The Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes FDA to  regulate the promotion of prescription drugs. The oversight of off- label promotions occurs within a broad review process meant to detect a  wide range of promotional violations—the agency does not have separate  activities designed specifically to detect off-label promotion of  prescription drugs. For example, FDA lacks a  tracking system to manage its review process. FDA also acknowledges  that it cannot review all submissions because of the volume of materials it  receives and that only a small portion of the required submissions of final  promotional materials are examined for potential violations. Although the  agency conducts additional monitoring and surveillance to detect  violations that could not be identified through a review of submitted  materials, the extent and variety of promotional activities make it difficult  for FDA to monitor these in a comprehensive manner. FDA’s Oversight Process Emphasizes Reviews of Materials Submitted by Drug Companies and Is Supplemented by Monitoring and Surveillance

The primary mechanism FDA uses to oversee the promotion of drugs for  off-label uses is to review promotional materials submitted to the agency  by drug companies. Currently, it prioritizes its reviews based on  whether the promotion involves  1.  an apparent, egregious violation;  2.  a drug that has undergone recent labeling changes and updates to its  3.  a television advertisement disseminated for the first time for a drug or  indication, or certain draft promotions that are associated with drugs  approved under FDA’s accelerated approval process and that reflect  central themes from a company’s promotion;  4.  new promotional campaigns that reflect central themes from the  company’s promotion;  5.  other television advertisements and other draft campaigns submitted  under the accelerated approval process;  6.  other new promotional campaigns; and  7.  other issues of concern. Limitations in FDA’s Oversight Process Make It Unlikely That All Off-Label Violations Are Detected

It is unlikely that FDA can detect all off-label promotion that occurs  because of limitations in its oversight process for reviewing the promotion  of prescription drugs. FDA’s oversight is hampered by the lack of a system  or process that consistently tracks its receipt and review of submitted  materials. In 2006,  GAO recommended that FDA track which materials it has reviewed but  the agency has not taken action to address this recommendation. This is because  inappropriate promotion can take many forms and occur in a myriad of  places. Regulatory and Enforcement Actions Have Been Taken in Response to Off-Label Promotions

FDA and DOJ have taken regulatory and enforcement actions against drug  companies for violative off-label promotions. During calendar years 2003  through 2007, FDA issued 42 regulatory letters—23 warning letters and 19  untitled letters—in response to off-label promotions. However, it took  FDA an average of about 7 months to issue these letters, during which  time violative material remained in the market. For example, it took drug companies receiving warning letters  issued in response to the more serious violations an average of 4 months  to take corrective action. However, DOJ initiated civil and criminal enforcement actions in response  to instances involving off-label promotion it identified from other sources. Eleven Settlements Related to Off-Label Promotion Have Occurred in the Past 5 Years

According to DDMAC officials, they did not refer any violations to DOJ for  enforcement action during calendar years 2003 through 2007 because drug  companies have generally complied with requests made in FDA’s  regulatory letters during that time period. Specifically, DOJ  enforcement action resulted in 11 settlements with drug companies, which  involved, at least partially, allegations of off-label promotion and resulted  in, among other things, a monetary settlement. First, HHS raised concerns with our finding that  DDMAC staff do not systematically prioritize all of the materials they  receive. Second, HHS commented that a tracking system would not improve the  agency’s ability to identify promotional violations nor would it change  which submissions are actually reviewed. We continue to believe that, as we recommended in 2006, a  tracking system would facilitate a more systematic approach to DDMAC’s  reviews, would allow FDA to more readily group materials for review, and  could enhance its monitoring and surveillance efforts by providing data on  materials reviewed and the findings of those reviews. In this case, violative promotional activities were cited for two different drugs, but off-label promotion  was cited for only one of these drugs. Encouraged sales representatives to send medical letters and other  marketing materials that were not requested by physicians in order to  promote off-label uses. Promoted drug for off-label uses, such as anti-aging, cosmetic use,  and athletic performance enhancement.
Why GAO Did This Study

The Food and Drug Administration (FDA), an agency within the Department of Health and Human Services (HHS), regulates the promotion of prescription drugs to ensure that promotional materials are not false and misleading and that they comply with applicable laws and regulations. Among other things, FDA prohibits drug companies from promoting drugs for off-label uses--that is, for a condition or patient population for which the drug has not been approved or in a manner that is inconsistent with information found on the approved drug label. Although doctors may prescribe drugs off label, it is not permissible for drug companies to promote drugs for off-label uses. FDA may take regulatory actions for violations, and may also pursue enforcement action through the Department of Justice (DOJ). GAO was asked for information about the promotion of drugs for off-label uses. GAO reviewed (1) how FDA oversees the promotion of off-label uses of prescription drugs and (2) what actions have been taken to address off-label promotions. GAO examined documentation related to the promotion of drugs for off-label uses and FDA correspondence with drug companies on identified violations and obtained information from DOJ on relevant actions. GAO also interviewed officials at FDA and the HHS Office of Inspector General and representatives of national medical and pharmaceutical associations.

What GAO Found

FDA oversees drug promotion for off-label uses by reviewing promotional materials that drug companies submit to the agency. However, because FDA does not have separate oversight activities to specifically capture off-label promotion, its oversight occurs within a broader process that targets a variety of promotional violations. Furthermore, FDA reports it is unable to review all submissions because of the volume of materials it receives and prioritizes its reviews in order to examine those with the greatest potential impact on human health. However, FDA does not prioritize its reviews in a systematic manner but rather relies on its staff to sort through large volumes of material and select submissions for review. FDA is also hampered by the lack of a system that consistently tracks the receipt and review of submitted materials. To address these shortcomings, GAO recommended in 2006 that FDA track which materials it has reviewed. FDA has not acted on this recommendation and still lacks a standardized tracking system to monitor its review efforts. GAO believes that this recommendation remains valid. In addition to its reviews, FDA conducts monitoring and surveillance to identify violations that would not be identified through its review of submitted material--for instance, discussions between doctors and sales representatives. These efforts are also limited because FDA cannot observe all off-label promotion activities as they can take many forms and occur in a myriad of places. FDA and DOJ have taken regulatory and enforcement actions against drug companies in response to off-label promotions. During calendar years 2003 through 2007, FDA issued 42 regulatory letters in response to off-label promotions requesting drug companies to stop dissemination of violative promotions. FDA took an average of 7 months to issue these letters from the time it first drafted them. In addition, drug companies that were cited for more serious violations took an average of 4 months to take the corrective actions requested. While FDA did not refer any of these violations to DOJ for enforcement action, during calendar years 2003 through 2007, DOJ settled both civil and criminal cases that involved, at least partially, off-label promotion. These actions were initiated as a result of violations identified by sources other than FDA and resulted in 11 settlements. In commenting on a draft of this report, HHS raised concerns with GAO's assessment that FDA does not systematically prioritize all of the promotional materials it receives. It also stated that a tracking system would not improve the agency's ability to identify promotional violations. GAO found that FDA does not screen all promotional materials. GAO continues to believe that a tracking system would help ensure that staff screen all material received, facilitate a more systematic approach to FDA's reviews, and help the agency manage the program.