Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

JANET REHNQUIST 

INSPECTOR GENERAL 

MARCH 2003 

OEI-01-01-00590 

FDA’s Review Process 

for New Drug Applications 

A Management Review 
OFFICE OF INSPECTOR GENERAL

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The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as amended, 

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The OIG's Office of Evaluation and Inspections (OEI) conducts short-term management and program 

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EXECUTIVE SUMMARY 

PURPOSE 

To assess how well the Food and Drug Administration manages its new drug application review 

process. 

BACKGROUND 

The Food and Drug Administration (FDA) receives new drug applications (NDAs) from 

sponsors, typically pharmaceutical companies, and reviews these applications for scientific 

evidence pertaining to the safety and efficacy of drugs. Based on its assessments, the FDA 

determines whether drugs can be marketed in the United States. 

The Prescription Drug User Fee Act (PDUFA), enacted in 1992, authorized FDA to collect 

user fees from sponsors to help speed up the review of NDAs. It also established time goals 

for FDA’s reviews. In 1997, the FDA Modernization Act reauthorized user fees for another 5 

years. It shortened the time goals and called for FDA to work more collaboratively with 

sponsors. In June 2002, the Public Health Security and Bioterrorism Preparedness Act of 

2002 once again reauthorized user fees. The part of this Act addressing user fees is referred to 

as PDUFA III. 

This inquiry focuses on FDA’s Center for Drug Evaluation and Research (CDER), which 

reviews NDAs. This inquiry does not assess the scientific merit of the decisions that FDA has 

made. Instead, it examines how well FDA carries out its NDA review process. This report 

draws heavily on the opinions of CDER officials. We surveyed CDER reviewers, receiving an 

estimated 47 percent response rate (N=401) and interviewed about 80 CDER officials, 

including managers. In addition, we surveyed sponsors, receiving a 60 percent response rate 

(N=72), reviewed files for all 15 new molecular entities approved by CDER in fiscal year (FY) 

2001, analyzed CDER data regarding the number of advisory committees, observed 17 CDER 

meetings, interviewed 20 stakeholders, and reviewed relevant FDA policies and procedures. 

We also drew on data from an internal survey conducted by CDER of a random sample of 188 

reviewers that had a 72 percent response rate. 

We conducted this inquiry prior to the implementation of PDUFA III. Where appropriate, we 

indicate the potential impact of PDUFA III on our findings. 

FDA’s Review Process for New Drug Applications i OEI-01-01-00590 
FINDINGS 

FDA’s new drug application review process has several strengths that contribute 

significantly to its effectiveness. 

Both FDA reviewers and sponsors have confidence in the decisions FDA makes. Our 

review underscored that FDA’s NDA review process is science-based and comprehensive. 

This is supported by the comments of both FDA reviewers and sponsors. Seventy-eight 

percent of FDA respondents and 86 percent of sponsors indicated in our surveys that they 

were confident in the decisions FDA makes with regard to a drug’s efficacy. 

FDA is highly responsive to the time goals required under the Prescription Drug User 

Fee Act and the FDA Modernization Act. In 1993, median total approval time for CDER 

was 27 months for standard NDAs classified as new molecular entities; in 2001, it was 19 

months. The reduction in approval times helps to ensure timely access to new medications that 

can benefit the public health. 

FDA works collaboratively with sponsors. In FY 2001, CDER conducted 1,021 formal 

meetings with sponsors. In these meetings, FDA provides valuable advice to sponsors that can 

help speed up the drug development process. 

FDA has taken numerous steps to improve efficiency and consistency. In 2000, CDER 

issued about 40 guidance documents, most of which it directed to sponsors. Between 1996 

and 2001, CDER issued about 140 policies to help guide reviewers. It also now accepts 

applications electronically. 

FDA relies on expert scientific reviewers. Both sponsors and reviewers agreed that 

FDA’s in-house expertise is a key asset of the review process. Funds from user fees have 

allowed FDA to increase the number of employees for drug reviews by about 700 employees 

over the past 10 years. 

But workload pressures increasingly challenge the effectiveness of the review 

process. 

Reviewers are under constant pressure to meet time goals. They not only review NDAs, but 

also other key documents submitted by sponsors, some of which also have time goals attached. 

At the same time, reviewers must provide advice to sponsors and stay abreast of the latest 

scientific advances in their fields. Below, we present the consequences of these workload 

pressures. 

FDA’s Review Process for New Drug Applications ii OEI-01-01-00590 
Reviewer concerns about time pressures. Forty percent of FDA survey respondents who 

had been at FDA at least 5 years indicated that the review process had worsened during their 

tenure in terms of allowing for in-depth, science-based reviews. Respondents cited lack of time 

as the main reason. According to 58 percent of FDA respondents, the allotted 6 months for a 

priority review is inadequate. This is considerably higher than the 25 percent of respondents 

who indicated that the allotted 10 months for a standard review is inadequate. 

Reviewer concerns about time constraints do not necessarily mean that there is a threat to 

public health. We have no evidence of a public health concern nor did we seek to obtain such 

evidence. Reviewers commented in interviews that they did not believe that they were ignoring 

key information or data contained in the applications in order to meet time goals. The FDA has 

also received the 4th highest composite score out of the 13 operating divisions within the 

Department of Health and Human Services on the 2002 Secretary’s Quality of Work Life 

Survey on Organizational Climate, which indicates a positive work environment. However, our 

survey data do indicate a significant management issue warranting attention. 

The PDUFA III should help to address reviewers’ concerns about time pressures, as CDER 

estimates hiring close to 300 additional employees over the next 5 years with funds from user 

fees. 

Less use of advisory committees. Advisory committees are comprised of independent 

scientific experts who provide advice to FDA during the review process. The number of 

advisory committee meetings CDER held for NDAs decreased from 40 in 1998 to 23 in 2001. 

Although the declining number of NDAs submitted by sponsors has contributed in part to this 

decline, FDA managers also pointed out that they have little time to hold these meetings. 

Insufficient time for raising scientific disputes. Pressure to meet time goals may inhibit the 

raising of disputes. Reviewers may be reluctant to raise disputes due to concerns about slowing 

down the process. Twenty-one percent of FDA respondents indicated that the work 

environment allowed for the expression of differing scientific opinions to a small or no extent. 

Contributing to staff turnover. The FDA data show that medical officers and 

pharmacologists had the highest attrition rates within CDER for FY 2001, 8.4 percent and 6.9 

percent respectively, compared to the overall rate of 5.5 percent. On an internal CDER 

survey, 50 percent of reviewers who responded indicated that their workloads are influential 

reasons to consider leaving FDA. 

FDA’s Review Process for New Drug Applications iii OEI-01-01-00590 
Less time for reviewers to participate in professional development and to conduct 

research to improve drug development. The FDA has policies and programs in place to 

encourage professional development, yet 59 percent of FDA respondents indicated that they 

have little time to participate in professional development activities. Similarly, reviewers have 

little time to conduct research on drug development using the clinical trial databases FDA has 

obtained from sponsors. 

Several factors have contributed to the workload pressures. 

Time goals have been beneficial, but at the same time they have created pressure on reviewers 

to work quickly. The FDA has little flexibility in reassigning staff to handle increased 

workloads. The FDA’s dual roles as advisor and reviewer demand substantial time and 

resources; the CDER held over 1,000 meetings with sponsors in FY 2001. Incomplete and 

disorganized applications can cause delays. The 15 new molecular entities we reviewed 

contained, on average, 38 amendments to the original application. Inefficiencies in the process 

also contribute to workload pressures. 

As we have already indicated, PDUFA III will provide FDA additional resources to hire more 

staff that should help address these workload pressures. It also calls for FDA to conduct 

several studies aimed at improving the efficiency of the process. 

Other factors also challenge the effectiveness of the review process. 

Rush to finalize drug labels at the end of the process. Although labeling negotiations must 

occur toward the end of the process, we found that negotiations were considerably 

compressed. Eighty-two percent of FDA respondents indicated that labeling negotiations 

contribute to delays. Twenty-seven percent of labeling amendments for the 15 new molecular 

entities we reviewed were submitted in the last 14 days of the review process. The rush to 

finalize labels at the end of the review process can be caused by the lengthy discussions that 

often occur between FDA and the sponsor regarding the information to include on the label. 

The FDA has numerous activities underway to help address this issue. 

Reviewers’ uncertainty about postmarketing commitments. Postmarketing commitments 

are made by the sponsor at the time of approval and can include additional studies to further 

define the safety and effectiveness of the drug. Reviewers indicated that they were often 

uncertain about what types of postmarketing commitments to request of sponsors. The 

PDUFA III calls for FDA to issue several guidance documents regarding risk management after 

the drug is approved. These documents should help to clarify the use of postmarketing 

commitments. 

FDA’s Review Process for New Drug Applications iv OEI-01-01-00590 
Limited public disclosure of FDA’s rationale for decisions. We reviewed the information 

on CDER’s website for 15 new molecular entities, and in no case did FDA provide a summary 

document that explained the overall basis for approval. The FDA does not routinely provide 

summary information for approved drugs, nor is it required to do so. We found it took 7.6 

months, on average, for FDA to post the technical information it does disclose on its website 

after a drug is approved. For drugs that FDA reviewed but did not approve, FDA disclosed 

almost no information regarding the basis for its decisions. The FDA’s regulations limit such 

disclosure. 

CONCLUSION 

FDA’s NDA review process has several strengths. However, reviewers face 

workload pressures that increasingly challenge the effectiveness of the process. 

Beyond these pressures, three other factors threaten the effectiveness of the process: the rushed 

review of drug labels that takes place toward the end of the review process, the limited 

guidance available to reviewers in determining the extent and type of postmarketing 

commitments to request of sponsors, and the limited information that FDA makes available to 

the public on the basis for its decisions concerning NDAs. Overall, these findings present a 

significant warning signal, one, that if not fully addressed, could jeopardize the gains that FDA 

has made in recent years. 

The enactment of PDUFA III presents significant opportunities to address many of 

the findings in this report. 

We recognize that FDA has already identified many of the concerns presented in this report 

and has numerous efforts underway to address them. In particular, the enactment of PDUFA 

III, which FDA played a critical role in developing with sponsors, presents significant 

opportunities to address many of our findings. It calls for an increase in user fees that CDER 

estimates will allow it to hire close to 300 additional employees over the next 5 years. Over 

time, this could help considerably in relieving the workload pressures that we have emphasized. 

In addition to resources, PDUFA III calls for FDA to conduct several activities aimed at 

improving the process. These activities will help to address many of the findings in this report, 

including efficiency, labeling negotiations, and the use of advisory committees. In addition, 

PDUFA III calls for significant attention to be placed on postmarketing commitments. For the 

first time, funds from user fees can be used to monitor drugs after they are on the market. It 

also calls for FDA to develop several guidance documents on risk management. 

Our first recommendation offers additional steps that FDA can take as it implements PDUFA 

III to ensure that it takes full advantage of these opportunities to address our 

FDA’s Review Process for New Drug Applications v OEI-01-01-00590 
findings. We also make four other recommendations to FDA to improve the NDA review 

process that are not addressed in PDUFA III. We direct all our recommendations to CDER. 

RECOMMENDATIONS 

1. Take full advantage of the opportunities in PDUFA III. 

< Conduct a retrospective examination of recent NDA reviews to determine the capacity of 

reviewers to conduct in-depth, science-based reviews. 

< Evaluate the adequacy of current staffing levels and the workload distribution among the 15 

review divisions within CDER, and implement a system that in real time would indicate the 

status of an NDA and the time spent in reviewing its specific parts. 

< Assess how amendments to the original application, internal processing delays, and labeling 

negotiations affect FDA’s capacity to make timely, first-cycle review decisions. 

< Offer further guidance on the best way to handle scientific disputes that occur among 

reviewers, and how to balance the role of reviewing NDAs and the role of advising 

sponsors throughout the drug development process. 

< Include case studies of past reviews as part of training programs for reviewers to illustrate 

good review principles and foster consistency among divisions. 

< Provide a list of the various postmarketing commitments that FDA reviewers can request of 

sponsors and suggestions for when each could be considered. 

2. Determine whether the significant workload pressures discussed in this report 

justify any exceptions to the current time goals regarding new drug applications 

to allow for more in-depth reviews. 

As we have indicated, the Prescription Drug User Fee Act and the FDA Modernization Act 

have been positive forces for the review process. However, it is important that an appropriate 

balance exists between timeliness and the ability to conduct a comprehensive review. Our data 

show that reviewers face significant workload pressures. Therefore, FDA could examine if it 

would be beneficial to extend the review clock by 1 or 2 months when it chooses to use an 

advisory committee and to consider modifying the current 10-month time goal for standard 

NDAs by 1 or 2 months. 

3. Reject applications that are incomplete and of poor quality that can create 

delays in the new drug application review process. 

FDA’s Review Process for New Drug Applications vi OEI-01-01-00590 
A timely review process depends not only on FDA, but also on sponsors submitting complete 

and well organized NDAs. Toward that end, FDA could reexamine its policies for refusal-tofile and its guidance to sponsors on the content and format of applications to ensure that they 

make explicit FDA’s requirements. 

4. Provide the public with a clear and timely explanation of decisions on new drug 

applications. 

The FDA could provide on its website a succinct explanation of its rationale for approving an 

NDA. It could also provide the same explanation when it decides not to approve an NDA. 

Disclosing such information could help convey to the public the independent role that FDA 

plays in the review process and that FDA does not approve all drugs. Further, this could help 

sponsors gain a better understanding of the criteria FDA uses in its review process and could 

lead to improved NDAs in the future. 

5. Conduct or support research that takes greater advantage of its vast clinical 

trial databases to identify ways to improve drug development. 

The results of this research, over time, could be highly cost-effective, contributing to better 

clinical trial designs and more efficient drug development. 

AGENCY COMMENTS 

The FDA reviewed a draft of this report, and overall, it concurred with our conclusions and 

recommendations. In its comments, FDA outlined numerous activities it has underway or 

planned to address our recommendations. Specifically, FDA indicated that it is reviewing its 

workload distribution and has studies underway to examine delays in the review process. The 

full text of FDA’s comments can be found in Appendix A. 

FDA’s Review Process for New Drug Applications vii OEI-01-01-00590 
TABLE OF CONTENTS 

EXECUTIVE SUMMARY ...................................................... i

INTRODUCTION ............................................................. 1

PRIMER ON FDA’S NDA REVIEW PROCESS .................................. 5

FINDINGS .................................................................. 6

Strengths of the Process .................................................... 6

Workload Pressures Challenge the Process ..................................... 9

Several Factors Have Contributed to the Workload Pressures ...................... 14

Other Factors Challenge the Process ......................................... 17

CONCLUSION ............................................................. 21

RECOMMENDATIONS ...................................................... 22

APPENDICES .............................................................. 25

Appendix A: FDA’s Comments on the Draft Report ............................ 25

Appendix B: Glossary .................................................. 29

Appendix C: Time Goals For CDER ........................................ 31

Appendix D: Highlights of PDUFA III ....................................... 32

Appendix E: Rate of Withdrawn Drugs ...................................... 35

Appendix F: Methodology ............................................... 37

Appendix G: Endnotes .................................................. 45

ACKNOWLEDGMENTS ..................................................... 47

FDA’s Review Process for New Drug Applications viii OEI-01-01-00590 
INTRODUCTION 

PURPOSE 

To assess how well the Food and Drug Administration manages its new drug application review 

process. 

BACKGROUND 

The Food, Drug, and Cosmetic Act requires the Food and Drug Administration (FDA) to 

review and approve all new drugs before they can be marketed in the United States. The FDA 

evaluates new drugs based upon the scientific evidence obtained from clinical studies and other 

research conducted by a drug’s sponsor, typically a pharmaceutical company. Sponsors 

submit this information to FDA in a new drug application (NDA). Based on its review of the 

application, FDA assesses the safety and efficacy of the drug and determines whether it can be 

marketed in the United States. (We provide a primer that gives an overview of the review 

process on page 5. Appendix B contains a glossary of key terms.) 

The Prescription Drug User Fee Act and the Food and Drug Administration 

Modernization Act 

In response to the public’s demand for greater access to new drugs to treat life-threatening 

illnesses, the 1992 Prescription Drug User Fee Act, referred to as PDUFA I, was enacted. The 

main purpose of PDUFA I was to reduce the time it takes FDA to review new drugs for 

market approval. It authorized FDA to collect user fees from sponsors to be used towards 

speeding up the NDA review process. It also established time goals for FDA’s review of 

NDAs. The FDA reports annually to Congress on how well it has met these time goals (see 

Appendix C for a list of the goals). 

In 1997, user fees were reauthorized as part of the Food and Drug Administration 

Modernization Act. The section of the Act that addresses user fees, referred to as PDUFA II, 

tightened the deadlines in the goals. It also added new provisions to help speed up the entire 

drug development process. Most notably, it required FDA to meet with sponsors upon request 

and codified many existing FDA policies intended to bring life-saving treatments to market 

faster. 

FDA’s Review Process for New Drug Applications 1 OEI-01-01-00590 
User fees have provided additional resources for FDA. The FDA’s Center for Drug 

Evaluation and Research (CDER) total costs in fiscal year (FY) 2000 for reviewing NDAs was 

$187 million, of which $86 million was paid for by user fees. The FDA primarily used the funds 

from user fees to hire more staff and to implement computer systems to speed up its review of 

NDAs. 

Prescription Drug User Fee Act III 

The PDUFA II expired on September 30, 2002. In June 2002, user fees were once again 

reauthorized, referred to as PDUFA III, as part of the Public Health Security and Bioterrorism 

Preparedness Act of 2002. The PDUFA III establishes time goals and outlines activities FDA 

will conduct over the next 5 years using the funds from user fees (see Appendix D).1 The 

PDUFA III went into effect on October 1, 2002. 

Most notably, PDUFA III increases user fees to help provide FDA with additional resources. 

According to a press release from the U.S. Department of Health and Human Services, “the 

law puts PDUFA III on sound financial basis.”2 In FY 2002, FDA, including both the Center 

for Biologics Evaluation and Research and CDER, estimates it collected about $160 million 

from user fees. Under PDUFA III, total funds from user fees should reach $223 million in FY 

2003, and gradually increase over the next 5 years to reach $260 million in FY 2007. With 

increased resources, CDER estimates it will hire close to 300 additional employees over the 

next 5 years. 

Concerns about the adequacy of FDA’s review process 

Critics allege that, in the rush to meet its time goals, FDA fails to identify key risks associated 

with drugs. Critics also raise concerns that FDA works too closely with pharmaceutical 

companies, lacks independence, has lowered its review standards, and conducts inadequate 

monitoring of drugs already on the market. Critics point to the recent drug withdrawals as 

evidence of their concerns. Between 1997 and 2001, sponsors voluntarily withdrew 13 drugs 

due to safety concerns. Five of them were approved prior to PDUFA, and one has since 

returned to the market. New molecular entities (NMEs) are drugs containing an active 

ingredient that has never been approved for marketing in the United States. According to 

CDER’s analysis, the rate of safety-based withdrawals for NMEs has remained relatively 

constant for periods prior to and after the enactment of the Prescription Drug User Fee Act in 

1992. According to CDER’s analysis, between FY 1983 and FY 1992, the rate of safetybased withdrawals for NMEs, based on the year of receipt, was 2.5 percent, and between FY 

1993 and FY 2002, it was 2.8 percent (see Appendix E for additional analysis). The FDA’s 

own review of many of these withdrawals concluded that they were not attributable to faster 

review times.3 

FDA’s Review Process for New Drug Applications 2 OEI-01-01-00590 
Our Inquiry 

Our inquiry focuses on CDER, one of two Centers within FDA that reviews NDAs. We did 

not evaluate the Center for Biologics Evaluation and Research’s process for reviewing NDAs. 

Our inquiry focuses on how well CDER carries out its NDA review process. We did not 

examine the scientific merit of FDA’s decisions. We conducted this inquiry at the request of the 

director of CDER and prior to the implementation of PDUFA III. Where appropriate, we 

indicate the potential impact of PDUFA III on our findings. We also highlight activities FDA 

has underway to address our findings. 

We use the term “FDA reviewers,” broadly, unless otherwise specified, to refer to CDER 

officials involved in the NDA review process. This includes office directors, division directors, 

primary reviewers, secondary reviewers, and project managers within the Office of New 

Drugs, the Office of Pharmacoepidemiology and Statistical Science, the Office of 

Pharmaceutical Science, and the Office of Medical Policy. 

Methodology 

This inquiry is based on multiple data sources (see Appendix F). This inquiry draws heavily on 

a web-based survey of all CDER primary reviewers, secondary reviewers, and division 

directors. We received 401 responses for an estimated response rate of 47 percent. We 

conducted a mail survey of all 119 sponsors, excluding one federal agency, that had at least one 

NDA approved by CDER in the years 1999, 2000, or 2001. We received 72 responses from 

sponsors, resulting in a 60 percent response rate. We also drew on data from an internal 

survey conducted by CDER of a random sample of 188 reviewers that had a 72 percent 

response rate. 

We conducted a file review of all new molecular entities that CDER approved in FY 2001 

(N=15). For these 15 drugs, we analyzed CDER’s receipt dates for all amendments submitted 

to the application. We analyzed CDER’s data on advisory committees. We observed 17 

CDER meetings that occurred throughout the drug development process, including internal 

meetings and meetings between CDER officials and sponsors. We also reviewed relevant 

FDA laws, regulations, policies, and procedures. 

To enhance our understanding, we conducted numerous interviews. We interviewed CDER 

officials, including 17 office directors, 27 division directors, and 18 primary and secondary 

reviewers of NDAs, including project managers. We conducted 9 interviews with 

representatives from pharmaceutical companies and 15 interviews with other stakeholders, such 

as consumer advocates, patient advocates, and scientific experts. 

FDA’s Review Process for New Drug Applications 3 OEI-01-01-00590 
We conducted this inspection in accordance with the Quality Standards for Inspections

issued by the President’s Council on Integrity and Efficiency. 

FDA’s Review Process for New Drug Applications 4 OEI-01-01-00590 
PRIMER ON FDA’S NDA REVIEW PROCESS 

This primer refers to the review of NDAs conducted by CDER. 

Review Clock. The review clock is the time between FDA’s receipt of the application and FDA’s decision. The PDUFA II calls 

for FDA in FY2002 to review and act upon 90 percent of standard NDAs within 10 months and 90 percent of priority applications 

within 6 months. Priority applications are for drugs that are a significant improvement over drugs already on the market to treat the 

same condition. Standard applications are applications not classified as priority. 

Contents of a New Drug Application. A sponsor, typically a pharmaceutical company, submits the NDA to FDA to obtain 

marketing approval for a drug within the U.S. The application contains data regarding the safety and efficacy of the drug that the 

sponsor obtained during its research and development. Thesedatainclude the results of clinical trials, pharmacology and toxicology 

data, chemistry and manufacturing data, and proposed packaging and labeling information. 

Filing Review. When FDA receives an application, the review clock begins. The FDA assigns the application to the appropriate 

therapeutic review division, of which there are 15. The FDA has 60 days, from the receipt of the application, to determine whether 

it is adequate for review. If the application is deemed inadequate or incomplete, FDA can refuse to file it and the sponsor can 

resubmit it later. If the application is complete, FDA notifies the sponsor that the application has been filed. 

Reviews within Individual Disciplines. After the application is filed, FDA assignsthe application to a team of multi-disciplinary 

reviewers. These reviewers are referred to as primary reviewers. They represent a variety of scientific disciplines, including 

medicine, pharmacology,statistics, and chemistry. The FDA also assigns a project manager that facilitates the review process and 

serves as a liaison between FDA and the sponsor. The reviewers, except for the project manager, evaluate the information in the 

application relevant to their areas. If necessary, the primary reviewer can request additional information from the sponsor. Based 

on the review, the primary reviewer may make a recommendation on the action FDA should take with respect to the drug. The 

primary reviewer’s work is checked by a secondary reviewer within the same discipline. 

Advisory Committees. The FDA may convene an advisory committee to assist with the review of an application. The committee 

comprises scientific experts from outside FDA and may also have consumer, patient, and industry representatives. The committee 

conductsits own review of the application, usually in a public forum, and advises FDA on scientific issues related to the application. 

It also votes on the action FDA should take with respect to the drug. The committee’s recommendations are not binding on FDA. 

Communication with Sponsors. Throughout the process, FDA and the sponsor communicate through in-person meetings, 

telephone conferences, letters, e-mails, and faxes. Communication allows sponsors and FDA to seek clarification, when necessary. 

Labeling Negotiations. Toward the end of the review process, FDA and the sponsor negotiatethe drug’s final package label. Each 

element of the label requires FDA approval, including the indications, dosing, directions for use, and safety information. 

Inspections of Manufacturing andClinical Sites. TheFDA inspectsthe manufacturingfacilities for the drug. It may also inspect 

a sample of clinical trial locations to verify the accuracy of the data contained within the application. 

Decision. Once all the reviews are complete, the division director and/or the office director evaluate the reviews and make FDA’s 

decision. Five office directors oversee the 15 review divisions. The FDA can take three actions: (1) approval – the drug can be 

marketed in the U.S., (2) approvable – problems exist with the application that need to be addressed before the drug may be 

approved, and (3) non-approvable – the application has more significant problems that may require additional research on the drug 

and may require reformulation of the drug product. The review clock ends once FDA makes its decision and issues a letter to the 

sponsor. 

ReviewCycles. The first-review cycle begins when FDA receives the application and ends when FDA makes its decision. Multiple 

review cycles occur when an application receives an approvable or non-approvable decision from FDA, and the sponsor revises the 

application and resubmitsit to FDA,startinganother cycle. When the sponsor resubmits the application, the review clock restarts 

and FDA receives either 2 or 6 months to review the revised application, depending on the information in the resubmission. 

Total Approval Time. Total approval time is from FDA’s receipt of the original application to the application’s approval. This 

time can include multiple review cycles and the time spent by the sponsor revising the application between review cycles. 

FDA’s Review Process for New Drug Applications 5 OEI-01-01-00590 
FINDINGS 

Our review of FDA’s NDA review process disclosed that it has several strengths that 

contribute significantly to its effectiveness. Both reviewers and sponsors have confidence in the 

decisions FDA makes. Review times have dropped considerably. FDA works more 

collaboratively with sponsors, and it has taken several steps to enhance efficiency and 

consistency. But we also found that workload pressures increasingly challenge its effectiveness. 

Our review included: (1) a survey of CDER reviewers resulting in 401 responses for an 

estimated 47 percent response rate, (2) interviews with over 100 CDER officials and 

stakeholders, including industry representatives, (3) a survey of sponsors resulting in 72 

responses for a 60 percent response rate, and (4) a detailed document review of all 15 new 

molecular entities approved drugs in FY 2001. 

Although reviewers have confidence in the decisions FDA makes, 40 percent of FDA survey 

respondents who had been at FDA at least 5 years indicated that the review process had 

worsened during their tenure in terms of allowing for in-depth, science-based reviews. 

Respondents cited lack of time as the main reason. Reviewer concerns about time goals do not 

mean there is a threat to public health, but they do indicate a significant management issue 

warranting attention. This pressure to meet time goals may also inhibit the raising of disputes as 

reviewers may be reluctant to raise them due to concerns about slowing down the process. 

Twenty-one percent of FDA respondents indicated that the work environment allowed for the 

expression of differing scientific opinions to a small or no extent. 

In addition to workload pressures, other factors challenge the effectiveness of the process. 

These other factors include the rush to finalize drug labels at the end of the review process, 

reviewers’ uncertainty about the types of postmarketing commitments to request of sponsors, 

and limited public disclosure. 

FDA’s new drug application review process has several strengths 

that contribute significantly to its effectiveness. 

Reviewers and sponsors have confidence in the decisions FDA makes. 

Our observations, a review of FDA documents, and extensive interviews with FDA reviewers 

and stakeholders underscored that FDA’s NDA review process is science-based and 

comprehensive. This is supported by the comments of FDA reviewers and sponsors. Seventyeight percent of FDA respondents and 86 percent of sponsors indicated in our surveys that they 

were confident in the decisions FDA makes with regard to a drug’s 

FDA’s New Drug Application Review Process 6 OEI-01-01-00590 
efficacy. And 64 percent and 82 percent, respectively, were confident in FDA’s decisions 

regarding the safety of a drug. 

FDA is highly responsive to the time goals required in the Prescription Drug User 

Fee Act and the FDA Modernization Act. 

The CDER met all but 2 of its 20 time goals in FY 2000 (see Appendix C). In meeting these 

goals, it reduced its total approval time for NDAs. In 1993, median total approval time for 

CDER was 27 months for standard NDAs classified as new molecular entities; in 2001 it was 

19 months. The reduction in approval times helps to ensure timely access to new medications 

that can benefit public health. Furthermore, the overall time to develop and market a new drug 

has decreased in part due to FDA’s assistance. In the early 1990s, drugs classified as new 

molecular entities took an average of 7 years to go from clinical testing to the marketplace; by 

1998, the elapsed time dropped to a little over 5 years.4 

FDA is highly responsive to the mandate in the Food and Drug Administration 

Modernization Act to work collaboratively with sponsors to expedite the drug 

review process. 

The FDA Modernization Act requires FDA to hold formal meetings with sponsors upon 

request. FDA has devoted substantial resources to meet this requirement; in FY 2001, CDER 

conducted 1,021 formal meetings with sponsors. In these meetings, most of which occur prior 

to the NDA review process, FDA provides valuable advice to sponsors. The FDA’s advice 

can play an important public health role by helping to facilitate efficient and high quality drug 

development. 

Formal meetings held prior to and during the clinical testing of drugs allow FDA to address 

problems early in the drug development process. Both FDA reviewers and sponsors identified 

early interaction as a strength of the process. According to 94 percent of FDA respondents 

and 96 percent of sponsors responding to our surveys, interaction between sponsors and 

reviewers during this stage contributed to an effective NDA review process. For example, in 

one meeting we observed that FDA encouraged additional toxicity testing of all human subjects 

in the clinical trial when the sponsor proposed testing just a sample of the subjects. In another 

meeting, FDA suggested, based on preliminary data, that the sponsor focus more carefully on 

safety issues as the research progressed. And in several meetings, FDA stressed the 

importance of statistical rigor and of developing a clinical trial design that anticipates how the 

product will be used in clinical practice. 

The FDA and sponsors also meet and discuss issues relating to the content and format of an 

NDA immediately prior to and during the review process. The purpose of this 

FDA’s New Drug Application Review Process 7 OEI-01-01-00590 
collaborative approach is to produce higher quality NDAs and more efficient reviews. Ninetyeight percent of sponsors and 89 percent of FDA respondents reported in our surveys that 

interaction during the NDA review process contributed to an effective review process. 

FDA gives considerable attention to synthesizing information across review 

disciplines. 

The FDA relies on multi-disciplinary teams to review NDAs. These teams meet throughout the 

review process to discuss the status of their reviews and to share ideas. We observed several 

of these internal meetings and found that the review teams addressed key issues, such as 

additional information to request from sponsors, unresolved safety concerns, labeling issues, 

and postmarketing commitments. 

Seventy-four percent of FDA respondents to our survey indicated that the NDA review 

process adequately integrates information across review disciplines. Time goals have provided 

an incentive for review team members to work on the same application at the same time. In the 

past, review team members tended to review the application sequentially. Now, more dialogue 

occurs among review team members throughout the process. Medical officers and statistical 

reviewers work particularly close and sometimes write a joint evaluation. The FDA also 

locates members of a review team close to one another to encourage more interaction. 

FDA has taken several steps to help foster efficiency and consistency in the 

process. 

With the funds from user fees, FDA implemented a computer infrastructure that allows it to 

receive NDAs electronically. CDER began accepting NDAs electronically in 1999. Currently, 

about 70 percent of NDAs have some electronic component and one-third are completely 

electronic. Reviewers can now use computer programs to conduct their own analysis of 

databases submitted by sponsors instead of requesting an analysis from sponsors, which can 

lead to delays. Reviewers can also conduct quick searches for key words or phrases in an 

electronic document instead of sifting through hundreds of pages by hand. This is particularly 

helpful when reviewing thousands of individual patient records. 

To help foster consistency, FDA has issued numerous guidance documents and internal 

policies. In 2000 alone, CDER issued about 40 guidance documents, mostly directed toward 

industry. Since 1996, it issued about 140 policies to guide reviewers covering a wide range of 

topics. Although some reviewers are concerned that guidance documents and policies are too 

rigid, FDA’s aim is to ensure that minimum standards are met and 

FDA’s New Drug Application Review Process 8 OEI-01-01-00590 
key issues are addressed. For example, CDER recently issued a policy requiring reviewers to 

use discipline-specific templates for their written evaluation of NDAs. These templates help to 

ensure that reviewers address key issues in the course of their evaluation and present them in a 

standard format. Sixty-nine percent of FDA survey respondents who had used the templates 

indicated that they were helpful. 

FDA relies on a core of expert scientific reviewers. 

The FDA’s in-house expertise is a key asset of the review process. The FDA is comprised of 

hundreds of scientific experts, including physicians, chemists, statisticians, pharmacologists, and 

toxicologists, most of whom have advanced degrees. Reviewers bring scientific and technical 

expertise and a strong commitment to public health. Many have left positions in academia and 

private industry to work at FDA and serve the public. With funds from user fees, FDA has 

expanded its cadre of reviewers. By the year 2002, CDER will have hired about 700 

additional employees using funds from user fees, in addition to the 750 funded through 

appropriations. 

But workload pressures increasingly challenge the 

effectiveness of the new drug application review process. 

Reviewers work under the constant pressure of the review clock. They not only review NDAs, 

but also conduct other types of review activities, some of which also have time goals attached. 

They must provide advice to sponsors throughout the drug development process and stay 

abreast of the latest scientific advances in their field, both of which contribute to the demands of 

the job. The importance of FDA’s decisions also adds to the pressure, as these decisions have 

serious consequences for public safety. In this section, we address the consequences of these 

workload pressures. In the next section, we address the causes of these pressures. 

Reviewer concerns about time pressures. 

An effective review process not only examines the information submitted by the sponsor, but 

also asks what, if any, additional information should have been submitted. For example, have 

all the reasonable safety considerations been explored, and should any additional studies be 

conducted to adequately address safety and efficacy? In raising these questions, reviewers 

must draw upon the experiences of FDA and their own scientific and regulatory knowledge. 

Yet, in this fast-paced environment, reviewers sometimes find it difficult to conduct reviews that 

are as in-depth as they would like. Forty percent of FDA respondents who 

FDA’s New Drug Application Review Process 9 OEI-01-01-00590 
had been at FDA at least 5 years indicated that the review process had gotten worse in terms 

of allowing sufficient time for in-depth, science-based reviews. Reviewers are particularly 

concerned with priority reviews. According to 58 percent of FDA respondents, the allotted 6 

months for a priority review is inadequate. This is considerably higher than the 25 percent of 

respondents who indicated that the allotted 10 months for a standard review is inadequate. 

Reviewer concerns about time do not necessarily mean that there is a threat to public health. 

We have no evidence of a public health concern nor did we seek such information. But, these 

concerns do indicate a significant management issue warranting attention. 

Despite these concerns, reviewers were confident that FDA’s final decisions regarding NDAs 

are appropriate. Seventy-eight percent of FDA respondents to our survey were confident in 

the efficacy decisions FDA makes. Although reviewers commented in interviews that time 

pressures have made their jobs more difficult, they did not believe that they were ignoring key 

information or data contained in NDAs in order to meet time goals. It is also important to 

acknowledge that FDA received the 4th highest composite score out of the 13 operating 

divisions within the Department of Health and Human Services on the 2002 Secretary’s Quality 

of Work Life Survey on Organizational Climate, which indicates a positive work environment. 

The CDER’s composite score was also high compared to the overall Department. 

The PDUFA III acknowledges the workload pressures that reviewers face and calls for FDA 

to receive more resources. With these additional resources, CDER estimates that it will hire 

close to 300 additional employees over the next 5 years. This will help to alleviate some of the 

workload pressures. 

Workload pressures may contribute to less use of advisory committees. 

Advisory committees provide valuable advice to FDA on NDAs. These committees consist of 

independent scientists, researchers, industry representatives, and consumer and patient 

advocates. In our surveys, 78 percent of FDA respondents and 81 percent of sponsors 

indicated that advisory committees were helpful in providing independent advice to the FDA. 

The majority of advisory committees are open to the public and provide an important 

opportunity for public discussion and involvement. 

However, there is little time to hold these meetings and still meet the time goals. Our analysis of 

data from CDER shows less use of advisory committees in recent years. The number of 

advisory committee meetings associated with an NDA decreased from 40 in 1998 to 23 in 

2001 (see Figure 1 on the following page). In part, this decrease may be 

FDA’s New Drug Application Review Process 10 OEI-01-01-00590 
due to a reduction in the number of NDAs that sponsors have submitted in recent years. The 

number of NDAs, including both priority and standard, filed by CDER has dropped from 124 

in 1997 to 97 in 2001. But, it is also likely that workload pressures are a key contributing 

factor. The FDA managers, who determine when an advisory committee should be held, 

commented in interviews that the current time goals can discourage the use of advisory 

committees. Furthermore, we estimated that the percentage of approved new drugs that had an 

advisory committee decreased from 19 percent in 1998 to 12 percent in 2001 (see Table 6 in 

Appendix F). 

Figure 1. 

and Research for New Drug Applications 

35 

40 39 

26 

23 

29 29 30 

20 

17 17

23 

17 

8 9 

6 

11 

9 

6 6 

0 

5 

10 

15 

20 

25 

30 

35 

40 

45 

1997 1998 1999 2000 2001 

Calendar Year 

No. of Advisory Committees 

Total Advisory Committees 

Advisory Committees for Standard Drugs 

Advisory Committees for New Molecular Entities 

Advisory Comittees for Priority Drugs 

Source: OIG Analysis of Data from FDA’s Center for Drug Evaluation and Research 

Number of Advisory Committees Held by FDA's Center for Drug Evaluation 

Advisory committees compress the time allowed for reviewers to complete their evaluations. 

Several reviewers estimated that planning and conducting an advisory committee meeting takes 

about 2 months, in part due to requirements for public disclosure. When planning for a meeting, 

FDA is required to prepare and submit relevant materials to the advisory committee staff 19 

days in advance of the meeting. This allows time for the materials to be distributed to advisory 

committee members and the public. The preparation for an advisory committee meeting 

compels reviewers to conduct their reviews earlier in the process in order to meet the time goal. 

Furthermore, meetings must 

FDA’s New Drug Application Review Process 11 OEI-01-01-00590 
be scheduled early enough in the process to allow time afterward for reviewers to consider the 

committee’s input. This can be particularly challenging for priority reviews.5 

To help address this issue, PDUFA III calls for FDA to issue guidance on good review 

management principles. One of the areas that this guidance will address is anticipating and 

planning for an advisory committee meeting. 

Workload pressures make it difficult to raise scientific disputes. 

It is important that reviewers have the opportunity to raise scientific disagreements, as they can 

help to raise critical questions about the safety and efficacy of a drug and can lead to more 

comprehensive reviews. For the 15 new molecular entities approved in FY 2001, we found 

one documented disagreement. We also found that some reviewers have concerns about 

raising disagreements. In fact, 21 percent of FDA survey respondents indicated that the work 

environment allowed for the expression of differing scientific opinions to a small or no extent. 

Similarly, an internal survey conducted by CDER of its reviewers found that one-third of 

respondents did not feel comfortable expressing their differing opinions. And, on our own 

survey, 18 percent of respondents indicated that they have felt pressure to approve or 

recommend approval for a drug, despite reservations about its safety, efficacy, or quality. 

Reviewers may be reluctant to raise disagreements because they fear slowing down the review 

process. The FDA’s current procedures for handling disputes lack timelines for handling them. 

Workload pressures contribute to staff turnover. 

An internal survey conducted by CDER of reviewers found that 50 percent of respondents 

indicated that their workloads are influential reasons to consider leaving FDA. According to 

FDA’s analysis, medical officers and pharmacologists had the highest attrition rates within 

CDER in FY 2001, 8.4 percent and 6.9 percent respectively, compared to the overall average 

attrition rate for reviewers of 5.5 percent.6 Many reviewers leave for private industry, which 

largely includes the pharmaceutical industry. The CDER officials indicated that often they 

cannot compete with the salaries offered by private industry. According to another CDER 

analysis, 26 percent of CDER’s employees went to private industry in FY 2000 and 24 percent 

in FY 2001.7 Hiring and training new reviewers adds to reviewers’ workloads and can take 

time away from review activities. 

The FDA has taken numerous steps to reduce turnover. For example, in October 2000, FDA 

implemented a pilot program to pay pharmacologists and statisticians a retention allowance of 

up to 10 percent of their basic pay. 

FDA’s New Drug Application Review Process 12 OEI-01-01-00590 
Workload pressures curtail time for professional development. 

Staying abreast of scientific developments is essential to reviewer performance. In the meetings 

we observed between FDA and sponsors, the sponsors’ consultants often included leading 

researchers in their fields who are aware of the latest research that bears on the sponsor’s drug 

development plans. They and other sponsor representatives often posed questions to reviewers 

that called for the reviewers to be equally informed of the current research and its implications. 

In our interviews with reviewers, they emphasized to us how vital it is for them to find time to 

stay abreast of the latest developments in their disciplines. 

Fifty-nine percent of FDA survey respondents indicated that they have little time to participate 

in professional development activities. An internal survey conducted by CDER of its reviewers 

obtained similar results; it found 60 percent of respondents did not feel that they had adequate 

time for professional development activities. The seriousness of this issue is further illustrated 

by that same CDER survey that found 25 percent of respondents regarded insufficient time for 

professional development as a reason to consider leaving FDA. 

The FDA has taken several steps to encourage reviewers to participate in professional 

development activities. The FDA has a policy in place to allow reviewers to spend up to one 

day a week participating in professional development activities. The FDA has also developed 

and implemented an extensive internal training program that includes a broad range of classes 

from statistics to technical writing from which reviewers can choose. 

Workload pressures allow little opportunity for reviewers to conduct research on 

drug development. 

From its review of investigational drug development plans of sponsors and of submitted NDAs, 

FDA has a unique repository of information concerning drug development. The FDA 

reviewers emphasized to us that this repository affords valuable potential that could be highly 

instructive to future drug development efforts. It could, they note, help guide clinical trial 

designs and help identify possible safety concerns that might be more fully addressed as part of 

the drug development process. 

The CDER does award small grants to reviewers to conduct research on drug development 

through its Regulatory Science and Review Enhancement Program. The program has about 

$250,000 of annual funding and funded about 21 projects in FY 2002. But, as we noted with 

respect to professional development, the time available for reviewers to conduct such research, 

without compromising their core review responsibilities, is limited. 

FDA’s New Drug Application Review Process 13 OEI-01-01-00590 
Several factors have contributed to the workload pressures. 

Tight deadlines. 

Although time goals have been beneficial, they place reviewers under constant pressure to meet 

deadlines. Reviewers conduct multiple activities, many of which have time goals attached. The 

same reviewers of NDAs also must review clinical trial designs, prepare for meetings with 

sponsors, and review supplements to approved NDAs. This pressure has increased as the 

goals have become progressively more challenging each year as required under PDUFA II. 

For example, in FY 1998, FDA’s goal was to review and act upon 90 percent of standard 

NDAs within 12 months. In FY 2002, the goal was for FDA to review and act upon 90 

percent of all standard NDAs within 10 months (see 

Appendix C). 

Staffing limitations. 

Ninety-one percent of FDA survey respondents indicated that their workloads contribute to 

delays. Forty percent of FDA respondents who had been at FDA at least 5 years indicated in 

our survey that the review process had gotten worse in terms of allowing for an in-depth 

review. Lack of staff was a common explanation offered by those respondents. Reviewers 

raised concerns about the need to work overtime to complete their work on time. 

The FDA cannot quickly reallocate its current staff to better accommodate changes in its 

workload. Workloads can vary by division, and staffing patterns do not always match up to the 

current workload. Administrative barriers to reassigning staff make it difficult to quickly adjust. 

Furthermore, FDA has difficulty estimating its workload from year to year. The FDA’s 

workload depends largely on what sponsors submit. The FDA does attempt to estimate the 

number of NDAs that sponsors will submit through discussions with industry. 

As we have already pointed out, PDUFA III acknowledges the limited staffing and calls for 

FDA to receive more resources to be used to hire additional reviewers. The CDER estimates 

it will hire close to 300 additional employees over the next 5 years using funds from user fees. 

This will help to alleviate some of the workload pressures. 

FDA’s New Drug Application Review Process 14 OEI-01-01-00590 
Expectations to serve as an advisor to sponsors as well as a reviewer of new drug 

applications. 

Reviewers’ dual roles as advisors and reviewers demand substantial time and resources and 

contribute to workload pressures. The CDER conducted 1,021 formal meetings with sponsors 

in FY 2001, mostly during the investigational new drug stage, prior to the NDA review process, 

when FDA provides advice. When a sponsor’s request is determined to require a meeting, 

which was the case for 94 percent of requests in FY 2001 according to FDA, it has 14 days 

from the receipt of the request to schedule the meeting date. The FDA’s analysis of data from 

CDER and the Center for Biologics Evaluation and Research found that the total hourly 

commitment for staff for a typical meeting ranges from about 124 to 543 hours.8 Reviewers 

expressed concerns about the amount of time these meetings require. 

During the investigational new drug stage, FDA provides advice and information in meetings 

with sponsors, based on an analysis of research plans or preliminary data. This advice is 

intended to improve the drug development process by ensuring that research is well designed, is 

well conducted, and results in pertinent data. Once research is complete and the application for 

a new drug is submitted, FDA reviewers continue to interact with the sponsor, not just as 

advisors, but as reviewers as well. The FDA is responsible for conducting an impartial review 

that will produce sufficient evidence to justify an approval or other decision. 

The FDA’s duties as advisor and reviewer are not necessarily conflicting, but the dual roles do 

add complexity and call for careful attention to boundaries. On the one hand, FDA must work 

with sponsors as partners, helping them to develop well-designed clinical trials and wellsupported NDAs. On the other hand, it must function as an impartial reviewer of these NDAs 

on the public’s behalf. The PDUFA III calls for FDA to develop guidance on good review 

management principles that will include advice on how to communicate with sponsors during the 

review process. 

Shortcomings in some new drug applications. 

Incomplete NDAs contribute to delays in the review process. The 15 drugs we reviewed 

contained, on average, 38 amendments to the original application. Combined, the 15 drugs had 

679 minor and major amendments. Of those amendments, the four most common types were: 

minor clinical (21 percent), minor chemistry (20 percent), minor multi-disciplinary (11 percent), 

and minor labeling (10 percent). 

Some amendments are expected as reviewers raise questions during their reviews. But a large 

number of amendments, especially ones that contain key information, can cause 

FDA’s New Drug Application Review Process 15 OEI-01-01-00590 
delays. Out of the 15 drugs we reviewed, 11 contained an amendment that FDA classified as 

major. None of those 11 drugs were approved in one review cycle. (FDA defines a major 

amendment as a submission from a sponsor that requires an extension of the time goal. The 

extension can vary from 45 days to 180 days, depending on the amount and type of information 

contained in the amendment.) According to 77 percent of FDA survey respondents, 

amendments that sponsors submit without a request from FDA contribute to delays. Similarly, 

when FDA requests an amendment, 91 percent of FDA respondents reported that waiting for 

sponsors contributes to delays. 

Given the large size of NDAs, disorganization also can create delays in the review process and 

leads to additional amendments. When NDAs are disorganized, reviewers must spend time 

reorganizing information or request that sponsors submit amendments in the proper format, both 

of which can cause delays. Ninety percent of FDA survey respondents indicated that they 

spend time reorganizing data in NDAs. Common concerns include: improperly formatted data, 

missing information, incorrect analyses, unedited data sets, large amounts of irrelevant data, 

inconsistent tables, and difficult-to-locate materials. 

Although FDA can refuse to file applications, it rarely does so. The CDER refused to file 4 

percent of submitted applications in FY 2000, down from 17 percent in 1993. In part, this 

decrease may be attributable to the advice FDA provides sponsors that helps them prepare 

higher quality applications. However, reviewers commented that FDA accepts some 

applications that it should not accept. One reviewer characterized FDA as a “victim of its own 

kindness,” referring to the time and effort required to assess and integrate so many amendments 

after it files an application that it should have refused. Even one application filed that should 

have been refused can have significant consequences for FDA’s workload. Once filed, FDA 

must take time to document the deficiencies and provide advice to sponsors on what to include 

if the sponsor chooses to resubmit the application. 

Concerns about inefficiencies in the review process. 

As we have already pointed out, FDA has taken numerous steps to enhance efficiency in the 

process. However, inefficiencies still remain, and they can contribute to workload pressures. 

Reviewers commented that they do not receive documents quickly enough. It can take days 

and sometimes weeks for documents to be routed to them. Many reviewers were concerned 

that they spend too much time handling administrative or basic research tasks that could be 

more easily addressed by others. For example, several of the scientific reviewers indicated that 

they spend time scanning documents into the computer, conducting basic literature searches, 

creating simple charts and tables, and preparing correspondence to sponsors. 

FDA’s New Drug Application Review Process 16 OEI-01-01-00590 
Sponsors also raised concerns about inefficiencies. They were concerned that reviewers do 

not start their reviews soon enough, creating bottlenecks later in the process. Sponsors 

suggested that if FDA communicated the deficiencies earlier, they could prepare the materials 

so that all the information FDA needs would be available when the actual review took place. 

Sponsors were also concerned about inconsistencies in the process. Seventy-five percent of 

sponsors responding to our survey indicated that FDA reviews are inconsistent across the 15 

review divisions within CDER. One sponsor commented that these inconsistencies may prompt 

some sponsors to shop for review divisions when a drug could be classified under different 

therapeutic review divisions. 

The FDA has conducted few efforts to identify and eliminate inefficiencies in the review 

process. Forty-eight percent of FDA survey respondents indicated that FDA was not doing 

enough quality improvement activities. The FDA lacks estimates of how long it takes reviewers 

to conduct their various activities, and has not conducted a comprehensive review to identify 

areas of bottlenecks. In 2001, CDER established the Review Standards Staff to lead quality 

improvement efforts. 

The PDUFA III calls for FDA to take numerous steps aimed at improving efficiency. Most 

notably, FDA will examine first-cycle reviews to determine best practices that facilitate a timely 

review. It calls for FDA to develop good review management principles that will include 

guidance on completing primary reviews early enough in the process to allow for sufficient 

deliberations. The PDUFA III calls for FDA to set aside $7 million from users fees to conduct 

a wide range of studies aimed at fostering efficiency and effectiveness. 

Other factors also challenge the effectiveness of the new 

drug application review process. 

Rush to finalize labels at the end of the review cycle. 

Labels, which FDA approves as part of the NDA review process, are a key leverage point for 

FDA. The label provides the parameters on how a company can market a drug and provides 

key information concerning its safe and effective use, such as indications, dosages, 

contraindications, warnings, and precautions.9 Both FDA respondents and sponsors were 

confident in the labeling decisions FDA makes, 70 and 81 percent respectively, indicated as 

such on our surveys. 

However, we found that labeling negotiations are considerably rushed at the end of the review 

process and can occur right up to the day the drug is actually approved. To some extent, 

labeling negotiations must occur toward the end of the review process, after 

FDA’s New Drug Application Review Process 17 OEI-01-01-00590 
reviewers have evaluated the data in the NDA and are familiar with the drug’s efficacy and 

safety, but it appears to be too compressed. For the 15 new molecular entities we reviewed, 

we found that 27 percent of labeling amendments were submitted in the last 14 days. Eightytwo percent of FDA respondents indicated on our survey that the labeling negotiations can 

contribute to delays. Labeling negotiation can even lead to another review cycle. FDA’s 

analysis of 26 new molecular entities approved by CDER between January 1, 2000, and 

October 31, 2001, found 2 drugs that were not approved in one review cycle primarily due to 

labeling. 

The rush to finalize labels at the end may be in part caused by the lengthy negotiations that can 

occur between FDA and the sponsor over the label. Some of this interaction reflects the 

different perspectives of each. Sponsors are looking to obtain the best position to market their 

drugs, as the label serves as the legal basis from which they can advertise their drugs. Sponsors 

may also be concerned with liability issues and may want to list every possible adverse event. 

The FDA is primarily concerned with ensuring that the label provides useful information to 

health care professionals. Tension can erupt between what information is clinically significant 

versus what information is important for advertising and liability purposes. 

The PDUFA III will help to address this issue. It calls for FDA to develop guidance on good 

review management principles. This guidance will address labeling feedback, including planning 

and holding meetings regarding labeling in advance of the time goal. In addition, FDA has 

several other efforts underway to further help alleviate the pressures associated with labeling 

negotiations. The FDA has proposed new regulations for the content and format of drug labels 

that make more explicit FDA’s expectations and call for key information to be prominently 

displayed in a new highlights section.10 The FDA issued two draft guidance documents 

regarding the adverse event section and the clinical studies section of labels that clarify what 

information sponsors should include in those areas.11 The FDA proposed new regulations 

requiring sponsors to submit labels in electronic format to facilitate the creation of a labeling 

database that would make it easier to compare labels. Finally, FDA has a pilot project called 

Targeted Product Information that allows sponsors to submit a draft label to FDA at any time 

throughout the drug development process to help focus labeling discussions earlier in the 

process. 

Uncertainty about the types of postmarketing commitments to request of 

sponsors. 

The ability to influence the postmarketing commitments made by the sponsor represents another 

key leverage point for FDA. As part of its approval decisions, FDA can request that sponsors 

commit to specific activities to manage the risks associated with their drugs. The most typical 

postmarketing commitment requested by FDA is to conduct additional 

FDA’s New Drug Application Review Process 18 OEI-01-01-00590 
studies after the drug is on the market to further define its safety and efficacy. When a drug 

raises serious safety concerns, FDA can also request that sponsors establish patient registries, 

restrict distribution to certain populations, and/or ensure patients receive counseling from a 

pharmacist. According to a recent FDA report submitted to Congress, between 1991 and 

2001, FDA approved 1,090 NDAs and sponsors agreed to conduct 2,328 postmarketing 

studies. That same report found that as of February 8, 2002, sponsors had completed 882 of 

the 2,400 postmarketing commitments on file at FDA for drugs. 

Postmarketing commitments are critical given that FDA does not know all the risks associated 

with a drug at the time of its approval. Reviewers commented that they are often unsure what 

types of postmarketing commitments to request of sponsors. Little empirical evidence is 

available that demonstrates the effectiveness of these commitments. Sponsors were also unsure 

how FDA determines what types of commitments to request of sponsors.12 Sixty-six percent 

of FDA respondents indicated on our survey that they were somewhat or not at all confident 

that FDA adequately monitors the safety of prescription drugs once they are on the market. 

The FDA has already taken numerous steps to help address this issue. In part due to a 1996 

OIG study, Postmarketing Studies of Prescription Drugs (OEI-03-94-00760), that found 

FDA lacked formal standards to track these commitments, FDA has put in place new policies 

and procedures to better track these commitments. The PDUFA III also gives considerable 

attention to the issue of postmarketing commitments. First, it calls for FDA to hold meetings 

with sponsors prior to the submission of the NDA to review and discuss sponsors’ preliminary 

risk management plan. Second, it calls for FDA to review sponsors’ proposed risk 

management plans as part of an NDA. Third, it allows FDA to use funds from user fees to 

review sponsors’ implementation of the risk management plans for a period of up to 2 years, 

and up to 3 years for products that require risk management beyond standard labeling. Finally, 

it calls for FDA to issue three guidance documents addressing risk assessment, risk 

management, and pharmacovigilance practices that should help to provide some clarity on 

FDA’s expectations. 

Limited disclosure to the public about the basis of key decisions concerning new 

drug applications. 

No summary basis for approval. We reviewed information on CDER’s website regarding 

the 15 new molecular entities approved in FY 2001, and in no case did it provide a summary 

document that explains the overall basis for the approval. It does not routinely provide this type 

of summary information nor is it required to do so.13 The lack of this summary information 

makes it difficult for sponsors and the public to understand the criteria FDA uses to make its 

decisions. FDA does provide technical information on 

FDA’s New Drug Application Review Process 19 OEI-01-01-00590 
its website on approved drugs, but it consists of hundreds of pages of highly scientific

documents for each drug. The FDA also posts approval letters on its website. However, they

are largely administrative documents. 

Drug approval documents are not promptly disclosed on FDA’s website. We found that

it took CDER 7.6 months after the date of approval, on average, to post reviewer evaluations

on its website for the 15 drugs we reviewed. The FDA’s goal is to have the reviewer

evaluations and other technical documents, such as the label and approval letter, posted on its

website within 6 weeks of approval. Redacting proprietary information and waiting for

reviewers to compile their documentation into a formal package after the drug has been

approved can cause delays.

Limited disclosure about FDA’s decisions not to approve drugs. When FDA decides not

to approve a drug, it issues one of two types of action letters: an approvable or non-approvable

letter. These letters explain in detail the deficiencies FDA found with the application. 

However, approvable letters are not disclosed to the public at the time they are issued, and

non-approvable letters are almost never disclosed. The FDA regulations limit the public

disclosure of approvable and non-approvable letters. An approvable letter is disclosed to the

public if the drug is later approved, which can be months or years after the letter was issued. 

As a result, the public remains largely unaware of FDA’s rationale for not approving drugs.

FDA’s New Drug Application Review Process 20 OEI-01-01-00590 
CONCLUSION 

Our review of FDA’s NDA review process disclosed that it has several strengths that 

contribute significantly to its effectiveness. Both reviewers and sponsors have confidence in the 

decisions FDA makes. Review times have dropped considerably. The FDA works 

collaboratively with sponsors and has taken several steps to enhance efficiency. But we also 

found that workload pressures increasingly challenge the effectiveness of the process. For 

example, 40 percent of FDA survey respondents who had been at FDA at least 5 years 

indicated that the review process had worsened during their tenure in terms of allowing for indepth, science-based reviews. Respondents cited lack of time as the main reason. Reviewer 

concerns about time goals do not mean that there is a threat to public health, but they do 

indicate a significant management issue warranting attention. These pressures can also 

discourage the use of advisory committees, inhibit the raising of scientific disputes, reduce the 

time available for professional development, and contribute to staff turnover. 

Three other factors also challenge the effectiveness of the review process: (1) the rushed review 

of drug labels toward the end of the review process, (2) the limited guidance available to 

reviewers in determining the extent and the type of postmarketing commitments to request of 

sponsors, and (3) the limited information that FDA makes available to the public on the basis 

for its decisions concerning NDAs. Considered as a whole, our findings present a significant 

warning signal, one that could jeopardize gains FDA has made in recent years, if not fully 

addressed. 

We recognize that FDA has already identified many of the concerns presented in this report 

and has numerous efforts underway to address them. In particular, the enactment of PDUFA 

III, which FDA played a critical role in developing with sponsors, presents significant 

opportunities to address many of our findings. It calls for an increase in user fees that will allow 

FDA to hire close to 300 additional employees. Over time, this could help considerably in 

relieving the workload pressures that we have emphasized. In addition, PDUFA III calls for 

FDA to conduct various activities that will address efficiency, consistency, labeling negotiations, 

and the use of advisory committees. It calls for significant attention to be placed on 

postmarketing commitments, by allowing user fees to be used to monitor drugs after they are on 

the market. It also calls for FDA to issue guidance on developing risk management plans. 

Our first recommendation offers additional steps for FDA to take as it implements PDUFA IIII 

to ensure that the agency takes full advantage of its opportunities. Although PDUFA III 

presents opportunities, other issues still remain. Accordingly, our last four recommendations 

outline additional actions that FDA can take to improve the NDA process. We direct all our 

recommendations to CDER. 

FDA’s New Drug Application Review Process 21 OEI-01-01-00590 
RECOMMENDATIONS 

1. Take full advantage of the opportunities in PDUFA III. 

< Conduct a retrospective examination of recent reviews to determine the capacity of 

reviewers to conduct in-depth, science-based reviews. Make this review a part of the $7 

million performance management fund that PDUFA III establishes. Include in this review 

drugs that were approved, as well as those that were not; different review divisions; and an 

assessment of the completeness and organization of applications submitted by sponsors. 

< Evaluate the adequacy of current staffing levels and the workload distribution among the 15 

review divisions within CDER, and implement a system that in real time would indicate the 

status of an application and the time spent in reviewing its specific parts. Conduct this 

evaluation as part of the comprehensive process review and analysis that PDUFA III 

requires FDA to undergo. 

< Assess how amendments to the original application, internal processing delays, and labeling 

negotiations affect FDA’s capacity to make timely, first-cycle review decisions. Include 

this assessment as part of the examination of first-cycle reviews that PDUFA III requires. 

< Examine how continuous marketing applications affect not just the efficiency, but also the 

quality of the review process. The PDUFA III requires FDA to conduct a pilot project to 

test the concept of continuous marketing applications that involves FDA reviewing sections 

of an application prior to the submission of the complete application. 

< Provide a guidance document for reviewers addressing the scope of the filing review and 

monitoring the effect that early notification to sponsors has on reviewer workloads. The 

PDUFA III requires FDA to notify sponsors within 14 days after the filing review of any 

deficiencies it has noted thus far in the application. 

< Offer further guidance on the best way to handle scientific disputes that occur among 

reviewers and how to balance the role of reviewing NDAs and the role of providing advice 

to sponsors concerning those applications. Provide this guidance as part of the good 

review management principles that PDUFA III requires FDA to develop and implement. 

FDA’s New Drug Application Review Process 22 OEI-01-01-00590 
< Include case studies of past reviews as part of the training on good review management 

principles that PDUFA III requires. Case studies serve as a way to illustrate good review 

principles and foster consistency among divisions. 

< Provide a list of the various postmarketing commitments that reviewers can request of 

sponsors and suggestions for when each could be considered. Include this as part of the 

risk management guidance documents that PDUFA III requires. In making suggestions on 

when to use each tool, take into account the population most likely to be using the drug, the 

severity of the disease, and drug interactions. 

2. Determine whether the significant workload pressures discussed in this report 

justify any exceptions to the current time goals regarding new drug applications 

to allow for more in-depth reviews. 

As we have indicated, the Prescription Drug User Fee Act and the FDA Modernization Act 

have been positive forces for the review process. They have fostered a productive, 

collaborative relationship between FDA and sponsors, a more expeditious drug development 

and review process, and a more efficient and systematic review process within FDA. Yet, it is 

important that an appropriate balance exists between timeliness and comprehensive reviews. 

Our data show that reviewers have concerns about the amount of time available to conduct 

their reviews, and this is an important management issue warranting attention. Accordingly, 

FDA could examine further if it would be beneficial to extend the review clock, perhaps by 1 or 

2 months, when it chooses to use an advisory committee. Also, it could examine if it would be 

beneficial to modify the current 10-month time goal for standard NDAs perhaps by 1 or 2 

months. Some moderation in time goals could help to reduce workload pressures and lead to 

fewer review cycles. 

3. Reject applications that are incomplete and of poor quality that can create 

delays in the new drug application review process. 

Toward that end, FDA could reexamine its policies regarding refusal-to-file decisions to ensure 

that they are adequately explicit. It could ensure that all review divisions within CDER 

appropriately apply its policies. It could also examine its current guidance to sponsors on 

submitting applications to ensure that it makes clear FDA’s expectations. 

FDA’s New Drug Application Review Process 23 OEI-01-01-00590 
4. Provide the public with a clear and timely explanation of decisions on new drug 

applications. 

Disclosure is particularly important given that so much of the process is closed to the public and 

that industry pays for these reviews. We recommend two directions that FDA take to enhance 

public disclosure. 

The FDA could include on its website, within a month, if possible, a succinct explanation of its 

rationale for approving an application. The agency is already moving in this direction by 

requiring reviewers to provide executive summaries as part of discipline-specific templates. 

These summaries could provide the basis for the overall summary. Such information would 

help convey to the public, as well as to sponsors, the criteria FDA uses in making its decisions. 

Over time, this could lead to improved drug applications. 

The FDA could provide the same public explanation on a timely basis when it decides not to 

approve an application. We recognize that this will likely require regulatory changes. The 

rationale for FDA’s decision could be conveyed in ways that protect proprietary 

considerations. Disclosing such information would help convey to the general public the 

independent role that FDA plays in the review process, and that FDA does not approve all 

drugs. 

5. Conduct or support research that takes greater advantage of its vast clinical 

trial databases to identify ways to improve drug development. 

We found that FDA has little time to take advantage of its unique perspective on the drug 

development process. Accordingly, we recommend that FDA conduct or support research 

that takes greater advantage of its vast clinical trial databases to identify ways to improve drug 

development. We recognize that such research will use scarce resources, but, over time, the 

results could be highly cost-effective, contributing to better clinical designs and more efficient 

drug development. 

AGENCY COMMENTS 

The FDA reviewed a draft of this report, and overall, it concurred with our conclusions and 

recommendations. In its comments, FDA outlined numerous activities it has underway or 

planned to address our recommendations. Specifically, FDA indicated that it is reviewing its 

workload distribution and has studies underway to examine delays in the review process. The 

full text of FDA’s comments can be found in Appendix A. 

FDA’s New Drug Application Review Process 24 OEI-01-01-00590 
APPENDIX A 

Agency Comments

FDA’s New Drug Application Review Process 25 OEI-01-01-00590 
APPENDIX A 

FDA’s New Drug Application Review Process 26 OEI-01-01-00590 
APPENDIX A 

FDA’s New Drug Application Review Process 27 OEI-01-01-00590 
APPENDIX A 

FDA’s New Drug Application Review Process 28 OEI-01-01-00590 
APPENDIX B 

Glossary

Approvable: An action assigned to the new drug application (NDA) at the end of the review process when problems 

exist with the application that need to be addressed before the drug product may be approved. 

Class I resubmission: An application resubmitted after an approvable or non-approvable letter has stated 

deficiencies in the following areas: final printed labeling, draft labeling, safety updates, stability updates, phase IV 

commitments, assay validation data, final release testing on the last 1-2 manufacturing lots (used to support 

approval), minor reanalysis of data previously submitted to the application, and/or other minor clarifying information. 

Class II resubmission: An application resubmitted after an approvable or non-approvable letter has stated other 

deficiencies not under a Class I resubmission including items that require an advisory committee meeting. 

Clinical hold: A decision made by the Food and Drug Administration (FDA) to stop a clinical trial if there is reason 

to believe the study cannot be conducted without unreasonable risk to the human subjects enrolled in the trial. The 

sponsor must address FDA’s concerns before the hold is lifted. 

Clinical trials or clinical studies: A scientific study with human subjects to examine a drug’s safety and efficacy. 

Drug development process: The entire process of bringing a drug to market. The process includes laboratory and 

animal testing of the drug, the investigational NDA to FDA, the clinical trials, and finally the submission of the NDA 

to FDA for marketing approval. 

Efficacy supplement: Additional efficacy data submitted by a sponsor to FDA for an already approved drug. FDA 

requires an efficacy supplement when a sponsor seeks approval for a new indication. 

Indications: Symptoms or conditions that indicate a specific medical treatment. When FDA approves a drug it is 

approved for a specific indication(s) that is described on the drug’s label. 

Investigational NDA: An application submitted by a sponsor to FDA technically seeking exemption from the federal 

law that prohibits the shipping of an unapproved drug across state lines. The intent of the application is to provide 

data to FDA documenting that it is reasonable to begin clinical trials in humans with the drug. If FDA determines that 

the data are insufficient to proceed, it can place the trials on hold. 

Manufacturing supplement: Information submitted by the sponsor to FDA on manufacturing changes to an already 

approved drug. 

New Drug Application (NDA): An application submitted by a sponsor to FDA to obtain approval to market a drug in 

the United States. 

New molecular entity: A drug that contains an active ingredient that has never been approved for marketing in the 

United States. It can be submitted as either a standard NDA or a priority NDA. 

Non-approvable: An action assigned to the NDA when, at the end of the review process, significant deficiencies exist 

in the application that may require additional research on the drug product or reformulation of the drug product before 

the application can be approved. 

FDA’s New Drug Application Review Process 29 OEI-01-01-00590 
APPENDIX B 

Primary reviewer: An FDA employee who conducts the bulk of the review by evaluating the data in the NDA and 

recommends the action FDA should take on a drug. Primary reviewers include clinicians, pharmacists, 

pharmacologists, statisticians, microbiologists, and chemists. 

Priority NDA: Priority applications are for drugs that are a significant improvement over drugs already on the market 

to treat the same condition. 

Project manager: An FDA employee who manages the NDA by tracking the application’s status and scheduling 

FDA internal meetings as well as meetings with sponsors. The project manager is a liaison between FDA and the 

sponsor. 

Postmarketing surveillance: FDA’s efforts to monitor the safety of a drug after it is on the market, which includes 

monitoring adverse event reports. 

Review clock: The review clock is the time between FDA’s receipt of the application and FDA’s decision. The 

PDUFA III calls for FDA to review and act upon 90 percent of standard NDAs within 10 months and 90 percent of 

priority applications within 6 months. 

Review cycle: The first review cycle is from FDA’s receipt of the initial application to FDA’s decision. Multiple 

review cycles occur when an application receives an approvable or non-approvable decision from FDA, and then the 

sponsor revises the application and resubmits it to FDA. When the sponsor resubmits the application, the review 

clock restarts and FDA receives either 2 or 6 months to review the revised application, depending on the information 

in the resubmission. 

Secondary reviewer: An FDA employee who reviews the primary reviewer’s work. Secondary reviewers include 

clinicians, pharmacists, pharmacologists, statisticians, microbiologists, and chemists. 

Sponsor: A person or entity that is responsible for a drug’s development. It can be an individual, government 

agency, or a pharmaceutical company. 

Standard NDA: Standard applications are for all applications not classified as priority. 

Total approval time: Total approval time is the time from the date of FDA’s receipt of the original application to the 

date of the application’s approval. This time can include multiple review cycles and the time spent by the sponsor 

revising the application between review cycles. 

FDA’s New Drug Application Review Process 30 OEI-01-01-00590 
APPENDIX C 

Time Goals for FDA’s Center for Drug Evaluation and Research 

Table 1. 

(M=met, F=failed to meet, N=data not yet available, and NA=not applicable) 

Action FY 2000 FY 2001 FY 2002 

1. Review and act on priority applications. 90% in 6 months (M) 90% in 6 months 

(M) 

90% in 6 months (N) 

2. Review and act on standard applications. 90% in 12 months (M) 90% in 12 months (N) (NA) 

3. Review and act on standard applications. 50% in 10 months (M) 70% in 10 months (N) 90% in 10 months (N) 

4. Review and act on Class I resubmissions. 90% in 4 months (M) (NA) (NA) 

5. Review and act on Class I resubmissions. 70% in 2 months (M) 90% in 2 months (F) 90% in 2 months (N) 

6. Review and act on Class II resubmissions. 90% in 6 months (M) 90% in 6 months 

(M) 

90% in 6 months (N) 

7. Review and act on priority efficacy supplements. 90% in 6 months (M) 90% in 6 months (F) 90% in 6 months (N) 

8. Review and act on standard efficacy supplements. 90% in 12 months (M) 90% in 12 months (N) (NA) 

9. Review and act on standard efficacy supplements. 50% in 10 months (M) 70% in 10 months (N) 90% in 10 months (N) 

10. Review and act on manufacturing supplements, prior 

approval not required. 

90% in 6 months (M) 90% in 6 months 

(M) 

90% in 6 months (N) 

11. Review and act on manufacturing supplements, prior 

approval required. 

90% in 6 months (M) 90% in 6 months 

(M) 

(NA) 

12. Review and act on manufacturing supplements, prior 

approval required. 

50% in 4 months (M) 70% in 4 months 

(M) 

90% in 4 months (N) 

13. Notify requestor of meeting within 14 days. 80% on time (M) 90% on time (F) 90% on time (N) 

14. Schedule Type A meetings within goal date or within 14 

days of requested date, if longer. 

80% on time (M) 90% on time (F) 90% on time (N) 

15. Schedule Type B meetings within goal date or within 14 

days of requested date, if longer. 

80% on time (F) 90% on time (F) 90% on time (N) 

16. Schedule Type C meetings within goal date or within 

14 days of requested date, if longer. 

80% on time (M) 90% on time (M) 90% on time (N) 

17. Prepare meeting minutes within 30 days of meeting. 80% on time (M) 90% on time (F) 90% on time (N) 

18. Respond to sponsor’s appeal of decision within 30 

days of receipt of sponsor’s appeal. 

80% on time (M) 90% on time (M) 90% on time (N) 

19. Respond to sponsor’s complete response to a clinical 

hold within 30 days of receipt of request. 

90% on time (F) 90% on time (F) 90% on time (N) 

Time Goals for FDA’s Center for Drug Evaluation and Research 

Goal date is 30 days. 

Goal date is 60 days. 

Goal date is 75 days. 

20. Respond to sponsor’s request for an evaluation of 

protocol design within 45 days of protocol and evaluations. 

70% on time (M) 80% on time (M) 90% on time (N) 

Source: FDA’s Center for Drug Evaluation and Research 

FDA’s New Drug Application Review Process 31 OEI-01-01-00590 
APPENDIX D 

Highlights of PDUFA III 

In June 2002, user fees were reauthorized as part of the Public Health Security and Bioterrorism 

Preparedness Act of 2002. The part of the Act addressing user fees is referred to as PDUFA 

III. Below, we highlight the provisions within PDUFA III that have the most relevance to our 

inquiry.14 

Increased resources 

According to a press release from the U.S. Department of Health and Human Services “the law 

puts PDUFA III on sound financial basis.”15 The PDUFA III calls for an increase in user fees. 

In FY 2002, FDA, including both the Center for Biologics Evaluation and Research and the 

Center for Drug Evaluation and Research (CDER), estimates that it will collect approximately 

$160 million in user fees. The PDUFA III increases the total funds from these fees to about 

$223 million in FY 2003, and gradually increases it over the next 5 years, to about $260 million 

in FY 2007. With these funds, CDER estimates that it will hire close to 300 employees over the 

next 5 years. The funds will also be used to improve CDER’s computer infrastructure. 

Time goals 

All existing time goals for FY 2002 for reviewing key documents and other administrative tasks 

remain in place under PDUFA III (see Appendix B for the current time goals). In addition, it 

adds four new goals. 

The first two new goals are for resubmitted efficacy supplements. The FDA will review and act 

on Class I resubmitted efficacy supplements within 6 months for 90 percent of supplements in 

FY 2003 and for 30 percent of supplements within 2 months. By FY 2007, the goal increases 

to 90 percent within 2 months. The PDUFA III also calls for FDA to review and act on Class II 

resubmitted efficacy supplements within 6 months of receipt. This goal remains constant over 

the next 5 years. 

The third new goal is for notifying sponsors of issues identified during the filing review. FDA will 

notify the sponsor within 14 days after the 60-day filing review of any deficiencies it has noted 

thus far in the application. It will meet this goal date for 50 percent of applications in FY 2003, 

70 percent in 2004, and 90 percent in FY 2005, 2006, and 2007. 

FDA’s New Drug Application Review Process 32 OEI-01-01-00590 
APPENDIX D 

The fourth new goal applies to reviewable units, which we address below. 

Studies to improve the management of the process 

The PDUFA III calls for FDA to set aside $7 million from user fees to undertake initiatives to 

improve the drug review process. These studies are intended to foster improvement in many 

areas, such as professional development, consistency, efficiency, effectiveness, and improved 

communication. 

One of these studies will seek to evaluate FDA’s first-cycle review performance and the impact 

of good review management principles. This assessment will examine all first-cycle reviews and 

identify best practices that allow for more efficient reviews. Another study will be a 

comprehensive process review and analysis that examines review management. 

Pilot programs to test the concept of continuous marketing applications 

The PDUFA III calls for FDA to conduct two pilot projects to determine whether early review 

of sections of new drug applications and additional feedback with sponsors throughout the drug 

development process lead to faster review times. The FDA will hire a consultant to evaluate 

each pilot project. 

Under the first pilot project, FDA will review a complete section of an NDA separately, prior to 

the submission of the entire application, in reviewable units. Each reviewable unit will have its 

own review time of 6 months. This pilot project only applies to fast-track drugs, which are 

drugs intended to treat serious or life-threatening illnesses and demonstrate the potential to meet 

an unmet medical need. Between 1998 and 2001, FDA approved 12 fast-track drugs. 

Under the second pilot project, FDA will enter into an agreement with a sponsor to provide 

feedback and interaction throughout the drug development process. This pilot project is also 

limited to fast-track drugs and further limited to one agreement with a sponsor per review 

division. 

FDA’s New Drug Application Review Process 33 OEI-01-01-00590 
APPENDIX D 

Good review management principles 

The PDUFA III calls for FDA to develop guidance on good review management principles that 

addresses the filing review process, communication with sponsors, planning for advisory 

committee meetings, primary review completion, and labeling feedback. The FDA will also 

develop and implement a training program for new and current employees on these good review 

management principles. 

Guidance on risk management practices 

For the first time, PDUFA III allows FDA to use funds from user fees towards postmarketing 

surveillance. The FDA anticipates hiring additional postmarketing reviewers. 

The PDUFA III calls for several new initiatives related to improving risk management. One of 

these is a package sponsors may submit prior to the submission of a new drug application that 

contains the sponsors’s anticipated risk management plan and safety assessment for the drug. 

This package serves as the basis for a meeting between FDA and the sponsor to discuss the 

safety profile and the risk management plan for the drug. The FDA will accept and review risk 

management plans as part of a new drug application and will communicate, as early in the 

process as practicable, any safety issues that must be addressed in order to obtain approval. 

After the drug is approved, FDA will review the sponsor’s implementation of the risk 

management plan for 2 to 3 years, referred to as the periapproval period, and will require safety 

reports during this period. 

Finally, FDA will issue guidance to address good risk assessment, risk management, and 

pharmacovigilance practices. And, FDA will inform the public if sponsors fail to complete their 

postmarketing commitments. 

Additional efforts 

The PDUFA III calls for the simplification of action letters. The FDA will move towards two 

types of action letters, approval and complete response, instead of the three types it currently 

uses — approval, approvable, and non-approvable. It calls for each reviewer to submit an 

information request letter immediately after an initial review that lists the deficiencies. It calls for 

an extension of the goal date by 3 months, when a sponsor submits a major amendment to an 

original application, efficacy supplement, or resubmission within 3 months of the goal date. 

FDA’s New Drug Application Review Process 34 OEI-01-01-00590 
APPENDIX E 

Rate of Withdrawn Drugs 

Figure 2 shows the percentage of new molecular entities withdrawn by the calendar year of their 

approval. The PDUFA was first implemented on 10/1/92. Data for calendar year 2002 is as of 

4/30/02. 

Figure 2. 

By Calendar Year of Their Approval 

3.70% 

2.50% 

3.60% 

1.70% 

0.0% 

0.5% 

1.0% 

1.5% 

2.0% 

2.5% 

3.0% 

3.5% 

4.0% 

4.5% 

5.0% 

1983-1987 1988-1992 1993-1997 1998-2002 

Calendar Year of Approval 

Rate of Withdrawal 

Source: CDER’s Analysis 

Rate of New Molecular Entities Withdrawn During 1983-2002 

FDA’s New Drug Application Review Process 35 OEI-01-01-00590 
APPENDIX E 

Figure 3 shows the percentage of new molecular entities withdrawn by the fiscal year of their 

receipt. The PDUFA was first implemented on 10/1/92. Data for calendar year 2002 

is as of 4/30/02. 

Figure 3. 

2002 By Fiscal Year of Their Receipt 

2.30% 

3.10% 

2.70% 2.60%

0.0% 

0.5% 

1.0% 

1.5% 

2.0% 

2.5% 

3.0% 

3.5% 

4.0% 

4.5% 

5.0% 

1983-1987 1988-1992 1993-1997 1998-2002 

Fiscal Year of Receipt 

Rate of Withdrawal 

Source: CDER’s Analysis 

Rate of New Molecular Entity Withdrawn During 1983-

FDA’s New Drug Application Review Process 36 OEI-01-01-00590 
APPENDIX F 

Methodology 

Survey of CDER Reviewers 

We created a web-based survey for CDER officials using Raosoft EZSurvey® software. We 

pretested the survey with several CDER reviewers and managers. The CDER hosted the survey 

on its Intranet. We sent an e-mail notifying all employees within CDER about our survey 

indicating the individuals who should participate. We asked for all primary, secondary (e.g., 

team leader) and tertiary reviewers (e.g., division director) across all review disciplines including 

postmarketing divisions to fill out the survey. The survey was voluntary and anonymous, unless 

respondents chose to disclose their name and contact information. Respondents could also print 

out the survey to send directly to our office or request a copy be sent to them. We sent one 

reminder electronically midway through the collection period. 

We used EZSurvey® software to tabulate the results of the survey. Based on numbers obtained 

from CDER, we estimated that 846 reviewers were eligible to complete the survey. After 

removing 2 duplicates, we received a total of 401 responses to our survey, yielding an estimated 

response rate of 47 percent. (See Tables 2 - 4 for descriptive information on the CDER 

respondents.) We tabulated the results by the length of service of the respondent; the level of 

the respondent i.e., primary, secondary, or tertiary reviewer; and the scientific discipline of the 

respondent. We were unable to do a non-respondent analysis since the survey was anonymous. 

This survey had three main limitations. First, non-responses may have occurred because of 

technical problems using the web-based survey. Some respondents complained that the website 

disconnected while they were filling out the survey. Second, although our survey was 

anonymous and we did not collect the Internet Protocol (a computer’s address), which could 

indirectly identify the respondent, some respondents may have not participated out of concerns 

for their anonymity. Third, although survey access was limited to CDER employees, the 

potential exists that some individuals not in our intended population completed the survey. 

FDA’s New Drug Application Review Process 37 OEI-01-01-00590 
APPENDIX F 

Table 2. 

Review Discipline No. of CDER Respondents Percent of CDER 

Respondents 

Blank 5 1% 

Chemistry, Manufacturing, and 

Controls 

48 12% 

Clinical 107 27% 

Clinical Pharmacology, 

Biopharmaceutics, Pharmacology, 

and Toxicology 

96 24% 

Labeling Reviewer (Division of Drug 

Marketing, Advertising, and 

Communications) 

14 3% 

Microbiology (product quality and 

clinical efficacy) 

13 3% 

Pharmacovigilance 12 3% 

Regulatory Project Management 46 11% 

Statistics 38 9% 

Trade Name Reviewer (Office of 

Drug Safety) 

6 1% 

Number of CDER Respondents by Review Discipline 

Other 16 4% 

TOTAL 401 100% 

Source: OIG Survey of CDER Officials 

FDA’s New Drug Application Review Process 38 OEI-01-01-00590 
APPENDIX F 

Table 3. 

Level of Reviewer No. of CDER 

Respondents 

Percent of CDER 

Respondents 

Blank 13 3% 

Primary reviewer 265 66% 

Secondary reviewer 64 16% 

Tertiary reviewer 23 6% 

Other 36 9% 

TOTAL 401 100% 

Source: 

Number of CDER Respondents by Level of Reviewer 

OIG Survey of CDER Officials 

Table 4. 

Length of Service at CDER No. of CDER 

Respondents 

Percent of CDER 

Respondents 

Blank 34 8% 

0-4 years 143 36% 

5-9 years 134 33% 

10 or more years 90 22% 

TOTAL 401 100% 

Source: 

Number of CDER Respondents by Length of Service at CDER 

OIG Survey of CDER Officials 

FDA’s New Drug Application Review Process 39 OEI-01-01-00590 
APPENDIX F 

Internal CDER Survey 

In this report, we also present data from a survey conducted by CDER of its reviewers in 

September 2000. The CDER mailed the survey to a random sample of 188 reviewers (i.e, 

medical, statistical, pharmacology/toxicology, biopharmacology, and chemistry) in numbers 

proportional to those of their scientific disciplines across CDER. It received a 72 percent 

response rate (N=136). 

Survey of Sponsors 

We mailed a survey to all sponsors, excluding one federal agency, that had at least one NDA 

approved by CDER in the calendar years 1999, 2000, and 2001. We obtained the list of 

companies and their addresses from FDA and removed any duplicates that we were able to 

identify, for a total of 119 sponsors in our population. We addressed the survey to the chief 

executive officer and/or senior regulatory official within the sponsor’s organization. The survey 

was voluntary and anonymous, unless respondents chose to disclose their name and contact 

information. We sent a reminder to all sponsors midway through the collection period. 

Sponsors returned the survey in the enclosed self-addressed envelope or by fax. We manually 

entered the responses into Raosoft EZSurvey® software for analysis. We received 72 

responses, yielding a response rate of 60 percent. (See Table 5 for more information on the 

sponsor respondents.) We were unable to do a non-respondent analysis since the survey was 

anonymous. 

Table 5. 

Total No. of NDA’s Approved 

Between 2001-1997 

No. of Sponsor 

Responses 

Percent of Sponsor 

Responses 

Blank 2 3% 

1 NDA 21 29% 

2-5 NDAs 38 53% 

More than 5 NDAs 11 15% 

TOTAL 72 100% 

Source: 

Number of Sponsor Respondents by the Number of Approved NDAs 

OIG Survey of Sponsors 

FDA’s New Drug Application Review Process 40 OEI-01-01-00590 
APPENDIX F 

The survey had three main limitations. First, the survey was not addressed to a specific 

individual, so it may not have been delivered to the appropriate official. Second, the list of 

identified sponsors may include a parent company and its subsidiaries that could lead to multiple 

responses by the same company. Lastly, several surveys were undeliverable because of 

inaccurate contact information. 

File Review of New Molecular Entities 

We reviewed CDER’s files associated with all 15 new molecular entities approved in FY 

2001. We obtained the paper copies of key documents for each drug’s review process, 

referred to by FDA as the drug’s action package. Each drug’s action package includes the 

reviewer evaluations, correspondences between FDA and the sponsor, and meeting minutes. 

For these new molecular entities, we also reviewed the documents posted on CDER’s website. 

The CDER posts on its website for each approved drug the approval letter, the label, and the 

reviewer evaluations. 

For these same 15 new molecular entities, we also obtained the receipt dates for all amendments 

to the application submitted by the sponsor from CDER’s decision support system. We entered 

these dates into Microsoft® Excel for analysis. Our analysis included the number and type of 

amendments CDER received, and when in the review process CDER received these 

amendments. 

Observations of CDER Meetings 

We observed 17 meetings held by CDER that were associated with NDAs. Nine of these 

meetings were between CDER and sponsors, 7 of which occurred during the investigational new 

drug phase and 2 of which occurred during the NDA review process. Seven of these meetings 

were internal CDER meetings during the NDA review process. And, we observed one advisory 

committee meeting. Many of these meetings occurred during the course of a 2-day observation 

of a division director of a review division within CDER. We developed a structured meeting 

observation guide to focus our observations and notes. 

Analysis of CDER’s Data on Advisory Committees 

We obtained data from CDER on advisory committee meetings it held between the calendar 

years 1997 - 2001 related to an NDA. The FDA can hold advisory committees 

FDA’s New Drug Application Review Process 41 OEI-01-01-00590 
APPENDIX F 

to address issues unrelated to a specific NDA. We did not include those meetings in our 

analysis. Based on this data, we calculated the number of advisory committees per year and 

estimated the percentage of approved NDAs that had an advisory committee meeting. We used 

Microsoft® Excel for our analysis. 

We estimated the percentage of approved drugs with an advisory committee using a database of 

all advisory committees associated with an NDA during the calendar years 1997 - 2001. It is 

possible that a drug that was approved between 1998 and 2001 could have had an advisory 

committee prior to 1997; therefore, the advisory committee was not included in our analysis. 

This is most likely to be the case for the year 1998, resulting in the percentage of approved new 

drugs with an advisory committee being an underestimate. If this is the case, this would not 

affect our overall conclusion that the percentage of approved new drugs with an advisory 

committee has declined (see Table 6). 

Table 6. Estimated Percentage of Approved Drugs By CDER 

with an Advisory Committee Meeting 

Calendar 

Year 

Percent of All 

Approved New 

Drugs with an 

Advisory 

Committee 

Meeting 

Percent of 

Approved 

Standard Drugs 

with an Advisory 

Committee 

Meeting 

Percent of 

Approved New 

Molecular Entities 

with an Advisory 

Committee 

Meeting 

Percent of 

Approved Priority 

Drugs with an 

Advisory Committee 

Meeting 

1998 19% (17/90) 3% (2/65) 40% (12/30) 60% (15/25) 

1999 24% (20/83) 11% (6/55) 37% (13/25) 50% (14/28) 

2000 11% (11/98) 6% (5/78) 19% (5/27) 30% (6/20) 

2001 12% (8/66) 9% (5/56) 21% (5/24) 30% (3/10) 

Source: OIG Analysis of Data From CDER 

FDA’s New Drug Application Review Process 42 OEI-01-01-00590 
APPENDIX F 

Interviews with CDER Officials 

We conducted 80 interviews with officials from CDER either in person or by telephone. We 

used a structured interview guide for each interview. 

Office Directors. We interviewed 17 office directors and the directors of the sub-offices 

within each of the following offices: the Office of New Drugs, the Office of Clinical 

Pharmacology and Biopharmaceutics, the Office of New Drug Chemistry, the Office of Drug 

Safety, and the Office of Medical Policy. 

Division Directors. We interviewed 27 division directors, including all 15 division directors 

within the Office of New Drugs. The remaining 12 division directors were from the Office of 

Clinical Pharmacology and Biopharmaceutics, the Office of New Drug Chemistry, and the 

Office of Drug Safety. 

Primary and Secondary Reviewers. We interviewed 18 primary and secondary reviewers. 

These primary and secondary reviewers represented a variety of review disciplines: 4 clinicians, 

3 project managers, 7 clinical pharmacologists and biopharmaceutics, 3 statisticians, and one 

postmarketing reviewer. Fourteen of these reviewers came from a random sample of 24 

primary and secondary reviewers who identified themselves on our survey as willing to be 

interviewed. The remaining 10 of the 24 individuals either declined, were unavailable, or could 

not be contacted for an interview. We identified the remaining 4 primary and secondary 

reviewers for interviews through the course of our inquiry. 

Other FDA officials. We conducted 20 interviews with other CDER officials, including the 

director and deputy director of CDER, and individuals from the Review Standards Staff, the 

Office of Management, the Office of Regulatory Policy, and managers of the project managers 

within the Office of New Drugs. 

Interviews with Stakeholders 

We conducted several in-person and telephone interviews with pharmaceutical representatives 

and other key stakeholders. We used a structured interview guide for each interview. 

FDA’s New Drug Application Review Process 43 OEI-01-01-00590 
APPENDIX F 

Interviews with pharmaceutical representatives. We interviewed 9 sponsors. Eight were 

selected because they were the first to respond to our survey and identified themselves as willing 

to be interviewed. The remaining sponsor we identified from prior inspection work. 

Interviews with other stakeholders. We conducted 17 interviews with a variety of 

stakeholders. Our stakeholders included clinical investigators, scientific and regulatory experts, 

advisory committee members, representatives from consumer and patient advocacy groups, and 

representatives from industry organizations. 

FDA’s New Drug Application Review Process 44 OEI-01-01-00590 
APPENDIX G 

Endnotes 

1. More information on PDUFA III can be found on FDA’s website at 

http://www.fda.gov/oc/pdufa/PDUFA3.html, accessed June 26, 2002. 

2. U.S. Department of Health and Human Services, “PDUFA Reauthorization Good for American 

Patients,” Press Release, June 18, 2002. 

3. M. Friedman et. al., “The Safety of Newly Approved Medicines,” Journal of the American 

Medical Association 281 (May 12, 1999) 18: 1728-1734. 

4. “User Fees Credited with 51% Drop in Average Approval Times Since 1993,” Tufts Center for 

the Study of Drug Development Impact Reports, October 2001. 

5. There is a provision in FDA’s draft guidance on advisory committees to extend the clock for a 

priority review for 2 months when the sponsor indicates that some of its material for advisory committee 

members cannot be disclosed to the public due to its proprietary nature. But according to FDA, there 

has been only one case since the draft guidance was issued where a sponsor indicated that the 

information was not to be disclosed to the public. In that case, the drug was not a priority review, and 

as such, the extension did not apply. See “Guidance for Industry: Disclosing Information Provided to 

Advisory Committees in Connection with Open Advisory Committee Meetings Related to the Testing 

or Approval of New Drugs and Convened by the Center for Drug Evaluation and Research, Beginning 

on January 1, 2000.” Draft Guidance, December 1999, Food and Drug Administration, U.S. 

Department of Health and Human Services. 

6. The FDA’s analysis of turnover does not include losses to other Centers within FDA. It only 

includes employees that left FDA entirely. The data do not include individuals in the Commission 

Corps and administrative support positions. The data include reviewers who are biologists, 

microbiologists, pharmacologists, medical officers, consumer safety staff, chemists, statisticians, and 

computer specialists. 

7. The FDA’s analysis includes losses to CDER and includes all employees within the Center. Leaving 

FDA for a position in private industry was the most common reason for leaving the agency. The next 

three most common reasons for leaving FDA were retirement, transferring to another agency within the 

Department of Health and Human Services, and transferring to another Center within FDA. 

8. The FDA’s data are specifically for end-of-phase 2 meetings for a new molecular entity submitted 

either as an NDA or a biologic license application. End-of-phase 2 meetings are held prior to the 

review of the NDA or biologic license application. 

FDA’s New Drug Application Review Process 45 OEI-01-01-00590 
APPENDIX G 

9. In some cases, FDA may also approve a patient package insert or a medication guide at the time of 

approval to be distributed to patients. Patient package inserts are voluntary, except for oral 

contraceptives, estrogens, and progestational drug products. Medication guides are required by FDA 

for drugs with serious adverse effects. 

10. See 65 Federal Register, 246, December 22, 2000, “Requirements on Content and Format of 

Labeling for Human Prescription Drugs and Biologics; Requirements for Prescription Drug Product 

Labels; Proposed Rule.” Food and Drug Administration, U.S. Department of Health and Human 

Services. 

11. “Draft Guidance for Industry: Clinical Studies Section of Labeling for Prescription Drugs and 

Biologics — Content and Format,” July 2001, Food and Drug Administration, U.S. Department of 

Health and Human Services; and “Draft Guidance for Industry: Content and Format of the Adverse 

Reactions Section of Labeling for Human Prescription Drugs and Biologics,” June 2000, Food and 

Drug Administration, U.S. Department of Health and Human Services. 

12. The FDA does require a pre-approval safety conference for all new molecular entities. The 

purpose of this internal meeting is to inform the postmarketing surveillance team of key safety issues 

related to the drug. These meetings can also be helpful in finalizing any postmarketing requirements 

FDA may request of the sponsors. “New Drug Applications: Pre-approval Safety Conference,” 

6010.1: Manual of Policies and Procedures, Center for Drug Evaluation and Research, Food and Drug 

Administration, U.S. Department of Health and Human Services. 

13. The FDA is not legally required to provide a summary document explaining the overall basis for 

approval. But, for drugs that are of particular interest, either because they are widely used or because 

of safety concerns, FDA provides summary information in terms understandable to the general public 

on its website. Currently, FDA provides this information for 17 drugs, some of which have been 

withdrawn. See “Major Drug Information Pages” on FDA’s website 

http://www.fda.gov/cder/drug/default.htm, accessed on April 29, 2002. 

14. More information on PDUFA III can be found on FDA’s website at 

http://www.fda.gov/oc/pdufa/PDUFAGoals.html, accessed June 26, 2002. 

15. U.S. Department of Health and Human Services, “PDUFA Reauthorization Good for American 

Patients,” Press Release, June 18, 2002. 

FDA’s New Drug Application Review Process 46 OEI-01-01-00590 
ACKNOWLEDGMENTS 

This report was prepared underthe directionofMark. R. Yessian, Ph.D., Regional Inspector General for

Evaluation and Inspections in Boston and Joyce M. Greenleaf, M.B.A., Assistant Regional Inspector

General. Other principal Office of Evaluation and Inspections staff who contributed include:

Aimee K. Golbitz, Project Leader Genevieve Nowolinski, Program Specialist

Steven P. Keenan, Program Analyst

Elizabeth W. Tong, Program Analyst

China D. Eng, Program Analyst

FDA’s New Drug Application Review Process 47 OEI-01-01-00590