By James C. Shehan –

On April 28th, FDA finalized the three biosimilar guidances that it issued in 2012.  Covering the topics of questions and answers regarding BPCIA implementation, scientific considerations in demonstrating biosimilarity, and quality considerations in demonstrating biosimilarity of proteins to reference products, the final guidances make a few significant changes to the drafts but the bulk of the draft guidances remain unchanged.  This posting will discuss the significant changes to the Q&A guidance and later ones will review the other two.  For a review of the draft Q&A guidance, see our post here.

After an introductory section, the questions and answers are grouped into three major categories: Biosimilarity and Interchangeability, What is a “Biological Product” and Exclusivity.  About three-quarters of the questions are related to the first category, Biosimilarity and Interchangeability. 

In that category, the largest changes have been made to the answer regarding use of non-US-licensed versions of reference product to generate biosimilarity data.  The draft guidance required that analytical studies, at least one clinical pharmacokinetic study and at least one pharmacodynamic study (if required), use US-licensed reference product.  The final guidance repeats that general rule but adds a possible exception – “unless it can be scientifically justified that such a study is not needed.” 

This answer in the final guidance also delves heavily into the topic of bridging studies.   FDA states that if non-US data is relied upon, analytical, PK and PD studies should directly compare all three products (biosimilar, US reference product and non-US comparator product).   FDA also added to the final guidance that the analytical studies should include  “degradation profiles under stressed conditions.” 

FDA lists a large number of factors that may affect the amount of bridging data needed:

• higher order structure;
• post-translational modifications (e.g., glycosylation);
• degree of heterogeneity;
• whether the formulations, dosage forms, strengths and routes of administration of the US-licensed reference product and the non-US-licensed comparator products are the same;
• the design of the physicochemical and biological/functional assessments and the use of multiple orthogonal methods with adequate sensitivity to detect differences among the products; and 
• the scientific justification for the selection of the non-US-licensed comparator lots used to establish the scientific bridge and how the selected lots relate to the material used in the nonclinical and clinical studies.  The scientific bridge should include a sufficient number of lots of non-US- licensed comparator product to adequately capture variability in product quality attributes. When possible, the non-U.S.-licensed comparator lots used in the nonclinical or clinical studies should be included in the assessment performed to establish the analytical bridge.

Given this level of complexity, it is unsurprising that in this answer FDA encourages sponsors are encouraged to discuss bridging with FDA during the development process.  It is also unsurprising that, as in its draft guidance, FDA notes that comparisons to non-US product are unlikely to be able to support an interchangeability determination.

FDA also significantly expanded its answer on how to extrapolate clinical data on one indication to support approval in another indication.  Immunogenicity of the biosimilar in different patient populations was added to the list of issues that should be addressed in justifying extrapolation.  In gathering the clinical data that will be extrapolated, sponsors are urged to choose a use that “would be adequately sensitive to detect clinically meaningful differences between the two products.”  And in perhaps the most significant change, FDA recommends that sponsors do not try to extrapolate from indications approved under Subpart E, accelerated approval.  Considering the “potential complications in the event that postmarketing trials fail to verify the clinical benefit of the reference product for the condition of use,” this seems to be a prudent addition to the guidance.

In its answer to the question discussing whether applicants can request licensure for fewer routes of administration than those approved for the reference product, the draft guidance noted that FDA may require studies using a route of administration for which the biosimilar sponsors is not requesting approval.  The final guidance adds that such an FDA request will be made only “in a limited number of circumstances.” 

Four biosimilarity\interchangeability Q&As from the draft guidance are not in the final guidance, but FDA promises to finalize them in the future and add them to the guidance.  These Q&As deal with (1) the need for biosimilars to perform cardiac repolarization and drug-drug interaction studies;
(2) the length of the retention period for samples from PK and PD studies; (3) what constitutes “publicly available information” that a reference product is safe, pure and potent; and (4) how to obtain a determination of interchangeability.  Reinforcing its intent to answer these questions, FDA did not renumber Q&As in the final guidance.  The precise timing of finalization is not provided. A chart in the guidance states that revisions to #s 1 & 2 are “forthcoming,” but does not do so for #s 3 & 4.  This may be a typographical error. 

In the second category, of Q&As, FDA retained its proposed definition of a “protein” as an amino acid polymer of more than 40 amino acids in size. It amended this definition however, by noting that the amino acids do not need to be in a contiguous sequence for a product to be a protein.  FDA slightly changed the wording justifying the basis for its 40 amino acid test, referencing a lack of clear scientific consensus for distinguishing proteins from peptides.  Given the potential consequences of this issue, it would not surprise this author if FDA sees future challenges on this point.

In the last category, Exclusivity, FDA removed a Q&A addressing how a sponsor may request 12 year reference product exclusivity. The afore-mentioned chart promises that a revision of this question is also forthcoming.  A separate draft guidance from 2014, covered in our post here, deals exclusively with biologics exclusivity. 

Additional guidances on interchangeability, biosimilars naming and statistical approaches to proving biosimilarity are expected later this year.

On April 27, 2015 the Drug Information Association journal, Therapeutic Innovation and Regulatory Science, published the findings of a study conducted by HP&M Attorneys Frank J. Sasinowski and James E. Valentine*, along with co-author, Erika B. Panico, RAC, head of U.S. Regulatory Affairs for Chiesi Pharmaceuticals Inc.  This study serves as a follow-up to a March 2012 analysis conducted by Frank J. Sasinowski that reviewed the quantum of effectiveness evidence that is required to secure FDA approval of therapies for rare diseases, or orphan drugs, from the 1983 enactment of the Orphan Drug Act through June 30, 2010.  This current study was designed to determine, over the 4 years since the original study, how frequently FDA has required marketing applications of drugs for rare diseases to provide the conventional level of proof of effectiveness that is ordinarily expected for most drugs for prevalent diseases.

This study employed methods similar to the original analysis, identifying the noncancer orphan drugs approved as new chemical entities by relying on FDA’s publicly available documents for drugs approved by FDA from July 1, 2010, to June 30, 2014. These materials were used to identify the basis for each drug’s approval, and each approval was analyzed and classified.

The results of this study show that for just over two-thirds of all noncancer orphan drugs approved between July 1, 2010, and June 30, 2014, FDA did not require the orphan drug applications to provide the conventional level of proof of effectiveness that is ordinarily expected for drugs for prevalent diseases. This is consistent with the results of the 2012 analysis (see Table below).

Table. Update to Analysis of Orphan Drug Efficacy Evidence 

* January 1, 1983 to June 30, 2010. ** July 1, 2010 to June 30, 2014.

The findings further support that FDA has demonstrated extraordinarily reasonable flexibility in its review of certain applications for orphan drugs and reinforce the need for FDA and drug companies to better understand and discuss the various types of flexibility.

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

By Jennifer D. Newberger –

As part of its 2014-2015 Strategic Priorities, the Center for Devices and Radiological Health (CDRH) committed to assuring the “appropriate balance between premarket and postmarket data collection to facilitate and expedite the development and review of medical devices.”  By December 31, 2014, it committed to reviewing 50% of the product codes subject to a Premarket Approval Application (PMA) to determine whether FDA could: (1) rely on postmarket controls to reduce premarket data collection, (2) shift some premarket data collection to the postmarket setting, or (3) pursue down-classification.  FDA exceeded the 50% review target, and had reviewed 69% of product codes by December 31, 2014.

Of the Class III product codes reviewed (see here and here), FDA does not propose making changes to classification or the balance of premarket and postmarket data for the majority of devices—approximately 96 product codes.  It does, however, propose down classifying to Class II the following 21 product codes:

FDA also proposes changing the data requirements for an additional 21 codes, and has specified the changes it anticipates for those devices.  For example, for toric intraocular lenses, FDA has stated that issues for higher cylinder power (i.e., higher myopes) related to visual distortions have been documented in previously approved PMAs.  For the approval to add a higher cylinder power lens to an already approved toric IOL platform, FDA is considering allowing a shift from premarket to postmarket for some clinical data requirements.  For in vitro diagnostics (IVDs) intended to detect prostate cancer, or to distinguish between benign conditions and prostate cancer, FDA is considering requiring performance standards or nonclinical tests that have been developed as potential surrogates for some of the clinical testing.  15 of the 21 codes for which FDA is proposing to change the data requirements are for IVDs. 

CDRH’s review and specific proposals for reducing premarket data collection are welcome.  The key issue will be whether and when FDA takes the initiative to implement these changes.

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.