products as “grandfathered.”

Anticipating inevitable regulation, manufacturers of e-cigarettes and other novel tobacco products almost immediately recognized that it could be difficult to find a product on the market before February 15, 2007 to which they could show substantial equivalence, thus leaving the more burdensome PMTA as the only route to market.  In April 2014, when FDA issued the proposed deeming regulations that would make e-cigarettes, cigars, pipe tobacco, nicotine gels, waterpipe (or hookah) tobacco, and certain dissolvable tobacco products subject to regulation under the Tobacco Control Act (see our story here), the Agency recognized this dilemma: 

Based on initial information FDA has gathered and received from industry, many tobacco products we are proposing to deem that are currently being sold may not be “grandfathered” tobacco products because many were not commercially marketed or modified until after February 15, 2007.  We understand that this may be particularly true in the case of e-cigarettes and similar novel products.  Moreover, new products that come on the market in the future would never be grandfathered tobacco products because they would be coming on the market after February 15, 2007. We do not believe that we have the authority to alter or amend this grandfathering date, which is set by statute.

Among its requests for comment on many elements of the proposed deeming regulation, FDA asked for public comment on whether the Agency should consider “other legal interpretations of the substantial equivalence grandfather provision.”

H.R. 2058 would eliminate this predicament.  The bill simply removes all references to February 15, 2007 and replaces it with “the effective date of the regulation under which a tobacco product is deemed subject to the requirements of” the Tobacco Control Act.  Thus, the new grandfather date would be tied to the date on which FDA makes the deeming regulations effective.  As a result, many more current tobacco products would be “grandfathered” and thus exempt from the premarket review requirements, and future tobacco products would have a larger number of products to reference for substantial equivalence.  Despite the simplicity of the bill, these larger consequences may be expected to generate much public debate.

By Riëtte van Laack –

On Monday April 20, 2015, Senators Dianne Feinstein (D-Calif.) and Susan Collins (R-Maine) introduced the Personal Care Products Safety Act (S. 1014).  The almost 100-page bill would significantly expand FDA's authority over cosmetic products sold in the United States.  The bill addresses a range of issues including registration of facilities, registration of products, mandatory recall authority, adverse and serious adverse event reporting, good manufacturing practices, and user fees.  The bill’s drafters seem to have drawn from existing provisions in the FDC Act applicable to nonprescription drugs, such as establishment and product registration requirements, and from certain provisions applicable to foods, such as the provision giving FDA mandatory recall authority. 

Interestingly, the requirements for adverse event reporting exceed requirements applicable to non-prescription drugs.  Under the proposed bill, companies must report “serious” adverse events (i.e., death; life-threatening experience; inpatient hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or significant disfigurement, including serious and persistent rashes and infections; or events that require a medical or surgical intervention to prevent any of these outcomes) within 15 business days.  Companies also must report all nonserious adverse events (broadly defined as health-related events that are adverse) in an annual report (this report may not include complaints about efficacy).  Presumably to facilitate contacting the cosmetic company, cosmetic labels must include a domestic phone number or electronic contact information.  A domestic address is not an option. 

FDA’s mandatory recall authority would be limited to instances in which the use of or the exposure to a cosmetic is likely to cause serious adverse health consequences or death and the company has refused to voluntarily recall the product.

For products that are both non-prescription drugs and cosmetics, and, therefore, are subject to the requirements for non-prescription drugs as well as cosmetics, compliance with the requirements for nonprescription drugs which are “substantially similar” to the requirements under the proposed law, will be deemed compliance with the new law.  The law does not define “substantially” similar and further clarification will undoubtedly be required.

The bill also proposes to task FDA with investigation of at least five different cosmetic ingredients for safety each year. The ingredients FDA would study during the first year after enactment are: propylparaben (a common cosmetic preservative); methylene glycol (a formaldehyde-releasing chemical previously used in some hair-straightening treatments); diazolidinyl urea (a preservative used in various cosmetics including shampoo and conditioner), Quaternium-15 (a preservative used in shaving cream, skin creams, etc.) and lead acetate (used in hair dye).  There is no indication that FDA would be able to rely on the current industry-sponsored Cosmetic Ingredient Review (CIR).

Implementation of these proposed amendments to the FDC Act, including development of cosmetic GMP regulations and ingredient review, is estimated to cost $20.6 million per year.  These costs would be covered by registration fees.  The bill proposes to link the registration fee to the gross annual sales from cosmetics of the registered companies with fees ranging from $250 (gross sales from $500,000 to $2.5 million) to $1.1 million (gross sales of $5 billion (i.e., $5,000,000,000) or more). 

This bill is not the first effort to provide FDA with additional authority regarding cosmetics.   However, it certainly is the most comprehensive.

In a new guidebook published by the Food and Drug Law Institute, David B. Clissold and James E. Valentine of Hyman, Phelps & McNamara, P.C. co-authored Chapter 3-1, “FDA Regulatory Scheme,” and Alexander J. Varond authored Chapter 3-7, “Orphan Drugs.”

Both chapters cover essential elements of development and approval of pharmaceutical products in the United States.  The “FDA Regulatory Scheme” chapter provides a thorough overview of FDA’s laws, regulations, and guidance on drug development, including regulatory approval pathways, preclinical and clinical development, expedited development, and postmarket requirements.  The “Orphan Drugs” chapter discusses FDA’s orphan drugs program, including the process for requesting orphan drug designation, the benefits associated with designation, and orphan drug exclusivity.  The chapter also discusses key aspects of drug development for rare diseases, including FDA’s tropical disease and rare pediatric disease voucher programs, clinical trial design for rare diseases, patient advocacy, special considerations for developing drugs for rare pediatric diseases, and FDA’s historic flexibility in orphan drug approval.

By Kurt R. Karst –     

As you enter the Courtroom 402 “dance hall” at the U.S. Court of Appeals for the Federal Circuit on Wednesday, June 3, 2015, you’ll have to decide whether to take an initial right step and join the Amgen Inc. (“Amgen”) crowd, or move to the left and side with the folks from Sandoz Inc. (“Sandoz”) as the two sides battle over the applicability and correct interpretation of various provisions of the the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) in the context of Sandoz’s biosimilar version of Amgen’s NEUPOGEN (filgrastim), ZARXIO (filgrastim-sndz), which FDA licensed on March 6, 2015 under BLA 125553.  You’ll need to RSVP soon, however, because space is filling up fast!  There’s already a lineup of parties who want to be at the “must attend” BPCIA event of the year. 

The party at the Federal Circuit was kicked off after Judge Richard Seeborg of the U.S. District Court for the Northern District of California ruled on March 19, 2015 in a 19-page decision that, among other things, the BPCIA’s reticulated information exchange and patent resolution procedures are not mandatory for Section 351(k) biosimilar applicants, and that the plain language of the statute allows for the 180-day notice of commercial marketing to come well before the licensure of a Section 351(k) application (see our previous post here).  

The decision was a total victory for Sandoz, and thus, a total defeat for Amgen, which promptly appealed the decision to the Federal Circuit (see our previous post here).  Meanwhile, back in District Court, Amgen filed a Motion for Injunction Pending Appeal.  But Judge Seeborg denied that motion as well, saying that Amgen’s “tenuous and highly contingent showing of irreparable harm forecloses injunctive relief.”  Undeterred, and facing a possible launch of ZARXIO as early as Monday, May 11, 2015, Amgen is now asking the Federal Circuit for an Injunction Pending Appeal.  Sandoz recently filed its Opposition to Amgen’s motion, saying that “Amgen’s appeal involves no claim of patent infringement,” and instead, “Amgen seeks to enjoin launch of Sandoz’s FDA-approved biosimilar filgrastim product based solely on Sandoz’s purported violations of procedures of the [BPCIA],” which “contains no mechanism for Amgen to preclude Sandoz from launching absent a showing of patent infringement.” 

Briefing on Amgen’s appeal is nearly complete.  As we previously reported, Amgen filed its Opening Brief on April 3, 2015 laying out the company’s arguments as to why Judge Seeborg erred in ruling on all fours for Sandoz.  Not long thereafter, Amgen received support from several parties that filed amicus briefs.  (Amgen’s Reply Brief is due on April 28, 2015.) 

Janssen Biotech, Inc. (“Janssen”) urges the Federal Circuit in its amicus brief to “clarify that the statutory patent dispute resolution procedures are intended to be followed as written, and are not merely optional choices or empty formalities, as Sandoz contends.”  Janssen is currently challenging, in the U.S. District Court for the District of Massachusetts, Celltrion, Inc.’s (“Celltrion’s”) and Hospira, Inc.’s (“Hospira’s”) decision to exit from the BPCIA’s patent dance procedures in the context of a biosimilar version of Janssen’s REMICADE (infliximab) (see our previous post here). 

AbbVie Inc. (“AbbVie”), which markets HUMIRA (adalimumab), among many other products, has not yet had to engage in litigation over the BPCIA’s information exchange and patent resolution provisions, but weighs in for Amgen in an amicus brief.  According to AbbVie, absent a reversal of Judge Seeborg’s decision, biosimilars patent litigation will devolve into chaos:

The outcome of this appeal will have a profound effect on the transparency, efficiency, and fairness of the legal process going forward. If Amgen’s positions are adopted—and Congress’s directives are enforced—parties will enter the litigation process well informed; they will be able to identify the patents truly at issue, engage in good-faith negotiations, narrow their disputes, and litigate only those issues that warrant the courts’ time and attention.  If Sandoz were to prevail, the entire biosimilar litigation process would become a free-for-all, where biosimilar companies would utilize the data and work of innovator companies but refuse to provide basic information about their products, including their compositions, indications, formulations, and manufacturing processes, as well as the timing of their planned launches, leaving innovators to blindly guess as to which patents they should sue on and when.  The first option will lead to more focused cases, more transparency, and more frequent and earlier settlements; the second will burden the courts with inefficient and protracted litigation for years to come.

Finally, the Biotechnology Industry Organization (“BIO”), whose members include both Amgen and Sandoz, says in its amicus brief that “the BPCIA patent dispute resolution process must be interpreted in accordance with its purpose — to provide a significant and real opportunity to resolve patent issues prior to the launch of the biosimilar,” which requires, in turn, “notice to the reference product sponsor of the initial submission of the biosimilar application and notice of potential commercial marketing upon approval.”

Sandoz, in the company’s April 21, 2015 Non-Confidential Brief, does an excellent job of laying out why the waltz preferred by Amgen and its supporters is not the only move on the dance floor, and why a shuffle (or perhaps a side step?) is perfectly reasonable under the BPCIA.  According to Sandoz: 

Read in the context of the BPCIA as a whole, the “shall” provision in Section 262(l)(2)(A) is a mandatory condition precedent to engaging in the patent-exchange process, not a mandatory requirement in all circumstances. . . .  This interpretation is consistent with uses of “shall” in other provisions in subsection (l), as well as with uses of “shall” in other statutory schemes.  It also gives full effect to both “shall” and “may” in subsection (l)(2)(A). . . .  Congress carefully balanced the interests between sponsors and applicants, determined what the consequences should be at each step of the process for not completing it, and allowed the parties to weigh the benefits of proceeding against the consequences of not.

With respect to notice, says Sandoz, “[t]he plain terms of the ‘[n]otice of commercial marketing’ provision are satisfied when an applicant provides notice at least 180 days before it commercially markets its product.”  “If, as Amgen argues, a biosimilar must be licensed before notice may be given, that would transform this mere ‘[n]otice’ provision into an automatic, six-month bar against marketing of every licensed biosimilar product. Had that been Congress’s intent, it would have said so.”

Sandoz’s arguments are reinforced in an amicus brief filed by the Generic Pharmaceutical Association (“GPhA”), which recently announced the launch of a new division, called the Biosimilars Council.  According to GPhA:

The question here is whether the BPCIA’s patent dispute resolution provisions should be interpreted according to the statute’s clear structure, which in turn supports Congress’s overarching goals of increased competition and consumer access to affordable biologics.  The answer, as the district court found, is yes.  The contrary readings advanced by Amgen and its amici depend on illogical, context-free interpretations of selected individual words that if read as Amgen suggests would render superfluous important sections of the BPCIA, undercut the statute’s overarching purposes, and produce results that Congress could not possibly have intended.

According to a recent docket entry, Celltrion and Hospira also tendered an amicus brief.  That brief is not yet public; however, we’ll update this post with a copy of the brief once it is available.  

UPDATE:  The amicus brief filed by Celltrion and Hospira was made public on Monday afternoon (April 27th) and is available here. 

By Allyson B. Mullen –

On April 22, 2015, FDA released a draft guidance regarding use of clinical data generated outside of the U.S. (OUS) in medical device premarket submissions.  A copy of the draft guidance can be found here. 

FDA states in the guidance that it has a longstanding policy of accepting OUS clinical data in device submissions.  However, as many of our readers know, FDA can be very picky when it comes to clinical study data that were not conducted in the U.S. under an Investigational Device Exemption.  In 2012, FDASIA attempted to allow greater use of OUS clinical data with the addition of Section 569B of the Federal Food, Drug, and Cosmetic Act.  Section 569B requires that FDA accept OUS clinical data if the sponsor has demonstrated that “such data are adequate under applicable standards to support approval, licensure, or clearance of the . . . device in the United States.”  21 U.S.C. § 360bbb-8b(a).  If FDA finds that the data are inadequate, FDA must provide written notice to the sponsor with FDA’s rationale for its conclusion. Id. § 360bbb-8b(b). 

The draft guidance provides some clarification as to why CDRH and CBER may find that OUS clinical data are inadequate.  Specifically, the draft guidance highlights that premarket submission reviewers carefully consider the following when evaluating OUS clinical data:

• Differences in Clinical Conditions.  The standard of care for clinical conditions may be different around the world.  FDA will likely want to understand how the clinical practice in the region(s) where the study was performed compare to the U.S. as differences in clinical practice can affect the risk benefit profile of the device.
• Differences in Study Population.  The patient populations can vary greatly depending on the country in which the study is performed.  This differences can affect the applicability of the data to the proposed U.S. population.  For example, there may be significant demographic differences (race, ethnicity), rates of certain diseases, or prevalence of other factors (obesity, smoking).  FDA will likely want to understand how the study population is representative of the proposed U.S. patient population and that any differences are adequately explained.
• Differences in Regulatory Requirements.  The draft guidance notes that the standards for regulatory approval vary depending on the region (e.g., safety and effectiveness versus safety and performance).  This difference could also affect a company’s selection of endpoints or control device, if one is used.  Thus, the draft explains that the outcome of the study must show that the probable benefits outweigh the probable risks, or although not stated, that the device meets the applicable premarket standard (e.g., substantial equivalence).

None of these considerations come as a surprise and they are routine comments that come up during premarket submission reviews for submissions including OUS data.  The draft guidance does provide a number of helpful examples for companies who are unfamiliar with these issues.

The draft guidance recommends that sponsors who intend to utilize OUS data in their submissions contact FDA through the pre-submission process as early as possible so that FDA can provide input.  This guidance, however, applies not to just prospective OUS studies, but also to those that have already been performed.  There may be little value in seeking FDA input through a pre-submission on a study that is already completed, when this same information can be obtained through the premarket submission review process.  This guidance could likely serve as a reminder checklist for sponsors utilizing OUS to data to confirm that they have addressed these considerations in their premarket submissions before submitting to FDA, regardless of whether a pre-submission meeting is held.

By David C. Gibbons –

On Tuesday, April 21, 2015, the U.S. Department of Health and Human Services Health Resources and Services Administration (“HRSA”) issued a Notice soliciting comments on its proposal to collect pricing data from drug manufacturers under the 340B drug discount program.  This Information Collection Request (“ICR”) is intended to implement § 340B(d)(1)(B)(i) of the Public Health Service Act (“PHSA”), a provision added in 2010 by the Affordable Care Act that requires HRSA to develop a system to verify the accuracy of calculated drug ceiling prices charged to 340B covered entities.

The notice explains that HRSA is developing a secure system for manufacturers to submit Average Manufacturer Price, Unit Rebate Amount, Package Sizes, National Drug Code (“NDC”), the quarter of sale, and the manufacturer’s calculated 340B ceiling price for each NDC.  All but the last of these data points are already reported by manufacturers to CMS under the Medicaid Drug Rebate Program.  HRSA will compare the 340B ceiling prices submitted by manufacturers against those calculated by HRSA using CMS data, and resolve any discrepancies.  Validated submissions will be made available to 340B covered entities and accessible through a secure, Internet-based platform, as required by PHSA § 340B(d)(1)(B)(iii).  HRSA unrealistically estimates that it will take manufacturers one-half hour to prepare and submit each quarterly report.  Comments on this ICR my be submitted through May 21, 2015.

By Riëtte van Laack –

As we previously reported, the U.S. Court of Appeals for the D.C. Circuit issued a decision in what some have identified as a landmark advertising case of the Federal Trade Commission (FTC) against POM Wonderful et al. (POM).  On April 6, 2015, POM requested a rehearing from the entire D.C. Circuit to address, what POM claims is, “the exceptionally important question whether the [DC Circuit] must defer to an agency [in this case the FTC] finding that speech is not protected by the First Amendment.”

In its January 2015 decision, a three-judge panel of the D.C. Circuit held that POM’s advertising made false claims that POM products could treat, prevent, or reduce the risk of heart disease, prostate cancer, and erectile dysfunction.  The panel gave deference to the FTC’s determination that 36 ads were false and misleading even though the Administrative Law Judge had previously determined that only 19 ads made improper claims.  In its Petition for Rehearing En Banc, POM argues that the panel should not have given deference to FTC’s determination regarding the additional 17 ads.  It claims that many of these 17 ads contained qualified language signaling that the research findings mentioned in the ads were not conclusive.  According to POM, the panel’s deference was inappropriate because all the FTC did was apply its own judgment as to how “reasonable” people would interpret the ads.

Which ads are false or misleading is relevant for POM because it determines the scope of the FTC’s injunction.  If the 17 additional ads are not false or misleading, POM has a right to publish them.  POM maintains that these ads convey important information to consumers.

POM further argues that the Court should grant the rehearing because 1). food advertising cases frequently settle and the Court is unlikely to get another chance to consider the present issues, 2). “the chilling effect of definitively endorsing the weak standard of review in this case will be immense,” and 3). a case like the present one with a large number of claims at issue is unlikely to arise again soon.

In the alternative, POM requests that the panel reconsider its opinion and remove two specific paragraphs.  Although this edit will not affect the results for POM, it claims that it is important to remove these paragraphs because they “might be mischaracterized by future litigants to vastly expand the conduct that actually underlies POM’s . . . liability.”

The FTC’s response to the Petition is due May 4, 2015.

By James E. Valentine* & Josephine M. Torrente –

During FDA’s April 1, 2015 public workshop on clinical outcome assessments (COAs), in a presentation on the future of COA development and utilization in drug development programs, officials from CDER’s Study Endpoints and Labeling Development (SEALD) staff announced the development of a compendium of COA tools.  A clinical outcome assessment (COA) measures patients’ symptoms, overall mental state, or the effects of a disease or condition on how the patients function.  There are four types of COA measures:

• Patient-reported outcome (PRO) measures
• Clinician-reported outcome (ClinRO) measures
• Observer-reported outcome (ObsRO) measures
• Performance outcome (PerfO) measures

The Compendium’s Two Stages of Development

The COA compendium will be developed in two stages.  In Stage 1, or the pilot stage, the compendium will consist of (1) qualified tools, (2) ongoing qualification programs, and (3) previously labeled COAs (from new molecular entity labeling approved 2003 and later).  The compendium would be published a table that can be accessed through the FDA website, organized by therapeutic area and disease/condition.

The measurement tools that will be in the Stage 1 compendium consist of those that have arisen under FDA’s two current pathways for review and use of COAs in drug development.  The first is the traditional way, which is within an individual drug development program under an IND.  These tools, when found acceptable in the course of drug development, can result in labeling claims.  The second pathway for use of COAs is through a relatively new process, the Drug Development Tool (DDT) qualification program, which is a formal way to qualify instruments outside of an individual drug development program.  These “qualified” COAs are published in the Federal Register and are available publically for use in drug development programs.  To date, there is only one qualified clinical outcome assessment, a PRO that is published here. 

Stage 2 would expand the compendium, but exactly what information would be included has not been determined.  Future expansion may include an expanded scope (e.g., COAs from efficacy supplements), as well as identify gaps in available measurements tools (e.g., concepts highlighted as important in Patient-Focused Drug Development meetings but for which no tool exists). 

Goals of the Compendium & Next Steps

Because it is unrealistic to qualify all COAs, CDER hopes creating a public list of COAs used to support labeling claims would be useful to increase their development and use in drug development programs.  The compendium would essentially serve as a list of “potentially acceptable endpoints” that could support labeling claims, as well as encourage development COAs more generally.  However, the compendium would not include detail on endpoints so that sponsors will still need to discuss with FDA the selection and design of endpoints in clinical trials.

CDER announced it plans to publish a Federal Register Notice in September 2015 in order to gather comments on the proposed compendium (and associated guidance to describe the compendium), with the roll-out of Stage 1 of the compendium following the notice-and-comment period. 

Note: This public workshop on COAs was held to satisfy FDA’s Advancing Development of Patient-Reported Outcomes (PROs) and Other Endpoint Assessment Tools commitment in PDUFA V which, in part, committed FDA to “hold a public meeting to discuss FDA’s qualification standards for drug development tools, new measurement theory, and implications for multi-national trials.”

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Riëtte van Laack –

On April 9, 2015, US Right to Know (USRTK, Petitioner) filed a Citizen Petition (CP) with FDA and sent a letter to the Federal Trade Commission (FTC) requesting action against what USRTK claims is false and misleading use of the term “diet” on beverages that contain non-nutritional artificial sweeteners (NNAS).  

Petitioner takes issue with the labeling of sodas sweetened with NNAS as “diet.”  Although the FDC Act section 403(r)(2)(D) and FDA’s regulations allow such labeling, the use of the term diet is only permitted if the labeling is not false and misleading.

Citing certain dictionaries, Petitioner asserts that the term “diet” in the brand name of Diet Coke and Diet Pepsi constitutes a deceptive (and possibly fraudulent) claim that drinking these soft drinks will promote weight loss.  Without data to support its allegation, USRTK claims that reasonable consumers buy diet sodas, labeled as diet, not because they do contain zero calories or no sugar, but because they believe that the mere consumption of these products, without energy restriction, exercise, or other actions, will result in weight loss or reduced weight gain.

Yet, according to USRTK, these diet sodas do not contribute to weight loss.  USRTK claims that certain scientific reviews and epidemiological studies suggest (USRTK does not claim certainty) that consumption of sodas containing NNAS is linked to weight gain.  It claims that evidence to the contrary should not be trusted because the underlying studies were funded by industry.  USRTK alleges that Coco-Cola Co. and PepsiCo Inc. are aware of these studies but continue to (fraudulently) use the term diet.

Petitioners request that FDA issue warning letters or take other enforcement action against Coca-Cola Company and Pepsi Co. because their diet sodas products are misbranded even though they fully comply with the regulation, 21 C.F.R. § 105.66.  Petitioners also request that FDA conduct a “sweeping” investigation of products containing NNAS to determine whether those products are misbranded because they use the term “diet.”

As mentioned above, USRTK also sent a letter to FTC requesting that FTC investigate and prohibit the apparently deceptive use of the term “diet” by Coke and Pepsi and conduct the sweeping investigation mentioned in the CP to FDA. 

By David B. Clissold –

In September 2011, the Center for Tobacco Products (“CTP”) issued a draft guidance entitled “Demonstrating the Substantial Equivalence of a New Tobacco Product: Responses to Frequently Asked Questions” (“Draft Guidance”).  In the Draft Guidance, the Food and Drug Administration (“FDA”) claimed that the Tobacco Control Act (“TCA”) requires manufacturers to submit information for FDA to review before changing the label of a tobacco product.  On March 4, 2015, FDA issued the guidance in final form (“Final Guidance”).  Among other things, the Final Guidance states that labeling changes that make a product “distinct” from the predecessor version of the product should be submitted to FDA in a “Same Characteristics SE Report.”  Although changes in product quantity were not discussed in the Draft Guidance, the Final Guidance also states that changes in the quantity of tobacco product in a package (e.g., from 20 to 24 cigarettes per pack) should be submitted in a “Product Quantity Change SE Report.”  The Final Guidance described these reports as “alternatives” to submitting a full substantial equivalence (“SE”) report or a premarket application under section 910(b) of the Federal Food, Drug, and Cosmetic Act for these types of changes.  The Final Guidance describes the contents of the “Same Characteristics SE Report” and the “Product Quantity Change SE Report.”  Among other requirements, each report must contain a certification statement, signed by a responsible official who is authorized to act on behalf of the company, using proscribed language.  For example, a “Same Characteristics SE Report” must include the following certification:

I, [insert name of responsible official], on behalf of [insert name of company], certify that [insert new tobacco product name] has a different [identify distinction] from [insert name of predicate tobacco product] but is otherwise identical to [insert name of predicate tobacco product]. I certify that [insert name of company] understands this means there is no modification, except for [identify distinction] from the predicate tobacco product, including any change in materials, ingredients, design features, heating source, or any other features. I certify that this information and the accompanying submission are true and correct, and that I am authorized to submit this on the company’s behalf. I understand that under section 1001 of title 18 of the United States Code, anyone who makes a materially false, fictitious, or fraudulent statement to the Government of the United States is subject to criminal penalties.

In a complaint filed on April 14, 2015 in the United States District Court for the District of Columbia, plaintiffs Philip Morris USA Inc., U.S. Smokeless Tobacco Company LLC, R.J. Reynolds Tobacco Company, American Snuff Company, LLC, Santa Fe Natural Tobacco Company, Inc., and Lorillard Tobacco Company argue that the Final Guidance was unlawful and ask the court to set it aside.  The tobacco company plaintiffs challenge the guidance on three principal grounds: The Administrative Procedure Act, and the First and Fifth Amendments to the U.S. Constitution.

• The Administrative Procedure Act:  The complaint alleges that the Final Guidance is arbitrary, capricious, and contrary to the TCA, and also exceeds FDA’s authority under the TCA because it conflicts with the TCA’s structure and text and with FDA’s prior interpretations of the TCA.  In addition, it does not adequately inform manufacturers which label changes may render a product “distinct,” and therefore subject to FDA pre-approval.  The complaint also alleges that the Final Guidance sets forth final agency positions, imposes legal obligations, establishes consequences for non-compliance, and effects changes in existing law, and is thus a substantive rule for which FDA is required to conduct notice-and-comment rulemaking.  Plaintiffs also state that the Final Guidance interprets statutory or regulatory requirements and represents a change in FDA’s interpretation of the TCA, and therefore FDA was required to provide an opportunity for public comment.
• First Amendment to the U.S. Constitution:  The complaint alleges that the Final Guidance prohibits manufacturers from changing the label of a tobacco product without first obtaining FDA’s pre-authorization, thus violating plaintiffs’ First Amendment right to communicate with consumers through product labels.
• First and Fifth Amendments to the U.S. Constitution:  Plaintiffs argue that the Final Guidance does not give manufacturers fair notice of the label changes that may result in a “distinct” product subject to FDA pre-approval or articulate clear standards that prevent arbitrary enforcement by FDA.  This uncertainty chills plaintiffs’ exercise of their First Amendment right to communicate with consumers through product labels because, if FDA concludes that a change rendered the product “distinct” and a Same Characteristics SE Report was not filed, the manufacturers will be subject to significant civil and criminal penalties.

Challenges to certain elements of the TCA on First Amendment grounds have been successful in the past.  For example, the D.C. Circuit struck down FDA regulations requiring graphic warnings on cigarette packaging on First Amendment grounds (see our analysis of that case here).  But what caught our eye in the latest complaint was the allegation that FDA is attempting to regulate industry through guidance instead of notice-and-comment rulemaking (we have previously commented on that issue here and here).  That allegation reminded us about a letter sent to FDA by Senator Lamar Alexander (R-TN), the ranking member of the Senate HELP Committee, along with Senators Richard Burr (R-NC), Johnny Isakson (R-GA), and Orrin Hatch (R-UT) “to express significant concern about [FDA’s] use of draft guidances to make substantive policy changes” (see our post on that letter here).  Last month, FDA responded to that letter with a letter of its own.  While the focus of the inquiry was on the use of draft guidances to implement FDA policy, FDA also explained how it uses guidance documents more generally:

Guidance documents generally do not create legally enforceable rights or responsibilities and do not legally bind the public or FDA—importantly, they do represent the Agency’s current thinking.  Therefore, FDA employees may depart from guidance documents only with appropriate justification and supervisory concurrence.  Because guidance is not binding, affected parties may choose to use an approach other than the one set forth in a guidance document . . . [but any] alternative approach must comply with the relevant statutes and regulations.  FDA is willing to discuss an alternative approach with affected parties to ensure it complies with the relevant statutes and regulations.

But if a guidance compels a submission to FDA, to be accompanied by a certificate made under penalty of perjury, and FDA believes that submission is required under its interpretation of the statute, doesn’t that “legally bind” the public to follow the guidance?  What “alternative approach,” following any amount of discussion with FDA would satisfy that perceived requirement?  We hope the court will address these issues during the course of this litigation.

By Allyson B. Mullen & Jeff N. Gibbs –

As we have previously blogged on numerous times (for example, here and here), FDA has released a framework for regulation of laboratory developed tests (LDTs).  FDA’s proposed framework has sparked much controversy, receiving support from diagnostic test manufacturers and some patient groups, while other patient groups and the laboratory community have strongly opposed the draft framework.  Numerous comments on the proposed framework were submitted to FDA earlier this year. 

Recently, a different approach to LDT regulation has been floated.  The Diagnostic Test Working Group (DTWG), an independent group consisting of representatives from diagnostic manufacturers and clinical laboratories, released an alternative to FDA’s LDT Framework. 
 
The DTWG proposal offers a compromise for those on both sides of the LDT debate.  For laboratories, it would mean greater regulation of LDTs while not trying to fit LDTs into the traditional medical device regulatory framework, and for IVD manufacturers, it would result in significant changes to the current regulatory model.  A few key points of interest in the DTWG proposal:

• The proposal would apply to all in vitro diagnostic tests – both kits and LDTs, and components of the same (collectively IVDs) and calls for establishment of a new center within FDA.
• The proposal allocates responsibility for oversight of IVDs across FDA, CMS and the individual states.  FDA would be responsible for IVD development, CMS would be responsible for laboratory operations, and the states would be responsible for medical applications (e.g., test result interpretation and consultation).  This allocation is designed to address the concern about overlapping regulation.
• IVDs will be classified as high risk, moderate risk and low risk, and the proposal sets out criteria for classification into each category.  Developers of a new IVD will propose a classification to FDA, and FDA will have 60 days to object. 
• • IVDs can move from high risk to low risk when the test and/or analyte become well characterized. 
• • The proposal sets a new standard for IVDs: the developer must “establish a reasonable assurance of analytical validity and clinical validity for the intended use.”  Reasonable assurance would be established through competent and reliable evidence, which includes a number of different types of information such as published literature and clinical guidelines.  There would be a presumption that clinical trials would not be required to demonstrate clinical validity. 
• The premarket requirements for each of the three classifications are different.  High and moderate risk IVDs require premarket submissions and low risk IVDs merely require notification to FDA.
• New submissions would be required for test modifications to high and moderate risk IVDs, if the modification has a “meaningful clinical impact” or changes the intended use of the IVD.  A submission would be required for a low risk IVD, if the modification changes the intended use, purpose of the assay or the target disease or condition. 
• The proposal includes special pathways for IVDs for rare diseases, emergency use IVDs, and IVDs for unmet needs. 
• Post-market quality system and recall reporting will be generally the same as FDA’s current medical device requirements.  Adverse event reporting would be clarified to better fit IVDs.
• There is a proposed three or four year transition period for LDTs currently on the market and those that would enter the market after the proposal goes into effect. 
• Instrument platforms will be automatically classified as low risk.  Platform manufacturers would also be granted a safe harbor for discussion of off-label uses.
• Paralleling a relatively new program for pharmaceuticals, the proposal also includes priority vouchers for innovative IVDs.

In our view, this proposal is an intriguing start towards a potential LDT compromise. There are certainly many areas of clarification and development that are still required and many key details will still need to be worked out.  We expect that many laboratories will prefer the DTWG’s proposal as it would mean less onerous regulation compared to FDA’s proposed LDT framework.  Manufacturers may also find the change to IVD regulation to be attractive.  This proposal could form the basis of legislation that may be released in the near future.  We will keep readers apprised of any legislative developments. 

By Allyson B. Mullen –

On April 13, CDRH released the final guidance document for “Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions.”  We previously blogged on the draft guidance here.  The goal of the program is to facilitate access to novel devices through more interactive communications between FDA and manufacturers during the development process and more interactive reviews of premarket applications (e.g., IDEs, PMAs and de novo requests) and by focusing on post-market data. 

This final guidance was issued merely a year after issuance of the draft, which is a short period of time for FDA.  This swift release of the final guidance is presumably due in part to the modest changes that were made to the guidance from the draft and lack of controversy.  These minor changes include:

• The scope of the program was expanded from PMA devices only to PMA devices and de novo devices.  510(k)s, however, continue to be excluded. 
• The guidance was generally revised to include an increased focus on patient benefit.
• The final guidance clarified that interactive review, senior management involvement, and case manager assignment will be provided in the program to the extent resources are available.  It is still unclear, however, how availability will be determined and if any resources will be specifically allocated for this program.   
• The expedited access program (EAP) designation process was clarified, including, in Appendix 1 where it indicates that CDRH plans to review a Pre-Submission requesting EAP designation within 30 days of receipt.  The guidance also clarifies that granting of EAP designation does not mean that CDRH agrees with the applicant’s draft Data Development Plan or that any proposed study design will support a subsequent marketing application. 
• Additional examples have been added to facilitate better understanding of cases in which the EAP may be the appropriate pathway to device approval or de novo clearance.
• The final guidance indicates that it may be possible for applicants to use registry data to satisfy post-approval study requirements. 

Finally, the guidance includes a new Program Evaluation through which CDRH will publish statistics regarding the program, including the number of designation requests received and granted, and corresponding pre-market submissions approved or cleared following designation.  This evaluation will begin one year after issuance of the guidance and will continue for three years thereafter, after which CDRH will consider whether changes to the program are necessary. 

This evaluation may be an important addition to the guidance because CDRH has attempted other priority review programs in the past, including the 510(k) Priority Review Program, and these programs have generally been unsuccessful.  In fact, since 1995, only 23 510(k)s have been designated for priority review, and between 2008 and 2012, a mere five 510(k)s were designated for expedited review.  These five 510(k)s had an only marginally better review time than the average time for all other 510(k)s during that same time period.  Perhaps CDRH’s commitment to track performance data will help spur better results than similar prior programs. 

By Riëtte van Laack –

In an effort to stop the implementation of the National Organic Program’s (NOP’s) interpretation of the sunset review process, a coalition of organic “stakeholders” have filed a lawsuit in the U.S. District Court for Northern California.  The lawsuit alleges that the NOP violated the federal rulemaking process when it changed procedures for the sunset review of substances included in the National List of Allowed and Prohibited Substances (National List).  Plaintiffs allege that the “unilateral” action by the NOP to adopt a major policy change without a public process violates a foundational principle and practice of the Organic Food Production Act (OFPA), namely public participation in organic policy-making.  Plaintiffs request that the court require the NOP to reconsider its decision on the alleged rule change and reinstitute the “customary public hearing and comment process.”

The OFPA creates standards for organic certification and establishes the National Organic Standards Board (NOSB).  A major function of the NOSB is to oversee the allowance of synthetic and non-agricultural materials based on a determination that they do not harm human health and the environment and are necessary in organic food production and processing.  The National List identifies the synthetic substances that are allowed (exemptions) and the nonsynthetic (natural) substances that are not allowed (prohibitions) in organic production.  7 C.F.R. §§  205.601–604.  In addition, the National List identifies the nonorganic and nonagricultural substances that may be used in organic handling.  Id. §§ 205.605–205.606.

At issue in the lawsuit is the interpretation of the so-called sunset provision of the OFPA.  Under the OFPA, a review of substances on the National List takes place on a five-year cycle.  This “sunset” provision provides that “No exemption or prohibition contained in the National List shall be valid unless the National Organic Standards Board has reviewed such exemption or prohibition as provided in this section within 5 years of such exemption or prohibition being adopted or reviewed and the Secretary has renewed such exemption or prohibition.” 7 U.S.C. § 6517(e).  Plaintiffs allege that, until September 2013, this provision had been interpreted to require that all substances included in the National List cycle off the list after five years unless the NOSB votes by a two-thirds majority to relist them and NOP accepts the recommendation. 

In September, 2013, NOP issued a notice that announced what plaintiffs characterize as a substantive change in the process NOP had been operating under since the inception of the organic program.  In its notice, NOP asserted that the previously used sunset review process did not allow for “robust” public participation and delayed the sunset review process.  Essentially, the pre-Sept. 2013 sunset review process treated sunset substances as newly petitioned substances and the sunset rulemaking process from start to finish took as long as 30 months.  However, adding a substance to the National List involves a rigorous rulemaking process.  Once a substance is on the list, organic farmers and processors invest significant time and money to update their organic system plans and adjust their product formulations to reflect the change.  NOP concluded that, in light of this rigorous process, and given the importance of the National List to organic farmers and processors, the process to remove a sunsetting substance from the National List should be an equally rigorous process.

Plaintiffs argue that the NOP 2013 notice represents a substantive rule under the Administrative Procedures Act (APA) and that NOP violated the APA rulemaking process when it changed procedures for reviewing the NOP’s sunset review process without using the notice and comment rulemaking procedures mandated by the APA and by the standards of the OFPA.

Because there are a significant number of substances subject to sunset in the next few years, the outcome of this lawsuit will be relevant for many organic farmers and processors.

By Jay W. Cormier – 

It has been quite some time since the September 2010 Veterinary Medicine Advisory Committee (“VMAC”) meeting that discussed FDA’s review of AquaBounty’s AquAdvantage Salmon application.  Earlier this month, Food and Water Watch – a long-time and very vocal opponent to the AquAdvantage Salmon – filed a Citizen Petition (“CP”) and a Food Additive Petition (“FAP”) in an effort to block marketing of AquAdvantage Salmon filets, should an approval ever occur (available here). 

In the interest of full disclosure, your author, while working for FDA, helped develop FDA’s approach to the review and approval of genetically engineered animals, was one of the lead reviewers at FDA’s Center for Veterinary Medicine (“CVM”) for the AquAdvantage Salmon, and presented at the 2010 VMAC meeting on behalf of FDA. 

By way of background, as it has been such a long time since the FDA Law Blog last discussed the AquAdvantage Salmon (here and here), the salmon is a genetically engineered Atlantic salmon that has had a single copy of a transgene inserted into its DNA.  Atlantic salmon typically take around 4 years of farming (Atlantic salmon are protected as an endangered species, so fishing and sale of wild Atlantic salmon is illegal) to reach market size.  During that time, the salmon only grow during specific times of the year, yet they require adequate food, clean water, and space to swim throughout the entire year.  The AquAdvantage Salmon, however, are engineered to grow all year; they do not grow any larger than their non-engineered counterparts – they just reach their size sooner.

Importantly, AquAdvantage Salmon are also produced such that, with the exception of a small breeding group of fish, they are rendered sterile.  This is done by breeding the salmon so that their genomes contain three copies of each chromosome instead of the usual two copies.

The shorter time to market size means that it would be economically feasible to grow salmon contained in inland tanks rather than in net pens in the open ocean.  As a result, water quality can be better managed and the salmon can be isolated from other species.  Thus, any number of issues that arise from high density ocean farming operations can be avoided.

AquaBounty first submitted data to FDA in the mid-1990s regarding its AquAdvantage Salmon.  It took FDA roughly 15 years, but in 2010, CVM convened its VMAC for a two-day meeting to discuss the scientific review of the data supporting approval of the AquAdvantage Salmon.  The review team from CVM presented the conclusions of its review to the VMAC – the AquAdvantage Salmon was as safe to eat as non-engineered salmon, the transgene and its expression product was safe to the salmon and was effective, and the engineered salmon did not pose a significant risk to the human environment. 

Over four-and-a-half years have passed since the VMAC meeting.  During that time, the AquAvantage Salmon application has languished.  CVM formally issued its draft Environmental Assessment and its draft Finding of No Significant Impact for public comment in 2012.  To date, FDA has not finalized these documents, and has not approved the AquAdvantage Salmon application.  Meanwhile, there have been several failed attempts in Congress to ban AquAdvantage Salmon or to deprive FDA of its ability to approve the application.

In a new twist to this saga, on April 2nd, Food and Water Watch took the very unusual step of filing both a Citizen Petition and a Food Additive Petition for the same issue.  Specifically, Food and Water Watch seek to have the AquAdvantage Salmon listed as a substance which is prohibited from use in human food.  Under Food and Water Watch’s petitions, FDA would promulgate a regulation that would specifically and explicitly deem AquAdvantage Salmon adulterated food as a matter of law, irrespective of whether the food from AquAdvantage Salmon poses any risk at all to consumers.  Seemingly unsure of how to go about making such a request of FDA, Food and Water Watch filed both petitions, each asking FDA to consider the other in the event that one of the petitions is not the proper avenue for making the unusual request. 

The Food and Water Watch petitions ask FDA to find that consuming the engineered salmon is injurious to health and should therefore be prohibited as a food additive.  The petitioners argue that, notwithstanding the fact that the statutory definition of a food additive excludes new animal drugs, FDA has the flexibility to consider AquAdvantage Salmon as both a new animal drug and a food additive.  The petitions take issue with FDA’s review process and the data used to support the approval of the AquAdvantage Salmon.  They further argue that the salmon must be reviewed as a food additive. 

Whether FDA will agree with these arguments will not be known for some time, but we will continue to watch for any further developments as FDA continues to consider approving AquAdavantage Salmon.