American Journal of Law & Medicine

Commercial speech and off-label drug uses: what role for wide acceptance, general recognition and research incentives?

This article provides an overview of how the constitutional protections for commercial speech affect the Food and Drug Administration's (FDA) regulation of drugs, and the emerging issues about the scope of these protections. A federal district court has already found that commercial speech allows manufacturers to distribute reprints of medical articles about a new off-label use of a drug as long as it contains disclosures to prevent deception and to inform readers about the lack of FDA review. This paper summarizes the current agency guidance that accepts the manufacturer's distribution of reprints with disclosures. Allergan, the maker of Botox, recently maintained in a lawsuit that the First Amendment permits drug companies to provide "truthful information" to doctors about "widely accepted" off-label uses of a drug. While the case was settled as part of a fraud and abuse case on other grounds, extending constitutional protections generally to "widely accepted" uses is not warranted, especially if it covers the use of a drug for a new purpose that needs more proof of efficacy, and that can involve substantial risks.

A health law academic pointed out in an article examining a fraud and abuse case that off-label use of drugs is common, and that practitioners may lack adequate dosage information about the off-label uses. Drug companies may obtain approval of a drug for a narrow use, such as for a specific type of pain, but practitioners use the drug for similar uses based on their experience. The writer maintained that a controlled study may not be necessary to establish efficacy for an expanded use of a drug for pain. Even if this is the ease, as discussed below in this paper, added safety risks may exist if the expansion covers a longer period of time and use by a wider number of patients. The protections for commercial speech should not be extended to allow manufacturers to distribute information about practitioner use with a disclosure about the lack of FDA approval. Distributions of information about unapproved uses should not be acceptable unless experts consider the expanded use to be generally recognized as safe and effective based on adequate studies.

The last part of this paper considers the need to develop better research incentives to encourage more testing and post-market risk surveillance by drug makers on off-label uses of their drugs. Violations of the Federal Food Drug and Cosmetic Act (FFDCA) can be considered violations of the False Claims Act, which opens the way to fraud and abuse suits. The scale of penalties involved in these suits may lead to more examination of the scope of FDA regulation and commercial speech protections. Thus this symposium's consideration of these issues is timely and important.

I. INTRODUCTION

This paper provides an overview of how the constitutional protections for commercial speech affect the Food and Drug Administration (FDA) regulation of drugs, and the emerging issues about the scope of the protections. Before a new drug can be sold, by law, the FDA must approve the drug based on adequate and well-controlled studies. (1) In Thompson v. Western States, the Supreme Court found that commercial speech permits pharmacies to advertise unapproved compounds of drugs to meet individual needs if there is a disclosure about the lack of FDA approval. (2) While pharmacy compounding is an obscure category of prescription use, the extent to which the Constitution permits disclosures as an alternative to regulation has become an important issue, perhaps the most important issue, in food and drug regulation. A federal district court has already found that commercial speech allows manufacturers to distribute reprints of medical articles about a new off-label use of a drug with disclosures to prevent deception and to inform readers of the lack of FDA review, a decision that remains influential even though it was vacated without reaching the merits. (3) This paper summarizes the current agency guidance on the distribution of reprints.

This article also examines the emerging debate about an expansion of the ability of drug companies to provide information to doctors about unapproved drug uses. Physicians can prescribe drugs for uses not approved by the FDA, as part of the practice of medicine, but promotion by the drug maker of off- label use is not permitted. (4) Allergan, the maker of Botox, recently maintained in a lawsuit that the First Amendment permits drug companies to provide "truthful information" to doctors about "widely accepted" off-label uses of a drug, such as those reimbursed by Medicare, as "medically accepted." (5) The company, though, later agreed to dismiss its suit as part of a costly settlement of a fraud and abuse case brought by the Government about off-label promotion of the drug. (6) Wide acceptance is an open-ended and ill-defined category. Wide acceptance is confusingly similar to, but less demanding than, the statutory test of "general recognition" by experts, based on adequate and well-controlled studies (7) that governs when FDA approval of a New Drug Application (NDA) with supporting studies is needed. If that recognition is lacking, FDA approval of a drug should be required before a manufacturer distributes information to doctors about "widely accepted" uses, given their potential to pose new safety risks.

An article by Sandra Johnson, a health law scholar who has also taught law in a medical school, found that practitioners often lack adequate information about off-label uses because of "deficiencies" in the studies, (8) and the absence of post-approval safety studies about the use of a drug. (9) While commercial speech protections were not an issue in her case study, the history illuminates the reasons why off-label uses occur. According to the article, the law "encourages the proliferation of off-label uses" because firms are allowed "to seek a narrow approved use" which can "minimize" delay and the cost of research for them. (10) Practitioners also have a "higher trust level for clinical experience over clinical trials." (11)

The article focused on Neurontin, a drug approved for use for the neuropathic pain of shingles. The drug was promoted by the manufacturer for some different uses, such as bipolar disorder, accompanied by some "suspect practices" that led to a fraud and abuse suit and settlement. (12) The author believes the expansion of use by doctors for "highly similar pain states" for neuropathic pain, though, may have provided "essential care" even in the absence of studies, and even if drug representatives provided detailing information about dosage levels or other matters. (13) Because neuropathic pain is "chronic and debilitating and does not respond to more common pain medications," doctors seek treatment that will work in practice. (14) Doctors increased their off-label prescribing of Neurontin notwithstanding the settlement. (15) In the author's view, the core problem is the deficiency in the "production and dissemination" of clinical knowledge about off-label uses. (16) The Neurontin dispute can provide a basis for assessing the wide acceptance theory. Some expanded uses may be similar in scope to the approved use. Some uses may be for a different condition, or involve use for a longer time and by a larger number of patients, which can lead to more side effects. Congress has required post-market surveillance to determine the additional risks that approved drugs may have, but off-label uses do not have this focused examination for added risks. (17)

The position of this paper is that the acceptability of distributions by the manufacturer about expanded uses should turn on whether experts would generally recognize the expanded use as safe and effective based on the adequacy of the available studies. Prior review of the disclosures may also be appropriate, as a court of appeals recognized with respect to health claims on foods that were protected by commercial speech. (18) This paper also recognizes the limits of the research incentives for manufacturers to do studies to support approval of a new use for approved drugs. If the incentives were stronger, the manufacturers might undertake more research and seek FDA approval for the new claim, rather than seek to make off-label claims based on commercial speech protections.

FDA regulation occurs against the background of fraud and abuse litigation. (19) The Allergan settlement and Neurontin dispute illustrate that the stakes are very high for drug companies when they cross the line and promote off-label uses. (20) In a recent article, a former drug company executive official maintains that the restrictions on the ability of the companies to "speak truthfully with physicians" about the companies' products is the "single greatest threat" to the industry. (21) According to the article, more than 100 ongoing civil and criminal investigations have been brought by federal and state officials against drug firms, resulting in "[b]illions of dollars in civil and criminal penalties" paid to date, and "billions more" expected to be paid in future years. (22) The Justice Department reached an all-time high in 2009 by bringing charges of healthcare fraud against over 800 defendants and obtaining over 580 convictions. (23) The author also complained about the FDA's lack of guidance on how to apply the law. …

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