Antibiotics: FDA Needs to Do More to Ensure That Drug Labels Contain Up-to-Date Information
Published: 2012-01-31T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.
section_title: What GAO Recommends
paragraphs: 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.

section_title: Letter
paragraphs: 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.  Meanwhile, the number of new antibiotics has steadily decreased since  the 1980s. 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,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. 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.
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. 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.
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.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   Specifically, we examined information related to 210  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. 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.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.
We received written or oral comments from 26 of the   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).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 also reviewed FDA’s efforts related to the FDAAA  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.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: FDA and the Drug Approval Process
paragraphs: 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.
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).
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.
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.
section_title: FDAAA Provisions Related to Antibiotic Effectiveness and Innovation
paragraphs: 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.
A second provision extended the duration of market exclusivity from   3 years to 5 years for new drugs that meet certain detailed, scientific  criteria. be for a new drug consisting of a single enantiomer of a previously  approved racemic drug. 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. 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.categories developed by this organization that were in effect on the date  of the enactment of FDAAA.
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). serious and life-threatening infectious diseases.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.
section_title: FDA’s and Drug Sponsors’ Responsibilities to Ensure Up-to-Date Breakpoints on Labels
paragraphs: 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. 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. 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.
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. Label changes of this type  require FDA’s approval. 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. 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.
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). to-date breakpoints, into their generic drugs’ labels. 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   In either  withdrawn from the market for safety or effectiveness reasons.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.
section_title: FDA Has Not Taken Sufficient Steps to Ensure That Antibiotic Labels Contain Up-to-Date Information
paragraphs: 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.
subsections: section_title: FDA Has Taken Some Steps, but Has Not Yet Confirmed That Breakpoint Information Is Up-to-Date for Many Antibiotics
paragraphs: 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.)
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. 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. 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.
section_title: FDA Issued Guidance on Sponsors’ Responsibility to Evaluate and Maintain Up- to-Date Breakpoints, but Has Not Been Tracking Their Responses
paragraphs: 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   FDA officials stated that in part because the agency received  date.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. 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. 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.
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.
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. 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. FDA officials told us that this is the approach FDA has  thus far used to make up-to-date breakpoints publicly available. Second,  FDA’s guidance also stated that it would, when appropriate, recognize  standards used to determine breakpoints from one or more standards-  FDA  setting organizations and publish these in the Federal Register.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.
section_title: FDAAA Provisions Related to Innovation Do Not Appear to Have Encouraged the Development of New Antibiotics
paragraphs: 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.
subsections: section_title: No New Drug Applications for Antibiotics Have Been Submitted under FDAAA’s Extended Market Exclusivity Provision
paragraphs: 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.
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.
section_title: FDA Public Meeting Required by FDAAA Facilitated Discussion of Existing and Potential Incentives for Antibiotic Innovation
paragraphs: 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.
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.
section_title: Conclusions
paragraphs: 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.
section_title: Recommendations for Executive Action
paragraphs: 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  clarify or provide new guidance on which antibiotic sponsors are  responsible for annually evaluating and maintaining up-to-date  breakpoints on drug labels.
section_title: Agency Comments and Our Evaluation
paragraphs: 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  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.
section_title: Appendix I: Drug Sponsors Contacted by FDA in 2008 Regarding Information on Antibiotic Labels
paragraphs: 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.
section_title: Appendix II: Status of Labels for 210 Antibiotics Specified in FDA’s 2008 Letters
paragraphs: Number of antibiotics for which  (NDA)
Abbreviated  new drug  applications  (ANDA)
section_title: Appendix III: Timeline of FDA Implementation of Certain Food and Drug Administration Amendments Act Provisions
paragraphs: Appendix III: Timeline of FDA Implementation  of Certain Food and Drug Administration  Amendments Act Provisions See FDA, Guidance for Industry: Updating Labeling for Susceptibility Test Information in Systemic  Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices (June 2009).
section_title: Appendix IV: Comments from the Department of Health and Human Services
section_title: Appendix V: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Staff Acknowledgments
paragraphs: 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.