FDA Drug Approval: Application Review Times Largely Reflect Agency Goals

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 GAO excluded NDAs that were withdrawn by the applicant before FDA completed a review, as well as NDAs for which FDA had not completed a review by March 31, 2019.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.

Getting safe, effective drugs to market in the United States typically  involves a lengthy drug development process. Before the drug can be  marketed, the Food and Drug Administration (FDA), an agency within the  Department Health and Human Services, must determine that the drug is  safe and effective for its intended use through a review of evidence that a  drug sponsor submits in a new drug application (NDA). The review is  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.

Four key features of NDAs are linked to drug development and review  processes. FDA’s goal for completing its initial review of certain standard  NDAs is 10 months after initial receipt, but some NDAs are subject to a  different initial review goal based on each of three key features of the  NDA:

FDA may designate NDAs for priority review when they are for drugs  that provide a significant improvement in safety or effectiveness for  treatment of a serious condition when compared to available drugs;  FDA’s goal is to review priority NDAs more rapidly than standard  ones.

FDA’s goal includes extra time if the NDA involves a new molecular  entity—an active ingredient that has not been previously marketed or  approved for use in the United States.

FDA may extend its goal if the applicant submits substantial additional  information while the NDA is under review.

A fourth key feature of NDAs is whether they qualify for one or more of  FDA’s expedited programs, which are intended to help reduce the  development or review time needed to bring a drug to market. NDAs for  therapies intended to treat serious or life-threatening conditions may  qualify for one or more of these programs.

NDA reviews are complex and may take multiple review cycles. While  conducting its initial review, FDA may determine that it needs additional  information or further evidence, and in such cases, the agency can end  the initial review with a letter to the applicant describing specific  deficiencies. The applicant can respond in a resubmission, initiating a  new cycle of review.

Because drug sponsors must collect evidence to demonstrate the safety  and effectiveness of new drugs, and these efforts represent a major  component of drug development time and cost, the amount and nature of  the evidence needed can be an important determinant of when and  whether new therapies become available to the public. The issue of what  constitutes sufficient evidence to support NDAs has been debated by  FDA, the scientific community, industry, and others. FDA has typically  required NDAs to include safety and effectiveness evidence for new  drugs from two adequate and well-controlled clinical trials. However,  under certain circumstances, drug sponsors can use different sources of  evidence to show that a new drug is safe and effective for its intended  use. The 21st Century Cures Act (Cures Act), enacted in 2016, directed  FDA to evaluate and facilitate the use of these different sources of  evidence by FDA reviewers and drug sponsors to inform the agency’s  assessment of drug safety and effectiveness.

FDA has published evidence showing that review times differ between  divisions. In light of this evidence, you asked us to examine NDA review  times across FDA’s divisions, as well as FDA’s use of certain tools to  inform the agency’s assessment of drug safety and effectiveness. This  report examines  1.  differences between FDA divisions in the proportion of NDAs they  review with key features;  2.  differences between FDA divisions in the time taken to complete initial  reviews and the extent to which the key NDA features contribute to  these differences; and  3.  actions FDA has recently taken to evaluate and facilitate the use of  different sources of evidence to support NDAs.

To address our first two objectives, we analyzed data from FDA regarding  637 NDAs—the NDAs that were initially submitted from fiscal years 2014  through 2018. (Appendix I provides a detailed description of the  methodologies we used to analyze these data.) Our examination  excluded NDAs that were withdrawn by the applicant before FDA  completed an initial review, as well as NDAs for which FDA had not  completed a review by March 31, 2019. For some analyses, we also  excluded five NDAs, as described in appendix I, bringing the count of  NDAs to 632. We reviewed the reliability of the data by conducting a  series of electronic and logic tests to identify missing data or other  anomalies and worked with FDA to correct information when we identified  discrepancies. We determined that the data were sufficiently reliable for  our purposes. In addition, although our focus was on initial review times,  we also collected information about total review times—review times  across all completed cycles of review; appendix II includes information  about these total review times. Finally, we interviewed FDA officials about  the agency’s review process and these review times.

To examine recent FDA actions to evaluate and facilitate the use of  different sources of evidence to support NDAs, we identified initiatives  FDA started implementing as a result of the enactment of the Cures Act in  late 2016. We focused our analysis on initiatives that (1) involve NDAs  reviewed by CDER divisions and (2) could affect a variety of diseases  and populations. We spoke with FDA officials and reviewed FDA  documentation to learn about the initiatives and determine steps FDA has  taken to implement the initiatives. We also interviewed two stakeholder  groups (Pharmaceutical Research and Manufacturers of America and  Biotechnology Innovation Organization) that represent drug sponsors  about the initiatives.

We conducted this performance audit from July 2018 to February 2020 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.

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.

FDA Divisions Differ in Proportions of NDAs Reviewed with One or More Key Features

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.

FDA Divisions Vary in Their Initial Review Times for NDAs, Largely Due to PDUFA Goals

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 Is Implementing Initiatives to Evaluate and Facilitate the Use of Different Evidence Sources to Support NDAs

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.

Appendix I: Methodology for Data Analyses

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.

Appendix II: Total Times Taken by FDA Divisions to Review New Drug Applications Received in Fiscal Years 2014 through 2018

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.

Appendix III: Requests for Breakthrough Therapy and Fast Track Designations, Fiscal Years 2013 through 2018

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.

Appendix IV: New Drug Applications with Key Features Linked to Time Frames for Review, Fiscal Years 2014 through 2018

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.

Appendix V: New Drug Applications That Qualified for Expedited Programs, Fiscal Years 2014 through 2018

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.

Appendix VI: Times Taken to Complete Initial Reviews of New Drug Applications Received from Fiscal Year 2014 through 2018

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.

Appendix VII: GAO Contact and Staff Acknowledgments

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.

Before a drug can be marketed in the United States, the FDA must determine it is safe and effective. The company or entity seeking to market the drug must submit evidence for review. FDA’s goal is to complete 90% of these reviews within deadlines that vary depending on the drug. Some drugs—ones that may provide significant improvement over what’s available—receive priority designations for expedited reviews.

We reviewed 637 new drug applications submitted from FY 2014-2018 and found the FDA met its goals. Differences in review times among FDA’s 17 divisions were largely driven by the characteristics of the applications being reviewed.