This is the accessible text file for GAO report number GAO-12-218 
entitled 'Antibiotics: FDA Needs to Do More to Ensure That Drug Labels 
Contain Up-to-Date Information' which was released on January 31, 2012. 

This text file was formatted by the U.S. Government Accountability 
Office (GAO) to be accessible to users with visual impairments, as 
part of a longer term project to improve GAO products' accessibility. 
Every attempt has been made to maintain the structural and data 
integrity of the original printed product. Accessibility features, 
such as text descriptions of tables, consecutively numbered footnotes 
placed at the end of the file, and the text of agency comment letters, 
are provided but may not exactly duplicate the presentation or format 
of the printed version. The portable document format (PDF) file is an 
exact electronic replica of the printed version. We welcome your 
feedback. Please E-mail your comments regarding the contents or 
accessibility features of this document to Webmaster@gao.gov. 

This is a work of the U.S. government and is not subject to copyright 
protection in the United States. It may be reproduced and distributed 
in its entirety without further permission from GAO. Because this work 
may contain copyrighted images or other material, permission from the 
copyright holder may be necessary if you wish to reproduce this 
material separately. 

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: 

GAO Highlights: 

Highlights of GAO-12-218, a report to congressional committees. 

Why GAO Did This Study: 

Antibiotics are critical drugs that have saved millions of lives. 
Growing bacterial resistance to existing drugs and the fact that few 
new drugs are in development are public health concerns. The Food and 
Drug Administration Amendments Act of 2007 (FDAAA) required the Food 
and Drug Administration (FDA), an agency within the Department of 
Health and Human Services (HHS), to identify, periodically update, and 
make publicly available up-to-date breakpoints, the concentrations at 
which bacteria are categorized as susceptible to an antibiotic. 
Breakpoints are a required part of an antibiotic’s label and are used 
by providers to determine appropriate treatments. FDAAA provided a 
financial incentive for antibiotic innovation and required FDA to hold 
a public meeting on antibiotic incentives and innovation. FDAAA 
directed GAO to report on the impact of these provisions on new drugs. 
This report (1) assesses FDA’s efforts to help preserve antibiotic 
effectiveness by ensuring breakpoints on labels are up to date and (2) 
examines the impact of the antibiotic innovation provisions. GAO 
examined FDA data, guidance, and other documents; interviewed FDA 
officials; and obtained information from drug sponsors, such as 
manufacturers, that market antibiotics. 

What GAO Found: 

What GAO Found
FDA has not taken sufficient steps to ensure that antibiotic labels 
contain up-to-date breakpoints. 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. Reference-
listed drugs are approved drug products to which generic versions are 
compared. As of November 2011, FDA had not yet confirmed whether the 
breakpoints on the majority of reference-listed antibiotics labels 
were up to date. FDA contacted sponsors of 210 antibiotics in early 
2008 to remind sponsors of the importance of maintaining their labels 
and requested that they assess whether the breakpoints on their drugs’ 
labels were up to date. Sponsors were asked to submit evidence to FDA 
showing that the breakpoints were either current or needed revision. 
As of November 2011, over 3.5 years after FDA contacted sponsors, the 
agency had not yet confirmed whether the breakpoints on the labels of 
70 percent, or 146 of the 210 antibiotics, were up to date. FDA has 
not ensured that sponsors have fulfilled the responsibilities outlined 
in the early 2008 letters. For those submissions FDA has received, it 
has often taken over a year for FDA to complete its review. Officials 
attributed this delay to reviewers’ workload, challenging scientific 
issues or difficulties in obtaining needed data, and incomplete 
submissions. FDA also issued guidance to clarify sponsors’ 
responsibility to evaluate and maintain up-to-date breakpoints. The 
guidance reminded sponsors that they are required to maintain accurate 
labels and stated that certain sponsors should submit an evaluation of 
breakpoints on their antibiotic labels to FDA annually. However, FDA 
has not been systematically tracking whether sponsors are providing 
these annual updates. Some sponsors remain confused about their 
responsibility to evaluate and maintain up-to-date breakpoints. At GAO’
s request, FDA reviewed a small sample of annual reports and 
determined that few sponsors appear to be responsive to the guidance. 

The FDAAA provisions related to antibiotic innovation have not 
resulted in the submission of new drug applications for antibiotics. 
FDAAA extended the period of time that sponsors of new drugs that meet 
certain criteria have exclusive right to market the drug. According to 
FDA officials, the agency has received very few inquiries regarding 
this provision and, as of November 2011, no new drug applications for 
antibiotics have been submitted that would qualify for this 
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. FDAAA also required that FDA hold a public 
meeting to discuss whether and how existing or potential incentives 
could be applied to promote the development of antibiotics. Both 
financial and regulatory incentives were discussed at FDA’s 2008 
meeting, including tax incentives for research and development and 
providing greater regulatory clarity during the drug approval process. 

What GAO Recommends: 

GAO recommends that the Commissioner of FDA take steps to help ensure 
antibiotic labels contain up-to-date information, such as by 
expediting the agency’s review of breakpoint submissions. HHS said it 
will consider implementing GAO’s recommendations. 

View [hyperlink, http://www.gao.gov/products/GAO-12-218]. For more 
information, contact Marcia Crosse at (202) 512-7114 or 
crossem@gao.gov. 

[End of section] 

Contents: 

Letter: 

Background: 

FDA Has Not Taken Sufficient Steps to Ensure That Antibiotic Labels 
Contain Up-to-Date Information: 

FDAAA Provisions Related to Innovation Do Not Appear to Have 
Encouraged the Development of New Antibiotics: 

Conclusions: 

Recommendations for Executive Action: 

Agency Comments and Our Evaluation: 

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

Appendix II: Status of Labels for 210 Antibiotics Specified in FDA's 
2008 Letters: 

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

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

Appendix V: GAO Contact and Staff Acknowledgments: 

Tables: 

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

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: 

Figure: 

Figure 1: Status of Labels for 210 Antibiotics: 

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: 

[End of section] 

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.[Footnote 1] Meanwhile, the number of new 
antibiotics has steadily decreased since the 1980s.[Footnote 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 reported that the drug 
pipeline is "distressingly devoid" of new antibiotics,[Footnote 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.[Footnote 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.[Footnote 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 
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.[Footnote 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.[Footnote 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 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.[Footnote 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.[Footnote 9] We received written or oral 
comments from 26 of the 39 sponsors, representing 176 of the 210 
antibiotics. (See appendix 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 (2001-2010).[Footnote 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. 

Background: 

FDA's mission is to protect the public health by ensuring the safety 
and 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. 

FDA and the Drug Approval Process: 

FDA oversees the drug development process. Among other things, FDA 
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.[Footnote 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).[Footnote 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. 

FDAAA Provisions Related to Antibiotic Effectiveness and Innovation: 

FDAAA contained three provisions related to antibiotic effectiveness 
and innovation, each of which required FDA to take certain actions. 
One 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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 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. 
[Footnote 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 serious and life-threatening infectious diseases.[Footnote 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' Responsibilities to Ensure Up-to-Date 
Breakpoints on Labels: 

Sponsors of all drugs are required to keep the information on their 
drug labels accurate. Unlike labels for most other types of drugs, 
labels for antibiotics contain breakpoints.[Footnote 19] These 
breakpoints may continue to change over time, and the sponsors of 
antibiotics are tasked with the 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 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.[Footnote 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.[Footnote 
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.[Footnote 22] Label changes 
of this type require FDA's approval.[Footnote 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.[Footnote 24] A drug is not 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.[Footnote 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.[Footnote 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-to-date breakpoints, into their generic drugs' labels.[Footnote 
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.[Footnote 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 Ensure That Antibiotic Labels 
Contain Up-to-Date Information: 

FDA has not taken sufficient steps to implement the FDAAA provision 
regarding preserving antibiotic effectiveness by ensuring that 
antibiotic labels contain up-to-date breakpoints. In 2008 FDA 
requested that sponsors respond to the agency regarding whether their 
antibiotics' labels included up-to-date breakpoints, but FDA has not 
yet confirmed whether the majority of these labels are accurate. FDA 
also took the step of issuing guidance in 2009 on sponsors' 
responsibility to maintain up-to-date breakpoints on their 
antibiotics' labels, but the agency has not been systematically 
tracking sponsors' responsiveness. 

FDA Has Taken Some Steps, but Has Not Yet Confirmed That Breakpoint 
Information Is Up-to-Date for Many Antibiotics: 

Although FDA has taken steps to update breakpoint information on 
antibiotic labels, as of November 2011, it has not confirmed that the 
information is up to date for most reference-listed antibiotics. As 
one step in FDA's efforts to implement the FDAAA provision regarding 
antibiotic effectiveness, FDA identified 210 antibiotics and, in 
January and February 2008, 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. 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 
figure 1). (See appendix II for more details on the status of the 
labels of the 210 antibiotics.) 

Figure 1: Status of Labels for 210 Antibiotics: 

[Refer to PDF for image: illustration] 

146 of the 210 antibiotics are labeled with breakpoints that have not 
been updated or confirmed to be up to date: 
* for 78 antibiotics, FDA has not yet received a submission; 
* for 12 antibiotics, submission is pending FDA review; 
* for 56 antibiotics, FDA is awaiting requested revision of submission. 

64 of the 210 antibiotics are labeled with breakpoints that have been 
updated or confirmed to be up to date: 
* for 50 antibiotics, breakpoints on the label have been updated; 
* for 14 antibiotics, FDA confirmed the breakpoints on the current 
label were still up to date. 

Source: GAO analysis of FDA data as of November 2011. 

[End of figure] 

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 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.[Footnote 29] Specifically, 3 of the 
26 sponsors we obtained comments from stated that they are concerned 
that the 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.[Footnote 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 Sponsors' Responsibility to Evaluate and 
Maintain Up-to-Date Breakpoints, but Has Not Been Tracking Their 
Responses: 

Another step FDA took to implement the FDAAA provision regarding 
preserving the effectiveness of antibiotics was to issue guidance that 
reminded sponsors of the requirement to maintain accurate labels, and 
thus, their responsibility to keep information about breakpoints up to 
date.[Footnote 31] FDA officials stated that in part because the 
agency received questions in response to its 2008 letters, officials 
determined that it would be useful to issue guidance. FDA first issued 
draft guidance in June 2008 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.[Footnote 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.[Footnote 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. 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.[Footnote 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. 

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.[Footnote 35] FDA officials told us that this 
is the approach FDA has thus far used to make up-to-date breakpoints 
publicly available.[Footnote 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.[Footnote 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. 
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. 

FDAAA Provisions Related to Innovation Do Not Appear to Have 
Encouraged the Development of New Antibiotics: 

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

No New Drug Applications for Antibiotics Have Been Submitted under 
FDAAA's Extended Market Exclusivity Provision: 

To date, drug sponsors, including those we received comments from, 
have not submitted any NDAs for antibiotics as a result of the FDAAA 
provision granting additional market exclusivity for new drugs 
containing single enantiomers of previously approved racemic drugs. 
According to FDA officials, they have received very few inquiries 
regarding this 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.[Footnote 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 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 Required by FDAAA Facilitated Discussion of 
Existing and Potential Incentives for Antibiotic Innovation: 

As required by FDAAA, FDA held a public meeting on April 28, 2008, to 
explore whether and how existing incentives and potential new 
incentives could be applied to promote the development of antibiotics 
as well as to discuss whether infectious diseases may qualify for 
grants or other incentives that may promote innovation. The meeting 
provided an opportunity to gather input from stakeholders and address 
their concerns. 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 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.[Footnote 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. 

[End of table] 

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 in a 2009 study on antibiotic innovation.[Footnote 
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. 
[Footnote 41] (Appendix III contains a timeline of FDA's actions to 
implement FDAAA provisions related to antibiotic effectiveness and 
innovation.) 

Conclusions: 

The growing public health threat associated with bacterial resistance 
to 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 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. 

Recommendations for Executive Action: 

We recommend that the Commissioner of FDA take the following six 
actions to help ensure that antibiotics are accurately labeled: 

* 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. 

Agency Comments and Our Evaluation: 

HHS reviewed a draft of this report and provided written comments, 
which are reprinted in appendix IV. In its comments, HHS acknowledged 
the 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. 

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 
[hyperlink, http://www.gao.gov]. 

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. 

Signed by: 

Marcia Crosse: 
Director, Health Care: 

[End of section] 

Appendix I: Drug Sponsors Contacted by 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: 

Drug sponsor: Abbott; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: APP; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Astellas; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: AstraZeneca; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: B. Braun; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Baxter; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Bayer; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Boehringer Ingelheim; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Bristol-Myers Squibb; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Cornerstone; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Cubist; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: DAVA; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Depomed; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Forest; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: GlaxoSmithKline; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Hospira; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: JHP; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Johnson & Johnson; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: King; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Lupin; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Medicis; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Merck; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Mutual; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Mylan; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Novartis; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Par; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Patheon; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Pfizer; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Ranbaxy; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Roche; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Sanofi-aventis; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Shionogi; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Teva; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: Victory; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: ViroPharma; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Warner Chilcott; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: Watson; 
Sponsor held brand-name antibiotic: [Check}; 
Sponsor held generic antibiotic: [Empty]. 

Drug sponsor: West-Ward; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Drug sponsor: X-GEN; 
Sponsor held brand-name antibiotic: [Empty]; 
Sponsor held generic antibiotic: [Check}. 

Source: FDA. 

[End of table] 

[End of section] 

Appendix II: Status of Labels for 210 Antibiotics Specified in FDA's 
2008 Letters: 

Breakpoints on antibiotic labels have been updated or confirmed to be 
up to date: 

Label supplement submitted and approved; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 50; 
Abbreviated new drug applications (ANDA): 0; 
Total: 50. 

Current label confirmed as up to date; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 13; 
Abbreviated new drug applications (ANDA): 1; 
Total: 14. 

Subtotal: 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 63; 
Abbreviated new drug applications (ANDA): 1; 
Total: 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; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 3; 
Abbreviated new drug applications (ANDA): 1; 
Total: 4. 

Sponsor responded stating that the antibiotic has been or would soon 
be discontinued; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 2; 
Abbreviated new drug applications (ANDA): 17; 
Total: 19. 

Sponsor responded stating that the antibiotic has been or would soon 
be withdrawn; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 14; 
Abbreviated new drug applications (ANDA): 6; 
Total: 20. 

Sponsor responded with general correspondence[A]; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 13; 
Abbreviated new drug applications (ANDA): 22; 
Total: 35. 

Subtotal: 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 32; 
Abbreviated new drug applications (ANDA): 46; 
Total: 78. 

Sponsor submission is under review by FDA; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 6; 
Abbreviated new drug applications (ANDA): 6; 
Total: 12. 

FDA reviewed sponsor submission and requested a revision or additional 
information; 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 25; 
Abbreviated new drug applications (ANDA): 31; 
Total: 56. 

Subtotal: 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 63; 
Abbreviated new drug applications (ANDA): 83; 
Total: 146. 

Total: 
Number of antibiotics for which specified action was taken: 
New drug applications (NDA): 126; 
Abbreviated new drug applications (ANDA): 84; 
Total: 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. 

[End of table] 

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

[Refer to PDF for image: timeline] 

September 27, 2007: 
The Food and Drug of Administration Amendments Act of 2007 (FDAAA) was 
signed into law.  

January & February of 2008: 
The Food and Drug Administration (FDA) sent letters to drug sponsors 
that held systemic antibiotics and were responsible for evaluating and 
maintaining their labels. FDA asked them to review the breakpoints and 
update them if necessary. 

April 28, 2008: 
FDA held a public meeting and requested public comments on antibiotic 
resistance, serious and life-threatening infectious diseases, and 
development incentives, such as those in the Orphan Drug Act, as 
required by FDAAA. 

June 12, 2008: 
FDA issued draft guidance explaining how it intended to comply with 
the FDAAA provision related antibiotic effectiveness.  

June 26, 2009: 
FDA issued final guidance explaining how it intended to comply with 
the FDAAA provision related antibiotic effectiveness[A].  

November 3, 2010: 
FDA published the United States Pharmacopeia (USP) Therapeutic Model 
Guidelines in effect as of September 27, 2007, as required by FDAAA. 

Source: GAO analysis of FDA information. 

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

[End of figure] 

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

Department of Health & Human Services: 
Office of The Secretary: 
Assistant Secretary for Legislation: 
Washington, DC 20201: 

December 19, 2011: 

Marcia Crosse: 
Director, Health Care: 
U.S. Government Accountability Office: 
441 G Street NW: 
Washington, DC 20548: 

Dear Ms. Crosse: 

Attached are comments on the U.S. Government Accountability Office's 
GAO) draft report entitled, "Antibiotics: FDA Needs to Do More to 
Ensure that Drug Labels Contain Up-to-Date Information" (GAO 12-218). 

The Department appreciates the opportunity to review this report 
before its publication. 

Sincerely, 

Signed by: 

Jim R. Esquea: 
Assistant Secretary for Legislation: 

Attachment: 

[End of letter] 

General Comments Of The Department Of Health and Human Services (HHS) 
On The Government Accountability Office's (GAO) Draft Report Entitled, 
"Antibiotics: FDA Needs To Do More To Ensure That Drug Labels Contain 
Up-To-Date Information" (GAO-12-218) 

The Department appreciates the opportunity to comment on this draft 
report. 

The Food and Drug Administration (FDA) views the updating of 
breakpoints for antibacterial drugs as an important area of work and 
is committed to continuing its efforts to ensure that breakpoint 
information is up-to-date. The agency acknowledges the importance of 
the issues that GAO has identified and indeed has been working very 
hard to address the concerns GAO raises. In fact, FDA already has 
taken steps to expedite the review of sponsor submissions regarding 
breakpoints for antibacterial drugs and obtain breakpoint information 
from sponsors that have not yet submitted information in response to 
the 2008 letters from the agency. Furthermore, FDA also has reminded 
sponsors on numerous occasions of their responsibility to evaluate and 
maintain up to date breakpoints. The agency will consider all of GAO's 
recommendations as it continues to improve its processes to ensure 
that antibacterial drug labels contain up-to-date breakpoint 
information. 

However, FDA is concerned that GAO's report does not fully capture the 
breadth of both FDA's efforts and the challenges associated with 
updating the labels of antibacterial drugs. We provide the following 
context for this draft report. 

The Food and Drug Administration Amendments Act (FDAAA) was signed 
into law in 2007, Section 1111 of FDAAA requires FDA to identify and 
periodically update susceptibility test interpretive criteria for 
antibacterial drug products and to make those findings publicly 
available.[[Footnote 1] In order to address this provision in FDAAA, 
the agency took several steps as described below. 

The agency sent letters to holders of certain antibacterial drug 
applications reminding them of the need to keep their drug product 
breakpoint information up-to-date and asking each firm for its plan to 
do so. In order to establish a streamlined process for industry and 
the agency to conduct this work, FDA published, a "Draft Guidance for 
Industry: Updating Labeling for Susceptibility Test Information in 
Systemic Antibacterial Drug Products and Antimicrobial Susceptibility 
Testing Devices" (breakpoints guidance) in June 2008. It described two 
general approaches that companies could use to update breakpoint 
information in drug product labeling: 

1. A more traditional approach, in which a company submits data in a 
labeling supplement that is then reviewed by the agency.[Footnote 2] 

2. A second approach, in which FDA would pre-review and publicly 
recognize (by publication in the Federal Register) individual drug and 
organism-specific susceptibility testing standards established by a 
nationally or internationally recognized standard development 
organization. Companies would then have the option of simply 
submitting labeling in compliance with the standard. 

FDA expected that the traditional approach of submitting a labeling 
supplement with scientific data to support a breakpoint change would 
be difficult for many sponsors to undertake, particularly firms that 
may not have clinical microbiology expertise. The FDA standards 
recognition process described in the second approach would allow 
companies with little expertise and resources to use scientifically 
sound, already FDA accepted standards, serve multiple firms who 
manufacture similar drugs with the same active ingredient (e.g., 
ampicillin), and avoid having each firm individually locate scientific 
data on how susceptibility patterns have evolved over time. In 
addition, the second approach would be a resource for firms that may 
not have clinical microbiology expertise. 

FDA finalized the breakpoint guidance in June 2009.[Footnote 3] The 
agency held a public Anti-Infective Drugs Advisory Committee Meeting 
on September 26, 2009 to get advice from the Committee on 
implementation of the procedures described in the guidance document 
and to provide information to stakeholders, including drug companies 
that market antibacterial drugs. 

Soon after the September 2009 Advisory Committee meeting, FDA received 
a Congressional letter that expressed serious concern about the 
propriety of FDA's use of the standards set by nationally or 
internationally recognized standard development organizations as 
described in FDA's breakpoints guidance. The letter also raised 
concerns about industry participation in the process of an outside 
organization setting the breakpoints. At this time, the agency shifted 
focus to work with companies to update labels for individual 
antibacterial drug products, using the traditional approach (i.e., by 
submission of individual labeling supplements for each drug 
application), as a practical way to continue making progress while the 
agency addressed the concerns raised by the Congressional letter. 

On February 4, 2010, FDA responded to the Congressional letter, 
explaining that the agency retains ultimate authority to either accept 
or reject standards set by nationally or internationally recognized 
standard development organizations, and that FDA will work with such 
organizations to promote transparency of procedures, evaluation of 
potential conflicts of interest, and the availability to the public of 
scientific explanations for changes to a standard. FDA asserted in its 
response that the process described in its guidance document and 
discussed at the Advisory Committee Meeting provides a means to 
appropriately update the labeling of antibacterial drugs. FDA 
continues to believe that the standards recognition process is an 
appropriate and feasible way to update breakpoints, and it may utilize 
this process in the future. 

Since 2009, a number of companies have submitted labeling supplements 
for their drug products (i.e., a traditional approach), and these 
supplements have varied in quality and completeness. 

Unfortunately, many submissions contain data that have been 
insufficient for FDA to arrive at updated breakpoints. FDA also notes 
that some companies have provided quality submissions leading to 
appropriate updates of their labels. 

As of December 12, 2011, the labeling for 66 antibacterial drugs has 
been updated or found to be correct. The agency has developed a public 
website that lists the systemic antibacterial drugs that have had 
their breakpoints updated, or were found to be up-to-date, and the 
date of the assessment.[Footnote 4] FDA expects this information will 
be useful to those interested in breakpoints. FDA also has a system 
for tracking such work and will soon be able to do so using its 
internal FDA electronic administrative record keeping system. 

The GAO report also notes some areas of either incorrect or incomplete 
knowledge on the part of some companies that they interviewed. It is 
critical that companies understand their responsibilities for keeping 
their antibacterial drug product labeling up-to-date, and that they 
submit labeling supplements with adequate data in order to update or 
keep antibacterial drug product labeling up-to-date. FDA has provided 
information to stakeholders on the topic of breakpoints and updating 
breakpoints through the previously mentioned breakpoints guidance 
document, a draft guidance document on submitting microbiological data 
for systemic antibacterial drugs,[Footnote 5] the October 26, 2009 FDA 
Anti-Infective Drugs Advisory Committee Meeting, interactions with 
sponsors in the setting of reviewing labeling supplements, and through 
presentations and attendance at scientific meetings on this topic. FDA 
looks forward to continued interactions with companies as they 
continue their efforts to update their drug product labeling. 

FDA has invested considerable time and effort over the last few years 
to update breakpoints. Evaluating and updating breakpoints is 
challenging, however. Before one can assess a breakpoint in product 
labeling, one needs to have data on the current breakpoint and how it 
is performing. Unfortunately, currently relevant and adequate 
scientific data to assess a breakpoint are not always available. When 
such data are not available from the drug sponsor, agency reviewers 
search the literature and query the archives of standard development 
organizations to identify such data. In some instances these efforts 
are successful, and in other cases the search may not yield data to 
address the question at hand. Even a successfully updated breakpoint 
may need to be updated as circumstances evolve. Despite these 
challenges, the agency is committed to the important public health 
goal of updating antibacterial drug breakpoints, and looks forward to 
continued progress in this area. 

Appendix IV Footnotes: 

[1] FDAAA (Public Law 110-85) available at: [hyperlink, 
http://www.gpo.gov/fdsys/pkg/PLAW-110pub185/pdf/PLAW-110pub185.pdf]. 

[2] The breakpoints guidance describes this approach in the context of 
when the sponsor believes that breakpoints different from the FDA 
recognized standard are appropriate for their product. It is also 
consistent with the general approach of submitting a labeling 
supplement with scientific data to support a labeling change. 

[3] Guidance for Industry: Updating Labeling for Susceptibility Test 
Information in Systemic Antibacterial Drug Products and Antimicrobial 
Susceptibility Testing Devices. (June 2009). available at: [hyperlink, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati
on/Guidances/UCM169359.pdf]. 

[4] FDA website on Antibacterial Product Labeling: Microbiology 
Susceptibility Interpretive Criteria (Breakpoints) and Quality Control 
Parameter Updates. Available at: [hyperlink, 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTob
acco/CDER/ucm275763.htm]. 

[5] Draft Guidance for Industry: Microbiological Data for Systemic 
Antibacterial Drug Products — Development, Analysis, and Presentation. 
(September 2009). available at: [hyperlink, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati
on/Guidances/UCM182288.pdf]. 

[End of section] 

Appendix V: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Marcia Crosse, (202) 512-7114 or crossem@gao.gov: 

Staff Acknowledgments: 

In addition to the contact named above, Geri Redican-Bigott, Assistant 
Director; Alison Binkowski; Ashley R. Dixon; Cathleen Hamann; Lisa 
Motley; Patricia Roy; Laurie F. Thurber; and Jocelyn Yin made key 
contributions to this report. 

[End of section] 

Footnotes: 

[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, [hyperlink, 
http://www.gao.gov/products/GAO-11-406] (Washington, D.C.: June 1, 
2011), and Antibiotic Resistance: Agencies Have Made Limited Progress 
Addressing Antibiotic Use in Animals, [hyperlink, 
http://www.gao.gov/products/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). 

[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). 

[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. 

[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. 

[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. 

[11] See [hyperlink, 
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. 

[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. 

[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. 

[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 [hyperlink, 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). 

[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). 

[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. 

[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. 

[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). 

[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. 

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

[35] FDA specified that it would publish labels with up-to-date 
breakpoints on the Drugs@FDA [hyperlink, 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda] or DailyMed 
[hyperlink, 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 [hyperlink, 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTob
acco/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. 

[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. 

[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. 

[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. 

[End of section] 

GAO’s Mission: 

The Government Accountability Office, the audit, evaluation, and 
investigative arm of Congress, exists to support Congress in meeting 
its constitutional responsibilities and to help improve the 
performance and accountability of the federal government for the 
American people. GAO examines the use of public funds; evaluates 
federal programs and policies; and provides analyses, recommendations, 
and other assistance to help Congress make informed oversight, policy, 
and funding decisions. GAO’s commitment to good government is 
reflected in its core values of accountability, integrity, and 
reliability. 

Obtaining Copies of GAO Reports and Testimony: 

The fastest and easiest way to obtain copies of GAO documents at no 
cost is through GAO’s website [hyperlink, http://www.gao.gov]. Each 
weekday afternoon, GAO posts on its website newly released reports, 
testimony, and correspondence. To have GAO e mail you a list of newly 
posted products, go to [hyperlink, http://www.gao.gov] and select “E-
mail Updates.” 

Order by Phone: 

The price of each GAO publication reflects GAO’s actual cost of 
production and distribution and depends on the number of pages in the 
publication and whether the publication is printed in color or black 
and white. Pricing and ordering information is posted on GAO’s 
website, [hyperlink, http://www.gao.gov/ordering.htm]. 

Place orders by calling (202) 512-6000, toll free (866) 801-7077, or 
TDD (202) 512-2537. 

Orders may be paid for using American Express, Discover Card, 
MasterCard, Visa, check, or money order. Call for additional 
information. 

Connect with GAO: 

Connect with GAO on facebook, flickr, twitter, and YouTube.
Subscribe to our RSS Feeds or E mail Updates. Listen to our Podcasts.
Visit GAO on the web at [hyperlink, http://www.gao.gov]. 

To Report Fraud, Waste, and Abuse in Federal Programs: 

Contact: 
Website: [hyperlink, http://www.gao.gov/fraudnet/fraudnet.htm]; 
E-mail: fraudnet@gao.gov; 
Automated answering system: (800) 424-5454 or (202) 512-7470. 

Congressional Relations: 

Katherine Siggerud, Managing Director, siggerudk@gao.gov, (202) 512-4400
U.S. Government Accountability Office, 441 G Street NW, Room 7125
Washington, DC 20548. 

Public Affairs: 
Chuck Young, Managing Director, youngc1@gao.gov, (202) 512-4800
U.S. Government Accountability Office, 441 G Street NW, Room 7149 
Washington, DC 20548.