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.

Recommendations for Executive Action

  1. Status: Open

    Comments: In 2014 FDA reported on its progress in updating the breakpoints of antibiotics that have been designated as Reference-Listed Drugs (RLD). Breakpoints represent the concentrations at which bacteria are categorized as susceptible to an antibiotic. RLDs are approved drug products to which generic versions are compared. Sponsors of RLDs play an important role in ensuring the accuracy of drug labels. FDA contacted sponsors of 210 antibiotics in early 2008 to requesting that that they assess whether the breakpoints on their drugs' labels were up to date. As of November 2011, the agency had confirmed the breakpoints on the labels of 64 of these 210 antibiotics were up to date. Information supplied in August 2013 show that 108 of 210 antibiotic labels were reviewed, and if appropriate, were updated. In September 2014 FDA reported that this number has increased 147.

    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

  2. Status: Open

    Comments: In September 2014 FDA clarified information contained in its 2013 response. Specifically, in August 2013 FDA reported that all sponsors who received a letter in 2008 and continue to market the product have "responded." However, FDA did not indicate whether these responses contained sufficient information to assess the accuracy of the breakpoints on the drugs' labels. In September 2014 FDA clarified that not all of sponsors' responses were found to be complete upon initial submission. In such cases FDA said it has requested additional information from the sponsor. FDA explained that this is a normal part of such reviews as some responses are incomplete, and thus there is often some "back-and-forth" dialogue with the company until a satisfactory response is received. However, FDA did not track how many supplements were complete with the initial submission.

    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

  3. Status: Closed - Not Implemented

    Comments: In September 2014 FDA stated that it has dedicated its available resources towards ensuring that breakpoints on the labels on antibiotics that are Reference-Listed Drugs (RLD) are updated as expeditiously as possible. FDA also said that, when it becomes aware of scientific information that suggests a change in breakpoints is needed, FDA will reach out to the company if the company has not already informed the agency of its plans for updating the breakpoints. FDA also reiterated information contained in GAO's 2012 report--that it has already communicated this responsibility to industry through a letter to all sponsors on January 6, 2008, stating that the breakpoint information on drugs' labels be updated on a regular basis. FDA also pointed out that it issued guidance in June 2009 directing RLD sponsors to review their product labeling at least annually. Because of these actions, taken several years before GAO's report was issued, FDA considers it unnecessary to implement GAO's 2012 recommendation.

    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

  4. Status: Closed - Not Implemented

    Comments: In September 2014 FDA stated that it is challenging to implement this recommendation. FDA said that progress on this front is difficult to quantify, which relates to some of the reasons that breakpoints became so outdated in the first place. While FDA said it is the policy and practice of the agency to review annual reports, and companies are expected to provide updated information on breakpoints in the summary section of their annual reports, there are several factors that make this task challenging. First, 21 CFR 314.81(b)(2)(i) states that the annual report "provide a brief summary of significant new information from the previous year that might affect the safety, effectiveness or labeling of the drug product." A company is not required to provide information on breakpoints if no changes are needed. There are no consistent formats or expectations for content in these updates, which makes the annual report a less than ideal place to review the currency of labeled breakpoints. Second, FDA stated that many sponsors of older antibacterials are generic companies that do not have microbiologists on staff, and are ill-equipped to provide meaningful information. When FDA becomes aware of scientific information that suggests a change in breakpoints is needed, it will reach out to the company if the company has not already informed FDA of plans for updating the breakpoints. FDA said it does not believe that tracking the sponsors' updating of the labeling by monitoring summary information in the annual report is the best way to meet the public health needs that the breakpoints are meant to address. FDA stated that it believes that a more effective way to keep breakpoints updated and available in a way that is meaningful to healthcare providers is to remove the breakpoints from the drug product labeling altogether. Instead, the approved breakpoints could be posted on FDA's website, so the Antimicrobial Susceptibility Testing (AST) device manufacturers could update their devices in a more timely manner.

    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

  5. Status: Closed - Not Implemented

    Comments: In September 2014 FDA stated it does not have a process to individually notify sponsors when a drug becomes, or ceases to be, a reference listed drug. FDA did not indicate it had any plans to implement this recommendation. Instead, FDA reiterated information it had previously provided to us. Specifically, it stated that if its Office of Generic Drugs (OGD) changes the reference listed drug, the change is reflected in the publication Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). This publication is updated monthly and is available on-line at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm and serves as notification. Other than notification through the Orange Book, OGD does not have a process established to individually notify sponsors when a drug becomes, or ceases to be, a reference listed drug. FDA stated that firms usually know when their product is no longer the reference listed drug because they have either discontinued or withdrawn their product from the market. In these instances notification is not necessary. Firms that want to market a version of a drug product that is not the reference listed drug submit a citizen petition to the agency to request this. This is a public process, and the notification is the petition response. FDA explained that OGD does notify in writing the holder of generic antibiotics when they are designated the reference listed drug, and it is necessary to update susceptibility interpretive criteria (breakpoints). In these cases OGD is proactive and able to notify most sponsors verbally that their drug is being designated the reference listed drug. OGD is in the process of hiring more people to assist with the notification process. However, FDA stated it 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 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

  6. Status: Closed - Not Implemented

    Comments: In September 2014 FDA stated that it believes that further guidance at this time would not contribute to a more timely updating of the breakpoints. It currently has no plans to implement GAO's recommendation. It also provided a perspective not previously shared with GAO. FDA stated that, in practice, the healthcare community relies on antimicrobial susceptibility results generated from Antimicrobial Susceptibility Testing (AST) devices. Results are subsequently communicated to clinicians. According to FDA, the healthcare community does not look to the breakpoints in the drug product labeling and many healthcare professionals may not even know that breakpoints are currently included in the drug product labeling, because they receive laboratory reports. Clinical microbiology laboratories generally rely upon standard development organizations as the reference source for interpretive criteria. FDA stated that there is no distinct public health benefit of keeping the breakpoint information in the drug labeling. FDA also said that AST device manufacturers cannot quickly update the breakpoints because there is an expectation that the information in drug and device labeling be the same. Manufacturers must wait to update labeling until each antibacterial drug manufacturer has had an application for proposed changes to product labeling approved by the FDA. This is a prolonged process, during which the interpretative criteria is updated and AST manufacturers update in accordance with new criteria. They then file an application for FDA clearance, and FDA clears the application. Outdated breakpoint information can sometimes lead to healthcare practitioners selecting inappropriate antibacterial drugs to treat their patients and it may contribute to the development of antimicrobial resistance. FDA also said that in cases where there are multiple generics and/or multiple dosage forms, it is unlikely that all sponsors would submit supplements at the same time. This means there is inevitably a period of time when there is a discrepancy between labeling of products that have been updated and those that have not, which could cause confusion in the healthcare community. Therefore, FDA does not believe that further guidance at this time would be helpful. If, however, the process were changed to remove the breakpoints from the drug labeling, that would be a more appropriate time to issue additional guidance.

    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

 

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