Drug Safety: FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement
Published: 2015-12-15T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: FDA oversees the safety and effectiveness of drugs sold on the U.S. market. When there is an unmet need for the treatment of a serious condition, FDA may use one or more of its expedited programs, such as fast track and breakthrough therapy designation, which are intended to bring drugs to market more quickly. FDA is also responsible for monitoring the safety of drugs and reporting on those efforts.
GAO was asked to provide information about FDA's expedited programs and its postmarket monitoring of expedited and nonexpedited drugs. This report examines (1) the number and types of requests for fast track or breakthrough therapy designation, (2) the number and types of FDA-approved drug applications that used an expedited program, and (3) the extent to which FDA's data on tracked safety issues and postmarket studies allowed the agency to meet its reporting and oversight responsibilities. GAO analyzed FDA data on requests for fast track or breakthrough therapy designation and approved drug applications that used an expedited program from October 1, 2006, to December 31, 2014 (the most recent available). GAO reviewed FDA information on tracked safety issues and postmarket studies, including FDA internal evaluations and guidance, and interviewed FDA officials.
section_title: What GAO Found
paragraphs: From October 1, 2006, to December 31, 2014, the Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) received about 1,000 requests for fast track designation and breakthrough therapy designation—two of the agency's four expedited programs to facilitate and expedite the development and review of new drugs. Drug sponsors are required to submit formal requests to use these two programs; for the other two expedited programs (accelerated approval and priority review) sponsors are not required to submit formal requests. Regardless of whether sponsors submit a request for an expedited program, they are required to submit a marketing application prior to offering a drug for sale in the United States; using an expedited program does not ensure FDA approval of the marketing application. Sponsors submitted more than 770 requests for fast track designation since fiscal year 2007, and FDA granted about two-thirds of these requests. Sponsors submitted more than 220 requests for breakthrough therapy designation since it was established in July 2012, and the agency denied more than half of these requests.
About a quarter of the drug applications CDER approved for the U.S. market from October 1, 2006, to December 31, 2014, used at least one expedited program, according to FDA data. Included among these applications were new drug applications, biologic license applications, and efficacy supplements, which allow for revisions to the original application, such as changes in the drug's indicated use. Although most of these applications used one program, some applications used two or more, including two oncology drug applications that used all four expedited programs (accelerated approval, breakthrough therapy designation, fast track designation, and priority review). The most common product area among these applications was oncology (19 percent).
FDA lacks reliable, readily accessible data on tracked safety issues and postmarket studies needed to meet certain postmarket safety reporting responsibilities and to conduct systematic oversight. Tracked safety issues are potential safety issues that FDA determines are significant and that it tracks using an internal database. Internal control standards for federal agencies specify that information should be recorded in a form and within a time frame that enables staff to carry out their responsibilities and that relevant, reliable, and timely information should be available for external reporting purposes. However, evaluations conducted by CDER of data in its database revealed problems with the completeness, timeliness, and accuracy of the data. These problems, as well as problems with the way data are recorded that impair their accessibility, have prevented FDA from publishing statutorily required reports on certain potential safety issues and postmarket studies in a timely manner, and have restricted the agency's ability to perform systematic oversight of postmarket drug safety. Although FDA has taken some steps to address the problems with its data, the agency lacks plans that comprehensively outline its efforts and establish related goals and time frames. Additionally, FDA does not have plans to use these data to inform its oversight of its expedited programs, such as determining if drugs that used an expedited program were subsequently associated with tracked safety issues at rates or of types that differed from drugs that used FDA's standard process.
section_title: What GAO Recommends
paragraphs: FDA should develop plans to correct problems with its postmarket safety data and ensure that these data can be easily used for oversight. HHS agreed with GAO's recommendations and provided additional information on FDA's postmarket safety efforts.

section_title: Letter
paragraphs: The Food and Drug Administration (FDA)—an agency within the  Department of Health and Human Services (HHS)—is responsible for  overseeing the safety and effectiveness of drugs sold in the United  States. Before a drug can be marketed, it must be approved by FDA,  which evaluates a drug application to determine whether the new drug is  safe and effective for its intended use. While FDA reviews most drug  applications using its standard review process, the agency may also  utilize one or more of its expedited programs—programs to facilitate and  expedite the development and review of new drugs—for drugs that have  the potential to address an unmet medical need for the treatment of  serious conditions. Although they do not guarantee approval of a  marketing application, FDA’s expedited programs—accelerated approval,  breakthrough therapy designation, fast track designation, and priority  review—are intended to reduce the development or review time needed  to bring a drug to market. For example, expedited programs may allow for  the approval of drugs based on fewer, smaller, or shorter clinical trials.  FDA has expressed support for proposals to further streamline the review  of certain kinds of drugs, such as antibiotics. However, some patient  advocates and researchers have raised questions about whether such  efforts could expose patients to drugs that have not been adequately  tested and increase the potential for previously unrecognized safety  issues to appear once those drugs are more widely used.
Once FDA approves a drug for marketing, whether using an expedited  program or not, the agency continues to monitor the drug’s safety and is  required by law to publicly report on certain aspects of the agency’s  postmarket safety efforts. For example, FDA identifies and evaluates  potential safety issues with marketed drugs, and those that are  considered significant are formally tracked in FDA’s internal database and  referred to as tracked safety issues. FDA also monitors drug sponsors’  progress in completing postmarket studies—studies that are conducted  after the drug is approved that provide information about a drug’s safety,  efficacy, or optimal use—that FDA has required or the sponsor has  agreed to conduct. However, we and others have found weaknesses in  FDA’s oversight of postmarket safety for drugs in the past, such as the  agency’s lack of reliable information to determine the progress of  postmarket studies. FDA’s use of certain expedited programs to reduce  the development time before a drug is approved further increases the  importance of the agency’s postmarket safety oversight, including the  extent to which it is monitoring for unforeseen problems once a drug is on  the market.
You asked us to provide information about FDA’s use of expedited  programs and how FDA monitors the safety of expedited and non- expedited drugs following approval for the U.S. market. This report  examines  1.  the number and types of requests for fast track or breakthrough  2.  the number and types of drug applications that FDA approved for  marketing that used one or more expedited programs, and  3.  the extent to which FDA’s data on tracked safety issues and  postmarket studies allowed the agency to meet its reporting and  oversight responsibilities.
To examine the number and types of requests for fast track or  breakthrough therapy designation, we requested and analyzed data from  FDA for these two expedited programs. We focused on the fast track and  breakthrough therapy designation programs because drug sponsors are  required to submit formal requests to use these two programs; for the  other two expedited programs (accelerated approval and priority review)  sponsors are not required to submit formal requests. Specifically, we  reviewed FDA data on requests for fast track designation and  breakthrough therapy designation, and the number of these requests that  FDA granted or denied or that were withdrawn by the sponsor. The  requests we analyzed were for fast track designation that were received  and reviewed by FDA’s Center for Drug Evaluation and Research (CDER)  from fiscal year 2007 through the first quarter of fiscal year 2015 (the  most recent quarter for which data were available at the time of our  review), and for breakthrough therapy designation from July 9, 2012, (the  date this program was established) through December 31, 2014. The  status of the request for fast track or breakthrough therapy designation— such as whether FDA granted or denied the request or if the request was  withdrawn by the sponsor—is as of the date that FDA extracted the data  we requested. We report data on sponsors’ requests for and FDA’s  decisions about fast track and breakthrough therapy designation by the  fiscal year in which the request was made, even if FDA’s decision to grant  or deny the designation occurred in a subsequent fiscal year. In addition  to analyzing the number of requests and the status of FDA’s decisions on  those requests, we also examined the extent to which requests were  granted by FDA product category, which generally corresponds to the  FDA review division (e.g., oncology or psychiatry drugs). Requests for  fast track and breakthrough therapy designations are generally made  before sponsors submit their applications for approval to market a drug,  and FDA’s decision to grant such a designation does not guarantee that  FDA will subsequently approve the application for marketing.
To examine the number and type of drug applications that FDA approved  for marketing that used one or more expedited programs, we requested  and analyzed data from FDA on all new drug applications (NDA), biologic  license applications (BLA), and NDA- and BLA-related efficacy  supplements that FDA approved from fiscal year 2007 through the first  quarter of fiscal year 2015. We determined the number of applications  approved that used FDA’s standard process and the number approved  that used one or more of FDA’s four expedited programs. We also  analyzed these data to determine the type of drugs FDA approved, such  as the product category.
To examine the extent to which FDA’s data on tracked safety issues and  postmarket studies allowed the agency to meet its reporting and oversight  responsibilities, we requested data from FDA on tracked safety issues  and postmarket studies and then interviewed FDA officials tasked with  compiling those data. We also reviewed the results of internal  evaluations conducted by CDER regarding the quality of the data on  tracked safety issues and postmarket studies in the agency’s internal  database. In addition, we interviewed FDA officials concerning these  internal evaluations and their use of data on tracked safety issues and  postmarket studies. We assessed FDA’s performance against federal  internal control standards.
For all three objectives, we reviewed relevant laws and regulations and  FDA policy and guidance documents. For our first two objectives, we  assessed the reliability of the FDA data by, for example, conducting  internal data checks and comparing data FDA provided to us with the  agency’s publicly available data on drugs approved in a calendar year.  We determined that these data were sufficiently reliable for the purposes  of this report.
We conducted this performance audit from February 2015 to December  2015 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: FDA’s four expedited programs—accelerated approval, breakthrough  therapy designation, fast track designation, and priority review—are  intended to facilitate and expedite development and review of new drugs  to address unmet medical needs in the treatment of a serious condition.
According to FDA, these programs are intended to help ensure that drugs  for serious conditions are approved and available to patients as soon as it  can be concluded that the benefits of the drugs justify their risks.  Depending on the specific expedited program, sponsors of new drugs  may receive a variety of benefits, such as additional opportunities to meet  with and obtain advice from FDA officials during drug development; a  rolling review—that is, when FDA reviews portions of the application as  they come in instead of waiting for the complete application; the ability to  use certain surrogate endpoints or an intermediate clinical endpoint that is  reasonably likely to predict clinical benefit; or a shorter goal for review  time for the drug application. According to FDA, its expedited programs  have the potential to shorten the amount of time necessary for a drug to  get to market and to reduce development costs for drug sponsors.
There are two different ways that drug applications are selected for  review using an expedited program. For breakthrough therapy  designation and fast track designation, the sponsor requests and then  FDA determines whether to grant or to deny the request, generally during  the drug development process before the sponsor submits the application  for approval to market the drug. For accelerated approval and priority  review, sponsors do not submit formal requests. Instead, discussions  between drug sponsors and FDA of the appropriateness of accelerated  approval generally begin during the drug development process. For  priority review designation, FDA assesses each new drug application  when it is submitted to determine if it should undergo priority review.  Additionally, drug applications can use multiple expedited programs. For  example, in December 2014, FDA granted accelerated approval for  Lynparza, a drug to treat advanced ovarian cancer—and this drug  application also received priority review. See table 1 for a summary of  FDA’s expedited programs.
FDA has acknowledged that expediting drug application approvals can  pose risks for patients. For example, for accelerated approval, FDA  guidance states that there is a risk that patients may be exposed to a  drug that ultimately will not be shown to provide an actual clinical  benefit. FDA’s guidance also states that with fewer, smaller, or shorter  clinical trials, there may be less information about rare or delayed adverse  events. FDA has stated, however, that its expedited programs do not  change the standard of evidence required for approval and that some  additional risk may be acceptable because patients and physicians are  generally willing to accept greater risk when treating life-threatening and  severely debilitating diseases.
After FDA approves a drug for marketing, the agency continues to  monitor the drug’s safety and is required by law to publicly report on  certain aspects of its postmarket safety efforts. For example, FDA tracks  information about certain potential safety issues, such as serious adverse  events and medication errors, in its internal database, the Document  Archiving, Reporting, and Regulatory Tracking System (DARRTS).  DARRTS is used, among other things, to generate a work plan and  assign responsibilities for managing these tracked safety issues, as well  as to provide updates on their status. Only those potential safety issues  that FDA determines are significant—that is, have the potential to result in  FDA taking one or more actions, such as requiring labeling changes—are  tracked in DARRTS. FDA is required to publish a quarterly report listing  certain potential safety issues that it has identified using its adverse event  reporting system; FDA identifies those potential safety issues from among  the tracked safety issues in DARRTS.
Another important aspect of FDA’s postmarket safety oversight is  monitoring the progress of postmarket studies—conducted after a drug  has been approved—that FDA can request or require. Under certain  circumstances, FDA can require sponsors to conduct a postmarket study  as a condition of approval, such as for drugs granted accelerated  approval. The results of postmarket studies provide further information  about a drug’s safety, efficacy, or optimal use that FDA can use to take  one or more actions, such as approving a drug for new uses. Under the  accelerated approval program, if sponsors do not conduct the required  postmarket study, called a confirmatory trial, with due diligence, or the  results of the trial do not confirm the drug’s clinical benefit, FDA has the  authority to begin procedures for withdrawing the drug’s approval for  marketing. For example, in 2012, FDA withdrew approval for the NDA for  the cancer drug Iressa after the results of its confirmatory trial failed to  show an improvement in survival for patients who took it compared with  patients who received a placebo. FDA tracks information about  postmarket studies, such as their status and projected completion date, in  DARRTS. FDA is required to publish an annual report in the Federal  Register on the status of certain postmarket studies. In its past reports,  FDA has summarized the number of postmarket studies and the extent to  which they were proceeding according to established time frames for  completion.
Although FDA is responsible for overseeing postmarket studies and  ensuring they are completed in a timely manner, we and others have  found that, in the past, FDA has not adequately done so. HHS’s Office of  Inspector General concluded in a 2006 report that FDA could not readily  identify whether or how timely postmarket study commitments were  progressing toward completion. In 2009, we found that FDA had not  been routinely monitoring the status of postmarket studies, primarily  because oversight of these studies was not considered a priority. Both  reports note that FDA’s inadequate oversight was due, in part, to staff not  meeting timeliness goals for the review of submissions from sponsors,  such as annual status reports that contain information on the progress of  postmarket studies and final reports that include results of completed  studies. In 2008, FDA hired a contractor to help meet requirements under  the Food and Drug Administration Amendments Act of 2007 (FDAAA) that  FDA annually review and report on the “backlog” of postmarket studies,  which FDA defined as studies that were open (i.e., not fulfilled or  released) as of the date of enactment of FDAAA (September 27, 2007).  The contractor found that this backlog contained more than 500  postmarket studies where a final report had been submitted that FDA had  not yet reviewed, including reports for confirmatory trials that were  required for drugs granted accelerated approval.
section_title: FDA Granted More than Half of Requests for Fast Track Designation and Denied Most Requests for Breakthrough Therapy Designation
subsections: section_title: FDA Granted Two-Thirds of Requests for Fast Track Designation and Denied Most Requests for Breakthrough Therapy Designation
paragraphs: Of the 772 requests for fast track designation FDA received from October  1, 2006, through December 31, 2014, FDA granted about two-thirds (or  525) of them. By receiving fast track designation, sponsors may have  increased communication with and guidance from FDA officials and may  have a rolling review of their drug application. FDA denied about one- fourth (or 207) of the requests for fast track designation; according to FDA  officials, requests are generally denied because the drug application does  not meet the criteria for fast track designation. For example, requests for  fast track designation in which the drug is not intended to treat a serious  medical condition will be denied. The 40 remaining requests were either  withdrawn by the sponsor or categorized as other by FDA. Since fiscal  year 2011, the number of requests FDA has granted fast track  designation has increased, from 54 requests granted in fiscal year 2011,  to 89 granted in fiscal year 2014. (See fig. 1.)
In contrast to granting most of the requests for fast track designation,  FDA denied more than half (or 120) of the 225 requests for breakthrough  therapy designation that the agency received since that expedited  program was established in July 2012 through the end of December  2014. According to FDA officials, most requests for this designation are  denied because of poor study design associated with the request. FDA  granted 71 requests for breakthrough therapy designation since the  program was established, including 31 requests granted in each of fiscal  years 2013 and 2014. (See fig. 2.) According to FDA data, 34 requests for  breakthrough therapy designation were withdrawn by the sponsor during  the period.
section_title: Antiviral and Oncology Drugs Were the Most Common Product Categories among Applications Granted Fast Track and Breakthrough Therapy Designation
paragraphs: Of the 525 requests for fast track designation that FDA granted from fiscal  year 2007 through the first quarter of fiscal year 2015, the most common  product category (with 112 requests granted) was for antiviral drugs. For  example, Isentress—an antiviral drug to treat human immunodeficiency  virus that was approved by FDA in 2007—used fast track designation.  This product category was followed by oncology (81 requests granted),  neurology (74 requests granted), anti-infectives (55 requests granted),  gastroenterology and inborn errors (46 request granted), hematology (34  requests granted), and cardiovascular and renal (32 requests granted).  The remaining requests that FDA granted for fast track designation (91  requests) were for drugs in other product categories. (See fig. 3.)  Appendix I has more information on requests for fast track designation  that FDA granted, by product category.
The most common product categories among the 71 requests for which  FDA granted breakthrough therapy designation from July 9, 2012,  through December 31, 2014, were oncology (15 requests granted),  antiviral (14 requests granted), and hematology (14 requests granted).
For example, FDA granted breakthrough therapy designation for the  oncology drug Keytruda (a drug to treat patients with advanced  melanoma who are no longer responding to other drugs) because,  according to FDA, the sponsor demonstrated through preliminary clinical  evidence that the drug may offer a substantial improvement over other  therapies. The rest of the requests for breakthrough therapy designation  FDA granted were for drugs in the FDA product categories of  pulmonology, allergy, and rheumatology (7 requests granted);  gastroenterology and inborn errors (5 requests granted); psychiatry (4  requests granted), and other (12 requests granted). (See fig. 4.)  Appendix II has more information on requests for breakthrough  designation that FDA granted, by product category.
section_title: One in Four Drug Applications Approved by FDA Used at Least One Expedited Program, and the Most Frequent Category Was Oncology Drugs
paragraphs: About a quarter of the 1,717 drug applications that FDA approved from  October 1, 2006, through December 31, 2014, used at least one  expedited program. Drug applications may use multiple expedited  programs, although most used one program. Of 444 approved drug  applications that used one or more expedited programs, 344 (77 percent)  used one expedited program, 78 used 2 programs, 20 used 3 programs,  and 2 used all four programs. (See fig. 5.) Priority review was the most  used program, with 408 of the 444 drug applications (92 percent)  receiving priority review. (See fig. 6.) Average FDA review time for  marketing applications for drugs that used at least one expedited program  was less than for drugs that did not. FDA review time was an average of  8.6 months for marketing applications for drugs that used at least one  expedited program compared with 12.1 months for marketing applications  for drugs that did not.
New molecular entities (NME) accounted for 216 (32 percent) of the 685  NDAs that were approved during the time frame of our review. NMEs  were more likely to have used an expedited program than NDAs that FDA  did not designate as NMEs. Of 216 approved applications for NMEs, FDA  data identified 110 (51 percent) of them as using at least one expedited  program while 59 of the 469 NDAs that were not NMEs (13 percent) used  at least one expedited program. (See fig. 7.)
The most common product category for drug applications approved by  FDA from October 1, 2006, through December 31, 2014, that used at  least one expedited program was oncology (83 of 444 applications, 19  percent), followed by antiviral (77 applications, 17 percent), and  hematology (55 applications, 12 percent). The remaining applications  were for drugs in other product categories. (See fig. 8.)
section_title: FDA Lacks Reliable Information for Postmarket Safety Reporting and Oversight
paragraphs: FDA lacks reliable, readily accessible data on tracked safety issues and  postmarket studies needed to meet certain postmarket safety reporting  responsibilities and to conduct systematic oversight. CDER’s internal  evaluations of data in its DARRTS database revealed problems with the  completeness, timeliness, and accuracy of the data. These problems, as  well as problems with the way data are recorded that impair their  accessibility, have prevented FDA from publishing some required  postmarket safety reports in a timely manner, and have restricted its  ability to perform systematic oversight. Internal control standards for the  federal government specify that information should be recorded in a form  and within a time frame that enables staff to carry out their responsibilities  and that relevant, reliable, and timely information should be available for  external reporting purposes. Although FDA has taken some steps to  address the problems with its data, it lacks comprehensive plans for doing  so.
CDER conducted internal evaluations of its data for tracked safety issues  and postmarket studies and found problems with their completeness,  timeliness, and accuracy. In addition, our review found that certain  information was not readily accessible to FDA staff for analysis.
Data on tracked safety issues were incomplete. CDER’s  evaluation indicated that the majority of potential safety issues that  staff had identified were not being tracked in DARRTS, CDER also  identified 144 issues that had not been formally tracked in DARRTS,  despite likely meeting CDER's critereia for tracked safety issues.  CDER’s evaluation indicated that a possible reason that staff were not  entering tracked safety issues into DARRTS was due to the time- consuming nature of data entry and the additional requirements  associated with conducting a structured, multidisciplinary review,  which staff considered burdensome, especially for more  straightforward issues. CDER’s evaluation compared the entry of  tracked safety issues before and after a change in policy that required  additional work and found that staff entered roughly two-thirds fewer  new tracked safety issues into DARRTS after the new policy went into  effect as compared with the year prior. FDA officials we spoke with  acknowledged that staff were not following CDER’s policies and  procedures for tracking and documenting potential safety issues, but  said that given the high workload of its review staff it had prioritized  identifying, assessing, and addressing potential safety issues over  administrative tracking.
Postmarket study data were outdated and contained inaccuracies. CDER’s evaluation showed that information on postmarket study status (e.g., whether the study was proceeding according to schedule or was delayed) was often outdated or otherwise inaccurate, partly due to delays in staff reviewing submissions, such as final study reports, from drug sponsors. For example, the evaluation found that over half of reviews of sponsors’ submissions associated with about 1,400 postmarket studies FDA  requested or required from March 2008 to September 2013 were  delayed or overdue. CDER’s evaluation also found inaccuracies in  the postmarket study data, such as statuses recorded as pending or  ongoing that should have been recorded as delayed, as well as  delays in data entry. Over a third (500) of the approximately 1,400  studies had their status updated or corrected during the course of  CDER’s internal evaluation. CDER’s evaluation indicated that this  pattern of results was similar to the findings of the contractor the  agency hired in 2008 to review the backlog of postmarket studies.  CDER’s internal evaluation of its postmarket study data attributed the  data reliability problems to weaknesses in its process that provided  numerous opportunities for failures, such as the need to enter data by  hand, which could introduce human error, rather than having them  automatically populated; lack of automatic linkage between  applications and related sponsor submissions, which make them  harder to locate; and limited oversight of core steps in the process.
FDA officials we spoke with also indicated that staffing limitations and  competing priorities contributed to problems identified with the  postmarket study data.
Tracked safety issue and postmarket study data were not readily accessible to staff for analysis. FDA officials told us that DARRTS cannot be queried to determine characteristics of tracked safety issues, such as the therapeutic area of the drug associated with a safety issue, the population affected, or what regulatory actions, if any, FDA took in response to a tracked safety issue. Officials said that such information is contained in the text of electronic documents and must be manually reviewed. Similarly, FDA officials told us that some information about postmarket studies, such as the date FDA requested or required a study, must be manually collected from the text of letters to sponsors; these letters are not automatically linked to information about the study in DARRTS, which can make them challenging to locate.
FDA’s lack of reliable, readily accessible postmarket safety data has  prevented the agency from publishing required reports in a timely manner  and has restricted its ability to conduct systematic oversight.
Lack of complete, timely, and accurate data has resulted in FDA  not publishing required reports in a timely manner. As of October  2015, FDA had not published required quarterly reports on potential  safety issues identified through its adverse event reporting system for  calendar year 2015; FDA officials said they had delayed the report  covering January through March 2015 due to ongoing efforts to  evaluate the data on tracked safety issues. CDER’s internal evaluation found that the number of tracked safety issues included in  quarterly reports during the time frame of its review showed a steep  decline that did not accurately reflect the agency’s actual efforts to  identify and evaluate safety issues. In addition, as of October 2015,  FDA had not published required annual reports containing data on  postmarket studies for fiscal years 2013 and 2014. FDA officials told  us that they had decided to delay publication of the reports primarily  due to CDER’s internal evaluation of the postmarket study data and  subsequent efforts to address the data problems that were  identified.
Lack of reliable and accessible data restricts FDA’s ability to  conduct systematic oversight of postmarket safety. CDER’s  evaluation of tracked safety issues found that when issues were not  centrally tracked in DARRTS, they were generally visible only to staff  within the division or office that had identified them, which prevented  senior management from using DARRTS to systematically determine  whether safety issues were being evaluated and actions were being  taken within reasonable time frames. FDA officials subsequently told  us that they have other mechanisms for informing management about  potential safety issues outside of DARRTS, such as including them in  weekly reports that are discussed at senior management team  meetings; however, none of these mechanisms is comprehensive of  all potential safety issues CDER staff are evaluating. FDA officials  also told us that they cannot readily conduct certain analyses, such as  how often and what type of actions FDA has taken for drugs by  therapeutic area (e.g., oncology or psychiatry drugs). Similarly,  problems with FDA’s postmarket study data limit FDA’s ability to  conduct certain analyses. Inability to quickly determine when  postmarket studies were established, for example, does not allow  agency staff to readily construct cohorts of studies requested or  required in a given fiscal year, which would be necessary for FDA to  conduct analyses on completion rates over time, or to review  information on studies that were requested or required before and  after certain legislative or policy changes to examine their effect.
FDA has reported taking steps to address the problems it identified with  the postmarket safety data in DARRTS, but the agency does not have  comprehensive plans with goals and time frames.
FDA intends to address its incomplete data on tracked safety  issues by revising and streamlining its processes for reviewing  and tracking these issues. FDA officials said that CDER has formed  a workgroup that is considering options to clarify which potential  safety issues should be centrally tracked, and how the tracking and  review processes could be streamlined. Officials did not provide an  estimate for when these processes would be revised. In the  meantime, the Office of New Drugs within CDER issued an interim set  of guidelines for staff in April 2015 that state that all potential safety  issues requiring further evaluation must be entered into DARRTS. The  guidelines also instruct staff to retroactively enter tracked safety  issues into DARRTS to enhance the completeness of the data.  According to FDA officials, these guidelines are an interim measure to  provide key information to staff while CDER’s processes for reviewing  and tracking safety issues are being revised.
FDA intends to increase the timeliness and accuracy of its  postmarket study data by improving tools for oversight and data  collection. FDA officials said the agency is aiming to facilitate more  timely review of sponsor submissions that contain information on  postmarket studies by improving internal oversight. In the fall of 2014,  FDA implemented new reporting capabilities that provide information  to the review divisions within CDER on a monthly basis about all open  postmarket studies those divisions oversee, such as annual status  reports and final reports received from sponsors and what the goal  dates are for their review. Officials said they have also begun meeting  with the Office of Business Informatics within CDER to discuss  improvements that could be made in FDA’s new information  technology platform, such as automated collection of certain types of  data. FDA officials told us that the new platform will include the date  FDA requested or required a postmarket study in a form that can be  queried.
FDA lacks comprehensive plans to address the problems with its  tracked safety issue and postmarket study data. FDA officials told  us that, while the agency has multiple efforts under way to improve its  tracked safety issue and postmarket study data, it has not developed  plans that comprehensively outline these efforts, establish related  goals, and provide time frames for their completion. Additionally, FDA  officials said they do not have plans to analyze tracked safety issue  and postmarket study data to inform the agency’s oversight of its  expedited programs, such as determining if drugs that used an  expedited program were subsequently associated with tracked safety  issues at rates or of types that differed from drugs that used FDA’s  standard process. FDA officials said that they do not subject  applications that used an expedited program to greater postmarket  safety monitoring and they do not have plans to do so because, to  obtain approval for marketing, these applications are required to meet  the same standard of evidence for safety and effectiveness as are  applications that used FDA’s standard process. However, some of  the expedited programs specifically permit the use of fewer, shorter,  or smaller clinical trials during development, and FDA’s lack of  analysis means that the agency lacks comprehensive information on  whether drugs that were developed under these programs pose  additional safety risks to patients once they are available on the  market.
section_title: Conclusions
paragraphs: Complete, accurate, and timely postmarket safety data, such as  information on tracked safety issues and the progress of postmarket  studies, are essential for FDA to meet its responsibility to monitor the  safety of marketed drugs. FDA’s monitoring efforts once drugs reach the  market are particularly important for those drugs that have used certain  expedited programs to reduce the development time before approval,  where there may be greater potential for previously unrecognized safety  issues to appear once a drug is more widely used. FDA has supported  efforts to shorten development and streamline the agency’s review of  drug applications through expedited pathways. However, we found  problems with the agency’s efforts to oversee and track potential safety  issues and postmarket studies once those drugs are on the market. While  internal control standards for the federal government specify that  information should be recorded in a form and within a time frame that  enables staff to carry out their responsibilities and that relevant, reliable,  and timely information should be available for external reporting  purposes, FDA’s data on postmarket safety issues and studies were  found to be incomplete, outdated, to contain inaccuracies, and to be  stored in a manner that made routine, systematic analysis difficult.
To effectively track potential safety issues and the agency’s response to  them, and to track and ensure postmarket studies are being conducted on  schedule, it is important that FDA have ready access to complete, timely,  and accurate information. This information also provides the basis for  FDA’s required reports, which are important for informing policymakers  and the public about emerging safety issues and the extent to which drug  sponsors are fulfilling their obligations to conduct studies on the safety,  efficacy, and optimal use of marketed drugs. Reliable and accessible data  would also provide FDA with information to conduct analyses to inform  oversight of its expedited programs. Although FDA officials have pointed  out that all applications have to meet the same statutory standards for  approval, and that additional risks posed by applications that used an  expedited program may be acceptable given the seriousness of  conditions being treated, we believe that reliable data to support  additional oversight is important given public concern about the safety  implications of streamlined drug development and review. While FDA has  begun some efforts to improve its data by issuing guidelines for staff and  adding tools for oversight, more concrete plans to correct known  problems with the completeness, timeliness, and accuracy of its data, and  to improve underlying data systems so that information important for  oversight is captured in a useable form, are critical.
section_title: Recommendations for Executive Action
paragraphs: To improve the data on tracked safety issues and postmarket studies that  are needed for required reporting and for systematic oversight of  postmarket drug safety, we recommend that the Secretary of HHS direct  the Commissioner of FDA to take the following two actions: develop comprehensive plans, with goals and time frames, to help  ensure that identified problems with the completeness, timeliness, and  accuracy of information in its database on tracked safety issues and  postmarket studies are corrected, and work with stakeholders within FDA to identify additional improvements  that could be made to FDA’s current database or future information  technology investments to capture information in a form that can be  easily and systematically used by staff for oversight purposes.
section_title: Agency Comments and Our Evaluation
paragraphs: We provided a draft of this report to HHS for comment. In its written  comments, reproduced in appendix III, HHS concurred with our  recommendations and stated that conducting rigorous oversight of  postmarket safety is a priority. HHS noted that FDA, by improving its data  on postmarket studies and tracked safety issues, can more effectively use  these data to monitor drugs in the postmarket setting. HHS also provided  technical comments that we incorporated, as appropriate.
In addition, HHS commented that drugs using an expedited program must  meet the same statutory standards for safety and effectiveness to be  approved for the U.S. market as other, non-expedited drugs—a point that  is included in our report. HHS noted that drugs using the accelerated  approval program are also required to complete postmarket studies for  the drug sponsors to verify the anticipated clinical benefits. We believe  that this reliance on postapproval studies for verification of the clinical  benefits of drugs entering the U.S. market using accelerated approval  underscores the importance of improved FDA oversight of postmarket  studies. HHS also pointed out the differences between the standards for  granting breakthrough therapy designation or fast track designation—that  is, the ability for a drug sponsor to use one of these two expedited  programs—and FDA approval of the drugs for marketing; these  distinctions are also noted in our report.
HHS also commented that FDA-approved drugs that used an expedited  program do not necessarily require different postmarket safety monitoring  than other drugs, noting that tracked safety issues and postmarket  studies are utilized to monitor all drugs after they are approved by FDA,  including drugs using an expedited program. However, as we note in our  report, some of the expedited programs specifically permit the use of  fewer, shorter, or smaller clinical trials during development, and FDA has  noted that additional risks posed by applications that use an expedited  program may be acceptable given the seriousness of conditions being  treated. FDA’s lack of analysis of data on tracked safety issues and  postmarket studies related to applications that used an expedited  program indicates that the agency lacks comprehensive information on  whether drugs that were developed under these programs pose additional  safety risks to patients once they are available on the market. We believe  that maintaining reliable data that could be used to conduct such analysis  is critical, given public concern about the safety implications of  streamlined drug development and review.
HHS acknowledged the challenges of FDA’s administrative tracking of  postmarket safety issues and commented that CDER’s internal  evaluations, which CDER initiated before we started our review, had  helped identify these challenges. HHS further noted that FDA is taking  steps to address some of these challenges related to its internal data.  HHS also listed other mechanisms FDA uses to monitor postmarket  safety issues and the status of its “backlog” of postmarket studies, noting  that CDER staff prioritized identifying, evaluating, communicating about,  and taking regulatory action to address safety issues over expending  limited resources on entering information about safety issues into FDA’s  tracking system. Nonetheless, given that FDA’s internal evaluations found  that information on postmarket studies was often outdated or otherwise  inaccurate, we continue to believe that complete, accurate, and timely  data are necessary for FDA managers to have the information required to  conduct systematic oversight and appropriately monitor tracked safety  issues and postmarket studies.
As agreed with your office, 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 Secretary of Health  and Human Services and other interested parties. In addition, the report  will be 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 crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs are on the last page  of this report. GAO staff who made major contributions to this report are  listed in appendix IV.
section_title: Appendix I: Number of Granted Requests for Fast Track Designation by Product Category, Fiscal Years 2007 through 2015
paragraphs: Appendix I: Number of Granted Requests for  Fast Track Designation by Product Category,  Fiscal Years 2007 through 2015 Number granted fast track designation by the Food and Drug Administration’s (FDA)
section_title: Appendix II: Number of Granted Requests for Breakthrough Therapy Designation by Product Category, July 9, 2012, through December 31, 2014
paragraphs: Percentage rows do not sum to 100 due to rounding.
section_title: Appendix III: Comments from the Department of Health and 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, Kim Yamane, Assistant Director;  Marisa Beatley; Carolyn Fitzgerald; Sandra George; Cathleen Hamann;  Gay Hee Lee; Jessica Lin; and Hannah Locke were major contributors to  this report.