Antibiotics: FDA Has Encouraged Development, but Needs to Clarify the Role of Draft Guidance and Develop Qualified Infectious Disease Product Guidance
Released: 2017-03-02T00:00:00


Highlights: section_title: Why GAO Did This Study
paragraphs: 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.

section_title: What GAO Found
paragraphs: 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.

section_title: What GAO Recommends
paragraphs: 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.

section_title: Letter
paragraphs: Antibiotics have long played an important role in the care and well-being  of people with various types of infections. However, this role is threatened  by the growing resistance of bacteria to existing antibiotics and the steady  decline in the development of new antibiotics since the 1980s. More than  2 million people are sickened every year in the United States with  antibiotic-resistant infections, with at least 23,000 dying as a result. The  number of new antibiotics approved for prescription use in the United  States has declined from 29 in the 1980s to 9 in the first decade of the  2000s. 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 the  approval of drugs for market in the United States.

In 2012, Congress passed the Food and Drug Administration Safety and  Innovation Act (FDASIA), title VIII of which is commonly referred to as the  Generating Antibiotic Incentives Now (GAIN) provisions. The GAIN  provisions required FDA to take certain steps to encourage drug sponsors  to develop qualified infectious disease products (QIDP), intended for the  treatment of serious or life-threatening infections. However, it is too soon  to determine if the GAIN provisions have actually stimulated the  development of new antibiotics. FDA has taken steps to implement these  provisions and drug sponsors have applied for and received the QIDP  designation for drugs already in development. The GAIN provisions were  passed 5 years ago, but it generally takes 10 to 15 years to develop a  new drug and obtain approval from FDA. Therefore, GAIN has not been  in place long enough yet to have been a factor in motivating any drug  sponsor to develop and submit an application to FDA to market a new  antibiotic.

You asked us to provide information on FDA’s implementation of the  GAIN provisions. This report examines  1.  the steps FDA has taken to encourage the development of antibiotics  to treat serious or life-threatening infections since the enactment of  GAIN, and  2.  drug sponsors’ perspectives on FDA’s efforts to encourage the  development of antibiotics to treat serious or life-threatening infections  since the enactment of GAIN.

To examine the steps FDA has taken to encourage the development of  antibiotics to treat serious or life-threatening infections since GAIN, we  reviewed the GAIN provisions included in FDASIA. We also reviewed  FDA guidance documents related to antibiotic drug development and  unmet medical need identified by the agency as being related to GAIN.  We analyzed FDA data on drug sponsors’ requests to FDA to obtain the  QIDP designation and the number of requests FDA granted from July 9,  2012, (when the QIDP designation was created) through December 31,  2015, (the most current available data at the time of our review). We  limited the requests that we examined to those associated with new  antibiotic drug applications and did not include applications for other types  of products. We also reviewed FDA data on the six drugs the agency  approved with the QIDP designation; these data included information  such as the drug’s proprietary name and indication for use. We assessed  the reliability of these data by, for example, conducting data checks and  interviewing knowledgeable FDA officials about the data. We determined  that these data were sufficiently reliable for the purposes of our reporting  objectives. We also interviewed FDA officials on their efforts to encourage  the submission of new drug applications by implementing GAIN.

To examine drug sponsors’ perspectives on FDA’s efforts to encourage  the development of antibiotics to treat serious or life-threatening infections  since GAIN, we contacted certain industry stakeholders for their  assistance in identifying drug sponsors to include in our study.  Information about FDA’s review of drug sponsors’ applications, including  information about whether a drug sponsor is seeking a QIDP designation  and FDA’s subsequent decision, is proprietary. Therefore, we asked two  organizations that represent drug sponsors and two organizations that  conduct research in the area of antibiotic innovation to ask drug sponsors  who had experience with FDA’s QIDP designation or antibiotic drug  development generally to participate in our study. Eight drug sponsors  agreed to participate—6 of which we interviewed and 2 of which  answered our questions in writing. Two of these 8 drug sponsors had  drugs approved with the QIDP designation. Because there are a total of 4  sponsors that had drugs approved with the QIDP designation and we  wanted to interview all of them, we contacted the other 2 drug sponsors,  both of which agreed to participate in our study. The 10 drug sponsors in  our study had different characteristics; for example, they included large  and small drug sponsors, those with approved antibiotics, and those with antibiotics in development that have a QIDP designation, according to  publicly available data. These drug sponsors’ perspectives are not  generalizable to all drug sponsors. We supplemented our understanding  of drug sponsors’ perspectives by analyzing FDA data on review times for  approved antibiotics with the QIDP designation from July 9, 2012, through  December 31, 2015. To assess the reliability of these data, we reviewed  relevant documentation, conducted data checks, and interviewed  knowledgeable FDA officials about the data. We determined that these  data were sufficiently reliable for the purposes of our reporting objectives.  We also reviewed FDA guidance related to other expedited programs that  FDA implements, including programs for which antibiotics qualify, to  understand what information the agency provides about the features and  benefits of these programs. Lastly, we compared the relevant federal  internal control standards related to information sharing and  communication with FDA’s guidance and other communications with drug  sponsors about the QIDP designation.

We conducted this performance audit from December 2015 to January  2017 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: 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.

section_title: FDA Created a Task Force to Coordinate the Release of Guidance and Used the QIDP Designation to Encourage the Development of New Antibiotics
subsections: section_title: FDA Created a Task Force to Coordinate the Release of Guidance Documents for Antibiotics
paragraphs: 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.”

section_title: FDA Used the QIDP Designation and Its Associated Incentives to Encourage the Development of Antibiotics
paragraphs: 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.

section_title: Drug Sponsors in Our Study Said That GAIN Has Facilitated FDA’s Review of Their Antibiotic Applications, but Also Expressed Concern about Available Guidance
subsections: section_title: All Drug Sponsors in Our Study Told Us That Increased Communication with FDA or the Expedited Review of Their Applications Were Beneficial to Their Drug Development Processes
paragraphs: 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.

section_title: Several of the Drug Sponsors in Our Study Expressed Concern about Available FDA Guidance Documents
paragraphs: 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.

section_title: Conclusions
paragraphs: 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.

section_title: Recommendations for Executive Action
paragraphs: 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.

section_title: Agency Comments and Our Evaluation
paragraphs: 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.

section_title: Appendix I: Additional Food and Drug Administration (FDA) Antimicrobial Resistance Efforts
paragraphs: 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.
subsections: section_title: FDA’s Antimicrobial Resistance Task Force
paragraphs: 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.

section_title: Center for Biologics Evaluation and Research
paragraphs: 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.

section_title: Center for Devices and Radiological Health
paragraphs: 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.

section_title: Appendix II: Antibiotic-Related Guidance Documents Released by the Food and Drug Administration
paragraphs: 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.

section_title: Appendix III: Comments from the Department of Health & Human Services

section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact

section_title: Staff Acknowledgments
paragraphs: 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.

Fast facts: Each year, over 2 million Americans get sick from bacterial infections that are resistant to antibiotics, and at least 23,000 die as a result. There has also been a steady decline in the development of new antibiotics since the 1980s—raising concerns that there may not be enough new antibiotics to replace those that have become ineffective.

In response, the FDA has encouraged drug companies to develop new antibiotics through incentives, such as expediting its review of these drug applications. However, we found that drug companies needed more information on how to use these incentives—and recommended that the FDA provide this guidance.

Question-summary annotations: questions: question: How has the FDA made use of QIDP designation?
answer: 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.

question: How has the FDA kept guidance documents up to date?
answer: 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.
child_questions: question: To what extent have these documents been finalized?
answer: However, half of these guidance documents remain in draft form.

question: Why are the guidance documents being rewritten?
answer: 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.

question: How does the FDA incentivize antibiotic development?
answer: 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.

question: To what extent has the FDA been granting QIDP designation requests?
answer: 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.

questions: question: How has GAIN affected FDA review of drug applications?
answer: 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.
child_questions: question: How do the drug sponsors view the FDA's draft guidance?
answer: 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.
child_questions: question: How might additional guidance from the FDA facilitate the application process (and allow it to be used to its fullest potential)?
answer: 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.

question: Why are the drug sponsors uncertain of the reliability of the draft guidance?
answer: 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.

question: How does the lack of clarity in the drafts affect the drug sponsors?
answer: 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.

question: How has the FDA maintained transparency about the guidance writing process?
answer: 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.”

question: How does the federal government regulate dissemination of agency information?
answer: 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.

questions: question: Why are antibiotics and their development critical?
answer: 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.
child_questions: question: How does the FDA factor into this process?
answer: FDA oversees the approval of drugs for the U.S. market.

question: How does GAIN attempt to remedy the decline in antibiotic developments?
answer: 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.

questions: question: How was the GAO involved in FDA’s efforts regarding GAIN implementation?
answer: 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.
child_questions: question: How did GAO source information for this review?
answer: 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.
child_questions: question: How did GAO supplement their raw data sources?
answer: GAO interviewed FDA officials and obtained information from a nongeneralizable selection of 10 drug sponsors about FDA efforts.

question: How does this report review the FDA's implementation of GAIN?
answer: 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.