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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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) SS FTEs were not separated from the center FTEs until FY 2004. 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.

Summary: 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. 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.