Post Caronia : Is a new paradigm needed for off-label medication usage?

Abstract

In United States v. Caronia (2012), a criminal misbranding, off-label promotion case, the Second Circuit ruled that the Food and Drug Administration’s (FDA) enforcement of pharmaceutical manufacturers violates the First Amendment. Pharmaceutical manufacturers view Caronia as a watershed for the end of deference to FDA’s oversight role as arbiter of off-label medication usage determinations and perhaps, the beginning of the demise of preemption. The central constitutional question is can FDA’s off-label promotion prohibition withstand First Amendment scrutiny of free speech in general and commercial speech in particular? Is a new paradigm required to promulgate a framework of laws and regulations that will minimize healthcare costs and patient injuries while allowing truthful off-label promotion?

Keywords

Off-label Caronia First Amendment Food and Drug Administration pharmaceutical promotion

Introduction

Off-label use encompasses unapproved indications, dosages, delivery systems, administration routes, patient populations (e.g. pediatric, geriatric, pregnant), or use inconsistent with the labeling. While estimates vary, for certain diseases states, e.g. cancer, the prevalence of off-label use is about 60%. Table 1 provides examples of widely accepted off-label uses which may represent the “standard of care.” Medicare, Medicaid, and private insurance often reimburse for off-label uses.

Table 1.

Examples of off-label use

Medication	Off-label use
Tricyclic antidepressants	Neuropathic pain
SSRIs	Alcoholism, addictive disorders, OCD, stuttering
Morphine	Pain in pediatric patients
Magnesium sulfate	Premature labor
Gabapentin	Migraines
Risperidone	Eating disorders
Propranolol	Infantile hemangiomas
Olanzapine	Nausea and vomiting
Coenzyme Q	Metabolic acidosis
Azathioprine	Atopic dermatitis, psoriasis
Trazodone	Insomnia
Phenytoin	Gastrointestinal fistulae

FDA’s authority flows from the misbranding provisions of the Food, Drug & Cosmetic Act (FDCA),¹ and specifically, Kefauver Harris Amendment provisions of safety and efficacy.² FDA has argued that off-label promotion of drugs is evidence of manufacturer intent to sell misbranded medications. That is, introduction of a medication into interstate commerce without adequate directions for use for all intended uses constitutes misbranding. The agency’s policy prohibits pharmaceutical manufacturers from promoting off-label uses either directly, through labels and package inserts, or indirectly through advertising and promotional activities. FDA’s authority has never extended to prescribers who remain free to both prescribe and promote approved medications for off-label uses. In fact, anyone except for pharmaceutical manufacturers can discuss off-label uses.

The federal government has been extremely successful in claiming FDCA violations and the Obama Administration has been particularly aggressive in prosecuting off-label promotion. The Department of Justice (DOJ) has repeatedly used the FDCA to pursue civil and criminal charges. Additionally, government cases increasingly rely on the False Claims Act with its treble damages provision.³ Off-label promotion is the most commonly asserted Medicaid fraud allegation in federal enforcement actions.⁴ Table 2 lists some settlements with pharmaceutical manufacturers amounting to billions of dollars.^5–7 Throughout the government contended that its authority over manufacturer off-label speech presented no First Amendment issue.

Table 2.

Federal Government success in claiming FDCA violations. Select recent off-label promotion cases

Pharmaceutical manufacturer	Cost
GlaxoSmithKline	US$3 billion, NPA, CIA
Pfizer	US$2.3 billion
Eli Lilly	US$1.4 billion
Abbott	US$1.6 billion
Forest	US$313 million, NPA
Merck & Co., Inc.	US$950 million, NPA
Elan Corporation	US$203 million, NPA

NPA: non-prosecution agreement; CIA: corporate integrity agreement.

However, the government has been extremely unsuccessful in actually deterring off-label use and pharmaceutical manufacturer promotion has been effective in expanding off-label use. Additionally, FDA does not seem to be working in tandem with other agencies giving complete prescribing discretion for off-label use while CMS limits Medicare reimbursement for same. Thus, despite increasing application of federal criminal law to regulate pharmaceutical promotion, a trend toward increased prescription of medications for off-label use exists.

Overview of off-label usage

Off-label use is commonplace and can be evidence-based and life-saving but abuses exist; it can be dangerous (e.g. fen-phen) and costly. For example, recently a manufacturer re-analyzed study results, withheld safety findings and continued to aggressively market the medication.⁸ Although manufacturers are not permitted to share promotional informational about off-label use, FDA does require them to inform prescribers about safety issues related to same.

The rules of the game for off-label promotion are found in the PhRMA Code on Interactions with Healthcare Professionals, Accreditation Council for Continuing Medical Education Standards, HHS OIG Compliance Program for Pharmaceutical Manufacturers,⁹ FDA’s Good Reprint Practices Guidance for Industry,¹⁰ FDA’s Guidance for Industry-Supported Scientific and Educational Activities,¹¹ and FDA’s Responding to Unsolicited Requests for Off-Label Information About Prescription Drug and Medical Devices Guidance for Industry.¹² The patchwork of regulations and guidance’s in and of itself would seem to run afoul of Due Process requirements of the Fifth Amendment. While there are at least four safe harbors: scientific exchange, responses to unsolicited requests, dissemination of reprints, and financial support for continuing medical education, the rules for off-label promotion have inched closer to confounding the First Amendment.

Basic tension with the First Amendment

The premise of the First Amendment is as follows: “Congress shall make no law … . abridging the freedom of speech.” The First Amendment does not permit restriction of communication based on content but may restrict context. Before the mid-1970s, First Amendment protection did not extend to commercial speech such as advertising. However, since Central Hudson Gas & Electric Co. v. Public Service Commission, which struck down a state law that prohibited advertisement by a public utility, this is no longer the case.¹³ Modern law to assess government regulation of commercial speech is crystallized in Central Hudson where the court set out a four prong test: the speech must concern lawful activity and not be misleading; the government interest in restricting the speech must be substantial, the restriction must directly advance the government interests asserted and not be more extensive than is necessary to serve that interest. Once the speech passes the first hurdle, not promoting sale of an unlawful product or be false or misleading (e.g. presenting drug superiority without head-to-head clinical trials or characterizing case reports or poorly designed studies as definitive evidence supporting an off-label use),¹⁴ then it must satisfy the remaining three prongs to be constitutional. Under Central Hudson, the burden shifts to the government to show its regulation is narrowly tailored to advance a substantial interest. That is, the party seeking to uphold the restriction carries the burden of justifying it. This intermediate scrutiny test has been used to overturn FDA’s efforts to restrict pharmaceutical advertising.

Central Hudson’s third prong has been particularly troublesome for FDA as it hollows the government’s argument that in some cases public health danger could be avoided by the provision of more information rather than less. It would be unethical for patients to be deprived of valuable medications because their prescribers were unaware of their existence.¹ Moreover, allowing non-FDA-approved medications (i.e. grandfather and/or DESI) while banning off-label promotion flies in the face of the “substantial interest” of protecting public safety.¹

Where the government is concerned about public safety, it is free under the Commerce Clause¹⁵ and the Necessary and Proper Clause¹⁶ to prohibit the actual activity itself, not merely the speech advocating the activity. Once the activity is illegal, the government is free to prohibit speech advocating that illegal activity. The government, in turn, has argued that off-label promotion is non-expressive conduct, making the First Amendment inapplicable. Even if the First Amendment applies, the government has a substantial interest in both preventing unsafe or unsupported use and inducing manufacturers to seek FDA approval for off-label uses.¹

Central Hudson’s fourth prong, however, has been FDA’s greatest challenge in defending the over inclusiveness and chilling effect of its off-label restrictions on some on-label speech. While the fourth prong does not require the least restrictive method to satisfy the government’s substantial interest, the existence of alternative non-speech means violates this prong. Impinging upon protected speech that fails to result in the harm sought to be prevented (off-label speech for beneficial or standard of care, albeit not FDA-approved uses) violates that aspect of the fourth prong.¹ In Thompson v. Western States Medical Center, the Supreme Court in applying Hudson struck down a restriction on pharmacist advertising of compounded medications.¹⁷ The court found the restriction unnecessarily broad and noted a number of alternatives to prevent the advertising from undermining the FDA approval process.

In the 1990s, pharmaceutical companies attempted to circumvent the prohibition on off-label use by distributing scientific literature and funding continuing medical education. FDA responded via issuance of several guidance documents. What followed in 1996 was a challenge to FDA’s jurisdictional authority when the Washington Legal Foundation (WLF) brought a First Amendment action.¹⁸ WLF won at trial but on appeal FDA asserted its guidance’s were not mandatory. The D.C. Circuit found no constitutional controversy between the parties, and held the matter was not ripe for determination. The following year, the FDA Modernization Act (FDAMA) formalized the supplemental NDA process and permitted distribution of certain published articles with disclaimers they were not FDA-approved. However, WLF brought a subsequent case, and the court enjoined the FDAMA provision relating to reprint dissemination.¹⁹ Following this case FDA unleashed a torrent of off-label investigations and actions against the pharmaceutical industry involving numerous settlements and billions in criminal and civil penalties.

Over the past fifteen years beginning with 44 Liquormart v. Rhode Island and in a number of cases since, an even more protective version of the Central Hudson test has emerged.²⁰ Under Sorrell v. IMS Health, Inc, the precursor to Caronia, data mining, the purchasing of prescription information and selling it to pharmaceutical companies, is protected by the First Amendment.¹⁶ The Vermont Prescription Confidentiality Law of 2007 prohibiting same was invalidated. Under Sorrell, strict scrutiny applies, i.e. a restriction on commercial speech that is content-based (off-label uses) and speaker-based (pharmaceutical manufacturers) is presumptively invalid.²¹ Sorrell stands for the proposition that where a law is viewpoint discriminatory (i.e. burdens particular content-marketing and particular speakers-drug manufacturers) it will be subject to strict scrutiny, regardless of whether it affects commercial speech, or not. The Sorrell ruling prompted additional legal challenges.

Many cases have evoked Central Hudson to contest FDA’s restrictions on off-label promotion claiming the agency is stifling commercial speech.²² Allergan filed one of the earlier First Amendment cases (2009) alleging that by requiring manufacturers of Botox® to warn users about the risk of serious side-effects, the FDA was restricting the company’s First Amendment rights to speak freely and truthfully with prescribers.²³ In its complaint, Allergan sought to overturn all FDA rules restricting off-label promotion and argued the speech restriction was more extensive than necessary: (1) with negative public health ramifications by preventing information dissemination, (2) included “factual” information widely implemented by prescribers, contained in peer-reviewed articles, approved by other similar regulatory bodies, and translated into payer decisions, and (3) the communications were to be communicated in responsible professional forums.^5,24 Allergan dropped its claim before the court reached the First Amendment issue when the case was settled.

In U.S. v. Caputo, several corporate officers were accused and convicted of promoting off-label uses.²⁵ They argued FDA’s off-label speech restrictions violated their First Amendment rights. Here, the court applied Central Hudson and not finding less restrictive alternatives, concluded the regulations were not more restrictive than necessary, and thus, constitutional.

The Caronia case

A recent Second Circuit case, U.S. v. Caronia has now found FDA’s enforcement regime to be in violation of the First Amendment.²⁶ The facts surrounding the case follow: In 2005, the government undertook criminal prosecution of Alfred Caronia for illegal promotion of Xyrem® (sodium oxybate), a central nervous system depressant for insomnia in pediatric patients and other off-label uses. In a DOJ sting operation Caronia met with a physician who was a government informant and discussed off-label uses which were caught on audiotape. The statements of Mr. Caronia were not untruthful or misleading. In fact, the uses had been studied in clinical trials but were not FDA approved. The government argued the promotional activities violated the FDCA misbranding provisions.²⁷ The government further contended that the First Amendment was a non-issue because Caronia’s speech was not the basis of its prosecution but merely provided an “evidentiary role” of “intended use.” The manufacturer pleaded guilty but Caronia did not. The Federal District Court in New York found against Caronia, holding that the marketing constraint was necessary to prevent circumvention of the FDA’s new drug requirements.²⁸ The District Court rejected First Amendment challenges based on overbreath and ambiguity. Caronia was convicted of conspiracy to introduce a misbranded drug into interstate commerce, sentenced to 1 year probation, 100 hours community service and fined US$25. He appealed on the basis that FDA’s speech restriction violates the First Amendment. Both WLF and the Medical Information Working Group filed amicus briefs, the former advocating manufacturers should be able to provide information about off-label use if the information is accompanied by a disclaimer. FDA countered that this would “turn back the regulatory clock more than seventy years…before the FDCA was enacted in 1938, and would radically undermine the incentives for manufacturers to go through the new drug approval process.”²⁹ However, in 1971 FDA made the same disclaimer suggestion when implementing the 1962 Drug Amendments.³⁰

In a landmark decision, the Second Circuit set aside Caronia’s conviction reasoning that it violated his right to freedom of speech, requiring a narrow construction of the relevant statutes and regulations. The government unsuccessfully argued that off-label promotion by Caronia was used only to demonstrate intent, not restrict speech. The majority identified that while the government can use such speech as evidence of intended off-label use, a conviction must rest on more than just speech. The court was persuaded by the argument that FDA’s regulations do not inhibit prescribing, only the free flow of information that would result in a full vetting of uses, limitations and side effects. The court ruled that the FDCA’s misbranding provisions cannot be used to prohibit off-label promotions.

The Caronia majority found that the government restriction was not content- and speaker-neutral inasmuch as speech about FDA-approved medication use was encouraged but not speech about off-label use. Additionally, health professionals are permitted to speak about off-label use but the same speech is prohibited when delivered by pharmaceutical manufacturers. Consequently, citing Sorrell, the court applied the strict scrutiny test to the speech restriction – that is, it must serve a substantial government interest, directly and materially advance that interest, and be no broader than necessary. While the restriction was found to serve government interests of drug safety and public health, the Court found that restricting off-label speech does not directly advance the government’s interest because: (1) off-label use itself is not prohibited, (2) others are allowed to promote off-label use, and (3) it blocks the free flow of information that could actually improve off-label prescribing decisions. Not only did the court find the restriction failed to advance the government’s interest for public safety, it had the opposite effect, “… such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions.”¹⁹ According to the Caronia majority, “the government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug.” The Court also found the restriction overly broad because the government could achieve its goal without inhibiting speech, for example, by educating prescribers and patients, requiring disclaimers, and/or capping the number of off-label prescriptions allowed.³¹ Clearly, regulating speech must be a last – not first – resort.

The dissent in Caronia agreed with the government’s argument that off-label speech, no matter how truthful, could be used to prove off-label intent and declared that the ruling potentially unravels the entire FDA drug approval process. The dissent adhered to the view that extreme deference must be given to FDA. The dissenting opinion provided an example of conduct which is not prohibited but which is unlawful to promote – it is not prohibited to consume arsenic but it is unlawful to advocate its consumption by others, stating “this would not endow Abby and Martha with a First Amendment right to offer arsenic-laced wine to lonely old bachelors with the intent that they drink it.” However, the dissent failed to note the difference in that Abby and Martha wanted to kill people (malum in se), not save lives and Caronia did nothing that offends fundamental social norms. Further, the dissent did not provide examples where the activity was legal for some but not others.

Caronia is the ninth First Amendment case where FDA has been judicially rebuked as violating the free speech provisions of the First Amendment. Two other notable cases are: U.S. v. Harkonen³² and three qui tam cases referred to collectively as U.S. v. Par.³³ In U.S. v Par, Par contended “right to convey truthful information to physicians is protected by the First Amendment” and cited data showing legitimacy of off-label uses, as determined by independent medical personnel. The case involved on-label promotion in an off-label setting: a marketing campaign for Megace® ES (mestrol acetate) for elderly nursing home residents. Par sought to enjoin FDA from prohibiting both truthful and non-misleading off-label speech and on-label speech to physicians who may prescribe for unapproved uses. The Appeal challenged FDA’s authority to censor truthful pharmaceutical company speech.³⁴ Par filed for declaratory relief prohibiting “FDA’s unconstitutional and invalid regulations” from restricting truthful non-misleading speech and stated it was seeking to “elicit tailored and constitutionally permissible regulatory guidance to ensure that physicians may be kept abreast of valuable, off-label information about prescription drugs to aid in their provision of quality and informed patient care.” FDA’s declaration sought to describe its policies and procedures with respect to communication of off-label use information. No information was provided explaining what evidence suffices to render “truthful speech” illegal. The government then sought to strike the FDA’s declaration from the public record because the statement demonstrates the regime for prosecuting off-label use runs afoul of the First Amendment. Par filed a motion seeking to depose FDA on the declaration statement stating it raises more questions than it answers.³⁵ In March 2013, PAR Pharmaceutical Co. Inc. pled guilty for violating the False Claims Act and agreed to pay US$45 million and be subject to a 5-year integrity agreement to resolve its criminal and civil liability. By the settlement terms, PAR withdrew its First Amendment challenge, the government thus avoiding having to litigate the merits of the First Amendment question in another jurisdiction outside the Second Circuit post-Caronia. The government’s interest in avoiding more First Amendment precedent seems acute.

In U.S. v. Harkonen, a former CEO was convicted for allegedly making false statements about Actimmune®, for rare pediatric diseases, in a press release. He expressed his scientific opinion about the development of the drug, but overstated the conclusiveness of clinical trial results, especially since FDA had already reviewed/rejected the data as insufficient for approval of the new indication. Harkonen concerned both speech and conduct (i.e. dissemination of speech). In this case, the speech was closer to commercial speech in that the press release was unquestionably disseminated for commercial benefit. As in Caronia, the statement was not false, a trigger for criminal liability. Harkonen received three years probation, 6 months home detention, community service, and a US$20,000 fine. The government appealed seeking a greater sentence and Harkonen sought to reverse the verdict. An Amicus Brief in support of Harkonen’s appeal by PhRMA asserted affirmance of the decision would threaten core First Amendment principles by establishing that scientific debate over how to interpret data can constitute a crime. The Ninth Circuit reviewed the First Amendment challenges, and found the fraud verdict was supported by the evidence presented. The appeal court did not address the First Amendment or Due Process issues raised and did not grant the government’s request to enhance the sentence stating that the government failed to “articulate a legal theory that made sense”. Some thought the Ninth Circuit in Harkonen would provide the requisite circuit split to allow for Supreme Court review of the First Amendment issues raised in Caronia. However, Harkonen is distinguished from Caronia and Par in that the speech at issue was debatable (evidence to support the information in the press release was based upon interpretation was submitted too late for court consideration). In August 2013, Harkonen filed a petition for writ of certiorari asking the Supreme Court to review his case and in November 2013, the DOJ filed a petition in opposition of same. According to Harkonen, the Ninth Circuit ruling creates a split regarding First Amendment protection in cases involving scientific interpretation. That is, the Second, Sixth, and Eighth Circuits would have overturned his conviction in that debate precludes a fraud conviction. If the Supreme Court declines to rule, the question remains, is debatable speech open to government speech restrictions?

What is the real effect of Caronia?

Caronia may signal the beginning of a new wave of private litigation. The Court noted that where there is a right to speak, corresponding duty follows. Private litigants may replace government prosecution and off-label promotion state tort claims could pose a new threat to pharmaceutical manufacturers.³⁶ As courts continue to question FDA deference, new theories are emerging to permit state laws claims to proceed. For example, a Texas Statute allows the claimants to rebut preemption (i.e. no liability where a product liability claim is based on a failure to warn…if the warnings…were those approved by FDA) where the manufacturer promoted the product for off-label use and the injury was causally related to that use.³⁷

The FDA and DOJ will need to reformulate their approach to prosecuting off-label cases- pursue only cases where they can prove that false or misleading information was conveyed to healthcare professionals. For whistleblower cases, the government is seeking false/misleading evidence that will hold up in court such as affirmative statements about clinical trial results or adverse drug reactions, intentionally misleading ghostwritten articles and sales representative training documents, or examples of clear misbranding.

The decision raises significant concerns about the state and federal government’s ability to impose a variety of regulatory programs targeting specific conduct or a particular industry.^38,39 Since manufacturers will be able to promote their products for truthful off-label uses, Caronia potentially opens the door for increased off-label marketing. The question is what will FDA do in response. FDA decided not to seek a re-hearing before the appeals court and did not request Supreme Court review of the decision. However, the decision only holds for the Second Circuit (i.e. New York, Connecticut, Vermont) and there is no way to know if other circuits will follow the ruling. The Federal government is free to pursue marketing violations in other parts of the country. The decision does not strike down any FDCA provision, nor does it find any conflict between the FDCA’s misbranding provisions and the First Amendment, or call into question the drug approval framework. In fact, even companies in the Second Circuit can still be pursued if any part of the off-label promotion is false or misleading. Free speech does not extend to activities that include false or misleading statements. Moreover, since making truthful off-label statements may not be a safe harbor as indictment often causes stocks to crash and fraud convictions preclude companies from participating in government healthcare programs, industry is currently taking a wait and see approach.

From Caronia the question emerges – will a new paradigm for off-label medication usage be required? FDA critics refer to its off-label regulation and enforcement as a pendulum – sometimes too lax and sometimes too strict, simultaneously over-regulating and under-regulating the practice, reflected in regulatory inconsistency. The Caronia majority called for Congress/FDA to create less speech restrictive means to incentivize companies to conduct research for new indications. However, the situation is complicated. Often, the costly clinical trials reveal that the new indication does not have the necessary efficacy/safety for FDA approval or new safety issues with an already marketed agent are uncovered. Some argue that FDA’s enforcement is only the tip of the iceberg of violative off-label promotion as FDA has limited resources and does not actually get to all promotional materials submitted by manufacturers (FDA tracks the number received but not the number reviewed), FDA attends only a small number of educational programs, and they cannot possibly monitor communications from physician’s offices.⁴⁰ Difficulties in balancing opposing concerns for off-label use are detailed in Table 3 – too much enforcement restricts patient access to best therapeutic treatments; too much flexibility increases the possibility of patient harm and increases healthcare spending.

Table 3.

Balancing public health goals and commercial speech

Too much flexibility	Too little flexibility
FDA approval involves many highly skilled scientist reviewers. Not possible for individual prescribers to conduct the same rigorous review.	The current process whereby federal prosecutors enter into “NPAs” and “CIAs” lacks transparency and judicial oversight.
All the data may not be available for individual prescribers to review. Nor can sales representatives effectively meet this need.	Adverse impact on public health-limiting ability to communicate.
Reduction in manufacturer’s incentives to conduct clinical trials for new indications.	Stifling of manufacturer’s willingness to respond to unsolicited requests for information about off-label uses from health care professionals; places barriers of prescribers and patients to receive relevant treatment information.
Proliferation of poorly documented off-label claims. Studies not meeting current FDA standards for scientific rigor (e.g. flawed study design).	Limited numbers of therapeutic choices for certain patient populations, e.g. pediatric patient; less identification of medications for orphan disease states.
Selection of studies which meet marketing goals while ignoring those that do not.	Shifting of off-label use to investigational use requiring informed consent.
Unraveling of FDA’s process as manufacturers market products for off-label uses.	Diminishing of, or end of, off-label use.
Lack of evidence-based information for payers to make informed reimbursement decisions; lack of insurance coverage for off-label uses.	Increased litigation characterizing off-label use as negligence per se.
Increased pharmaceutical company revenue and reduced costs because of less rigorous FDA review.	Potential valuable treatments tied up in years of red tape or manufacturers might decide that seeking FDA approval is not worth the investment.
Increased use of medications with dangerous side effect profiles or high risk of adverse drug reactions.
Possible distortion of practice away from agents listed in clinical practice guidelines.
Increased healthcare costs as incentives would exist to promote newest most expensive products for off-label uses.

Some have advocated moving away from the concept of off-label to one of “emerging uses” with a warning that the use is not FDA-approved and that safety and efficacy are still emerging.⁴¹ Others advocate the recognition of a continuum of different types of off-label use ranging from totally new indication to related indication to dosage variation. This continuum could be the basis of a scaled oversight or an accelerated approval process rather than the lengthy Supplemental New Drug Application (NDA) process. One suggestion is to have this accelerated review occur when a particular off-label use reaches a certain threshold.³ Possible FDA next moves, some of which were set out in Caronia, are found in Table 4. Mechanisms should be explored to balance medication safety while preventing irrational delay in approving off-label uses which could improve the lives of millions of Americans on a daily basis.

Table 4.

A new paradigm may be needed for off-label use

• Guide the differentiation between misleading and false promotion and truthful or non-misleading information.

• Develop a warning or disclaimer system or develop safety tiers within the off-label market.

• Require manufacturers to list all applicable or intended indications when they first apply for FDA approval.

• Disclaimer.

• Mandate safety and effectiveness data for wide-spread uses (e.g. based on percentage of sales) or those based on questionable evidence (e.g. based on numbers of lawsuits).

• Allow some private organization to enforce off-label uses.

• Expand Third Party Payer role in off-label regulation.

• Better incentives – such as patent extensions or tax credits or rebates on off-label prescribing to fund off-label research efforts.

• Tax manufacturers on off-label use; use funds for FDA’s clinical trial efforts.

• FDA streamline and expedite the Supplemental NDA process.

• FDA develop a fast track approval process for off-label uses.

• FDA work to facilitate communication of the best science available to prescribers (safe harbors) – truthful science-based off-label use.

• To minimize off-label use, FDA could create ceilings or caps on off-label prescriptions.

• Allow supplemental warning that a use is off-label and that safety and efficacy is still emerging.

• Where off-label use is particularly concerning, the government could prohibit it altogether.

• FDA could remind prescribers and manufacturers of legal liability (i.e. medical malpractice and negligence). Alternatively, FDA could regulate such liability.

• Amend the FDCA and its regulations for clarification for prosecutors.

• Better integration of FDA and CMS off-label policies – develop national Medicare coverage standards for off-label use.

• Require healthcare providers to inform patients when they are being prescribed an off-label use.

In the future, as the government seeks to avoid further First Amendment precedent from off-label promotions, cases resembling Harkonen involving false or debatable promotion are more likely to be pursued than those resembling Par or Caronia. While it may be too early to predict if Caronia will cause a sea change in FDA’s off-label policymaking and enforcement efforts, FDA will be unlikely to pursue similar cases until resolution of the legal issues.

Conclusion

Caronia is consistent with the position that there is, in fact, no current, express federal law or regulation that prohibits off-label promotion. At most, there are non-binding FDA Guidance documents. Beyond the 52-page opinion and 30-page dissent, Caronia represents a significant development in the enforcement of pharmaceutical marketing practices. The decision could serve as a strong defense against FDA enforcement actions since it holds off-label speech restrictions up to the heightened scrutiny for which the government bears the burden of proof that any such restriction complies with the First Amendment. Whether the courts apply some form of strict scrutiny, pursuant to Sorrell or intermediate scrutiny, pursuant to Central Hudson, the FDA’s off-label restrictions violate pharmaceutical manufacturer’s First Amendment rights.

The First Amendment issues in Caronia are very significant, making eventual Supreme Court review likely. However, there is no certainty how a Supreme Court torn between extreme deference to legislation on economic and commercial issues and a suspicious attitude toward regulation of commercial speech will rule. Cases such as Caronia, Par and Harkonen should be watched closely as they will begin a course of events that impact how medications are promoted in the United States. Questions remain – should the government ever be able to block the sale of medication not tainted by false or misleading information? Can the government impose a categorical ban on truthful promotion of off-label use without contravening the U.S. Constitution notion of free speech?

Footnotes

Author biography

Martha M Rumore (PharmD, JD) is Assistant Director of Pharmacy, Cohen Children’s Medical Center, New Hyde Park, NY and Professor, Pharmacy & Health Outcomes at Touro College of Pharmacy in New York, NY Her research focuses on Pharmacy and Food, Drug and Cosmetic Law.

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