Bound guidance: FDA rulemaking for off-label pharmaceutical drug marketing.

• Author: Andersen, Michael Jon

INTRODUCTION

On December 30, 1993, the United States Food and Drug Administration ("FDA") approved gabapentin, a drug marketed and distributed by Parke-Davis Pharmaceuticals Company, for "adjunctive therapy in the treatment of partial seizures ... in patients above the age of 12 years." (1) The drug was hailed as a welcome advance in the study of epilepsy, a field that scientists are only beginning to understand. (2) In clinical trials, gabapentin's results were impressive. In one study, gabapentin corresponded with a fifty percent reduction in seizures for twenty-three percent of epileptic patients, in comparison to a nine percent reduction in the placebo group. (3) Gabapentin's potential use, however, may well extend beyond treatment of seizures. Although it will not be a 'miracle solution' to all ailments involving neuropathic pain, (4) numerous studies suggest that gabapentin may have uses far beyond the scope of its FDA approval. (5)

Parke-Davis' marketing budget makes it clear that encouraging these potential alternative uses for the drug was a priority. In 1998 alone, Parke-Davis budgeted over $11 million for professional education events, such as dinner meetings with doctors, intended to "[m]aximize [o]pportunities in '[e]merging [[u]napproved] [u]ses.'" (6) In total, Parke-Davis allocated approximately $40 million for its Neurontin advertising budget in 1998. (7) Due in part to its marketing practices, Neurontin has been prescribed by physicians for a plethora of uses outside the scope of its FDA approval, including treatment of bipolar disorder, attention deficit disorder, restless leg syndrome, and migraine headaches. (8) As much as seventy-eight percent of Neurontin's $1.3 billion in sales for 2000 can be attributed to uses outside the scope of the drug's FDA approval "without clinical evidence of safety or effectiveness." (9)

The use of drugs like gabapentin for purposes not approved by the FDA is referred to as off-label use. (10) Although drug companies are not allowed to promote drugs for off-label uses, the FDA "does not regulate the practice of medicine and recognizes that physicians may determine that prescribing a drug off label constitutes good care." (11) Thus, despite the marketing restrictions, manufacturers utilize a number of methods to promote off-label uses of pharmaceuticals, including paying for professional education sessions, hiring speakers, engaging in direct mail campaigns, and reprinting favorable journal articles. (12) In recent years, many of these tactics have come under fire in a barrage of qui tam lawsuits brought against pharmaceutical companies under the False Claims Act. (13) As a result, while pharmaceutical companies are facing record-breaking fines for their unlawful business practices--Pfizer's $2.3 billion settlement for off-label marketing included the largest criminal fine in history and was its fourth settlement over illegal marketing since 2002--these same companies continue to engage in off-label marketing. (14)

Pfizer's strategy for Neurontin is no exception to this trend. According to Dr. Kay Dickersin of the Johns Hopkins Bloomberg School of Public Health, Pfizer, through its Parke-Davis division, used "a publication strategy meant to convince physicians of Neurontin's effectiveness and misrepresent or suppress negative findings." (15) For example, although physicians prescribe Neurontin to treat depression, (16) recent studies have shown that its use doubles the risk of suicidal behavior. (17) However, despite the drug's generic status and the ongoing controversy surrounding its off-label use, Neurontin continues to generate substantial income for Pfizer, grossing $387 million in sales in 2008. (18)

Rather than addressing these recent high-profile litigations, this Note will focus on the regulatory underpinnings of off-label marketing. While the FDA does not regulate a physician's decision to prescribe FDA-approved drugs for off-label uses, its recent "Guidance for Industry on Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices" ("Guidance") does offer regulatory guidelines that permit manufacturers to use medical journals as promotional materials. (19) This Note will argue that this guidance is problematic for a number of reasons. First, despite its claims to the contrary, the Guidance attempts to implement a legislative rule under the guise of a non-legislative document. (20) Second, and more importantly, the measures proposed in the Guidance are insufficient both to protect the public and keep physicians properly informed of medical advances regarding off-label uses of prescription drugs. In effect, the current Guidance allows pharmaceutical companies to market their products for uses that have not been approved as safe and effective by the FDA.

Section I will outline the notice and comment rulemaking procedures under both the Administrative Procedure Act and the Good Guidance Practices adopted by the FDA. Section II will then recount the evolution of regulations restricting the distribution of journal articles promoting off-label uses of drugs by pharmaceutical manufacturers, while Section III will explore the current regulatory structure. Section IV will then evaluate whether the current Guidance satisfies the qualities of a guidance document, or whether it should have been promulgated as a legislative rule. Finally, Section V will recommend that the FDA replace the current Guidance with a legislative rule that prohibits manufacturers from distributing journal articles that primarily promote off-label uses for their drugs.

1. NOTICE AND COMMENT RULEMAKING

   In 1938, Congress passed the Food, Drug, and Cosmetic Act ("FDCA") in response to public outcry against the marketing of untested drugs, (21) delegating additional power to the FDA. (22) In order to act within Congress's authority, the FDA must comply with the minimum requirements imposed by the APA's notice-and-comment procedures. (23) In addition, the FDA has created additional, self-imposed procedural requirements for interpreting the Congressional Act or carving out new legislative rules. (24) Taken together, these requirements shape the FDA's exercise of its rulemaking power.

   Much of the FDA's regulatory power, including its ability to regulate off-label drug use, stems from its informal rulemaking authority. The Administrative Procedure Act ("APA") defines a rule as "the whole or a part of an agency statement of general or particular applicability and future effect designed to implement, interpret, or prescribe law or policy or describing the organization, procedure, or practice requirements of an agency...." (25) This definition includes legislatively binding rules, as well as policy statements, such as guidance documents, intended to establish non-binding best practices for agencies. (26) According to the APA, informal rules must undergo "notice and comment" (27) unless the agency is attempting to promulgate "interpretative rules, general statements of policy, or rules of agency organization, procedure, or practice." (28)

   Notice-and-comment rulemaking exists to allow for public participation and input into the informal rulemaking process. (29) Such participation "increases accountability and oversight, provides better quality information for both decision makers and participants, minimizes excessive influence of powerful interests, and promotes proceduralist values that enhance the fairness and legitimacy of a rule." (30) Agencies can impose stricter procedures for notice-and-comment rulemaking, but the procedures outlined in the APA provide a baseline for agency action: reviewing courts turn first to the agency's rulemaking procedures, and then to the APA procedures. (31)

   The FDA is one of many agencies that impose stricter procedures than are required by the APA for non-legislative rulemaking. (32) Under section 553(b) of the APA, interpretative rules and general statements of policy do not have to go through notice-and-comment proceedings. (33) Despite this exemption, the FDA, however, still imposes requirements akin to notice and comment on its interpretative rules and general policy statements, placing both under the umbrella of guidance documents. FDA guidance documents include "documents prepared for FDA staff, applicants/sponsors, and the public that describe the agency's interpretation of or policy on a regulatory issue." (34) Guidance documents are subject to two different levels of public scrutiny based on the nature of the document. Level 1 guidance documents "(i) [s]et forth initial interpretations of statutory or regulatory requirements; (ii) [s]et forth changes in interpretation or policy that are of more than a minor nature; (iii) [i]nclude complex scientific issues; or (iv) [c]over highly controversial issues." (35) Level 2 guidance documents include all guidance documents not classified as Level 1 that "set forth existing practices or minor changes in interpretation or policy." (36)

   For Level 1 guidance documents, the FDA must publish a notice of proposed rulemaking in the Federal Register and invite public comment, requirements that largely (37) mirror the APA notice-and comment procedures for legislative rules. (38) Even after the Level 1 document has been finalized, the public can continue submitting comments for consideration should the agency deem it appropriate to undertake future revisions. (39) In comparison, Level 2 guidance documents are implemented as soon as the FDA posts the document on the Internet. (40) The FDA still allows for the submission of public comments following publication of Level 2 guidance documents, and reserves the right to revise the documents when appropriate. (41)

2. THE EVOLUTION OF OFF-LABEL REGULATION

   As a default rule, the FDCA prohibits the marketing of drugs for uses the...