How Will FDA Regulate Off-Label Communications in the Post-Facteau World?

Vol. 6, Issue 3 // September 26, 2016
By David L. Rosen, Jason L. Drori, Melissa Y. Lerner (Foley & Lardner LLP)

Regulations promulgated by the U.S. Food and Drug Administration (FDA) prohibit drug manufacturers from promoting a drug for any non-FDA approved, or “off-label,” indication.  FDA historically has relied on the new drug and misbranding provisions of the Federal Food, Drug, and Cosmetic Act (FDCA) for authority to regulate “off-label promotion.”[1]

The FDCA prohibits misbranding and the introduction or receipt of an unapproved new drug into interstate commerce.  See 21 U.S.C. § 331(a), (c); 21 U.S.C. § 355(a).  Accordingly, the statute prohibits off-label promotion but not off-label use of approved drugs and medical devices, yet health care professionals need truthful scientific and medical information about unapproved uses of approved products.  Access to such information is important, because many off-label uses have become readily accepted, and in some cases, commonplace, in medical practice.  And, invariably, pharmaceutical companies have the information at the ready.  Litigation in just the past few years has called into question the constitutionality (and desirability) of FDA’s practice of restricting drug manufacturers’ off-label marketing when such practice impedes truthful, non-misleading commercial speech.  Some recent court decisions have found overreach of FDA’s enforcement authority and ordered limitations on that authority.  We discuss these judicially-imposed limitations and how FDA may continue regulating drug promotion without trampling on the commercial speech rights of pharmaceutical and medical device marketers.

I. BRIEF OVERVIEW OF DEVELOPMENTS IN THE LAW OF OFF-LABEL MARKETING

A. Sorrell

A survey of the regulatory landscape of off-label promotion of pharmaceuticals and medical devices necessarily begins with a discussion of the United States Supreme Court’s 2011 opinion in Sorrell v. IMS Health Inc.[2]  Sorrell involved two consolidated suits— “[o]ne [ ] brought by three Vermont data miners, the other by an association of pharmaceutical manufacturers that produce brand-name drugs”—challenging Vermont’s Prescription Confidentiality Law, under which prescriber-identifying information could not be sold by pharmacies and similar entities, disclosed by those entities for marketing purposes, or used for marketing by pharmaceutical manufacturers.[3]  Sorrellbolstered First Amendment protection for commercial speech, recognizing the value of the “prescriber-identifying information” targeted by the Vermont statute: “Knowledge of a physician’s prescription practices . . . enables a detailer better to ascertain which doctors are likely to be interested in a particular drug and how best to present a particular sales message.”[4]

By a 6-3 vote, the Court concluded the “law on its face burdens disfavored speech by disfavored speakers,” i.e., speech promoting brand-name drugs by drug detailers, warranting “heightened judicial scrutiny.”[5]  The majority explained “the creation and dissemination of information are speech within the meaning of the First Amendment,” and even though “restrictions directed at commerce or conduct . . . imposing incidental burdens on speech” may withstand scrutiny, the Vermont statute’s “more than incidental burden on protected expression” rendered it unconstitutional.[6]

Sorrell clarified the appropriate “commercial speech inquiry”: “[I]t is the State’s burden to justify its content-based law as consistent with the First Amendment,” and “[t]o sustain the targeted content-based burden [the Vermont law] impose[d] on protected expression, the State must show at least that the statute directly advances a substantial governmental interest and that the measure is drawn to achieve that interest.”[7]  “[T]he fear that people would make bad decisions if given truthful information cannot justify content-based burdens on speech.”[8]  Ultimately, the Court invalidated the Vermont law because “[t]he State has burdened a form of protected expression that it found too persuasive.  At the same time, the State has left unburdened those speakers whose messages are in accord with its own views.  This the State cannot do.”[9]

In his dissent, Justice Breyer argued the majority had incorrectly subjected the law to heightened First Amendment scrutiny instead of applying the four-pronged Central Hudson test previously considered the gold standard for analyzing government constraints on commercial speech.[10]  Justice Breyer “g[a]ve significant weight to [the] legitimate commercial regulatory objectives” of the Vermont statute, admonishing—presciently—that applying greater scrutiny when regulatory activity affects commercial speech would extend to “regulatory actions taken by other States or by the Federal Government acting, for example, through [FDA] regulation.”[11]

B. Caronia

In United States v. Caronia,[12] the U.S. Court of Appeals for the Second Circuit vacated the felony misbranding conviction of Alfred Caronia on First Amendment grounds.  Caronia, a Specialty Sales Consultant for Orphan Medical, Inc., allegedly engaged in “off-label promotion” of Xyrem, a prescription narcoleptic medication, by promoting it to “prospective physician-customers” for unapproved indications and unapproved patient populations.[13]  By a 2-1 vote, the Second Circuit rejected FDA’s “constru[ction] [of] the FDCA [as] prohibit[ing] promotional speech as misbranding itself.”[14]  Recognizing “[s]peech in aid of pharmaceutical marketing . . . is a form of expression protected by the Free Speech Clause of the First Amendment,”[15] the majority concluded Caronia’s criminal prosecution based on his promotional statements was unconstitutional.  Practically speaking, the Caronia majority held that restricting and criminalizing off-label promotion is incompatible with FDA’s public health mission:[P]rohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use “paternalistically” interferes with the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions.[16]

From a constitutional standpoint, “a complete and criminal ban on off-label promotion by pharmaceutical manufacturers is more extensive than necessary to achieve the government’s substantial interests.”[17]

Caronia thus drew a legal distinction between the communication of truthful, non-misleading health information and false or misleading commercial speech.  Although the former is entitled to First Amendment protection, the latter receives none.  Indeed, the Second Circuit admonished that “[o]ur conclusion is limited to FDA-approved drugs for which off-label use is not prohibited, and we do not hold, of course, that the FDA cannot regulate the marketing of prescription drugs.”[18]  Further, while non-misleading speech may not form the basis of a prosecution for misbranding, “[o]ff-label promotional statements could . . . presumably constitute evidence of an intended use of a drug that the FDA has not approved.”[19]  Caronia, most thought, would usher in a wholesale change in marketing enforcement policy.

C. Back to the Drawing Board: Amarin, Pacira, Vascular Solutions, and Facteau/Fabian

FDA’s public response to Caronia was, perhaps unsurprisingly, fairly tepid.  Thomas Abrams, Director of the Office of Prescription Drug Promotion (OPDP) at FDA’s Center for Drug Evaluation and Research (CDER), announced: “FDA does not believe that the Caronia decision will significantly affect the agency’s enforcement of the drug misbranding provisions of the Food, Drug, and Cosmetic Act.”[20]  Less publicly, however, FDA officials were (and still are) actively considering Caronia’s implications, “horrified” by “the consequences . . . if people could promote uses that they hadn’t . . . bothered to get through the system.”[21]  Perhaps recognizing Caronia’s potential to upend the regulatory scheme created by the FDCA’s 1962 Drug Amendments, FDA continued to bring enforcement actions targeting truthful and non-misleading statements.  In a series of high-profile rulings, beginning with Amarin Pharma, Inc. v. U.S. Food & Drug Administration,[22] judges explicitly rejected FDA’s narrow reading of Caronia.

1. Amarin

Amarin Pharma involved an as-applied First Amendment challenge to FDA regulations preventing Amarin Pharma, Inc. (Amarin) from “making completely truthful and non-misleading statements about its product to sophisticated healthcare professionals.”[23]  Amarin sought declaratory and injunctive relief, proactively attempting to protect planned promotional statements beyond the approved labeling of its hypertriglyceridemia drug, Vascepa; namely, those regarding the results of a phase 3 clinical trial (the ANCHOR trial) showing statistically significant reductions in persistently high triglyceride levels with Vascepa among statin-treated patients.  When Amarin filed a supplemental NDA seeking to expand Vascepa’s approved labeling, FDA issued a Complete Response Letter stating that, “for regulatory approval purposes, there are insufficient data at this time to support a drug-induced change in serum [triglycerides] as a surrogate for reducing cardiovascular risk in the ANCHOR population.”[24]  FDA ultimately “determined not to approve label expansion reflecting the ANCHOR clinical trial efficacy data.”[25]Amarin filed a complaint in U.S. District Court for the Southern District of New York and subsequently moved for a preliminary injunction and a declaration permitting the company to engage in truthful and non-misleading speech about the potential effects of Vascepa on coronary heart disease in patients with persistently high triglycerides.  Judge Engelmayer granted the motion, “reject[ing] the FDA’s reading of Caronia as a mere artifact of that case’s particular facts and circumstances.  By its explicit terms and its clearly-articulated reasoning, Caronia simply cannot be read as the proverbial ‘ticket good for one day only.’”[26]  Because “the speech is the act” for the crime of misbranding, “[w]here the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.”[27]  The opinion reached the merits of Amarin’s case and underscored the protected status of truthful, non-misleading speech about off-label use in the Second Circuit, while reiterating that false, fraudulent, and misleading speech on the subject was not entitled to any First Amendment protection.  In March 2016, the parties filed a proposed Stipulation and Order of Settlement, pursuant to which FDA agreed to be bound by Judge Engelmayer’s ruling and committed to a “preclearance procedure” for future off-label communications concerning Vascepa.[28]

2. Pacira

Following Amarin’s lead, Pacira Pharmaceuticals, Inc. (Pacira), a biopharmaceutical company, sued FDA last fall, challenging the constitutionality of an FDA Warning Letter concerning Pacira’s flagship product, a postsurgical anesthetic called Exparel.  OPDP issued a Warning Letter to Pacira in connection with “administration guides” describing techniques for administering Exparel in cholecystectomy and colectomy procedures although “[t]he approved labeling for Exparel does not provide instructions for, or otherwise indicate that Exparel will be safe and effective for postsurgical pain if used in surgical procedures other than bunionectomy and hemorrhoidectomy.”[29]  Despite “the inclusion of several disclaimers or disclosures in the administration guides,” FDA found “these presentations provide[d] evidence that Exparel is intended for new uses for which it lacks approval” and “suggest[ed] an extensive promotional campaign by Pacira to promote the use of Exparel in surgical procedures other than those for which the drug has been shown to be safe and effective.”[30]            On October 13, 2015, less than a month after Pacira sued, FDA withdrew the Warning Letter.  When the parties settled four weeks later, FDA agreed to clarify in writing “the reasons for the withdrawal of the Warning Letter” and to approve revised labeling for Exparel.[31]  FDA confirmed “EXPAREL has, since October 28, 2011, been approved for ‘administration into the surgical site to produce postsurgical analgesia’ for use in a variety of surgeries not limited to those studied in its pivotal trials.”[32]  On December 14, 2015, FDA publicly issued a letter to Pacira’s CEO “explain[ing] the reasons for [its] decision [to] rescind[] the 2014 Warning Letter and remove[] it from the agency’s website[.]”  Litigants defending against charges of misbranding relied on Pacira to argue “the government repeatedly has taken aggressive enforcement positions regarding promotion of off-label uses, only to retreat when challenged.”[33]

3. Vascular Solutions

Before Pacira, the U.S. Department of Justice (DOJ) filed an 18-count indictment against a Vascular Solutions, Inc. (VSI), a Minnesota-based medical devices company, and company CEO Howard Root for engaging in an unlawful off-label marketing campaign and criminal conspiracy by selling a misbranded medical device; namely, the “Vari-Lase” laser ablation device for treatment of poor-performing, i.e., varicose, perforator veins.  FDA previously had approved the Vari-Lase system for treatment of superficial veins; however, Root and VSI had promoted Vari-Lase for deeper “perforator” vein treatment.[34]Root and VSI argued, based on Amarin, that marketing Vari-Lase for ablation of perforator veins was truthful and non-misleading speech protected by the First Amendment and therefore could not support criminal liability.  They filed a motion in limine, arguing, in part, “the Court should hold that speech about an off-label use of a medical device is not misleading merely because FDA has not approved that off-label use or reviewed or approved the speech.”[35]  Judge Royce Lamberth, a Senior Judge in the U.S. District Court for the District of Columbia and sitting by designation in the U.S. District Court for the Western District of Texas, “agree[d] such a principle goes without saying” but was satisfied “any risk of such argument can be addressed by an appropriate jury instruction.”[36]

Sure enough, Judge Lamberth instructed the jury:

Doctors may use medical devices that have been approved or cleared for one use for a different use that has not been cleared or approved by the FDA. This is often referred to as unapproved use or off-label use.  This is not illegal.  It is also not a crime for a device company or its representatives to give doctors wholly truthful and non-misleading information about the unapproved use of a device.  If you find that VSI’s promotional speech to doctors was solely truthful and not misleading, then you must find the Defendants not guilty of the misbranding offense.[37]

After one day of deliberation, the jury unanimously acquitted VSI and Root on all counts.[38]  Vascular Solutions stands as the first case outside the Second Circuit to apply Caronia’s reasoning.

4. Facteau/Fabian

On the heels of Vascular Solutions, the Government charged two former executive officers of Acclarent, Inc. (Acclarent), a medical device manufacturer and subsidiary of Johnson & Johnson, with wire fraud, conspiracy, and FDCA violations based on off-label marketing of Acclarent’s Relieva Stratus Microflow Spacer, a drug-eluting stent.  Although FDA had approved the stent to “to maintain an opening to a patient’s sinus,” prosecutors indicted William Facteau and Patrick Fabian for “launch[ing] the product intending it to be used as a steroid delivery device,” claiming “FDA had specifically refused Acclarent’s request to clear the Stratus for marketing as a drug delivery device without further submissions to support that use.”[39]Before and during trial, Facteau and Fabian argued their statements about using implanted spacers for steroid delivery were non-misleading and truthful, precluding a criminal conviction based on Vascular Solutions’ interpretation and application of Caronia.  Facteau argued Acclarent had engaged in a common industry practice of obtaining regulatory approval for a “basic use” of a medical device before pursuing an additional, more complex use.  He cited the morass of FDA regulations and bureaucratic hurdles to approval as the impetus for Acclarent’s approach.  Ultimately, after a six-week trial and three days of deliberation, a jury acquitted Facteau and Fabian, finding Acclarent’s stratus spacer was mislabeled but the defendants did not intentionally act to defraud or mislead as required to prevail on the criminal misbranding and adulteration charges.[40]

After this rapid succession of legal victories for pharmaceutical and medical device companies, meaningful reform of FDA enforcement policies on the subject is needed.

II. THE PROBLEM: LACK OF UNIFORM REGULATORY GUIDANCE STOKES UNCERTAINTY AMONG STAKEHOLDERS AND STIFLES INNOVATION AND TE PROVISION OF SUPERIOR PATIENT-CENTERED CARE.  

Despite repeatedly promising to update its marketing and advertising policies and industry guidance to account for First Amendment considerations, FDA has yet to do so.  For example, on June 6, 2014, FDA granted Citizen Petitions submitted by the Medical Information Working Group in 2011 and 2013, which requested clarification of FDA’s position on drug and device manufacturer communications concerning unapproved uses of approved products in light of recent First Amendment case law.  FDA acknowledged “the draft guidance documents we have issued do not as of yet provide a comprehensive answer to all of your questions and concerns,” but it promised “to issue guidance that addresses unsolicited requests, distributing scientific and medical information on unapproved new uses, and manufacturer discussions regarding scientific information more generally, by the end of the calendar year.”  The year passed without guidance purporting to square FDA’s regulatory approach with constitutional requirements.

During the FDA/CMS Summit for Biopharma Executives on December 14, 2015, Janet Woodcock, MD, Director of CDER, announced CDER’s “front burner priorities” for 2016.  Chief among these was to “[r]e-evaluate [the] regulation of drug advertising and promotion in light of current jurisprudence around the 1^st Amendment: ongoing, progress made, but more work needed.”

Dissatisfied with FDA/CDER’s lack of progress, Rep. Fred Upton, R-MI, Chairman of the House Committee on Energy and Commerce (FDA’s authorizing congressional committee), wrote to the U.S. Department of Health & Human Services Secretary Sylvia Burwell on May 26, 2016, “perplexed by the agency’s unwillingness or inability to publicly clarify its current thinking on these issues in a coherent manner.”[41]  “Ensuring that doctors and others involved in influencing treatment decisions are informed about scientifically accurate new ‘off-label’ information in a timely yet responsible manner is often critical to optimizing patient care,” Upton stated, noting “[r]ecent litigation has raised significant questions about FDA’s authority to restrict such communication.”[42]

Congressman Upton’s frustration with FDA’s hesitancy has been echoed by public health policymakers and stakeholders.  It reflects the uncertainty plaguing the law and rules surrounding off-label promotion.  Such uncertainty demands immediate, clear guidance from FDA concerning the interplay between constitutionally-protected commercial speech and FDA’s role as arbiter of the safety and efficacy of pharmaceutical and medical device products.  “If FDA continues to remain silent,” warned Upton, “settlement agreements will be the only means by which policy is formulated—and it will be in an ad hoc manner lacking any semblance of consistency and cohesiveness.”[43]

III. THE SOLUTION: BALANCING FDA’S REGULATORY OVERSIGHT WITH FIRST AMENDMENT LIMITATIONS ON OFF-LABEL ENFORCEMENT

Developments in medical science and off-label jurisprudence over just the past four years have altered the legal landscape in which FDA regulates off-label promotion.  So far, FDA has been reluctant to adapt its enforcement approach.  To reduce uncertainty, increase transparency, and avoid unsuccessful, costly litigation that distracts from its strategic priorities, FDA must provide meaningful guidance to stakeholders and reform its enforcement priorities to monitor—but not prohibit—truthful and non-misleading communications about off-label use of pharmaceuticals and medical devices.  At a minimum, FDA should eschew the artificial distinctions between solicited versus unsolicited requests for off-label information and provide clear, definitive guidance on (1) how it differentiates between promotional statements and dissemination of medical or scientific information; and (2) the criteria by which off-label communications may be deemed truthful and non-misleading.

A. Differentiating Between Promotional and Non-Promotional Speech

Unlike purely promotional statements, which primarily concern the “bottom line,”[44] the free flow of non-promotional, non-misleading health information about a product’s safety and efficacy in treating unapproved indications supports innovation and contributes to a higher standard of medical care.  FDA’s traditional “construction of the FDCA essentially legalizes the outcome [i.e., off-label use] but prohibits the free flow of information that would inform that outcome.”[45]  The traditional approach, in addition to hindering the exchange of vital scientific and health information, runs afoul of the First Amendment.

The resources of private industry can and should be leveraged by regulators to help improve the delivery of health care.  If drug companies and medical device manufacturers can disseminate truthful, non-misleading off-label information about drugs and devices, practitioners and patients alike can make more informed treatment decisions.  The result can mean dramatic improvements to public health and health outcomes.

Current FDA guidance includes a list of factors to consider when determining whether industry-supported scientific and educational activities are “truly independent and nonpromotional” and, consequently, exempt from advertising and labeling restrictions.[46]  FDA should provide clear, detailed descriptions of the types of information that must be disclosed in connection with such presentations and activities to render them truthful and non-misleading from a regulatory standpoint.  Although a multi-factor, situation-specific analysis is generally appropriate to avoid unacceptable constraints on truthful, non-misleading statements about off-label uses, additional guidelines for making legally sufficient disclosures will provide greater certainty to pharmaceutical, biotech, and medical device companies while allowing FDA to ensure recipients of promotional messages have adequate information to exercise professional skepticism and informed decision-making.

To protect truthful and non-misleading statements and the dissemination of health information, FDA should adopt a broader program modeled on the review and approval mechanism negotiated during the Amarin settlement.  A drug manufacturer could submit a set number of off-label communications per product each year for FDA preclearance.  FDA would respond with specific concerns, comments, or objections within 60 or 90 days.  At that point, the manufacturer would have 45 or 60 days to submit a response, along with any objections to FDA’s position.  Finally, within another 30 days, FDA would contact the manufacturer to provide details about any remaining disputes and potential methods for resolving them.  FDA also could request or negotiate a voluntary user fee so it has the resources necessary to perform timely review of manufacturer submissions.

B. Clear and Consistent Marketing Compliance Guidance

In addition, FDA should establish rules setting forth the form and manner in which drug and medical device marketers may engage in non-promotional “scientific exchange” about off-label use.  For instance, FDA may require certain standard disclaimers and disclosures to be included in off-label marketing materials, including whether: (1) the company has sought and been denied approval for the particular use; (2) whether the company has performed studies concerning the subject use in accordance with FDA’s guidelines for adequate and well-controlled studies; and (3) other drugs or devices approved for the particular use that already are commercially available.  Restrictions on the manner in which speech is presented, as opposed to content-based restrictions, would face lower scrutiny under the First Amendment.[47]

C. Refocusing Enforcement Priorities

Given its scarce enforcement resources, FDA should shift its off-label enforcement priorities away from truthful statements concerning off-label use to those that are factually false, inaccurate, unsupported, or unsupportable.  In Caronia and its progeny, judges have emphasized the principle that “off-label promotion that is false or misleading is not entitled to First Amendment protection.”[48]  With (1) more robust regulations and/or agency guidance to enable drug and device makers to differentiate between permissible communications and those at risk of enforcement action, and (2) a communications review mechanism at FDA (mandatory or optional), FDA will be able to focus on dangerous off-label communications, i.e., verifiably false and/or unsubstantiated statements, without inhibiting the flow of potentially life-saving medical information.  In addition to refocusing enforcement efforts, FDA and DOJ must improve coordination to ensure indictments are sought only (or primarily) where the Government can marshal proof of scienter.

D. Developing Expedited Pathways for Communicating Scientific, non-Promotional Information

 “[T]he FDA has stated . . . its goal in pursuing misbranding charges against manufacturers based on the off-label promotion of drugs is to encourage use of FDA’s drug review and approval process,” claiming that “[s]uch prosecutions . . . deter manufacturers from evading the FDA’s review process for additional uses of approved drugs.”[49]  The bright-line prohibition on off-label promotion is “not intended to restrict the full exchange of scientific information.”[50]  Because FDA drug and medical device review is complex, costly, and slow, FDA should develop an intermediate tier of expedited review for off-label use(s) of approved products, validated by independent, high-quality, post-market research and evidence outside of FDA’s extant approval process.  Such a system would recognize the value of other types of studies accepted in the scientific community, such as observational studies,[51] which may support the safety and efficacy of treatment for an unapproved indication.  It also would facilitate meaningful scientific exchange and, in turn, more informed, individualized care.  The end result would be FDA-approved materials for dissemination about an unapproved use, one which could be considered a “pending unapproved use” to reflect the limited FDA review already conducted.  FDA could provide companies with a higher number of promotional and/or marketing material submissions for such intermediate uses or “fast track” their review.

IV. CONCLUSION

Based on the proliferation of pharmacological, biotechnological, and other health care data and information, information concerning unapproved new uses of drugs and medical devices can provide an invaluable tool for health care providers to deliver individualized, effective care to patients.  “Off-label drug use may be particularly beneficial to the 20 million Americans with ‘orphan diseases’ who often rely on off-label drug uses for treatment.”[52]  The information’s value, of course, depends on its accuracy and reliability.  FDA will continue to play an integral role in safeguarding public health by ensuring post-market communications do not misrepresent the benefits or risks of a particular treatment.  FDA, to its credit, has invited industry stakeholders and the public at large to weigh in on the process of overhauling off-label communications regulations.

FDA currently is soliciting public input on its policies for regulating off-label communications.  On August 31, 2016, FDA announced it is holding a two-day public hearing on November 9 and 10 as part of a comprehensive review of FDA regulations and policies governing communications about unapproved uses of approved/cleared medical products.[53]  More specifically, FDA is “seeking feedback from a broad group of stakeholders, including, but not limited to, health care professionals and professional societies, patients and their caregivers, patient advocates, representatives from regulated industry, health care organizations, payors and insurers, academic institutions, public interest groups, and the general public” regarding, among other things, (1) “how increased communications from firms about unapproved uses could impact the public health, and on whether the impact would differ across different categories of medical products”; (2) “the extent to which additional communications from firms about unapproved uses can provide access to information that is relevant, scientifically sound, responsibly presented, and provides as full an understanding as possible about the limitations of the available evidence”; and (3) “standards that should apply to unapproved use communications to minimize the potential of these communications to be misleading or otherwise cause harm.”[54]  Affected stakeholders should seriously consider submitting their feedback, as “the input from this meeting will inform FDA’s policy development in this area.”[55]