AARON S. KESSELHEIM AND MICHELLE M. MELLO
IN DECEMBER 2012, a three-judge panel of the U.S. Court of Appeals for the Second Circuit set down a decision that shook the very foundation of how the U.S. Food and Drug Administration (FDA) regulates pharmaceutical marketing and promotion. The case, United States v. Caronia, involved the Department of Justice’s criminal misdemeanor prosecution of a pharmaceutical sales representative named Alfred Caronia who was caught on tape promoting a drug for conditions not approved by FDA (United States v. Caronia 2012). FDA generally prohibits manufacturers and their representatives from engaging in so-called “off-label” promotion, considering intent to sell a product for a non-FDA-approved use to violate the Federal Food, Drug, and Cosmetic Act (FDCA), which requires all prescription drugs sold in the United States to be supported by substantial evidence from adequate and well-controlled investigations (21 USC § 355(d)). At trial, Caronia argued that his First Amendment right to free speech protected him from being prosecuted for his statements. A majority of the Second Circuit panel agreed. Although only formally controlling in the states covered by the Second Circuit, the decision calls into question FDA’s ability to regulate off-label promotional speech going forward.
This chapter first reviews the main principles guiding FDA’s regulation of pharmaceutical promotion. It then discusses the Caronia case and the legal basis for the Second Circuit court’s decision, as well as its public health implications. Finally, the chapter analyzes the range of options available for FDA to maintain oversight of off-label prescription drug promotion if the Caronia reasoning were to become the dominant judicial perspective. We discuss three strategies available to investigators and policy makers interested in preventing unsafe off-label marketing and focus on two that we believe hold the greatest promise for protecting the public health from non-evidence-based promotional speech about health care products: making a stronger case that FDA’s regulations on off-label promotion satisfy the Supreme Court’s interpretation of the First Amendment and modifying FDA regulations concerning off-label promotion to rely on reasonable “safe harbors.”
I. OFF-LABEL USE AND FDA REGULATION OF PHARMACEUTICAL PROMOTION
FDA certifies the efficacy and safety of new drugs before they reach the market by examining the evidence that has been collected by manufacturers, but FDA does not directly regulate the practice of medicine, including how physicians actually prescribe drugs. If “adequate and well-controlled investigations” (21 USC § 355(d)) show that a drug’s benefits outweighs its risks, FDA will approve the drug and authorize a label that describes the clinical trials it reviewed and the indication it has authorized. However, physicians can then prescribe the approved drug for any medical condition or patient group, or at any dose, even outside of the parameters of the label. Many off-label uses have a reasonable biological basis. For example, if a drug was approved to treat colon cancer, there is a strong basis for thinking it might also be successful in treating cancer of the appendix because the appendix is an outgrowth of the colon and made up of similar cells. Off-label uses may also be supported by considerable evidence (Walton et al. 2008). The drug gabapentin (marketed under the trade name Neurontin), for instance, was approved to treat epilepsy, but subsequent studies showed its efficacy in specific types of chronic pain. The drug was widely used for those purposes by the medical community even though the manufacturer had never submitted these studies to the FDA as part of a formal supplemental new drug application (NDA) package.
However, off-label uses may also be dangerous and non-evidence based. One widely cited study of prescribing patterns for 160 commonly used drugs found a 21 percent off-label prescription rate and concluded that 73 percent of such off-label uses lacked evidence (Radley et al. 2006). Antipsychotic drugs are commonly used off label in elderly patients with dementia and affective disorders (Alexander et al. 2010), but such use has been associated with a higher mortality risk (Wang et al. 2005).
Thus, a major concern about off-label drug use is that it may involve considerable risk for patients without proven benefit (Levi et al. 2010). A second concern is that high spending on drugs used for non-evidence-based, off-label purposes strains the budgets of payers like Medicaid, leading them to tighten eligibility requirements or reduce the services they provide (Pear 2011).
Although FDA does not restrict physicians from prescribing drugs off label, it does forbid pharmaceutical manufacturers from promoting the use of drugs for off-label purposes (Kesselheim 2011). This stance is not a capricious attempt to restrict manufacturers from communicating to physicians about their products. Rather, FDA’s approach was a response to major problems caused by the lack of such regulation. Widespread manufacturer promotion of the safety of medical products in the absence of formal regulatory approval of those products led to cases in which patients died after taking products with poisonous constituents (sulfanilamide elixir, 1938), gave birth to babies with devastating congenital anomalies (thalidomide, 1962) (Avorn 2012), or used contraceptive devices that caused bacterial sepsis (Dalkon Shield, 1974) (Wood 2005). Even more common was the promotion of drugs to treat conditions for which they lacked efficacy (Waxman 2003). Thus, consensus grew that it was in the public’s interest for manufacturers to prove that a medication actually worked and was safe for that use before it could be sold and promoted.
Notwithstanding FDA’s prohibition on off-label promotion, it persists. Recent examples of pharmaceutical promotion of non-evidence-based off-label uses leading to widespread patient morbidity and mortality include rofecoxib (Vioxx) (Krumholz et al. 2007), rosiglitazone (Avandia) (Moynihan 2010), paroxetine (Paxil) (Wadman 2004), fenfluramine/phentermine (Fen-Phen) (Kolata 2007), and telithromycin (Ketek) (Ross 2007).
FDA considers off-label promotion to violate the provision of the FDCA that bars pharmaceutical manufacturers from introducing a new drug into interstate commerce unless it and its label have secured FDA approval (21 USC § 355(d)). Manufacturer-distributed materials that explain the uses of the drug are considered part of the labeling even if not packaged with the drug (21 USC § 321(m)). A second provision prohibits manufacturers from introducing into interstate commerce “misbranded” drugs (21 USC § 352). Drugs can be misbranded for false or misleading labeling information or labeling that does not bear “adequate directions for use” (21 USC § 352(f)(1)). The combination of the requirements for approval and the misbranding provision provides two avenues for FDA to argue that it is illegal for a drug’s labeling to discuss uses of the drug that FDA has not validated as being supported by substantial evidence.
Notably, FDA’s prohibition on manufacturers’ ability to discuss off-label uses is not absolute. Companies can respond to unsolicited questions from health care professionals and others about unapproved uses. Companies can also distribute reprints of medical journal articles and support continuing medical education programs in which off-label uses are discussed. These “safe harbors” have been set forth in clear, explicit FDA guidance documents (Food and Drug Administration 2014) and the 1997 FDA Modernization Act (FDAMA).
II. COMMERCIAL SPEECH AND THE COURTS
Drug manufacturers and some affiliated activists have objected to FDA control over the scope of their marketing, arguing that it unfairly limits manufacturers’ ability to disseminate truthful information about their products. They have found legal grounds for their objections in the Supreme Court’s expanding protection of commercial speech or speech that primarily proposes a commercial transaction.
The First Amendment to the U.S. Constitution states that “Congress shall make no law…abridging the freedom of speech.” Although the First Amendment has always been understood to protect speech regarding political or religious views and other forms of social speech, corporate advertising was not initially considered worthy of protection because it was seen as having less benefit for the public and a more distant relationship to the reasons the First Amendment was adopted. However, in a 1976 case, the Supreme Court struck down a law that prevented pharmacies from advertising the prices of prescription drugs, finding value in the free flow of commercial information that can allow consumers to make “intelligent and well informed” decisions (Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, Inc. 1976:765).
The Supreme Court did not grant commercial speech the same level of protection as noncommercial speech. The Court established a framework to evaluate regulation of commercial speech in Central Hudson Gas & Electric Corp. v. Public Service Commission of New York (1980), directing courts to answer four questions. First, is the speech false or misleading, or does it concern unlawful activity? If so, it will receive no protection. Second, is the government’s interest in regulating the speech substantial? Third, does the regulation directly and materially advance the government’s interest? Finally, is the regulation narrowly tailored, meaning no more extensive than necessary to serve that interest?
The Supreme Court most recently applied the Central Hudson framework to drug product promotion in Sorrell v. IMS Health (2011). The underlying dispute in that case concerned a Vermont law that restricted the commercial sale, disclosure, and use of prescribing records revealing prescribers’ identities without prescribers’ consent and prohibited pharmaceutical manufacturers from using that information for marketing or promotion. The law aimed to curtail the practice of pharmaceutical “detailing,” in which pharmaceutical sales representatives used data about each physician’s prescribing practices to tailor their sales messages to each physician. The Supreme Court struck down the law, holding that it was not narrowly tailored to achieving any of the asserted interests. Justice Kennedy, writing for the majority, characterized the law as a speaker- and viewpoint-based restriction because it was limited to pharmaceutical manufacturers and was adopted because of the Vermont legislature’s disagreement with the message that the sales staff of manufacturers were trying to convey: that the physician should prescribe expensive, branded drugs more often.
In Sorrell, as in previous commercial speech cases, the Court voiced suspicion about speech restrictions that smacked of “paternalism” or a governmental attempt to keep consumers in the dark for what it has determined to be their own good. The Court found such overtures especially objectionable when directed at physicians, “sophisticated and experienced” consumers who are highly capable of critically weighing the information provided by pharmaceutical sales representatives (Sorrell v. IMS Health 2011:2658). As in prior cases, the Court stressed the role of commercial speech rights in supporting manufacturers’ direct contribution to the marketplace of ideas, which leads to optimal economic decision making. Indeed, Kennedy cited the principle that “[t]he commercial marketplace, like other spheres of our social and cultural life, provides a forum where ideas and information flourish….But the general rule is that the speaker and the audience, not the government, assess the value of the information presented.” (Sorrell v. IMS Health 2011:2671–72). The Court did not examine whether the marketplace of ideas actually functions well in the case of prescription drugs, except insofar as it judged that the market’s functioning would be worse in a world where pharmaceutical-related speech was restricted. Embedded within this affection for the marketplace-of-ideas concept is an important presumption: that the information at issue is true and, therefore, useful. However, the Supreme Court in Sorrell and other courts have generally declined to evaluate the quality of the information at issue.
III. THE CARONIA CASE
Alfred Caronia was a sales representative for the brand-name drug company Orphan Medical. In 2005, his job was to promote the drug sodium oxybate (Xyrem) to physicians. Sodium oxybate—also known as gamma hydroxybutyrate, a chemical that when used for recreational purposes has been associated with drug-assisted sexual assault—had been approved by FDA in 2002 for use in the rare clinical condition of narcolepsy with severe cataplexy, a condition marked by sudden onset of lethargy, sleepiness, and full loss of muscle tone. To grow the revenues and position for a lucrative acquisition, Orphan Medical encouraged sales representatives to suggest non-FDA-approved uses for the product (United States ex rel. Lauterbach v. Orphan Medical 2006).
In one physician’s office, Caronia suggested that sodium oxybate was effective for conditions including insomnia, fibromyalgia, restless leg syndrome, chronic pain, Parkinson’s disease, and multiple sclerosis. He also claimed that the drug could safely be used in elderly and pediatric patients despite clear statements on FDA-approved labeling that the drug had not been tested in those populations. Caronia’s statements came to light because the physician to whom he was speaking was wearing a wire—he had earlier been recruited by the Department of Justice, which was investigating Orphan Medical for improper promotion of its drugs.
Based on this evidence, Caronia was prosecuted and convicted by a jury for conspiracy to introduce a misbranded drug into interstate commerce. Caronia sought to overturn his conviction in an appeal led by the Washington Legal Foundation (WLF), a libertarian advocacy group.
Caronia’s case proved to be an excellent opportunity for the WLF to test the constitutionality of FDA’s restrictions on off-label marketing. Most previous prosecutions of alleged off-label marketing had targeted drug companies and led to settlements rather than courtroom adjudication, because the companies could not take the business risk of losing a case and facing treble damages or the “corporate death sentence” penalty of exclusion from participation in federal health care programs such as Medicare and Medicaid (Schiff 1995). Caronia may have been more comfortable pursuing the appeal because his original conviction carried the modest penalty of probation, community service, and a $25 fine.
The Second Circuit overturned Caronia’s conviction. Applying the Central Hudson test, Judge Denny Chin—writing for himself and Judge Reena Raggi—averred that the speech at issue was not false or misleading because the government, in presenting its case, had not tried to paint Caronia’s statements as such. He also agreed that the government had substantial interests at stake, which he identified as “preserving the efficacy and integrity of the FDA’s drug approval process and reducing patient exposure to unsafe and ineffective drugs” (United States v. Caronia 2012:166).
However, Judge Chin ruled that restriction on off-label promotion did not directly advance the government’s interest in reducing unsafe drug use because it prohibited the “free flow of information” that would inform the legal practice of off-label use (United States v. Caronia 2012:167). Rather than advancing patient safety, “paternalistically” interfering with information dissemination about legal uses of a drug inhibited “informed and intelligent treatment decisions” (United States v. Caronia 2012:166). Judge Chin emphasized that physicians were a skilled and sophisticated audience, and it was their—not the government’s—role to determine which information was useful.
Finally, the court held that restricting manufacturers’ off-label promotion was not a narrowly tailored intervention because other options could achieve the same goal without inhibiting speech. The court proposed that the government could educate physicians and patients about how to distinguish between “misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information”; require disclaimers for off-label uses; limit the number of off-label prescriptions a physician may write; or warn physicians and manufacturers about their potential exposure to malpractice claims if adverse outcomes resulted from off-label treatment decisions (United States v. Caronia 2012:167–68).
IV. THE FUTURE OF REGULATIONS RESTRICTING OFF-LABEL PROMOTION
The Caronia decision has been hailed by advocates of expanded commercial speech rights for the pharmaceutical and medical device industries (Hall 2013). These commentators have argued that FDA’s restrictions on off-label promotion are too broad because they cover potentially truthful speech about off-label uses and because those off-label uses are lawful and can be clinically indicated. They claim the combination of these factors “prevents promotion of valuable off-label uses of which doctors otherwise may well be unaware” (Klasmeier and Redish 2011).
However, the Caronia decision is also a setback in the government’s effort to avoid the dangerous public health outcomes that may arise from non-evidence-based industry marketing. FDA insisted that Caronia would not “significantly affect the agency’s enforcement of the drug-misbranding provisions of the Food, Drug and Cosmetic Act,” as it “does not strike down any provision of the…act or its implementing regulations, nor does it find a conflict between the act’s misbranding provisions and the First Amendment or call into question the validity of the act’s drug approval framework” (Sell 2013). FDA’s characterization of the scope of the opinion is correct: the Caronia court barred a particular avenue of criminal prosecution rather than striking down any statutory or regulatory provision per se. Notably, in the first year after the Caronia decision, pharmaceutical manufacturers Amgen and Ista settled prosecutions in the Second Circuit alleging improper off-label marketing for civil and criminal fines of $762 million and $33.5 million, respectively.
Despite those enforcement victories, it is hard to imagine the Caronia case not hampering the government’s ongoing enforcement efforts. If the government seeks to prosecute other individuals like Caronia in the future in other jurisdictions, the effort will inspire similar appeals, and the prospect of other courts following the Second Circuit’s lead will cast a shadow over future settlement negotiations with manufacturers, potentially reducing the government’s ability to seek punitive fines or changes in corporate behavior. The Second Circuit court’s prohibition on prosecuting manufacturer representatives for making off-label promotional statements therefore muddies the waters in terms of regulatory possibilities going forward.
At least three potential pathways remain, however. First, FDA could focus on the false or misleading nature of promotional materials or statements. Second, in defending its policies against future claims of commercial speech infringement, FDA could make a stronger case that its regulations meet the criteria of the Central Hudson test. Finally, FDA could reconfigure its regulatory regime to adapt its restrictions on commercial speech in ways that still permit oversight of public safety.
A. Off-Label Promotion as False or Misleading Speech
For many statements that sales representatives make to promote off-label uses, the government could make a reasonable argument that the speech qualifies as misleading and therefore lies outside the ambit of First Amendment protection. In previous Supreme Court cases, commercial speech has been found to be misleading if it omits essential information that can lead to “deception” of consumers (Zauderer v. Office of Disciplinary Counsel of Supreme Court of Ohio 1985:650) or where “most commercial uses” of a statement “are likely to be confusing” (San Francisco Arts & Athletics Inc. v. United States Olympic Committee 1987:539).
Among well-trained sales representatives, the tactic of communicating “non-demonstrably false information” (United States v. Caronia 2012:181) is common. Most off-label uses of drugs have little or no scientific support (Radley et al. 2006), but sales representatives may omit that material fact or misrepresent the strength of evidence. For example, a psychiatrist, Daniel Carlat, acting as a representative on behalf of a Wyeth antidepressant, addressed a physician’s concern about a dangerous side effect of the drug by downplaying its significance. He later reflected, “I knew I had not lied—I had reported the data exactly as they were reported in the paper. But still, I had spun the results of the study in the most positive way possible, and I had not talked about the limitations of the data” (Carlat 2007). Such presentations may not be false, but they are misleading.
This approach has clear disadvantages. First, not all off-label promotion cases involve the pristine evidence available to the government in the Caronia case because of the willingness of a cooperating physician to record conversations. Second, even if the nature of the promotional statements can be clearly established, the government must prove that the statements are false or misleading, which requires a case-by-case evaluation. The boundary line between protected speech and false or misleading speech in the area of off-label promotion is unclear and likely to be heavily contested if the government pursues this strategy. Establishing that promotional speech is false or misleading will require assessing the strength, validity, and appropriateness of evidence for each claim. Consequently, it will also require a considerable amount of complex expert testimony and pose heavy cognitive demands on lay jurors (Silverman 2013). The misleading-speech strategy for prosecuting off-label promotion will be useful only in a narrow range of cases.
B. Readdressing the Remaining Requirements of Central Hudson
A second potential strategy for the FDA is simply to continue to prosecute off-label promotion on the theory that—debates over the nature of the speech as true, false, or misleading aside—its regulatory approach satisfies the Central Hudson test. This strategy relies on a belief that the Second Circuit’s reasoning in Caronia is unsound and may not be followed by other courts, particularly if the government strengthened its argument concerning each of the three main prongs of the test: (1) substantiality of the government interest; (2) direct advancement; and (3) narrow tailoring.
1. Substantial Government Interest
The broader the interests that courts accept as legitimate justifications for restricting commercial speech, the broader the government’s latitude will be in designing the regulatory scheme. Thus, it is worth honing the argument that the government has an important interest in ensuring that physicians receive accurate, unbiased information to support informed treatment choices. Even when off-label communications do not rise to the level that courts would define as false or misleading, they may fall well short of accurate, unbiased information. In particular, oral conversations in the confines of physician offices involve few mechanisms to ensure accountability for the accuracy of the information. The government has a substantial interest in preventing the communication of unsubstantiated information in such settings and should seek to disrupt courts’ apparent assumption that off-label communications are truthful.
In making such an argument, the government could also emphasize that courts have had greater confidence than is warranted in physicians’ ability to evaluate claims about off-label uses. Some promotional claims may be inherently impossible for physicians to verify, such as a claim that other physicians are already widely prescribing the drug for an off-label use and have encountered no serious safety problems. Even when documents supporting claims about the safety or effectiveness of off-label uses are offered, they may convey only a slice of the full empirical picture. There may be countervailing study findings or important study limitations that were omitted. The FDA approval process serves as a bulwark against such problems by deploying highly skilled scientists to analyze all of the available information about a drug’s use, verify analyses conducted by the drug’s sponsor independently, and scrutinize the design of the studies offered to support the new use. Individual physicians cannot approach this level of evaluation—even if they have the time and inclination to explore the veracity of claims made in off-label promotional communications, they lack access to the information necessary to do so thoroughly.
For these reasons, it is worthwhile for the government to continue to assert an interest in imposing reasonable restrictions on off-label communications for the purpose of ensuring that the information communicated to physicians is accurate and unbiased. It should also, of course, assert the other interests that courts have had less difficulty accepting as substantial, such as protecting the integrity of the drug approval process and protecting the public from unsafe prescribing (Spurling et al. 2010).
2. Direct Advancement
The next component of a reinvigorated defense of restrictions on off-label promotion under Central Hudson is establishing that the regulation directly advances the asserted government interests. First, the government should make clear that if off-label prescribing is to be allowed, it should be as informed as possible. The Caronia court assumed that obstructing the free flow of information about off-label uses works against this goal. But that conclusion is premised on the unchallenged assumption that off-label promotional communications are sufficiently accurate and unbiased to support informed decision making. Because there is reason to doubt this assumption, regulating off-label promotional communications is by no means incompatible with the decision to permit off-label prescribing.
In the context of this argument, it is worth recalling that FDA’s current regulatory approach does not impose a blanket prohibition on off-label promotion but instead focuses on forms of communication most amenable to corruption. Unprompted oral communications from sales representatives in the personal confines of a physician’s office are not permitted. By contrast, peer-reviewed journal articles and independent continuing medical education programs may discuss off-label uses, and manufacturers can respond to physician-initiated questions about off-label uses. These safe harbors bolster the case that FDA’s regulation of off-label promotion is not a paternalistic attempt to keep physicians in the dark about off-label uses. Rather, FDA’s intent is to permit the flow of truthful information while preventing companies from disseminating unsubstantiated claims through nontransparent mechanisms. The risk against which FDA is trying to guard is not that consumers will respond irrationally to the truth but that they will not be told the whole truth.
In arguing the direct-advancement prong, the government should also underscore the ways in which unfettered off-label promotion destabilizes its long-accepted drug-approval system. If companies are free to promote their products for any use or any population, once the product has been approved for one use or population, the incentive to invest in clinical studies to secure approval for new uses is dramatically undercut. A world in which off-label promotion is unregulated is likely to be one in which poorly substantiated marketing claims about unapproved uses proliferate, with attendant effects on prescribing decisions and patients’ health and safety. The literature is clear that there is a strong, consistent, specific, and independent association between physician prescribing and exposure to pharmaceutical marketing messages (Manchanda and Honka 2005).
3. Narrow Tailoring
Two lines of argument could help establish that FDA’s regulatory scheme for off-label promotion is narrowly tailored. First, the creation of several safe harbors represents thoughtful, adequate tailoring. Second, the policy approaches proposed by the Caronia majority as alternatives to speech restrictions fall well short of the mark.
On the latter point, the suggestions offered by the Caronia majority run the gamut from the merely ineffectual to the baldly ridiculous. For example, the Caronia majority proposed to train physicians and patients in differentiating misleading from truthful promotional statements. Even if didactic strategies for distinguishing among the types of claims made in off-label promotion and understanding the evidence base underlying them could be identified, along with strategies for effectively reaching every physician with this information, it is inconceivable that the government would appropriate funding at a level sufficient to create an effective counterweight to the $50 billion that pharmaceutical companies spend each year on promotion to physicians (Kesselheim et al. 2013).
Alternatively, the Caronia majority proposed to let FDA “develop its warning or disclaimer systems or develop safety tiers within the off-label market” (United States v. Caronia 2012:168). But drug risk communications emerging from FDA have been shown to have little impact on U.S. health care utilization or health behaviors (Dusetzina et al. 2013), and FDA does not commonly engage in de novo review of the evidence supporting off-label uses of drugs unless a manufacturer formally files a supplemental application requesting such a review. FDA thus would not be able to assign “safety tiers” to off-label uses of all prescription drugs without congressional action specifically authorizing it to do so and providing sufficient resources to support the effort. Legislators have been loath to expand FDA’s regulatory authority in recent years even in the face of major public health crises (Outterson 2013). Even if FDA’s ability to issue disclaimers were not at issue, the utility of such a strategy is doubtful. Consumers spend billions of dollars on vitamins and minerals that have no proof of efficacy, even in the presence of warning labels that alert consumers that FDA has not validated the health claims made about the products (Guallar et al. 2013).
The court also suggested that FDA impose “ceilings or caps on off-label prescriptions” or other mechanisms to restrict the amount of off-label prescribing directly—or prohibit off-label prescribing entirely (United States v. Caronia 2012:168). As previously stated, direct regulation of the practice of medicine is outside FDA’s jurisdiction. FDA also recognizes that off-label prescribing can be helpful and, indeed, lifesaving in some clinical situations and has no apparent wish to deprive the public of those benefits (Schultz 1996).
Because no non–speech-restricting alternative policy could achieve the government’s interest even marginally and because FDA has taken reasonable steps to allow companies to communicate truthful information about off-label uses in a responsible way, FDA’s regulatory scheme for off-label promotion should be considered narrowly tailored.
C. Expanded Use of “Safe Harbors” for Off-Label Promotion
A third strategy that FDA could pursue to preserve its ability to regulate off-label promotion is to provide expanded pathways for such promotion while providing mechanisms to help ensure the reliability of the communications. This might bolster the argument that the regulatory scheme is narrowly tailored to advancing the goal of protecting the public from unsafe prescribing.
One mechanism would be to permit off-label communications in circumstances in which the manufacturer can document that the statements reflect substantial clinical experience. FDA rules stipulate that advertisements about a drug’s efficacy for uses described in the labeling may rest on documentation of “substantial clinical experience” as an alternative to “substantial evidence” (evidence from “well-controlled investigations”) (21 CFR § 202.1(e)(4)(ii)). For instance, a 2011 guidance document permitted manufacturers to promote antihypertensive drugs as efficacious in preventing deaths from cardiovascular events based on a “substantial clinical experience” rationale (Food and Drug Administration 2011). The endpoints in the clinical trials testing the drugs had only included intermediate outcomes such as blood pressure control, not cardiovascular deaths, but FDA explained that “blood pressure control is well established as beneficial in preventing serious cardiovascular events.”
FDA’s 2011 decision was based on decades of clinical experience with hypertension, antihypertensive drugs, and patient outcomes. The announcement also came in an official, prospective FDA guidance document, which involves months of internal deliberation and may involve input from outside experts (Colman 2012). These two features increase the likelihood that information disseminated about off-label uses based on “substantial clinical experience” will be evidence based and reliable. FDA could modify its regulation to apply the same standard to promotion of off-label uses and take steps to publicize the availability of this avenue of off-label promotion. The main advantage of the process is that it would be less rigid—and less expensive—than a formal supplemental NDA.
Second, FDA could permit more evidence-based off-label marketing by expanding its view of what constitutes “substantial evidence.” Specifically, it could allow manufacturers to receive prospective approval for off-label promotion if the manufacturer submitted well-controlled observational research (in lieu of clinical trials) establishing the safety of the use (Silverman 2009). Indeed, large-scale observational studies are particularly well suited for detecting and quantifying drug safety problems, when they are conducted properly (Avorn 2007).
There is already flexibility within the FDCA to permit FDA to consider observational studies or other evidence short of prospective, randomized trials as offering “substantial evidence” for a given finding because the FDCA does not specify that substantial evidence needs to be supported by randomized controlled trials but only “adequate and well-controlled investigations.” However, because of the risk that such studies can yield unreliable results if not carefully designed and conducted, FDA’s current wariness about authorizing off-label marketing based on them is understandable. To clarify its expectations, FDA could issue a formal guidance document describing the features of high-quality observational research and the circumstances under which such research might be sufficient to support off-label marketing claims. For example, use of high-quality observational research could be initially limited to support claims about the safety of off-label uses and not be allowed to support claims about effectiveness. This approach would permit manufacturers to engage in truthful, evidence-based communications about certain types of off-label uses that observational research could validly support, while helping to assure that unsubstantiated marketing claims do not provoke inappropriate, unsafe prescribing.
V. CONCLUSION
The Second Circuit’s decision in Caronia evinces judicial distaste for attempts to regulate pharmaceutical promotion, based in part on the claimed public health importance of the free flow of truthful information about medical products and in part on the role that physicians, as sophisticated intermediaries, play as receptors of pharmaceutical promotional communications. In the case of off-label promotion, neither of these assumptions withstands scrutiny. Years of experience with industry marketing practices leading to dangerous, non-evidence-based, off-label uses of medical products establishes the need for regulation in this arena.
Unfortunately, FDA did not pursue an appeal in Caronia. Its decision may reflect FDA’s curious conclusion that Caronia will not significantly affect its enforcement activities, but the decision may have also been a strategic calculation. With the Supreme Court and Courts of Appeals showing ever stronger support for commercial speech rights, it is a treacherous time to pursue such an appeal.
As it stands, the Caronia decision would appear to preclude some of FDA’s traditional enforcement practices, at least in the Second Circuit states. Significant retrenchment in the agency’s enforcement activity would likely lead to adverse health consequences for patients. Companies would likely feel emboldened to engage in more promotional communications with fewer incentives to ensure that promotional statements have an evidentiary basis, and they would find less reason to seek FDA approval for new uses of their products. Such moves would heighten the prevalence of prescribing decisions that put patients at undue risk without clear benefits.
To help avoid such consequences, we have suggested several avenues along which FDA might continue to prosecute off-label promotion and defend its regulatory framework against future challenges. Fighting to ensure that a regulatory regime is in place to promote accurate and unbiased promotional communications is a public health imperative.
NOTE
This work is derived from an article previously published in the North Carolina Law Review: Kesselheim, Aaron S. and Michelle M. Mello. 2014. “Prospects for Regulation of Off-Label Drug Promotion in an Era of Expanding Commercial Speech Protection,” North Carolina Law Review 92: 101–62.
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