BioLawGics

In a split decision today, a panel of the Second Circuit Court of Appeals overturned ― on First Amendment grounds ― the criminal conviction of a pharmaceutical sales representative who had promoted Jazz Pharmaceutical’s Xyrem for off-label use.  Caronia.pdf. 

As an aside, Xyrem, is also known as gamma-hydroxybutyrate or “GHB.” GHB is a powerful and fast-acting central nervus system depressant that has been subject to abuse as a recreational drug and is classified by the Department of Health and Human Services (HHS) as a “date rape” drug.

Caronia was convicted under 21 U.S.C. § 333(a)(2) which makes misbranding an FDA-licensed drug product criminal.  A drug is misbranded if, inter alia, its labeling fails to bear "adequate directions for use," 21 U.S.C. § 352(f), which FDA regulations define as "directions under which the lay[person] can use a drug safely and for the purposes for which it is intended," 21 C.F.R. § 201.5.  The Food and Drug Act itself does not expressly prohibit or criminalize off- label promotion, but the FDA’s policy has been to consider off-label promotion as showing intent to misbrand per se in that the label would not have adequate directions for the off-label use.

In overturning Caronia’s conviction, the panel held:   

Accordingly, even if speech can be used as evidence of a drug's intended use, we decline to adopt the government's construction of the FDCA's misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA- approved prescription drugs.  Slip Op. at 51.

The panel majority reasoned that the pharmaceutical company’s First Amendment rights to speak about off-label uses is not trumped by any legitimate governmental purpose under Constitutional standards.  In fact, the panel made much of the fact that off-label prescription is not illegal and emphasized that as a result, the dissemination of truthful information about off-label uses has positive effects:

As off-label drug use itself is not prohibited, it does not follow that prohibiting the truthful promotion of off-label drug usage by a particular class of speakers would directly further the government's goals of preserving the efficacy and integrity of the FDA's drug approval process and reducing patient exposure to unsafe and ineffective drugs.   Slip Op. at 42-42.

It was the majority’s opinion that criminalizing off-label promotion is an ineffective means to achieve the FDA’s mission:

If the government's objective is to shepherd physicians to prescribe drugs only on-label, criminalizing manufacturer promotion of off-label use while permitting others to promote such use to physicians is an indirect and questionably effective means to achieve that goal. Thus, the government's construction of the FDCA's misbranding provisions does not directly advance its interest in reducing patient exposure to off-label drugs or in preserving the efficacy of the FDA drug approval process because the off-label use of such drugs continues to be generally lawful. Accordingly, the government's prohibition of off-label promotion by pharmaceutical manufacturers "provides only ineffective or remote support for the government's purpose."  Slip Op. at 47.

One panel judge, Debra Ann Livingston, strongly dissented from the holding.  She emphasized the long enforcement against off-label promotion and disagreed with the majority’s Constitutional reasoning.  This decision can be appealed to the entire Second Circuit sitting en banc, and/or the U.S. Supreme Court.

Enforcement against off-label promotion is a huge aspect of FDA regulatory power, and a major concern of pharma companies.  Many companies have paid fines in excess of a billion dollars to settle off-label marketing prosecutions.  Indeed, in 2007, Caronia’s employer, Jazz Pharmaceuticals, itself paid a $20 million settlement for off-label promotion of Xyrem.  Hence, companies heavily invest in compliance strategies to avoid prosecution, and are heavily limited in the means they have to convey information about their drugs.

It will be fascinating to see whether other courts follow the Caronia decision, and whether pharma companies alter their promotional techniques as a result of this case or its aftermath.

Last week FDA approved tbo-filgrastim, a recombinant human granulocyte colony-stimulating factor (or “G-CSF”) produced by Sicor Biotech, a Lithuanian subsidiary of Teva Pharmaceutical Industries. tbo-filgrastim approval letter  Teva press release.  Amgen has sold billions of dollars of its recombinant G-CSF called Neupogen® since approval in 1991.  While Amgen has exclusive rights in the U.S., Teva and others have been selling G-CSF products in Europe for several years.  Under the terms of a 2011 patent litigation settlement between Amgen and Teva, Teva’s product should launch in the U.S. in November 2013.

As we addressed in an earlier post , Teva filed for approval of its G-CSF product before the U.S. biosimilar pathway was available.  Thus, Teva submitted a full BLA for its product.  In its press release, made it clear that it does not deem it to be biosimilar to Neupogen: “FDA has not approved tbo-filgrastim as a biosimilar to Neupogen (filgrastim), which is a previously licensed biological product that contains a related drug substance.”  Teva currently markets filgrastim in Europe under the trade name Tevagrastim, which is approved as a biosimilar to Neupogen®.  Returning to the U.S. BLA, comparison of the product inserts for the two products is interesting.  Tbo-filgrastim is approved for similar indications:

The adverse reactions and warnings and precautions are also similar between the two labels.  Also it appears that the phase three clinical trials included approximately the same number of patients.  Also, no comparison studies to establish any superiority were included in the BLA.  And, even though Neupogen® has been marketed for 20 years, FDA has required extensive post-marketing studies including development of an assay for neutralizing antibodies and a 426-person clinical study assessing anti-G-CSF antibody formation. Approval letter <>  So essentially FDA did not allow Teva to cut any corners compared to the Neupogen® regulatory package.

Although not a biosimilar per se, Teva’s approach to marketing tbo-filgrastim in the U.S. will be a guidepost for the nascent U.S. biosimilar industry.  Other than the fact that Teva will not be able to make any comparability claims, market conditions for tbo-filgrastim will be similar to biosimilars. So presumably, Teva’s approach and eventual experience with marketing, pricing, reimbursement, patient education, and post-marketing monitoring will inform biosimilar manufacturers.  And, tbo-filgrastim’s market share dynamics and financial performance should allow industry watchers to better predict the performance of biosimilars when they arrive.

One does wonder though, will prescribers prefer a “me-too” drug with completely independent proof of safety and efficacy, or a biosimilar whose performance has been validated against the established brand product?  It is not inconceivable that Teva is or will go back to FDA to acquire biosimilar or interchangeable status in order to better compete against Neupogen® and the biosimilars when they come.

With this morning’s Supreme Court affirmance of the bulk of the Affordable Care Act, the specter that the BPCIA framework for biosimilar introduction could be dismantled is no longer a concern.  Presumably it will be full speed ahead through the regulatory process, and we will see biosimilar applications for approval and attendant patent litigation before too long.  It will be years, though, before there will be sufficient experience to assess whether the BPCIA will achieve its goals of spurring competition for important biologics without undermining the incentives for new innovations.  In the meantime, one wonders whether there will be appetite among the stakeholders for preemptively amending the Act (for example, by changing the 12 year exclusivity period) when the firestorm over changing or repealing the ACA begins in the next Congress.

FDA recently published its Response to a 2009 Citizen Petition from Therapeutic Proteins, Inc. which requested FDA “exercise its authority and make necessary amendments to its rules to allow submission of biological drug marketing authorization applications [including BLAs submitted under the PHS Act] under aNDA ….”  In short, FDA concluded that there is no ANDA end-around to the recently enacted biosimilar approval pathway under the BPCIA:

The 505(b)(2) and 505(j) approval pathways are available only for products for which the listed drug relied upon or RLD, respectively, was approved under section 505(c) of the FD&C Act.  Because the 505(j) pathway is not available for a proposed product that seeks to rely upon a biological product licensed under section 351(a) of the PHS Act, your Petition is denied in part.  The BPCI Act was enacted after the submission of your Petition.  A sponsor seeking to submit an abbreviated marketing application for a biological product that can be demonstrated to be “highly similar” (biosimilar) to, or interchangeable with, a reference product licensed under section 351(a) of the PHS Act may submit a 351(k) application. 

Response at 5.  The authors of the FDA Law Blog have written an interesting post about this and two earlier Citizen Petition Responses concerning biosimilars:  You Had Us At “Biosimilars,” FDA; Agency Ties Up Yet Another Biosimilars Loose End With Petition Response Concerning Certain “Biological Drugs.”

We’re still awaiting the first biosimilar litigation and/or approval under the BPCIA to see whether the biosimilar route is truly going to be an attractive opportunity in the U.S.

On the 26^th of July, the FDA’s Center for Drug Evaluation and Research (CDER) published a draft report entitled “Identifying CDER's Science and Research Needs.”  The document describes seven major regulatory science needs CDER believes are important to its mission.

Of most interest here, the seventh category CDER identifies is “Enhance Individualization of Patient Treatment.”  This document amplifies the themes recently sounded in the FDA’s Draft Guidance Concerning In Vitro Companion Diagnostic Devices that was released a few weeks ago.  In short, CDER is emphasizing the importance of, and encouraging further research into, qualifying different biomarkers for making decisions concerning dosing, patient selection for efficacy, and patient exclusion for safety.  Clearly, CDER has the expectation that many clinical trials and approved treatment regimens will have one or more integrated diagnostic genetic tests and that personalizing treatments will lead to better patient outcomes.  But, as suggested in the report, large public/private collaborations will be necessary to identify novel biomarkers and to develop the tools to properly validate them for clinical use.

Major generics player Teva preempted the new biosimliar pathway by filing a standard BLA for its GCSF (filgrastim) product callled Neutroval, which is intended to compete with Amgen's Neupogen.  Commentators have suggested that filing a 42 USC 262(a) standard BLA instead of a Section 262(k) biosimilar application with the FDA may be the favored route for biosimilar manufactures because (1) the 12 year exclusivity period for innovators does not apply to new 262(a) applications; and (2) the differential between the data the FDA requires under the two sections might be minimal, given the FDA's discretion to develop standards for biosimilar applications. 

The FDA has now acted on Teva's Neutroval BLA.  On September 30, 2010 the FDA issued a complete response letter, which requested further information, but no additional clinical trials.  As discussed in an October 13 article in FDA Week entitled "Decision on Teva's Neutroval Forecasts Agency Posture on Biologics Data," it is believed that Teva relied on some Amgen data in its BLA package, given that it obtained European regulatory approval for the drug using the European biosimilar pathway.  The article therefore speculates that the FDA may be amenable to "skinny BLAs" that rely on reference product data.

While it seems unlikely that the FDA will allow companies to use BLAs in lieu of 262(k) biosimilar applications as an end-around the 12 year exclusivity period set in the new legislation by permitting use of reference product data, it may very well be that many prospective biosimilar entrants will stick with the tried and true BLA approach.  The FDA Week article quotes a Teva official as stating that given the regulatory uncertainty surrounding biosimilars, "Teva will continue to file BLAs in order to bring affordable biologics to the American public sooner."  Until at least one 262(k) application is fully reviewed by the FDA, we won't know whether the advantages of using innovator data are outweighed by the long exclusivity period and the uncertainty surrounding the requirements for approval.

While the biosimilar regime is brand-new and untested in the United States, the European community has more than five years’ experience with a similar program.  We expect the FDA to look to the European Medicines Agency (EMA) as it begins to define the requirements for a “section (k)” abbreviated biosimilar marketing application. Of course, the specifics of the rules and regulations differ between the jurisdictions. The following is a high-level comparison of the regulatory and patent litigation regimes between the U.S. and Europe.

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