Antibiotics are drugs used to treat bacterial infections; antibiotic resistance is the result of changes in bacteria that reduce or eliminate the effectiveness of antibiotics to treat infection. Experts have raised concerns about the lack of new antibiotics being developed to replace antibiotics that have become ineffective because of resistance. This lack of development has been attributed to various challenges. For example, 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 drug sponsor must conduct extensive research in order to demonstrate that the drug is both safe and effective. Although high costs and failure rates make drug development risky for drug sponsors, creating a safe and effective new drug can be financially rewarding for the drug sponsor and beneficial to the public. However, antibiotics are often less profitable than other drugs because they are generally designed to work quickly and are typically administered for only a brief time. FDA oversees the drug development process and the approval of new drugs for marketing in the United States. FDA generally reviews drug sponsors’ plans for conducting clinical trials and assesses drug sponsors’ applications for the approval of new antibiotics. FDA also releases guidance for industry as a way to communicate its current thinking on a particular topic with the purpose of assisting drug sponsors in the development of drugs. For example, FDA has released several guidance documents to assist drug sponsors with the development of antibiotics, including information on designing clinical trials and measures to demonstrate a drug’s effectiveness. The GAIN provisions required FDA to take certain steps to encourage drug sponsors to develop antibiotics, particularly those that treat serious or life-threatening infections. Specifically, FDA was required each year to review, and revise as appropriate, at least three guidance documents related to the development of antibiotics. FDA was also required to finalize a guidance document on the development of antibacterial drugs for serious or life-threatening infections, particularly in areas of unmet medical need. The GAIN provisions also established the QIDP designation and made incentives available to sponsors of QIDPs—fast track designation, priority review designation, and 5 years of additional market exclusivity. Fast track designation may expedite FDA’s review of an application by allowing drug sponsors to have increased communication with FDA and by allowing FDA to review portions of the application as they come in rather than waiting for a complete application. Although drug sponsors that receive QIDP designation are also entitled to receive fast track designation, drug sponsors must still request this designation and typically do so prior to submitting their application to FDA for review. Priority review has been automatically granted to applications with the QIDP designation. It reduces FDA’s goal time for the review of an application from 10 months to 6 months. Market exclusivity is a statutory provision for exclusive marketing rights for certain periods upon approval of a drug application, if certain statutory requirements are met. Market exclusivity periods last different lengths of time and have different scopes. For example, drugs designated for treatment of rare diseases or conditions may be eligible for orphan drug exclusivity, which lasts for 7 years for the specified conditions. New chemical entity exclusivity provides 5 years of market exclusivity if a drug includes a new active moiety that has not been previously approved by FDA. QIDP-related market exclusivity adds an additional 5 years of exclusivity to certain qualifying drugs. For example, a drug receiving orphan drug exclusivity receives 7 years of exclusivity. If that drug’s application also received a QIDP designation, then the drug may receive an additional 5 years of exclusivity, for a total of 12 years of market exclusivity. Table 1 provides more information on the different incentives associated with the QIDP designation. In 2012, FDA created an internal group called the Antibacterial Drug Development Task Force (Task Force) to coordinate the release of guidance documents for antibiotics as part of its role to promote the development of these types of drugs. The GAIN provisions required FDA to review and revise each year, as appropriate, at least three guidance documents related to antibiotics, in part to ensure the documents reflected scientific developments. FDA officials also reviewed the list of available guidance documents and released guidance on new topics, where needed. Established after the passage of the GAIN provisions, the Task Force is a multidisciplinary group that comprises scientists and clinicians who participate in FDA’s oversight of the drug development process. Members of this Task Force work with experts, such as those from academia, industry, and professional societies, and with patient advocacy groups, to promote the development of new antibiotics. As of August 2016, FDA and the Task Force had coordinated the release of 14 updated or new guidance documents related to the development of antibiotics, although half of these documents remain in draft form. Table 2 lists guidance documents for antibiotics that FDA released in accordance with the GAIN provisions. Half of these 14 documents were finalized versions of prior draft guidance documents, such as FDA’s 2015 guidance on uncomplicated gonorrhea. FDA released the remaining guidance documents in draft form—specifically, the guidance either updated a prior draft guidance or was a brand new draft guidance for a new topic. For example, FDA’s most recent draft guidance on bacterial vaginosis, released in July 2016, is an update to prior draft guidance from July 1998, while FDA’s draft guidance on pulmonary tuberculosis, released in November 2013, is the first guidance on this topic FDA has released. FDA made these draft guidance documents publicly available on its website, in keeping with the agency’s good guidance practices. According to FDA, these draft guidance documents are made available to encourage public comment. Further, the draft guidance documents on developing antibiotics we examined indicated on the title page and on subsequent pages that they were intended for comment purposes only, not for implementation, and would represent the agency’s current thinking “when finalized.” Thus, because the draft documents on the FDA website for public comment have not been finalized, drug sponsors are left without written guidance indicating FDA’s current thinking on a given issue until the agency finalizes the guidance. As of January 2017, FDA had not responded to questions we provided in June 2016 about why some guidance documents remain in draft form or whether drug sponsors should rely on draft guidance documents while developing their drugs. FDA informed us that its responses were in agency clearance. FDA also had previously received a similar request from Congress and told us it would provide responses to us and to Congress simultaneously when the responses are finalized. FDA did not indicate when those responses would be finalized and provided to us. According to FDA officials, they selected the antibiotic-related guidance to review, and potentially revise, for various reasons, such as the emergence of new scientific information. Officials said that they also coordinate with external stakeholders on identifying and addressing challenges to antibiotic development, such as consulting with them about any changes they make to guidance documents. For example, FDA participated in meetings with the Foundation for the National Institutes of Health and worked with the Clinical Trials Transformation Initiative when it revised two of its guidance documents on developing drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and on drug development for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). In 2013, FDA finalized its revision of a 2010 draft guidance document on developing drugs to treat ABSSSI based, in part, on work on clinical endpoints conducted by the Foundation for the National Institutes of Health. Differences between the finalized 2013 document and the draft 2010 document included changes in the minimum number of clinical trials FDA recommended that a drug sponsor conduct and the clinical endpoints FDA recommended that a sponsor use to assess the effectiveness of a drug. The 2010 guidance document recommended that drug sponsors conduct at least two adequate and well-controlled trials. When FDA released the finalized guidance in 2013, the agency noted that drug sponsors could also provide evidence from a single adequate and well-controlled clinical trial supported by independent evidence, such as data from another trial for a treatment of a different type of infection. Also, the recommended primary clinical endpoint was redefined as a reduction in lesion size of at least 20 percent compared to the lesion size of those patients that did not receive treatment at 48 to 72 hours. FDA made similar changes to its draft 2010 guidance on HABP/VABP based, in part, on work resulting from its coordination with both the Foundation for the National Institutes of Health and the Clinical Trials Transformation Initiative. Industry stakeholders expressed concerns about this 2010 guidance document that included the agency’s use of all-cause mortality (i.e., death from any cause) as the only clinical endpoint recommended to measure the effectiveness of a drug. Stakeholders also raised concerns about the restrictive inclusion criteria that were used to determine which patients could be enrolled in clinical trials. In 2014, FDA released a revised draft HABP/VABP guidance document that included changes aimed at addressing these concerns. Specifically, FDA’s recommendations included endpoints besides all-cause mortality and modified the criteria for clinical trial enrollment. Making the criteria for enrollment less restrictive could make it easier to enroll more patients into clinical trials. Enrolling patients into clinical trials is a particular challenge noted by most of the drug sponsors included in our study. The GAIN provisions included another requirement for FDA to release a draft guidance document on unmet medical need by the end of June 2013, and a final version of this guidance by the end of 2014. In July 2013, FDA released its draft guidance—Guidance for Industry Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases. According to FDA, the agency did not meet the statutory deadline for publishing finalized guidance because of concerns that release of such guidance could create confusion within the industry while Congress considers draft legislation for a potential limited population antibacterial drug approval pathway. In October 2016, FDA told us that the agency intended to release the final guidance later that year, once the legislative disposition of this limited population approval pathway was clear. However, as of January 2017, this guidance document remained in draft form, and FDA had not released a finalized version. FDA recently told us that the agency plans to release finalized guidance “soon.” Although it is too soon to determine if GAIN has actually stimulated the development of new antibiotics, FDA has taken steps to implement the GAIN provision related to the QIDP designation and the incentives associated with the approval of a QIDP drug. Since 2012, FDA has granted 101 requests for the designation. Six drugs with the designation have been approved, but they were in the later stages of the drug development process than the other drugs for which the designation was requested when they received this designation. FDA data from July 9, 2012, (when the QIDP designation was created) through December 31, 2015, showed that FDA granted almost all of the requests that it received for the QIDP designation. Specifically, drug sponsors submitted more than 100 requests to FDA for QIDP designation during this time, of which FDA granted more than 90 percent. (See table 3.) Drug sponsors whose products received the QIDP designation are also eligible to receive fast track designation. From July 2012 through December 2015, FDA granted fast track designation to all of the drug sponsors whose applications received QIDP designation and also requested fast track designation. (See table 4.) However, not all drug sponsors that requested the QIDP designation also requested fast track designation. For example, in fiscal year 2015 (the most recent year for which a full year of data are available), FDA granted 25 requests from drug sponsors for the QIDP designation, making them also eligible for fast track designation. While FDA granted 11 requests from sponsors for fast track designation, sponsors could have requested fast track designation in 14 additional instances, but they did not do so. According to FDA officials, this is likely the case for one of three reasons: (1) a drug sponsor has chosen not to request fast track designation, (2) a drug sponsor has not yet requested fast track designation but may intend to; or (3) the drug sponsor received fast track designation prior to the creation of the QIDP designation in 2012, and this is not reflected in the counts. As of October 2016, FDA had approved applications for six drugs that received the QIDP designation for marketing in the United States, though these drugs were in the later stages of their development program when the designation was created in July 2012. (See table 5.) Four of the six approved drug applications also had fast track designation, and all of them received priority review. FDA did not grant fast track designation to two of these applications because, according to the sponsors, they did not apply for it. To date, FDA has determined that five of these six drugs are eligible for 5 years of additional market exclusivity because each drug were eligible for at least one other type of market exclusivity and the statutory requirements for the 5 additional years were met. All 10 of the drug sponsors in our study said that increased communication with FDA or the expedited review of their QIDP- designated drug applications due to GAIN were beneficial to their drug development processes. Five drug sponsors said that the QIDP designation was particularly helpful to smaller sponsors. This was confirmed by 3 of the smaller drug sponsors in our study that said the QIDP designation helped continue their respective development programs for antibiotics. Research indicates that as of May 2016, over 80 percent of the antibiotic products in development were being developed by small drug sponsors. Eight of the drug sponsors in our study attributed this increase in communication with FDA, typically associated with the fast track designation, to the agency’s implementation of the GAIN provisions and general commitment to supporting the development of new antibiotics. For example, 2 of the 10 sponsors specifically noted that they had not experienced this level of access to FDA officials during the review of their other, non-QIDP-designated drug applications. Five of the 10 sponsors said that FDA was receptive to considering new approaches to the design of their clinical trials. For example, one drug sponsor stated that FDA officials worked with sponsors to find innovative ways to design antibiotic clinical trials allowing them to more quickly advance their drugs through the development process. All of the four drug sponsors in our study whose drugs were approved with a QIDP designation also received priority review designation, which helped to advance their applications more quickly through the FDA review process. FDA data showed that these drugs had an average total review time of about 8 months, which is consistent with FDA’s priority review goal time for new molecular entities. Five drug sponsors told us that priority review, for which QIDP-designated drugs have automatically qualified, was a particularly valuable incentive associated with the QIDP designation and GAIN provisions. According to FDA, the agency did not typically provide priority review to antibiotic drug applications before the GAIN provisions were enacted because these drugs generally do not meet the criteria to receive this designation. Several of the drug sponsors in our study expressed concern about how much they could rely on FDA’s draft guidance documents or the lack of guidance describing the QIDP designation and its requirements. FDA released half of the guidance documents it revised in accordance with the GAIN provisions in draft form, and several of these documents were updates to prior draft guidance. Although these guidance documents were in draft form, FDA made them publicly available on its website and offered them as examples of guidance they had revised to encourage antibiotic development in response to GAIN. According to FDA, guidance documents represent FDA’s current thinking on a topic and serve as a way for the agency to communicate with drug sponsors for the purpose of assisting them in developing drugs. However, the FDA draft guidance documents on developing antibiotics that we examined indicated on the title page and on subsequent pages that they were intended for comment purposes only, not for implementation, and would represent the agency’s current thinking “when finalized.” Thus, while these draft guidance documents can include updated information, it is unclear if the new information represents FDA’s current thinking on a topic or if the purpose of the draft guidance is limited to generating public comment. Three of the 10 drug sponsors expressed concern about the role of FDA’s draft guidance. For example, a drug sponsor called some of FDA’s guidance “dated” and noted that FDA’s guidance documents have remained in draft form for a long time. Another drug sponsor said it would rather rely on final guidance not directly applicable to its work than on draft guidance that was directly applicable. A third drug sponsor noted FDA’s draft unmet need guidance was issued in 2013, and said that it would be helpful if FDA finalized it. Further, five sponsors in our study said that elements of the QIDP designation were unclear and that written guidance from FDA related to the QIDP designation and its incentives would help them to better understand the requirements and associated benefits. For example, one of these five drug sponsors told us that guidance about the eligibility requirements and process for obtaining a fast track designation for sponsors’ QIDP-designated drug applications would be helpful. Our review of FDA data showed that from July 2012 through December 2015, drug sponsors that were eligible for fast track designation because they had received QIDP designation for their drug applications could have made 40 additional requests for fast track designation, but did not. Further, we found that the number of requests for fast track designation for eligible QIDP-designated drugs decreased from 20 in fiscal year 2014 to 11 in fiscal year 2015 (the two most recent years for which a full year of data were available). This same drug sponsor told us that the sponsors who did not request a fast track designation might have been unsure about what information to include in their request or could have been unsure if their applications qualified for the designation. These five drug sponsors also said that elements associated with the market exclusivity incentive for which a QIDP-designated drug application might qualify were also unclear. For example, a drug sponsor we spoke with said that uncertainty about how FDA was implementing the additional years of market exclusivity associated with this designation could affect a drug sponsor’s long-term planning for drug development. FDA did not provide us with answers to our questions about why some QIDP-related guidance documents remain in draft form or whether drug sponsors should rely on draft guidance when developing antibiotics, FDA officials did agree that guidance related to the QIDP designation might be helpful to drug sponsors. FDA officials said the agency frequently receives questions about the QIDP designation and application process, but did not provide an explanation for why they have not yet developed QIDP guidance. They said they consider a range of factors when determining which guidance documents to develop, such as new scientific developments. Federal internal control standards on information and communication state that sharing quality information with external parties is necessary to achieving an entity’s objectives. FDA uses its guidance documents to communicate its current thinking on a topic to drug sponsors with the purpose of assisting them as they develop new drugs, including antibiotics. FDA also implements other expedited programs and has developed written guidance that details their features and the criteria a drug sponsor must meet to take advantage of them. However, a lack of clarity on the role of draft guidance documents for and a lack of guidance on the QIDP designation could create uncertainty for drug sponsors about how much reliance they should place on these draft documents and could diminish the likelihood that some drug sponsors apply for the designation because they do not fully understand its requirements and benefits. As a result, drug sponsors that are working to develop new antibiotics could be doing so without the benefit of clear current guidance and the likelihood that the QIDP designation will encourage the development of new antibiotics may be diminished. Amid growing concern about antibiotic resistance to existing drugs and a steady decline in the number of new antibiotics under development, the QIDP designation is a tool for FDA to encourage drug sponsors to develop new antibiotics by facilitating the review of applications for these drugs prior to their approval. FDA revised guidance documents related to antibiotic development in accordance with GAIN, but then released many of them in draft form with language suggesting that the guidance is for discussion purposes only. Several of the drug sponsors with whom we spoke expressed concern about the agency’s use of draft guidance and how much reliance they could place upon it. Although FDA has granted 101 requests for the QIDP designation since being implemented in 2012, half of the sponsors that we spoke with said they were unclear about how to apply for fast track designation if QIDP designation has been granted and about how FDA is interpreting and applying the market exclusivity incentive. Moreover, FDA has not produced written guidance that describes the requirements and benefits of the QIDP designation. Without a clear understanding of the role of draft guidance documents for and the requirements and benefits of the QIDP designation, drug sponsors’ antibiotic development programs might not be based on FDA’s most current thinking and sponsors might not take advantage of the designation. Therefore, the likelihood that revised guidance on antibiotic development and the QIDP designation will encourage the development of new antibiotics may be diminished. In order for drug sponsors to benefit from FDA’s revised guidance on antibiotic development and take full advantage of the QIDP designation, we recommend that FDA clarify how drug sponsors should utilize draft guidance documents that were released in accordance with GAIN, and develop and make available written guidance on the QIDP designation that includes information about the process a drug sponsor must undertake to request the fast track designation and how the agency is applying the market exclusivity incentive. We provided a draft of this report to HHS for its review and comment. HHS provided written comments, which are reprinted in appendix III. In its written comments, HHS agreed to consider our first recommendation and to implement our second recommendation. With regard to our first recommendation, which calls for FDA to clarify how drug sponsors should utilize the draft GAIN guidance documents, HHS stated that these documents are provided to enable public comment on ideas FDA is considering. HHS noted that they are not binding and that drug sponsors can use an alternative approach, if the approach satisfies the requirements of applicable statutes. We appreciate FDA’s consideration of this recommendation, and firmly believe this clarification is warranted. GAIN called for FDA to issue draft guidance documents and to review and revise them, as appropriate, to reflect scientific developments. FDA’s practice of releasing guidance that remains in draft form for years has created uncertainty for drug sponsors in this area. This approach leaves sponsors to plan their antibiotic drug development programs and determine how to meet statutory requirements without the benefit of written guidance representing FDA’s most current thinking. Therefore, we believe our recommendation that FDA clarify how drug sponsors should use these draft documents is appropriate and well- supported. HHS agreed with our second recommendation that FDA develop and issue written guidance on the QIDP designation. HHS said that FDA intends to proceed promptly with this task and that it will include information about the process for requesting the fast track designation and the criteria for determining whether an application qualifies for the 5 additional years of QIDP market exclusivity. HHS also provided technical comments, which we incorporated as appropriate. As agreed with your offices, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies to the appropriate congressional committees, the Secretary of HHS, and other interested parties. In addition, the report is available at no charge on the GAO website at http://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-7114 or dickenj@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix IV. FDA has other efforts related to antimicrobial resistance beyond the steps taken to implement the Generating Antibiotic Incentives Now provisions described in this report. The following describes some of the agency’s activities outside of the Center for Drug Evaluation and Research and the Antibiotic Drug Development Task Force. According to FDA, the FDA Antimicrobial Resistance Task Force comprises principle subject matter experts from across the agency. Members include the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health. According to FDA, this Task Force is intended to foster dialogue between the Centers and to ensure that senior staff are apprised of major activities and developments related to antimicrobial resistance across the agency. In addition to coordinating activities within FDA, the Antimicrobial Resistance Task Force coordinates with external stakeholders, such as the Biomedical Advanced Research and Development Authority on developing a network of sites for clinical trials for antibiotics. It also serves as the agency’s primary lead on other efforts, such as the President’s Combating Antibiotic-Resistant Bacteria initiative. The Center for Biologics Evaluation and Research within FDA regulates biological products for human use, including nontraditional therapies that have the potential to be marketed as alternatives to antibiotics. According to officials, there are three types of nontraditional therapies under development—phage therapy, probiotics, and fecal microbiota. Lytic bacteriophage (phage) therapy involves the use of viruses to destroy the cell membrane of bacteria. Interest in this type of therapy has become relevant, in part, because of the growing global threat of antimicrobial resistance. This type of therapy has been reported to have been used in Eastern Europe; however, use in the United States has only been investigational. Probiotics, also referred to as live biotherapeutic products, are products that contain live organisms, such as bacteria, that are found naturally in humans. Proposed uses include the prevention or treatment of diarrhea associated with infections by certain bacteria or with use of antibiotics. Fecal microbiota for transplantation refers to a procedure in which fecal matter or bacteria from the stool of healthy individuals are administered to a patient to treat a disease. Infection by certain bad bacteria can result in debilitating and sometimes fatal diarrhea. The Center for Devices and Radiological Health is the Center within FDA that is responsible for overseeing the safety and effectiveness of medical devices sold in the United States, including in vitro diagnostics. In vitro diagnostics include antimicrobial susceptibility testing devices, which are used by laboratories to assess whether a particular bacterium is susceptible or resistant to single or multiple antibiotics. These tests are based on antibiotic breakpoints, which are the antibiotic concentrations used to determine bacterial susceptibility. Officials said they work with the Center for Drug Evaluation and Research to jointly publish guidance related to antimicrobial susceptibility testing devices. According to officials, the challenges to the development of antimicrobial susceptibility testing devices are mostly scientific. For example, they said it is inherently challenging to develop a diagnostic test that quickly and accurately identifies if a patient’s symptoms are caused by a bacteria or virus, and for bacterial infections, whether the bacterium is resistant to standard therapies. The guidance documents listed below were released by the Food and Drug Administration in relation to the Generating Antibiotic Incentives Now statute as of August 2016. Department of Health and Human Services. Food and Drug Administration. Bacterial Vaginosis: Developing Drugs for Treatment Guidance for Industry (Draft). Silver Spring, Md.: 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM510948.pdf Department of Health and Human Services. Food and Drug Administration. Vulvovaginal Candidiasis: Developing Drugs for Treatment Guidance for Industry (Draft). Silver Spring, Md.: 2016. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs- gen/documents/document/ucm509411.pdf Department of Health and Human Services. Food and Drug Administration. Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax Guidance for Industry (Draft). Silver Spring, Md.: 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM070986.pdf Department of Health and Human Services. Food and Drug Administration. Uncomplicated Gonorrhea: Developing Drugs for Treatment Guidance for Industry. Silver Spring, Md.: 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM401620.pdf. Department of Health and Human Services. Food and Drug Administration. Complicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry. Silver Spring, Md.: 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM070981.pdf. Department of Health and Human Services. Food and Drug Administration. Complicated Intra-Abdominal Infections: Developing Drugs for Treatment Guidance for Industry. Silver Spring, Md.: 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM321390.pdf. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment (Draft). Silver Spring, Md.: 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM234907.pdf. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. Silver Spring, Md.: 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM123686.pdf. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Pulmonary Tuberculosis: Developing Drugs for Treatment (Draft). Silver Spring, Md.: 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM373580.pdf. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment. Silver Spring, Md.: 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/ucm071185.pdf Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases (Draft). Silver Spring, Md.: 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM359184.pdf. In addition to the contact named above, Tom Conahan, Assistant Director; Gay Hee Lee, Analyst-in-Charge; George Bogart; Laurie Pachter; Sarah M. Sheehan; and Katherine A. Singh made key contributions to this report.

Summary: Antibiotics have long played a key role in treating infections, but this role is threatened by growing resistance to existing antibiotics and the decline in the development of new drugs. FDA oversees the approval of drugs for the U.S. market. The GAIN provisions created the QIDP designation and its associated incentives to encourage the development of new drugs to treat serious or life-threatening infections. While it is too soon to tell if GAIN has stimulated the development of new drugs, GAO was asked to provide information on FDA's efforts to implement GAIN. This report examines (1) steps FDA has taken to encourage the development of antibiotics since GAIN, and (2) drug sponsors' perspectives on FDA's efforts. GAO analyzed FDA data on requests for the QIDP designation from July 2012 through December 2015 (the most recent data available at the time of GAO's review), and on drugs approved with this designation during the same time frame. GAO reviewed relevant FDA guidance documents and internal controls. GAO interviewed FDA officials and obtained information from a nongeneralizable selection of 10 drug sponsors about FDA efforts. The Food and Drug Administration (FDA) released updated or new guidance for antibiotic development, and used the qualified infectious disease products (QIDP) designation to encourage the development of new antibiotics. As of August 2016, FDA, an agency within the Department of Health and Human Services (HHS), had coordinated the release of 14 updated or new guidance documents on antibiotic development, in compliance with Generating Antibiotic Incentives Now (GAIN) provisions of the Food and Drug Administration Safety and Innovation Act of 2012. However, half of these guidance documents remain in draft form. The GAIN provisions required FDA to review and, as appropriate, revise guidance documents related to antibiotics, in part to ensure that they reflected scientific developments. FDA used the QIDP designation and its incentives, created under the GAIN provisions, to encourage drug sponsors to develop new antibiotics. Incentives available under the QIDP designation include eligibility for fast track designation—which allows drug sponsors to have increased interaction with FDA and allows FDA to review portions of sponsors' applications as they come in rather than waiting for a complete application. FDA granted 101 out of 109 requests for the QIDP designation from July 2012, when the designation was created, through December 2015. FDA also approved six drugs with the QIDP designation for market in the United States. The 10 drug sponsors in GAO's study said that GAIN has facilitated FDA's review of their drug applications, and 8 said they experienced increased communication with FDA due to the agency's implementation of GAIN and general commitment to supporting the development of new antibiotics. However, several were uncertain whether they could rely on FDA's draft guidance or were concerned about the lack of guidance describing the QIDP designation and its requirements. For example, 2 drug sponsors expressed concern about the role of FDA's draft guidance. A third sponsor said it would be helpful if certain draft guidance was finalized. Five additional drug sponsors in GAO's study stated that written guidance from FDA related to the QIDP designation and its incentives, such as the process for obtaining fast track designation for a QIDP-designated application, would help them to better understand the requirements and its associated benefits. FDA released some of its updated guidance documents in draft form on its website, in response to GAIN, which indicated that they were intended for comment purposes only, not for implementation, and would represent the agency's current thinking “when finalized.” While these draft guidance documents can include updated information, it is unclear if the new information represents FDA's current thinking on a topic or if the purpose of the draft guidance is limited to generating public comment. Internal control standards for the federal government on information and communication state that sharing quality information with external parties is necessary to achieving an entity's objectives. The lack of clarity on the role of draft guidance for and the lack of written guidance on the QIDP designation create uncertainty for drug sponsors about how much reliance they should place on these draft documents and could diminish the likelihood that drug sponsors apply for the designation because they do not fully understand its requirements and benefits. GAO recommends that FDA clarify the role of draft guidance for and develop written guidance on the QIDP designation to help drug sponsors better understand the designation and its associated incentives. HHS said it would consider GAO's first recommendation and agreed with the second. GAO believes the first recommendation should also be adopted.