Regulating Off-label Promotion of Medications: Has the Pendulum Swung Too Far?

Melissa B. Hoffman, BS¹; Brad A. Yentzer, MD²; Steven R. Feldman, MD, PhD³

¹University of Buffalo School of Medicine, Buffalo, NY, USA
²The Corvallis Clinic, Corvallis, OR, USA
³Center for Dermatology Research, Departments of Dermatology, Pathology and Public Health Sciences; Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT
Prescribing medications off-label is commonplace in dermatology. Recent policy changes on the regulatory abilities of the US FDA and legal precedents regarding this topic have led to intense debate on free speech about off-label drug use by physicians and drug manufacturers. Here, we summarize and discuss the risks and benefits of off-label promotion and how this relates to quality patient
care in dermatology.

Key Words:
labeling, pharmaceutical, promotion, advertising, FDA, regulations, dermatology

Introduction

Pharmaceuticals are often prescribed for uses beyond those listed on the drug’s US Food and Drug Administration (FDA) approved label. This off-label use includes treatments for disorders not formally reviewed by the FDA, dosages or delivery mechanisms not approved by the agency, or use of the agents in patient populations not tested in FDA approved clinical trials.¹ In order for a drug company to market a medicine for a particular use or disease, it must go through rigorous evaluation by the FDA. This entire process, which includes preclinical testing and three clinical phases, takes an average of 8 to 12 years.² This course is so rigorous that for every 5,000 to 10,000 compounds that enter preclinical testing, only one is approved for marketing.³ Off-label prescribing compensates for this scrupulous and time-consuming approval process by allowing physicians to use treatment options that are readily available. The off-label use of drugs has significantly contributed to the therapeutic armamentarium of many different diseases in medicine.

Off-label prescribing is particularly common in dermatology. This can in part be explained by the relative lack of clinical trials evaluating the multitude of therapeutic options for any given dermatologic condition. For many skin diseases, few – if any – medications are FDA-approved, and use of off-label medications is the standard of care in dermatology.^4,5 Off-label prescribing is used in a wide range of dermatologic conditions, from disorders that are common and have multiple treatment options, such as actinic keratosis and acne vulgaris, to the more rare conditions that have very few if any FDA-approved treatments, such as pyoderma gangrenosum, pemphigus vulgaris, and lichen planus. Off-label options can be used for common conditions when treatment with approved medications have been exhausted or have proved unsuccessful or even when the off-label treatment is deemed better than on-label options.

Increasing prevalence of off-label prescribing has come with a fair share of conflicts between the FDA, insurance companies, physicians and pharmaceutical companies, as the FDA has sought to regulate the pharmaceutical industry’s promotion of unapproved therapies. During the past decade, pharmaceutical companies have faced government investigations regarding the marketing and promotion of their products. Companies have been fined billions of dollars for promoting their product for indications other than those listed on the FDA-approved label. Although regulations on the pharmaceutical industry were designed to protect the public, they may have unexpected negative consequences. Branding a drug’s particular use as “off-label” not only limits the dissemination of information about the drug, but also decreases patient access to the agent. While patients, physicians not employed by pharmaceutical companies, insurers and government researchers are free to discuss whatever they want about off-label uses, the pharmaceutical company is prohibited from entering the discussion. These limitations on the dissemination of information have become a major topic of controversy in recent years. Because the off-label use of drugs and devices will remain a major part of the practice of medicine in the future, there needs to be a balance between the regulatory authority of the FDA, the circulation of information coming from the pharmaceutical companies, and the ability of physicians to provide the best possible care for their patients. In this paper we discuss a brief history on the drug approval process and the development of FDA regulations over off-label drug promotion, recent legal cases surrounding off-label drug speech, and the risks and benefits of off-label drug promotion in dermatology (Table 1).

A Brief History of Drug Regulation

The process of bringing to market a new drug or new use of a drug is rigorous, involving preclinical testing with animals, three phases of human clinical trials, and two stages of approval from the FDA. This process is a multi-year, multi-stage course and generally costs millions of dollars. If a drug survives all three phases of clinical trials, a New Drug Application (NDA) containing all the preclinical and clinical information obtained during testing is submitted to the FDA. The FDA then performs an independent review, after which a NDA may be approved or rejected. After FDA approval for a given disease, a medication is often subject to phase 4 post-marketing studies, which are designed to evaluate long-term efficacy and safety in a larger patient population and a longer time period. It is reported that this entire process from lab to patient may take as long as 10 to 15 years, with clinical trials accounting for 7 of those years, and may cost an average of $1.2 billion per drug.⁶ Even when drug manufacturers desire to obtain FDA approval for an off-label use that is similar to indications listed on the label, they must submit a “supplemental new drug” application. The drug then has to undergo extensive clinical trials to determine the efficacy of this off-label use. While the FDA claims they are speeding up the supplemental new drug approval process, the data show there are still long delays.⁷

The first federal laws to regulate the sale and content of food and drugs came in 1906 with the Pure Food and Drug Act. Since then, the passage of over 200 laws has created a stringent regulatory system with the goal of protecting consumers.⁸ The federal Food, Drug and Cosmetic Act (FDCA) of 1938 was one of the major milestone laws that gave the FDA authority to regulate promotional materials of the pharmaceutical companies. The FDCA indirectly prohibits the promotion of off-label use in two ways: 1) By prohibiting drug manufacturers from introducing a new drug into interstate commerce unless both the drug and the label have gained FDA approval, and 2) By prohibiting the drug manufacturer from introducing a “misbranded” drug. A drug is considered misbranded if the label contains information about unapproved uses or misleading information. Visual aids and handouts used by sales representatives are considered part of the drugs label even if they are not packaged with the product.¹ The FDA has long held to these rules when reviewing promotional materials of pharmaceutical companies. The off-label promotion of drugs was further restricted by the indirect effects of the 1962 Amendments, which gave the FDA stricter control over how companies performed clinical trials.⁸ These amendments were a major contribution in shaping the rigorous structure that is currently in place for FDA approval.

The FDA’s strict regulations on the promotion of unapproved drugs have become slightly more permissive over time. While the FDA previously had an absolute authority to prohibit the dissemination of off-label information, newer guidelines under the FDA Modernization Act of 1997 (FDAMA) allow drug manufacturers to distribute reprints of peer-reviewed articles that describe unapproved use of their products.⁹ However, even this change of policy came with its fair share of regulations. The FDA imposed a list of conditions to be met before companies could circulate the articles. Some of these requirements include: the information must be published in a peer-reviewed scientific or medical journal, the company must submit a supplemental new drug application and they must provide the FDA with advance copies of the articles they intend to redistribute.¹ Despite the series of laws and amendments, there remains a considerable amount of uncertainty about what exactly manufacturers are able to promote.

Recent Legal Precedents

There are now more than one hundred ongoing civil and criminal investigations involving the US Department of Justice and the US Department of Health and Human Services. These investigations, in which pharmaceutical companies were accused of off-label promotion, held companies liable under both the FDCA and the False Claims Act (FCA).¹⁰ The FCA makes it unlawful to file a false claim with the government. This theory has been applied to off-label promotion, regardless of whether the information about off-label use is truthful or not. These legal actions have had a major hit on pharmaceutical companies, with settlements ranging from tens of millions to hundreds of millions of dollars and occasionally even jail time for company executives.¹

A recent legal case could have broad ramifications for the pharmaceutical industry and the role of off-label promotion in medicine. In this landmark case of United States v. Caronia, No. 09–5006–CR, 2012 WL 5992141 (2d Cir. December 23, 2012), the US Court of Appeals for the Second Circuit overturned the conviction of a pharmaceutical sales representative who was accused of promoting a drug for its off-label uses. The Court’s holding, in full, reads: “[W]e decline to adopt the government’s construction of the [Food, Drug, and Cosmetic Act’s (FDCA’s)] misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs.” Ibid., 15. The case has led to an increased focus on the issues that exist with the FDA’s regulation on off-label use of drugs, and the negative impact this has had on healthcare. There is a distinction between truthful communication about off-label drug uses, many of which are proven efficacious and safe by the medical community, and claims that are not validated or are simply factitious. References to the First Amendment have hampered the FDA’s ability to regulate offlabel promotion and will likely have an impact on the future of off-label drug discussions.

While some may believe that dermatologists are free from the FDA litigations over off-label promotion, this is not necessarily true for physicians who participate in clinical trials or promote products on behalf of manufacturers. In January 2010, the FDA sent a warning to a Florida dermatologist for mentioning in interviews with magazines that an anti-wrinkle drug she was conducting a clinical trial on had demonstrated to work better than a competitor’s product.¹¹ Upsetting the FDA by promoting an off-label indication in dermatology may have far worse consequences than a warning letter. In 2004, oral tazarotene for the treatment of psoriasis was denied FDA approval. While the advisory board claimed there was not enough data to support that the benefits outweigh the risks, the committee repeatedly asked Allergan about how they had promoted the off-label of oral tazarotene for acne via posters at an American Academy of Dermatology conference.¹² Approval for oral tazarotene, a product that had the potential to benefit patients with psoriasis, was eventually denied, perhaps in part because of concerns over off-label promotion. Although physicians are supposedly free to discuss any off-label indications with colleagues and patients, this freedom is limited when the physician is acting as an agent of a pharmaceutical company. With the FDA’s authoritative power in approving medication uses, a company could potentially win a First Amendment battle over off-label promotion but lose a war if the FDA chose to delay or not to approve future products.

Risks with Off-Label Promotion

Before regulations on the content and promotion of pharmaceutical agents, drug makers were able to produce and sell products that would seem criminal in today’s day and age. For instance, “Peter’s Specific, The Great Blood Purifier System Regulator” was recommended as a treatment for dermatologic disease and as an alternative tonic, invigorator and blood purifier.¹³ While drug manufacturers are no longer able to make scientifically unfounded claims, many physicians prescribe offlabel for uses that lack significant scientific support.¹⁴ By “word of mouth” marketing, highly influential academic physicians may, for better or worse, indirectly help pharmaceutical companies promote products’ off-label uses.¹⁵ This promotion often comes in the form of industry-sponsored abstracts, posters and publications. If a poster demonstrates promising preliminary results but the follow-up studies show no benefit, the negative findings may not get widespread notice. This leaves the medical community with the potential for an incomplete, overly favorable, impression of the product. The spread of invalid data is not only the fault of pharmaceutical companies, but also of physicians who may try and promote new off-label uses out of desperation when all conventional therapies have failed. While many efficacious treatment strategies are discovered by trial and error, this also lends to the potential widespread use of products that are not beneficial. In 2008, topical bimatoprost (Latisse®) was approved for the treatment of eyelash hypotrichosis. Since then, some have advocated the use of bimatoprost to stimulate hair growth in other areas such as the scalp or eyebrows, despite the lack of any published scientific evidence on this use.¹⁶ Furthermore, allowing drug manufacturers to redistribute information about off-label uses may disincentivize companies to conduct clinical trials to gain FDA approval.¹⁷ Without the rigorous scientific scrutiny that comes with FDA approval, the safety and efficacy of off-label uses may not be well elucidated. Limiting manufacturers from promoting off-label use is the primary method used by the FDA to “protect the public from promotional claims that are unsubstantiated at best, and false at worst.”¹⁸ The FDA regulations are designed to protect not only patients, but also physicians as they prevent them from receiving biased information that may inappropriately influence their prescription choices. However, limiting the dissemination of information may be harmful to public health as it decreases the data readily available to physicians when making treatment decisions.

Benefits of Off-Label Promotion in Dermatology

“FDA restrictions on off-label promotion has made it more difficult for physicians to learn about new uses of drugs and devices.”¹⁹ The medical community, federal courts and even the FDA all agree that drug manufacturers are often the best source of information on the data regarding the risks and benefits of offlabel drug uses. Any speech on off-label use is subject to the same penalties, regardless of whether or not the information is true. With the wide range of dermatologic disorders and the limited number of well-designed clinical trials assessing the multitude of therapeutic options, off-label prescribing is now commonplace in dermatology. Clinical trials often reveal significant evidence supporting the benefit of off-label uses long before these agents gain FDA approval. This lag time to FDA approval is evident in a wide variety of dermatologic disorders, most recently in the treatment of complicated infantile hemangiomas. On March 17th, 2014, Pierre Fabre Dermatologie obtained marketing authorization from the FDA for the pediatric drug Hemangeol™ (propranolol hydrochloride), making it the first and only FDA approved treatment for proliferating infantile hemangioma requiring systemic therapy.¹³ However, since 2008, when the efficacy of propranolol for hemangiomas was first proposed,propranolol has proven efficacious in accelerating the involution infantile hemangiomas through a wide variety of case series and clinical trials.²⁰ Also common in dermatology is the wide spread use of products to treat conditions well beyond those reflected on their FDA approved label. Tacrolimus (Protopic™), while only FDA approved for the treatment of atopic dermatitis, has been used off-label to treat many other skin disorders including lichen planus, allergic contact dermatitis, seborrhoeic dermatitis, vitiligo, pyoderma gangrenosum, and balanitis xerotica obliterans.^21,22 While some of these uses are based on small case series, there is statistically significant evidence from multiple randomized, double-blind studies that supports the use of 0.1 % tacrolimus ointment in some forms of psoriasis.^23,24 Despite this proven efficacy in a multitude of conditions, the manufactures are confined to only discussing the product’s one FDA approved use. These restrictions may contribute to the underuse of products that have tremendous potential to help other patients.

Moving Forward

The increasing popularity of off-label prescribing combined with recent law proceedings that have undermined the FDA’s ability to regulate off-label marketing activities, has led to some concerns about how to most effectively keep physicians informed while still protecting patients. The FDA’s concerns over protecting physicians from inappropriate influence by pharmaceutical companies are often seen as unnecessary and even insulting to the practitioners. With the recent legal cases highlighting protection under the First Amendment, there may be an increase in the free speech by pharmaceutical companies. The necessity of clinical trial transparency and a greater emphasis on improving research quality will become even more important in this setting. The requirements of advanced registration for clinical trials and the stipulation that summary results of clinical trials must be published have made it more difficult to hide negative studies, ensuring that physicians and patients will have access to the most honest and up to date information.²⁵

Many have proposed that to decrease off-label drug use and promotion the FDA must modify their approval system into a streamlined process for approving new uses of drugs. However, such changes to the regulatory system are not likely to occur anytime soon. Off-label promotion will continue to be a necessity as the FDA’s current drug approval process is unlikely to keep pace with the rapid expansion of therapeutic options in dermatology. The evolving nature of the FDA’s regulatory guidelines on the dissemination of information regarding off-label uses, combined with efforts to improve research quality and transparency, will hopefully expand the realm of knowledge available to physicians, allowing for the best possible management of their patients’ dermatologic conditions. Allowing for open discussion about off-label uses should be seen not as a form of pharmaceutical promotion but as a form of education.

References

1. Mello MM, Studdert DM, Brennan TA. Shifting terrain in the regulation of off-label promotion of pharmaceuticals. N Engl J Med. 2009 Apr 9; 360(15):1557-66.
2. Heilman RD. Drug development history, “overview,” and what are GCPs? Qual Assur. 1995 Mar;4(1):75-9.
3. Klees JE, Joines R. Occupational health issues in the pharmaceutical research and development process. Occup Med. 1997 Jan;12(1):5-27.
4. Sugarman JH, Fleischer AB, Jr., Feldman SR. Off-label prescribing in the treatment of dermatologic disease. J Am Acad Dermatol. 2002 Aug; 47(2):217-23.
5. Li VW, Jaffe MP, Li WW, et al. Off-label dermatologic therapies. Usage, risks, and mechanisms. Arch Dermatol. 1998 Nov;134(11):1449-54.
6. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003 Mar;22(2): 151-85.
7. Tabarrok A. Assessing the FDA via the anomaly of off-label drug prescribing. The Independent Review. 2000 Jul 1;5(1).
8. Nasr A, Lauterio TJ, Davis MW. Unapproved drugs in the United States and the Food and Drug Administration. Adv Ther. 2011 Oct;28(10):842-56.
9. O’Reilly J, Dalal A. Off-label or out of bounds? Prescriber and marketer liability for unapproved uses of FDA-approved drugs. Ann Health Law. 2003;12(2):295-324, table.
10. Osborn JE. Can I tell you the truth? A comparative perspective on regulating off-label scientific and medical information. Yale J Health Policy Law Ethics. 2010;10(2):299-356.
11. Singer N. F.D.A. aims at doctors’ drug pitches. New York Times. 2010 Jan 31. Available at: http://www.nytimes.com/2010/02/01/business/01wrinkle.html?pagewanted=all&_r=0. Accessed March 8, 2015.
12. Department of Health and Human Services FaDACfDEaR. Tazarotene capsules in the treatment of psoriasis. 2004.
13. Barkan ID. Industry invites regulation: the passage of the Pure Food and Drug Act of 1906. Am J Public Health. 1985 Jan;75(1):18-26.
14. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among officebased physicians. Arch Intern Med. 2006 May 8;166(9):1021-6.
15. Fugh-Berman A, Melnick D. Off-label promotion, on-target sales. PLoS Med. 2008 Oct 28;5(10):e210.
16. Schweiger ES, Pinchover L, Bernstein RM. Topical bimatoprost for the treatment of eyebrow hypotrichosis. J Drugs Dermatol. 2012 Jan; 11(1):106-8.
17. Ventola CL. Off-label drug information: regulation, distribution, evaluation, and related controversies. P T. 2009 Aug;34(8):428-40.
18. Copland H HP. Off-label, not off-limits: the FDA needs to create a safe harbor for off-label drug use. Issue brief no.15 January 2013. Manhattan Institute for Policy Research.
19. Conko G. Hidden truth: the perils and protection of off-label drug and medical device promotion. Health Matrix Clevel. 2011;21(1):149-87.
20. Leaute-Labreze C, Dumas de la RE, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):2649-51.
21. Kaliakatsou F, Hodgson TA, Lewsey JD, et al. Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol. 2002 Jan;46(1):35-41.
22. Ebert AK, Vogt T, Rosch WH. Topical therapy of balanitis xerotica obliterans in childhood. Long-term clinical results and an overview. Urologe A. 2007 Dec;46(12):1682-6.
23. Remitz A, Reitamo S, Erkko P, et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol. 1999 Jul;141(1):103-7.
24. Carroll CL, Fleischer AB, Jr. Tacrolimus ointment: the treatment of atopic dermatitis and other inflammatory cutaneous disease. Expert Opin Pharmacother. 2004 Oct;5(10):2127-37.
25. Outterson K. Clinical trial transparency–antidote to weaker off-labelpromotion rules? N Engl J Med. 2014 Jul 3;371(1):1-3.