In 1992, the Prescription Drug User Fee Act (PDUFA) was enacted, in part, to provide additional funds for FDA to support the process of reviewing NDAs. PDUFA authorized FDA to collect user fees from drug sponsors to supplement its annual appropriation for salaries and expenses. PDUFA has been reauthorized every 5 years since 1992; most recently PDUFA VI reauthorized the prescription drug user fee program from fiscal year 2018 through fiscal year 2022. As part of each reauthorization process, FDA identifies goals in a commitment letter to Congress. In general, these goals identify a percentage of certain types of applications that FDA is expected to review within specified time frames, including goals for the time the agency takes to complete reviews of different types of NDAs upon initial submission and resubmission. For example, in its commitment letters for PDUFA V and VI, FDA committed to completing its initial review of 90 percent of priority NDAs that involve previously marketed or approved active ingredients within 6 months of receipt. As previously noted, four key features of NDAs are linked to drug development and review processes. For initial NDA reviews, the time frames for FDA’s review that would meet its PDUFA V and VI commitments—its PDUFA goals—vary and are linked to three key features of the NDA. (See table 1.) The target time frame for the initial review of any specific NDA under these user fee commitments reflects the goals associated with all three of the key features. The fourth key feature of NDAs is whether they qualify for one of FDA’s expedited programs. Whether designated as priority or standard, FDA may determine that NDAs for drugs intended to treat serious or life- threatening conditions qualify for development and review under one or more expedited programs. These programs confer specific benefits with the potential to help reduce the development or review time needed to bring a drug to market. For example, some expedited programs provide for more intensive drug development guidance from FDA officials or allow the applicant to submit completed sections of the NDA for review before submitting the entire application. FDA’s expedited programs include accelerated approval, breakthrough therapy designation, and fast track designation. (See table 2.) NDAs must include substantial evidence of a drug’s effectiveness, which is typically drawn from clinical trials. In traditional clinical trials, patients receiving a new drug are often compared with patients receiving a placebo or a different drug. To maximize data quality, these clinical trials are usually randomized (patients are randomly assigned to either the group receiving the new drug or a comparison group) and double-blinded (neither the patients nor the investigators know who is receiving a particular treatment). According to FDA, although this type of study design is often the most powerful tool for evaluating the safety and effectiveness of new drugs, many traditional clinical trials are becoming more costly and complex to administer. Additionally, according to FDA, many new drugs are not easily evaluated using traditional approaches. For example, drugs intended for patients with rare diseases are difficult to evaluate due to the limited number of patients affected by the disease and available for study. The Cures Act was enacted on December 13, 2016, to accelerate the discovery, development and delivery of new treatments—including drugs—for patients. Among other things, the Cures Act includes provisions for FDA to evaluate and facilitate the use of evidence from sources other than traditional clinical trials to support safety and effectiveness determinations for new drugs. For example, FDA was directed to evaluate the potential use of evidence based on data that is routinely collected outside of traditional clinical trials from sources such as electronic health records, medical claims data, and disease registries; evidence from such data sources is referred to as real-world evidence. In the commitment letter associated with PDUFA VI, which was enacted on August 18, 2017, the agency agreed to certain goals relating to the use of real-world evidence in regulatory decision-making and also agreed to certain activities intended to facilitate the development and application of an additional source of evidence known as model-informed drug development. Although these nontraditional sources of evidence were included in NDAs prior to the enactment of the Cures Act and PDUFA VI, at the time this legislation was enacted, most of them were not widely used. For example, according to FDA officials, the NDAs that included real-world evidence were generally for drugs to treat oncology diseases or rare diseases. Our analysis of the 637 original NDAs submitted from fiscal years 2014 through 2018 indicates that divisions differed in the proportions of NDAs they reviewed that had any one of three key features that are linked to time frames for initial review under FDA’s PDUFA goals. As examples: 6 percent of the NDAs reviewed by the dermatology and dental division had a priority review designation, while 56 percent of the NDAs reviewed by the anti-infective division had a priority review designation; 4 percent of the NDAs reviewed by the anesthesia, analgesia, and addiction division involved a new molecular entity, while 52 percent of the NDAs reviewed by the neurology division involved one; and None of the NDAs reviewed by the transplant and ophthalmology division involved a major amendment, while 36 percent of the applications reviewed by the gastroenterology and inborn errors division involved one. (See fig. 1. App. IV provides more detailed information about differences between divisions in the number and proportion of NDAs with these key features.) We also found differences between divisions in the proportion of NDAs that they reviewed under an expedited program—the fourth key feature of NDAs. For example, none of the NDAs reviewed by the metabolism and endocrinology division qualified for one or more expedited programs, while 52 percent of the NDAs reviewed by the antiviral division qualified for one or more expedited programs. (See fig. 2. App. V provides more detailed information about differences between divisions in the number and proportion of NDAs that qualified for one or more expedited programs.) It is not unexpected that divisions differ in the proportion of their applications with key features linked to FDA’s time frames for review or qualification for expedited programs because the divisions are responsible for different products. For example, some divisions, such as the oncology divisions, regulate products for conditions that are more likely to be serious or life-threatening, and therefore the NDAs reviewed by these divisions are more likely to qualify for priority review designation and expedited programs, compared with other divisions, such as the dermatology and dental division. Our analysis of review times for the 637 original NDAs submitted from fiscal years 2014 through 2018 shows that FDA divisions differed in the number of days they took to complete their initial reviews. For example, the median time taken to complete an initial review of an NDA by the anti- infective division was about 2 months faster than the median time taken by the gastroenterology and inborn errors division. (For more information about initial review times, see app. VI.) We found, however, that these differences in initial review times largely reflected key features of the NDAs reviewed by the divisions, particularly those features linked to FDA’s time frames for review under its PDUFA goals. We analyzed initial review times using a statistical regression with two variables reflecting key features of the NDAs—target time frame for review of the application under FDA’s PDUFA goals (in days, from FDA’s receipt of the NDA to FDA’s targeted date for completion of the initial review) and number of expedited programs (0, 1, or 2 or more)—along with division as independent variables. We found that each of these variables was a significant determinant of initial review times. Specifically, our regression analysis shows that on average The shorter the target time frame for initial review of the NDA under FDA’s PDUFA goals, the shorter the initial review, and this target time frame was responsible for the majority of variation in initial review times. The greater the number of expedited programs for which the NDA qualified, the shorter the time FDA took to complete the initial review. Controlling for the effects of these key NDA features, however, we found that most of the divisions’ average review times were similar to (within 2 weeks of) each other. In contrast, the hematology and oncology divisions reviewed applications a bit more rapidly—about 2 or 3 weeks faster—than other divisions. Figure 3 illustrates the results of our analyses. The panel on the left shows the variation in the divisions’ actual average review times. The panel on the right shows the estimated average review times, after accounting for key application features, that is, what the review times would have been if each division had reviewed equal numbers of applications with these key features. We asked FDA officials what might contribute to somewhat faster review times by the hematology and oncology divisions, and FDA officials told us that a number of variables could have contributed to these differences. For example, the officials told us that applicants differ in their level of experience, which can affect the quality of the NDA or the speed of response to FDA’s requests for information; applications differ in complexity; and the oncology and hematology divisions could differ from others in their risk/benefit considerations. As previously noted, some divisions, such as the oncology divisions, regulate products for conditions that are more likely to be serious or life-threatening compared with other divisions, such as the dermatology and dental division, and risk/benefit considerations can differ across conditions that vary in how serious or life- threatening they are. For example, the potential benefits of drugs that carry substantial risks for dangerous side effects would likely be weighed differently if the drug is intended to address a life-threatening illness for which there is no other treatment than if the drug is intended to address an illness that is not life-threatening or for which there is an alternative treatment. FDA has several initiatives underway to evaluate and facilitate FDA review divisions’ and drug sponsors’ use of evidence derived from sources other than traditional clinical trials to support NDAs. (See table 3 for a description of these different evidence sources and each initiative.) According to FDA officials, implementing these initiatives can help ensure that when drug sponsors utilize these sources of evidence in NDAs, the evidence is of sufficient quality to be used in regulatory decision-making and that there is consistency across FDA review divisions in their evaluation of the evidence. FDA officials also said that although complex innovative trial designs might replace traditional clinical trials as evidence in NDAs, real-world evidence is more likely to be used to supplement clinical trial data. Although the initiatives are not restricted to any particular type of disease or patient population, according to FDA officials, some initiatives may be more relevant for certain types of diseases or patient populations than others. For example, according to FDA officials: real-world evidence may be most relevant for diseases that have outcomes that are consistently collected in the health care system. clinical outcome assessments (one aspect of patient-focused drug development) may be most relevant for diseases that are chronic, symptomatic, or affect functioning and activities of daily living. complex innovative trial designs may be most relevant for situations in which the population size is small or limited, such as pediatric populations, or where there is an unmet medical need, such as rare diseases. Our review of FDA documentation and interviews with FDA officials show that FDA has taken steps to implement each of these five initiatives. These steps include conducting public workshops with key stakeholders, issuing guidance for industry and FDA staff, initiating pilot programs, and developing FDA staff capacity, including by providing training and other educational resources. (See table 4 for examples of key activities by initiative.) These and future planned activities—including issuing additional guidance and revising relevant FDA policies and procedures— are intended to address deliverables for FDA to accomplish through 2021 that are outlined in the Cures Act and the PDUFA VI commitment letter. According to FDA officials, the agency intends to meet these deliverables, though, according to these officials, some of the activities implemented under the initiatives, such as certain pilot programs, will likely extend beyond 2021. Although implementation is still in progress for all of the initiatives, FDA officials reported some outcomes. For example, since the launch of the model-informed drug development pilot program, the agency has received two NDA supplements that incorporated model-informed drug development concepts discussed during pilot program meetings. Additionally, officials told us there has been a recent increase in investigational new drug submissions utilizing complex innovative trial designs. FDA officials also reported an increase in biomarker submissions under the drug development tool qualification program, and continued growth of the clinical outcome assessment qualification program. FDA expects that fully implementing the initiatives will lead to further increases in the use of evidence from sources other than traditional clinical trials. We provided a draft of this report to the Department of Health and Human Services for review and comment. The department provided technical comments, which we incorporated as appropriate. As agreed with your offices, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies of this report to the appropriate congressional committees, the Secretary of the Department 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 dickenj@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix VII. To determine (1) how Food and Drug Administration (FDA) divisions differ in the proportion of new drug applications (NDA) they review with key features linked to review time goals and expedited programs and (2) how FDA review divisions differ in the time taken to complete initial reviews and the extent to which key features of NDAs contribute to those differences, we analyzed data from FDA. We also interviewed FDA officials about the data and their review processes. We obtained data regarding all NDAs submitted to FDA’s Center for Drug Evaluation and Research (CDER) from fiscal years 2014 through 2018. These data included information about features that distinguish NDAs from one another, including which division was responsible for the review. The data also included information through March 31, 2019, about the dates when FDA received and completed a review of each NDA, along with the target dates for completion of review under FDA’s goals in commitment letters associated with the Prescription Drug User Fee Act (PDUFA) reauthorizations for fiscal years 2013 through 2017 (PDUFA V) and fiscal years 2018 through 2022 (PDUFA VI). To ensure meaningful analysis of review times, we excluded NDAs for which FDA had not completed an initial cycle of review. Of 686 NDAs submitted in fiscal years 2014 through 2018, the applicant withdrew 10 NDAs prior to completion of FDA’s initial review and 39 NDAs were still under FDA review as of March 31, 2019, leaving 637 NDAs for which FDA had completed an initial review. To assess the reliability of these data, we conducted a series of electronic and logic tests to identify missing data or other anomalies. These analyses were informed by our review of relevant documentation and interviews with knowledgeable FDA officials. As part of our assessment of reliability, we worked with FDA to identify and correct information about certain NDAs in a small number of instances in which we identified discrepancies. Using these methods, we determined that the remaining data were sufficiently reliable for our purposes. Unless otherwise specified, the results we present are statistically significant at the 0.05 level. To determine how FDA divisions differ in the proportion of NDAs they review with key features linked to FDA’s time frames for initial reviews and expedited programs, we conducted a series of chi-square tests comparing the distributions of the 637 NDAs with and without specific features across divisions. These key features included: whether the NDA had a priority review designation (a designation applied by FDA if the product would provide a significant therapeutic improvement in the safety and effectiveness of the prevention, diagnosis, or treatment of a serious condition when compared to available drugs) or instead had a standard designation; whether the NDA did or did not involve a new molecular entity—an active ingredient that had not previously been marketed or approved for use as a drug in the United States, whether the NDA did or did not involve a major amendment (a submission, while a pending NDA is under FDA review, of additional information that may include a major new clinical safety or efficacy study report or major new analyses of studies, among other things); and whether the NDA did or did not qualify for an expedited program (accelerated approval, breakthrough therapy designation, or fast track designation), programs intended to help reduce the time involved in developing or reviewing certain drugs that have the potential to treat serious or life-threatening conditions. (See table 5 for relevant statistics from these chi-square tests.) To determine how FDA review divisions differ in the time taken to complete initial reviews, we conducted a preliminary regression analysis of 637 NDAs with the number of days an FDA division took to complete its initial review as the dependent variable and division as a single independent variable. We defined the time to complete a review as the number of days from FDA’s receipt of the NDA to the agency’s completion of the initial review by taking regulatory action. To determine the extent to which key NDA features contributed to differences between divisions in the time taken to complete initial reviews, we conducted a multiple regression analysis of the number of days FDA took to complete its initial review with division as an independent variable, along with two other independent variables to control for the key NDA features: Target time frame for initial review of the NDA under FDA’s PDUFA goals. Three key NDA features are linked to time frames for FDA’s initial review under its PDUFA goals—whether the NDA was priority or standard, did or did not involve a new molecular entity, and did or did not involve a major amendment. To control for these three features simultaneously, we counted the number of days from FDA’s receipt of the NDA until FDA’s target date for completion of the initial review under FDA’s PDUFA goals, and used that variable—the target time frame for review under FDA’s PDUFA goals—as an independent variable. We identified five NDAs for which FDA’s review time was exceptionally long in comparison to the target time frame for review under its PDUFA goals, and we asked FDA officials about them. FDA officials stated that these reviews were substantially delayed because of complicated manufacturing site issues, complicated legal and regulatory issues, or emerging public health issues requiring last minute advisory committee meetings—conditions that we deemed sufficiently unusual to exclude these five NDAs from further statistical analyses of review times. Number of expedited programs for which the NDA qualified. Another key NDA feature is whether it qualified for one or more expedited programs, programs with the potential to help reduce the development or review time needed to bring a drug to market. We controlled for this feature by including number of expedited programs (0, 1, or 2 or more) as an independent variable in our multiple regression analysis. Thus, we tested the effect of division on initial review times for 632 NDAs while controlling for the target time frame for review under FDA’s PDUFA goals and qualification for expedited programs. (See tables 6 and 7 for relevant statistics from this multiple regression analysis.) Our multiple regression analysis allowed us to test a specific hypothesis about the effect of division on review times, namely, whether divisions differed in their review times after controlling for the key features of NDAs. This regression analysis did not test a model of review times—that is, we did not attempt to identify all variables that affect review times, nor did we seek to identify the specific set or combination of variables within our data that had maximum explanatory power. Our analyses indicated that variation remained in initial review times, even after we controlled for these variables. It is important to note that an array of factors might be expected to influence review times, including not just those factors that were captured in our analysis, but also factors such as state of the science and quality of the application. With data from 632 NDAs distributed unevenly across 15 divisions, meaningful tests of additional variables or their interactions were not possible. Nonetheless, we conducted exploratory analyses that included other potentially relevant variables in addition to the target time frame for review under FDA’s PDUFA goals, number of expedited programs, and division. In separate regression analyses, we examined (a) the fiscal year in which FDA received the NDA and (b) whether the application was a BLA, an NDA based on information from studies conducted by the applicant, or an NDA based on at least some information from studies not conducted by or for the applicant. We did not find evidence of a consistent effect of either of these additional factors on review times, but in light of the number of NDAs, we cannot exclude the possibility that one or more of these factors affects review times. In a third exploratory analysis, we examined the outcome of the initial review—(a) approval; (b) tentative approval, which FDA grants if the NDA meets requirements for approval, but cannot be approved due to a patent or exclusivity period for a listed drug; or (c) issuance of a letter to the applicant called a complete response letter, in which FDA describes the specific deficiencies the agency identified and recommends ways to make the application viable for approval. This analysis suggested that NDAs that were approved for marketing at the end of the initial cycle of review were reviewed slightly faster on average than other NDAs, but this result should be viewed with caution because a small number of NDAs with certain initial review outcomes were distributed unequally. For example, very few of the NDAs (11) reviewed through one or more expedited programs resulted in tentative approval. The Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) divisions differed in the total number of days they took to complete reviews of 637 new drug applications (NDA) submitted from fiscal years 2014 through 2018 and completed by March 31, 2019. (See fig. 4.) Importantly, these times reflect differences associated with the number of completed review cycles, FDA’s target time frames for review under its goals in commitment letters associated with the Prescription Drug User Fee Act (PDUFA) reauthorizations for fiscal years 2013 through 2017 (PDUFA V) and fiscal years 2018 through 2022 (PDUFA VI), and number of expedited programs. Number of review cycles. The number of cycles of review to which the NDAs we examined were subject was largely dependent on factors that were not under FDA’s control, namely, the applicant’s actions and timing. When a cycle of review ends with an FDA action, that action can be (a) approval, which allows the applicant to market the drug, (b) tentative approval, which FDA grants if the NDA meets requirements for approval, but cannot be approved due to a patent or exclusivity period for a listed drug, or (c) issuance of a letter to the applicant called a complete response letter, in which FDA describes the specific deficiencies the agency identified and recommends ways to make the application viable for approval. The applicant may respond to either tentative approval or a complete response letter by resubmitting a revised application, triggering a new cycle of review; it is up to the applicant to decide whether to resubmit the application. In addition, NDAs that were submitted earlier in time would have a greater chance of being resubmitted and reviewed by March 31, 2019, than applications submitted later in time. The number of completed review cycles ranged from one to four cycles: 637 NDAs went through a completed first (initial) cycle review; 99 of those 637 NDAs went through a completed second cycle review; 20 of those 99 NDAs went through a completed third cycle review; 3 of those 20 NDAs went through a completed fourth cycle review. Target time frames for review. Review times reflect differences in time frames for review under FDA’s PDUFA goals. The target time frames for review ranged from less than 6 months to 15 months for the first cycle and from less than 2 months to 9 months for later cycles of review. Number of expedited programs. These review times also reflect differences associated with the number of FDA’s expedited programs for which NDAs qualified. In general, these expedited programs are designed to help reduce the development or review time needed for drugs intended to treat serious or life-threatening conditions. Two of the Food and Drug Administration’s (FDA) expedited programs for new drugs intended to treat serious or life-threatening conditions— breakthrough therapy designation and fast track designation—must be requested by the drug sponsor. These programs are intended to help reduce the development or review time needed to bring a drug to market by offering benefits such as more intensive drug development guidance from FDA officials or by allowing the applicant to submit completed sections of the NDA for review before submitting the entire application. The request is normally made while the drug sponsor is conducting clinical trials or when seeking FDA’s permission to collect clinical trial data, although the request may also be made when submitting a new drug application (NDA) or while the NDA is under review. FDA’s Center for Drug Evaluation and Research (CDER) divisions are responsible for determining whether requests qualify for these expedited programs based on evidence the drug sponsors provide in support of the requests. To qualify for breakthrough therapy designation, the drug sponsor must present preliminary clinical evidence involving one or more clinically significant endpoints that indicate that the drug may demonstrate substantial improvement over available therapies. To qualify for fast track designation, the drug sponsor must either provide evidence demonstrating the drug’s potential to address unmet need or document that the drug is designated as a qualified infectious disease product. FDA may grant or deny the request, or the drug sponsor may withdraw the request before FDA renders a decision. If FDA grants the designation, the drug sponsor may subsequently withdraw from the designation, or FDA may rescind either designation if the drug no longer meets the qualifying criteria. We obtained data regarding all requests for breakthrough therapy and fast track designations submitted to CDER from fiscal years 2013 through 2018. These data included information about which division was responsible for the review and the outcome of the request—whether it was granted or denied or whether the drug sponsor withdrew the request before FDA reached a decision. To assess the reliability of these data, we conducted a series of electronic and logic tests to identify missing data or other anomalies. These analyses were informed by our review of relevant documentation and interviews with knowledgeable FDA officials. Using these methods, we determined that the data were sufficiently reliable for our purposes. We examined these data to determine whether there were any material differences between divisions in the frequency of possible outcomes. Our analyses focused on the outcomes and did not allow us to determine whether divisions differed in their application of the stated criteria. Breakthrough therapy designation. We found few differences across divisions in the frequency of the possible outcomes of requests for breakthrough therapy designation: Of 634 requests for breakthrough therapy designation (including nine requests submitted with or after the NDA submission), 39 percent were granted, 48 percent were denied, and 13 percent were withdrawn by the drug sponsor before FDA reached a decision. Divisions differed widely in the number of requests for breakthrough therapy designation they received, from 0 for the nonprescription drug division to 102 for one of FDA’s two oncology divisions. With two exceptions, the numbers of these requests that were granted, denied, or withdrawn for each division were similar to what would be expected based on the overall frequency of the possible outcomes. Requests to the hematology division were withdrawn more frequently than requests to other divisions (32 percent) and that division denied requests less frequently (17 percent) than other divisions. The neurology division denied more (81 percent), and granted fewer (13 percent), requests for breakthrough therapy designation than other divisions. Within the time period we studied, the drug sponsor withdrew from breakthrough therapy designation after it was granted in six cases and FDA rescinded the designation in 14 cases. Fast track designation. Similarly, we found few differences across divisions in the frequency of the possible outcomes of requests for fast track designation: Of 965 requests for fast track designation (including 35 requests submitted with or after the NDA submission), 71 percent were granted, 24 percent were denied, and 5 percent were withdrawn by the drug sponsor before FDA reached a decision. Again, divisions differed widely in the number of requests for fast track designation they received, from 2 for the nonprescription drug division to 133 for the neurology division. The numbers of these requests that were granted, denied, or withdrawn for each division were generally similar to what would be expected based on the overall frequency of the possible outcomes, although the anti-infective division granted more (91 percent), and denied fewer (6 percent), requests for fast track designation than other divisions. Within the time period we studied, no drug sponsor withdrew from fast track designation after it was granted, nor did FDA rescind any such designation. Pursuant to the Prescription Drug User Fee Act (PDUFA) and its subsequent reauthorizations, the Food and Drug Administration (FDA) collects user fees from drug sponsors to supplement its annual appropriation for salaries and expenses. As part of each reauthorization process, FDA identifies goals in a commitment letter to Congress, including goals for the time the agency takes to complete reviews of different types of drug applications upon initial submission and resubmission. In general, these goals identify a percentage of certain types applications that FDA is expected to review within specified target time frames. For initial NDA reviews—reviews of the NDA as originally submitted—FDA’s target time frames for review that would meet its PDUFA goals vary and are linked to three key NDA features that reflect the drug or the applicant’s action: (1) whether or not the application receives priority review designation, which indicates that the drug could provide significant therapeutic improvements in the safety and effectiveness of the prevention, diagnosis, or treatment of a serious condition when compared to available drugs; (2) whether or not the application involves a new molecular entity—an active ingredient that has not been previously marketed or approved for use in the United States; and (3) whether or not the applicant submitted a major amendment while the NDA was pending, that is, while under FDA’s review. The target time frame for review for any specific NDA reflects all three of these features. Reviews are conducted by one of the agency’s Center for Drug Evaluation and Research (CDER) divisions, each of which specialize in a specific group of drug products, such as hematology or neurology. As shown in table 8, divisions differed in the numbers and proportions of NDAs they reviewed that had the features linked to time frames for review under FDA’s PDUFA goals. The Food and Drug Administration (FDA) may determine that NDAs for drugs intended to treat serious or life-threatening conditions qualify for one or more expedited programs. These programs confer specific benefits with the potential to help reduce the development or review time needed to bring a drug to market, for example, some expedited programs provide for more intensive drug development guidance from FDA officials or allow the applicant to submit completed sections of the NDA for review before submitting the entire application. FDA’s expedited programs include accelerated approval, breakthrough therapy designation, and fast track designation. Reviews are conducted by one of the agency’s Center for Drug Evaluation and Research (CDER) divisions, each of which specialize in a specific group of drug products, such as hematology or neurology. As shown in table 9, divisions differed in the proportions of NDAs they reviewed that qualified for expedited programs. The Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) divisions differed in the total number of days they took to complete initial reviews of new drug applications (NDA) received from fiscal years 2014 through 2018 and completed by March 31, 2019. (See fig. 5.) These review times reflect differences associated with FDA’s target time frames for initial review under its goals in commitment letters associated with the Prescription Drug User Fee Act (PDUFA) reauthorizations for fiscal years 2013 through 2017 (PDUFA V) and fiscal years 2018 through 2022 (PDUFA VI). These target time frames for review are linked to specific features of the NDA and ranged from less than 6 months to 15 months for the initial review. These review times also reflect differences associated with the number of expedited programs for which NDAs qualified. John E. Dicken, (202) 512-7114 or dickenj@gao.gov. In addition to the contact named above, William Hadley (Assistant Director), Geri Redican-Bigott (Assistant Director), Aubrey Naffis (Analyst- in-Charge), and Kristen Joan Anderson made key contributions to this report. Also contributing were Sam Amrhein, Todd D. Anderson, Leia Dickerson, Kaitlin Farquharson, Rich Lipinski, and Ethiene Salgado- Rodriguez.

Summary: Before a drug can be marketed in the United States, FDA must determine that the drug is safe and effective for its intended use through a review of evidence that a drug sponsor—the entity seeking to market the drug—submits in an NDA. The review is conducted by one of FDA's divisions (17, at the time of GAO's review) that each specialize in a specific group of drug products, such as hematology products. NDA reviews are complex, and may involve not only an initial review, but also reviews of resubmissions if the initial review does not result in approval. Under FDA's PDUFA commitments, FDA's goal is to complete reviews of 90 percent of NDAs within specific time frames linked to key features of the NDAs. GAO was asked to examine NDA review times across FDA's divisions. In this report, GAO examines (among other things) differences between FDA divisions in the key features of the NDAs they review and initial review times, as well as the extent to which key NDA features contribute to these differences. GAO analyzed data from FDA's Center for Drug Evaluation and Research regarding 637 NDAs submitted from fiscal years 2014 through 2018. These data also included biologic license applications submitted to the center. GAO excluded NDAs that were withdrawn by the applicant before FDA completed a review, as well as NDAs for which FDA had not completed a review by March 31, 2019. GAO also interviewed FDA officials about the agency's review process and these review times. Four key features of new drug applications (NDA) are linked to the time the Food and Drug Administration (FDA) takes to complete initial reviews of NDAs. Three key NDA features determine the time frames for initial review that would meet FDA's goals under the Prescription Drug User Fee Act (PDUFA) and its reauthorizations, which authorize FDA to collect user fees from drug sponsors: Whether or not the NDA qualifies for the priority review program, which is generally an expedited program for drugs that provide significant therapeutic improvements in the prevention, diagnosis, or treatment of a serious condition when compared to available drugs. The PDUFA goal for review of a priority NDA is 4 months less than for an otherwise similar standard NDA, for which the goal is to complete the review in 10 months. Whether or not the NDA involves a new molecular entity (an active ingredient that has not been previously marketed or approved in the United States). The PDUFA goal for review of an NDA with a new molecular entity is 2 months longer than for an NDA without one. Whether or not the applicant submits a major amendment (additional or new information, such as a major new clinical study) while the NDA is under review. The PDUFA goal for a review of an NDA may be extended by 3 months if the applicant submits a major amendment. The fourth key NDA feature is whether or not it qualified for one or more of three other expedited programs for drugs intended to treat serious or life-threatening conditions. GAO's analysis of 637 NDAs submitted from fiscal years 2014 through 2018 indicated that the proportion of NDAs with these key features differed among FDA review divisions. For example, 6 percent of the NDAs reviewed by the dermatology and dental division had a priority designation, compared to 56 percent for the anti-infective division. FDA has reported that some divisions, such as the oncology divisions, generally regulate products for conditions that are more likely to be serious or life-threatening, and, therefore, those products may be more likely to qualify for priority designation and other expedited programs. GAO found that FDA's divisions differed in the average number of days they took to complete an initial review of NDAs, and these differences largely reflected the key features of the NDAs they reviewed. GAO's analysis shows that the time FDA took to complete an initial review of NDAs was affected by (1) the target time frame for completion of the review under the agency's PDUFA goals, (2) the number of expedited programs for which the NDA qualified, and (3) the division performing the review. GAO also found that the target time frame for review was largely responsible for differences in initial review times. Specifically, NDAs with key features that resulted in shorter target time frames for review under FDA's PDUFA goals had shorter initial review times. Controlling for the effects of these target time frames and the number of expedited programs for which the NDA qualified, GAO found that most of the divisions' average review times were similar to (within 2 weeks of) each other.