Drug Safety: FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement
Released: 2016-01-14T00:00:00

Letter

Background

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.

FDA Granted More than Half of Requests for Fast Track Designation and Denied Most Requests for Breakthrough Therapy Designation

FDA Granted Two-Thirds of Requests for Fast Track Designation and Denied Most Requests for Breakthrough Therapy Designation

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.

Antiviral and Oncology Drugs Were the Most Common Product Categories among Applications Granted Fast Track and Breakthrough Therapy Designation

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.

One in Four Drug Applications Approved by FDA Used at Least One Expedited Program, and the Most Frequent Category Was Oncology Drugs

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.)

FDA Lacks Reliable Information for Postmarket Safety Reporting and Oversight

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.

Conclusions

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.

Recommendations for Executive Action

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.

Agency Comments and Our Evaluation

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.

Appendix I: Number of Granted Requests for Fast Track Designation by Product Category, Fiscal Years 2007 through 2015

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)

Appendix II: Number of Granted Requests for Breakthrough Therapy Designation by Product Category, July 9, 2012, through December 31, 2014

Percentage rows do not sum to 100 due to rounding.

Appendix III: Comments from the Department of Health and Human Services

Appendix IV: GAO Contact and Staff Acknowledgments

GAO Contact

Staff Acknowledgments

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.