ANTIBIOTICS

FDA Needs to Do 

More to Ensure That 

Drug Labels Contain 

Up-to-Date 

Information

Report to Congressional Committees

January 2012

GAO-12-218

United States Government Accountability Office

GAO
United States Government Accountability Office

Highlights of GAO-12-218, a report to 

congressional committees

January 2012

ANTIBIOTICS

FDA Needs to Do More to Ensure That Drug Labels 

Contain Up-to-Date Information

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 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. 

What GAO Found

FDA has not taken sufficient steps to ensure that antibiotic labels contain up-todate 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.

View GAO-12-218. For more information, 

contact Marcia Crosse at (202) 512-7114 or 

crossem@gao.gov.
Page i GAO-12-218 Antibiotics

Letter 1 

Background 5

FDA Has Not Taken Sufficient Steps to Ensure That Antibiotic 

Labels Contain Up-to-Date Information 11

FDAAA Provisions Related to Innovation Do Not Appear to Have 

Encouraged the Development of New Antibiotics 19

Conclusions 22

Recommendations for Executive Action 24

Agency Comments and Our Evaluation 24

Appendix I Drug Sponsors Contacted by FDA in 2008 Regarding Information 

on Antibiotic Labels 27

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

Appendix III Timeline of FDA Implementation of Certain Food and Drug 

Administration Amendments Act Provisions 30

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

Appendix V GAO Contact and Staff Acknowledgments 35

Tables 

Table 1: Incentives Discussed at 2008 FDA Public Meeting to 

Promote Antibiotic Innovation 21

Table 2: Drug Sponsors Receiving Letters from FDA in 2008 in 

Response to the Food and Drug Administration 

Amendments Act of 2007 Regarding Information on 

Antibiotic Labels 27

Contents
Page ii GAO-12-218 Antibiotics

Figure

Figure 1: Status of Labels for 210 Antibiotics 13

Abbreviations

ANDA abbreviated new drug application

FDA Food and Drug Administration

FDAAA Food and Drug Administration Amendments Act of 

 2007

HHS Department of Health and Human Services 

NDA new drug application

NME new molecular entity

This is a work of the U.S. government and is not subject to copyright protection in the 

United States. The published product may be reproduced and distributed in its entirety 

without further permission from GAO. However, because this work may contain 

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Page 1 GAO-12-218 Antibiotics

United States Government Accountability Office

Washington, DC 20548

January 31, 2012 

The Honorable Tom Harkin

Chairman

The Honorable Michael B. Enzi

Ranking Member

Committee on Health, Education, Labor, and Pensions

United States Senate

The Honorable Fred Upton

Chairman

The Honorable Henry A. Waxman

Ranking Member

Committee on Energy and Commerce

House of Representatives

Since the discovery of penicillin in 1928, antibiotics have played an 

important role in the care and well-being of people around the world. By 

destroying bacteria or inhibiting their growth in individuals with serious or 

potentially serious infections, antibiotics have saved millions of lives. 

Today, however, bacteria that cause serious infections in the United 

States and elsewhere are becoming resistant to antibiotics, making 

infections that once responded to these drugs more difficult to treat.1

Meanwhile, the number of new antibiotics has steadily decreased since 

the 1980s.2

 

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, 

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 

GAO-11-406 (Washington, 

D.C.: June 1, 2011), and Antibiotic Resistance: Agencies Have Made Limited Progress 

Addressing Antibiotic Use in Animals, GAO-11-801 (Washington, D.C.: Sept. 7, 2011). 

2

H.W. Boucher, et.al., Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious 

Diseases Society of America (Arlington, Va.: Clinical Infectious Diseases, 2009).

 
 

Page 2 GAO-12-218 Antibiotics

reported that the drug pipeline is “distressingly devoid” of new antibiotics,3

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.

and the scientific community recognizes the lack of new antibiotics in 

development as a significant concern.

4 Although high costs and failure rates 

make drug development risky for drug sponsors, creating a safe and 

effective new drug can be financially rewarding for the drug sponsor and 

beneficial to the public. However, antibiotics are often less profitable than 

other drugs because they are designed to work quickly and are typically 

administered for a brief duration. This makes them less lucrative 

investments for sponsors than drugs that treat chronic conditions, such as 

diabetes and arthritis, which may be taken for an extended period of time 

or even indefinitely. In addition, given the growing problem of resistance, 

an antibiotic may not remain effective long enough to produce a 

meaningful return on a sponsor’s investment.5

Maintaining the effectiveness of antibiotics, and the need for innovation, 

was addressed in several provisions of the Food and Drug Administration 

Amendments Act of 2007 (FDAAA). Regarding the effectiveness of 

antibiotics already on the market, FDAAA required FDA to identify, 

periodically update, and make publicly available, such as on the Internet, 

up-to-date antibiotic “breakpoints,” which are included on an antibiotic’s 

label and reflect the concentrations at which bacteria are categorized as 

susceptible to treatment with a given antibiotic. Labels that contain up-todate breakpoints are considered to be as accurate as possible and are 

used by health care providers to help determine the best antibiotic to treat 

a particular bacterial infection. Out-of-date breakpoints on antibiotic labels 

can result in providers unknowingly selecting ineffective antibiotic 

 

3

M.A. Hamburg, M.D., “FDA’s Efforts to Facilitate Antibiotic Approvals,” Infectious 

Diseases Society of America World Health Day Event, (Washington, D.C.: Apr. 7, 2011).

4

A drug sponsor is the person or entity that assumes responsibility for the marketing of a 

new drug, including responsibility for complying with applicable provisions of laws, such as 

the Federal Food, Drug, and Cosmetic Act and related regulations. The sponsor is usually 

an individual, partnership, corporation, government agency, manufacturer, or scientific 

institution.

5

Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates...A Public Health Crisis Brews

(Alexandria, Va.: Infectious Diseases Society of America, 2004). 
 

Page 3 GAO-12-218 Antibiotics

treatments, which can contribute to additional bacterial resistance to 

antibiotics. An antibiotic’s breakpoint, along with other information, is a 

required part of a drug’s label. However, determining whether a 

breakpoint has changed can be complex and scientifically challenging. 

FDA has found it difficult to ensure that sponsors maintain labels on 

antibiotics that contain up-to-date breakpoints. Regarding the need for 

innovative antibiotics, FDAAA extended the duration of “market 

exclusivity” for new drugs, including antibiotics that meet certain criteria. 

Specifically, FDAAA extended the period of time that the sponsor of a 

drug meeting the criteria has exclusive rights to market the drug. In 

addition, FDAAA directed FDA to convene a public meeting to discuss the 

circumstances under which infectious diseases may qualify for grants or 

other incentives that may promote innovation, such as those offered by 

the Orphan Drug Act.6

FDAAA directed us to report on the impact of these provisions on new 

drugs. This report (1) assesses FDA’s efforts to implement the FDAAA 

provision to help preserve antibiotic effectiveness by ensuring that 

breakpoints on labels are up to date and (2) examines the impact of the 

FDAAA provisions related to antibiotic innovation.

To examine FDA’s efforts to implement the FDAAA provision related to 

antibiotic effectiveness by ensuring that breakpoints on labels are up to 

date, we obtained information on FDA’s efforts to contact antibiotic 

sponsors regarding the accuracy of their antibiotics’ labels, including their 

breakpoints.7

 

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. 

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 

7

Breakpoints have been established for systemic antibiotics, which are administered 

intravenously, orally, or intramuscularly and affect the entire body. However, they have not 

been established for topical antibiotics, which are medicines applied to a localized area on 

the skin. In discussing breakpoints in this report, we use the term antibiotics to refer to 

systemic antibiotics for human use. 
 

Page 4 GAO-12-218 Antibiotics

consistency, and interviewed knowledgeable agency officials. Through 

this review, we determined that FDA’s information was incomplete. 

However, we found these data sufficiently reliable for our purposes. Of 

the 210 antibiotics, 126 were brand-name antibiotics and 84 were generic 

antibiotics—copies of brand-name drugs.8 We contacted each of the 

39 sponsors associated with the 210 antibiotics to obtain their views on 

FDA’s actions in response to the FDAAA provision on antibiotic 

effectiveness.9

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 

We received written or oral comments from 26 of the 

39 sponsors, representing 176 of the 210 antibiotics. (See app. I for a list 

of the 39 sponsors.) We discussed with FDA officials their plans to make 

up-to-date breakpoints on labels publicly available. We also reviewed 

FDA’s guidance to drug manufacturers on maintaining up-to-date 

breakpoints on labels.

 

8

When a new drug is developed it is classified by its chemical type and therapeutic 

potential. Once FDA approves a new drug, it is marketed under a brand name—a 

proprietary, trademark-protected name—by a single sponsor. Only that original sponsor 

may use the brand name. A generic drug uses a name reflecting its chemical makeup and 

must be the same as the original drug in dosage form, strength, route of administration, 

and conditions of use. When a sponsor submits an application to FDA to bring a generic 

version onto the market, it must provide evidence that the generic drug is bioequivalent—a 

drug containing identical amounts of the same active ingredient(s) as the brand-name 

drug. There may be more than one sponsor marketing a generic version of the same 

brand-name drug. 

9

In most cases we attempted to contact the sponsor FDA identified. However, in some 

cases, such as when the original sponsor had since merged with another sponsor, been 

divested of its assets, or gone bankrupt, we contacted the subsequent sponsor. After 

performing these adjustments, we found that the 126 brand-name antibiotics were 

associated with 29 drug sponsors and the 84 generic antibiotics were associated with 23 

drug sponsors. Thirteen of the sponsors marketed both brand-name and generic 

antibiotics among the 210 identified by FDA, so we contacted a total of 39 sponsors; 26 

agreed to speak to us or to provide us with written or oral comments.
 

Page 5 GAO-12-218 Antibiotics

(2001-2010).10

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 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.

We conducted this performance audit from December 2010 to January 

2012 in accordance with generally accepted government auditing 

standards. Those standards require that we plan and perform the audit to 

obtain sufficient, appropriate evidence to provide a reasonable basis for 

our findings and conclusions based on our audit objectives. We believe 

that the evidence obtained provides a reasonable basis for our findings 

and conclusions based on our audit objectives.

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

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.

 

10An 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.

Background 
 

Page 6 GAO-12-218 Antibiotics

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.11

FDA’s Center for Drug Evaluation and Research is responsible for 

ensuring the safety and efficacy of drugs. Within this center, the Office of 

New Drugs is responsible for reviewing new drug applications (NDA), 

while the Office of Generic Drugs is responsible for reviewing applications 

for generic drugs, which are abbreviated new drug applications (ANDA).12

NDAs and ANDAs must be submitted by sponsors and approved by FDA 

before a new brand-name or generic drug can be marketed in the United 

States. As part of the approval process, FDA reviews proposed labeling 

for both brand-name and generic drugs; a drug cannot be marketed 

without an FDA-approved label. Among other things, a drug’s label 

contains information for health care providers and specifically cites the 

conditions and populations the drug has been approved to treat, as well 

as effective doses of the drug. Sponsors of both new brand-name and 

generic drugs are required to submit annual reports to FDA that include, 

for example, updates about the safety and effectiveness of their drugs; 

these annual reports are one way FDA monitors the safety and efficacy of 

drugs once they are available for sale.

 

11See http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. 

12Manufacturers 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.

FDA and the Drug 

Approval Process
 

Page 7 GAO-12-218 Antibiotics

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 upto-date breakpoints publicly available within 30 days of identifying or 

updating them.13

A second provision extended the duration of market exclusivity from 

3 years to 5 years for new drugs that meet certain detailed, scientific 

criteria.14 Specifically, to obtain this additional exclusivity the NDA must 

be for a new drug consisting of a single enantiomer of a previously 

approved racemic drug.15 The application for the drug must also be 

submitted for approval in a different therapeutic category than the 

previously approved drug and meet certain other requirements.16 FDAAA 

specified that FDA use the therapeutic categories established by the 

United States Pharmacopeia to determine whether an application has 

been submitted for a separate therapeutic category than the previously 

approved drug.17

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 

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.

 

13Pub. L. No. 110-85, § 1111, 121 Stat. 823, 975-76 (2007).

14The 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).

15A 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.

16Other 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.

17The 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. 

FDAAA Provisions Related 

to Antibiotic Effectiveness 

and Innovation
 

Page 8 GAO-12-218 Antibiotics

serious and life-threatening infectious diseases.18 Incentives are intended 

to counter some of the business risks a drug sponsor must undertake 

when developing antibiotics. For example, the Orphan Drug Act provides 

incentives including a 7-year period of marketing exclusivity to sponsors 

of approved orphan drugs, a tax credit of 50 percent of the cost of 

conducting human clinical testing, research grants for clinical testing of 

new therapies to treat orphan diseases, and exemption from the fees that 

are typically charged when sponsors submit NDAs for FDA’s review. 

Sponsors may also be eligible for a faster review of their applications for 

market approval.

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.19

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 

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.

 

18Pub. L. No. 110-85, § 1112, 121 Stat. 823, 976 (2007).

19See 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.

FDA’s and Drug Sponsors’ 

Responsibilities to Ensure 

Up-to-Date Breakpoints on 

Labels
 

Page 9 GAO-12-218 Antibiotics

be the case for antibacterial drugs. There are no rapid diagnostic tests 

available to help a researcher identify patients with antibiotic-resistant 

infections who would be eligible for such trials. Laboratory studies, such 

as susceptibility testing, can be less costly than clinical trials; however, 

they still require significant microbiology expertise. Susceptibility testing 

reveals an antibiotic’s breakpoint—that is, its ability to kill or inhibit the 

growth of a specific bacterial pathogen. As such, the results of such tests 

can provide a sponsor with some data to help update its antibiotic label 

with more accurate information. Guidelines for developing appropriate 

susceptibility tests are available from standards-setting organizations, 

such as the Clinical and Laboratory Standards Institute.20 Sponsors may 

obtain information from such organizations to help them conduct 

susceptibility tests for their antibiotics or otherwise determine if the 

breakpoints on their antibiotic labels are up to date. According to FDA 

officials, much of this information is available free online and at 

conferences.21

When new information becomes available that may cause the label to 

become inaccurate, false, or misleading—such as information on 

increased bacterial resistance to antibiotics—drug sponsors are 

responsible for updating their drug labels.22 Label changes of this type 

require FDA’s approval.23 A sponsor must submit an application 

supplement to FDA with evidence to support the need for a label change. 

A sponsor’s responsibility for maintaining a drug’s label persists 

throughout the life cycle of the drug—that is, from the time the drug is first 

approved until FDA withdraws its approval of the drug.24

 

20The 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. 

A drug is not 

21For example, FDA told us that scientific information is discussed twice yearly at the 

Clinical and Laboratory Standards Institute meetings and may be available to interested 

persons by request or online at its website (http://www.clsi.org). 

22See 21 C.F.R. § 201.56(a)(2) (2011).

23See 21 C.F.R. §§ 314.70, 314.97 (2011).

24The process to withdraw approval of a drug can be initiated by either FDA or the drug 

sponsor, for a variety of reasons (e.g., if the drug poses an imminent hazard to public 

health, if there are other safety concerns, or if there are concerns about the drug’s 

effectiveness in dosage or strength) or if the sponsor makes a business decision to no 

longer manufacture the drug. See 21 C.F.R. § 314.150 (2011).
 

Page 10 GAO-12-218 Antibiotics

considered withdrawn until FDA publishes a Federal Register notice 

officially announcing its withdrawal. A sponsor may also decide to 

discontinue manufacturing a drug without withdrawal. Sponsors that 

decide to discontinue marketing a drug are still responsible for 

maintaining accurate labels. Unlike a drug that is withdrawn, a 

discontinued drug for which approval has not been withdrawn is one that 

the sponsor has stopped marketing, but that it may resume marketing 

without obtaining permission to do so from FDA. Discontinued drugs are 

identified as such in the discontinued section of the Orange Book.25

FDA designates certain drugs as “reference-listed drugs” and the 

sponsors of these drugs play an important role in ensuring the accuracy 

of drug labels, especially for antibiotic labels. A reference-listed drug is an 

approved drug product to which generic versions are compared. FDA 

assigns at least one marketed drug per active ingredient, dosage, and 

route of administration as a reference-listed drug and indicates this status 

in the Orange Book. FDA generally designates brand-name drugs—those 

approved through the NDA process—as reference-listed drugs at the time 

of their approval. Sponsors of generic drugs—those approved through the 

ANDA process—must cite or “reference” the reference-listed drug in their 

applications. Sponsors of ANDAs must demonstrate that their generic 

drugs are bioequivalent to, and perform in the same manner as, the 

reference-listed drug. In addition, sponsors of generic drugs are required 

to follow the labels of the corresponding reference-listed drug.26

 

25FDA 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.

They 

therefore are expected to incorporate any updates made to the label of

the reference-listed drug, such as new safety warnings, indications, or up26Federal regulations allow ANDA’s labels to differ from the label of the corresponding 

reference-listed drug in certain ways, such as manufacturer name or expiration date. See 

21 C.F.R. § 314.94(a)(8)(iv) (2011).
 

Page 11 GAO-12-218 Antibiotics

to-date breakpoints, into their generic drugs’ labels.27 A drug maintains its 

reference-listed drug designation until its approval is withdrawn or a 

finding is made by FDA that a discontinued reference-listed drug was 

withdrawn from the market for safety or effectiveness reasons.28 In either 

of these cases, FDA will designate a different drug as the reference-listed 

drug and publish this change in the Orange Book. FDA will generally 

designate the generic version of the drug with the largest market share as 

the new reference-listed drug. In this case, the labels of other generic 

versions of the drug will be expected to follow the label of the newly 

designated generic, reference-listed drug.

FDA has not taken sufficient steps to implement the FDAAA provision 

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-todate breakpoints on their antibiotics’ labels, but the agency has not been 

systematically tracking sponsors’ responsiveness.

 

27A 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.

28See 21 C.F.R. § 314.161(e) 2011.

FDA Has Not Taken 

Sufficient Steps to 

Ensure That 

Antibiotic Labels 

Contain Up-to-Date 

Information
 

Page 12 GAO-12-218 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 fig. 1). (See app. II for more details on the 

status of the labels of the 210 antibiotics.)

FDA Has Taken Some 

Steps, but Has Not Yet

Confirmed That 

Breakpoint Information Is 

Up-to-Date for Many 

Antibiotics 
 

Page 13 GAO-12-218 Antibiotics

Figure 1: Status of Labels for 210 Antibiotics

One reason so many antibiotics still have breakpoints that FDA has not 

confirmed to be up to date is that many sponsors have not fulfilled the 

responsibilities outlined in FDA’s 2008 letters. FDA officials stated that the 

agency has followed up with sponsors that had not responded at all to the 

2008 letters; however, it did not begin to do so until 2010—2 years after it 

asked sponsors to respond within 30 days—and two sponsors have still 

not informed FDA when they intend to submit the requested information. 

FDA officials told us that they routinely monitor the status of all requested 

submissions that they have not yet received. In particular, they told us 

that they have contacted sponsors to set time frames for submitting the 

requested information, and that they follow up with sponsors that do not 

submit information within the time frames established. FDA has not 
 

Page 14 GAO-12-218 Antibiotics

pursued regulatory action against any of these sponsors. FDA officials 

stated that the agency could take regulatory action against a sponsor 

whose label contained outdated breakpoints, as federal regulations 

require all sponsors of drugs to maintain accurate labels. However, the 

officials added that in order for FDA to take regulatory action against a 

sponsor, FDA would first have to be able to prove that the breakpoint on 

the antibiotic label was not up to date.

Another reason many antibiotics still have breakpoints on their labels that 

FDA has not confirmed to be up to date is that FDA faced difficulty in 

keeping up with the workload that resulted from sponsors’ breakpoint 

submissions. According to FDA officials, it should take 1 to 3 months for 

the agency to review such submissions when staff are available and the 

submissions include all of the necessary information. However, it took 

FDA longer than a year to review many of the submissions it received, 

and as of November 2011, FDA still had a backlog of five submissions 

from 2008. FDA officials identified four factors that have contributed to the 

lengthy time between when the agency received a submission and when 

it completed its review. First, FDA officials explained that the submissions 

sent in response to the agency’s 2008 letter generated a larger number of 

supplements than normal, adding significantly to FDA’s existing workload 

of label supplements. Second, some of the submissions required 

significantly more resources to review than typical label supplements, 

because of challenging scientific issues or difficulties obtaining data. 

Third, some of the sponsors’ submissions were inaccurate or did not 

include all necessary information. Fourth, FDA staff spent a significant 

amount of time answering questions from sponsors, tracking responses, 

and following up when needed.

Some of the sponsors we obtained comments from expressed frustration 

at how long it took FDA to review their submissions, especially given that 

bacterial resistance to antibiotics is not static and breakpoints may 

continue to change over time.29

 

29When 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.

Specifically, 3 of the 26 sponsors we 

obtained comments from stated that they are concerned that the 
 

Page 15 GAO-12-218 Antibiotics

breakpoints they submitted may be outdated by the time FDA completes 

its review. One of these sponsors told us that it was advised by FDA to 

refrain from submitting new information before the agency completed its 

review of the sponsor’s previously submitted label supplement. According 

to the sponsor, FDA officials said that providing new information would 

result in the sponsor’s submission going to the end of FDA’s review

queue.

While the fact that breakpoints on the labels of 146 antibiotics may not be 

up to date is troubling, there are additional reasons for concern. First, 

nearly all of these 146 antibiotics are reference-listed drugs—thus, in 

addition to the labels of these drugs, the labels of the generic antibiotics 

that follow the labels of the reference-listed antibiotics are also uncertain. 

Second, because bacterial resistance to antibiotics is not static, some of 

the breakpoints for the 64 antibiotics that FDA has confirmed through its 

review as up to date may have since become out of date. Third, FDA’s list 

of 210 drugs did not include a complete list of all the antibiotics for which 

sponsors are responsible for evaluating and maintaining the breakpoints 

on their labels. For example, FDA did not include any brand-name drugs 

that were discontinued at the time the agency compiled its list, and also 

did not include some antibiotics that were reference-listed drugs at that 

time.30 FDA officials were unsure how many antibiotics were omitted, but 

estimated that the number was low. Given the uncertainty surrounding the 

146 antibiotics whose breakpoints have not yet been confirmed as well as 

the antibiotics omitted from FDA’s 2008 request to sponsors, more than 

two-thirds of reference-listed antibiotic labels may contain out-of-date 

breakpoints.

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.31

 

30Sponsors of discontinued, brand-name antibiotics retain responsibility for evaluating and 

maintaining the breakpoints on their labels.

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 

31See 21 C.F.R. § 201.56(a)(2) (2011).

FDA Issued Guidance on 

Sponsors’ Responsibility to 

Evaluate and Maintain Upto-Date Breakpoints, but 

Has Not Been Tracking 

Their Responses
 

Page 16 GAO-12-218 Antibiotics

and finalized it a year later, in June 2009. The guidance specified that the 

sponsors of brand-name and generic antibiotics that are designated as 

reference-listed drugs are responsible for evaluating their breakpoints on 

labels at least annually and should include this evaluation in the sponsor’s 

annual report to FDA.32

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.

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.

33

 

32See FDA, Guidance for Industry: Updating Labeling for Susceptibility Test Information in 

Systemic Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices

(June 2009).

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.

33FDA looked at a subset of the 64 antibiotics that were also brand-name drugs and for 

which the sponsor had submitted its most recent annual report electronically. Three of the 

19 antibiotics in FDA’s sample had annual reports that noted that a label supplement was 

recently approved but had not been implemented in time to be reflected in the report.
 

Page 17 GAO-12-218 Antibiotics

Because bacterial resistance to antibiotics is not static, sponsors that do 

not follow the guidance by evaluating their breakpoints on a regular basis 

and sharing the results of their evaluation with FDA are unlikely to be able 

to maintain accurate labels. FDA officials stated that they plan to track 

compliance with the guidance in one of the agency’s drug databases by 

January 1, 2012. FDA plans to have all annual reports for antibiotics 

reviewed by FDA microbiologists who will use a standardized form to 

document the assessment of the antibiotics’ breakpoints. In addition, the 

agency plans to track whether the annual report included an evaluation of 

the antibiotics’ breakpoints in an FDA database. FDA plans to follow up 

with sponsors that do not include a complete evaluation of antibiotic 

breakpoints in their annual reports to inform them about what information 

was missing.

Some sponsors, particularly sponsors of generic, reference-listed 

antibiotics, may not be following FDA’s guidance because they are 

confused as to whether the responsibility to evaluate and maintain up-todate breakpoints on their labels, as described in the guidance, applies to 

them. Fifteen sponsors we obtained comments from manufactured at 

least one generic, reference-listed antibiotic—all were responsible for 

evaluating and maintaining their breakpoints. Of these 15, 7 sponsors 

expressed some form of confusion regarding their responsibility.34 Five of 

these 7 sponsors stated that their strategy for ensuring that the 

breakpoints on their generic antibiotic labels were up to date was to follow 

the breakpoints on the label of the corresponding brand-name drug. Two 

of the 5 were even more specific and added that their generic antibiotics 

were only designated reference-listed drugs “by default” and that their 

strategy was to follow the label of the brand-name drug—even if the 

brand-name drug was discontinued. One other sponsor was unsure

whether any of its generic antibiotics were reference-listed drugs or what 

implications such a designation would have. A seventh sponsor 

understood the responsibilities associated with having a generic antibiotic 

that was designated a reference-listed drug, but was under the 

impression that its generic antibiotic was not a reference-listed drug.

 

34Cumulatively, as of early 2008, these sponsors manufactured 35 generic, referencelisted antibiotics.
 

Page 18 GAO-12-218 Antibiotics

FDA officials told us that it is a sponsor’s responsibility to routinely 

monitor FDA’s Orange Book to determine if any of its drugs become 

designated a reference-listed drug. However, FDA’s June 2009 guidance 

is silent on sponsors’ responsibility to consistently monitor the Orange 

Book to determine if one of their drugs has become, or ceases to be, a 

reference-listed drug. The officials acknowledged that there is no process 

or mechanism for notifying sponsors when one of their drugs becomes, or 

is no longer, a reference-listed drug. The guidance was also not explicit 

about FDA’s view that the responsibility described in the guidance also 

applied to sponsors of discontinued brand-name antibiotics.

The guidance also explained that FDA intended to comply with FDAAA’s 

requirement that it identify, periodically update, and make publicly 

available up-to-date breakpoints by using two approaches. First, the 

guidance explained that the agency would review breakpoints referenced 

in the labeling of individual drug products and post any approved labels 

on the Internet.35 FDA officials told us that this is the approach FDA has 

thus far used to make up-to-date breakpoints publicly available.36 Second, 

FDA’s guidance also stated that it would, when appropriate, recognize 

standards used to determine breakpoints from one or more standardssetting organizations and publish these in the Federal Register.

37

 

35FDA specified that it would publish labels with up-to-date breakpoints on the 

Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda) or DailyMed 

(http://dailymed.nlm.nih.gov/dailymed/about.cfm) websites.

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. 

36In October 2011, FDA notified us that it had also begun posting on a separate website a 

list of all the antibiotic labels it has reviewed since 2008, along with the date on which FDA 

determined the breakpoints on each label to be current. This list includes both antibiotics 

for which FDA approved a label supplement and those for which FDA determined the 

breakpoints on the current label were up to date. See 

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER

/ucm275763.htm. 

37The guidance also contained information on how sponsors should respond to the 

publication of a recognized standard in the Federal Register. According to the guidance, 

sponsors of brand-name antibiotics and generic, reference-listed antibiotics would have 90 

days from FDA’s publication of a standard to submit updated product labeling, including 

breakpoints based on the newly recognized standard, or provide a written explanation of 

why the recognized standard was not applicable to their antibiotics.
 

Page 19 GAO-12-218 Antibiotics

For example, publishing this information may be helpful for some 

sponsors, such as those that do not have the microbiology expertise to 

update their own breakpoints. While FDA officials said that they have 

been making updated breakpoints publicly available, the agency’s 

guidance regarding these alternative approaches may be causing 

confusion among some sponsors that are anticipating the publication of 

breakpoints from standards-setting organizations in the Federal Register. 

This was the case for one sponsor we obtained comments from, which 

stopped purchasing data from a standard-setting organization because it 

believed FDA would be publishing recognized standards in the Federal 

Register. 

The FDAAA provision that grants extended market exclusivity has not 

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. 

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.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 

 

38One 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.

FDAAA Provisions 

Related to Innovation 

Do Not Appear to 

Have Encouraged the 

Development of New 

Antibiotics 

No New Drug Applications 

for Antibiotics Have Been 

Submitted under FDAAA’s 

Extended Market 

Exclusivity Provision
 

Page 20 GAO-12-218 Antibiotics

therapeutic category would be challenging for antibiotic sponsors to meet. 

The officials noted that this market exclusivity was not limited to 

antibiotics. One drug sponsor we spoke with stated that it is pursuing this 

market exclusivity for a drug that is not an antibiotic.

The lack of NDAs for antibiotics submitted in response to this FDAAA 

provision is consistent with the overall trend in the approval of innovative 

antibiotic NDAs. The number of annual approvals of antibiotic NMEs from 

2001 through 2010 has not changed significantly since the passage of 

FDAAA. Specifically, the annual number of antibiotic NME approvals was 

two or less for the years prior to, and one or less for the years following, 

the enactment of FDAAA. Because drug development is a lengthy 

process—sponsors spend, on average, 15 years developing a new 

drug—it may be too early to ascertain the full impact of FDAAA on 

antibiotic innovation. However, the extended exclusivity provided for in 

FDAAA is only available to sponsors submitting qualifying NDAs before 

October 1, 2012.

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 

FDA Public Meeting 

Required by FDAAA 

Facilitated Discussion of 

Existing and Potential 

Incentives for Antibiotic 

Innovation 
 

Page 21 GAO-12-218 Antibiotics

that received orphan drug designation following FDAAA’s enactment in 

2007 has remained constant at this rate through 2010. Additionally, not all 

antibiotics that have been awarded orphan drug designation have been or 

will apply to be approved for marketing. Of the 15 antibiotics that received 

an orphan drug designation from 2001 through 2010, only 1 was 

approved for marketing as of November 2011.39

In addition to discussing the applicability of the Orphan Drug Act, the 

agency gathered input during the public meeting from drug sponsors and 

other parties—such as those in academia and professional 

associations—on serious and life-threatening infectious diseases, 

antibiotic resistance, and incentives for antibiotic innovation. The 

incentives mentioned as useful mechanisms to encourage the innovation 

and marketing of antibiotics were both financial and regulatory in nature 

and are summarized in table 1.

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

Innovation

• Tax incentives for research and development

• Federal funding for certain early research activities

• Intellectual property incentives, such as extended market exclusivity

• Fast track approval process—a process designed to facilitate the innovation of and 

expedite FDA’s review of drugs that treat serious diseases and fill an unmet need

• Priority review voucher for quicker FDA review of a future drug application

• Regulatory clarity during the drug approval process, such as clearer guidelines for 

conducting clinical trials

• Placing antibiotics in a separate regulatory category so that sponsors may receive 

unique economic benefits, such as extended market exclusivities or tax benefits

Source: GAO analysis of the transcript of FDA’s public meeting held on April 28, 2008.

Consistent with the types of incentives identified by the participants at 

FDA’s public meeting, sponsors that we obtained comments from 

mentioned multiple incentives. They suggested that a combination of both 

financial and regulatory incentives may prompt sponsors to develop new 

antibiotics. These comments were consistent with the findings presented 

 

39This antibiotic—Inhalational Aztreonam—provides inhalation therapy for the control of 

gram-negative bacteria in the respiratory tract of patients with cystic fibrosis. It was 

granted orphan drug designation before the enactment of FDAAA, on March 12, 2002, 

and was approved for marketing on February 22, 2010.
 

Page 22 GAO-12-218 Antibiotics

in a 2009 study on antibiotic innovation.40 When we asked these 26 drug 

sponsors to identify the incentives that would encourage them to develop 

antibiotics, market exclusivities were the most frequently identified 

incentive to develop antibiotics, mentioned by half (13 of 26) of the 

sponsors. Six drug sponsors noted that regulatory clarity, including 

specific guidance, would be an incentive to promote the innovation of 

antibiotics. Three drug sponsors also stated that priority review vouchers 

for new antibiotics—similar to those FDAAA made available to certain 

sponsors that received approval of treatments for tropical diseases—

would promote antibiotic innovation because they could allow a future 

antibiotic to reach the market faster. For NDAs, FDA’s goal for priority 

review is to make a decision regarding drug approvals on 90 percent of 

the applications within 6 months of their submission. However, when 

considering incentives to promote antibiotic innovation, it is important to 

note that any incentive that extends market exclusivity for an innovator of 

antibiotics will, by definition, delay the entry of generic versions of those 

antibiotics into the market.41 (App. III contains a timeline of FDA’s actions 

to implement FDAAA provisions related to antibiotic effectiveness and 

innovation.)

The growing public health threat associated with bacterial resistance to 

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 

 

40London School of Economics and Political Science, Policies and Incentives for 

Promoting Innovation in Antibiotic Research (London: 2009).

41As 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.

Conclusions 
 

Page 23 GAO-12-218 Antibiotics

of the corresponding reference-listed drugs. However, more than 4 years 

after FDAAA’s enactment, there continues to be uncertainty about the 

accuracy of the labels of more than two thirds of reference-listed 

antibiotics, as well as those of the generic antibiotics that are required to 

follow these drugs’ labels.

The steps FDA has taken since the enactment of FDAAA have been 

insufficient to ensure that all antibiotics have up-to-date breakpoints on 

their labels. The agency has acted with neither decisiveness nor a sense 

of urgency. First, FDA has not yet completed reviewing the submissions it 

received in response to its 2008 request and many sponsors still have not 

provided FDA with needed information. Further, FDA officials told us that 

they sent letters to sponsors of 210 antibiotics. These sponsors were 

responsible for evaluating and maintaining, and if necessary, updating the 

breakpoints on their labels; however, FDA’s request was not made to all 

the antibiotic sponsors that held this responsibility. While the agency did 

follow up with sponsors, this was not done in a timely manner. FDA’s 

review of sponsors’ submissions has also been time-consuming; given 

that sponsors are expected to provide information on the effectiveness of 

these breakpoints annually. It is unclear how the agency plans to keep up 

with this workload if sponsors’ fulfillment of this responsibility improves.

Second, FDA’s issuance of guidance to specify the responsibilities of 

antibiotics’ sponsors to evaluate breakpoints appears to have been 

unsuccessful at encouraging all sponsors to fulfill these responsibilities. 

The comments we received from drug sponsors indicate that some 

antibiotic sponsors remain confused about this responsibility—either 

because they did not know that their antibiotics were reference-listed 

drugs or because they interpreted the June 2009 FDA guidance 

differently than FDA intended. Without formal notification that their 

antibiotics have been designated as reference-listed drugs and a 

clarification of their responsibilities, sponsors may continue to be unaware 

of, or have differing interpretations of a responsibility that ultimately helps 

preserve antibiotic effectiveness.

The pace of FDA’s actions—many of which remain incomplete—means 

that the majority of antibiotics we examined may have out-of-date 

breakpoints on their labels that could result in the prescription of 

ineffective treatments by health care providers and further contribute to 

antibiotic resistance. This requires concerted action on the part of the 

agency to help preserve the effectiveness of currently available 

antibiotics.
 

Page 24 GAO-12-218 Antibiotics

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 brandname antibiotics and reference-listed antibiotics designated since 

2008—have been reminded of their responsibility to evaluate and 

maintain up-to-date breakpoints;

• establish a process to track sponsors’ submissions of breakpoint 

information included in their annual reports to ensure that such 

information is submitted to FDA and reviewed by the agency in a 

timely manner;

• notify sponsors when one of their drugs becomes or ceases to be a 

reference-listed drug; and

• clarify or provide new guidance on which antibiotic sponsors are 

responsible for annually evaluating and maintaining up-to-date 

breakpoints on drug labels.

HHS reviewed a draft of this report and provided written comments, which 

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.

Recommendations for 

Executive Action

Agency Comments 

and Our Evaluation
 

Page 25 GAO-12-218 Antibiotics

In addition, HHS expressed concern that our report did not fully capture 

the challenges associated with updating the labels of antibacterial drugs. 

HHS summarized the approach FDA used to address the provision in 

FDAAA related to antibiotic effectiveness and highlighted the challenges 

sponsors face in obtaining currently relevant and adequate scientific data 

to assess antibiotic breakpoints. However, we believe that our report 

accurately describes the same actions that HHS outlined in its comments. 

Similarly, we believe that our report acknowledges the challenges 

surrounding sponsors’ responsibility to maintain up-to-date breakpoints.

We recognize that these challenges pose difficulties for both sponsors 

and FDA. However, FDA is ultimately responsible for ensuring that drugs, 

including antibiotics, are safe and effective. Despite the agency’s efforts, 

4 years have elapsed since FDA first began contacting drug sponsors 

regarding the accuracy of the breakpoints on 210 of their antibiotics’ 

labels. Yet there continues to be uncertainty about the accuracy of the 

labels for two-thirds of these drugs. Given the serious threat to public 

health posed by antibiotic resistance, we believe that it is important that 

our recommendations are implemented, in order to help preserve the 

effectiveness of these critical drugs.

Finally, HHS provided us with new information, reporting that as of 

December 12, 2011, the labeling for 66 antibacterial drugs has been 

updated or found to be correct. This is an increase of 2 antibacterial 

drugs, up from the 64 antibacterial drugs that are cited in our report. We 

include this information here, but did not revise our report, as HHS did not 

provide a complete update regarding all of the 210 antibiotics discussed 

in this report. HHS also provided technical comments that were 

incorporated, as appropriate.

We are sending copies of this report to the Secretary of Health and 

Human Services and appropriate congressional committees. In addition, 

the report will be available at no charge on the GAO website at 

http://www.gao.gov. 
 

Page 26 GAO-12-218 Antibiotics

If you or your staffs have any questions about this report, please contact 

me at (202) 512-7114 or crossem@gao.gov. Contact points for our Office 

of Congressional Relations and Public Affairs may be found on the last 

page of this report. GAO staff who made major contributions to this report 

are listed in appendix V.

Marcia Crosse

Director, Health Care
Appendix I: Drug Sponsors Contacted by FDA 

in 2008 Regarding Information on Antibiotic 

Labels

Page 27 GAO-12-218 Antibiotics

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

Sponsor held brand-name 

antibiotic

Sponsor held generic 

antibiotic

Abbott x x 

APP x x 

Astellas x x 

AstraZeneca x 

B. Braun x x 

Baxter x x 

Bayer x 

Boehringer Ingelheim x 

Bristol-Myers Squibb x x 

Cornerstone x 

Cubist x 

DAVA x 

Depomed x 

Forest x 

GlaxoSmithKline x x 

Hospira x x 

JHP x 

Johnson & Johnson x 

King x x 

Lupin x 

Appendix I: Drug Sponsors Contacted by 

FDA in 2008 Regarding Information on 

Antibiotic Labels
Appendix I: Drug Sponsors Contacted by FDA 

in 2008 Regarding Information on Antibiotic 

Labels

Page 28 GAO-12-218 Antibiotics

Drug sponsor

Sponsor held brand-name 

antibiotic

Sponsor held generic 

antibiotic

Medicis x 

Merck x 

Mutual x 

Mylan x 

Novartis x x 

Par x 

Patheon x 

Pfizer x x 

Ranbaxy x 

Roche x x 

Sanofi-aventis x 

Shionogi x 

Teva x x 

Victory x 

ViroPharma x 

Warner Chilcott x 

Watson x 

West-Ward x 

X-GEN x 

Source: FDA.
Appendix II: Status of Labels for 210 

Antibiotics Specified in FDA’s 2008 Letters

Page 29 GAO-12-218 Antibiotics

Number of antibiotics for which 

specified action was taken

New drug 

applications 

(NDA) 

Abbreviated 

new drug 

applications 

(ANDA) Total

Breakpoints on antibiotic labels have been 

updated or confirmed to be up to date

Label supplement submitted and approved 50 0 50

Current label confirmed as up to date 13 1 14

Subtotal 63 1 64

No update nor confirmation of currency 

has been made for breakpoints on 

antibiotic labels

FDA has not yet received a submission 

regarding the currency of breakpoints 

No response from sponsor 3 1 4 

Sponsor responded stating that the 

antibiotic has been or would soon be 

discontinued 2 17 19

Sponsor responded stating that the 

antibiotic has been or would soon be 

withdrawn 14 6 20

Sponsor responded with general 

correspondencea 13 22 35

Subtotal 32 46 78

Sponsor submission is under review by FDA 6 6 12

FDA reviewed sponsor submission and 

requested a revision or additional information 25 31 56

Subtotal 63 83 146

Total 126 84 210

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

a

The “general correspondence” category includes all communications by sponsors that did not consist 

of a submission regarding the currency of breakpoints included on their antibiotics’ labels or a 

communication that the antibiotic has been or would be withdrawn or discontinued. For example, 

some sponsors responded with questions about what information they needed to submit.

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

Page 30 GAO-12-218 Antibiotics

a

See FDA, Guidance for Industry: Updating Labeling for Susceptibility Test Information in Systemic 

Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices (June 2009).

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

Page 31 GAO-12-218 Antibiotics

Appendix IV: Comments from the 

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

of Health and Human Services

Page 32 GAO-12-218 Antibiotics
Appendix IV: Comments from the Department 

of Health and Human Services

Page 33 GAO-12-218 Antibiotics
Appendix IV: Comments from the Department 

of Health and Human Services

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

Acknowledgments

Page 35 GAO-12-218 Antibiotics

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

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.

Appendix V: GAO Contact and Staff 

Acknowledgments 

GAO Contact 

Staff 

Acknowledgments 

(290899)
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