By Kurt R. Karst –      

Earlier this week, the U.S. District Court for the District of Maine came one step closer to a merits ruling in a lawsuit filed last September by two Maine pharmacists, three Maine trade associations (the Maine Pharmacy Association, Maine Society of Health-System Pharmacists, and Retail Association of Maine), and the Pharmaceutical Research and Manufacturers of America (“PhRMA”) against Maine’s Attorney General (Janet T. Mills) and Commissioner of Administrative & Financial Services (H. Sawin Millett, Jr.) in an effort to stop implementation of a state law permitting the importation of drug products into the U.S. from licensed retail pharmacies located in certain foreign countries.  That state law, titled “An Act To Facilitate the Personal Importation of Prescription Drugs from International Mail Order Prescription Pharmacies,”  2013 Me. Legis. Serv. Ch. 373 (S.P. 60) (L.D. 171) (West) (the “2013 Act”), went into effect on October 9, 2013, and has been challenged as preempted by the FDC Act pursuant to the U.S. Constitution’s Supremacy Clause (U.S. Const. art. VI, cl. 2) and by the Foreign Commerce Clause of the U.S. Consittution (U.S. Const. art. I, § 8 cl. 3).  We’ve previously reported on the case here and here, so you can refer to those posts for additional background information. 

The challenge to the 2013 Act is the topic of a fully briefed Motion for Preliminary Injunction (here, here, and here) and a fully briefed Motion to Dismiss for lack of standing and for failure to state a claim for which relief may be granted (here, here, and here).  Both motions came under advisement late last October.  Several weeks later, the Plaintiffs filed a notice of intent to file a Motion for Summary Judgment saying that the case can be resolved purely as a matter of law on Cross-Motions for Summary Judgment on the issue of whether the 2013 Act is preempted by federal law.  Summary Judgment motions have not yet been filed – and there’s been some dispute about that process, leading up to a recent Motion for Expedition and request to initiate summary judgment briefing – but before even going there, the Court must first dispense with the Defendants’ Motion to Dismiss (and Motion for Preliminary Injunction, unless it is withdrawn). 

Earlier this week, Judge Nancy Torresen issued a 17-page Order dispensing with Defendants’ Motion to Dismiss.  The outcome: trimmed down lists of Plaintiffs and claims.    

In its Motion to Dismiss, the State contends that the Plaintiffs lack both constitutional and prudential standing to challenge the 2013 Amendment (and also argues that all claims against Commissioner Millett should be dismissed).  According to the State:

This suit should be dismissed because no plaintiff has standing to assert violations of these constitutional provisions.  The 2013 [Act], which restricts the reach of the Maine Pharmacy Act, does not directly affect plaintiffs. . . .  In short, no plaintiff alleges that it has engaged or plans to engage in conduct covered by the 2013 Amendment.  Plaintiffs seek to enjoin the enforcement of an amendment that does not apply to them. . . .  Moreover, plaintiffs purportedly seek to vindicate the interests of third persons. . . .  Finally, plaintiffs’ constitutional claims fall far outside the “zone of interests” protected by the constitutional provisions they invoke.

Plaintiffs struck back, saying that the Motion to Dismiss should be denied in its entirety:

The [2013 Act] exposes Maine patients to the exact risk of harm from unregulated imports of prescription drugs that Congress sought to eliminate in the FDCA.  The Law inflicts this injury by subjecting licensed Maine pharmacists to unlicensed foreign competition, stripping them of their exclusive right to dispense prescription drugs in Maine, and imposing significant obstacles to the discharge of their legal, ethical, and fiduciary duties to their patients.  The Law also threatens reputational harm to domestic drug manufacturers, who will lose consumer confidence and goodwill if Maine consumers receive from a foreign source adulterated, counterfeit, or expired prescription drugs purporting to be genuine.  And the Law has frustrated the mission of several trade associations and forced them to divert resources away from other purposes and toward advocating against the Law.

Any one of these injuries in fact is sufficient to invoke the Court’s jurisdiction and to allow it to adjudicate Plaintiffs’ claims for injunctive and declaratory relief.  Defendants’ motion to dismiss thus not only overlooks Plaintiffs’ well-pleaded allegations, but also fails to address the controlling case law.

In her May 15th Order, Judge Torresen agreed that the Mainers in the case (i.e., the pharmacists and trade associations) have Article III standing under a theory of loss of market share, but tossed PhRMA from the case.  “PhRMA’s claims rest on a ‘chain of contingencies’ that amount to ‘mere speculation’ that it and its member companies may suffer reputational injuries arising out of physical injuries to Maine consumers who, following the 2013 Act, may be injured by unsafe foreign drugs associated with PhRMA member companies” (emphasis in original), wrote Judge Torreson.  Moreover, “PhRMA has no standing to assert harm to the public arising out of the 2013 Act’s dilution of [FDC Act § 801(d)(1)],” which generally prohibits reimportation into the U.S. of domestically manufactured drug products.

Moving on to the Mainers’ prudential standing under the FDC Act (Supremacy Clause) and the Foreign Commerce Clause in light of the State’s claim that Plaintiffs lack standing because they are not within the so-called “zone of interests,” Judge Torresen made another split decision.  Relying on the First Circuit’s decision in Pharm. Research and Mfrs. of Am. v. Concannon, 249 F.3d 66 (1st Cir. 2001) aff'd sub nom. Pharm. Research & Mfrs. of Am. v. Walsh, 538 U.S. 644 (2003) – a case in which PhRMA challenged, under the Supremacy Clause, a Maine statute requiring drug companies to participate in a rebate program or else have their products subject to the State Medicaid program’s prior authorization requirements – Judge Torresen ruled that the Mainers “are entitled under the Supremacy Clause to argue that the FDCA preempts the 2013 Act.”  But the Court declined to adjudicate Plaintiffs’ Foreign Commerce Clause claims (and dismissed Count II of the Complaint) not finding any “zone of interests.”  “The Plaintiffs have not identified any Foreign Commerce Clause case where the plaintiffs were United States citizens and the object of their complaint was a state law,” wrote Judge Torreson.  “The interest of certain Maine citizens in striking down a Maine law which addresses foreign trade does not logically fit within the zone of any interest the Foreign Commerce Clause seeks to protect. ”

Judge Torreson also denied the State’s plea for Commissioner Millett to exit the case on the basis that he has no responsibility for enforcement or oversight of the 2013 Act, saying that it is at least plausible that the Plaintiffs’ requested relief will encompass his actions.

By Riëtte van Laack –

FDA’s proposed rule regarding nutrition labeling (see our previous post here) will have far-reaching consequences that may not be obvious.  For example, FDA intends to make major changes in its approach to defining and measuring dietary fiber – changes that could have a significant impact on those who have a stake in the manufacture or use of fiber ingredients.  Those changes include:

• FDA proposes to establish a definition for dietary fiber that is the same as the Institute of Medicine’s (IOM’s) definition of total fiber and would include:

1. soluble and insoluble non-digestible carbohydrates (with 3 or more monomeric units) and lignin that are intrinsic and intact in plants, and

2. certain isolated and synthetic non-digestible carbohydrates (with 3 or more monomeric units).  However, these isolated and synthetic carbohydrates would qualify as dietary fiber only pursuant to FDA’s approval of a citizen petition or a health claim petition.  FDA proposes that the citizen petition must provide evidence of a physiological effect beneficial to human health. According to FDA, there are currently only two isolated non-digestible carbohydrates, ß-glucan and barley ß-fiber, that would meet the proposed definition of dietary fiber.  The vast range of other non-digestible carbohydrates currently marketed would not qualify as dietary fiber until FDA approves a citizen petition providing the “evidence of a physiological effect beneficial to human health” for that carbohydrate.  FDA does not provide further information as to the type of evidence required.  Although FDA states that it intends to publish a guidance addressing the type of evidence that will be required, the Agency does not indicate when it would publish this guidance.  Moreover, the Agency does not give any indication about the timing of the review of these citizen petitions.  Thus, FDA’s proposal potentially will call into question (at least temporarily) the status of various ingredients marketed as fiber. 

• FDA also proposes to change the method of verification of dietary fiber content.  Because of limitations of analytical methods, for products that contain a mixture of non-digestible carbohydrates that meet the proposed dietary fiber definition and those that do not, FDA proposes to require manufacturers to make and keep written records to verify the amount of added non-digestible carbohydrates that do not meet the proposed definition of dietary fiber.  The amount of non-digestible carbohydrate measured analytically (by established AOAC methods) minus the amount of added non-digestible carbohydrate that has not been determined by FDA to have a physiological effect that is beneficial to human health would reflect the amount of dietary fiber lawfully declared on the label. 
• FDA also proposes to increase the daily reference value for dietary fiber from 25g to 28g.  Consequently, products may need to contain more dietary fiber to be eligible for a nutrient content claim for dietary fiber.   Since the proposed dietary fiber definition excludes (at least until FDA’s approval of a citizen petition) certain non-digestible carbohydrates that currently are included in the calculation, a significant number of products may no longer be eligible for nutrient content claims for dietary fiber.

The proposed changes concerning dietary fiber are likely to have a profound effect on the marketing of certain foods and many dietary supplements that frequently are formulated with “isolated and synthetic non-digestible carbohydrates” rather than “non-digestible carbohydrates that are intrinsic and intact in plants.”   Companies manufacturing and marketing these types of products would be well-advised to review FDA’s proposal and consider the potential ramifications.

Unless FDA grants an extension, the comment period closes on June 2, 2014.

By Kurt R. Karst –      

In a May 14, 2014 Order following a hearing earlier that day, Judge Ellen Segal Huvelle of the U.S. District Court for the District of Columbia granted on ripeness grounds FDA’s Motion to Dismiss a lawsuit brought by Teva Pharmaceutical Industries Ltd. and Teva Neuroscience, Inc. (collectively “Teva”) alleging that FDA’s May 2, 2014 denial “without comment” of a December 2013 Citizen Petition (Docket No. FDA-2013-P-1641) concerning COPAXONE (glatiramer acetate injection) violates the FDC Act and the Administrative Procedure Act.  At the same time, Judge Huvelle denied as moot Teva’s Motion for a Preliminary Injunction.

As we previously reported, Teva filed the lawsuit seeking declaratory and injunctive relief after FDA denied “without comment” several citizen petitions Teva submitted to FDA since 2008 concerning the approval of ANDAs for generic COPAXONE and considered by FDA under the citizen petition procedures added to the FDC Act at Section 505(q).  According to Teva, “FDA’s tactics make it virtually impossible for a court to provide aggrieved petitioners with meaningful relief before they are harmed irreparably.”  Each patent listed in the Orange Book for the 20MG/ML strength of COPAXONE is set to expire on Saturday, May 24, 2014.  After patent expiration, FDA could make ANDA approval decisions.

The D.C. District Court almost immediately denied Teva’s Motion for a Temporary Restraining Order after it was filed, and scheduled a May 14th hearing on Teva’s Motion for a Preliminary Injunction.  Teva pitched its requested relief as follows:

The relief Teva seeks could be structured in either of two ways.  First, this Court could simply enjoin the FDA from approving any purported generic version of Copaxone® until the Court has conducted an expedited trial on the administrative record defined by Congress and ruled on the merits of Teva’s petitions.  In the alternative, this Court could employ a variant of the procedure Judge Bates first crafted in the Hi-Tech case, permitting the Agency to finally offer its views on the issues Teva has raised on a negotiated timetable—though whatever views the Agency might offer would be, by the law’s plain terms, outside the administrative record and thus entitled to no deference—but enjoining the Agency from acting to approve any purported generic version of Copaxone® until this Court can provide meaningful judicial review of the critically important matters Teva has raised.

The so-called “Bates procedure” in Hi-Tech Pharmacal Co. v. FDA, Case No. 08-cv-1495, was established by Judge John D. Bates, who has been particularly critical of FDA’s handling of exclusivity decisions, to give the parties (i.e., FDA and a drug manufacturer) a chance to sit down in court where FDA would reveal an exclusivity decision, thereby allowing a potentially aggrieved generic manufacturer the opportunity to challenge that decision (see our previous post here). 

FDA, in the Agency’s Motion to Dismiss, argued that Teva’s lawsuit should be dismissed for a litany of reasons.  According to FDA:

Not only are Teva’s claims unripe and unjusticiable for want of standing, but Teva has not established that it will suffer certain, great, and irreparable injury in the absence of a preliminary injunction.  If Teva ever suffers the loss that it claims it will here, such loss will be a small percentage of its multibillion dollar portfolio of generic and brand drugs, and thus would not threaten or even seriously injure the business.  And finally, the balance of harms weighs against the entry of preliminary relief because Teva’s desire to further delay generic competition does not outweigh FDA’s interest in the thoughtful and careful exercise of its generic approval decisions without premature judicial interference.

FDA’s efforts to get Teva’s lawsuit tossed were backed by briefs (here and here) filed by Intervenor-Defendants Mylan Pharmaceuticals Inc., Sandoz Inc., and Momenta Pharmaceuticals, Inc., which reportedly have ANDAs pending at FDA for generic COPAXONE. 

After a hearing that went on for over three hours, Judge Huvelle rendered her decision: granting FDA’s Motion to Dismiss and denying Teva’s Motion for a Preliminary Injunction.  Her decision was grounded in previous decisions in Pfizer Inc. v. Shalala, 182 F.3d 975, 980 (D.C. Cir. 1999), AstraZeneca Pharmaceuticals v. FDA, 850 F. Supp. 2d 230 (D.D.C. 2012), and Mylan Pharmaceuticals Inc. v. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011), where ripeness was a central issue to deciding the cases.  Judge Huvelle also refused to employ the “Bates procedure;” however, she did ask for a 24-hour “heads-up” from FDA on ANDA action.  According to Judge Huvelle at the May 14th hearing:

What we have here is a fact-specific complicated, complex scientific issue that has to be determined; and it hasn’t been determined yet.  To force them to decide the really difficult scientific issues at this time, I don’t have the power to do so, and it has to wait until there is a concrete application of the requirements for bioequivalency and sameness.  When that is determined, then Teva has the right to have a review of the administrative record and a speedy decision, and they can fight at that point about whether they're entitled to a preliminary injunction.  That is the only protective-window ability the court has.  Although if, in fact, we have an approval of an ANDA and this case comes back to this Court, I can assure you the FDA will have a matter of days to get together the administrative record because that is the only thing that holds us up. . . . 

Your right here is to get a final agency action.  That doesn't mean that it has to be the final agency action on what you want.  They have said that we need to take it up in the context of a specific ANDA.  That is an action.  We haven’t got to that point yet.  You cannot force us to take a premature action on this.

The Court rests on jurisdictional grounds and will grant the motion to dismiss, deny the [Preliminary Injunction].  To the extent that anything is going to happen, I am requiring the FDA . . . to give the Court notice so that we’re available to decide the difficult issues that come up here.  I’m not in the position of doing what Judge Bates did because you don’t have a deadline, you’re not in that position, but I certainly think that as a courtesy to all people, you should give us 24 hours’ notice before if you’re going to issue anything . . . just to let us know.

The 24-hour notice from FDA is apparently intended to allow the Court to adequately prepare and schedule for what may be the next Teva lawsuit – this time challenging an FDA decision to approve ANDAs for generic COPAXONE.  That decision could come any time after May 24th.

By Riëtte van Laack –

In 2011, the National Organic Program (“NOP”) of the USDA announced the availability of a draft guidance for “Made with Organic” claims.  Of the four categories of organic claims (“100% organic,” “organic,” “made with organic,” “x% organic”), this category of organic claims appears to raise the most questions and further clarification was needed. 

A “Made with Organic” claim may be used if a product contains more than 70% organic ingredients (excluding salt and water) and the remaining ingredients are either non-organic agricultural ingredients or (non-organic) nonagricultural ingredients included in the National List, 7 C.F.R. § 205.605.  Moreover, none of the non-organic ingredients (be they agricultural or nonagricultural) may be produced by excluded methods.

In addition, although the category is often referred to as “Made with Organic” claims, a claim “Made with Organic Ingredients,” or “Made with x% Organic Ingredients” is not permitted.  Specifically, the claim must specify the organic ingredients or organic food categories, i.e., “Made with Organic [specify ingredients and or food categories].”  However, the claim may not list more than three ingredients or food categories, i.e., a claim “Made with Organic [list four ingredients and categories]” is not permitted.  In addition, the regulation specifies the food categories that may be used.   

These are only the basic requirements, and certifiers and organic trade raised questions about possible % organic statements, claims when a product contains organic and non-organic ingredients in a food category (e.g., organic and non-organic vegetables), and other issues.  According to NOP, the guidance seeks to clarify such issues.  Concurrent with the final guidance, NOP issued a document summarizing its responses to comments to the 2011 draft guidance.  It also issued a separate document with examples of correct and incorrect “Made with Organic” labeling claims.      

The guidance took effect on May 2.  As noted in the Federal Register notice of availability, the guidance is not intended to be binding, and alternative approaches that demonstrate compliance are acceptable.  However, “the NOP strongly encourages industry to discuss alternative approaches with the NOP before implementing them to avoid unnecessary or wasteful expenditures of resources and to ensure the proposed alternative approach complies with the Act and its implementing regulations.”

By Jessica A. Ritsick & William T. Koustas –

On May 8th and 9th, FDA got the ball rolling on the implementation of Title II of the Drug Quality & Security Act (“DQSA”), the Drug Supply Chain Security Act (“DSCSA”), by hosting a public workshop for interested parties.  The workshop was just that – a workshop – bringing together different members of the supply chain to collaborate on the potential challenges of exchanging Transaction Information/Transaction History/Transaction Statement (“TI/TH/TS” or “the three Ts”).  Supply chain members must start passing TI/TH/TS on January 1, 2015, and the DSCSA requires FDA to issue guidance on this no later than November 27, 2014, giving supply chain participants approximately six weeks to comply with whatever standards may be set forth in the guidance.  The purpose of this workshop was to get supply chain participants talking with each other, as well as with FDA, about which mechanisms would be best and most feasible to implement by the January 1, 2015, deadline.  The workshop participants were also asked to think about future interoperability, as the goal of the DSCSA is to move to a fully electronic interoperable system in 10 years.  FDA seemed very interested in getting all participants talking to each other:  every attendee was assigned to a table, and that table included various members from different areas of the supply chain.  Discussion was not just encouraged, but necessary.

The meeting agenda and discussion topics (here and here) facilitated discussion of potential gaps in the DSCSA, such as definitions and requirements that required clarity, as well as the challenges of complying with the three Ts by January 1, 2015.  At the end of the first day of the workshop, each table provided a summary of what it considered to be the most feasible “tools” for exchanging the three Ts in an interoperable fashion by January 1, 2015.  Surprisingly, all tables’ preferences and suggestions were strikingly similar, and there were many areas of consensus throughout the room.  The overall consensus was that, by January 1, 2015, the most logical means to transmit TI/TH/TS would be the same means frequently used now to transmit certain transaction information:  paper packing slips and Electronic Data Interchange ("EDI"), including Advance Ship Notices ("ASN").  Web portals were also seen as a viable option for January 1, 2015, compliance.  Looking 10 years down the road, the ultimate goal would be to transition all parties to one electronic system, such as Electronic Product Code Information Services ("EPCIS").  Unsurprisingly, participants requested that FDA produce its TI/TH/TS guidance document sooner rather than later.  FDA seemed to hear the suggestions loud and clear. 

Without an issued guidance, however, what are supply chain members to do in the meantime?  Perhaps the most important thing to do is to try to understand the DSCSA, and how different sectors of the supply chain are expected to interact, or “interoperate,” with each other.  Several resources are available, including some from FDA, as well as a fairly comprehensive DSCSA implementation timeline recently released by The Pew Charitable Trusts.  This timeline illustrates the requirements for each supply chain member, as well as how that supply chain member must interact with others in the supply chain.  As the FDA workshop made clear, the better the supply chain members understand their own responsibilities and challenges, as well as the responsibilities and challenges faced by the parties they work with in the supply chain, the better and more interoperable this new system could be.

By James C. Shehan –

As previously reported here, in February 2012, FDA released three highly-anticipated guidances on biosimilars.  Those of us interested in biosimilars have naturally been eagerly awaiting the next usual step in the process, the issuance of final guidances and perhaps the first approval of a biosimilar product under the 2010 BPCIA.  Dashing these expectations, however, FDA has instead issued another draft guidance, one that expands upon some previously-covered topics but also repeats much of what was said in 2012.  Forgive us for wondering whether the guidance moves us one step closer to approval of the first BPCIA biosimilar or moves the date further out into the future.  Put another way, will the stepwise process FDA first unveiled in 2012 be a walk in the park for sponsors or an ultra-marathon?

On May 13, 2014, FDA released a draft guidance entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product.  It lays out an elaborate step-by-step process for demonstrating that the hoped-for biosimilar and the reference product are “highly similar” and pegs clinical pharmacology studies as a likely piece of the “totality of evidence” needed to meet the statutory standard of  “no clinically meaningful differences … in terms of “safety, purity, and potency.” 

Similar to what is laid out in the 2012 draft guidance, the step-by-step process is described as a risk-based approach under which FDA will consider the totality of the data submitted.  Sponsors are encouraged to collect data in the following order: structural and functional characterization, nonclinical evaluations, human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity studies, clinical safety studies and when necessary clinical effectiveness studies.  The criterion for sponsors to use in determining whether the next step in this process is necessary is the amount of “residual uncertainty” that remains regarding similarity of the products.

In keeping with the step-by-step process envisioned by FDA but actually exceeding the “clinical pharmacology” scope implied by its title, the draft guidance, again echoing the 2012 draft guidance, recommends that “extensive and robust comparative structural and functional studies” precede clinical pharmacology studies.  This “extensive analytical characterization” should include “state-of-the-art” analytical assays that assess, for example “the molecular weight of the protein, its higher order structure and post-translational modifications, heterogeneity, functional properties, impurity profiles, and degradation profiles denoting stability.”   Intriguingly, FDA recommends that the attributes of the biosimilar and the reference product be compared through use of a “meaningful fingerprint-like analysis algorithm.”  FDA expects that this comparative analytical characterization will lead sponsors to one of four conclusions about their biosimilar product: not similar, similar, highly similar or highly similar with fingerprint-like similarity. “Not similar” products are not recommended to follow the biosimilar pathway; “similar” products require additional data and studies; and products in the “highly similar” and “highly similar with fingerprint-like similarity” categories are directed to “conduct targeted and selective animal and/or clinical studies” to support biosimilarity, with studies for the last category being more targeted and selective than those for the highly similar category. 

Moving on to the next step in the process, the draft guidance states that clinical pharmacology studies are “normally a critical part of demonstrating biosimilarity.”  Such studies are required to contain pharmacokinetic and pharmacodynamic elements, which are viewed as necessary to allow assessment of exposure and response.  One clue to FDA’s mentality in drafting the guidance is perhaps found in this section – the statement that determining exposure to a biological product is “particularly challenging” because biological products are “mixture[s] of closely related, complex biological substances that, in aggregate, make up the active component.”  Some may question whether this statement accurately describes all biologics.

The guidance contains detailed requirements for the pharmacokinetic and pharmacodynamic data types to be collected, specifying, for example, that all pharmacokinetic parameters should be collected for both products.  FDA also stresses that the integrity of the bioanalytical methods (assays) used in theses studies is critical, and it specifies that ligand binding assays, concentration and activity assays, and pharmacodynamic assays must be included.   There is also a recommendation that safety and immunogenicity data be collected from the clinical pharmacology studies and be used to determine whether the next step in the process, e.g., clinical studies, is required.

The guidance also includes a section that gives guidance on nine critical study design issues, for example, a recommendation that statistical comparisons of the biosimilar and the reference product include a valid criterion to allow the comparison, a confidence interval and an acceptable limit.  FDA notes that simulation tools can be useful in designing pharmacology studies and in data analysis.  Sponsors are encouraged to meet with FDA in the early stages of development to discuss their clinical pharmacology plan.   

Left unsaid in the guidance is what FDA will issue next relevant to the biosimilar approval process.  FDA recently received a letter from four senators that, among other things, asked for an update on FDA activities to implement best practices to make the finalization of guidances more efficient and expeditious (reported on here).  Perhaps a final guidance is not too much to wish for.

By Ricardo Carvajal –

FDA issued a draft guidance for industry that sets out the agency’s expectations for the content of petitions and notifications for exemption from food allergen labeling requirements.  To date, such petitions and notifications have met with very limited success – a situation that guidance might help ameliorate.

As explained in the guidance, the FDCA (as amended by the Food Allergen Labeling and Consumer Protection Act) provides petition and notification mechanisms through which an ingredient derived from a major food allergen can be exempt from the labeling requirements of section 403(w)(1).  A petition must demonstrate that the ingredient does not cause an allergic response that poses a risk to human health, whereas a notification must demonstrate that the ingredient does not contain allergenic protein or that the ingredient was previously determined not to cause an allergic response to human health pursuant to review under section 409. 

The guidance provides recommendations for preparing both types of submissions, including information on the identity and manufacture of the ingredient, characterization of its protein content, and methods of analysis.  The guidance also provides recommendations specific to petitions, including the need for information on consumer exposure and either clinical testing or risk modeling.  The guidance also provides recommendations specific to notifications, which can rest heavily on protein characterization.  An appendix to the guidance explains the agency’s thinking with respect to evaluation of subjective symptoms of allergic reaction, and makes clear that the agency views animal testing data to be of limited utility.  Comments on the draft guidance are due September 5.

By Riëtte van Laack –

The FDC Act, as amended by the Dietary Supplement Health and Education Act (“DSHEA”) of 1994, excludes from the definition of dietary supplement any article that is approved as a new drug and any article “authorized for investigation as a new drug . . . for which substantial clinical investigations have been instituted and for which the existence of such investigations have been made public” unless the article was “before such approval, . . . or authorization marketed as a dietary supplement or as a food.”  FDC Act § 201(ff)(3)(B).

A recent Warning Letter from FDA suggests that the Agency interprets the second part of this “exclusionary clause” to set the date the IND was made effective rather than the date the substantial clinical investigations under the IND were completed and made public as the critical date to determine who wins the race to market, the drug or the dietary supplement. 

In a Warning Letter to Deseo Rebajar Inc. the Agency asserted, inter alia, that Burn 7, a dietary supplement containing sibutramine, cannot be a dietary supplement because it is excluded under section 201(ff)(3)(B)(ii) of the FDC Act.

FDA states the following in the Warning Letter:

The [IND] application for Meridia (sibutramine) was received by FDA on December 24, 1985, and sibutramine became authorized for investigation as a new drug under an IND on January 23, 1986.  When Meridia was approved for marketing as a new drug [on November 22, 1997] in the United States, the existence of substantial completed clinical investigations of sibutramine became public.  Given that sibutramine was not marketed as a dietary supplement or as a food before Meridia was authorized for investigation as a new drug, your product Burn 7 is excluded from the definition of a dietary supplement.  [(Emphasis added)] 

Thus, it appears that FDA took the date that the IND was granted rather than the date that the existence of the substantial investigations was made public (more than 10 years later) as the date for the exclusion.  This, in our opinion, is an untenable, and unconstitutional, interpretation. 

FDA does not disclose the existence of an IND.  Consequently, unless the drug company makes the IND public, a dietary supplement company cannot determine whether an IND for its ingredient exists.  Moreover, even if the dietary supplement company knows that an IND exists, the marketing of the ingredient as a dietary supplement is legal in the absence of publication of the existence of substantial clinical investigation.  The statute does not simply exclude any article “authorized for investigation as a new drug.”  In fact, such investigations may never be instituted or publicized. 

As a result, a dietary supplement company could find itself in the situation where it for years lawfully markets a dietary supplement that suddenly, without advance notice, becomes illegal because a company publishes the existence of substantial clinical investigations.  This interpretation of the exclusionary clause not only is at odds with the intent of this provision, the lack of fair notice also runs afoul of the Due Process Clause of the Fifth Amendment.  FDA’s interpretation does not allow the dietary supplement industry to “steer between lawful and unlawful conduct” and does not give a manufacturer a reasonable opportunity to know what” constitutes a dietary supplement that may legally be marketed.  See Grayned v. City of Rockford, 408 U.S. 104, 108-109 (1972); see also United States v. Farinella, 558 F.3d 695 (7th Cir. 2009)(It is a denial of due process of law to hold a person liable for violation of an agency’s “secret” understanding of the law).

By Kurt R. Karst –      

In a Complaint (and Motion for Temporary Restraining Order and Expedited Preliminary Injunction) lodged in the U.S. District Court for the District of Columbia, Teva Pharmaceutical Industries Ltd. and Teva Neuroscience, Inc. (collectively “Teva”) allege that FDA’s May 2, 2014 denial “without comment” of a December 2013 Citizen Petition (Docket No. FDA-2013-P-1641) concerning COPAXONE (glatiramer acetate injection) violates the FDC Act and the Administrative Procedure Act (“APA”).  The lawsuit comes just weeks before each patent listed in the Orange Book for the 20MG/ML strength of COPAXONE will expire (on May 24, 2014), and at which time FDA could make ANDA approval decisions. 

Teva’s December 2013 Citizen Petition is one of several such petitions the company has filed over the past few years, including Docket Nos. FDA-2008-P-0529, FDA-2009-P-0555, FDA-2010-P-0642, FDA-2012-P-0555, FDA-2013-P-0025.  In each instance (except for one petition that was apparently withdrawn – FDA-2013-P-1128), FDA has denied the petition without comment.  Teva’s December 2013 petition requests that FDA refrain from approving any ANDA referencing COPAXONE “unless and until” such an ANDA provides:

1. Information demonstrating that the proposed generic product contains the identical active ingredient as Copaxone®, not merely an active ingredient that is similar (or even highly similar) to Copaxone®’s;

2. Results of non-clinical and clinical investigations demonstrating that the immunogenicity risks associated with the proposed generic product are no greater than the risks associated with Copaxone®, including a demonstration that the risks of alternating or switching between use of the proposed product and Copaxone® are not greater than the risks of using Copaxone® without such alternation or switching; and

3. Results of comparative clinical investigations in RRMS patients using relevant safety and effectiveness endpoints demonstrating that the proposed generic drug is bioequivalent to Copaxone®.

According to Teva:

Despite Congress’s clear command, FDA has never provided a meaningful response addressing the merits of the core issues Teva has raised.  Instead, it repeatedly has denied Teva’s petitions “without comment” on the merits of Teva’s request to have FDA establish clinical trial requirements for ANDAs referencing Copaxone®, repeatedly asserting that “it would be premature and inappropriate” to “comment on the approvability of any ANDA or NDA for any glatiramer acetate injection drug product . . . before the Agency has had an opportunity . . . to fully consider specific data and information in such an application.”  

That “clear command” from Congress, says Teva, comes from FDC Act § 505(q), which was added to the statute in 2007 and governs FDA’s response timeframe (originally 180 days and now 150 days) to certain citizen petitions.  “The May 2, 2014 Response violates the plain text, structure, and history of the FDCA and fundamentally undermines the statutory scheme,” argues Teva.  For more on 505(q) petitions see our previous post here.

Teva is seeking declaratory and injunctive relief.  Among other things, Teva wants a declaration that FDA’s May 2, 2014 petition response violates the APA, a declaration “that FDA may not approve or otherwise permit the introduction into interstate commerce of any ANDA product referencing Copaxone® that does not comply with the conditions requested in Teva’s December 5, 2013 citizen petition,” and the court to enjoin FDA from approving any ANDA for generic COPAXONE that does not comply with its December 2013 petition to FDA.

UPDATE:

May 9, 2014: The following Minute Order was entered:

MINUTE ORDER denying plaintiffs' motion for a temporary restraining order. For the reasons stated on the record during the hearing held this day, plaintiffs' motion for a temporary restraining order is DENIED. Defendants' opposition to plaintiffs' motion for a preliminary injunction, along with an outline of the administrative record, is due Monday, May 12, 2014 at 5:00 p.m. A motions hearing on plaintiffs' motion for a preliminary injunction is set before the Honorable Ellen Segal Huvelle on Wednesday, May 14, 2014, at 2:00 p.m. in Courtroom 23A. Signed by Judge Beryl A. Howell on May 9, 2014.

By Larry K. Houck –

Prescriptions issued for controlled substances must contain the patient’s name and address; the drug name, strength and dosage form; the quantity prescribed; directions for use; and the practitioner’s name, address and Drug Enforcement Administration (“DEA”) registration number.  DEA advised in its current Pharmacist’s Manual: An Informational Outline of the Controlled Substances Act (Rev. 2010) that pharmacists are responsible for ensuring that prescriptions are issued by appropriately registered or exempt practitioners and that “it is helpful to be familiar with how a DEA registration number is constructed and to whom such registrations are issued.”  DEA has taken enforcement action against pharmacies that it believes failed to verify that practitioner registrations were valid and active.  Pharmacies have implemented elaborate electronic systems to detect invalid registrations based on DEA’s formula for valid registration numbers.  However, pharmacists should be aware that DEA has issued valid practitioner registrations that do not follow the agency’s prescribed formula which would be identified by pharmacy verification systems as invalid.

DEA registration numbers consist of a formulaic combination of nine alpha and numeric characters specific to each registrant.  Registration numbers for practitioners (that is physicians, dentists, veterinarians, hospitals and clinics) begin with the letters “A,” “B” or “F.”  Mid-level practitioner registration numbers begin with the letter “M.”  DEA recently began issuing registrations to U.S. Department of Defense “personal service contractors” beginning with the letter “G.”

DEA has stated that the first letter of the registration number is “almost always followed by the first letter of the registrant’s last name” (for example, “F” for Dr. William Feelgood), then a computer-generated sequence of seven numbers (for example AF1234567).  However, when the registrant’s name begins with a number (such as 42nd Street Pharmacy), DEA issues a registration number with a “9” as the second character in place of an alpha character.  So, the DEA registration for 42nd Street Pharmacy might be A91234567.

We recently learned that DEA has issued registrations with a second character of “9” to individual practitioners whose last names do not begin with a number.  For example, DEA may have issued registration number A91234567 to Dr. William Feelgood.  Though very rare, pharmacists should be aware that DEA has issued a handful of such registrations and that these registrations are nevertheless valid.

By Allyson B. Mullen –

On May 1, 2014, FDA issues a final version of the guidance document “Providing Information about Pediatric Uses of Medical Devices”  (the “Final Guidance”).  The draft of this guidance document was originally issued on February 19, 2013, at the same time FDA issued a supplemental notice of proposed rulemaking to implement the pediatric submission requirements from the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), which was finalized earlier this year (see our earlier posts here and here). 

Section 515A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that PMAs, HDEs and PDPs (PDP stands for Product Development Protocol, a premarket pathway that essentially exists only on paper) include “if readily available – (A) a description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and (B) the number of affected pediatric patients.”  The Final Guidance provides useful information for applicants regarding the pediatric information requirement in a question and answer format.  Such information includes what is meant by “readily available,” definitions of the pediatric populations, some acceptable sources that could address the pediatric information requirements, and where and how to include this information in a submission. 

The Final Guidance explains that the applicant should provide in narrative form “(1) a description of the uses of the device (proposed indication for the device) and (2) an estimate of the number of affected pediatric patients in the United States that suffer from the disease or condition that the device is intended to treat, diagnose or cure (including an estimate of the affected pediatric patient population size as a whole and according to the pediatric subpopulations).”  Final Guidance at 6.  The Final Guidance also provides a suggested table format for providing FDA with the required pediatric information.  In addition, the Final Guidance provides examples of acceptable and unacceptable data sources for obtaining the required pediatric information.  Generally speaking, acceptable sources are reliable, publicly available sources, and unacceptable sources are internal sources, including marketing and sales data. 

Most notably, the Final Guidance explains that if the submitted pediatric information suggests that there is a potential for harm from off-label use in pediatric populations, FDA may require limitations, warnings or contraindications in the device labeling.  Labeling limitations seems like a logical result if there is a potential for harm to pediatric patients from off-label use of the device, but what if the effect of the device on pediatric populations is simply unknown or what if the pediatric information shows that the disease the device is intending to treat is widely present in pediatric populations, but the applicant is only seeking approval for an adult indication?  It remains to be seen whether FDA will require labeling limitations or something greater (e.g., data to support a pediatric indication).

Finally, the Final Guidance explains that the required pediatric information (discussed above) is not alone sufficient to establish the safety and effectiveness of a device for a new pediatric indication for use.  The requirement to include pediatric information in PMAs, HDEs and PDPs took effect on April 10, 2014 for all newly submitted applications.

By Jeffrey N. Wasserstein –

We have previously noted that FDA has increasingly regulated through issuance of guidance documents – rather than through notice-and-comment rulemaking as required by the Administrative Procedure Act.  The U.S. Senate Committee on Health, Education, Labor, and Pensions (the Senate HELP Committee) has also taken note of it, albeit without the flair and occasional snark our readers have come to expect from the FDA Law Blog!
   
Earlier this week, 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), sent a letter to FDA Commissioner Margaret Hamburg “to express significant concern about [FDA’s] use of draft guidances to make substantive policy changes.”  The letter notes that draft guidances are becoming default FDA policy, notwithstanding that they are issued for comment purposes only.  Moreover, draft guidances are not revised, finalized, or withdrawn in a timely manner.  Although the letter doesn’t mention it specifically, we note that some guidances (see, e.g., here) have been kicking around in draft form since the last century.  The letter also notes that these guidances often do not take into account – or even worse, conflict with – the views of the scientific community.  As we’ve noted in the past, this would be solved with notice-and-comment rulemaking.  

The letter requests FDA to respond to the following information requests and questions:

1. A list of all Level I Draft Guidances, including the date issued, and the timeline with which you plan to withdraw, revise, or finalize each guidance.

2. An update on Agency-wide activities to implement the “best practices” to make the finalization of guidance more efficient and expeditious, as discussed in the 2011 report Food and Drug Administration Report on Good Guidance Practices:  Improving Efficiency and Transparency.

3. Have you implemented the President’s Council of Advisors on Science and Technology recommendation to rely more on the biomedical community in help developing and revising guidances, and if so, could you provide examples of specific guidances?

4. For the guidances still in draft form, how do you ensure your staff does not follow the guidance in the absence of any other policy or final guidance?

5. What is the average amount of time in calendar days that the FDA has taken to finalize draft guidances in the last five years?  What is the range?

Now that the Senate has had its interest piqued by this issue, will it ultimately change FDA’s penchant for issuing draft guidance documents instead of taking the harder (yet ultimately more beneficial) step of implementing substantive policy changes through notice-and-comment rulemaking?  Time will tell, but we’re not overly optimistic.

By Anne K. Walsh & Kurt R. Karst –      

Earlier this week, Hyman, Phelps & McNamara, P.C. submitted a Citizen Petition to FDA on behalf of a client requesting that the Agency determine that Ranbaxy Laboratories, Ltd. (“Ranbaxy”) has forfeited or is not eligible for first-to-file status for any ANDA subject to FDA’s Application Integrity Policy (“AIP”) (e.g., valsartan, esomeprazole magnesium, and valganciclovir hydrochloride), and that FDA immediately approve all tentatively approved ANDAs for these drugs and any other tentatively approved drugs for which final approval is blocked by Ranbaxy’s alleged eligibility for 180-day exclusivity.

As the Citizen Petition describes in detail, Ranbaxy has a long history of data integrity and manufacturing issues that have resulted in countless recalls of Ranbaxy’s products, the imposition of a Consent Decree requiring strict compliance with current good manufacturing practices, import bans from Ranbaxy’s manufacturing facilities in India, the payment of a multi-million dollar civil fine, and a criminal conviction of the company.  FDA itself recognized that the problems at Ranbaxy were so egregious that they warranted invoking FDA’s rarely used AIP to withhold review of data in Ranbaxy’s applications. 

But, as the Citizen Petition describes, FDA has not gone far enough to protect the public health.  Immediate action is needed.

This petition seeks to level the playing field for all generic drug manufacturers who have not submitted fraudulent applications and seek to comply with FDA’s requirements.  More importantly, this petition seeks to lift the roadblock created by FDA that prevents patients and health care providers from accessing generic versions of drugs while FDA chooses to honor Ranbaxy’s first-to-file status.  . . .  FDA can, and must, declare that Ranbaxy is not eligible for 180-day marketing exclusivity in connection with ANDAs that are subject to FDA’s [AIP], and must immediately approve those ANDAs that have met FDA’s standards and are tentatively approved.  

The Citizen Petition goes on to provide numerous bases for FDA to determine that Ranbaxy’s status as a first applicant otherwise making the company eligible for 180-day exclusivity for drug products subject to the AIP should be revoked.  As noted in the petition: 

Ranbaxy has admitted to submission of fraudulent data to FDA.  FDA has recognized that data in Ranbaxy’s ANDAs are so materially flawed that it invoked the AIP against Ranbaxy to assure that FDA could review applications that contained credible and reliable information. . . .  [T]here are numerous bases for FDA to determine that Ranbaxy’s status as a first applicant on any pending ANDA should be revoked.  To not do so is to reward Ranbaxy for its illegal behavior at the cost of denying consumers low cost high quality generic drugs from other manufacturers.  FDA should immediately approve any and all ANDAs that are being blocked by Ranbaxy’s wrongfully obtained eligibility for marketing exclusivity. 

By Anne K. Walsh –

Most news involving the False Claims Act reports that a company paid large sums of money to the government and relators to settle allegations of off-label promotion.  Not so in this post about a recent decision dismissing a relator’s complaint.  Not only did the company win, for now, but the court made some helpful statements to support dismissal of other complaints with similarly defective allegations. 

The relator, Laurie Simpson, worked for seven years at Bayer Corporation, during which tenure she helped market and promote Trasylol, a prescription drug approved by FDA for patients undergoing coronary artery bypass graft using a cardiopulmonary bypass pump to prevent excess bleeding.  Simpson alleged that Bayer violated the False Claims Act by “engag[ing] in a campaign of concealment and disinformation concerning Trasylol’s safety and efficacy.”  At the heart of Simpson’s Eighth Amendment of the 131-page Complaint containing 30 causes of action, is the allegation that Bayer promoted Trasylol for other types of surgeries and failed to provide safety and efficacy information about those other uses, resulting in the drug being misbranded under the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  

On April 11, 2014, the U.S. District Court for the District New Jersey ruled favorably on Bayer’s motion to dismiss the complaint.  Bayer raised several bases for dismissal, but the focus of this post is Bayer’s argument that Simpson failed to adequately plead a false claim for payment, a critical element of an FCA violation.  In the Third Circuit, and other jurisdictions, there are two categories of false claims:  factually false claims (when the claimant misrepresents what goods or services are provided) or legally false claims (when there is a knowing false certification of compliance with a legal requirement on which payment is conditioned). 

The allegations Simpson presented were that the claims were legally false because they were based on the alleged misbranding of Trayslol in violation of the FDC Act.  To adequately plead a legally false claim, and survive dismissal, the relator had to establish that Bayer had made an implied certification that Trasylol complied with the FDC Act restriction against misbranding, and that such compliance with the FDC Act was a “condition of payment” from the government. 

The court systematically reviewed each of the government programs that Bayer allegedly defrauded (e.g., Medicare, DOD, Tricare) to determine whether the government conditioned its payments for Trasylol on the limited on-label use of the drug.  The court concluded that Simpson’s “bare legal conclusions” did not adequately plead the existence of a condition of payment and that the inference required by Simpson “would be speculative at best.”  Thus, the court dismissed these counts, albeit without prejudice. 

As part of its analysis, the court notably reminds of the purpose of the False Claims Act: “the False Claims Act was not designed for use as a blunt instrument to enforce compliance with all medical regulations—but rather only those regulations that are a precondition to payment.”   This reminder may not do much to quell the tide of relators’ claims, but it provides continued support to industry in defending these actions.

By Kurt R. Karst –      

We’ve said it before, and we’ll say it again: 180-day generic drug marketing exclusivity governed by the version of the FDC Act in effect prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”) is alive and kicking. . . . and will likely be around for years to come.  Sometimes FDA’s decisions under that pre-MMA regime are contentious, as recent lawsuits against FDA (here, here, and here) concerning generic CELEBREX (celecoxib) Capsules and stemming from an FDA Letter Decision show.  Other times, FDA’s decisions are made quietly and go unnoticed (by most).  It’s this latter case that we want to bring to light today.  And it concerns a generic version of the bone resorption inhibitor EVISTA (raloxifene HCl) Tablets, 60 mg, approved under NDA No. 020815.

Under the pre-MMA version of FDC Act § 505(j), 180-day exclusivity is patent-based, such that an ANDA applicant is (or different applicants are) eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the brand-name Reference Listed Drug if such applicant submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered by the earlier of either the first commercial marketing (for all patents certified to as Paragraph IV by a first-filer), or by a court decision favorable to an ANDA applicant (with respect to a particular patent). 

As a result of an effective date provision in the MMA (Section 1102(b)(1)), a drug product subject to the pre-MMA rules on 180-day exclusivity is forever evaluated under the old version of the statute.  This means that if an application – an ANDA with a number less than or equal to 076933 – containing a patent certification was submitted to FDA before December 8, 2003, then any subsequent ANDA, whether or not it contains the first Paragraph IV certification to a patent, is subject to the pre-MMA 180-day exclusivity rules (see our previous post here).

Raloxifene HCl Tablets, 60 mg, is a pre-MMA drug.  As far as we can tell, Barr Laboratories, Inc. (“Barr”) submitted the first ANDA to FDA in the latter part of 2002 – ANDA No. 076441.  The ANDA contained Paragraph IV certifications to several patents listed in the Orange Book for EVISTA, including U.S. Patent Nos. 6,458,811 (“the ‘811 patent”), 6,797,719 (“the ‘719 patent”), and 6,894,064 (“the ‘064 patent”) (all expiring on March 10, 2017).   A fourth patent – U.S. Patent No. 8,030,330 (“the ‘330 patent”), also expiring on March 10, 2017 – was listed in the Orange Book in 2011 (as reflected in the October 2001 Cumulative Supplement).  Barr promptly certified Paragraph IV, making it a first-filer with respect to the ‘330 patent.

Meanwhile, in March 2006, Teva Pharmaceuticals USA (“Teva”) submitted ANDA No. 078193 to FDA for a generic version of EVISTA.  Teva’s original ANDA apparently contained certifications to the ‘811, ‘719, and ‘064 patents.  Like Barr, Teva also promptly amended its ANDA to contain a Paragraph IV certification to the ’330 patent.  In fact, Barr and Teva certified to the ‘330 patent on the same day. 

If we stop at this point in the story, then applying FDA’s seemingly ever-evolving pre-MMA patent-by-patent approach to 180-day exclusivity – see, e.g., here and here – would mean that Barr’s status as a first-filer on all four patents, and, therefore, Barr’s eligibility for 180-day exclusivity based on all four patents, would serve as a barrier to FDA’s approval of Teva’s ANDA No. 078193.  That is, this is not a scenario in which FDA has been willing to recognize shared 180-day exclusivity.  FDA has limited shared 180-day exclusivity to situations where there is an exclusivity stand-off – i.e., where there are cross-Paragraph IV certifications to different patents, such that one ANDA applicant is first-to-file on Patent 1 (but subsequent on Patent 2) and another applicant is first-to-file on Patent 2 (but subsequent on Patent 1), and each applicant’s eligibility for 180-day exclusivity blocks the other from getting approval.

The twist with Raloxifene HCl Tablets, 60 mg, came when Barr notified FDA that it relinquished any claim to 180-day exclusivity with respect to the ‘811, ‘719, and ‘064 patents, but not with respect to the ‘330 patent.  As such, FDA had to address for the first time the question of whether or not relinquishment of blocking 180-day exclusivity altered the ANDA approval equation such that the Agency could approve a subsequent filer’s application.  According to FDA’s approval letter, the relinquishment freed things up for Teva:

With respect to 180-day generic drug exclusivity, Teva and another applicant were the first ANDA applicants to submit a substantially complete ANDA with a paragraph IV certification to the ‘330 patent.  The other applicant was the first ANDA applicant to submit a substantially complete ANDA with a paragraph IV certification to the ‘811, ‘719 and ‘064 patents.  The other applicant has relinquished its entitlement to exclusivity with respect to these three patents.  Therefore, with this approval Teva is eligible for 180 days of generic drug exclusivity for Raloxifene Hydrochloride Tablets, 60 mg.  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, will begin to run from the earlier of the commercial marketing or court decision dates identified in section 505(j)(5)(B)(iv).

Although we don’t always agree with FDA’s decisions in the 180-day exclusivity realm, this one seems to make good sense and to have been decided correctly.