Prescription Drugs
FDA's Oversight of the Promotion of Drugs for Off-Label Uses Gao ID: GAO-08-835 July 28, 2008The 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.
GAO-08-835, Prescription Drugs: FDA's Oversight of the Promotion of Drugs for Off-Label Uses
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Report to the Ranking Member, Committee on Finance, U.S. Senate:
United States Government Accountability Office:
GAO:
July 2008:
Prescription Drugs:
FDA's Oversight of the Promotion of Drugs for Off-Label Uses:
GAO-08-835:
GAO Highlights:
Highlights of GAO-08-835, a report to the Ranking Member, Committee on
Finance, U.S. Senate.
Why GAO Did This Study:
The Food and Drug Administration (FDA), an agency within the Department
of Health and Human Services (HHS), regulates the promotion of
prescription drugs to ensure that promotional materials are not false
and misleading and that they comply with applicable laws and
regulations. Among other things, FDA prohibits drug companies from
promoting drugs for off-label uses”that is, for a condition or patient
population for which the drug has not been approved or in a manner that
is inconsistent with information found on the approved drug label.
Although doctors may prescribe drugs off label, it is not permissible
for drug companies to promote drugs for off-label uses. FDA may take
regulatory actions for violations, and may also pursue enforcement
action through the Department of Justice (DOJ).
GAO was asked for information about the promotion of drugs for off-
label uses. GAO reviewed (1) how FDA oversees the promotion of off-
label uses of prescription drugs and (2) what actions have been taken
to address off-label promotions. GAO examined documentation related to
the promotion of drugs for off-label uses and FDA correspondence with
drug companies on identified violations and obtained information from
DOJ on relevant actions. GAO also interviewed officials at FDA and the
HHS Office of Inspector General and representatives of national medical
and pharmaceutical associations.
What GAO Found:
FDA oversees drug promotion for off-label uses by reviewing promotional
materials that drug companies submit to the agency. However, because
FDA does not have separate oversight activities to specifically capture
off-label promotion, its oversight occurs within a broader process that
targets a variety of promotional violations. Furthermore, FDA reports
it is unable to review all submissions because of the volume of
materials it receives and prioritizes its reviews in order to examine
those with the greatest potential impact on human health. However, FDA
does not prioritize its reviews in a systematic manner but rather
relies on its staff to sort through large volumes of material and
select submissions for review. FDA is also hampered by the lack of a
system that consistently tracks the receipt and review of submitted
materials. To address these shortcomings, GAO recommended in 2006 that
FDA track which materials it has reviewed. FDA has not acted on this
recommendation and still lacks a standardized tracking system to
monitor its review efforts. GAO believes that this recommendation
remains valid. In addition to its reviews, FDA conducts monitoring and
surveillance to identify violations that would not be identified
through its review of submitted material”for instance, discussions
between doctors and sales representatives. These efforts are also
limited because FDA cannot observe all off-label promotion activities
as they can take many forms and occur in a myriad of places.
FDA and DOJ have taken regulatory and enforcement actions against drug
companies in response to off-label promotions. During calendar years
2003 through 2007, FDA issued 42 regulatory letters in response to off-
label promotions requesting drug companies to stop dissemination of
violative promotions. FDA took an average of 7 months to issue these
letters from the time it first drafted them. In addition, drug
companies that were cited for more serious violations took an average
of 4 months to take the corrective actions requested. While FDA did not
refer any of these violations to DOJ for enforcement action, during
calendar years 2003 through 2007, DOJ settled both civil and criminal
cases that involved, at least partially, off-label promotion. These
actions were initiated as a result of violations identified by sources
other than FDA and resulted in 11 settlements.
In commenting on a draft of this report, HHS raised concerns with GAO‘s
assessment that FDA does not systematically prioritize all of the
promotional materials it receives. It also stated that a tracking
system would not improve the agency‘s ability to identify promotional
violations. GAO found that FDA does not screen all promotional
materials. GAO continues to believe that a tracking system would help
ensure that staff screen all material received, facilitate a more
systematic approach to FDA‘s reviews, and help the agency manage the
program.
To view the full product, including the scope and methodology, click on
[hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-08-835]. For more
information, contact Marcia Crosse at (202) 512-7114 or
crossem@gao.gov.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
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:
Regulatory and Enforcement Actions Have Been Taken in Response to Off-
Label Promotions:
Agency Comments and Our Evaluation:
Appendix I: FDA Regulatory Letters That Cited Off-Label Promotion,
Calendar Years 2003-2007:
Appendix II: Examples of Alleged Drug Company Actions Cited in
Settlements Involving Off-Label Promotion:
Appendix III: Comments from the Department of Health and Human
Services:
Appendix IV: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: Examples of Drug Company Promotions:
Table 2: Frequency of Violations in 117 Regulatory Letters, Calendar
Years 2003-2007:
Table 3: Drugs for Which FDA Cited Off-Label Promotion in More Than One
Regulatory Letter:
Table 4: Settlements Involving Off-Label Promotion, Calendar Years 2003-
2007:
Table 5: FDA Regulatory Letters Issued during Calendar Years 1997
through 2007 for Drugs Cited in Settlements, Involving Promotional
Violations, Calendar Years 2003-2007:
Figures:
Figure 1: Number of Final Promotional Materials Submitted to FDA,
Calendar Years 2003-2007:
Figure 2: Targeted Audience for Off-Label Promotions:
Abbreviations:
ACCME: Accreditation Council for Continuing Medical Education:
AMA: American Medical Association:
CME: Continuing Medical Education:
DDMAC: Division of Drug Marketing, Advertising, and Communications:
DOJ: Department of Justice:
DTC: Direct-to-consumer:
FDA: Food and Drug Administration:
FDAMA: Food and Drug Administration Modernization Act:
FFDCA: Federal Food, Drug, and Cosmetics Act:
HHS: Department of Health and Human Services:
NDA: New Drug Application:
OCC: Office of the Chief Counsel:
OCI: Office of Criminal Investigation:
OIG: Office of Inspector General:
PhRMA: Pharmaceutical Research and Manufacturers of America:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
July 28, 2008:
The Honorable Charles E. Grassley:
Ranking Member:
Committee on Finance:
United States Senate:
Dear Senator Grassley:
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.[Footnote 1] 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.[Footnote 2] 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.[Footnote 3] 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.[Footnote 4]
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.[Footnote 5]
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.
[Footnote 6] 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.[Footnote 7] 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.[Footnote 8] 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.
Results in Brief:
FDA's review of the final and draft versions of promotional materials
submitted to the agency by drug companies is its primary mechanism for
overseeing the promotion of drugs for off-label uses. The agency does
not have separate oversight activities designed specifically for off-
label promotion. Instead, its oversight of off-label promotion occurs
within a broad oversight process that targets all promotional
violations. According to DDMAC officials, staff rely on a process to
prioritize their review of submissions that is intended to address
those submissions that have the greatest potential to impact public
health. However, because DDMAC staff are not able to examine all
submissions to the agency, this process is not systematically applied
to all submissions. In addition, limitations in FDA's oversight process
make it unlikely that the agency is able to detect all off-label
violations that occur. FDA lacks a standardized tracking system to
manage its reviews. In 2006, GAO recommended that FDA track which
materials it has reviewed and the agency has not taken action to
address this recommendation. However, FDA still does not track all
submissions or the status of reviews, which further impedes its efforts
to identify any potential promotional violations, including off-label
promotion. As these are the issues that led us to our 2006
recommendation, we believe that this recommendation remains valid.
DDMAC officials also told us that while they review most of the drafts
submitted for advisory review, they can only review a small portion of
final materials submitted for review. They attribute this to the high
volume of materials submitted--over 68,000 final submissions were
received in calendar year 2007 alone. In addition to its review of
submitted materials, FDA has limited monitoring and surveillance
efforts that are intended to detect violations that may be missed or
would not be detected through FDA's review processes. However, the
extent and variety of promotional activities that occur make it
difficult for FDA to oversee them in a comprehensive manner. For
example, FDA staff can only attend a small number of the thousands of
continuing medical education (CME) activities that take place every
year and depend on voluntary complaints from physicians to identify off-
label promotions, such as statements made by sales representatives in
physicians' offices when the information was not requested by the
physician.
FDA and DOJ have taken regulatory and enforcement action 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 promotion, which was the third most common promotional violation
identified by FDA during this time frame. Our analysis of FDA
documentation showed that it took FDA an average of about 7 months to
issue the 42 regulatory letters--19 untitled letters and 23 warning
letters--from the time these letters were first drafted. Because
violative materials remain in circulation prior to the issuance of
regulatory letters, the length of time it takes FDA to issue these
letters limits their effectiveness. In 2002, GAO recommended that the
agency issue regulatory letters more quickly. As these are the issues
that led us to our 2002 recommendation, we believe that this
recommendation remains valid. According to DDMAC officials and our
analysis, drug companies have generally complied with the agency's
proposed actions as suggested in these letters. For example, in most
instances, drug companies ceased dissemination of identified violative
materials upon receipt of a regulatory letter. However, we found that
it took drug companies an average of about 4 months to take corrective
actions in response to 23 warning letters that were issued for the more
serious violations. DDMAC officials told us that because drug companies
have generally complied with FDA's requests in the untitled and warning
letters, they have not taken any enforcement action through referrals
to DOJ. However, we found that during the same time period, DOJ took
action against drug companies in response to violative off-label
promotions. DOJ enforcement action resulted in 11 settlements with drug
companies that included allegations of off-label promotion. These
settlements often involved promotional practices that are more
difficult for FDA to detect, such as violative discussions between
physicians and drug company sales representatives. While none of these
actions were initiated by DDMAC, the agency's DDMAC, OCC, and OCI were
ultimately involved in their resolution.
In commenting on a draft of this report, HHS raised concerns with our
assessment that FDA's prioritization process is not systematically
applied to all of the promotional materials it receives. However, we
found that FDA does not screen all of the tens of thousands of final
promotional materials it receives per year to determine which ones need
to be reviewed. Without a systematic application of FDA's criteria to
every submission, the agency cannot be certain that it is reviewing the
highest-priority materials submitted or that violative materials are
not being circulated. HHS also stated that a tracking system would not
improve the agency's ability to identify promotional violations. We
disagree. We continue to believe that a tracking system would help
ensure that staff systematically prioritize all materials and would
provide key information for managing the program. HHS also provided
technical comments, which we incorporated as appropriate.
Background:
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.[Footnote 9] FFDCA and
implementing regulations require that prescription drug promotional
materials not be false or misleading.[Footnote 10] 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.[Footnote 11] Any approved new drug promoted for an
off-label use is "misbranded" and in violation of FFDCA.[Footnote 12]
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.
[Footnote 13] 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.
[Footnote 14] 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.[Footnote 15]
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.
Table 1: Examples of Drug Company Promotions:
Type of promotion: Printed materials;
Method of promotion:
* Brochures;
* Magazine advertisements;
* Professional journal advertisements.
Type of promotion: Other media;
Method of promotion:
* Television and radio advertisements;
* Web sites.
Type of promotion: Oral statements;
Method of promotion:
* Discussions between physicians and drug company representatives in
physicians' offices;
* Presentations by drug company representatives at conference booths;
* Speeches at drug-company-sponsored events.
Source: GAO.
[End of table]
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.[Footnote 16] 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.[Footnote 17]
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.[Footnote 18] 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.[Footnote 19]
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.[Footnote 20] 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.[Footnote 21] 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.[Footnote 22]
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.[Footnote 23] 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.[Footnote 24] 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.[Footnote
25] 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.[Footnote 26] We also noted that the amount of time
it takes to issue regulatory letters has continued to lengthen.
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:
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.
FDA's Oversight Process Emphasizes Reviews of Materials Submitted by
Drug Companies and Is Supplemented by Monitoring and Surveillance:
The primary mechanism FDA uses to oversee the promotion of drugs for
off-label uses is to review promotional materials submitted to the
agency by drug companies. 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
risk information;
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;[Footnote 27]
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.
Limitations in FDA's Oversight Process Make It Unlikely That All Off-
Label Violations Are Detected:
It is unlikely that FDA can detect all off-label promotion that occurs
because of limitations in its oversight process for reviewing the
promotion of prescription drugs. FDA's oversight is hampered by the
lack of a system or process that consistently tracks its receipt and
review of submitted materials. 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.[Footnote 28] 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.
Figure 1: Number of Final Promotional Materials Submitted to FDA,
Calendar Years 2003-2007:
[See PDF for image]
This figure is a vertical bar graph depicting the following data:
Fiscal year: 2003;
Number of submissions: 40,097.
Fiscal year: 2004;
Number of submissions: 52,848.
Fiscal year: 2005;
Number of submissions: 54,661.
Fiscal year: 2006;
Number of submissions: 61,013.
Fiscal year: 2007;
Number of submissions: 68,288.
Source: FDA.
[End of figure]
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.[Footnote 29] 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.[Footnote 30]
Regulatory and Enforcement Actions Have Been Taken in Response to Off-
Label Promotions:
FDA and DOJ have taken regulatory and enforcement actions against drug
companies for violative off-label promotions. During calendar years
2003 through 2007, FDA issued 42 regulatory letters--23 warning letters
and 19 untitled letters--in response to off-label promotions. However,
it took FDA an average of about 7 months to issue these letters, during
which time violative material remained in the market. 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.
FDA Issued 42 Regulatory Letters Citing Off-Label Promotion in the Past
5 Years:
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.
Table 2: Frequency of Violations in 117 Regulatory Letters, Calendar
Years 2003-2007:
Cited violation: Omission or minimization of risk;
Number of regulatory letters: 95;
Percentage of total letters[A]: 81.
Cited violation: Overstated effectiveness or unsubstantiated
effectiveness claims;
Number of regulatory letters: 54;
Percentage of total letters[A]: 46.
Cited violation: Off-label promotion;
Number of regulatory letters: 42;
Percentage of total letters[A]: 36.
Cited violation: Unsubstantiated superiority or comparative claims;
Number of regulatory letters: 40;
Percentage of total letters[A]: 34.
Cited violation: Failure to submit required material to FDA;
Number of regulatory letters: 18;
Percentage of total letters[A]: 15.
Cited violation: Other;
Number of regulatory letters: 27;
Percentage of total letters[A]: 23.
Source: GAO analysis of FDA regulatory letters.
[A] Percentages do not add to 100 because most letters cite more than
one violation.
[End of table]
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.[Footnote 31] 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.
Figure 2: Targeted Audience for Off-Label Promotions:
[See PDF for image]
This figure is a pie-chart depicting the following data:
Targeted Audience for Off-Label Promotions:
Medical professionals only: 50% (21);
Medical professionals and consumers: 33% (14);
Consumers only: 17% (7).
Source: GAO analysis of FDA regulatory letters.
[End of figure]
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.[Footnote 32] 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.[Footnote 33] 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.[Footnote 34] 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.
Table 3: Drugs for Which FDA Cited Off-Label Promotion in More Than One
Regulatory Letter:
Drug product (company)[A]: Ciloxan (Alcon Research, Ltd.);
Approved condition: Specific eye infections;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited oral statements by company representatives--
specifically, statements by the representatives claiming that Ciloxan
is safe and effective to treat otitis media and otitis externa.
(7/18/2003);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a sales aid, a brochure, and "homemade" promotional
materials that claim that Ciloxan treats pink eye in 3 days. However,
the letter stated that the dosing regimen for pink eye is 7 days.
(6/12/2000);
* Letter cited a sales aid that claims that Ciloxan may be used as a
prophylaxis in eye surgery. However the letter stated that Ciloxan is
only indicated for infections caused by specific organisms.
(4/15/1999).
Drug product (company)[A]: Climara (BERLEX Laboratories, Inc.);
Approved condition: Certain menopausal symptoms;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a professional journal ad and exhibit panel that
suggest that Climara has been demonstrated to be useful in treating
hypertension, hypertriglyceridemia, or gallstones. (1/6/2003);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited convention panels that claim Climara is as effective as
Premarin. The letter stated Climara had not been shown to be as
effective as Premarin in treating osteoporosis. (10/21/1998);
* Letter cited a 1997 desk calendar that claims there are
cardiovascular benefits from prolonged use of Climara. The letter
stated that this claim has not been proven. (7/22/1997);
* Letter cited mailing targeting customers with prescriptions for a
competing treatment (Estraderm) and the mailing failed to disclose that
Climara is not approved for all uses for which Estraderm is approved.
(3/26/1997).
Drug product (company)[A]: Diovan (Novartis Pharmaceuticals
Corporation);
Approved condition: High blood pressure and heart failure (in specific
instances);
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a sales aid that claims Diovan is effective in
treating patients with type 2 diabetes and high blood pressure to
preserve renal function. (4/21/2004);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a sales presentation that implied Diovan is useful for
decreasing cardiovascular morbidity and mortality and treating patients
with congestive heart failure. (9/23/1999).
Drug product (company)[A]: Effexor XR (Wyeth Pharmaceuticals);
Approved condition: Major depressive disorder;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a radio advertisement and states that the ad does
not draw a clear distinction between major depressive disorder and
normal periodic feelings of low interest or energy. (3/18/2004);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited various promotional materials that depict children and
stated that the disclaimer indicating that the efficacy and safety of
Effexor XR for pediatric use has not been established is not prominent.
(10/11/2000);
* Letter cited journal ads and stated that the ads imply that
Effexor[B] has been shown to be safe and effective in depressed
patients with concomitant cardiovascular disease, and Effexor has not
been evaluated for this condition. (6/25/1997).
Drug product (company)[A]: Flonase (GlaxoSmithKline);
Approved condition: Nasal symptoms related to types of allergic and
nonallergic rhinitis in adults and children 4 years of age or older;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a professional detail aid that fails to reveal that
the safety and effectiveness of Flonase have not been established for
children below 4 years of age. (5/7/2007);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a radio and newspaper print ad that claims Flonase is
equivalent to oral antihistamines. It stated that Flonase has not been
approved to treat nonnasal symptoms while oral antihistamines are
approved to treat those symptoms. (6/19/2003);
* Letter cited television ads that claim Flonase relieves postnasal
drip. The letter stated that there is not substantial evidence
demonstrating that Flonase is effective in treating this symptom. (3/
10/2000).
Drug product (company)[A]: OxyContin (The Purdue Frederick Company);
Approved condition: Pain relief under specific circumstances;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited professional journal ads that promote OxyContin for
use in a much broader range of patients with pain than has been proven
safe and effective. (1/17/2003);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a professional journal ad that claims, among other
things, that any dose of OxyContin can be used for the treatment of
moderate to severe osteoarthritis pain. Such claims, according to the
letter, are not supported. (5/11/2000).
Drug product (company)[A]: Paxil CR (GlaxoSmithKline);
Approved condition: Social anxiety disorder;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a television ad that suggests that anyone
experiencing anxiety, fear, or self-consciousness in social or work
situations is an appropriate candidate for Paxil CR. (6/9/2004);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a T-shirt distributed at a health fair. The letter
stated that the ad implies that Paxil[B] is a product that is useful in
children; however, the safety and effectiveness of Paxil in children
have not been established. (3/9/1998).
Drug product (company)[A]: Pravachol (Bristol-Myers Squibb Company);
Approved condition: Prevention of cardiovascular events in patients
with diagnosed coronary heart disease and prevention of coronary events
in patients who have high cholesterol but are not diagnosed with
coronary heart disease;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited ads and other promotions that imply Pravachol is
approved for prevention of stroke in patients who do not have
clinically evident coronary heart disease. (8/7/2003);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited a professional visual aid that fails to convey that
Pravachol should be used in addition to diet and other measures and is
not indicated to reduce heart attacks and lower cholesterol when used
alone. (3/29/ 2001);
* Letter cited two journal ads that feature women and imply that
Pravachol reduces the risk of a first heart attack in women up to one-
third. However, the letter stated that it has not been proven if
Pravachol will reduce the risk of a first heart attack for women. (10/
19/1998);
* Letter cited a newspaper and broadcast ad that do not adequately
convey that Pravachol should be used in addition to diet and other
nonpharmacological measures. (5/1/1998);
* Letter cited brochures and a journal ad that fail to prominently
present that Pravachol is indicated as an adjunct to diet. (1/26/1998).
Drug product (company)[A]: Provigil (Cephalon, Inc.);
Approved condition: Improve wakefulness in specific groups of patients
with excessive sleepiness;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited a promotional piece that stated that Provigil is
safe and effective for use in the treatment of various disorders
associated with fatigue, sleepiness, or inattentiveness. The letter
stated that Provigil is not indicated for fatigue and is only indicated
for specific patients with excessive sleepiness. (2/27/2007);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited promotional materials that implied that Provigil is safe
and effective for use in the treatment of sleepiness, tiredness,
decreased activity, lack of energy, and fatigue. The letter stated that
Provigil is not indicated for such symptoms. (1/3/2002).
Drug product (company)[A]: Tracleer (Actelion Pharmaceuticals US,
Inc.);
Approved condition: Pulmonary arterial hypertension in patients with
specific symptoms;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited the product Web site that fails to present the fact
that Tracleer is only indicated for patients with specific symptoms.
(7/20/2005);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited statements made by a company representative suggesting
that Tracleer may be useful in treating patients with congestive heart
failure. Such treatment, according to the letter, is not supported by
the clinical evidence. (10/30/2002).
Drug product (company)[A]: Viread (Gilead Sciences, Inc.);
Approved condition: Combination antiretroviral treatment for HIV-1
infection;
Off-label promotion cited in FDA letter: Most recent letter (CY 2003-
2007): Letter cited oral statements made by a company representative
that failed to mention that Viread is only approved for use in
combination with other antiretroviral agents. (7/29/2003);
Off-label promotion cited in FDA letter: Prior letters:
* Letter cited oral statements by a company representative who stated
that Viread was approved for a broad indication and that it was a
miracle drug. (3/14/2002).
Source: GAO analysis of FDA regulatory letters.
Note: To determine past FDA enforcement action related to the 42
regulatory letters citing off-label promotion that FDA issued during
calendar years 2003 through 2007, we reviewed FDA's Web site for any
related regulatory letters the agency may have issued as early as 1997.
[A] Company name reflects information in the most recent regulatory
letter.
[B] This drug is a variation of the drug cited in the most recent
regulatory letter. It is a timed release version of that drug, used to
treat the same condition(s) and promoted by the drug company under the
same name.
[End of table]
Eleven Settlements Related to Off-Label Promotion Have Occurred in the
Past 5 Years:
According to DDMAC officials, they did not refer any violations to DOJ
for enforcement action during calendar years 2003 through 2007 because
drug companies have generally complied with requests made in FDA's
regulatory letters during that time period. 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.[Footnote 35] 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.
Table 4: Settlements Involving Off-Label Promotion, Calendar Years 2003-
2007:
Date: May 2004;
Drug company: Pfizer, Inc.;
Drug name: Neurontin;
Approved indication: Adjunctive or supplemental antiseizure use by
epilepsy patients;
Alleged off-label promotion: Bipolar disorder, various pain disorders,
Amyotrophic Lateral Sclerosis, attention deficit disorder, migraines,
etc.;
Settlement amount[A] (nearest $100,000): $430,000,000.
Date: Dec. 2005;
Drug company: Eli Lilly and Company;
Drug name: Evista;
Approved indication: Prevention and treatment of osteoporosis in
postmenopausal women;
Alleged off-label promotion: Prevention and reduction in the risk of
breast cancer and reduction in the risk of cardiovascular disease;
Settlement amount[A] (nearest $100,000): $36,000,000.
Date: Oct. 2005;
Drug company: Serono, S.A.;
Drug name: Serostim;
Approved indication: AIDS wasting--the involuntary loss of more than 10
percent of body weight, plus more than 30 days of either diarrhea or
weakness and fever;
Alleged off-label promotion: Lipodystrophy and body cell mass wasting;
Settlement amount[A] (nearest $100,000): $704,000,000.
Date: Aug. 2006;
Drug company: Schering-Plough Corporation;
Drug name: Temodar and Intron A;
Approved indication: Certain types of brain tumors, specific types of
cancer, and chronic hepatitis B and C;
Alleged off-label promotion: Other types of brain tumors and metastases
and superficial bladder cancer;
Settlement amount[A] (nearest $100,000): $435,000,000.
Date: Oct. 2006;
Drug company: InterMune, Inc.;
Drug name: Actimmune;
Approved indication: Disorders of the immune system caused by defects
in immune system cells and severe malignant osteopetrosis;
Alleged off-label promotion: Lung scarring;
Settlement amount[A] (nearest $100,000): $36,900,000.
Date: Apr. 2007;
Drug company: Pfizer, Inc.;
Drug name: Genotropin;
Approved indication: Certain growth failure and related diseases in
children and adults;
Alleged off-label promotion: Anti-aging, cosmetic use, and athletic
performance enhancement;
Settlement amount[A] (nearest $100,000): $34,700,000.
Date: Apr. 2007;
Drug company: Cell Therapeutics, Inc.;
Drug name: Trisenox;
Approved indication: A specific and rare type of leukemia;
Alleged off-label promotion: Various forms of cancer;
Settlement amount[A] (nearest $100,000): $10,500,000.
Date: May 2007;
Drug company: Medicis Pharmaceutical Corporation;
Drug name: Loprox;
Approved indication: Fungicide for patients over 10 years of age;
Alleged off-label promotion: Treatment for children under the age of
10;
Settlement amount[A] (nearest $100,000): $9,800,000.
Date: May 2007;
Drug company: The Purdue Frederick Company;
Drug name: OxyContin;
Approved indication: Management of moderate to severe pain in specific
instances;
Alleged off-label promotion: Wider pool of patients and conditions;
Settlement amount[A] (nearest $100,000): $635,500,000.
Date: July 2007;
Drug company: Jazz Pharmaceuticals, Inc.;
Drug name: Xyrem;
Approved indication: Weak or paralyzed muscles and excessive daytime
sleepiness in narcolepsy patients;
Alleged off-label promotion: Fatigue, insomnia, chronic pain, weight
loss, depression, bipolar disorders, etc.;
Settlement amount[A] (nearest $100,000): $20,000,000.
Date: Sept. 2007;
Drug company: Bristol-Myers Squibb Company;
Drug name: Abilify;
Approved indication: Treatment of adult schizophrenia and bipolar
disorder;
Alleged off-label promotion: Pediatric use and dementia-related
psychosis;
Settlement amount[A] (nearest $100,000): $515,000,000.
Source: Compiled from DOJ's Web site [hyperlink, http://www.usdoj.gov],
HHS Web sites [hyperlink, http://www.cancer.gov[ and [hyperlink,
http://www.fda.gov], and FDA's OCC.
Note: For the purposes of this report, we have defined an off-label
settlement to be any civil and/or criminal settlement or disposition of
a matter where a sponsor's promotion of a drug for a use not contained
in FDA-approved labeling was investigated, regardless of whether that
alleged conduct was the basis for the ultimate disposition.
[A] Settlement amounts may include penalties for offenses not involving
off-label promotion.
[End of table]
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.
Table 5: FDA Regulatory Letters Issued during Calendar Years 1997
through 2007 for Drugs Cited in Settlements, Involving Promotional
Violations, Calendar Years 2003-2007:
Drug name cited in off-label settlement (2003-2007): Neurontin;
FDA letters citing promotional violations (1997-2007): June 2001;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Neurontin;
FDA letters citing promotional violations (1997-2007): July 2002;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Evista;
FDA letters citing promotional violations (1997-2007): November 1997;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Evista;
FDA letters citing promotional violations (1997-2007): December 1998;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Evista;
FDA letters citing promotional violations (1997-2007): January 1999;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Evista;
FDA letters citing promotional violations (1997-2007): September 2000;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Serostim;
FDA letters citing promotional violations (1997-2007): April 1999;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Temodar;
FDA letters citing promotional violations (1997-2007): June 2001;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Check].
Drug name cited in off-label settlement (2003-2007): Intron A;
FDA letters citing promotional violations (1997-2007): None;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Actimmune;
FDA letters citing promotional violations (1997-2007): None;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Genotropin;
FDA letters citing promotional violations (1997-2007): December 2001;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Trisenox;
FDA letters citing promotional violations (1997-2007): None;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Loprox;
FDA letters citing promotional violations (1997-2007): March 2000;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): OxyContin;
FDA letters citing promotional violations (1997-2007): May 2000;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): OxyContin;
FDA letters citing promotional violations (1997-2007): January 2003;
Letters citing off-label promotion: [Check];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Xyrem;
FDA letters citing promotional violations (1997-2007): None;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Drug name cited in off-label settlement (2003-2007): Abilify;
FDA letters citing promotional violations (1997-2007): None;
Letters citing off-label promotion: [Empty];
Letters citing off-label promotion related to settlement: [Empty].
Source: GAO analysis of FDA regulatory letters issued during calendar
years 1997 through 2007 and DOJ information on settlements involving
off-label promotion.
[End of table]
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.
Agency Comments and Our Evaluation:
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,[Footnote 36] 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.[Footnote 37] 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 [hyperlink, 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.
Sincerely yours,
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: FDA Regulatory Letters That Cited Off-Label Promotion,
Calendar Years 2003-2007:
Warning letters:
Drug cited: OxyContin;
Date of letter: 1/17/2003;
Drug company: Purdue Pharma L.P.;
Approved condition: Pain relief for specific conditions and specific
patient populations;
Off-label promotion cited: Pain relief in a much broader range of
conditions and patients with pain.
Drug cited: Xeloda;
Date of letter: 5/29/2003;
Drug company: Hoffmann-La Roche, Inc.;
Approved condition: Treatment of certain cases of metastatic colorectal
and breast cancer;
Off-label promotion cited: Treatment of gastric, cervical, uterine,
ovarian, renal, bladder, thyroid, and liver cancers.
Drug cited: Viread;
Date of letter: 7/29/2003;
Drug company: Gilead Sciences, Inc.;
Approved condition: In combination with other drugs for treatment of
Human Immunodeficiency Virus-1 infection;
Off-label promotion cited: Monotherapy.
Drug cited: Pravachol;
Date of letter: 8/7/2003;
Drug company: Bristol-Myers Squibb Company;
Approved condition: Prevention of cardiovascular or coronary events in
certain patients, and reducing risk of stroke in patients with
clinically evident coronary heart disease;
Off-label promotion cited: Prevention of stroke in all patients;
reducing cholesterol and the risk of cardiovascular outcomes
specifically with diabetic patients; and being effective for all
patients with borderline-high cholesterol.
Drug cited: Diovan;
Date of letter: 4/21/2004;
Drug company: Novartis Pharmaceuticals Corporation;
Approved condition: Treatment of hypertension and heart failure in
particular patients;
Off-label promotion cited: Treatment of patients with type 2 diabetes
and hypertension to preserve renal function.
Drug cited: Norvir;
Date of letter: 6/10/2004;
Drug company: Abbott Laboratories;
Approved condition: In combination with other drugs for treatment of
Human Immunodeficiency Virus-1 infection;
Off-label promotion cited: Monotherapy and subtherapeutic dosing.
Drug cited: Cubicin;
Date of letter: 8/17/2004;
Drug company: Cubist Pharmaceuticals;
Approved condition: Treatment of complicated skin and skin structure
infections, not including pneumonia, caused by certain Gram-positive
microorganisms;
Off-label promotion cited: Treatment of all infections, including
pneumonia, caused by Staphylococcus aureus.
Drug cited: Enbrel;
Date of letter: 2/18/2005;
Drug company: Amgen, Inc.;
Approved condition: Treatment of chronic moderate to severe plaque
psoriasis for certain patients;
Off-label promotion cited: Treatment of milder forms of psoriasis.
Drug cited: Tindamax;
Date of letter: 3/30/2005;
Drug company: Presutti Laboratories, Inc.;
Approved condition: Treatment of certain types of trichomoniasis,
giardiasis, and amebiasis;
Off-label promotion cited: Treatment of other types of trichomoniasis
and giardiasis, and anaerobic bacteria.
Drug cited: Tracleer;
Date of letter: 7/20/2005;
Drug company: Actelion Pharmaceuticals US, Inc.;
Approved condition: Treatment of pulmonary arterial hypertension in
particular patient groups;
Off-label promotion cited: Treatment of pulmonary arterial hypertension
in all patient groups.
Drug cited: Zyvox;
Date of letter: 7/20/2005;
Drug company: Pfizer, Inc.;
Approved condition: Treatment of nosocomial pneumonia and complicated
skin and skin structure infections caused by Staphylococcus aureus or
Streptococcus pneumoniae;
Off-label promotion cited: Treatment of all infections caused by
Staphylococcus aureus or Streptococcus pneumoniae.
Drug cited: Sotradecol;
Date of letter: 4/4/2006;
Drug company: Bioniche Pharma Group Limited;
Approved condition: Treatment of small uncomplicated varicose veins in
particular patients;
Off-label promotion cited: Treatment of small uncomplicated varicose
veins in all patients.
Drug cited: Zovirax;
Date of letter: 6/30/2006;
Drug company: GlaxoSmithKline;
Approved condition: Management of initial genital herpes in limited
cases;
Off-label promotion cited: Prevention of transmission of genital
herpes.
Drug cited: Rythmol SR;
Date of letter: 9/14/2006;
Drug company: Reliant Pharmaceuticals, Inc.;
Approved condition: Treatment to prolong the time to recurrence of
symptomatic atrial fibrillation in some patient populations;
Off-label promotion cited: Treatment of all patients with atrial
fibrillation.
Drug cited: Orapred;
Date of letter: 10/11/2006;
Drug company: BioMarin Pharmaceuticals, Inc.;
Approved condition: Treatment of severe allergic conditions asthma,
intractable to conventional treatment, with asthma or other respiratory
diseases;
Off-label promotion cited: Treatment of all types of asthma.
Drug cited: Nevanac;
Date of letter: 10/20/2006;
Drug company: Alcon Research, Ltd.;
Approved condition: Treatment of pain and inflammation from cataract
surgery, only involving the anterior portion of the eye;
Off-label promotion cited: Treatment of ocular conditions in the
posterior part of the eye and after any type of eye surgery.
Drug cited: Ontak and Targretin;
Date of letter: 10/23/2006;
Drug company: Ligand Pharmaceuticals, Inc.;
Approved condition: 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)[A];
Off-label promotion cited: Treatment of T-cell lymphoma in a broader
patient population (Ontak and Targretin)[A].
Drug cited: Provigil;
Date of letter: 2/27/2007;
Drug company: Cephalon, Inc.;
Approved condition: Improve wakefulness in patients with excessive
sleepiness associated with certain medical conditions; adjunct to
standard treatment for Obstructive Sleep Apnea/Hyponea Syndrome;
Off-label promotion cited: Treatment of various disorders associated
with fatigue, sleepiness, or inattentiveness.
Drug cited: Ciprodex;
Date of letter: 4/20/2007;
Drug company: Alcon Laboratories, Inc.;
Approved condition: Treatment of acute otitis media and externa caused
by certain microorganisms;
Off-label promotion cited: Treatment of acute otitis media and externa
caused by a wider range of microorganisms.
Drug cited: Levulan Kerastick;
Date of letter: 4/20/2007;
Drug company: DUSA Pharmaceuticals, Inc.;
Approved condition: Treatment of minimally to moderately thick actinic
keratoses of the face or scalp;
Off-label promotion cited: Treatment of other types of actinic
keratosis.
Drug cited: Acular LS;
Date of letter: 5/25/2007;
Drug company: Allergan, Inc.;
Approved condition: Solution for the reduction of ocular pain and
burning/stinging following corneal refractive surgery;
Off-label promotion cited: Solution for use in patients undergoing
phacoemulsification, a different type of surgery.
Drug cited: Exelon;
Date of letter: 8/8/2007;
Drug company: Novartis Pharmaceuticals Corporation;
Approved condition: Treatment of mild to moderate dementia from
Alzheimer's;
Off-label promotion cited: Combination therapy with another product not
indicated for same population of Alzheimer's patients.
Drug cited: Lindane;
Date of letter: 12/13/2007;
Drug company: Morton Grove Pharmaceuticals, Inc.;
Approved condition: Treatment of head lice, crab lice, and their ova in
limited circumstances in particular populations;
Off-label promotion cited: Dosing claims inconsistent with prescribing
information and in broader population.
Untitled letters:
Drug cited: Climara;
Date of letter: 1/6/2003;
Drug company: BERLEX Laboratories, Inc.;
Approved condition: Estrogen replacement;
Off-label promotion cited: For patients with hypertension,
hypertriglyceridemia, or gallstones.
Drug cited: Quixin;
Date of letter: 2/20/2003;
Drug company: Santen, Inc.;
Approved condition: Treatment of external bacterial eye infections;
Off-label promotion cited: Prevention of internal eye infections due to
eye surgery.
Drug cited: Amnesteem;
Date of letter: 6/18/2003;
Drug company: Genpharm, Inc.;
Approved condition: Treatment of severe acne not responsive to
conventional therapy;
Off-label promotion cited: Treatment of psychosocial problems.
Drug cited: Flonase;
Date of letter: 6/19/2003;
Drug company: GlaxoSmithKline;
Approved condition: Management of nasal symptoms of rhinitis;
Off-label promotion cited: Treatment of nonnasal symptoms of rhinitis.
Drug cited: Cipro HC and Ciloxan;
Date of letter: 7/18/2003;
Drug company: Alcon Research, Ltd.;
Approved condition: Treatment of eye infections caused by specific
microorganisms in the conditions of corneal ulcers and conjunctivitis
(Ciloxan)[B];
Off-label promotion cited: Treatment of otitis media and otitis externa
(Ciloxan)[B].
Drug cited: Merrem I.V.;
Date of letter: 10/3/2003;
Drug company: AstraZeneca Pharmaceuticals, LP;
Approved condition: Treatment of intra-abdominal infections and
bacterial meningitis when caused by specific pathogens that are not
drug resistant;
Off-label promotion cited: Treatment of infections caused by particular
bacteria and drug-resistant pathogens.
Drug cited: Migranal and D.H.E. 45;
Date of letter: 12/19/2003;
Drug company: Xcel Pharmaceuticals;
Approved condition: Acute treatment of migraine headaches with or
without aura and the acute treatment of cluster headache episodes
(D.H.E. 45)[B];
Off-label promotion cited: Treatment of status migrainosis or
intractable migraine (D.H.E. 45)[B].
Drug cited: Effexor XR and Effexor;
Date of letter: 3/18/2004;
Drug company: Wyeth Pharmaceuticals;
Approved condition: Treatment of major depressive disorder (Effexor
XR)[B];
Off-label promotion cited: Treatment of normal periodic feelings of low
interest or energy (Effexor XR)[B].
Drug cited: Paxil CR;
Date of letter: 6/9/2004;
Drug company: GlaxoSmithKline;
Approved condition: Treatment of social anxiety disorder;
Off-label promotion cited: Lesser degrees of performance anxiety or
shyness that don't generally require psychopharmacological treatment.
Drug cited: Foradil Aerolizer;
Date of letter: 12/9/2004;
Drug company: Schering Corporation;
Approved condition: Long-term maintenance treatment of Chronic
Obstructive Pulmonary Disease and asthma that cannot be managed by
occasional use of inhaled, short-acting beta2-agonists;
Off-label promotion cited: Treatment of any type or severity of asthma.
Drug cited: Strattera;
Date of letter: 6/14/2005;
Drug company: Eli Lilly and Company;
Approved condition: Treatment of attention deficit/hyperactivity
disorder;
Off-label promotion cited: Treatment of a variety of symptoms, such as
disorganization, distraction, and difficulty finishing things.
Drug cited: Fuzeon;
Date of letter: 7/15/2005;
Drug company: Hoffman-La Roche, Inc.;
Approved condition: In combination with other drugs for treatment of
Human Immunodeficiency Virus-1 infection in certain treatment-
experienced patients;
Off-label promotion cited: Therapy for all treatment-experienced
patients.
Drug cited: Travatan;
Date of letter: 9/22/2005;
Drug company: Alcon Research, Ltd.;
Approved condition: Reduction of interocular pressure in certain
patients;
Off-label promotion cited: Protection of the visual field.
Drug cited: Loprox;
Date of letter: 1/4/2006;
Drug company: Medicis Pharmaceutical Corp;
Approved condition: Topical treatment of seborrheic dermatitis of the
scalp in adults;
Off-label promotion cited: Long-term maintenance treatment of
seborrheic dermatitis.
Drug cited: NeutroSpec;
Date of letter: 2/16/2006;
Drug company: Palatin Technologies, Inc.;
Approved condition: Diagnostic imaging for assisting in the diagnosis
of equivocal appendicitis in patients who are 5 years of age or older;
Off-label promotion cited: Diagnostic test that can, by itself,
diagnose appendicitis.
Drug cited: Alimta;
Date of letter: 7/27/2006;
Drug company: Eli Lilly and Company;
Approved condition: Treatment of advanced or metastatic nonsmall lung
cancer after prior chemotherapy and in combination with cisplatin for
patients with malignant mesothelioma that is unresectable or who are
not candidates for curative surgery;
Off-label promotion cited: Treatment of a wide range of cancers.
Drug cited: Rozerem;
Date of letter: 3/5/2007;
Drug company: Takeda Pharmaceuticals North America, Inc.;
Approved condition: Treatment of insomnia, the safety and effectiveness
of which in pediatric patients have not been established;
Off-label promotion cited: Treatment of insomnia in pediatric
population.
Drug cited: Flonase;
Date of letter: 5/7/2007;
Drug company: GlaxoSmithKline;
Approved condition: Management of nasal symptoms of allergic and
nonallergic rhinitis in adults and pediatric patients 4 years of age
and older;
Off-label promotion cited: Management of nasal symptoms of allergic and
nonallergic rhinitis in all populations.
Drug cited: Solaraze;
Date of letter: 7/17/2007;
Drug company: Doak Dermatologics;
Approved condition: Topical treatment of actinic keratoses used as
monotherapy;
Off-label promotion cited: Treatment of actinic keratoses in
combination with cryotherapy.
Source: GAO analysis of FDA regulatory letters.
Note: Regulatory letters are available online from Food and Drug
Administration, Center for Drug Evaluation and Research, Warning
Letters and Notice of Violation Letters to Pharmaceutical Companies,
[hyperlink, http://www.fda.gov/cder/warn/] (accessed on Apr. 25, 2008).
[A] 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.
[B] 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.
[End of table]
[End of section]
Appendix II: Examples of Alleged Drug Company Actions Cited in
Settlements Involving Off-Label Promotion:
Date: May 2004;
Drug company: Pfizer, Inc.;
Drug name: Neurontin;
Alleged actions:
* 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.
Date: Dec. 2005;
Drug company: Eli Lilly and Company;
Drug name: Evista;
Alleged actions:
* 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.
Date: Oct. 2005;
Drug company: Serono, S.A.;
Drug name: Serostim;
Alleged actions:
* 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.
Date: Aug. 2006;
Drug company: Schering-Plough Corporation;
Drug name: Temodar and Intron A;
Alleged actions:
* 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.
Date: Oct. 2006;
Drug company: InterMune, Inc.;
Drug name: Actimmune;
Alleged actions:
* 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.
Date: Apr. 2007;
Drug company: Pfizer, Inc.;
Drug name: Genotropin;
Alleged actions:
* Promoted drug for off-label uses, such as anti-aging, cosmetic use,
and athletic performance enhancement.
Date: Apr. 2007;
Drug company: Cell Therapeutics, Inc.;
Drug name: Trisenox;
Alleged actions:
* 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.
Date: May 2007;
Drug company: Medicis;
Drug name: Loprox;
Alleged actions:
* 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.
Date: May 2007;
Drug company: The Purdue Frederick Company;
Drug name: OxyContin;
Alleged actions:
* Promoted the drug as less addictive, less subject to abuse, and less
likely to cause withdrawal symptoms than other pain medications without
FDA approval.
Date: July 2007;
Drug company: Jazz Pharmaceuticals, Inc.;
Drug name: Xyrem;
Alleged actions:
* 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.
Date: Sept. 2007;
Drug company: Bristol-Myers Squibb Company;
Drug name: Abilify;
Alleged actions:
* Promoted the sale of the drug for pediatric use and dementia-related
psychosis, both off-label uses.
Source: Compiled from FDA and DOJ sources [hyperlink,
http://www.usdoj.gov] and [hyperlink, http://www.fda.gov].
[End of table]
[End of section]
Appendix III: Comments from the Department of Health and Human
Services:
Department of Health & Human Services:
Office of the Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
July 11, 2008:
Marcia Crosse:
Director, Health Care:
441 G Street NW:
U.S. Government Accountability Office:
Washington, D.C. 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on the U.S. Government
Accountability Office's (GAO) draft report entitled, "Prescription
Drugs: FDA's Oversight of the Promotion of Drugs for Off-Label Uses"
(GAO 08-835).
The Department appreciates the opportunity to comment on this draft
before its publication.
Sincerely,
Signed by:
Jennifer R. Luong, for:
Vincent J. Ventimiglia, Jr.
Assistant Secretary for Legislation:
Attachment:
General Comments Of The U.S. Department Of Health And Human Services
(HHS) On The U.S. Government Accountability Office's (GAO) Draft Report
Entitled: Prescription Drugs: FDA's Oversight Of The Promotion Of Drugs
For Off-Label Uses (GAO 08-835):
The draft report discusses topics that GAO identified as part of its
Congressional request to provide information about the promotion of
drugs for off-label uses and recommends a standardized tracking system
for DDMAC.
The draft report indicates that reviewers use a process to review
submitted materials, but don't apply this process systematically. DDMAC
has established documented criteria for reviewers to use in determining
how to prioritize their overall workload and which of the thousands of
disseminated pieces they receive should be reviewed. The reviewers
apply these criteria systematically to all advisory submissions,
complaints, labeling reviews, and pending enforcement actions, and
actively track all such materials in their assigned therapeutic areas.
For submissions of disseminated materials, reviewers consistently apply
the documented criteria to determine which of the tens of thousands of
pieces received should be reviewed.
FDA, like other regulatory agencies, exercises its discretion in order
to focus its limited resources on actions that will most impact the
public health. The GAO proposal for a tracking system does nut deal
with the fact that not all of the approximately 68,000 submitted copies
of disseminated pieces received in a year by DDMAC can be reviewed. To
address this, FDA established documented criteria to optimally use
DDMAC's limited resources. According to these criteria, FDA chooses for
review the pieces that raise the most issues in terms of potential
public health impact, as described on pages 14-15 of the report - this
process represents a systematic prioritization.
This recommended tracking system would also not improve the agency's
ability to identify promotional violations, nor would it change which
pieces are actually reviewed (with the exception of taking resources
away from review activities), as this is determined based on DDMAC's
documented criteria. While a tracking system would be of benefit to
persons interested in calculating the numbers of pieces looked at, it
would not enable DDMAC to more efficiently regulate off-label
promotion.
Adding tracking functions to reviewers' current duties would not
improve efforts to facilitate identification and review of materials
that contain off-label promotion. The agency's limited resources are
better spent on substantive review activities aimed at stopping or
preventing false and misleading promotion.
[End of section]
Appendix IV: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
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.
[End of section]
Footnotes:
[1] We will refer to "promotion and advertising activities" as
"promotion."
[2] See 21 U.S.C. § 352(a), (n), and 21 C.F.R. § 202.1(e) (2007).
[3] However, the federal government has placed limitations on
reimbursements for drugs that have been prescribed off label in both
the Medicare program--the federal health care program that serves the
nation's elderly and disabled--and the Medicaid program--the federal-
state health care program that serves low-income individuals. Although
both programs make reimbursements for off-label prescriptions, the off-
label use for a drug generally must be supported by its being listed in
one or more of several named compendia. See, for example, 42 U.S.C. §§
1395x(t)(2), 1395w-102(e)(1), 1396r-8(k)(6).
[4] D.C. Radley, S.N. Finkelstein, and R.S. Stafford, "Off-Label
Prescribing Among Office-Based Physicians," Archives of Internal
Medicine, vol. 166, no. 9 (2006). Similarly, we previously reported
that one-third of the drug treatments prescribed by cancer physicians
were for off-label uses and that more than half of cancer patients
received at least one drug for an off-label indication. See GAO, Off-
Label Drugs: Reimbursement Policies Constrain Physicians in Their
Choice of Cancer Therapies, [hyperlink, http://www.gao.gov/cgi-
bin/getrpt?GAO/PEMD-91-14] (Washington, D.C.: Sept. 27, 1991).
[5] Among other things, the settlement provides for a $21 million grant
program designed to provide health care professionals and consumers
information relating to prescription drugs, including drug marketing
and the conditions for which drugs are prescribed. In June 2000,
Pfizer, Inc. acquired Warner-Lambert, the drug company cited in the
settlement, and agreed to comply with the terms of the settlement.
[6] We used the date that the agency first drafted a regulatory letter
to calculate this time period because FDA does not track the date when
violations are actually identified.
[7] For example, we did not review FDA's oversight of promotions of
medical devices, such as diagnostic ultrasound products and X-ray
machines, and biologics, such as vaccines. These products are beyond
the scope of this review.
[8] 21 C.F.R. pt. 314 subpts. H, I (2007).
[9] 21 U.S.C. §§ 352(a), (n), 393(d)(2).
[10] 21 U.S.C. § 352(a), (f)(1), (n); 21 C.F.R. § 202.1(e)(5)(i)
(2007).
[11] 21 C.F.R. § 202.1(e)(4) (2007); see also 21 C.F.R. §§
201.100(c)(1) and 201.128 (2007).
[12] 21 U.S.C. § 352(a), (f)(1), (n). See, e.g., U.S. v. Articles of
Drug, 625 F.2d 665 (5th Cir. 1980).
[13] Pub. L. No. 105-115, § 401, 111 Stat. 2296, 2356-65.
[14] The public comment period for this draft guidance closed on April
21, 2008. FDA is in the process of reviewing comments it received but
has not yet established a date for finalizing the guidance.
[15] Previously, drug companies could submit the material to FDA for
review 60 days prior to dissemination to take advantage of a "safe
harbor provision," which resulted from litigation challenging the
constitutionality of the FDAMA provision. The "safe harbor provision"
was explained in a Federal Register notice, 65 Fed. Reg. 14286 (Mar.
16, 2000). DDMAC officials said that they received 79 such submissions.
The provisions also required drug companies to submit new safety and
effectiveness data on the off-label use to obtain FDA's approval for a
new indication, but DDMAC officials could not provide information on
how often that occurred.
[16] However, CME programs are subject to review by the ACCME, which
accredits CME providers by ensuring that they meet certain standards.
For example, the ACCME helps to ensure that the programs themselves and
any presenters do not violate FDA regulations by requiring disclosures
of any conflicts of interest. According to the ACCME Annual Report, in
2006, 93,582 CME programs took place in the United States, reaching
over 8 million physicians. [hyperlink,
http://www.accme.org/index.cfm/fa/home.popular/popular_id/127a1c6f-462d-
476b-a33a-6b67e131ef1a.cfm] (accessed on May 14, 2008.) Unlike CME
programs whose content is independent of drug companies, FDA regulates
educational programs that are substantively influenced by drug
companies.
[17] 21 C.F.R. § 314.81(b)(3)(i) (2007).
[18] PhRMA issued guidance effective January 2006 that states that
"[drug] companies should submit all new DTC television advertisements
to FDA before releasing these advertisements for broadcast." PhRMA
Guiding Principles: Direct to Consumer Advertisements about
Prescription Medicines (Washington, D.C.: PhRMA, Nov. 2005),
[hyperlink, http://www.phrma.org/principles_and_guidelines/] (accessed
on May 5, 2008).
[19] If FDA notifies the drug company that a draft material is not in
violation and subsequently changes its opinion, the agency must notify
the drug company in writing and provide it with a reasonable amount of
time for correction before any regulatory action is taken. 21 C.F.R. §
202.1(j)(4) (2007).
[20] DDMAC officials told us that FDA issues regulatory letters to
request drug companies to take certain actions as a means of bringing
about voluntary compliance with applicable laws and regulations. These
letters do not require drug companies to take such actions.
[21] Food and Drug Administration, Center for Drug Evaluation and
Research, Warning Letters and Notice of Violation Letters to
Pharmaceutical Companies (Rockville, MD.: 2008), [hyperlink,
http://www.fda.gov/cder/warn/] (accessed on May 5, 2008).
[22] Pub. L. No. 110-85, § 901(d)(4), 121 Stat. 823, 940-42.
[23] GAO, Prescription Drugs: FDA Oversight of Direct-to-Consumer
Advertising Has Limitations, [hyperlink, http://www.gao.gov/cgi-
bin/getrpt?GAO-03-177] (Washington, D.C.: Oct. 28, 2002).
[24] GAO, Prescription Drugs: Improvements Needed in FDA's Oversight of
Direct-to-Consumer Advertising, [hyperlink, http://www.gao.gov/cgi-
bin/getrpt?GAO-07-54] (Washington, D.C.: Nov. 16, 2006).
[25] In 2002, FDA implemented a policy change requiring all draft
regulatory letters to be reviewed by OCC, to ensure that all warning
and untitled letters were reviewed for "legal sufficiency and
consistency with agency policy." We reported that this reduced the
agency's ability to issue these letters in a timely manner in 2002 and
reiterated this finding in 2006. [hyperlink, http://www.gao.gov/cgi-
bin/getrpt?GAO-03-177] and [hyperlink, http://www.gao.gov/cgi-
bin/getrpt?GAO-07-54].
[26] GAO, Prescription Drugs: Trends in FDA's Oversight of Direct-to-
Consumer Advertising, [hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-
08-758T] (Washington, D.C.: May 8, 2008).
[27] Drug companies must submit to FDA draft promotional materials
prior to dissemination for drugs approved under FDA's accelerated
approval process. The accelerated approval process is authorized for
drugs that treat serious or life-threatening illnesses. Under the
accelerated approval process, drug companies are required to submit all
promotional material, in draft form, during the preapproval process
and, after a drug is approved, prior to dissemination. 21 C.F.R. §
314.550. See also, 21 C.F.R. § 314.640 (2006).
[28] DDMAC issued approximately 3,000 letters in response to requests
for advisory review during calendar years 2003 through 2007.
[29] While FDA supports the full exchange of scientific information,
including dissemination of scientific findings in scientific or lay
media, it regulates promotional activities involving off-label drug use
and takes action where such activities are inconsistent with the
applicable laws and regulations. For example, when activities are
performed by or on behalf of the drug companies that market the
products being discussed (e.g., company-sponsored dinner meetings),
these activities would be regulated by FDA as promotion and the
materials used for the programs would have to be submitted to FDA. See
21 C.F.R. § 314.81(b)(3)(i)(2007).
[30] AMA is currently developing programs to educate physicians about
inappropriate drug company promotional behavior, including off-label
promotion, with funds received through the Neurontin settlement. AMA
was one of 28 grantees receiving such funds.
[31] Regulatory letters may cite more than one promotion. In addition,
FDA may cite violations it identified through submissions and through
monitoring and surveillance in the same letter. For example, one letter
cited an exhibition panel, which was submitted to FDA for review, and
promotional material on the drug company's Web site that FDA identified
through monitoring and surveillance.
[32] FDA could not provide us with data on when the final material was
first disseminated or when FDA identified a potential violation.
Therefore, we used the date FDA first drafted the regulatory letter and
the date of issuance of the letter to determine how long it takes the
agency to issue a regulatory letter. We calculated the average length
of time using data from 40 of the 42 identified off-label regulatory
letters. We were unable to determine from FDA's documentation the date
the regulatory letter was drafted for the remaining 2 letters.
[33] Regulatory letters also request that drug companies remove all
other promotional materials that make similar claims as the identified
violative promotional materials. FDA continues to monitor related
promotions by reviewing all submissions related to that drug for 6
months.
[34] Our analysis is based on 22 of the 23 warning letters citing off-
label promotion, which have been resolved.
[35] Some settlements include money for offenses not related to the
alleged off-label promotion.
[36] [hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-54].
[37] [hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-03-177].
[End of section]
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