Antibiotics:

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

GAO-12-218: Published: Jan 31, 2012. Publicly Released: Jan 31, 2012.

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Marcia G. Crosse
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crossem@gao.gov

 

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What GAO Found

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

The FDAAA provisions related to antibiotic innovation have not resulted in the submission of new drug applications for antibiotics. FDAAA extended the period of time that sponsors of new drugs that meet certain criteria have exclusive right to market the drug. According to FDA officials, the agency has received very few inquiries regarding this provision and, as of November 2011, no new drug applications for antibiotics have been submitted that would qualify for this exclusivity. None of the drug sponsors GAO received comments from said that this provision provided sufficient incentive to develop a new antibiotic of this type. FDAAA also required that FDA hold a public meeting to discuss whether and how existing or potential incentives could be applied to promote the development of antibiotics. Both financial and regulatory incentives were discussed at FDA’s 2008 meeting, including tax incentives for research and development and providing greater regulatory clarity during the drug approval process.

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.

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

Status Legend:

More Info
  • Review Pending-GAO has not yet assessed implementation status.
  • Open-Actions to satisfy the intent of the recommendation have not been taken or are being planned, or actions that partially satisfy the intent of the recommendation have been taken.
  • Closed-implemented-Actions that satisfy the intent of the recommendation have been taken.
  • Closed-not implemented-While the intent of the recommendation has not been satisfied, time or circumstances have rendered the recommendation invalid.
    • Review Pending
    • Open
    • Closed - implemented
    • Closed - not implemented

    Recommendations for Executive Action

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should expeditiously review sponsors' submissions regarding the breakpoints on their antibiotics' labels.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but in August 2013 stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. FDA also said that it has already taken steps to expedite the review of sponsor submissions regarding updated breakpoint information, which is consistent with our recommendation. FDA reported in 2013 that the agency has made "considerable progress" in reviewing and updating breakpoints, and is striving to address breakpoint updates in a timely manner. Information supplied in August 2013 show that 108 of 210 antibiotic labels were reviewed, and if appropriate, were updated. According to information on FDA's website in mid-November 2013, that number had risen to 136 of 210.

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should 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.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. FDA reported in August 2013 that all sponsors who received a letter in 2008 and continue to market the product have "responded". However, FDA did not indicate what the response consisted of (questions regarding reporting format, a request for an extension to submit data, etc.). Regardless, the breakpoints could have changed since the 2008 letters were sent.

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should 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.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. In August 2013 FDA said it has "worked proactively" to review and update the susceptibility interpretive criteria for 108 products and is in the process of completing this review for the remaining reference-listed antibacterial drugs. It added that it maintains a database for all supplements related to breakpoints and conducts regular meetings to facilitate the management of these supplements.

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should 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.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. FDA reported in August 2013 that it uses Excel worksheets to track the breakpoint update status of all antibacterial reference-listed drugs (RLD). Once the breakpoints for a product are updated, FDA said it reviews the need for additional updates at the time the applicant submits its annual report. Once breakpoints are updated, FDA said it updates the publicly available list of products on FDA's website. FDA stated it continues to work proactively to review and update as needed the susceptibility interpretive criteria for the remaining RLDs. If an update is needed, FDA sends the sponsor a Supplement Request Letter, which includes the recommended labeling update. The sponsor has the option of submitting data if they do not agree with the recommendation.

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should notify sponsors when one of their drugs becomes or ceases to be a reference-listed drug.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but in August 2013 stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. FDA reported in August 2013 that notification of FDA changes to the list of reference listed drugs (RLD) are done through changes in the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), which is updated monthly, available on-line at and serves as notification. FDA has no other process established to individually notify sponsors when a drug becomes, or ceases to be, an RLD. FDA reported that notification is not necessary where a product is no longer the RLD because a firm has either discontinued or withdrawn its product from the market. Firms that want to market a version of a drug product that is not the RLD submit a citizen petition to FDA to request this. This is a public process, and the notification is the petition response. FDA does notify in writing the holder of Abbreviated New Drug Applications for antibiotics when they are designated the RLD, and it is necessary to update susceptibility interpretive criteria (breakpoints). In these cases FDA is proactive and able to notify most sponsors verbally that their drug is being designated the RLD. FDA is in the process of hiring more people to assist with the notification process. However, FDA does notify applicants regarding new safety information that should be included in the labeling.

    Recommendation: To help ensure that antibiotics are accurately labeled, the Commissioner of FDA should clarify or provide new guidance on which antibiotic sponsors are responsible for annually evaluating and maintaining up-to-date breakpoints on drug labels.

    Agency Affected: Department of Health and Human Services: Food and Drug Administration

    Status: Open

    Comments: FDA did not specifically indicate whether it agreed with this recommendation, but stated that it will consider it as it continues to improve its processes to ensure that antibacterial drug labels contain up-to-date breakpoint information. FDA did not indicate whether it believes this recommendation should be considered open or closed. In August 2013, FDA said it published guidance for industry regarding sponsor responsibilities for maintaining up-to-date breakpoints on labels. It was published to inform industry how FDA intends to comply with section 1111 of FDAAA, which addresses the identification of breakpoints in antibacterial drug products. The guidance cites the long-standing requirement at 21 CFR 201.56(a)(2) for applicants to periodically update labeling when new information becomes available that causes the labeling to become inaccurate. It also notes the Annual Report requirement which provides an ongoing opportunity for applicants to review and update breakpoints. In addition FDA has sent letters to companies that have helped to provide clarity regarding their responsibility to maintain updated breakpoints.

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