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 However, on February 15, 2008, FDA released draft guidance that recommends good practices for drug companies concerning the dissemination of articles and publications that address off-label use. Among other things, this draft guidance recommends that drug companies limit such activities to the distribution of reprints of peer-reviewed research from scientific or medical journals published by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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

Summary: 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. 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.