Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
FDAs Review Process 
for New Drug Applications 
A Management Review 
JANET REHNQUIST 
INSPECTOR GENERAL 
MARCH 2003 
OEI-01-01-00590  O I G
FFICE OF  NSPECTOR  ENERAL

http://www.oig.hhs.gov/ 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as amended, 
is to protect the integrity of the Department of Health and Human Services (HHS) programs, as well as 
the health and welfare of beneficiaries served by those programs.  This statutory mission is carried out 
through a nationwide network of audits, investigations, and inspections conducted by the following 
operating components: 
Office of Audit Services 
The OIG's Office of Audit Services (OAS) provides all auditing services for HHS, either by conducting 
audits with its own audit resources or by overseeing audit work done by others.  Audits examine the 
performance of HHS programs and/or its grantees and contractors in carrying out their respective 
responsibilities and are intended to provide independent assessments of HHS programs and operations in 
order to reduce waste, abuse, and mismanagement and to promote economy and efficiency throughout the 
Department. 
Office of Evaluation and Inspections 
The OIG's Office of Evaluation and Inspections (OEI) conducts short-term management and program 
evaluations (called inspections) that focus on issues of concern to the Department, the Congress, and the 
public.  The findings and recommendations contained in the inspections reports generate rapid, accurate, 
and up-to-date information on the efficiency, vulnerability, and effectiveness of departmental programs. 
Office of Investigations 
The OIG's Office of Investigations (OI) conducts criminal, civil, and administrative investigations of 
allegations of wrongdoing in HHS programs or to HHS beneficiaries and of unjust enrichment by 
providers.  The investigative efforts of OI lead to criminal convictions, administrative sanctions, or civil 
monetary penalties.  The OI also oversees State Medicaid fraud control units which investigate and 
prosecute fraud and patient abuse in the Medicaid program. 
Office of Counsel to the Inspector General 
The Office of Counsel to the Inspector General (OCIG) provides general legal services to OIG, rendering 
advice and opinions on HHS programs and operations and providing all legal support in OIGs internal 
operations.  The OCIG imposes program exclusions and civil monetary penalties on health care providers 
and litigates those actions within the Department.  The OCIG also represents OIG in the global settlement 
of cases arising under the Civil False Claims Act, develops and monitors corporate integrity agreements, 
develops model compliance plans, renders advisory opinions on OIG sanctions to the health care 
community, and issues fraud alerts and other industry guidance.  E X E C U T I V E   S U M M A R Y  
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 FDAs 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 FDAs 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. 
i 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  FINDINGS 
FDAs 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 FDAs 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 drugs 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 
FDAs 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. 
ii 
FDAs Review Process for New Drug Applications  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 Secretarys 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. 
iii 
FDAs Review Process for New Drug Applications  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 FDAs 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. 
iv 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  Limited public disclosure of FDAs rationale for decisions. We reviewed the information 
on CDERs 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 FDAs regulations limit such 
disclosure. 
CONCLUSION 
FDAs 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 
v 
FDAs Review Process for New Drug Applications  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 FDAs 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. 
vi 
FDAs Review Process for New Drug Applications  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-to-
file and its guidance to sponsors on the content and format of applications to ensure that they 
make explicit FDAs 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 FDAs comments can be found in Appendix A. 
vii 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  T A B L E   O F   C O N T E N T S  
EXECUTIVE SUMMARY ...................................................... i

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

PRIMER ON FDAS 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:  FDAs 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

viii 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  I N T R O D U C T I O N  
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 drugs 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 publics 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 FDAs 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. 
1 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  User fees have provided additional resources for FDA. The FDAs 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 FDAs 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 
CDERs 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 CDERs analysis, between FY 1983 and FY 1992, the rate of safety-
based 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 FDAs 
own review of many of these withdrawals concluded that they were not attributable to faster 
review times.3 
2 
FDAs Review Process for New Drug Applications  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 Researchs 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 FDAs 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 CDERs receipt dates for all amendments submitted 
to the application. We analyzed CDERs 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. 
3 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  We conducted this inspection in accordance with the Quality Standards for Inspections 
issued by the Presidents Council on Integrity and Efficiency. 
4 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  P R I M E R  O N  F D A  S  N D A  R E V I E W  P R O C E S S  
This primer refers to the review of NDAs conducted by CDER. 
Review Clock. The review clock is the time between FDAs receipt of the application and FDAs decision. The PDUFA II calls 
forFDAinFY2002toreviewandactupon90 percent of standard NDAs within 10 months and 90 percent ofpriorityapplications 
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. Thesedataincludetheresultsofclinicaltrials,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. Aftertheapplicationisfiled,FDAassignstheapplicationtoa 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 reviewers work is checked by a secondary reviewer within the same discipline. 
AdvisoryCommittees. 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 
conductsitsownreviewoftheapplication,usually inapublic forum, and advises FDA on scientificissues relatedtotheapplication. 
It also votes on the action FDA should take with respect to the drug. The committees 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. Towardtheendofthereviewprocess,FDAandthesponsornegotiatethe drugs 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. TheFDAinspectsthemanufacturingfacilitiesforthedrug. 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 FDAs 
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 resubmitsittoFDA,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 FDAs receipt of the original application to the applications approval. This 
time can include multiple review cycles and the time spent by the sponsor revising the application between review cycles. 
5 
FDAs Review Process for New Drug Applications  OEI-01-01-00590  F I N D I N G S  
Our review of FDAs 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. 
FDAs 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 FDAs NDA review process is science-based and 
comprehensive. This is supported by the comments of 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 drugs 
6 
FDAs New Drug Application Review Process  OEI-01-01-00590  efficacy.  And 64 percent and 82 percent, respectively, were confident in FDAs 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 FDAs 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 FDAs 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 
7 
FDAs New Drug Application Review Process  OEI-01-01-00590  collaborative approach is to produce higher quality NDAs and more efficient reviews.  Ninety-
eight 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, FDAs aim is to ensure that minimum standards are met and 
8 
FDAs New Drug Application Review Process  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 FDAs 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 FDAs 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 
9 
FDAs New Drug Application Review Process  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 FDAs 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 Secretarys Quality 
of Work Life Survey on Organizational Climate, which indicates a positive work environment. 
The CDERs 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 
10 
FDAs New Drug Application Review Process  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. Number of Advisory Committees Held by FDA's Center for Drug Evaluation 
and Research for New Drug Applications 
Total Advisory Committees 
45 
40  Advisory Committees for Standard Drugs 
39 
40 
Advisory Committees for New Molecular Entities 
35 
35 
Advisory Comittees for Priority Drugs 
s  30 
e 29  29 
e 30 
t
t 26 
mi
m 25  23  23 
o
C 20 
y  20  17  17  17
r
o
s
vi 15 
d 11 
A
f  10  9  8  9 
o
o.  6  6  6 
N 5 
0 
1997  1998  1999  2000  2001 
Calendar Year 
Source: OIG Analysis of Data from FDAs Center for Drug Evaluation and Research 
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 
11 
FDAs New Drug Application Review Process  OEI-01-01-00590  be scheduled early enough in the process to allow time afterward for reviewers to consider the 
committees 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 FDAs 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 
FDAs 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 CDERs 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. 
12 
FDAs New Drug Application Review Process  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 sponsors 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. 
13 
FDAs New Drug Application Review Process  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, FDAs 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 FDAs 
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. 
14 
FDAs New Drug Application Review Process  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 sponsors 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 FDAs 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 FDAs 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 well-
supported NDAs.  On the other hand, it must function as an impartial reviewer of these NDAs 
on the publics 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 
15 
FDAs New Drug Application Review Process  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 FDAs 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. 
16 
FDAs New Drug Application Review Process  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 
17 
FDAs New Drug Application Review Process  OEI-01-01-00590  reviewers have evaluated the data in the NDA and are familiar with the drugs 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. Eighty-
two 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. FDAs 
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 FDAs 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 
18 
FDAs New Drug Application Review Process  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 
FDAs 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 CDERs 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 
19 
FDAs New Drug Application Review Process  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 FDAs 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 FDAs 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 FDAs 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 FDAs rationale for not approving drugs.

20 
FDAs New Drug Application Review Process  OEI-01-01-00590  C O N C L U S I O N  
Our review of FDAs 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 in-
depth, 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. 
21 
FDAs New Drug Application Review Process  OEI-01-01-00590  R E C O M M E N D A T I O N S  
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 FDAs 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. 
22 
FDAs New Drug Application Review Process  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 FDAs expectations. 
23 
FDAs New Drug Application Review Process  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 FDAs 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 FDAs comments can be found in Appendix A. 
24 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX A 
Agency Comments

25 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX A 
26 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX A 
27 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX A 
28 
FDAs New Drug Application Review Process  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 FDAs concerns before the hold is lifted. 
Clinical trials or clinical studies: A scientific study with human subjects to examine a drugs 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 drugs 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. 
29 
FDAs New Drug Application Review Process  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 applications 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: FDAs 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 FDAs receipt of the application and FDAs 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 FDAs receipt of the initial application to FDAs 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 reviewers work. Secondary reviewers include 
clinicians, pharmacists, pharmacologists, statisticians, microbiologists, and chemists. 
Sponsor: A person or entity that is responsible for a drugs 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 FDAs receipt of the original application to the 
date of the applications approval. This time can include multiple review cycles and the time spent by the sponsor 
revising the application between review cycles. 
30 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX C 
Time Goals for FDAs Center for Drug Evaluation and Research 
Table 1. Time Goals for FDAs Center for Drug Evaluation and Research 
(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  90% in 6 months  (N) 
(M) 
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  90% in 6 months  (N) 
(M) 
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  90% in 6 months  (M)  90% in 6 months  90% in 6 months  (N) 
approval not required.  (M) 
11. Review and act on manufacturing supplements, prior  90% in 6 months  (M)  90% in 6 months  (NA) 
approval required.  (M) 
12. Review and act on manufacturing supplements, prior  50% in 4 months  (M)  70% in 4 months  90% in 4 months  (N) 
approval required.  (M) 
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  80% on time  (M)  90% on time  (F)  90% on time  (N) 
days of requested date, if longer. Goal date is 30 days. 
15. Schedule Type B meetings within goal date or within 14  80% on time  (F)  90% on time  (F)  90% on time  (N) 
days of requested date, if longer. Goal date is 60 days. 
16. Schedule Type C meetings within goal date or within  80% on time  (M)  90% on time  (M)  90% on time  (N) 
14 days of requested date, if longer. Goal date is 75 days. 
17. Prepare meeting minutes within 30 days of meeting.  80% on time  (M)  90% on time  (F)  90% on time  (N) 
18. Respond to sponsors appeal of decision within 30  80% on time  (M)  90% on time  (M)  90% on time  (N) 
days of receipt of sponsors appeal. 
19. Respond to sponsors complete response to a clinical  90% on time  (F)  90% on time  (F)  90% on time  (N) 
hold within 30 days of receipt of request. 
20. Respond to sponsors request for an evaluation of  70% on time  (M)  80% on time  (M)  90% on time  (N) 
protocol design within 45 days of protocol and evaluations. 
Source: FDAs Center for Drug Evaluation and Research 
31 
FDAs New Drug Application Review Process  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 CDERs 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. 
32 
FDAs New Drug Application Review Process  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 FDAs 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. 
33 
FDAs New Drug Application Review Process  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 sponsorss 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 sponsors 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. 
34 
FDAs New Drug Application Review Process  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. Rate of New Molecular Entities Withdrawn During 1983-2002 
By Calendar Year of Their Approval 
5.0% 
4.5% 
  4.0% 
l
a 3.70% 
w 3.5%  3.60% 
a
dr 3.0% 
h
it 2.5%  2.50% 
W
f  2.0% 
o
  1.70% 
e 1.5% 
t
a
R 1.0% 
0.5% 
0.0% 
1983-1987  1988-1992  1993-1997  1998-2002 
Calendar Year of Approval 
Source: CDERs Analysis 
35 
FDAs New Drug Application Review Process  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.  Rate of New Molecular Entity Withdrawn During 1983-
2002 By Fiscal Year of Their Receipt 
5.0% 
4.5% 
l  4.0% 
a
w 3.10% 
a 3.5% 
dr 2.70%  2.60%
3.0% 
h
t
Wi 2.5% 
2.30% 
 
of 2.0% 
 
e
t 1.5% 
a
R
1.0% 
0.5% 
0.0% 
1983-1987  1988-1992  1993-1997  1998-2002 
Fiscal Year of Receipt 
Source: CDERs Analysis 
36 
FDAs New Drug Application Review Process  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 computers 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. 
37 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX F 
Table 2. Number of CDER Respondents by Review Discipline 
Percent of CDER 
Review Discipline  No. of CDER Respondents 
Respondents 
Blank  5  1% 
Chemistry, Manufacturing, and  48  12% 
Controls 
Clinical  107  27% 
Clinical Pharmacology,  96  24% 
Biopharmaceutics, Pharmacology, 
and Toxicology 
Labeling Reviewer (Division of Drug  14  3% 
Marketing, Advertising, and 
Communications) 
Microbiology (product quality and  13  3% 
clinical efficacy) 
Pharmacovigilance  12  3% 
Regulatory Project Management  46  11% 
Statistics  38  9% 
Trade Name Reviewer (Office of  6  1% 
Drug Safety) 
Other  16  4% 
TOTAL  401  100% 
Source: OIG Survey of CDER Officials 
38 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX F 
Table 3. Number of CDER Respondents by Level of Reviewer 
No. of CDER  Percent of CDER 
Level of Reviewer 
Respondents  Respondents 
Blank  13  3% 
Primary reviewer  265  66% 
Secondary reviewer  64  16% 
Tertiary reviewer  23  6% 
Other  36  9% 
TOTAL  401  100% 
Source: OIG Survey of CDER Officials 
Table 4. Number of CDER Respondents by Length of Service at CDER 
Length of Service at CDER  No. of CDER  Percent of CDER 
Respondents  Respondents 
Blank  34  8% 
0-4 years  143  36% 
5-9 years  134  33% 
10 or more years  90  22% 
TOTAL  401  100% 
Source: OIG Survey of CDER Officials 
39 
FDAs New Drug Application Review Process  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 sponsors 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. Number of Sponsor Respondents by the Number of Approved NDAs 
Total No. of NDAs Approved  No. of Sponsor  Percent of Sponsor 
Between 2001-1997  Responses  Responses 
Blank  2  3% 
1 NDA  21  29% 
2-5 NDAs  38  53% 
More than 5 NDAs  11  15% 
TOTAL  72  100% 
Source: OIG Survey of Sponsors 
40 
FDAs New Drug Application Review Process  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 CDERs files associated with all 15 new molecular entities approved in  FY 
2001. We obtained the paper copies of key documents for each drugs review process, 
referred to by FDA as the drugs action package.  Each drugs 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 CDERs 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 CDERs 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 CDERs 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 
41 
FDAs New Drug Application Review Process  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  Percent of All  Percent of  Percent of  Percent of 
Year  Approved New  Approved  Approved New  Approved Priority 
Drugs with an  Standard Drugs  Molecular Entities  Drugs with an 
Advisory  with an Advisory  with an Advisory  Advisory Committee 
Committee  Committee  Committee  Meeting 
Meeting  Meeting  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 
42 
FDAs New Drug Application Review Process  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. 
43 
FDAs New Drug Application Review Process  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. 
44 
FDAs New Drug Application Review Process  OEI-01-01-00590  APPENDIX G 
Endnotes 
1. More information on PDUFA III can be found on FDAs 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 FDAs 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 FDAs 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 FDAs 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 FDAs 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. 
45 
FDAs New Drug Application Review Process  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 FDAs website 
http://www.fda.gov/cder/drug/default.htm, accessed on April 29, 2002. 
14. More information on PDUFA III can be found on FDAs 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. 
46 
FDAs New Drug Application Review Process  OEI-01-01-00590  A C K N O W L E D G M E N T S  
This reportwaspreparedunderthe 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

47 
FDAs New Drug Application Review Process  OEI-01-01-00590