Prescription Drugs: FDA's Oversight of the Promotion of Drugs for Off-Label Uses
Published: 2008-07-28T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: Drug companies provide medical professionals and consumers with  information about prescription drugs in a variety of ways, such as direct- to-consumer (DTC) advertising on television or the Internet, presentations  by drug company sales representatives, and patient brochures provided in  physicians’ offices. The Food and Drug Administration (FDA), an agency  within the Department of Health and Human Services (HHS), regulates the  promotion and advertising of prescription drugs. Although drug  companies are permitted to promote their drugs, these promotions may  not be false or misleading and must comply with applicable laws and  regulations. Among other things, drug companies are prohibited 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 in the drug’s labeling that has been  approved by FDA.
FDA’s Division of Drug Marketing, Advertising, and Communications  (DDMAC) has responsibility for overseeing materials and activities that  promote prescription drugs and identifying potential violations. For  example, in addition to off-label promotions, it may identify violations  such as minimizing the risk of a drug or overstating a drug’s safety or  effectiveness. To do this, DDMAC reviews written materials submitted by  drug companies, including final promotional materials that companies are  required to submit at the time the materials are first disseminated to the  public. DDMAC may also review submissions of draft promotional  materials that drug companies voluntarily submit for advisory review. In  addition to reviewing submitted materials, DDMAC conducts monitoring  and surveillance of promotional activities that drug companies may engage  in, such as sponsoring information booths and distributing literature at  medical conferences. If a promotional violation is identified, the agency  may take regulatory action by issuing one of two types of regulatory  letters, depending on the severity of the violation. FDA may issue either an  untitled letter or, for more serious violations, a warning letter. Both types  of letters request the drug company to take specific actions, such as  stopping the dissemination of violative materials and issuing corrections  of previously distributed information. When drug companies fail to take  appropriate action in response to regulatory letters, FDA may refer  violations to the Department of Justice (DOJ) for enforcement actions. For  example, FDA may work with DOJ to have a violative product seized. DOJ  may opt to further investigate drug companies and prosecute them for  violations identified by FDA, as well as for promotional violations  identified by other sources.
While it is not permissible for drug companies to promote drugs for off- label uses, FDA does not regulate the practice of medicine and recognizes  that physicians may determine that prescribing a drug off label constitutes  good care. Off-label prescribing occurs frequently. For example, a 2006  study found that more than 20 percent of prescriptions written for 100 of  the 500 most commonly used prescription drugs, and 60 prescription drugs  chosen by random selection, in the United States were for off-label use.
However, concerns about the off-label use of drugs and associated  promotions have mounted in recent years. Instances of patients being  improperly medicated and consequently injured have been reported. In  addition, the federal government, through DOJ, has reached settlements  with drug companies for off-label promotion. For example, in May 2004,  Pfizer, Inc. agreed to pay $430 million in connection with its promotion of  the antiseizure drug Neurontin for a variety of off-label uses, such as  bipolar disorder and migraines.
You expressed concern about the potential impact of off-label promotion  on physicians’ prescribing practices and patients’ safety and well-being,  and interest in FDA’s oversight of off-label promotion. This report  examines (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.
To determine how FDA oversees the promotion of off-label uses of  prescription drugs, we interviewed DDMAC officials about their review of  promotional materials and their monitoring and surveillance efforts  relating to off-label promotion. We also obtained data on the volume of  final promotional materials submitted to FDA for review and FDA’s  responses to draft materials submitted by drug companies for advisory  review. Based on interviews with DDMAC officials and our review of  related documentation, we determined that these data were sufficiently  reliable for the purposes of our report. We also interviewed DDMAC  officials to obtain information about the process they use to prioritize their  oversight efforts and the methods they use to identify potential  promotional violations. We reviewed pertinent laws, regulations, and  guidance applicable to each of these activities. We contacted  representatives from the Pharmaceutical Research and Manufacturers of  America (PhRMA), the American Medical Association (AMA), and the  Accreditation Council for Continuing Medical Education (ACCME) to  obtain their views on requirements related to off-label promotion. In  addition, we reviewed various academic studies on off-label use and  promotion.
To determine actions taken to address off-label promotion, we obtained all  of the 117 regulatory letters FDA issued during calendar years 2003  through 2007 in response to violative promotions of prescription drugs. We  reviewed the content of these letters to determine how often they cited  off-label promotion versus other promotional violations. In addition, we  further analyzed the letters that cited off-label promotion to determine the  specific circumstances of each violation, the market to which the  promotion was directed, and whether the drug company had additional  contact with FDA concerning violative promotional materials. We also  reviewed all letters that FDA issued during calendar years 1997 through  2007 for violative promotions of drugs to determine if any of the off-label  promotions we identified during calendar years 2003 through 2007 were  repeat violations. We did not evaluate the appropriateness of cited  violations or evaluate the legal sufficiency of these letters. We interviewed  DDMAC officials on the process of issuing regulatory letters and also  confirmed that our list of regulatory letters citing off-label promotion was  complete and accurate. We reviewed available FDA documentation to  determine the length of time taken to issue regulatory letters citing off- label promotion. To calculate this time period, we used the date on which  FDA first drafted a regulatory letter as the earliest date in this process and  the date the letter was issued as the last date in the process. We discussed  drug companies’ responses to the regulatory letters and the monitoring of  these responses with DDMAC officials. We supplemented this information  by reviewing documentation associated with the regulatory letters to  obtain additional details about drug companies’ response and compliance  with any corrective actions requested by FDA. Finally, because they may  also become involved in investigations involving off-label promotion, we  interviewed officials at FDA’s Office of Chief Counsel (OCC) and Office of  Criminal Investigations (OCI) and HHS’s Office of Inspector General  (HHS-OIG). We also obtained information from DOJ’s Web site for  calendar years 2003 through 2007 to identify settlements between drug  companies and the federal government that involved off-label promotion.  Our examination was limited to FDA’s oversight of human drugs; we did  not examine FDA’s oversight of promotions for other types of products  under FDA’s jurisdiction. We also did not include information on FDA’s  review of draft materials submitted to the agency under the accelerated  approval process for new drugs to treat serious or life-threatening  illnesses, or for the approval of new drugs when human efficacy studies  are not ethical or feasible. We conducted our work from September 2007  through July 2008 in accordance with generally accepted government  auditing standards. Those standards require that we plan and perform the  audit to obtain sufficient, appropriate evidence to provide a reasonable  basis for our findings and conclusions based on our audit objectives. We  believe that the evidence obtained provides a reasonable basis for our  findings and conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: Before FDA will approve a new drug application (NDA), allowing the drug  to be marketed in the United States, its manufacturer must demonstrate to  FDA’s satisfaction that the drug is safe and effective for its intended use  and patient populations. The review process includes examination of the  proposed drug labeling, which specifically cites, among other things, the  conditions and population the drug has been approved to treat. After the  NDA and labeling are approved, any promotional materials used or  distributed by the drug companies must be consistent with and limited to  the information included in the approved labeling. Drug companies that  want to expand the approved uses for their products, and promote those  new uses, must submit new safety and effectiveness data and obtain FDA’s  approval prior to marketing them for new uses.
The Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes FDA to  regulate the promotion of prescription drugs. FFDCA and implementing  regulations require that prescription drug promotional materials not be  false or misleading. FDA has issued implementing regulations that  attempt to prevent overstatement in product claims and require balanced  disclosure of side effects, contraindications, and warnings. They state, in  part, that drug promotions may not recommend or suggest any use that is  not in the approved labeling. Any approved new drug promoted for an  off-label use is “misbranded” and in violation of FFDCA.
FDA has traditionally differentiated between industry-supported scientific  and educational activities that are otherwise independent and  nonpromotional from other industry activities that are neither. For drugs,  only the latter have been treated as labeling or advertising and therefore  subject to the applicable provisions of FFDCA and its implementing  regulations. In 1997, Congress passed the Food and Drug Administration  Modernization Act (FDAMA), which included a provision authorizing drug  manufacturers to disseminate journal articles and referenced publications  on off-label uses under certain conditions. The FDAMA provision expired  on September 30, 2006. However, on February 15, 2008, FDA released draft  guidance that recommends good practices for drug companies concerning  the dissemination of articles and publications that address off-label use.  Among other things, this draft guidance recommends that drug companies  limit such activities to the distribution of reprints of peer-reviewed  research from scientific or medical journals published by organizations  with editorial boards that use experts who have demonstrated expertise in  the subject of the article. The draft guidance also states that these reprints  should not be material that is written, edited, or otherwise influenced by  drug companies or individuals with financial ties to them, nor would false  or misleading information be allowed. While some aspects of the draft  guidance are similar to the FDAMA provision and its implementing  regulations, there are two key differences. The draft guidance does not  address, recommend, or suggest that (1) reprints of journal articles and  reference publications on off-label uses of drugs be previewed by FDA or  (2) supplemental NDAs containing new safety and effectiveness data on  the off-label use discussed in the reprint should be sent to FDA.
FDA regulates the content of all drug promotional materials and activities,  whether directed to medical professionals or consumers. These materials  and activities may take many forms, as shown in table 1.
FDA does not generally regulate the exchange of scientific information,  but when such information is provided by or on behalf of a drug company  regarding one of the company’s products, the information may be subject  to the labeling and advertising provisions of the law and regulations. For  example, while information provided at CME programs—such as medical  conferences and professional gatherings intended to enhance physicians’  knowledge and enable them to meet certain practice requirements—is not  generally subject to FDA regulation, it will be if the program has been  funded and substantially influenced by a drug company. Similarly, FDA’s  position is that companies may respond to unsolicited requests for  information from health care professionals, even if responding to requests  requires the companies to provide information regarding off-label uses.
As of March 2008, DDMAC had the equivalent of 44 full-time staff devoted  to overseeing prescription drug promotions. This oversight involves  reviews of submitted materials and monitoring and surveillance efforts.
The two types of promotional materials submitted to the agency for review  are:    Required submissions of final promotional materials: Drug companies  are required to submit all final materials associated with promotions to  FDA when they are first disseminated to the public. These materials  include everything that a drug company may use as part of a promotion,  such as print advertisements; professional slides, exhibit panels, and  reprints; and Internet promotions. Once submitted to FDA, promotional  materials are distributed to DDMAC staff. When a concern is identified,  the agency determines whether it represents a violation and merits a  regulatory letter.
Voluntary submissions of draft promotional materials: Drug companies  have the option of voluntarily submitting draft promotional materials to  FDA for advisory review. For example, they may exercise this option  before launching expensive promotions, such as a marketing campaign for  a new drug or a new television advertisement. For these draft materials,  FDA may provide the drug company with advisory comments to consider  before the materials are disseminated, particularly if claims are identified  that could violate applicable laws and regulations. As part of its  comments, FDA provides guidance to the drug company on how to  address the agency’s concerns regarding the promotional materials.
FDA supplements its reviews of final and draft material that drug  companies submit with monitoring and surveillance efforts. These efforts  include attending medical conferences, reviewing drug company Web  sites, and following up on complaints received.
Once DDMAC identifies a violation—whether it be detected through its  review processes or its monitoring and surveillance activities—it makes a  determination on whether to pursue regulatory action, by issuing an  untitled letter or a warning letter. The warning letter is issued for more  serious violations with regulatory significance and may lead to  enforcement action if corrections are not made. An untitled letter cites  violations that do not meet this threshold. Both types of regulatory letters  cite any identified violation and ask the drug company to cease  dissemination of the violative promotion and any other promotions with  the same or similar claims. A warning letter also goes a step further and  requests that the company take action to correct the misleading  impression left by the violative promotion. Such action may include  issuing a correction in the same media as the original violative promotion  or notifying appropriate health care professionals. DDMAC prepares these  regulatory letters and, prior to their issuance, OCC reviews and approves  them to ensure that the letters are legally sufficient and consistent with  agency policy. FDA generally posts regulatory letters on its Web site  within several days of issuance. Upon receiving either type of letter, drug  companies are requested to send FDA a written response within 10  business days. While FDA does not have explicit authority to require drug  companies to act upon regulatory letters, when matters raised in these  letters, particularly warning letters, are not resolved, the agency may  initiate enforcement action through DOJ, which could include seizures of  violative products and injunctions prohibiting the company from  continuing off-label promotions. In addition, the Food and Drug  Administration Amendments Act of 2007 authorizes FDA to impose civil  monetary penalties against anyone disseminating false or misleading DTC  advertisements, which could include promoting off-label use.
OCC provides legal opinions within FDA and participates in both civil and  criminal cases, including those related to off-label promotions. FDA’s OCI  conducts criminal investigations and may work closely with OCC as well  as HHS-OIG and DOJ in conducting off-label investigations.
We previously reported on shortcomings in FDA’s oversight of the  promotion of prescription drugs in DTC advertising. In 2002 we reported  that FDA’s oversight was generally effective but had limitations in halting  the dissemination of violative materials or in preventing companies from  repeatedly committing violations. We also reported that FDA took  increased time to issue regulatory letters, therefore prolonging the time  violative materials remained on the market. We recommended that HHS  expedite its issuance of regulatory letters to ensure that misleading  materials are withdrawn as soon as possible. In 2006, we reported that  FDA reviews a small portion of the DTC materials it receives. We also  reported that it did not have a process to systematically prioritize its  submissions for review. Consequently, we recommended that FDA  develop such a process for all of the materials it receives and track which  materials it has reviewed—a recommendation we believe remains valid.  We also reported that FDA was taking longer to issue regulatory letters  than it did in 2002 and we stated that the recommendation in our 2002  report—that the agency issue regulatory letters more quickly—remained  valid. In May 2008, we updated this work and testified that FDA still did  not systematically prioritize its review of all of the DTC materials it  receives and thus could not ensure that it was reviewing the highest- priority materials. We also noted that the amount of time it takes to issue  regulatory letters has continued to lengthen.
section_title: FDA’s Oversight of Off-Label Promotion Consists Primarily of Review of Materials Submitted by Drug Companies, but It Is Unlikely to Detect All Violations
paragraphs: The primary mechanism FDA uses to oversee off-label promotions is its  review of materials submitted by drug companies. 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. DDMAC staff use a process to prioritize their review of  submitted materials, but they do not apply this process systematically. In  addition, limitations in FDA’s oversight make it unlikely that it is able to  detect all off-label violations that occur. 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.
subsections: section_title: FDA’s Oversight Process Emphasizes Reviews of Materials Submitted by Drug Companies and Is Supplemented by Monitoring and Surveillance
paragraphs: 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. DDMAC staff examine submitted materials for a  variety of potential violations simultaneously, such as minimizing the risk  of the drug or overstating the safety or effectiveness of the drug, as well as  off-label promotions.
Although DDMAC staff are tasked with reviewing final versions of  materials that are required to be submitted and draft materials voluntarily  submitted for advisory review, officials emphasized that advisory review  of draft materials is particularly important. They said that this is because  the advisory review process encourages voluntary compliance and allows  FDA to identify potential violations, including off-label promotion, before  materials are disseminated to the public. FDA’s goal is to review all draft  materials submitted for advisory review. Consequently, DDMAC staff  spend the majority of their time reviewing and responding to these  voluntary submissions. DDMAC officials told us that responding to the  requests for advisory review can be very time consuming and labor  intensive because staff want to ensure that the agency identifies all  potential violations during this time.
To manage the workload associated with their reviews of final materials  that drug companies are required to submit and draft materials submitted  for advisory review, DDMAC staff rely on a process to prioritize their  reviews that is intended to address those submissions that have the  greatest potential to impact public health. DDMAC officials told us that  DDMAC’s priorities are regularly updated to reflect changes in agency  needs and legal requirements. 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.
DDMAC officials acknowledged that this process for prioritizing its  reviews is not systematically applied to all of the materials it receives.  Absent a systemic approach, DDMAC staff sort through large volumes of  materials submitted and use the process to review as many submissions as  possible. During their reviews of both final and draft materials, staff may  use their clinical knowledge about a particular type of drug and its history  to help determine if a submission contains an off-label promotion. DDMAC  staff are organized into therapeutic review groups by drug category, such  as allergy medications, to maximize individual knowledge about specific  drugs and the marketing issues related to those drugs. Staff are assigned  promotional materials based on their therapeutic review group. DDMAC  officials told us that this organization allows staff to develop familiarity  with certain types of drugs, making them knowledgeable about  information in the approved labeling and better able to identify off-label  promotions.
In addition to its reviews of submitted materials, FDA also engages in  monitoring and surveillance efforts. These efforts are intended to detect  violations that could not be identified through FDA’s reviews—such as  violative oral statements made by sales representatives in discussions with  physicians. These efforts may also identify violations that may be missed  by FDA’s review of submitted materials. As part of their monitoring and  surveillance efforts, DDMAC and other FDA staff may attend educational  events, such as CME programs, to monitor for inappropriate promotions.  For example, an FDA official attending a CME conference might obtain a  brochure discussing off-label use, which should have been submitted to  the agency but was never provided to the agency. AMA and ACCME  officials acknowledged that even though there are safeguards built into the  CME accreditation process to ensure presenter independence and CME  compliance with FDA regulations, violations may still occur. FDA’s  monitoring and surveillance efforts also include reviewing and following  up on complaints it receives. These may be submitted by a drug company’s  competitors, health care providers, consumers, and former drug company  personnel who have knowledge about violative promotions. DDMAC  officials said that these complaints may inform FDA of potentially  inappropriate oral promotions and also provide a backup system for  identifying violations that may be on submitted materials that FDA never  examined.
section_title: Limitations in FDA’s Oversight Process Make It Unlikely That All Off-Label Violations Are Detected
paragraphs: 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. For example, DDMAC does not track the number of drafts it  receives for advisory review. Despite its goal of reviewing all such  submissions, DDMAC is unable to do so because, as officials explained,  some drug companies release their promotions before they receive FDA’s  advisory comments. However, DDMAC does track the number of letters it  issues in response to the draft submissions staff are able to review.  Conversely, DDMAC tracks the number of final submissions it receives but  does not track the number of the final submissions staff review. In 2006,  GAO recommended that FDA track which materials it has reviewed but  the agency has not taken action to address this recommendation. For  example, DDMAC officials could not provide us with information on the  prevalence of off-label promotions among material reviewed, the time it  takes to complete reviews, or the status of their reviews. DDMAC officials  said that obtaining this type of information is not currently possible due to  the design of existing systems. As these are the issues that led us to our  2006 recommendation, we believe that this recommendation remains valid.
In addition, DDMAC officials told us that they receive substantially more  materials than the agency can review. FDA received approximately  277,000 final promotional materials that drug companies were required to  submit during calendar years 2003 through 2007. As shown in figure 1,  FDA has received a steadily increasing number of final promotional  materials during this time—the annual number increased from just over  40,000 in 2003 to over 68,000 in 2007. DDMAC officials generally attribute  this growth to increases in DTC advertising as well as the increase in  materials that drug companies are using to promote more complex new  drugs.
DDMAC and other FDA officials acknowledge that it is very difficult, if not  impossible, for FDA’s supplementary monitoring and surveillance efforts  to identify all off-label promotion that may occur. This is because  inappropriate promotion can take many forms and occur in a myriad of  places. For instance, DDMAC and other FDA staff attend only a small  number of the thousands of CME programs that occur each year. FDA is  further challenged by the possibility that off-label promotional material,  unrelated to a CME presentation, may be available to participants at  nearby exhibition booths that drug companies often sponsor in  conjunction with CME events. Although drug companies are required to  submit such material to FDA for review, they might not do so or FDA  might not review these materials until the conference or activity is  completed. DDMAC officials told us that they consistently follow up on  all complaints received as part of their monitoring and surveillance efforts,  including those related to off-label promotion. According to DDMAC  officials, FDA received and investigated an average of 150 complaints  annually on possible promotional violations from 2003 through 2007.  However, they could not provide us with data on the total number of their  monitoring and surveillance efforts because this information is not  tracked.
FDA’s monitoring and surveillance efforts are further complicated by  difficulties in assessing the merits of potential violations and the validity of  complaints received. For example, according to FDA officials, the agency  does not have sufficient authority to gather the key evidence necessary to  determine whether educational activities are independent of the influence  of drug companies. For example, DDMAC may not be able to determine  whether a speaker at a CME event has been paid by the drug company to  promote a drug for off-label uses. In such instances, DDMAC officials told  us that they may work with other agencies, such as HHS-OIG and DOJ,  which have the necessary investigative tools, such as subpoena authority,  to investigate. Similarly, complaints can be difficult to validate. For  example, a physician may complain to FDA about promotional material  that was shown during a sales visit, but FDA staff may not be provided or  have access to the material and therefore may be unable to determine if its  use was violative. In addition, because FDA allows the exchange of  information upon a request from a physician, it may be difficult to  determine if information a sales representative provided orally to a  physician was not requested. Without physicians’ complaints, however,  FDA would be unaware of these violative conversations. FDA not only  depends on a physician’s initiative to make a complaint but also on the  physician’s knowledge of when such conversation is inappropriate.
section_title: Regulatory and Enforcement Actions Have Been Taken in Response to Off-Label Promotions
paragraphs: 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. Most of the off-label  promotional violations cited in those regulatory letters were identified  through FDA’s review of required drug company submissions. The  promotional violations typically were targeted toward physicians and  other medical professionals. According to DDMAC officials and our own  analysis of correspondence between drug companies and FDA, drug  companies have generally complied with the agency’s directives as  suggested in these letters, but may not have always done so in a timely  manner. 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. According to DDMAC officials, they did not refer  any violations to DOJ for enforcement action during 2003 through 2007.  However, DOJ initiated civil and criminal enforcement actions in response  to instances involving off-label promotion it identified from other sources.  DOJ actions resulted in 11 settlements with drug companies that dealt, at  least partially, with off-label promotion. While none of these were initiated  by DDMAC, entities within FDA were ultimately involved in their  resolution.
subsections: section_title: FDA Issued 42 Regulatory Letters Citing Off-Label Promotion in the Past 5 Years
paragraphs: Overall, FDA issued 117 regulatory letters for promotional violations  during calendar years 2003 through 2007. However, according to DDMAC  officials, there were more identified violations than those for which FDA  issued regulatory letters because FDA prioritizes violations. Specifically,  they said that in this regard, FDA’s first priority is to issue warning letters  because they generally address the most serious violations. For less  serious violations—those involving untitled letters—these officials said  that the issuance of such letters may be delayed, depending on the  agency’s workload. Our analysis of the 117 regulatory letters indicates that  off-label promotion was the third most common violation, cited in 42, or  approximately 36 percent, of the regulatory letters, as shown in table 2.
Our analysis of the 42 regulatory letters citing off-label promotion  indicates that review of submissions was the primary manner in which  FDA identified off-label promotion. Specifically, for 31 of these letters, or  74 percent, FDA identified at least one violative promotion through its  review of required submissions of final promotional materials. Fourteen  letters indicate that FDA identified at least one violative promotion  through monitoring and surveillance activities. For more information on  the off-label promotions cited in the 42 letters, see appendix I.
Half of the promotions cited in the 42 regulatory letters were targeted  toward physicians and other medical professionals. Our analysis showed  that 21 of the 42 off-label regulatory letters were issued in response to off- label promotions that included materials such as professional journal ads  and exhibit panels, which solely targeted physicians and other medical  professionals. Seven letters were issued in response to promotions  directed solely to consumers, such as DTC magazine, television, or radio  advertisements. The remaining 14 letters addressed promotions directed  toward both medical professionals and consumers, such as product Web  sites, as shown in figure 2. only (7)
Medicl profession nd consumer (14)
Medicl profession only (21)
Our analysis of FDA documents related to the 42 regulatory letters citing  off-label promotion indicated that it took FDA an average of about   7 months to issue the letters after DDMAC staff first drafted the letters.  For example, on March 7, 2006, FDA drafted a warning letter to Alcon, Inc.  for off-label promotion, among other things. Over 7 months later, on  October 20, 2006, FDA issued the letter. In 2002, GAO recommended that  the agency issue regulatory letters more quickly. Because violative  materials remain in circulation prior to the issuance of related regulatory  letters, the length of time it takes FDA to issue these letters limits their  effectiveness. As these are the issues that led us to our 2002  recommendation, we believe that this recommendation remains valid.
According to DDMAC officials, drug companies sent FDA written  responses to the regulatory letters, and in most instances, they ceased  dissemination of identified violative materials upon receipt of a regulatory  letter. However, DDMAC officials noted that there were occasions when  they engaged in extensive discussions with drug companies that  challenged the agency’s assessment of a violation or the action requested  in the regulatory letter. For example, a drug company may seek to  negotiate with FDA in order to avoid having to take corrective actions,  such as retracting an expensive DTC advertisement. DDMAC officials told  us that during calendar years 2003 through 2007, FDA did not have to  reverse any of its regulatory letter decisions as a result of such  negotiations. Although FDA cannot ensure that a drug company has  ceased dissemination of all violative materials related to a regulatory  letter, it obtains a company’s written agreement to stop dissemination of  such materials, ensures that the list of materials a company is to stop  disseminating is comprehensive, and reviews any new material submitted  by the company for 6 months after issuance of a regulatory letter.
Twenty-three of the 42 off-label regulatory letters issued were warning  letters, which, according to DDMAC officials, are issued for more serious  violations than those cited in untitled letters. Ultimately, they said all but  one company—which was issued a warning letter on May 25, 2007, and  remained in negotiations with FDA as of April 22, 2008—had taken the  necessary action requested in these warning letters. Consequently,  DDMAC did not refer any violations regarding off-label promotions to DOJ  for enforcement action. However, corrective action may not have always  occurred in a timely manner. Our review of FDA documentation related to  the 23 warning letters showed that it took drug companies an average of   4 months to implement corrective action from the time FDA issued the  regulatory letter. For example, on September 14, 2006, FDA issued a  warning letter to Reliant Pharmaceuticals, Inc. for, among other things,  off-label promotion of its drug Rythmol SR. Following the company’s  formal response letter on September 29, 2006, FDA and Reliant  Pharmaceuticals, Inc. participated in at least three teleconferences and  FDA wrote two letters in response to Reliant’s proposed corrective action.  Over 7 months after the letter was issued, the drug company disseminated  the first set of corrective materials on April 17, 2007.
While DDMAC officials told us that drug companies have generally  complied with FDA requests in the 42 regulatory letters, such letters do  not prevent drug companies from repeatedly disseminating violative  promotional materials. Our analysis of the 42 regulatory letters showed  that for 11 of the 42 drugs cited in those letters for off-label promotion,  FDA had issued regulatory letters citing off-label promotion in the past, as  shown in table 3. For example, on March 18, 2004, Wyeth Pharmaceuticals  was issued an untitled letter citing off-label promotion, among other  things, for its drug Effexor XR. Prior to that letter, FDA had issued two  other regulatory letters issued for off-label promotion of Effexor XR and  Effexor, a related drug, on October 11, 2000, and June 25, 1997,  respectively. Additionally, in another 2 of the 42 drugs FDA had prior  communication with the drug companies about off-label promotion  concerns.
section_title: Eleven Settlements Related to Off-Label Promotion Have Occurred in the Past 5 Years
paragraphs: 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. However, in the same time  period, DOJ pursued a number of alleged violations in response to off- label promotion that it identified from other sources. 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. These settlements involved  the types of promotional practices that are most difficult for FDA to  identify, such as violative discussions between physicians and drug  company sales representatives. For example, at least 3 of the settlements  involved specific allegations of off-label promotion between sales  representatives and physicians. For more information on the alleged  actions by drug companies, see appendix II.
The resulting monetary settlements ranged from almost $10 million to over  $700 million. For example, in September 2007, Bristol-Myers Squibb  Company agreed to pay over $500 million for, among other things,  promoting its drug Abilify—approved to treat schizophrenia and bipolar  disorder—for pediatric use and for the treatment of dementia-related  psychosis. In this instance, DOJ alleged that Bristol-Myers Squibb  Company created a group of salespeople to target nursing homes where  dementia is much more prevalent than schizophrenia or bipolar disorder.  See table 4 for a summary of the 11 settlements negotiated by DOJ.
FDA had previously taken action against the drug companies with which  DOJ reached settlements. We reviewed regulatory letters that FDA issued  to drug companies from calendar years 1997 through 2007 for the same 12  drugs cited in the 11 settlements. This review indicated that, since 1997,  FDA had identified promotional violations and issued one or more  regulatory letters to drug companies for 7 of the 12 drugs. Of these 7 drugs,  drug companies received regulatory letters for 5 drugs that cited off-label  promotion. For 1 of these 5 drugs, the drug company received an FDA  regulatory letter in June 2001 citing off-label promotion that was directly  linked to the settlement. In response to the letter, the drug company  assured FDA that the cited violation was an isolated incident. In the 2006  settlement, the company agreed, among other things, to plead guilty to  criminal conspiracy to make false statements to FDA regarding its  promotion cited in the 2001 regulatory letter. Specifically, the company  acknowledged in the settlement that it knowingly misled FDA by claiming  the violation was an isolated incident instead of a nationwide campaign.  The regulatory letters FDA issued to drug companies for the other 4 drugs  cited companies for off-label promotions that were not cited as the basis  for the settlement. For example, for 1 of these 4 drugs, FDA issued an  untitled letter to the drug company in September 2000, citing off-label  promotion in a submitted DTC television advertisement. The related  December 2005 DOJ settlement, however, was in response to off-label  promotion conducted by the drug company’s sales representatives and not  the DTC advertisement cited in FDA letter. Table 5 provides information  on the 12 drugs cited in the 11 settlements for off-label promotion and any  prior regulatory letters issued by FDA.
While DDMAC did not refer the violations to DOJ that resulted in the 11  settlements, it participated in their resolution. Specifically, DDMAC  officials told us that they provided input to DOJ, such as information on  whether the matter promoted off-label use or was otherwise violative, as  well as opinions on the seriousness of the violation. Similarly, FDA’s OCC  and OCI participated in almost all of the investigations by providing legal  counsel and conducting criminal investigations, respectively. Specifically,  in all 11 settlements, one or more of FDA’s offices—OCC, OCI, or both— were involved. In many of those instances, FDA became involved at DOJ’s  request and remained involved from the preliminary investigation through  the final settlement. FDA’s OCC and OCI officials told us that these  investigations can be long term and very resource intensive. According to  an FDA official, FDA is currently working on approximately 40  investigations regarding off-label promotion.
section_title: Agency Comments and Our Evaluation
paragraphs: HHS reviewed a draft of this report and provided comments, which are  reprinted in appendix III.
HHS’s comments focused on our discussion of FDA’s process for  prioritizing and tracking promotional materials submitted by drug  companies for review. First, HHS raised concerns with our finding that  DDMAC staff do not systematically prioritize all of the materials they  receive. HHS stated that DDMAC staff apply prioritization criteria  systematically to, among other things, the advisory submissions they  receive. In addition, HHS stated that DDMAC staff also use criteria to  determine which of the submissions of disseminated materials—that is,  those final materials submitted for review—should be examined. However,  we found no evidence that FDA systematically prioritizes all of the  submissions it receives. We found that DDMAC staff do not screen all of  the tens of thousands of final promotional materials they receive per year  to determine which ones need to be reviewed. This means that FDA is not  systematically applying its prioritization criteria to the majority of  submissions the agency receives. We recognize that the volume of  materials FDA receives presents a challenge for completing a detailed  review of each submission, but without a systematic application of its  criteria to screen submissions, it cannot be certain that it is reviewing the  highest-priority materials or that violative materials are not being  circulated. Applying the current criteria to the submissions DDMAC staff  review, even if done consistently, is not the same as systematically  screening all submissions in order to determine which ones should be  reviewed.
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. HHS said that such a system  would not enable DDMAC to more efficiently regulate off-label promotion.  We disagree. 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 short, a simple  tracking system would provide key information for managing the program.
HHS did not comment on our reiteration of our 2002 recommendation that  the agency issue regulatory letters more quickly. HHS also provided  technical comments, which we have incorporated as appropriate.
As agreed with your office, unless you publicly announce its contents  earlier, we plan no further distribution of this report until 30 days after its  issuance date. At that time, we will send copies to the Secretary of HHS,  the Commissioner of FDA, and other interested parties. In addition, the  report will be available at no charge on GAO’s Web site at  http://www.gao.gov.
If you or your staff have any questions about this report, please contact me  at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of  Congressional Relations and Public Affairs may be found on the last page  of this report. GAO staff who made major contributions to this report are  listed in appendix IV.
section_title: Appendix I: FDA Regulatory Letters That Cited Off-Label Promotion, Calendar Years 2003-2007
subsections: section_title: Date of letter Drug company
paragraphs: Purdue Pharma L.P.
Hoffmann-La Roche, Inc.
Gilead Sciences, Inc.
Amgen, Inc.
Actelion Pharmaceuticals  US, Inc.
Pfizer, Inc.
Reliant Pharmaceuticals,  Inc.
BioMarin Pharmaceuticals,  Inc.
Alcon Research, Ltd.
Ligand Pharmaceuticals,  Inc.
Treatment of persistent or  recurrent cutaneous T-cell  lymphoma in particular patients  (Ontak) and treatment of  cutaneous manifestations of  cutaneous T-cell lymphoma in  certain patients (Targretin)
Treatment of T-cell lymphoma  in a broader patient population  (Ontak and Targretin)
Cephalon, Inc.
Alcon Laboratories, Inc.
DUSA Pharmaceuticals,  Inc.
Allergan, Inc.
Pharmaceuticals, Inc.
Santen, Inc.
Genpharm, Inc.
Alcon Research, Ltd.
Treatment of eye infections  caused by specific  microorganisms in the  conditions of corneal ulcers  and conjunctivitis (Ciloxan)
Treatment of otitis media and  otitis externa (Ciloxan)
Acute treatment of migraine  headaches with or without aura  and the acute treatment of  cluster headache episodes  (D.H.E. 45)
Treatment of status migrainosis  or intractable migraine   (D.H.E. 45)
Treatment of major depressive  disorder (Effexor XR)
Treatment of normal periodic  feelings of low interest or  energy (Effexor XR)
Hoffman-La Roche, Inc.
Alcon Research, Ltd.
Takeda Pharmaceuticals  North America, Inc.
Treatment of actinic keratoses  in combination with cryotherapy In this case, off-label promotional activities were cited for two different drugs. Therefore, information  on the approved condition and the off-label promotion cited for both drugs is presented.
In this case, violative promotional activities were cited for two different drugs, but off-label promotion  was cited for only one of these drugs. Only information on the approved condition and the off-label  promotion cited for that drug is presented.
section_title: Appendix II: Examples of Alleged Drug Company Actions Cited in Settlements Involving Off-Label Promotion
paragraphs: Encouraged sales representatives to provide one-on-one sales  pitches to physicians about off-label uses.
Sponsored “independent medical education” events on off-label uses  and misled the medical community on the content and lack of  independence.
Trained sales representatives to prompt or bait questions by  physicians to promote the drug for off-label uses.
Encouraged sales representatives to send medical letters and other  marketing materials that were not requested by physicians in order to  promote off-label uses.
Conspired with a medical device manufacturer to market computer  software packages to diagnose AIDS-wasting, although the device  was not approved by FDA for this use. The drug company then tried  to increase the market for such devices in order to increase the  market for the drug.
Offered physicians all-expense paid trip to encourage off-label  prescriptions.
Conspired to make false statements to FDA regarding its improper  promotional activity in response to FDA’s inquiry regarding certain  illegal promotional activities by the company’s sales representatives  at a national medical conference for oncologists. These false  statements were designed to reassure FDA that the promotional  activities were isolated and not directed by the home office, when  they were actually widespread and part of the national marketing  plan.
Conducted a clinical trial, which failed to establish statistically  significant evidence of benefit, but published press releases  indicating false outcomes from the clinical trials.
Conducted sales of the drug from August 2002 through January 2003  that were attributable to the prescribing of the drug for the treatment  of Idiopathic Pulmonary Fibrosis, an off-label use.
Promoted drug for off-label uses, such as anti-aging, cosmetic use,  and athletic performance enhancement.
Falsely marketed to physicians by suggesting that it was FDA  approved for treating a different type of cancer than approved for,  and was listed as medically accepted in the compendia for treating  other types of cancers.
Used illegal kickbacks to induce physicians to prescribe the drug and  paid them to attend dinners or conferences on off-label uses.
Targeted pediatricians and urged them to use the drug as a  treatment for diaper rash—the drug is approved as a fungicide and  not for treating children under 10 years of age.
Promoted the drug as less addictive, less subject to abuse, and less  likely to cause withdrawal symptoms than other pain medications  without FDA approval.
Made sales calls to physicians, who did not specialize in the area that  the drug was approved for, and promoted the drug for off-label  treatments and distributed off-label promotional materials.
Paid a psychiatrist to give talks around the country to promote the  drug for off-label uses.
Promoted the sale of the drug for pediatric use and dementia-related  psychosis, both off-label uses.
section_title: Appendix III: Comments from the Department of Health and Human Services
section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Acknowledgments
paragraphs: In addition to the contact named above, Geri Redican-Bigott,   Assistant Director; Cathy Hamann; Mollie Hertel; Julian Klazkin;   Michaela M. Monaghan; and Pauline Seretakis made key contributions to  this report.