By Alan M. Kirschenbaum –

CMS has posted relevant dates, instructions and other information regarding “Phase 2” of the 2014 reporting process under the Physician Payment Sunshine Act.  (Background on this law and the 2014 reporting process can be found here.)  CMS announced that Phase 2 of the Open Payments data submission, during which applicable manufacturers will report, and attest to the accuracy of, detailed data concerning each payment to physicians and teaching hospitals during the last five months of 2013, will begin on June 1 and end at close of business on June 30.  (Phase 1, which ended on March 31, involved the submission of aggregate data only.)

Among the newly-posted information on CMS’ Open Payments web site are detailed instructions for the Phase 2 submission, a Phase 2 tutorial, updated submission data mapping documents (i.e., templates), and the text of the lengthy attestations that applicable manufacturers will have to make in order to submit the required payment data.  These materials and other information can be found on CMS’ Open Payments website here.

By James C. Shehan –

According to St Francis of Assisi, “where there is charity and wisdom, there is neither fear nor ignorance.”  As we contemplate the policy changes announced in the just-issued OIG Supplemental Special Advisory Bulletin on Independent Charity Patient Assistance Programs (PAPs), we wonder whether the charities and pharmaceutical companies affected by them will find comfort in the OIG’s enunciated wisdom, or rather ignorance and fear stemming from the suggestions therein that activities previously condoned by the OIG are now potentially subject to government enforcement actions under the anti-kickback statute.  To be more precise, the new Special Advisory Bulletin notifies us that PAPs with a narrow focus on specific diseases and specific products will be subject to “more scrutiny,” explicitly states that existing advisory opinions that endorsed the practices of some independent charities “will need to be modified,” but also provides little specific guidance and instead leaves many current practices in a gray area.    

The Special Advisory Bulletin (SAB) begins by acknowledging that PAPS can achieve the important goal of helping patients obtain needed medicines and that an SAB on PAPs issued in 2005 found that “lawful avenues” exist for pharmaceutical manufacturers to ensure that patients can afford medically necessary drugs.  The new SAB also reiterates that donor contributions to PAPS and PAPs’ grants to patients implicate the anti-kickback statute if either influences the recommending, arranging or purchasing of federally reimbursable products.  Noting that the previous SAB preceded the existence of the Medicare Part D prescription drug benefit, OIG explains that it has since become aware of “specific risks” with these programs relating to three areas: disease funds, eligible recipients and the conduct of donors.

In addressing its concern with “disease funds,” OIG cautions that funds may be so narrowly defined that a donor is effectively subsidizing its own products. Put another way, the independent charity PAP must not be a “conduit for payments … from the pharmaceutical manufacturer to patients” and therefore as an “impermissibl[e] influence” of beneficiaries’ drug choices.  It is in the specifics following these statements that the SAB becomes vaguer.  A number of suspect eligibility-limiting criteria are mentioned – e.g., specific symptoms, severity of symptoms, specific methods of administration, stages of a disease.  None of these limitations are specifically prohibited, however; rather, the guidance cites them as areas of OIG “concern” and subject to “scrutiny.”  The OIG also is “concerned” about disease funds limited to a subset of available products — particularly expensive and specialty drugs — rather than all products approved by FDA for the disease covered by the fund, or all products covered by a Federal health care program for the disease (including generics). 

The SAB specifically addresses situations where there is only one reimbursed drug for a disease or one manufacturer who makes all of the drugs for a disease.  The new SAB does not retract the statement of the 2005 SAB that these circumstances alone do not create anti-kickback violations. It does rather inscrutably state, however, that such situations are “subject to scrutiny” and that, among other factors, OIG will consider whether the disease fund “appears to be narrowly defined in a manner that favors any of the fund’s donors.”   How a manufacturer who makes the only approved drug for a particular disease could avoid favoring itself in donations to a PAP that covers that disease is not addressed.

The summary of the disease fund section muddles the guidance even further by proclaiming that “disease funds should be defined in accordance with widely recognized clinical standards and in a manner that covers a broad spectrum of products.”  These “widely recognized clinical standards” are not further defined nor are they mentioned anywhere else in the guidance.   Similarly, the summary proclaims that “disease funds should not be defined for the purpose of limiting the drugs for which the Independent Charity PAP provides assistance.” This very broad statement seems to contradict other sections of the SAB.  For example, it might be interpreted to prohibit a PAP that distributed all available antiviral drugs to needy patients with HIV.

As for eligible recipients, the SAB does stand by an earlier advisory opinion that allows PAPs to provide assistance only to Medicare patients.  PAPS are instructed to base eligibility on reasonable, verifiable and uniform measures of financial need that are consistently applied.  OIG does caution, however, that the cost of a particular drug is not an appropriate stand-alone factor in determining financial need and that overly-generous financial need criteria may be suspect. 

The SAB section on donors is more cryptic than the eligible recipients section.  Referencing the certifications that PAPs make when applying for OIG advisory opinions, it states a material fact relied upon by OIG in issuing favorable opinions is that a PAP does not give donors information that allows the donor to correlate the amount or frequency of its donations with the number of patients  or the volume of product dispersed.  Noting that these advisory opinions do not address donor actions, the SAB nevertheless states that “actions by donors to correlate their funding of PAPs with support for their own products… may be indicative of a donor’s intent to channel its financial support to copayments of its own products, which would implicate the anti-kickback statute.”

It is in the concluding section that OIG changes course on some existing advisory opinions.  Repeating that independent charity PAPS are a valuable resource for a needy patients but raise serious issues of fraud, waste and abuse, OIG states that some independent charity PAPS “have received favorable advisory opinions that may include features that are discouraged in this [SAB.]”  OIG volunteers that it is writing to these PAPS to explain how it will work with them and notes that some advisory opinions will need to be modified.  In the interim, the suspect features will be “protected.”   Finally, OIG voices its intent that there should be “no disruption of patient care during this process.” 

While the new SAB might have done a somewhat better job of reducing fear and ignorance, we believe that St. Francis would join us in heartily endorsing this last sentiment regarding the well-being of patients.

It’s been nearly 30 years since President Ronald Reagan, on September 24, 1984, held a ceremony in the Rose Garden to sign into law the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) – better known to most as the Hatch-Waxman Amendments.  To celebrate the upcoming anniversary, the William Mitchell Law Review of the William Mitchell College of Law has put out an issue – Volume 40, Issue 4: The 30th Anniversary of the Hatch-Waxman Act – with several articles dedicated to the anniversary.

A Foreword to the new volume by Senator Orrin Hatch provides some interesting insights into the triumphs and tribulations of the legislative process that led to the enactment of the Hatch-Waxman Amendments (and that aren’t in the legislative history).

Robert A. Armitage, in a piece titled “The Hatch-Waxman Act: A Path Forward for Making It More Modern,” offers some commentary on the economic and regulatory environment that led to the development of the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures Act of 2013 (“MODDERN Cures Act of 2013”) (H.R. 3116).  According to Mr. Armitage:

What may be the best next-generation thinking on defining a common regime for copied versions of all new medicines to be able to come to market can be found in a bill that is now pending before Congress.  This latest congressional effort is the MODDERN Cures Act.  The MODDERN Cures Act, according to its proponents, has the potential to be a quantum improvement over both the Hatch-Waxman Act and the Biosimilars Act in terms of meeting the needs and expectations of patients for access to lowcost, high quality medicines—while spurring greater industry focus on the development of new medicines of the greatest potential benefits for patients (i.e., those addressing unmet medical needs).  Compared to the IP interface provisions of either the Hatch-Waxman Act or the Biosimilars Act, the MODDERN Cures Act is a virtual paragon of simplicity and directness.

This blogger (Kurt R. Karst), in an article titled “Letting the Devil Ride: Thirty Years of ANDA Suitability Petitions Under the Hatch-Waxman Act,” provides the first ever analysis of the FDA’s nearly 30-year track record of responding to ANDA suitability petitions submitted pursuant to FDC Act § 505(j)(2)(C).  The article traces the history of generic drug development and the petitioned ANDA from a regulation promulgated shortly before the enactment of the Hatch-Waxman Amendments to the current statute; analyzes almost 1,300 suitability petitions submitted to FDA since September 24, 1984 (and provides various data tables on suitability petitions submitted to and acted on by FDA each year from 1984 to 2013); suggests some reasons for the decline in the popularity of the petitioned ANDA as a vehicle for obtaining approval of a generic drug; and recommends that FDA implement procedures to meet the statutory 90-day deadline for approving or disapproving an ANDA suitability petition, or that Congress amend the FDC Act to provide FDA with a more practical deadline to rule on a suitability petition.

Shashank Upadhye’s article, titled “There’s a Hole in My Bucket Dear Liza, Dear Liza: The 30-Year Anniversary of the Hatch-Waxman Act: Resolved and Unresolved Gaps and Court-Driven Policy Gap Filling,” examines how implementation of the Hatch-Waxman Amendments (and amendments to that law) has caused significant problems in the marketplace and how court-driven policy has also been a culprit in the Act’s interpretations and executions.  Mr. Upadhye has been a busy writer of late.  In another article published in the Boston University Journal of Science and Technology Law, and titled “The FDA and Patent, Antitrust, and Property Takings Laws: Strange Bedfellows Useful To Unblock Access To Blocked Drugs,” he discusses the impact of REMS (Risk Evaluation & Mitigation Strategies) on generic drug development.

Lars P. Taavola, in a piece titled “Jumping into the Actavis Briar Patch—Insight into How Courts May Structure Reverse Payment Antitrust Proceedings and the Questions That Actavis Left Unanswered,” looks at how courts will have to decide some seminal questions in light of the U.S. Supreme Court’s decision in Federal Trade Commission v. Actavis, Inc., 133 S. Ct. 2223 (2013) (see here), concerning drug patent settlement agreements.

Brian P. Wallenfelt argues in his article, titled “Hatch-Waxman and Medical Devices,” that the similarities between medical devices and drugs outweigh the differences, and, accordingly, that there should be an abbreviated review process for medical devices.

In an essay titled “When Patents Aren’t Enough: Why Biologics Necessitate Data Exclusivity Protection” Kristina M. Lybecker, Associate Professor of Economics at Colorado College, says that the Trans-Pacific Partnership Trade Agreement currently being negotiated (see our previous post here) “should include the proposed twelve years of data exclusivity and provide innovative firms with the incentives needed to continue to invest in the breakthrough therapies that will extend and enhance life for years to come.”

By Alexander J. Varond & James E. Valentine –

On May 20, 2014, Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski appeared on a panel before the House Energy and Commerce’s Subcommittee on Health to present testimony at the first hearing on the 21st Century Cures Initiative.  The Subcommittee sought expert testimony about the proposals put forth in the 2012 “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation” by the President’s Council of Advisors on Science and Technology ("PCAST") (see our previous post here).  The Subcommittee asked the panel to discuss how recommendations presented in the PCAST report could be used by FDA and drug sponsors to advance the mandate of the 21st Century Cures initiative to “ensure that the U.S. owns the discovery, development, and delivery cycle and thus, remains the world leader in innovation.”

On behalf of the National Organization of Rare Disorders and himself, Mr. Sasinowski offered four recommendations:

Proposal #1: FDA should consider the appropriateness of the Accelerated Approval process for every new therapy.

Proposal #2: FDA and sponsors should use intermediate clinical endpoints ("ICE") more often to secure Accelerated Approvals.

Proposal #3: FDA should increase its use of the statutory authority conferred by FDAMA to approve drugs with one adequate and well-controlled study with “confirmatory evidence” and by FDASIA to approve drugs via the Accelerated Approval pathway (Proposal #1) using a simple chart (see below).

Proposal #4:  FDA should issue a guidance on cumulative distribution analyses of clinical study results as a way to help understand the clinical meaningfulness of a new therapy.

Mr. Sasinowski’s written testimony provides greater detail for each of his four proposals, and includes findings from the Subpart H analysis (see our previous post here) he and Alexander J. Varond submitted on August 26, 2013, in response to FDA’s draft guidance entitled “Expedited Programs for Serious Conditions – Drugs and Biologics” (Docket No. FDA-2013-D-0575).  A press release is available online (here), and a video recording of the hearing will also be available online (here).

 Chart for Proposal #3:

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.