American Journal of Law & Medicine

Bias at the Gate?: The Pharmaceutical Industry's Influence on the Federally Approved Drug Compendia

I. INTRODUCTION

As of 2002, the Federal Food and Drug Administration (FDA) had approved Neurontin, a drug developed by the pharmaceutical company Pfizer, for two uses, the treatment of epilepsy and pain related to shingles. (1) A staggering ninety-four percent of Neurontin prescriptions in the prior five years, however, were for other (non-FDA) approved uses. (2) These other uses effectively tripled Medicaid's costs for the drug between 1998 and 2003. (3) Insurance companies covered the off-label uses because they appeared in the Drugdex compendium, a federally authorized listing of drugs that includes evidence regarding the drug's effectiveness, clinical indications, and proper dosing. (4) Drugdex included an additional forty-eight uses for Neurontin, ranging from bipolar disorder to the hiccups. (5) Two other federally approved compendia existed at that time; one listed seven uses for Neurontin while the other listed only one. (6)

A 2003 Wall Street Journal article identified several concerns with Drugdex's off-label listing standards. (7) First, Drugdex did not adhere to strict FDA protocols. Instead, it often relied on one-patient observations for evidence of efficacy, and sometimes even disregarded studies showing that certain off-label uses were ineffective. (8) Second, Drugdex publisher Thomson ran "continuing medical education" seminars for the pharmaceutical industry. (9) Thomson's customers included companies whose drugs are listed in Drugdex, such as Pfizer, GlaxoSmithKline, and Eli Lilly. (10) Third, one of the six authors of the Neurontin section in Drugdex had a financial relationship with Parke-Davis, the company that initially manufactured Neurontin, which Pfizer subsequently acquired. (11) This author received at least $75,000 for speaking engagements on the uses of Neurontin. (12) The article cited concerns with this compendium that spanned from personal conflicts of interest that could affect the interpretation of clinical evidence to corporate conflicts of interest that could produce an overall desire to please the pharmaceutical industry. (13)

Concerns still exist about conflicts of interest, relationships with the pharmaceutical industry, and a lack of transparency in the creation of the drug compendia. These concerns are especially rampant in the field of oncology, which features one of the highest rates of prescriptions for off-label drugs. (14) For instance, in 2006 the American Society of Clinical Oncology estimated that fifty percent of cancer treatment drugs are prescribed off-label. (15) Concerns about the integrity of the four federally authorized drug compendia that provide cancer treatment information are substantial. Problems such as a lack of transparency and a failure to employ systematic methods for determining which drug indications to include are particularly prevalent in the oncology compendia. (16) Furthermore, the steep costs of oncology drugs coupled with favorable reimbursement policies for off-label uses listed in the compendia provide added encouragement for drug manufacturers to go to great lengths to have multiple indications listed for their oncology drugs. (17)

Not only do these conflicts of interest have the potential to harm patients by condoning dangerous off-label uses, but they also provide a de facto safe harbor for pharmaceutical companies engaged in illegal off-label marketing when the federal government brings actions under the False Claims Act (FCA). (18) Pharmaceutical companies that influence off-label compendia listings can increase drug reimbursement while protecting themselves from false claims liability; federal prosecutors are unlikely to bring actions if the federal health insurance programs already are reimbursing for a drug use listed in the compendia.

Part II of this Note explains the relevant legal and factual background for off-label drug approval and marketing under the Food, Drug, and Cosmetic Act (FDCA). It also details Medicare and Medicaid reimbursement for off-label uses and liability for off-label marketing under the False Claims Act. Part III describes the drug compendia, their intended functions, and their current practices. Part IV outlines industry conflicts of interest and lack of transparent practices, both of which have compromised the integrity of the compendia. Finally, Part V addresses two policy implications of these practices: first, that reimbursement levels may be inflated by the compendia showing greater efficacy for drugs than the record might objectively support; and, second, that at a practical level compendia data can serve as a defense to otherwise meritorious off-label prosecutions under the False Claims Act and the FDCA.

II. THE PRESCRIPTION DRUG CYCLE AND THE FCA

A. Drug Approval and Labeling Under the FDCA

The Federal Food, Drug, and Cosmetic Act provides that "[n]o person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application ... is effective with respect to such drug." (19) Before granting its approval, the FDA requires manufacturers to submit a New Drug Application (NDA) that includes (1) reports of investigations of the drug's safety and efficacy; (2) the components of the drug; (3) a statement of the composition of the drug; (4) a description of the drug's manufacturing, processing, and packaging processes; (5) samples of the drug; and (6) and the proposed labeling for the drug. (20) The NDA facilitates the FDA's review of whether the drug "is safe and effective in its proposed use(s);" "whether the benefits of the drug outweigh the risks;" whether the proposed labeling is appropriate; and whether the manufacturing methods "are adequate to preserve the drug's identity, strength, quality, and purity." (21)

The FDA approves a drug for the specific use or uses specified in the NDA only if it finds that the "benefits to the public health outweigh the risks." (22) A drug's label will reflect the approved uses for that drug. (23) Manufacturers must submit a supplemental application to have other uses added to the label. (24) The supplemental application requires many of the same elements as the NDA and requires a significant waiting period for manufacturers, as the average time for approval for a new drug use is 90.3 months. (25)

Despite its stringent drug approval processes, the FDA does not regulate the practice of medicine itself. Physicians therefore may prescribe an approved drug for any medical condition regardless of whether the label lists that use. (26) Given the lengthy approval process, "[i]f an off-label use is already well known among physicians, adding it to the label would likely have little effect on sales." (27) Because an estimated twenty-five to sixty percent of all prescriptions are for off-label use, drug companies may lack incentives to obtain the additional approval. (28) Furthermore, manufacturers may be concerned with the impact of an FDA denial of an application for a new indication. Manufacturers therefore may apply for approval only for new indications that would be both financially lucrative and likely to obtain FDA approval. (29) The category of "off-label uses" can cover a vast range of treatments:

   [f]rom experimental to standard therapy and even state-of-the-art
   treatment. In some instances, off-label use represents first-line
   treatment, in others second- and third-line therapy, and still
   others last resort therapy. Off-label use may originate from a
   presumed therapeutic class effect ... [o]r, off-label use may
   involve extension to a broader population, such as with the
   antidepressant paroxetine, indicated for depression in adults, but
   also prescribed off-label for depression in children. Further,
   off-label use may represent an extension to a related condition,
   such as with the antipsychotic quetiapine, which is frequently
   prescribed off-label for depression. Finally, off-label use may
   concern expansion of use to distinct conditions sharing a
   physiological link, such as use of the antiasthmatic montelukast
   for chronic obstructive pulmonary disorder (COPD). (30)

The FDA allows physicians to prescribe approved drugs for any use because it acknowledges that some non-approved uses may be beneficial to certain patients: (31) "[the] FDA recognizes that 'off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care.'" (32) One reason for allowing off-label treatment is that the length of the NDA process may cause a delay between new medical discoveries and any addition to the drug's label. (33) Additionally, some patient populations, the "so-called orphan populations and orphan diseases-population[s]," (34) may lack an on-label drug treatment because they are too small for pharmaceutical companies to justify the expense of the drug application and clinical trial process. (35) Finally, certain medical fields such as oncology, pediatrics, psychiatry, geriatrics, and obstetrics rely on off-label uses to such a degree that they "could not proceed if off-label prescribing did not occur." (36)

Despite these benefits, off-label drug prescriptions can put patients at risk because they lack the FDA's safeguards ensuring efficacy and safety. A 2006 study found that seventy-three percent of off-label drug uses lacked clinical evidence of efficacy and only twenty-seven percent were supported by strong clinical evidence. (37) The study also found that while many off-label uses were "a logical extension of the FDA-approved indication," some uses were significantly different from those approved by the FDA. (38) For instance, researchers found that a drug approved for glycemic control for patients with type 2 diabetes was also prescribed for several patients with polycystic ovary syndrome. (39) Physicians may have difficulty differentiating between off-label uses with and without scientific support due to "time pressures, information overload, and the involvement of industry in research and education about off-label uses." (40) This degree of uncertainty about the safety and efficacy of some off-label uses puts patients at risk of receiving treatments that are not only ineffective, but may be harmful as well.

These concerns are particularly worrisome in the field of oncology. The National Comprehensive Cancer Network (NCCN) estimated that 50% to 75% of cancer treatment drugs in the United States were prescribed off-label, (41) and in 2006, the American Society of Clinical Oncology estimated that 50% of cancer drugs were prescribed off-label. (42) Many factors account for these high rates. While the FDA must approve drug therapies separately for different cancers, many cancers share a similar biology and, as a result, respond similarly to drug treatments. (43) Additionally, pediatric oncology and certain rare cancers place more pressure on treating physicians to deliver timely results. (44) This may cause physicians to balance the risks and benefits of a course of treatment differently than they would in treating other diseases. (45) Finally, current reimbursement methods encourage high rates of off-label prescription use, (46) a trend that will be discussed further below.

B. PROHIBITIONS ON OFF-LABEL MARKETING FOR DRUG MANUFACTURERS UNDER THE FDCA

While physicians may prescribe drugs for off-label uses, the FDCA prohibits drug manufacturers from promoting off-label drug uses. (47) Although the design of off-label promotional materials by drug companies may differ, such materials are often delivered through "printed materials, journal articles, 'detailing' visits to physicians by sales [representatives], and lectures in various settings--from luncheons to destination seminars--delivered to prescribers by influential peers." (48) To avoid scrutiny, the content of the materials often contains carefully worded indications of off-label uses, such as references to "'expanded' or 'emerging' uses. …

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