Prescription Drugs: FDA Has Met Most Performance Goals for Reviewing Applications
Published: 2012-03-30T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: The Food and Drug Administration (FDA) within the Department of Health and Human Services (HHS) is responsible for overseeing the safety and efficacy of drugs and biologics sold in the United States. New drugs and biologics must be reviewed by FDA before they can be marketed, and the Prescription Drug User Fee Act (PDUFA) authorizes FDA to collect user fees from the pharmaceutical industry to support its review of prescription drug applications, including new drug applications (NDA), biologic license applications (BLA), and efficacy supplements that propose changes to the way approved drugs and biologics are marketed or used. Under each authorization of PDUFA since 1992, FDA committed to performance goals for its drug and biologic reviews.
In preparation for the next PDUFA reauthorization, GAO was asked to examine FDAs drug and biologic review processes. In this report, we (1) examine trends in FDAs NDA and BLA review performance for fiscal years (FY) 2000 through 2010, (2) examine trends in FDAs efficacy supplement review performance for FYs 2000 through 2010, and (3) describe issues stakeholders have raised about the drug and biologic review processes and steps FDA is taking that may address these issues. To do this work, GAO examined FDA drug and biologic review data, reviewed FDA user fee data, interviewed FDA officials, and interviewed two industry groups and five consumer advocacy groups. All of the stakeholder groups participated in at least half of the meetings held by FDA to discuss the reauthorization of the prescription drug user fee program.
section_title: What GAO Found
paragraphs: FDA met most performance goals for priority and standard NDAs and BLAs received from FY 2000 through FY 2010. FDA meets its performance goals by completing its review and issuing an action lettersuch as an approval or a response detailing deficiencies that are preventing the application from being approvedfor a specified percentage of applications within a designated period of time. FDA designates NDAs and BLAs as either priorityif the product would provide significant therapeutic benefits when compared to available drugsor standard. FDA met the performance goals for both priority and standard NDAs and BLAs for 10 of the 11 fiscal years GAO examined; FDA did not meet either of the goals for FY 2008. Although FDA had not yet issued an action letter for all of the applications it received in FY 2011 and results are therefore preliminary, FDA was meeting the goals for both priority and standard NDAs and BLAs on which it had taken action. Meanwhile, FDA review time for NDAs and BLAsthe time elapsed between FDAs receipt of an application and issuance of an action letterincreased slightly from FY 2000 through FY 2010. In addition, the percentage of NDAs and BLAs receiving an approval letter at the end of the first review cycle generally increased, although that percentage has decreased for priority NDAs and BLAs since FY 2007.
FDA met most of its performance goals for efficacy supplements from FY 2000 through FY 2010. Specifically, FDA met the performance goals for both priority and standard efficacy supplements for 10 of the 11 fiscal years GAO examined. FDA review time generally increased during the analysis period for both priority and standard efficacy supplements. The percentage of priority efficacy supplements receiving an approval letter at the end of the first review cycle fluctuated from FY 2000 through FY 2010, ranging between 47 percent and 80 percent during this time. The results for standard efficacy supplements showed a steadier increase with the percentage of first-cycle approval letters rising from 43 percent for FY 2000 applications to 69 percent for FY 2010 applications.
The industry groups and consumer advocacy groups we interviewed noted a number of perceived issues related to FDAs review of drug and biologic applications. The most commonly mentioned issues raised by industry and consumer advocacy stakeholder groups were actions or requirements that can increase review times (such as taking more than one cycle to approve applications) and insufficient communication between FDA and stakeholders throughout the review process. Industry stakeholders also noted a perceived lack of predictability and consistency in reviews. Consumer advocacy group stakeholders noted issues related to inadequate assurance of the safety and effectiveness of approved drugs. FDA is taking steps that may address many of these issues, including issuing new guidance, establishing new communication-related performance goals, training staff, and enhancing scientific decision making.
In commenting on a draft of this report, HHS generally agreed with GAOs findings and noted that they reflect what the agency reported for the same time period. HHS also called attention to activities FDA has undertaken to improve the prescription drug review process.

section_title: Letter
paragraphs: The Food and Drug Administration (FDA) within the Department of Health  and Human Services (HHS) is responsible for overseeing the safety and  efficacy of drugs and biological products sold in the United States. In  1992, Congress passed the Prescription Drug User Fee Act (PDUFA) to  provide additional resources for FDA to support the process of reviewing  applications for new drugs. PDUFA authorized FDA to collect user fees  from the pharmaceutical and biotechnology industries to supplement its  annual appropriation for salaries and expenses; these user fees include  application fees, annual establishment registration fees, and annual  product fees. The prescription drug user fee program has been  reauthorized every 5 years since 1992, most recently as part of the Food  and Drug Administration Amendments Act of 2007 (FDAAA), which  authorizes FDA to collect user fees for fiscal years (FY) 2008 through   User fees have become a larger part of FDA’s funding for drug  2012.review processes, rising from 26.1 percent of costs in FY 1993—the first  year FDA collected user fees for drugs—to 61.5 percent in FY 2010, the  most recent year for which data are available. In FY 2010, PDUFA user  fees collected by FDA—including application, establishment, and product  fees—totaled more than $529 million, including over $172 million in  application fees.
Application fees are collected for a variety of drug and biologic application  types, including new drug applications (NDA), biologic license  applications (BLA), and efficacy supplements to approved NDAs and  BLAs; the amount of the user fee varies for different types of   An NDA is an application to market a new drug—either an  applications. innovative drug or a variation of a previously marketed drug. A BLA is an  application to market a new biologic. FDA categorizes innovative drugs  that have not previously been marketed in any dosage or form as new  molecular entities (NMEs); FDA also considers nearly all BLAs to be  innovative drugs. An efficacy supplement to an NDA or BLA is submitted  to propose changes to the way an approved drug is marketed or used,  such as adding or modifying an indication or claim, revising the dose or  dose regimen, providing for a new route of administration, or changing the  marketing status from prescription to over-the-counter use.
Under each authorization of the prescription drug user fee program, FDA  committed to performance goals related to the review of drug  applications. and issuing an action letter (i.e., an approval, denial, or complete  response) for a specified percentage of applications within a designated   These performance goals, as well as user fee amounts,  period of time.
For applications submitted in FY 2012, the fee for the review of an application (e.g., an  NDA or BLA) that requires clinical data is $1,841,500. The user fee for applications that do  not require clinical data is half this amount ($920,750), as is the fee for efficacy  supplements requiring clinical data. Some applications—such as those for orphan  designated products to treat rare diseases or conditions—are exempt from user fees. In  addition, abbreviated new drug applications, which are applications for the approval of  generic drugs, are not subject to user fees.
See Pub. L. No. 110-85, § 101(c), 121 Stat. 823, 825 (2007). The performance goals are  identified in letters sent by the Secretary of Health and Human Services to the Chairman  of the Senate Committee on Health, Education, Labor, and Pensions and the Chairman of  the House Committee on Energy and Commerce, and are published on FDA’s website.  Each fiscal year, FDA is required to submit a report on its progress in achieving those  goals and future plans for meeting them. See 21 U.S.C. § 379h-2(a). are negotiated between FDA and industry stakeholders and submitted to  congressional committees prior to each reauthorization. FDA’s authority  to collect user fees for drugs expires on October 1, 2012, and the  prescription drug user fee program will need to be reauthorized in order  for FDA to continue to collect user fees. In preparation for the  reauthorization of the prescription drug user fee program, you requested  that we examine FDA’s prescription drug review process. In this report,  we (1) examine trends in FDA’s NDA and BLA review performance for  FYs 2000 through 2010, (2) examine trends in FDA’s efficacy supplement  review performance for FYs 2000 through 2010, and (3) describe the  issues stakeholders have raised about the prescription drug review  processes and steps FDA is taking that may address these issues. We  provide additional details on FDA’s NDA and BLA review performance in  appendix I and efficacy supplement review performance in appendix II.  You also asked us to provide information on the number of full-time  equivalent (FTE) staff involved in the prescription drug review process;  this information is provided in appendix III.
To determine the trends in FDA’s review performance for NDAs, BLAs,  and efficacy supplements to approved NDAs and BLAs for FYs 2000  through 2010, we examined data obtained from FDA on the review  process for all such applications submitted to FDA in those years.  Additionally, we reviewed data on FY 2011 applications in order to  provide preliminary performance results for that year. FDA had not yet  completed its first review for a majority of the FY 2011 applications at the  time we received FDA’s data; as these reviews are completed, the   We reviewed the data for  preliminary results are likely to change.reasonableness and consistency, including screening for missing data,  outliers, and obvious errors. We also interviewed FDA officials about  steps they take to ensure data reliability. We determined that these data  were sufficiently reliable for our purposes. Our analyses focused on the  proportion of drug applications in each fiscal year for which FDA met or  did not meet the applicable performance goal(s); the FDA review time  (i.e., the time counted toward user fee performance goals, from the date  of receipt of an application to the date FDA issued an action letter to end  the first review cycle); the time to final decision (i.e., the total time  between submission of an application and the sponsor’s withdrawal of the  application or FDA’s issuance of an approval or denial action letter in the  last completed review cycle); and the percentage of first-cycle decisions  that were approvals. We also reviewed user fee data from FDA’s annual  PDUFA financial reports to Congress for FYs 1993 through 2010 and  interviewed FDA staff regarding drug review processes and the data we  received from FDA.
To describe the issues stakeholders have raised about the drug review  processes and what steps FDA is taking that may address these issues,  we interviewed two industry groups representing drug manufacturers and  five consumer advocacy groups.  All of these groups have participated in  at least half of the meetings held by FDA to discuss the reauthorization of  the prescription drug user fee program. We performed content analyses  of the interviews to determine the most pressing issues based on how  often each issue was raised. To describe steps FDA is taking that may  address some of these issues, we examined publicly available FDA  documents, including the draft agreement between FDA and industry on  the user fees and performance goals for FYs 2013 through 2017.
We conducted this performance audit from October 2011 through March  2012 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: Drug applications—including NDAs, BLAs, and efficacy supplements— are reviewed primarily by FDA’s Center for Drug Evaluation and  Research (CDER), with a smaller proportion reviewed by the Center for   Prior to submission of an  Biologics Evaluation and Research (CBER).
When we refer to consumer advocacy groups, we are referring to groups that advocate  on behalf of consumers and patients. application, sponsors may choose to seek accelerated approval status if  the drug is intended to treat a serious or life-threatening illness (such as  cancer) and has the potential to provide meaningful therapeutic benefit to  patients over existing treatments. Sponsors of a drug with accelerated  approval status may be granted approval on the basis of clinical trials  conducted using a surrogate endpoint—such as a laboratory  measurement or physical sign—as an indirect or substitute measurement  for a clinically meaningful outcome such as survival. According to FDA,  the agency generally also speeds its review of drug applications with  accelerated approval status by granting them priority review, although  priority review can also be granted to an application without accelerated  approval status. FDA grants priority review for applications that it  expects, if approved, would provide significant therapeutic benefits,  compared to available drugs, in the treatment, diagnosis, or prevention of  a disease. Applications for which there are no perceived significant  therapeutic benefits beyond those for available drugs are granted  standard review.
See 21 U.S.C. § 355(d); 42 U.S.C. § 262(j). prevent FDA from approving the application. In response, sponsors can  submit additional information to FDA in the form of amendments to the  application. Certain applications are also subject to review by an  independent advisory committee. FDA convenes advisory committees  to provide independent expertise and technical assistance to help the  agency make decisions about drug products. Additionally, FDA might  require the sponsor to submit a Risk Evaluation and Mitigation Strategy  (REMS) for the drug under review to ensure that the benefits of the drug  outweigh its risks.
FDA review time for an original application is calculated as the time  elapsed from the date FDA receives the application and associated user  fee to the date it issues an action letter; it is calculated using only the first  review cycle and therefore does not include any time that may elapse  while FDA is waiting for a sponsor to respond to FDA’s first-cycle action  letter or any review time that elapses during subsequent review cycles.  In order to close the review cycle for NDAs, BLAs, and efficacy  supplements, FDA must complete its review and issue an approval letter,  a denial letter, or a “complete response” letter (i.e., a letter delineating  any problems FDA identified in the application that prevented it from  being approved). The review cycle will also be closed if the application  is withdrawn by the sponsor. The date on which one of these actions  occurs is used to determine whether the review was completed within the  PDUFA goal time frame. If FDA issues a complete response letter, the  sponsor may choose to submit a revised application to FDA. These are  known as resubmissions and their review is covered under the user fee  paid with the original submission. Resubmissions are classified as   Class 1 or Class 2 according to the complexity of the information they  contain, with Class 2 being the most complex.
Although the prescription drug performance goals have continued to  evolve with each reauthorization of the prescription drug user fee  program, the goals for NDAs, BLAs, and efficacy supplements have  remained fairly stable for recent cohorts—a cohort being comprised of all  the submissions of a certain type filed in the same fiscal year (see   table 1). For standard NDAs, BLAs, and efficacy supplements, the current  goal was phased in until it reached the current level (90 percent of  reviews completed within 10 months) in FY 2002. Similarly, the goal for  Class 1 NDA and BLA resubmissions was phased in, reaching its current  level of 90 percent of reviews completed within 2 months in FY 2001.  FDA can extend the review time frame for NDAs, BLAs, or Class 2  resubmissions by 3 months if it receives a major amendment to the  application from the sponsor within 3 months of the goal date.
section_title: FDA Met Most Performance Goals for Original NDAs and BLAs While FDA Review Time Increased Slightly
paragraphs: FDA met most of its performance goals for priority and standard original  NDA and BLA submissions for the FYs 2000 through 2010 cohorts.  However, the average FDA review time increased slightly during this  period for both priority and standard NDAs and BLAs. The percentage of  FDA first-cycle approvals for both priority and standard NDAs and BLAs  generally increased from FY 2000 through FY 2010; however, the  percentage of first-cycle approvals has decreased for priority NDAs and  BLAs since FY 2007.
subsections: section_title: FDA Met Most Performance Goals for Original NDAs and BLAs for FYs 2000 through 2010
paragraphs: FDA met most of its performance goals for priority and standard original  NDA and BLA submissions during our analysis period by issuing the  proportion of action letters specified in the performance goals within the  goal time frames. Specifically, for priority original NDAs and BLAs, FDA  met the performance goals for 10 of the 11 completed cohorts we  examined (see fig. 1). FDA also met the performance goals for 10 of the  11 completed standard NDA and BLA cohorts we examined. However,  FDA did not meet the goals (i.e., issue the specified proportion of action  letters within the goal time frames) for priority or standard NDAs and  BLAs in the FY 2008 cohort. FDA and industry stakeholders we  interviewed suggested that the reason FDA did not meet the goals for this  cohort was that extra time was required for implementation of REMS  requirements, which were introduced as part of the implementation of  FDAAA. Although the FY 2011 cohort was still incomplete at the time we  received FDA’s data, FDA was meeting the goals for both priority and  standard original NDAs and BLAs on which it had taken action.
For the subset of priority NDAs and BLAs that were for innovative drugs,  FDA met the performance goals for 9 of the 11 completed cohorts—all  cohorts except FYs 2008 and 2009. For the subset of standard NDAs and  BLAs that were for innovative drugs, FDA also met the performance goals  for 9 of the 11 completed cohorts—all cohorts except FYs 2007 and 2008.  For the incomplete FY 2011 cohort, FDA was meeting the goals for the  subsets of both priority and standard NDAs and BLAs that were for  innovative drugs.
If FDA issues a complete response letter to the sponsor noting  deficiencies with the original submission, the sponsor can resubmit the  application with the deficiencies addressed. For Class I NDA and BLA  resubmissions, FDA met the performance goals for 8 of the 11 completed  cohorts we examined. For Class 2 NDA and BLA resubmissions, FDA  met the performance goals for 10 of the 11 completed cohorts we  examined. Although the FY 2011 cohort was still incomplete at the time  we received FDA’s data, FDA was meeting the goals for both the Class 1  resubmissions and the Class 2 resubmissions on which it had taken  action.
section_title: Average FDA Review Time Increased Slightly for Original NDAs and BLAs from FY 2000 through FY 2010
paragraphs: Overall, average FDA review time—the time elapsed from when FDA  received a submission until it issued an action letter—increased slightly  from FY 2000 through FY 2010 for both priority and standard NDAs and  BLAs. There was a larger increase in average review time for both types  of applications beginning in FY 2006. However, average review time  began decreasing after FY 2007 for standard applications and after   FY 2008 for priority applications, bringing the review times back near the  FY 2000 levels (see fig. 2). As mentioned previously, FDA and industry  stakeholder groups noted the implementation of REMS requirements as a  contributing factor to increased review times for the FY 2008 cohort.  Although the FY 2011 cohort was still incomplete at the time we received  FDA’s data, average FDA review time for applications on which FDA had  taken action was 186 days for priority NDAs and BLAs and 308 days for  standard NDAs and BLAs.
Trends in average FDA review time for the subset of NDAs and BLAs that  were for innovative drugs were similar to trends for all priority or standard  NDAs and BLAs. For the subset of priority NDAs and BLAs that were for  innovative drugs, average FDA review times were sometimes longer and  sometimes shorter than those for all priority NDAs and BLAs; review  times for the subset of standard NDAs and BLAs that were for innovative  drugs were generally slightly longer than review times for all standard  NDAs and BLAs.
We were unable to calculate the average time to final decision for original  NDAs and BLAs—that is, the average time elapsed between submission  of an application and the sponsor’s withdrawal of the application or FDA’s  issuance of an approval or denial action letter in the last completed  review cycle. Time to final decision includes FDA review time as well as  time that elapsed between review cycles while FDA was waiting for the  sponsor to resubmit the application. We were unable to complete this  calculation because most cohorts were still open for these purposes   (i.e., fewer than 90 percent of submissions had received a final action  such as approval, denial, or withdrawal). Specifically, for priority NDAs  and BLAs, only four cohorts (FYs 2001, 2002, 2005, and 2006) had at  least 90 percent of submissions closed, and for standard NDAs and  BLAs, only one cohort (FY 2002) had at least 90 percent of submissions  closed. (See app. I, table 4 for details.) As a result, there were too few  completed cohorts available to calculate the time to final decision in a  meaningful way. FDA may opt to consider an application withdrawn (and  thus closed) if the sponsor fails to resubmit the application within 1 year  after FDA issues a complete response letter. When we examined the  open applications using this criterion, we identified 194 open NDAs and  BLAs in FYs 2000 through 2010 for which FDA had issued a complete  response letter in the most recent review cycle but had not yet received a  resubmission from the sponsor. FDA had issued the complete response  letter more than 1 year earlier for 162 (84 percent) of these applications.
section_title: Percentage of FDA First-Cycle Approvals Generally Increased from FY 2000 through FY 2010 but Decreased for Priority NDAs and BLAs Since FY 2007
paragraphs: The percentage of priority NDAs and BLAs receiving an approval letter at  the end of the first review cycle exhibited a sharp 1-year decline from   FY 2000 to FY 2001, then increased substantially from FY 2001 through  FY 2007, before decreasing again from FY 2007 through FY 2010 (see  fig. 3). The percentage of first-cycle approvals for standard NDAs and  BLAs showed a similar 1-year decline from FY 2000 to FY 2001, then  varied somewhat but generally increased from FY 2002 through FY 2010.  Although review of the FY 2011 cohort was incomplete at the time we  received FDA’s data, 93 percent of the priority NDAs and BLAs that had  received a first-cycle action letter had been approved, as had 42 percent  of the standard NDAs and BLAs.
Trends for FYs 2000 through 2010 in the percentage of first-cycle  approvals were similar for the subset of NDAs and BLAs that were for  innovative drugs when compared to trends for all priority or standard  NDAs and BLAs. For the subset of priority NDAs and BLAs for innovative  drugs, the percentage of first-cycle approvals was generally higher than  for all priority NDAs and BLAs. For standard submissions, the percentage  of first-cycle approvals for innovative drugs was generally lower than for  all standard NDAs and BLAs; for some cohorts (e.g., FYs 2000, 2004– 2006, and 2008) this difference was substantial.
section_title: FDA Met Most Performance Goals for Original Efficacy Supplements While FDA Review Time Increased Slightly
paragraphs: FDA met most of its performance goals for priority and standard original  efficacy supplements to approved NDAs and BLAs for the FYs 2000  through 2010 cohorts. However, the average FDA review time generally  increased during this period for both priority and standard efficacy  supplements. The percentage of FDA first-cycle approvals fluctuated for  priority efficacy supplements but generally increased for standard efficacy  supplements for the FYs 2000 through 2010 cohorts.
subsections: section_title: FDA Met Most Performance Goals for Original Efficacy Supplements in FYs 2000 through 2010
paragraphs: FDA met most of its performance goals for efficacy supplements to  approved NDAs and BLAs during our analysis period. Specifically, FDA  met the performance goals for both priority and standard efficacy  supplements for 10 of the 11 completed cohorts we examined (see fig. 4).  Although the FY 2011 cohort was still incomplete at the time we received  FDA’s data, based on efficacy supplements on which it had taken action,  FDA was meeting the goal for both priority and standard efficacy  supplements.
Average FDA review time generally increased during our analysis period  for both priority and standard efficacy supplements. Specifically, average  FDA review time for priority efficacy supplements increased from   173 days in the FY 2000 cohort to a peak of 205 days in the FY 2009  cohort and then fell in the FY 2010 cohort to 191 days (see fig. 5). For  standard efficacy supplements, average FDA review time rose from   285 days in the FY 2000 cohort to a peak of 316 days in the FY 2008  cohort and then fell in the FY 2010 cohort to 308 days. Although the   FY 2011 cohort was still incomplete at the time we received FDA’s data,  average FDA review time for efficacy supplements on which FDA had  taken action was 195 days for priority submissions and 284 days for  standard submissions.
As with NDA and BLA submissions, we were unable to calculate the  average time to final decision for efficacy supplements in any meaningful  way because there were too few completed cohorts. Specifically, for  priority efficacy supplements, only four cohorts (FYs 2000, 2001, 2004,  and 2007) had at least 90 percent of submissions closed, and for  standard efficacy supplements, only one cohort (FY 2005) had at least 90  percent of submissions closed. (See app. II, table 9 for details.) FDA may  opt to consider an application withdrawn (and thus closed) if the sponsor  fails to resubmit the application within 1 year after FDA issues a complete  response letter. When we examined the open applications using this  criterion, we identified 196 open efficacy supplements in FYs 2000  through 2010 for which FDA had issued a complete response letter in the  most recent review cycle but had not yet received a resubmission from  the sponsor. FDA had issued the complete response letter more than   1 year earlier for 168 (86 percent) of these submissions.
section_title: Percentage of FDA First-Cycle Approvals Fluctuated for Priority Efficacy Supplements but Generally Increased for Standard Efficacy Supplements from FYs 2000 through 2010
paragraphs: The percentage of priority efficacy supplements receiving an approval  decision at the end of the first review cycle fluctuated for FYs 2000  through 2010, ranging between 47 percent and 80 percent during this  time (see fig. 6). The results for standard efficacy supplements showed a  steadier increase than for priority submissions. Specifically, the  percentage of first-cycle approvals rose from 43 percent in the FY 2000  cohort to 69 percent in the FY 2010 cohort. Although the FY 2011 cohort  was still incomplete at the time we received FDA’s data, 63 percent of  first-cycle action letters for standard submissions and 92 percent of   first-cycle action letters for priority submissions issued by that time were  approvals.
section_title: Stakeholders Noted Issues with the Prescription Drug Review Process and FDA Is Taking Steps That May Address Many of Those Issues
paragraphs: The industry groups and consumer advocacy groups we interviewed  noted a number of issues related to FDA’s review of prescription drug  applications. The most commonly mentioned issues raised by industry  and consumer advocacy stakeholder groups were actions or  requirements that stakeholders believe can increase review times and  insufficient communication between FDA and stakeholders throughout the  review process. Industry stakeholders also noted a lack of predictability  and consistency in reviews. Consumer advocacy group stakeholders  noted issues related to inadequate assurance of the safety and efficacy of  approved drugs. FDA is taking steps that may address many of these  issues.
subsections: section_title: Stakeholders Noted Actions or Requirements That They Believe Can Increase Review Times
paragraphs: Most of the seven stakeholder groups we interviewed told us that there  are actions and requirements that can lengthen FDA’s review process.  For example, four of the five consumer advocacy group stakeholders  noted that FDA does not require sponsors to submit electronic  applications; three of these stakeholders noted that requiring electronic  applications could make the review process faster. Additionally, the two  industry stakeholders told us that they believe FDA should approve more  applications during the first review cycle. We found that an average of   44 percent of all original NDAs and BLAs submitted in FYs 2000 through  2010 were approved during the first review cycle, while 75 percent were  ultimately approved.
In addition, the two industry stakeholders that we interviewed raised  requirements that can make review times longer, but the consumer  advocacy group stakeholders did not agree with these points. For  example, both industry stakeholders noted that working out the  implementation of REMS requirements introduced in FDAAA slowed  FDA’s review process. One industry stakeholder stated that discussions  about REMS often happened late in the review process, resulting in an  increase in review times; another noted that REMS requirements have  not been standardized, contributing to longer review times. In contrast,  one consumer advocacy group stakeholder that we interviewed  suggested that standardized REMS requirements or a “one size fits all”  approach would not be meaningful as a risk management strategy. The  industry and consumer advocacy group stakeholders also disagreed on  another issue that can potentially lengthen the review process—FDA’s  process for using outside scientific expertise for the review of  applications. The two industry stakeholders we interviewed stated that  the rules surrounding consultation with an advisory committee— particularly those related to conflicts of interest—can extend the time it  takes FDA to complete the review process. In contrast, two of the  consumer advocacy group stakeholders we interviewed specifically stated  that FDA should be concerned with issues of conflict of interest in  advisory committees used during the drug review process.
FDA has taken or plans to take several steps that may address issues  stakeholders noted can lengthen the review process, including issuing  new guidance, commissioning and issuing assessments of the review  process, training staff, and establishing programs aimed at helping  sponsors. For example, according to the draft agreement with industry for  the upcoming prescription drug user fee program reauthorization, FDA  would issue guidance on the standards and format for submitting  electronic applications and would begin tracking and reporting on the  number of electronic applications received. In addition, according to the  draft agreement, FDA would publish both an interim and a final  assessment of the review process for innovative drugs and then hold  public meetings for stakeholders to present their views on the success of  the program, including its effect on the efficiency and effectiveness of  first-cycle reviews. FDA would also provide training to staff on reviewing  applications containing complex scientific issues, which may improve  FDA’s ability to grant first-cycle approvals where appropriate. In addition,  FDA would issue guidance on assessing the effectiveness of REMS for a  particular drug and would hold public meetings to explore strategies to  standardize REMS, where appropriate. However, we did not identify any  examples of steps FDA has taken to address industry stakeholder issues  with leveraging outside expertise during the drug review process in any of  the recently released strategy, assessment, and guidance documents we  reviewed.
section_title: Stakeholders Cite Insufficient Communication between FDA and Stakeholders throughout the Review Process
paragraphs: Most of the two industry and five consumer advocacy group stakeholders  that we interviewed told us that there is insufficient communication  between FDA and stakeholders throughout the review process. For  example, both of the industry stakeholders noted that FDA does not  clearly communicate the regulatory standards that it uses to evaluate  applications. In particular, the industry stakeholders noted that the  regulatory guidance documents issued by FDA are often out of date or  the necessary documents have not yet been developed. Additionally, both  industry stakeholders and two consumer advocacy group stakeholders  noted that after sponsors submit their applications, insufficient  communication from FDA prevents sponsors from learning about  deficiencies in their applications early in FDA’s review process. According  to these four stakeholders, if FDA communicated these deficiencies  earlier in the process, sponsors would have more time to address them;  this would increase the likelihood of first-cycle approvals. Finally, three  consumer advocacy group stakeholders also noted that FDA does not  sufficiently seek patient input during reviews. One stakeholder noted that  it is important for FDA to incorporate patient perspectives into its reviews  of drugs because patients might weigh the benefits and risks of a certain  drug differently than FDA reviewers.
FDA has taken or plans to take several steps that may address  stakeholders’ issues with the frequency and quality of its communications  with stakeholders, including conducting a review of its regulations,  establishing new review programs and communication-related  performance goals, providing additional staff training, and increasing its  efforts to incorporate patient input into the review process. FDA is in the  process of reviewing its regulations to identify burdensome, unclear,  obsolete, ineffective, or inefficient regulations and is soliciting stakeholder  input on additional rules that could be improved. In addition, according to  the draft agreement with industry, FDA would establish a review model  with enhanced communication requirements for innovative drugs,  including requirements to hold pre- and late-cycle submission meetings  with sponsors as well as to update sponsors following FDA’s internal  midcycle review meetings. Additionally, under the draft user fee  agreement, FDA would inform sponsors of the planned review timeline  and any substantive review issues identified thus far within 74 days of  receipt for 90 percent of original NDAs, BLAs, and efficacy supplements.  FDA would also issue guidance, develop a dedicated drug development  training staff, and provide training on communication for all CDER staff  involved in the review of investigational new drugs.increase its utilization of patient representatives as consultants to provide  patient views early in the product development process and to ensure  those perspectives are considered in regulatory discussions. More  specifically, FDA would expect to start with a selected set of disease  areas and meet with the relevant patient advocacy groups and other  interested stakeholders to determine how to incorporate patient  perspectives into FDA’s decision making.
section_title: Industry Stakeholders Report a Lack of Predictability and Consistency in Reviews
paragraphs: The two industry stakeholders that we interviewed also told us that there  is a lack of predictability and consistency in FDA’s reviews of drug  applications. For example, both stakeholders noted that there is  sometimes inconsistent application of criteria across review divisions or  offices. Further, both industry stakeholders we interviewed noted that  FDA lacks a structured benefit-risk framework to refer to when making  decisions, which they believe would improve the predictability of the  review process.
FDA has taken or plans to take steps that may address stakeholders’  issues with the predictability and consistency of its reviews of drug  applications. For example, FDA plans to provide training related to the  development, review, and approval of drugs for rare diseases, which may  help to improve the consistency of FDA’s review of those drugs. In  addition, FDA has appointed a Deputy Commissioner for Medical  Products to oversee and manage CBER, CDER, and the Center for  Devices and Radiological Health (CDRH) in an attempt to improve  integration and consistency between the centers. Furthermore, FDA has  agreed to create a 5-year plan to develop and implement a structured  benefit-risk framework in the review process. FDA will also revise its  internal guidance to incorporate a structured benefit-risk framework and  then train its review staff on these revisions.
section_title: Consumer Advocacy Group Stakeholders Suggest That FDA May Provide Inadequate Assurance of the Safety and Efficacy of Approved Drugs
paragraphs: Three of the five consumer advocacy group stakeholders that we spoke  with raised issues about whether FDA is adequately ensuring the safety  and efficacy of the drugs it approves for marketing. All three of these  stakeholders told us that FDA should place greater priority on safety and  efficacy over review speed. In addition, three stakeholders told us that  FDA does not gather enough data on long-term drug safety and efficacy  through methods such as postmarket surveillance. One stakeholder  suggested that FDA should more effectively utilize its Sentinel System for  adverse event reporting. These concerns have also been extensively  discussed elsewhere.
FDA has taken or plans to take steps that may address stakeholders’  issues with the safety and efficacy of approved drugs, including  publishing a regulatory science strategic plan. This document describes  various plans FDA has for emphasizing safety and efficacy, such as  developing assessment tools for novel therapies, assuring safe and  effective medical innovation, and integrating complex data (including  postmarket data) to allow for better analyses. FDA has also published a  report identifying needs that, if addressed, would enhance scientific  decision making in CDER. Some of the needs identified included  improving access to postmarket data sources and exploring the feasibility  of different postmarket analyses; improving risk assessment and  management strategies to reinforce the safe use of drugs; and developing  and improving predictive models of safety and efficacy in humans. Finally,  in the draft agreement with industry, FDA has committed to conducting  both an interim and a final assessment of the strengths, limitations, and  appropriate use of the Sentinel System for helping FDA determine the  regulatory actions necessary to manage safety issues.
section_title: Concluding Observations
paragraphs: FDA met most of the performance goals for the agency to review and  issue action letters for original NDA and BLA submissions, Class 1 and  Class 2 resubmissions, and original efficacy supplements for the   FYs 2000 through 2010 cohorts. FDA review times increased slightly for  original NDAs, BLAs, and efficacy supplements during this period while  changes in the percentage of first-cycle approvals varied by application  type. While FDA has met most of the performance goals we examined,  stakeholders we spoke with point to a number of issues that the agency  could consider to improve the drug review process; FDA is taking or has  agreed to take steps that may address these issues, such as issuing new  guidance, establishing new communication-related performance goals,  training staff, and enhancing scientific decision making. It is important for  the agency to continue monitoring these efforts in order to increase the  efficiency and effectiveness of the review process and thereby help  ensure that safe and effective drugs are reaching the market in a timely  manner.
section_title: Agency Comments
paragraphs: HHS reviewed a draft of this report and provided written comments, which  are reprinted in appendix IV. HHS generally agreed with our findings and  noted that they reflect what the agency reported for the same time period.  HHS also called attention to activities FDA has undertaken to improve the  prescription drug review process. It highlighted FDA’s performance in  approving innovative drugs in FY 2011. HHS also noted steps FDA will  take to contribute to medical product innovation including expediting the  drug development pathway and streamlining and reforming FDA  regulations. Finally, HHS discussed enhancements to the drug review  program that were included in the proposed recommendations for the  2012 reauthorization of the prescription drug user fee program, such as  establishing a new review program for innovative drugs, enhancing  benefit-risk assessment, and requiring electronic submissions and  standardization of electronic application data to improve efficiency. HHS  also provided technical comments, which we incorporated as appropriate.
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 of this report to the  Secretary of Health and Human Services, the Commissioner of the Food  and Drug Administration, 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 may be found on  the last page of this report. GAO staff who made key contributions to this  report are listed in appendix V.
section_title: Appendix I: FDA NDA and BLA Review Performance for Fiscal Years (FYs) 2000 through 2011
paragraphs: Includes only those submissions that had received a final FDA action letter (i.e., approval) in their  last completed review cycle or were withdrawn by the sponsor at the time we received FDA’s data,  which include reviews by CBER and CDER through November 30, 2011.
subsections: section_title: Percentage of first-cycle actions that were:
paragraphs: Includes only those submissions that had received a final FDA action letter (i.e., approval) in their  last completed review cycle or were withdrawn by the sponsor at the time we received FDA’s data,  which include reviews by CBER and CDER through November 30, 2011.
We defined a submission as open if the most recent review cycle was still underway (i.e., pending) or  if FDA had issued a complete response letter in the most recent review cycle and the sponsor still  had the option of resubmitting the application under the original user fee. Submissions that have  received a complete response letter are considered complete for purposes of determining whether  FDA met the PDUFA performance goals, but the review is not closed. Prior to August 2008, FDA also  issued “approvable” and “not approvable” letters, which served the same purpose as the complete  response letters currently used. We grouped these three types of letters together in our analysis.
Yes  The FY 2011 cohort was not complete at the time we received FDA’s data, which include reviews by  CBER and CDER through November 30, 2011. Therefore, values indicated for FY 2011 in the table  above may change as these reviews are completed.  Our analysis was limited to resubmissions made in FYs 2000 through 2011 for original NDAs and  BLAs that were also submitted in FYs 2000 through 2011. Resubmissions made in FYs 2000 through  2011 for original NDAs and BLAs submitted prior to FY 2000 were not captured by our analysis.  “I.D.” stands for innovative drugs, a subset of all priority original NDAs and BLAs that includes nearly  all BLAs and those NDAs designated as new molecular entities (NMEs).  In FY 2000, Class 1 resubmissions were also subject to a 4-month goal time frame which is not  shown in our analysis.
Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal  time frames for Class 2 resubmissions can be extended for 3 months if the sponsor submits a major  amendment to the resubmission within 3 months of the goal date. For Class 2 NDA/BLA  resubmissions in these cohorts, 45 out of 463 submissions (9.7 percent) received goal extensions.
For the FY 2011 cohort, 55 out of 79 standard NDA and BLA submissions (70 percent) and 7 out of  22 priority submissions (32 percent) were still under review at the time we received FDA’s data, which  include reviews by CBER and CDER through November 30, 2011. Therefore, values indicated for   FY 2011 in the table above may change as these reviews are completed.
Includes only those submissions that had received an approval letter in their last completed review  cycle at the time we received FDA’s data, which include reviews by CBER and CDER through  November 30, 2011. Dashes (—) indicate cohorts for which no submissions met the criteria.
section_title: Appendix II: FDA Efficacy Supplement Review Performance for Fiscal Years (FYs) 2000 through 2011
paragraphs: Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal  time frames can be extended for 3 months if the sponsor submits a major amendment to the  application within 3 months of the goal date. For priority efficacy supplements in FYs 2000 through  2011, 24 out of 400 submissions (6 percent) received PDUFA goal extensions.
Average review time for the first review cycle for original submissions. Resubmissions are subject to  different PDUFA goal time frames. Dashes (—) indicate cohorts for which no submissions met the  criteria.  Includes only those submissions that had received a first-cycle FDA action letter at the time we  received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.  Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the  same purpose as the complete response letters currently used. We grouped these three types of  letters together in our analysis.
Includes only those submissions that had received a final FDA approval letter in their last completed  review cycle or were withdrawn by the sponsor at the time we received FDA’s data, which include  reviews by CBER and CDER through November 30, 2011.
subsections: section_title: Percentage of first-cycle actions that were:
paragraphs: 17  Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal  time frames can be extended for 3 months if the sponsor submits a major amendment to the  application within 3 months of the goal date. For standard efficacy supplements in FYs 2000 through  2011, 90 out of 1,528 submissions (6 percent) received PDUFA goal extensions.  FYs 2008 through 2011 calculations exclude submissions for which FDA had not yet issued an  action letter.  Includes only those submissions that had received a first-cycle FDA action letter at the time we  received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.  Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the  same purpose as the complete response letters currently used. We grouped these three types of  letters together in our analysis.
Includes only those submissions that had received a final FDA approval letter in their last completed  review cycle or were withdrawn by the sponsor at the time we received FDA’s data, which include  reviews by CBER and CDER through November 30, 2011.
section_title: Percentage of submissions for which FDA had issued a complete response and the sponsor had not resubmitted the application
section_title: Appendix III: Full-time Equivalent (FTE) FDA Staff Supporting Prescription Drug User Fee Activities, FYs 2000 through 2010
paragraphs: FDA centers and offices  Center for Drug Evaluation and Research (CDER)    Office of the Center Director (OCD)
Office of Information Technology (OIT/OIM)
Office of Planning and Informatics (OPI)
Office of Counter-Terrorism and Emergency     Coordination (OCTEC)
Office of Pharmaceutical Science (OPS)
FDA centers and offices  Office of Regulatory Affairs (ORA)
Office of the Commissioner (OC)
Shared Service (SS)
subsections: section_title: All Centers and Offices Total 2,345 2,340 2,337 2,432 2,608 2,540 2,691 2,738 2,925 3,526
paragraphs: SS FTEs were not separated from the center FTEs until FY 2004.
section_title: Appendix IV: Comments from the Department of Health and Human Services
section_title: Appendix V: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Staff Acknowledgments
paragraphs: In addition to the contact named above, Robert Copeland, Assistant  Director; Carolyn Fitzgerald; Cathleen Hamann; Karen Howard; Hannah  Marston Minter; Lisa Motley; Aubrey Naffis; and Rachel Schulman made  key contributions to this report.