oversight

Antibiotics: FDA Needs to Do More to Ensure That Drug Labels Contain Up-to-Date Information

Published by the Government Accountability Office on 2012-01-31.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

               United States Government Accountability Office

GAO            Report to Congressional Committees




January 2012
               ANTIBIOTICS

               FDA Needs to Do
               More to Ensure That
               Drug Labels Contain
               Up-to-Date
               Information




GAO-12-218
                                             January 2012

                                             ANTIBIOTICS
                                             FDA Needs to Do More to Ensure That Drug Labels
                                             Contain Up-to-Date Information
Highlights of GAO-12-218, a report to
congressional committees




Why GAO Did This Study                       What GAO Found
Antibiotics are critical drugs that have     FDA has not taken sufficient steps to ensure that antibiotic labels contain up-to-
saved millions of lives. Growing             date breakpoints. FDA designates certain drugs as “reference-listed drugs” and
bacterial resistance to existing drugs       the sponsors of these drugs play an important role in ensuring the accuracy of
and the fact that few new drugs are in       drug labels. Reference-listed drugs are approved drug products to which generic
development are public health                versions are compared. As of November 2011, FDA had not yet confirmed
concerns. The Food and Drug                  whether the breakpoints on the majority of reference-listed antibiotics labels were
Administration Amendments Act of             up to date. FDA contacted sponsors of 210 antibiotics in early 2008 to remind
2007 (FDAAA) required the Food and           sponsors of the importance of maintaining their labels and requested that they
Drug Administration (FDA), an agency
                                             assess whether the breakpoints on their drugs’ labels were up to date. Sponsors
within the Department of Health and
                                             were asked to submit evidence to FDA showing that the breakpoints were either
Human Services (HHS), to identify,
periodically update, and make publicly
                                             current or needed revision. As of November 2011, over 3.5 years after FDA
available up-to-date breakpoints, the        contacted sponsors, the agency had not yet confirmed whether the breakpoints
concentrations at which bacteria are         on the labels of 70 percent, or 146 of the 210 antibiotics, were up to date. FDA
categorized as susceptible to an             has not ensured that sponsors have fulfilled the responsibilities outlined in the
antibiotic. Breakpoints are a required       early 2008 letters. For those submissions FDA has received, it has often taken
part of an antibiotic’s label and are        over a year for FDA to complete its review. Officials attributed this delay to
used by providers to determine               reviewers’ workload, challenging scientific issues or difficulties in obtaining
appropriate treatments. FDAAA                needed data, and incomplete submissions. FDA also issued guidance to clarify
provided a financial incentive for           sponsors’ responsibility to evaluate and maintain up-to-date breakpoints. The
antibiotic innovation and required FDA       guidance reminded sponsors that they are required to maintain accurate labels
to hold a public meeting on antibiotic       and stated that certain sponsors should submit an evaluation of breakpoints on
incentives and innovation. FDAAA             their antibiotic labels to FDA annually. However, FDA has not been
directed GAO to report on the impact         systematically tracking whether sponsors are providing these annual updates.
of these provisions on new drugs. This       Some sponsors remain confused about their responsibility to evaluate and
report (1) assesses FDA’s efforts to         maintain up-to-date breakpoints. At GAO’s request, FDA reviewed a small
help preserve antibiotic effectiveness       sample of annual reports and determined that few sponsors appear to be
by ensuring breakpoints on labels are        responsive to the guidance.
up to date and (2) examines the impact
of the antibiotic innovation provisions.
                                             The FDAAA provisions related to antibiotic innovation have not resulted in the
GAO examined FDA data, guidance,
and other documents; interviewed FDA         submission of new drug applications for antibiotics. FDAAA extended the period
officials; and obtained information from     of time that sponsors of new drugs that meet certain criteria have exclusive right
drug sponsors, such as manufacturers,        to market the drug. According to FDA officials, the agency has received very few
that market antibiotics.                     inquiries regarding this provision and, as of November 2011, no new drug
                                             applications for antibiotics have been submitted that would qualify for this
What GAO Recommends                          exclusivity. None of the drug sponsors GAO received comments from said that
                                             this provision provided sufficient incentive to develop a new antibiotic of this type.
GAO recommends that the
Commissioner of FDA take steps to            FDAAA also required that FDA hold a public meeting to discuss whether and how
help ensure antibiotic labels contain        existing or potential incentives could be applied to promote the development of
up-to-date information, such as by           antibiotics. Both financial and regulatory incentives were discussed at FDA’s
expediting the agency’s review of            2008 meeting, including tax incentives for research and development and
breakpoint submissions. HHS said it          providing greater regulatory clarity during the drug approval process.
will consider implementing GAO’s
recommendations.

View GAO-12-218. For more information,
contact Marcia Crosse at (202) 512-7114 or
crossem@gao.gov.

                                                                                       United States Government Accountability Office
Contents


Letter                                                                                      1
               Background                                                                   5
               FDA Has Not Taken Sufficient Steps to Ensure That Antibiotic
                 Labels Contain Up-to-Date Information                                    11
               FDAAA Provisions Related to Innovation Do Not Appear to Have
                 Encouraged the Development of New Antibiotics                            19
               Conclusions                                                                22
               Recommendations for Executive Action                                       24
               Agency Comments and Our Evaluation                                         24

Appendix I     Drug Sponsors Contacted by FDA in 2008 Regarding Information
               on Antibiotic Labels                                                       27



Appendix II    Status of Labels for 210 Antibiotics Specified in FDA’s 2008 Letters       29



Appendix III   Timeline of FDA Implementation of Certain Food and Drug
               Administration Amendments Act Provisions                                   30



Appendix IV    Comments from the Department of Health and Human Services                  31



Appendix V     GAO Contact and Staff Acknowledgments                                      35



Tables
               Table 1: Incentives Discussed at 2008 FDA Public Meeting to
                        Promote Antibiotic Innovation                                     21
               Table 2: Drug Sponsors Receiving Letters from FDA in 2008 in
                        Response to the Food and Drug Administration
                        Amendments Act of 2007 Regarding Information on
                        Antibiotic Labels                                                 27




               Page i                                                   GAO-12-218 Antibiotics
Figure
         Figure 1: Status of Labels for 210 Antibiotics                                            13




         Abbreviations

         ANDA              abbreviated new drug application
         FDA               Food and Drug Administration
         FDAAA             Food and Drug Administration Amendments Act of
                            2007
         HHS               Department of Health and Human Services
         NDA               new drug application
         NME               new molecular entity



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         Page ii                                                             GAO-12-218 Antibiotics
United States Government Accountability Office
Washington, DC 20548




                                   January 31, 2012

                                   The Honorable Tom Harkin
                                   Chairman
                                   The Honorable Michael B. Enzi
                                   Ranking Member
                                   Committee on Health, Education, Labor, and Pensions
                                   United States Senate

                                   The Honorable Fred Upton
                                   Chairman
                                   The Honorable Henry A. Waxman
                                   Ranking Member
                                   Committee on Energy and Commerce
                                   House of Representatives

                                   Since the discovery of penicillin in 1928, antibiotics have played an
                                   important role in the care and well-being of people around the world. By
                                   destroying bacteria or inhibiting their growth in individuals with serious or
                                   potentially serious infections, antibiotics have saved millions of lives.
                                   Today, however, bacteria that cause serious infections in the United
                                   States and elsewhere are becoming resistant to antibiotics, making
                                   infections that once responded to these drugs more difficult to treat. 1
                                   Meanwhile, the number of new antibiotics has steadily decreased since
                                   the 1980s. 2 The limited number of antibiotics under development is a
                                   matter of concern for the Food and Drug Administration (FDA), the
                                   agency within the Department of Health and Human Services (HHS)
                                   responsible for overseeing the safety and effectiveness of drugs
                                   marketed in the United States. The Commissioner of FDA recently




                                   1
                                    Scientists, public health officials, and clinicians agree that antibiotic resistance has
                                   become a national and global health challenge. This resistance is a natural phenomenon
                                   caused by a variety of factors, including the inappropriate or prolonged use of antibiotics.
                                   We recently reported on antibiotic resistance. See GAO, Antibiotic Resistance: Data Gaps
                                   Will Remain Despite HHS Taking Steps to Improve Monitoring, GAO-11-406 (Washington,
                                   D.C.: June 1, 2011), and Antibiotic Resistance: Agencies Have Made Limited Progress
                                   Addressing Antibiotic Use in Animals, GAO-11-801 (Washington, D.C.: Sept. 7, 2011).
                                   2
                                    H.W. Boucher, et.al., Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious
                                   Diseases Society of America (Arlington, Va.: Clinical Infectious Diseases, 2009).




                                   Page 1                                                              GAO-12-218 Antibiotics
reported that the drug pipeline is “distressingly devoid” of new antibiotics, 3
and the scientific community recognizes the lack of new antibiotics in
development as a significant concern.

The development of new drugs, including antibiotics, is often a costly and
lengthy process; to obtain FDA’s approval to market a new drug, a
sponsor must conduct extensive research in order to demonstrate that a
new drug is both safe and effective. 4 Although high costs and failure rates
make drug development risky for drug sponsors, creating a safe and
effective new drug can be financially rewarding for the drug sponsor and
beneficial to the public. However, antibiotics are often less profitable than
other drugs because they are designed to work quickly and are typically
administered for a brief duration. This makes them less lucrative
investments for sponsors than drugs that treat chronic conditions, such as
diabetes and arthritis, which may be taken for an extended period of time
or even indefinitely. In addition, given the growing problem of resistance,
an antibiotic may not remain effective long enough to produce a
meaningful return on a sponsor’s investment. 5

Maintaining the effectiveness of antibiotics, and the need for innovation,
was addressed in several provisions of the Food and Drug Administration
Amendments Act of 2007 (FDAAA). Regarding the effectiveness of
antibiotics already on the market, FDAAA required FDA to identify,
periodically update, and make publicly available, such as on the Internet,
up-to-date antibiotic “breakpoints,” which are included on an antibiotic’s
label and reflect the concentrations at which bacteria are categorized as
susceptible to treatment with a given antibiotic. Labels that contain up-to-
date breakpoints are considered to be as accurate as possible and are
used by health care providers to help determine the best antibiotic to treat
a particular bacterial infection. Out-of-date breakpoints on antibiotic labels
can result in providers unknowingly selecting ineffective antibiotic


3
 M.A. Hamburg, M.D., “FDA’s Efforts to Facilitate Antibiotic Approvals,” Infectious
Diseases Society of America World Health Day Event, (Washington, D.C.: Apr. 7, 2011).
4
 A drug sponsor is the person or entity that assumes responsibility for the marketing of a
new drug, including responsibility for complying with applicable provisions of laws, such as
the Federal Food, Drug, and Cosmetic Act and related regulations. The sponsor is usually
an individual, partnership, corporation, government agency, manufacturer, or scientific
institution.
5
 Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates…A Public Health Crisis Brews
(Alexandria, Va.: Infectious Diseases Society of America, 2004).




Page 2                                                              GAO-12-218 Antibiotics
treatments, which can contribute to additional bacterial resistance to
antibiotics. An antibiotic’s breakpoint, along with other information, is a
required part of a drug’s label. However, determining whether a
breakpoint has changed can be complex and scientifically challenging.
FDA has found it difficult to ensure that sponsors maintain labels on
antibiotics that contain up-to-date breakpoints. Regarding the need for
innovative antibiotics, FDAAA extended the duration of “market
exclusivity” for new drugs, including antibiotics that meet certain criteria.
Specifically, FDAAA extended the period of time that the sponsor of a
drug meeting the criteria has exclusive rights to market the drug. In
addition, FDAAA directed FDA to convene a public meeting to discuss the
circumstances under which infectious diseases may qualify for grants or
other incentives that may promote innovation, such as those offered by
the Orphan Drug Act. 6

FDAAA directed us to report on the impact of these provisions on new
drugs. This report (1) assesses FDA’s efforts to implement the FDAAA
provision to help preserve antibiotic effectiveness by ensuring that
breakpoints on labels are up to date and (2) examines the impact of the
FDAAA provisions related to antibiotic innovation.

To examine FDA’s efforts to implement the FDAAA provision related to
antibiotic effectiveness by ensuring that breakpoints on labels are up to
date, we obtained information on FDA’s efforts to contact antibiotic
sponsors regarding the accuracy of their antibiotics’ labels, including their
breakpoints. 7 Specifically, we examined information related to 210
antibiotics identified by FDA as those for which sponsors were
responsible for evaluating and maintaining and, if necessary, updating the
antibiotics’ breakpoints on their labels. To assess the reliability of the
information FDA used to identify these 210 antibiotics, we reviewed
agency publications and related documentation, examined these data for



6
 See 21 U.S.C. §§ 360aa-360ee. The Orphan Drug Act provides incentives for the
development of products that treat rare conditions affecting fewer than 200,000 people in
the United States, including extended market exclusivity and grants to public and private
entities and individuals to defray the costs of development.
7
 Breakpoints have been established for systemic antibiotics, which are administered
intravenously, orally, or intramuscularly and affect the entire body. However, they have not
been established for topical antibiotics, which are medicines applied to a localized area on
the skin. In discussing breakpoints in this report, we use the term antibiotics to refer to
systemic antibiotics for human use.




Page 3                                                              GAO-12-218 Antibiotics
consistency, and interviewed knowledgeable agency officials. Through
this review, we determined that FDA’s information was incomplete.
However, we found these data sufficiently reliable for our purposes. Of
the 210 antibiotics, 126 were brand-name antibiotics and 84 were generic
antibiotics—copies of brand-name drugs. 8 We contacted each of the
39 sponsors associated with the 210 antibiotics to obtain their views on
FDA’s actions in response to the FDAAA provision on antibiotic
effectiveness. 9 We received written or oral comments from 26 of the
39 sponsors, representing 176 of the 210 antibiotics. (See app. I for a list
of the 39 sponsors.) We discussed with FDA officials their plans to make
up-to-date breakpoints on labels publicly available. We also reviewed
FDA’s guidance to drug manufacturers on maintaining up-to-date
breakpoints on labels.

To examine the impact of the provisions contained in FDAAA related to
antibiotic innovation, we determined whether drug sponsors had indicated
an interest in the extended duration of market exclusivity for certain
drugs, as specified in the law. We did this by determining whether
sponsors (1) had been granted this extended market exclusivity for a new
drug or (2) had submitted inquiries to FDA about this exclusivity. For
context, we obtained data from FDA to determine the number of
innovative antibiotics that had been developed both prior to and after the
enactment of FDAAA. Specifically, we obtained data on all approvals for
antibiotics containing new molecular entities (NME) for a 10-year period



8
 When a new drug is developed it is classified by its chemical type and therapeutic
potential. Once FDA approves a new drug, it is marketed under a brand name—a
proprietary, trademark-protected name—by a single sponsor. Only that original sponsor
may use the brand name. A generic drug uses a name reflecting its chemical makeup and
must be the same as the original drug in dosage form, strength, route of administration,
and conditions of use. When a sponsor submits an application to FDA to bring a generic
version onto the market, it must provide evidence that the generic drug is bioequivalent—a
drug containing identical amounts of the same active ingredient(s) as the brand-name
drug. There may be more than one sponsor marketing a generic version of the same
brand-name drug.
9
 In most cases we attempted to contact the sponsor FDA identified. However, in some
cases, such as when the original sponsor had since merged with another sponsor, been
divested of its assets, or gone bankrupt, we contacted the subsequent sponsor. After
performing these adjustments, we found that the 126 brand-name antibiotics were
associated with 29 drug sponsors and the 84 generic antibiotics were associated with 23
drug sponsors. Thirteen of the sponsors marketed both brand-name and generic
antibiotics among the 210 identified by FDA, so we contacted a total of 39 sponsors; 26
agreed to speak to us or to provide us with written or oral comments.




Page 4                                                             GAO-12-218 Antibiotics
             (2001-2010). 10 We also reviewed FDA’s efforts related to the FDAAA
             requirement that it hold a public meeting to discuss incentives that may
             promote antibiotic innovation, and we examined the transcript of this
             meeting. We discussed with FDA whether drug sponsors had indicated
             an interest in marketing a new antibiotic under the provisions of the
             Orphan Drug Act. In addition, we reviewed FDA’s policies and guidance
             regarding the application of existing incentives to antibiotics, including
             those found in the Orphan Drug Act, and obtained data on all approvals
             for antibiotics that received an orphan drug designation from 2001
             through 2010. We asked the 26 antibiotic sponsors described above if
             incentives found in the FDAAA provision extending the period of
             exclusivity for certain drugs or the possible applicability of the Orphan
             Drug Act to antibiotics had or may affect their decisions to market, seek
             approval, or develop antibiotics. We also asked these sponsors to
             describe the incentives that would motivate them to develop and market
             antibiotics.

             For both objectives, we reviewed FDA documents and interviewed FDA
             officials. In addition, to obtain stakeholder views on FDA’s implementation
             of the relevant FDAAA provisions, we interviewed representatives from
             the Infectious Diseases Society of America, the Pharmaceutical Research
             and Manufacturers of America, the Generic Pharmaceutical Association,
             and the Clinical and Laboratory Standards Institute.

             We conducted this performance audit from December 2010 to January
             2012 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.


             FDA’s mission is to protect the public health by ensuring the safety and
Background   effectiveness of human drugs marketed in the United States. The
             agency’s responsibilities begin years before a drug is marketed and
             continue after a drug’s approval.


             10
               An NME is a drug that contains an active chemical substance that has never been
             approved for marketing in the United States in any form and is therefore generally
             considered innovative.




             Page 5                                                           GAO-12-218 Antibiotics
FDA and the Drug   FDA oversees the drug development process. Among other things, FDA
Approval Process   reviews drug sponsors’ proposals for conducting clinical trials, assesses
                   drug sponsors’ applications for the approval of new drugs, and publishes
                   guidance for industry on various topics. Once drugs are marketed in the
                   United States, FDA has the responsibility to continue to monitor their
                   safety and efficacy and to enforce drug sponsors’ compliance with
                   applicable laws and regulations. FDA also annually publishes a list of
                   drugs approved for sale within the United States, the Approved Drug
                   Products with Therapeutic Equivalence Evaluations, also known as the
                   Orange Book. In addition, since February 2005, FDA has provided
                   updates via the Electronic Orange Book on brand-name drug approvals
                   the month they are approved and on generic drug approvals daily. 11

                   FDA’s Center for Drug Evaluation and Research is responsible for
                   ensuring the safety and efficacy of drugs. Within this center, the Office of
                   New Drugs is responsible for reviewing new drug applications (NDA),
                   while the Office of Generic Drugs is responsible for reviewing applications
                   for generic drugs, which are abbreviated new drug applications (ANDA). 12
                   NDAs and ANDAs must be submitted by sponsors and approved by FDA
                   before a new brand-name or generic drug can be marketed in the United
                   States. As part of the approval process, FDA reviews proposed labeling
                   for both brand-name and generic drugs; a drug cannot be marketed
                   without an FDA-approved label. Among other things, a drug’s label
                   contains information for health care providers and specifically cites the
                   conditions and populations the drug has been approved to treat, as well
                   as effective doses of the drug. Sponsors of both new brand-name and
                   generic drugs are required to submit annual reports to FDA that include,
                   for example, updates about the safety and effectiveness of their drugs;
                   these annual reports are one way FDA monitors the safety and efficacy of
                   drugs once they are available for sale.




                   11
                    See http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.
                   12
                     Manufacturers may submit an ANDA to FDA to seek approval to market a generic
                   version of the drug after the period of exclusivity and any patents for a brand-name drug
                   expire.




                   Page 6                                                              GAO-12-218 Antibiotics
FDAAA Provisions Related      FDAAA contained three provisions related to antibiotic effectiveness and
to Antibiotic Effectiveness   innovation, each of which required FDA to take certain actions. One
and Innovation                provision required FDA to identify breakpoints “where such information is
                              reasonably available,” to periodically update them, and to make these up-
                              to-date breakpoints publicly available within 30 days of identifying or
                              updating them. 13

                              A second provision extended the duration of market exclusivity from
                              3 years to 5 years for new drugs that meet certain detailed, scientific
                              criteria. 14 Specifically, to obtain this additional exclusivity the NDA must
                              be for a new drug consisting of a single enantiomer of a previously
                              approved racemic drug. 15 The application for the drug must also be
                              submitted for approval in a different therapeutic category than the
                              previously approved drug and meet certain other requirements. 16 FDAAA
                              specified that FDA use the therapeutic categories established by the
                              United States Pharmacopeia to determine whether an application has
                              been submitted for a separate therapeutic category than the previously
                              approved drug. 17 It also required FDA to publish the list of therapeutic
                              categories developed by this organization that were in effect on the date
                              of the enactment of FDAAA.

                              A third provision authorized funding for grants and contracts under the
                              Orphan Drug Act and required FDA to convene a public meeting to
                              discuss incentives, such as those included in the Orphan Drug Act, to
                              develop or otherwise obtain market exclusivity for antibiotics that treat


                              13
                                Pub. L. No. 110-85, § 1111, 121 Stat. 823, 975-76 (2007).
                              14
                               The provision applies to new drugs of any type that meet the criteria, not just antibiotics.
                              Pub. L. No. 110-85, § 1113, 121 Stat. 823, 976-77 (2007).
                              15
                                A racemic drug consists of two enantiomers—molecules that are identical in atomic
                              constitution and bonding, but are mirror images of each other—in equal proportions. There
                              may be therapeutic benefits from isolating a single enantiomer from a racemic drug.
                              16
                                Other criteria necessary to qualify for this extended market exclusivity include a
                              requirement that the sponsor must submit full reports of new clinical investigations and the
                              application must not rely on any investigations that are part of the application submitted for
                              the previously approved drug. The extended exclusivity is only available for applications
                              submitted before October 1, 2012.
                              17
                                The United States Pharmacopeia is a nongovernmental, official public standards-setting
                              authority for prescription and over-the-counter drugs. It sets standards for the quality,
                              purity, identity, and strength of these products. Its Model Guidelines is a list of therapeutic
                              categories and pharmacologic classes.




                              Page 7                                                                 GAO-12-218 Antibiotics
                             serious and life-threatening infectious diseases. 18 Incentives are intended
                             to counter some of the business risks a drug sponsor must undertake
                             when developing antibiotics. For example, the Orphan Drug Act provides
                             incentives including a 7-year period of marketing exclusivity to sponsors
                             of approved orphan drugs, a tax credit of 50 percent of the cost of
                             conducting human clinical testing, research grants for clinical testing of
                             new therapies to treat orphan diseases, and exemption from the fees that
                             are typically charged when sponsors submit NDAs for FDA’s review.
                             Sponsors may also be eligible for a faster review of their applications for
                             market approval.


FDA’s and Drug Sponsors’     Sponsors of all drugs are required to keep the information on their drug
Responsibilities to Ensure   labels accurate. Unlike labels for most other types of drugs, labels for
Up-to-Date Breakpoints on    antibiotics contain breakpoints. 19 These breakpoints may continue to
                             change over time, and the sponsors of antibiotics are tasked with the
Labels
                             additional responsibility of maintaining up-to-date breakpoints on labels.
                             Although sponsors are required to maintain up-to-date breakpoints on
                             their labels, FDA has acknowledged that many antibiotics are labeled with
                             outdated breakpoints. Outdated breakpoints can result in health care
                             providers unknowingly selecting ineffective treatments, which can also
                             contribute to additional bacterial resistance to antibiotics.

                             Monitoring breakpoints on labels and keeping them up to date can be a
                             challenging process. The most accurate way to monitor and determine if
                             a breakpoint on a label is up to date is to conduct both clinical trials and
                             laboratory studies, but these can be difficult and expensive and may not
                             be appropriate in all circumstances. For example, clinical trials require the
                             enrollment of large numbers of patients, which may be difficult to achieve,
                             to ensure an understanding of a drug’s safety and effectiveness against
                             specific bacteria. Enrollment may also be difficult for clinical trials
                             involving antibiotic-resistant bacteria. Unlike clinical trials for a new
                             cancer drug, for example, where researchers are able to target drugs to a
                             patient population with a specific type of cancer, this may not necessarily



                             18
                              Pub. L. No. 110-85, § 1112, 121 Stat. 823, 976 (2007).
                             19
                               See 21 C.F.R. § 201.57(c)(2)(i)(C) (2011). In general, breakpoints are established based
                             on in vivo and in vitro information provided by the sponsor. In vivo testing is that which is
                             performed in a living organism, such as an animal, while in vitro testing is performed in a
                             laboratory using components of a living organism.




                             Page 8                                                               GAO-12-218 Antibiotics
be the case for antibacterial drugs. There are no rapid diagnostic tests
available to help a researcher identify patients with antibiotic-resistant
infections who would be eligible for such trials. Laboratory studies, such
as susceptibility testing, can be less costly than clinical trials; however,
they still require significant microbiology expertise. Susceptibility testing
reveals an antibiotic’s breakpoint—that is, its ability to kill or inhibit the
growth of a specific bacterial pathogen. As such, the results of such tests
can provide a sponsor with some data to help update its antibiotic label
with more accurate information. Guidelines for developing appropriate
susceptibility tests are available from standards-setting organizations,
such as the Clinical and Laboratory Standards Institute. 20 Sponsors may
obtain information from such organizations to help them conduct
susceptibility tests for their antibiotics or otherwise determine if the
breakpoints on their antibiotic labels are up to date. According to FDA
officials, much of this information is available free online and at
conferences. 21

When new information becomes available that may cause the label to
become inaccurate, false, or misleading—such as information on
increased bacterial resistance to antibiotics—drug sponsors are
responsible for updating their drug labels. 22 Label changes of this type
require FDA’s approval. 23 A sponsor must submit an application
supplement to FDA with evidence to support the need for a label change.
A sponsor’s responsibility for maintaining a drug’s label persists
throughout the life cycle of the drug—that is, from the time the drug is first
approved until FDA withdraws its approval of the drug. 24 A drug is not



20
  The Clinical and Laboratory Standards Institute is a consensus-based organization that
develops standards with input from stakeholders in government, industry, and laboratories
to promote accurate antimicrobial susceptibility testing and appropriate reporting.
21
  For example, FDA told us that scientific information is discussed twice yearly at the
Clinical and Laboratory Standards Institute meetings and may be available to interested
persons by request or online at its website (http://www.clsi.org).
22
 See 21 C.F.R. § 201.56(a)(2) (2011).
23
 See 21 C.F.R. §§ 314.70, 314.97 (2011).
24
  The process to withdraw approval of a drug can be initiated by either FDA or the drug
sponsor, for a variety of reasons (e.g., if the drug poses an imminent hazard to public
health, if there are other safety concerns, or if there are concerns about the drug’s
effectiveness in dosage or strength) or if the sponsor makes a business decision to no
longer manufacture the drug. See 21 C.F.R. § 314.150 (2011).




Page 9                                                             GAO-12-218 Antibiotics
considered withdrawn until FDA publishes a Federal Register notice
officially announcing its withdrawal. A sponsor may also decide to
discontinue manufacturing a drug without withdrawal. Sponsors that
decide to discontinue marketing a drug are still responsible for
maintaining accurate labels. Unlike a drug that is withdrawn, a
discontinued drug for which approval has not been withdrawn is one that
the sponsor has stopped marketing, but that it may resume marketing
without obtaining permission to do so from FDA. Discontinued drugs are
identified as such in the discontinued section of the Orange Book. 25

FDA designates certain drugs as “reference-listed drugs” and the
sponsors of these drugs play an important role in ensuring the accuracy
of drug labels, especially for antibiotic labels. A reference-listed drug is an
approved drug product to which generic versions are compared. FDA
assigns at least one marketed drug per active ingredient, dosage, and
route of administration as a reference-listed drug and indicates this status
in the Orange Book. FDA generally designates brand-name drugs—those
approved through the NDA process—as reference-listed drugs at the time
of their approval. Sponsors of generic drugs—those approved through the
ANDA process—must cite or “reference” the reference-listed drug in their
applications. Sponsors of ANDAs must demonstrate that their generic
drugs are bioequivalent to, and perform in the same manner as, the
reference-listed drug. In addition, sponsors of generic drugs are required
to follow the labels of the corresponding reference-listed drug. 26 They
therefore are expected to incorporate any updates made to the label of
the reference-listed drug, such as new safety warnings, indications, or up-




25
   FDA does not have a standard mechanism for determining whether a company has
actually discontinued marketing a drug. Agency officials stated that they most often
become aware of a discontinued drug when they review sponsors’ annual reports or when
a generic sponsor contacts FDA and informs the agency that an approved drug included
in the Orange Book no longer appears to be marketed, and thus cannot be referenced in
the generic sponsor’s ANDA as the product it intends to copy. The officials added that
there is no specific amount of time that must pass before a nonmarketed drug becomes
listed as discontinued.
26
  Federal regulations allow ANDA’s labels to differ from the label of the corresponding
reference-listed drug in certain ways, such as manufacturer name or expiration date. See
21 C.F.R. § 314.94(a)(8)(iv) (2011).




Page 10                                                           GAO-12-218 Antibiotics
                      to-date breakpoints, into their generic drugs’ labels. 27 A drug maintains its
                      reference-listed drug designation until its approval is withdrawn or a
                      finding is made by FDA that a discontinued reference-listed drug was
                      withdrawn from the market for safety or effectiveness reasons. 28 In either
                      of these cases, FDA will designate a different drug as the reference-listed
                      drug and publish this change in the Orange Book. FDA will generally
                      designate the generic version of the drug with the largest market share as
                      the new reference-listed drug. In this case, the labels of other generic
                      versions of the drug will be expected to follow the label of the newly
                      designated generic, reference-listed drug.


                      FDA has not taken sufficient steps to implement the FDAAA provision
FDA Has Not Taken     regarding preserving antibiotic effectiveness by ensuring that antibiotic
Sufficient Steps to   labels contain up-to-date breakpoints. In 2008 FDA requested that
                      sponsors respond to the agency regarding whether their antibiotics’ labels
Ensure That           included up-to-date breakpoints, but FDA has not yet confirmed whether
Antibiotic Labels     the majority of these labels are accurate. FDA also took the step of
Contain Up-to-Date    issuing guidance in 2009 on sponsors’ responsibility to maintain up-to-
                      date breakpoints on their antibiotics’ labels, but the agency has not been
Information           systematically tracking sponsors’ responsiveness.




                      27
                        A case decided by the U.S. Supreme Court, Pliva, Inc. v. Mensing, addressed the
                      obligations of generic drug sponsors to keep their drug labels up to date. The Supreme
                      Court ruled on June 23, 2011, that such sponsors cannot be held liable under state law for
                      failing to include new safety warnings on their labels because warnings need to be
                      identical to those on the label of the corresponding reference-listed drug. The court ruled
                      that it is impossible for sponsors to comply with both federal law prohibiting generic drug
                      sponsors from changing their labels from that of the reference-listed drug without FDA’s
                      permission and state law requiring sponsors to update their labels when they learn of new
                      safety information, and that generic manufacturers must comply with the federal
                      requirement. See Pliva, Inc. v. Mensing, 131 S.Ct. 2567 (2011). FDA is in the process of
                      reviewing the court’s decision and determining what impact it may have on generic drug
                      sponsors and sponsors of reference-listed drugs and what action FDA should take.
                      28
                       See 21 C.F.R. § 314.161(e) 2011.




                      Page 11                                                             GAO-12-218 Antibiotics
FDA Has Taken Some          Although FDA has taken steps to update breakpoint information on
Steps, but Has Not Yet      antibiotic labels, as of November 2011, it has not confirmed that the
Confirmed That              information is up to date for most reference-listed antibiotics. As one step
                            in FDA’s efforts to implement the FDAAA provision regarding antibiotic
Breakpoint Information Is   effectiveness, FDA identified 210 antibiotics and, in January and February
Up-to-Date for Many         2008, sent letters to the sponsors of these drugs reminding them of the
Antibiotics                 importance of regularly updating the breakpoints on their antibiotic labels.
                            In addition, the letters requested that sponsors evaluate and maintain the
                            currency of breakpoints included on their labels and within 30 days submit
                            evidence to FDA showing that the breakpoints were either current or
                            needed revision. Sponsors that could not submit this evidence within
                            30 days were advised to provide the agency with a timetable for when
                            they expected to respond with this information. If sponsors determined
                            that their antibiotic labels needed revision, the agency’s letter instructed
                            them to submit a label supplement. FDA’s letters also highlighted to
                            sponsors that all subsequent annual reports should include an evaluation
                            of these breakpoints and document the status of any needed changes to
                            the antibiotic label.

                            As of November 2011, over 3.5 years after FDA sent its letters, 146, or
                            70 percent, of the 210 antibiotics are still labeled with breakpoints that
                            have not been updated or confirmed to be up to date. For 78 of the
                            146 antibiotics, FDA has not yet received a submission regarding the
                            currency of the breakpoints; for 12 of the antibiotics, the sponsors’
                            submissions are pending FDA review; and for 56 of the antibiotics, FDA
                            determined that the sponsors’ submission was inaccurate or incomplete
                            and therefore requested a revision or additional information. Thus far,
                            FDA has determined that 64, or 30 percent, of the 210 antibiotics have
                            up-to-date breakpoints (see fig. 1). (See app. II for more details on the
                            status of the labels of the 210 antibiotics.)




                            Page 12                                                 GAO-12-218 Antibiotics
Figure 1: Status of Labels for 210 Antibiotics




One reason so many antibiotics still have breakpoints that FDA has not
confirmed to be up to date is that many sponsors have not fulfilled the
responsibilities outlined in FDA’s 2008 letters. FDA officials stated that the
agency has followed up with sponsors that had not responded at all to the
2008 letters; however, it did not begin to do so until 2010—2 years after it
asked sponsors to respond within 30 days—and two sponsors have still
not informed FDA when they intend to submit the requested information.
FDA officials told us that they routinely monitor the status of all requested
submissions that they have not yet received. In particular, they told us
that they have contacted sponsors to set time frames for submitting the
requested information, and that they follow up with sponsors that do not
submit information within the time frames established. FDA has not



Page 13                                                   GAO-12-218 Antibiotics
pursued regulatory action against any of these sponsors. FDA officials
stated that the agency could take regulatory action against a sponsor
whose label contained outdated breakpoints, as federal regulations
require all sponsors of drugs to maintain accurate labels. However, the
officials added that in order for FDA to take regulatory action against a
sponsor, FDA would first have to be able to prove that the breakpoint on
the antibiotic label was not up to date.

Another reason many antibiotics still have breakpoints on their labels that
FDA has not confirmed to be up to date is that FDA faced difficulty in
keeping up with the workload that resulted from sponsors’ breakpoint
submissions. According to FDA officials, it should take 1 to 3 months for
the agency to review such submissions when staff are available and the
submissions include all of the necessary information. However, it took
FDA longer than a year to review many of the submissions it received,
and as of November 2011, FDA still had a backlog of five submissions
from 2008. FDA officials identified four factors that have contributed to the
lengthy time between when the agency received a submission and when
it completed its review. First, FDA officials explained that the submissions
sent in response to the agency’s 2008 letter generated a larger number of
supplements than normal, adding significantly to FDA’s existing workload
of label supplements. Second, some of the submissions required
significantly more resources to review than typical label supplements,
because of challenging scientific issues or difficulties obtaining data.
Third, some of the sponsors’ submissions were inaccurate or did not
include all necessary information. Fourth, FDA staff spent a significant
amount of time answering questions from sponsors, tracking responses,
and following up when needed.

Some of the sponsors we obtained comments from expressed frustration
at how long it took FDA to review their submissions, especially given that
bacterial resistance to antibiotics is not static and breakpoints may
continue to change over time. 29 Specifically, 3 of the 26 sponsors we
obtained comments from stated that they are concerned that the



29
  When asked how the FDAAA provision on antibiotic effectiveness influenced their
interest in developing, seeking FDA approval to market, or continuing to market
antibiotics, officials from all sponsors that replied to this question told us that it did not
have an influence. However, eight sponsors noted that the financial burdens associated
with maintaining up-to-date breakpoints could deter a sponsor from marketing an
antibiotic.




Page 14                                                                 GAO-12-218 Antibiotics
                              breakpoints they submitted may be outdated by the time FDA completes
                              its review. One of these sponsors told us that it was advised by FDA to
                              refrain from submitting new information before the agency completed its
                              review of the sponsor’s previously submitted label supplement. According
                              to the sponsor, FDA officials said that providing new information would
                              result in the sponsor’s submission going to the end of FDA’s review
                              queue.

                              While the fact that breakpoints on the labels of 146 antibiotics may not be
                              up to date is troubling, there are additional reasons for concern. First,
                              nearly all of these 146 antibiotics are reference-listed drugs—thus, in
                              addition to the labels of these drugs, the labels of the generic antibiotics
                              that follow the labels of the reference-listed antibiotics are also uncertain.
                              Second, because bacterial resistance to antibiotics is not static, some of
                              the breakpoints for the 64 antibiotics that FDA has confirmed through its
                              review as up to date may have since become out of date. Third, FDA’s list
                              of 210 drugs did not include a complete list of all the antibiotics for which
                              sponsors are responsible for evaluating and maintaining the breakpoints
                              on their labels. For example, FDA did not include any brand-name drugs
                              that were discontinued at the time the agency compiled its list, and also
                              did not include some antibiotics that were reference-listed drugs at that
                              time. 30 FDA officials were unsure how many antibiotics were omitted, but
                              estimated that the number was low. Given the uncertainty surrounding the
                              146 antibiotics whose breakpoints have not yet been confirmed as well as
                              the antibiotics omitted from FDA’s 2008 request to sponsors, more than
                              two-thirds of reference-listed antibiotic labels may contain out-of-date
                              breakpoints.


FDA Issued Guidance on        Another step FDA took to implement the FDAAA provision regarding
Sponsors’ Responsibility to   preserving the effectiveness of antibiotics was to issue guidance that
Evaluate and Maintain Up-     reminded sponsors of the requirement to maintain accurate labels, and
                              thus, their responsibility to keep information about breakpoints up to
to-Date Breakpoints, but      date. 31 FDA officials stated that in part because the agency received
Has Not Been Tracking         questions in response to its 2008 letters, officials determined that it would
Their Responses               be useful to issue guidance. FDA first issued draft guidance in June 2008


                              30
                               Sponsors of discontinued, brand-name antibiotics retain responsibility for evaluating and
                              maintaining the breakpoints on their labels.
                              31
                               See 21 C.F.R. § 201.56(a)(2) (2011).




                              Page 15                                                            GAO-12-218 Antibiotics
and finalized it a year later, in June 2009. The guidance specified that the
sponsors of brand-name and generic antibiotics that are designated as
reference-listed drugs are responsible for evaluating their breakpoints on
labels at least annually and should include this evaluation in the sponsor’s
annual report to FDA. 32 When we asked for clarification as to whether the
guidance language limited this responsibility to the sponsors of those
brand-name antibiotics that are reference listed, FDA officials told us that
the guidance applied to sponsors of all brand-name antibiotics—both
those that were and were not reference listed, including those that are
discontinued—as well as sponsors of reference-listed, generic antibiotics.
The guidance also described approaches sponsors could take to
determine up-to-date breakpoints for their antibiotics. While FDA’s 2008
letters to certain sponsors communicated much of the same information,
FDA’s guidance was the first time that FDA specified (1) which sponsors
are responsible for evaluating their breakpoints, including that this
responsibility applied to sponsors of generic, reference-listed antibiotics,
and (2) the frequency with which sponsors needed to perform these
evaluations.

FDA has not been systematically tracking whether sponsors have been
responsive to the guidance. Specifically, FDA does not know what
percentage of antibiotic annual reports have included an evaluation of
breakpoints. At our request, FDA reviewed a small sample of annual
reports and this review suggested that sponsors’ responsiveness to the
annual reporting responsibility is low. FDA reviewed the most recent
annual reports for 19 of the 64 antibiotics that FDA confirmed to be
labeled with up-to-date breakpoints after receiving a response to the
agency’s 2008 letters. FDA found that 10 of the 19, or just over half, of
these annual reports included an evaluation of the antibiotics’
breakpoints. 33 Given the low level of sponsors’ responsiveness for this
group of antibiotics—that is, those for which a sponsor already responded
to FDA’s 2008 letter with a submission regarding the currency of their
breakpoints—the overall rate for all antibiotics is likely even lower.


32
  See FDA, Guidance for Industry: Updating Labeling for Susceptibility Test Information in
Systemic Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices
(June 2009).
33
  FDA looked at a subset of the 64 antibiotics that were also brand-name drugs and for
which the sponsor had submitted its most recent annual report electronically. Three of the
19 antibiotics in FDA’s sample had annual reports that noted that a label supplement was
recently approved but had not been implemented in time to be reflected in the report.




Page 16                                                            GAO-12-218 Antibiotics
Because bacterial resistance to antibiotics is not static, sponsors that do
not follow the guidance by evaluating their breakpoints on a regular basis
and sharing the results of their evaluation with FDA are unlikely to be able
to maintain accurate labels. FDA officials stated that they plan to track
compliance with the guidance in one of the agency’s drug databases by
January 1, 2012. FDA plans to have all annual reports for antibiotics
reviewed by FDA microbiologists who will use a standardized form to
document the assessment of the antibiotics’ breakpoints. In addition, the
agency plans to track whether the annual report included an evaluation of
the antibiotics’ breakpoints in an FDA database. FDA plans to follow up
with sponsors that do not include a complete evaluation of antibiotic
breakpoints in their annual reports to inform them about what information
was missing.

Some sponsors, particularly sponsors of generic, reference-listed
antibiotics, may not be following FDA’s guidance because they are
confused as to whether the responsibility to evaluate and maintain up-to-
date breakpoints on their labels, as described in the guidance, applies to
them. Fifteen sponsors we obtained comments from manufactured at
least one generic, reference-listed antibiotic—all were responsible for
evaluating and maintaining their breakpoints. Of these 15, 7 sponsors
expressed some form of confusion regarding their responsibility. 34 Five of
these 7 sponsors stated that their strategy for ensuring that the
breakpoints on their generic antibiotic labels were up to date was to follow
the breakpoints on the label of the corresponding brand-name drug. Two
of the 5 were even more specific and added that their generic antibiotics
were only designated reference-listed drugs “by default” and that their
strategy was to follow the label of the brand-name drug—even if the
brand-name drug was discontinued. One other sponsor was unsure
whether any of its generic antibiotics were reference-listed drugs or what
implications such a designation would have. A seventh sponsor
understood the responsibilities associated with having a generic antibiotic
that was designated a reference-listed drug, but was under the
impression that its generic antibiotic was not a reference-listed drug.




34
   Cumulatively, as of early 2008, these sponsors manufactured 35 generic, reference-
listed antibiotics.




Page 17                                                           GAO-12-218 Antibiotics
FDA officials told us that it is a sponsor’s responsibility to routinely
monitor FDA’s Orange Book to determine if any of its drugs become
designated a reference-listed drug. However, FDA’s June 2009 guidance
is silent on sponsors’ responsibility to consistently monitor the Orange
Book to determine if one of their drugs has become, or ceases to be, a
reference-listed drug. The officials acknowledged that there is no process
or mechanism for notifying sponsors when one of their drugs becomes, or
is no longer, a reference-listed drug. The guidance was also not explicit
about FDA’s view that the responsibility described in the guidance also
applied to sponsors of discontinued brand-name antibiotics.

The guidance also explained that FDA intended to comply with FDAAA’s
requirement that it identify, periodically update, and make publicly
available up-to-date breakpoints by using two approaches. First, the
guidance explained that the agency would review breakpoints referenced
in the labeling of individual drug products and post any approved labels
on the Internet. 35 FDA officials told us that this is the approach FDA has
thus far used to make up-to-date breakpoints publicly available. 36 Second,
FDA’s guidance also stated that it would, when appropriate, recognize
standards used to determine breakpoints from one or more standards-
setting organizations and publish these in the Federal Register. 37 FDA
has not yet used this approach and did not mention a specific plan or
timetable to do so. FDA officials told us that publishing this information in
the Federal Register could make the review process quicker as sponsors
would then have ready access to standards already recognized by FDA.



35
  FDA specified that it would publish labels with up-to-date breakpoints on the
Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda) or DailyMed
(http://dailymed.nlm.nih.gov/dailymed/about.cfm) websites.
36
   In October 2011, FDA notified us that it had also begun posting on a separate website a
list of all the antibiotic labels it has reviewed since 2008, along with the date on which FDA
determined the breakpoints on each label to be current. This list includes both antibiotics
for which FDA approved a label supplement and those for which FDA determined the
breakpoints on the current label were up to date. See
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER
/ucm275763.htm.
37
  The guidance also contained information on how sponsors should respond to the
publication of a recognized standard in the Federal Register. According to the guidance,
sponsors of brand-name antibiotics and generic, reference-listed antibiotics would have 90
days from FDA’s publication of a standard to submit updated product labeling, including
breakpoints based on the newly recognized standard, or provide a written explanation of
why the recognized standard was not applicable to their antibiotics.




Page 18                                                               GAO-12-218 Antibiotics
                            For example, publishing this information may be helpful for some
                            sponsors, such as those that do not have the microbiology expertise to
                            update their own breakpoints. While FDA officials said that they have
                            been making updated breakpoints publicly available, the agency’s
                            guidance regarding these alternative approaches may be causing
                            confusion among some sponsors that are anticipating the publication of
                            breakpoints from standards-setting organizations in the Federal Register.
                            This was the case for one sponsor we obtained comments from, which
                            stopped purchasing data from a standard-setting organization because it
                            believed FDA would be publishing recognized standards in the Federal
                            Register.


                            The FDAAA provision that grants extended market exclusivity has not
FDAAA Provisions            resulted in any sponsors submitting NDAs for antibiotics that qualify for
Related to Innovation       this exclusivity. Additionally, as required by FDAAA, FDA held a public
                            meeting to discuss incentives, such as those available under the Orphan
Do Not Appear to            Drug Act, to encourage antibiotic innovation. However, no changes were
Have Encouraged the         made to the availability of current incentives nor were any new incentives
Development of New          established following the public meeting.

Antibiotics
No New Drug Applications    To date, drug sponsors, including those we received comments from,
for Antibiotics Have Been   have not submitted any NDAs for antibiotics as a result of the FDAAA
Submitted under FDAAA’s     provision granting additional market exclusivity for new drugs containing
                            single enantiomers of previously approved racemic drugs. According to
Extended Market             FDA officials, they have received very few inquiries regarding this
Exclusivity Provision       provision and as of November 2011, no NDAs for antibiotics have been
                            submitted that would qualify for this exclusivity. FDA officials noted that
                            because it is a narrowly targeted provision, they are unsure if any existing
                            racemic drug could qualify. None of the drug sponsors from which we
                            obtained comments said that this FDAAA provision provided a sufficient
                            incentive to develop a new antibiotic of this type. 38

                            FDA officials stated that it was unlikely that this provision would have an
                            impact on antibiotic innovation. The officials stated that the requirement
                            that the single enantiomer of the approved drug be in a separate


                            38
                              One of the 26 drug sponsors we obtained information from did not provide a response to
                            our questions on the FDAAA provision related to antibiotic innovation.




                            Page 19                                                          GAO-12-218 Antibiotics
                            therapeutic category would be challenging for antibiotic sponsors to meet.
                            The officials noted that this market exclusivity was not limited to
                            antibiotics. One drug sponsor we spoke with stated that it is pursuing this
                            market exclusivity for a drug that is not an antibiotic.

                            The lack of NDAs for antibiotics submitted in response to this FDAAA
                            provision is consistent with the overall trend in the approval of innovative
                            antibiotic NDAs. The number of annual approvals of antibiotic NMEs from
                            2001 through 2010 has not changed significantly since the passage of
                            FDAAA. Specifically, the annual number of antibiotic NME approvals was
                            two or less for the years prior to, and one or less for the years following,
                            the enactment of FDAAA. Because drug development is a lengthy
                            process—sponsors spend, on average, 15 years developing a new
                            drug—it may be too early to ascertain the full impact of FDAAA on
                            antibiotic innovation. However, the extended exclusivity provided for in
                            FDAAA is only available to sponsors submitting qualifying NDAs before
                            October 1, 2012.


FDA Public Meeting          As required by FDAAA, FDA held a public meeting on April 28, 2008, to
Required by FDAAA           explore whether and how existing incentives and potential new incentives
Facilitated Discussion of   could be applied to promote the development of antibiotics as well as to
                            discuss whether infectious diseases may qualify for grants or other
Existing and Potential      incentives that may promote innovation. The meeting provided an
Incentives for Antibiotic   opportunity to gather input from stakeholders and address their concerns.
Innovation                  However, although potential new incentives and changes to current ones
                            were suggested at the meeting, many of these suggestions—such as tax
                            incentives and extended market exclusivities—would require a statutory
                            change.

                            One of the discussion topics at the public meeting related to the
                            circumstances under which antibiotics could qualify for incentives
                            provided under the Orphan Drug Act, which is intended to stimulate the
                            development of drugs for rare diseases—conditions that affect fewer than
                            200,000 people in the United States. Following the public meeting, FDA
                            responded in writing to an inquiry from one stakeholder to clarify that an
                            antibiotic could qualify for an orphan drug designation when the drug’s
                            use is restricted to the treatment of a small population of patients with an
                            infection caused by a specific pathogen. Our examination of FDA data
                            suggests that orphan drug designation is not common for antibiotics.
                            These data show that the annual number of antibiotics that received an
                            orphan drug designation from 2001 to 2007—when FDAAA was
                            enacted—was three drugs or fewer each year. The number of antibiotics


                            Page 20                                                  GAO-12-218 Antibiotics
that received orphan drug designation following FDAAA’s enactment in
2007 has remained constant at this rate through 2010. Additionally, not all
antibiotics that have been awarded orphan drug designation have been or
will apply to be approved for marketing. Of the 15 antibiotics that received
an orphan drug designation from 2001 through 2010, only 1 was
approved for marketing as of November 2011. 39

In addition to discussing the applicability of the Orphan Drug Act, the
agency gathered input during the public meeting from drug sponsors and
other parties—such as those in academia and professional
associations—on serious and life-threatening infectious diseases,
antibiotic resistance, and incentives for antibiotic innovation. The
incentives mentioned as useful mechanisms to encourage the innovation
and marketing of antibiotics were both financial and regulatory in nature
and are summarized in table 1.

Table 1: Incentives Discussed at 2008 FDA Public Meeting to Promote Antibiotic
Innovation

 •     Tax incentives for research and development
 •     Federal funding for certain early research activities
 •     Intellectual property incentives, such as extended market exclusivity
 •     Fast track approval process—a process designed to facilitate the innovation of and
       expedite FDA’s review of drugs that treat serious diseases and fill an unmet need
 •     Priority review voucher for quicker FDA review of a future drug application
 •     Regulatory clarity during the drug approval process, such as clearer guidelines for
       conducting clinical trials
 •     Placing antibiotics in a separate regulatory category so that sponsors may receive
       unique economic benefits, such as extended market exclusivities or tax benefits
Source: GAO analysis of the transcript of FDA’s public meeting held on April 28, 2008.



Consistent with the types of incentives identified by the participants at
FDA’s public meeting, sponsors that we obtained comments from
mentioned multiple incentives. They suggested that a combination of both
financial and regulatory incentives may prompt sponsors to develop new
antibiotics. These comments were consistent with the findings presented



39
  This antibiotic—Inhalational Aztreonam—provides inhalation therapy for the control of
gram-negative bacteria in the respiratory tract of patients with cystic fibrosis. It was
granted orphan drug designation before the enactment of FDAAA, on March 12, 2002,
and was approved for marketing on February 22, 2010.




Page 21                                                                                  GAO-12-218 Antibiotics
              in a 2009 study on antibiotic innovation. 40 When we asked these 26 drug
              sponsors to identify the incentives that would encourage them to develop
              antibiotics, market exclusivities were the most frequently identified
              incentive to develop antibiotics, mentioned by half (13 of 26) of the
              sponsors. Six drug sponsors noted that regulatory clarity, including
              specific guidance, would be an incentive to promote the innovation of
              antibiotics. Three drug sponsors also stated that priority review vouchers
              for new antibiotics—similar to those FDAAA made available to certain
              sponsors that received approval of treatments for tropical diseases—
              would promote antibiotic innovation because they could allow a future
              antibiotic to reach the market faster. For NDAs, FDA’s goal for priority
              review is to make a decision regarding drug approvals on 90 percent of
              the applications within 6 months of their submission. However, when
              considering incentives to promote antibiotic innovation, it is important to
              note that any incentive that extends market exclusivity for an innovator of
              antibiotics will, by definition, delay the entry of generic versions of those
              antibiotics into the market. 41 (App. III contains a timeline of FDA’s actions
              to implement FDAAA provisions related to antibiotic effectiveness and
              innovation.)


              The growing public health threat associated with bacterial resistance to
Conclusions   antibiotics makes the development of new antibiotics critical. Although
              FDAAA contained a provision to encourage the development of certain
              antibiotics, no sponsor has submitted an application for a new drug that
              meets the law’s specific criteria. FDAAA also recognized that up-to-date
              breakpoints are vital to preserving the effectiveness of antibiotics.
              Antibiotic labels containing out-of-date breakpoints can lead clinicians to
              choose less effective treatments and provide additional opportunities for
              bacteria to develop resistance. Out-of-date breakpoints on labels of
              reference-listed antibiotics also have a ripple effect on the accuracy of the
              labels of other antibiotics because other sponsors must match the labels



              40
                London School of Economics and Political Science, Policies and Incentives for
              Promoting Innovation in Antibiotic Research (London: 2009).
              41
                As members of the Interagency Task Force on Antimicrobial Resistance, which includes
              a variety of other federal agencies, HHS and FDA are involved in additional efforts to
              encourage the development of new antibiotics. For example, HHS is currently sponsoring
              a study to evaluate incentives to promote the development of antibacterial drugs for
              human use as well as rapid diagnostic tests. A report describing the study results is
              expected to be issued in 2012.




              Page 22                                                           GAO-12-218 Antibiotics
of the corresponding reference-listed drugs. However, more than 4 years
after FDAAA’s enactment, there continues to be uncertainty about the
accuracy of the labels of more than two thirds of reference-listed
antibiotics, as well as those of the generic antibiotics that are required to
follow these drugs’ labels.

The steps FDA has taken since the enactment of FDAAA have been
insufficient to ensure that all antibiotics have up-to-date breakpoints on
their labels. The agency has acted with neither decisiveness nor a sense
of urgency. First, FDA has not yet completed reviewing the submissions it
received in response to its 2008 request and many sponsors still have not
provided FDA with needed information. Further, FDA officials told us that
they sent letters to sponsors of 210 antibiotics. These sponsors were
responsible for evaluating and maintaining, and if necessary, updating the
breakpoints on their labels; however, FDA’s request was not made to all
the antibiotic sponsors that held this responsibility. While the agency did
follow up with sponsors, this was not done in a timely manner. FDA’s
review of sponsors’ submissions has also been time-consuming; given
that sponsors are expected to provide information on the effectiveness of
these breakpoints annually. It is unclear how the agency plans to keep up
with this workload if sponsors’ fulfillment of this responsibility improves.

Second, FDA’s issuance of guidance to specify the responsibilities of
antibiotics’ sponsors to evaluate breakpoints appears to have been
unsuccessful at encouraging all sponsors to fulfill these responsibilities.
The comments we received from drug sponsors indicate that some
antibiotic sponsors remain confused about this responsibility—either
because they did not know that their antibiotics were reference-listed
drugs or because they interpreted the June 2009 FDA guidance
differently than FDA intended. Without formal notification that their
antibiotics have been designated as reference-listed drugs and a
clarification of their responsibilities, sponsors may continue to be unaware
of, or have differing interpretations of a responsibility that ultimately helps
preserve antibiotic effectiveness.

The pace of FDA’s actions—many of which remain incomplete—means
that the majority of antibiotics we examined may have out-of-date
breakpoints on their labels that could result in the prescription of
ineffective treatments by health care providers and further contribute to
antibiotic resistance. This requires concerted action on the part of the
agency to help preserve the effectiveness of currently available
antibiotics.



Page 23                                                    GAO-12-218 Antibiotics
                      We recommend that the Commissioner of FDA take the following six
Recommendations for   actions to help ensure that antibiotics are accurately labeled:
Executive Action
                      •   expeditiously review sponsors’ submissions regarding the breakpoints
                          on their antibiotics’ labels;

                      •   take steps to obtain breakpoint information from sponsors that have
                          not yet submitted breakpoint information in response to the 2008
                          letters sent by the agency;

                      •   ensure that all sponsors responsible for the annual review of
                          breakpoints on their antibiotics’ labels—including discontinued brand-
                          name antibiotics and reference-listed antibiotics designated since
                          2008—have been reminded of their responsibility to evaluate and
                          maintain up-to-date breakpoints;

                      •   establish a process to track sponsors’ submissions of breakpoint
                          information included in their annual reports to ensure that such
                          information is submitted to FDA and reviewed by the agency in a
                          timely manner;

                      •   notify sponsors when one of their drugs becomes or ceases to be a
                          reference-listed drug; and

                      •   clarify or provide new guidance on which antibiotic sponsors are
                          responsible for annually evaluating and maintaining up-to-date
                          breakpoints on drug labels.



                      HHS reviewed a draft of this report and provided written comments, which
Agency Comments       are reprinted in appendix IV. In its comments, HHS acknowledged the
and Our Evaluation    importance of updating antibacterial breakpoints and said that FDA is
                      committed to ensuring that breakpoint information on drug labels is up to
                      date. Although HHS did not specifically indicate whether it agreed with
                      our recommendations, the agency stated that it will consider all of them
                      as it continues to improve its processes to ensure that antibacterial drug
                      labels contain up-to-date breakpoint information. HHS also stated that
                      FDA has already taken steps to expedite the review of sponsor
                      submissions regarding updated breakpoint information, which is
                      consistent with our recommendations.




                      Page 24                                                 GAO-12-218 Antibiotics
In addition, HHS expressed concern that our report did not fully capture
the challenges associated with updating the labels of antibacterial drugs.
HHS summarized the approach FDA used to address the provision in
FDAAA related to antibiotic effectiveness and highlighted the challenges
sponsors face in obtaining currently relevant and adequate scientific data
to assess antibiotic breakpoints. However, we believe that our report
accurately describes the same actions that HHS outlined in its comments.
Similarly, we believe that our report acknowledges the challenges
surrounding sponsors’ responsibility to maintain up-to-date breakpoints.
We recognize that these challenges pose difficulties for both sponsors
and FDA. However, FDA is ultimately responsible for ensuring that drugs,
including antibiotics, are safe and effective. Despite the agency’s efforts,
4 years have elapsed since FDA first began contacting drug sponsors
regarding the accuracy of the breakpoints on 210 of their antibiotics’
labels. Yet there continues to be uncertainty about the accuracy of the
labels for two-thirds of these drugs. Given the serious threat to public
health posed by antibiotic resistance, we believe that it is important that
our recommendations are implemented, in order to help preserve the
effectiveness of these critical drugs.

Finally, HHS provided us with new information, reporting that as of
December 12, 2011, the labeling for 66 antibacterial drugs has been
updated or found to be correct. This is an increase of 2 antibacterial
drugs, up from the 64 antibacterial drugs that are cited in our report. We
include this information here, but did not revise our report, as HHS did not
provide a complete update regarding all of the 210 antibiotics discussed
in this report. HHS also provided technical comments that were
incorporated, as appropriate.


We are sending copies of this report to the Secretary of Health and
Human Services and appropriate congressional committees. In addition,
the report will be available at no charge on the GAO website at
http://www.gao.gov.




Page 25                                                 GAO-12-218 Antibiotics
If you or your staffs have any questions about this report, please contact
me at (202) 512-7114 or crossem@gao.gov. Contact points for our Office
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 V.




Marcia Crosse
Director, Health Care




Page 26                                                GAO-12-218 Antibiotics
Appendix I: Drug Sponsors Contacted by
              Appendix I: Drug Sponsors Contacted by FDA
              in 2008 Regarding Information on Antibiotic
              Labels


FDA in 2008 Regarding Information on
Antibiotic Labels
              As one step in FDA’s efforts to implement the provision in the Food and
              Drug Administration Amendments Act of 2007 regarding antibiotic
              effectiveness, FDA identified 210 antibiotics for which sponsors were
              responsible for evaluating and maintaining and, if necessary, updating the
              breakpoints on their antibiotics’ labels. In January and February of 2008,
              FDA sent letters to the sponsors of these drugs reminding them of the
              importance of regularly updating the breakpoints on their antibiotic labels.
              In addition, the letters requested that sponsors evaluate and maintain the
              currency of breakpoints included on their labels and within 30 days submit
              evidence to FDA showing that the breakpoints were either current or
              needed revision. Of the 210 antibiotics, 126 were brand-name antibiotics
              and 84 were generic antibiotics, manufactured by 39 different sponsors.
              Table 2 identifies these 39 sponsors and whether the sponsor held a
              brand-name antibiotic, a generic antibiotic, or both.

              Table 2: Drug Sponsors Receiving Letters from FDA in 2008 in Response to the
              Food and Drug Administration Amendments Act of 2007 Regarding Information on
              Antibiotic Labels

                                        Sponsor held brand-name     Sponsor held generic
              Drug sponsor                     antibiotic                antibiotic
              Abbott                                 x                       x
              APP                                    x                       x
              Astellas                               x                       x
              AstraZeneca                            x
              B. Braun                               x                       x
              Baxter                                 x                       x
              Bayer                                  x
              Boehringer Ingelheim                                           x
              Bristol-Myers Squibb                   x                       x
              Cornerstone                            x
              Cubist                                 x
              DAVA                                                           x
              Depomed                                x
              Forest                                 x
              GlaxoSmithKline                        x                       x
              Hospira                                x                       x
              JHP                                    x
              Johnson & Johnson                      x
              King                                   x                       x
              Lupin                                                          x



              Page 27                                                  GAO-12-218 Antibiotics
Appendix I: Drug Sponsors Contacted by FDA
in 2008 Regarding Information on Antibiotic
Labels




                          Sponsor held brand-name   Sponsor held generic
 Drug sponsor                    antibiotic              antibiotic
 Medicis                                                     x
 Merck                                 x
 Mutual                                x
 Mylan                                                       x
 Novartis                              x                     x
 Par                                                         x
 Patheon                                                     x
 Pfizer                                x                     x
 Ranbaxy                                                     x
 Roche                                 x                     x
 Sanofi-aventis                        x
 Shionogi                              x
 Teva                                  x                     x
 Victory                               x
 ViroPharma                            x
 Warner Chilcott                       x
 Watson                                x
 West-Ward                                                   x
 X-GEN                                                       x
Source: FDA.




Page 28                                                GAO-12-218 Antibiotics
Appendix II: Status of Labels for 210
               Appendix II: Status of Labels for 210
               Antibiotics Specified in FDA’s 2008 Letters



Antibiotics Specified in FDA’s 2008 Letters


                                                                        Number of antibiotics for which
                                                                          specified action was taken
                                                                                        Abbreviated
                                                                         New drug         new drug
                                                                       applications     applications
                                                                             (NDA)           (ANDA)        Total
                   Breakpoints on antibiotic labels have been
                   updated or confirmed to be up to date
                   Label supplement submitted and approved                        50                  0       50
                   Current label confirmed as up to date                          13                  1       14
                   Subtotal                                                       63                  1       64
                   No update nor confirmation of currency
                   has been made for breakpoints on
                   antibiotic labels
                   FDA has not yet received a submission
                   regarding the currency of breakpoints
                       No response from sponsor                                    3                  1        4
                       Sponsor responded stating that the
                       antibiotic has been or would soon be
                       discontinued                                                2                17        19
                       Sponsor responded stating that the
                       antibiotic has been or would soon be
                       withdrawn                                                  14                  6       20
                       Sponsor responded with general
                                      a
                       correspondence                                             13                22        35
                       Subtotal                                                   32                46        78
                   Sponsor submission is under review by FDA                       6                  6       12
                   FDA reviewed sponsor submission and
                   requested a revision or additional information                 25                31        56
                   Subtotal                                                       63                83       146
                   Total                                                        126                 84       210
               Source: GAO analysis of FDA data as of November 2011.
               a
                The “general correspondence” category includes all communications by sponsors that did not consist
               of a submission regarding the currency of breakpoints included on their antibiotics’ labels or a
               communication that the antibiotic has been or would be withdrawn or discontinued. For example,
               some sponsors responded with questions about what information they needed to submit.




               Page 29                                                                  GAO-12-218 Antibiotics
Appendix III: Timeline of FDA
             Appendix III: Timeline of FDA Implementation
             of Certain Food and Drug Administration
             Amendments Act Provisions


Implementation of Certain Food and Drug
Administration Amendments Act Provisions




             a
              See FDA, Guidance for Industry: Updating Labeling for Susceptibility Test Information in Systemic
             Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices (June 2009).




             Page 30                                                                    GAO-12-218 Antibiotics
Appendix IV: Comments from the
             Appendix IV: Comments from the Department
             of Health and Human Services



Department of Health and Human Services




             Page 31                                     GAO-12-218 Antibiotics
Appendix IV: Comments from the Department
of Health and Human Services




Page 32                                     GAO-12-218 Antibiotics
Appendix IV: Comments from the Department
of Health and Human Services




Page 33                                     GAO-12-218 Antibiotics
Appendix IV: Comments from the Department
of Health and Human Services




Page 34                                     GAO-12-218 Antibiotics
Appendix V: GAO Contact and Staff
                  Appendix V: GAO Contact and Staff
                  Acknowledgments



Acknowledgments

                  Marcia Crosse, (202) 512-7114 or crossem@gao.gov
GAO Contact
                  In addition to the contact named above, Geri Redican-Bigott, Assistant
Staff             Director; Alison Binkowski; Ashley R. Dixon; Cathleen Hamann; Lisa
Acknowledgments   Motley; Patricia Roy; Laurie F. Thurber; and Jocelyn Yin made key
                  contributions to this report.




(290899)
                  Page 35                                               GAO-12-218 Antibiotics
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