FDA and the Drug Approval Process

FDA oversees the drug development process. A second provision extended the duration of market exclusivity from   3 years to 5 years for new drugs that meet certain detailed, scientific  criteria. Label changes of this type  require FDA’s approval. FDA will generally  designate the generic version of the drug with the largest market share as  the new reference-listed drug. FDA Has Not Taken Sufficient Steps to Ensure That Antibiotic Labels Contain Up-to-Date Information

FDA has not taken sufficient steps to implement the FDAAA provision  regarding preserving antibiotic effectiveness by ensuring that antibiotic  labels contain up-to-date breakpoints. In 2008 FDA requested that  sponsors respond to the agency regarding whether their antibiotics’ labels  included up-to-date breakpoints, but FDA has not yet confirmed whether  the majority of these labels are accurate. 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. 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 Issued Guidance on Sponsors’ Responsibility to Evaluate and Maintain Up- to-Date Breakpoints, but Has Not Been Tracking Their Responses

Another step FDA took to implement the FDAAA provision regarding  preserving the effectiveness of antibiotics was to issue guidance that  reminded sponsors of the requirement to maintain accurate labels, and  thus, their responsibility to keep information about breakpoints up to   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 has not been systematically tracking whether sponsors have been  responsive to the guidance. 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. 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. 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 Public Meeting Required by FDAAA Facilitated Discussion of Existing and Potential Incentives for Antibiotic Innovation

As required by FDAAA, FDA held a public meeting on April 28, 2008, to  explore whether and how existing incentives and potential new incentives  could be applied to promote the development of antibiotics as well as to  discuss whether infectious diseases may qualify for grants or other  incentives that may promote innovation. The  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. Conclusions

The growing public health threat associated with bacterial resistance to  antibiotics makes the development of new antibiotics critical. Recommendations for Executive Action

We recommend that the Commissioner of FDA take the following six  actions to help ensure that antibiotics are accurately labeled: expeditiously review sponsors’ submissions regarding the breakpoints  on their antibiotics’ labels; take steps to obtain breakpoint information from sponsors that have  not yet submitted breakpoint information in response to the 2008  letters sent by the agency; ensure that all sponsors responsible for the annual review of  breakpoints on their antibiotics’ labels—including discontinued brand- name antibiotics and reference-listed antibiotics designated since  2008—have been reminded of their responsibility to evaluate and  maintain up-to-date breakpoints; establish a process to track sponsors’ submissions of breakpoint  information included in their annual reports to ensure that such  information is submitted to FDA and reviewed by the agency in a  timely manner; notify sponsors when one of their drugs becomes or ceases to be a  clarify or provide new guidance on which antibiotic sponsors are  responsible for annually evaluating and maintaining up-to-date  breakpoints on drug labels. We are sending copies of this report to the Secretary of Health and  Human Services and appropriate congressional committees. GAO staff who made major contributions to this report  are listed in appendix V.

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

As one step in FDA’s efforts to implement the provision in the Food and  Drug Administration Amendments Act of 2007 regarding antibiotic  effectiveness, FDA identified 210 antibiotics for which sponsors were  responsible for evaluating and maintaining and, if necessary, updating the  breakpoints on their antibiotics’ labels. In 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.
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 antibiotics 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 FDAs efforts to help preserve antibiotic effectiveness by ensuring breakpoints on labels are up to date and (2) examines the impact of the antibiotic innovation provisions. GAO examined FDA data, guidance, and other documents; interviewed FDA officials; and obtained information from drug sponsors, such as manufacturers, that market antibiotics.

What GAO Found

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 GAOs 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 FDAs 2008 meeting, including tax incentives for research and development and providing greater regulatory clarity during the drug approval process.

What GAO Recommends

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