United States General Accounting Office

GAO Report to Congressional Requesters

October 1995 FDA DRUG

APPROVAL

Review Time Has

Decreased in Recent

Years

GAO/PEMD-96-1

GAO United States

General Accounting Office

Washington, D.C. 20548

Program Evaluation and

Methodology Division

B-266023 

October 20, 1995

The Honorable Nancy Landon Kassebaum

Chairman

The Honorable Edward M. Kennedy

Ranking Minority Member

Committee on Labor and Human Resources

United States Senate

New drugs marketed in the United States must be approved first by the

Food and Drug Administration (FDA).1

 Approval comes after FDA has

determined from data submitted by a drug’s sponsor that the drug is safe

and effective for use as indicated on its label and that the manufacturer

can ensure its quality. Various parties calling for the legislative reform of

FDA in recent months are concerned with the length of the approval

process. Advocates of reform argue that shortening the time it takes to get

new drugs approved will contribute both to public health, by making

effective therapies available sooner to people who need them, and to the

economic health of the pharmaceutical industry, by allowing drug

manufacturers to sell their products sooner. Opposed to major reform, FDA

claims that in recent years review time has been reduced considerably.

Purpose Time—specifically the period that begins with the submission to FDA of a

new drug application (NDA) and that ends when a final decision is made on

that application (the period known as the NDA review phase of drug

development)—is the focus of this report. At your request, we have

assembled data on all new drug applications submitted to FDA in 1987-94 to

answer three questions:

• Has the timeliness of the review and approval process for new drugs

changed in recent years?

• What factors distinguish NDAs that are approved relatively quickly from

those that take longer to be approved?

• What distinguishes NDAs that are approved from those that are not?

Additionally, as you asked, we obtained the most recently available data

on how long it takes for drugs to be approved in the United Kingdom and

compared them with approval times in the United States.

1

See 21 U.S.C. 355 (1988).

Page 1 GAO/PEMD-96-1 FDA Review Time for Drugs
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Because GAO has access to all applications, both those that have been

approved and those that have not, our report is the first to present

comprehensive data on review time for all NDAs submitted to FDA.

2

Background The process of bringing a drug to market is lengthy and complex and

begins with laboratory investigations of the drug’s potential. For drugs that

seem to hold promise, preclinical animal studies are typically conducted to

see how a drug affects living systems. If the animal studies are successful,

the sponsoring pharmaceutical firm designs and initiates clinical studies in

which the drug is given to humans. At this point, FDA becomes directly

involved for the first time.

Before any new drug can be tested on humans, the drug’s sponsor must

submit an investigational new drug application to FDA that summarizes the

preclinical work, lays out a plan for how the drug will be tested on

humans, and provides assurances that appropriate measures will be taken

to protect them. Unless FDA decides that the proposed study is unsafe,

clinical testing may begin 31 days after this application is submitted to FDA.

While clinical trials progress through several phases aimed at establishing

safety and efficacy, the manufacturer develops the processes necessary to

produce large quantities of the drug that meet the quality standards for

commercial marketing.

When all this has been done, the pharmaceutical firm submits an NDA that

includes the information FDA needs to determine whether the drug is safe

and effective for its intended use and whether the manufacturing process

can ensure its quality. The first decision FDA must make is whether to

accept the NDA or to refuse to file it because it does not meet minimum

requirements. Once FDA has accepted an NDA, it decides whether to

approve the drug on the basis of the information in the application and any

supplemental information FDA has requested. FDA can approve the drug for

marketing (in an “approval letter”) or it may indicate (in an “approvable

letter”) that it can approve the drug if the sponsor resolves certain issues.

Alternatively, FDA may withhold approval (through a “nonapprovable

letter” that specifies the reasons). Throughout the process, the sponsor

remains an active participant by responding to FDA’s inquiries and

concerns. The sponsor has the option, moreover, of withdrawing the

application at any time.

2

Much of the information in an NDA (and even its existence) remains proprietary until FDA approves

it. This means that information on NDAs that are not approved has not been publicly available, so that

previous studies of review and approval times have been unable to include it.

Page 2 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

Method For each NDA submitted between 1987 and 1994, we obtained from FDA

information on the dates of its significant events between initial

submission and final decision as well as the last reported status of the

application as of May 1995. To ensure that the data were valid, we

independently checked them against values in published reports and other

sources. (The variables that we used in our analysis and the procedures

that we used to validate the data can be found in appendix I.)

We computed time by measuring the interval between all significant

events. Results using other ways to calculate review time are compared to

ours in appendix II. We used regression analysis to determine the factors

that were significantly related to time and to determine which factors were

significantly related to approval. (The results of the regression analyses on

time are in appendix IV, on approval in appendix V.3

)

Some of our analyses include all the NDAs, while others focus on specific

subgroups. Most notably, we restricted analyses of overall time to NDAs

that had been submitted by the end of 1992 to avoid the bias introduced by

including applications that have had an insufficient time to “mature.”

(Appendix VI describes the implications of this decision for our results.)

Because our analyses of final decisions concentrate on NDAs submitted

through the end of 1992, the data we present do not address the

consequences of the full implementation of the Prescription Drug User Fee

Act of 1992.4

 Our findings pertain only to FDA’s Center for Drug Evaluation

and Research and do not reflect the activities of the agency’s five other

centers.5

We focused only on the NDA review phase—the final critical step of

bringing a drug to market. We did not address the lengthier process of

initial exploration and clinical testing, which together with the NDA phase

average more than a decade, nor did we study the phase that follows a

drug’s approval, during which additional studies can be conducted and

3

In appendix III, we discuss intermediate outcomes from FDA’s review process.

4

The Congress passed the act (Public Law 102-571) in October 1992 to provide FDA with additional

resources to expedite drug review and approval. Because it takes time to hire and train reviewers and

for fees to accrue, the effects of full implementation may not be evident for several years. The act is

due for reauthorization after 1997, by which time FDA has agreed to meet the act’s goals for improved

performance.

5

The other centers are the Center for Biologics Evaluation and Research, the Center for Devices and

Radiological Health, the Center for Food Safety and Applied Nutrition, the Center for Veterinary

Medicine, and the National Center for Toxicological Research. Even within the Center for Drug

Evaluation and Research, our findings pertain only to the review and approval process for NDAs and

not to other functions such as the investigational new drug phase or the regulation of generic drugs.

Page 3 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

attention paid to potential adverse events associated with its widespread

use in the general population.

Results in Brief We found a considerable reduction in approval time for NDAs submitted

between 1987 and 1992. It took an average of 33 months for NDAs

submitted in 1987 to be approved but only 19 months on average to

approve NDAs submitted in 1992. Further, the reduction in time was

observed for all NDAs and not just for those that had been approved. As

figure 1 shows, the overall decrease in approval times was achieved

through gradual reductions in time for applications submitted in each

successive year.

Figure 1: Months Between Submission

and Approval for NDAs Submitted

1987-92a

Months

0

6

12

18

24

30

36

1987 1988 1989 1990 1991 1992

Year of submission

aNumber of approved NDAs: 1987, 80; 1988, 75; 1989, 65; 1990, 53; 1991, 64; 1992, 53.

The priority FDA assigns to an NDA and the experience of its sponsor are the

two factors that significantly affect the likelihood that the NDA will be

decided on quickly. FDA assigns priority status to applications for drugs

that are expected to provide therapeutic benefit to consumers beyond that

of drugs already marketed. These NDAs take an average of 10 months less

to be approved than do standard applications (those for which there is no

Page 4 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

perceived therapeutic benefit beyond that for available drugs).

Applications from the most experienced sponsors take an average of 4

months less time to be approved than those from less experienced

sponsors.

Priority status and sponsor experience are also the two factors that

predict the likelihood that an NDA will be approved. Priority NDAs are four

times more likely to be approved than standard NDAs. Applications

submitted by the most experienced sponsors are three times more likely to

be approved than those submitted by the least experienced companies.

Finally, the limited comparable data available on review time for FDA and

the counterpart agency in the United Kingdom paint a more ambiguous

picture than that presented in many recent reports. In fact, the latest data

published by the regulatory agency in the United Kingdom show that it

does not have faster approval times than FDA.

Our Analysis FDA received 905 NDAs in 1987-94. The total number of NDAs fell from 1987

but remained relatively stable in the ensuing years through 1994 (with the

exception of the uncharacteristically small number of submissions in

1993). The number of NDAs for new molecular entities (NMEs) and priority

NDAs remained relatively stable over the years.5 Overall, 17 percent of the

NDAs were for priority drugs. (See table 1.)

Table 1: Number of NDAs Submitted 1987-94a

Type 1987 1988 1989 1990 1991 1992 1993 1994 Total

All NDAs 142 129 117 99 110 103 87 118 905

Priority NDAs 18 20 16 21 21 23 14 19 152

NMEs 29 33 32 29 37 34 34 37 265

aThirty-six percent of the NMEs are classified as priority applications, 9 percent of non-NMEs.

A large percentage of the applications were not approved. Only 390 of the

700 NDAs submitted through 1992 had been approved by May 16, 1995. In

other words, 44 percent of the applications submitted were for drugs that

FDA did not find to be safe and effective or that sponsors chose not to

pursue further. NMEs were approved at a higher rate than non-NMEs

(64 percent to 52 percent), and priority drugs were approved more often

5

Data on NDAs are often presented separately for NMEs (which are drugs with active components that

are new) and for priority drugs because these NDAs may require a different type of review than other

NDAs. The types of NDAs that are classified as non-NMEs are listed in appendix I.

Page 5 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

than standard drugs (76 percent to 52 percent). This means that whether

an NDA is or is not ultimately approved is as relevant a question as how

long approval takes.6

 (See table 2.)

Table 2: Final Status of NDAs Submitted 1987-92a

Type Approved Withdrawn Refused Approvable Not approvable

NDA

NMEs 64% 18% 2% 3% 12%

Non-NMEs 52 22 8 3 15

Priority 76 14 0 0 10

Standard 52 22 7 3 15

Sponsor

Most experienced group 63 22 3 3 9

Least inexperienced group 41 17 15 2 25

All 56 21 6 3 14

aFinal status as of May 16, 1995. All rows sum to 100 percent except for rounding.

The data in table 2 show that NDAs that are submitted by experienced

sponsors and priority NDAs are more likely to be approved than standard

NDAs or NDAs submitted by sponsors with little experience with the

process. These results are supported by a regression analysis that shows

that both the NDA’s priority and the sponsor’s experience are statistically

significant predictors of outcome (see appendix I for our definition of

sponsor experience and appendix V for the regression analysis). The

regression analysis found that, statistically controlling for the effects of

the other explanatory variables in the model, priority NDAs are four times

more likely to be approved than standard NDAs and that applications

submitted by the most experienced companies are three times more likely

to be approved than those submitted by less experienced sponsors.

How Long Does the

Review Process Take?

Table 3 shows for 1987-92 the average time (in months) from when NDAs

were first submitted to when final decisions were made for both NDAs that

6

Some other studies of the drug review process have reported higher rates of approval. These studies

either have looked at subsets of the population of NDAs that have higher approval rates (such as

NMEs) or have not included in their calculations applications that FDA refused to file. In contrast, our

report of a 56-percent approval rate includes all types of NDAs and all applications listed in FDA’s

records, even those that FDA refused to file.

Page 6 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

were approved and those that were not.7 The table also distinguishes

between all NDAs and those that were approved in three categories: new

molecular entities, priority applications, and standard applications.

Table 3: Average Number of Months

From Initial NDA Submission to Final

Decision for NDAs Submitted 1987-92

Year of initial submission

Type 1987 1988 1989 1990 1991 1992

All NDAs 33 31 24 23 21 18

Approved NDAs 33 30 25 25 21 19

All NMEs 31 32 21 21 25 20

Approved NMEs 33 26 23 23 23 21

All priority 29 29 16 23 17 17

Approved priority 23 23 16 22 18 16

All standard 34 32 26 23 21 18

Approved standard 35 32 28 27 22 20

As can be seen from the table, the processing time for all eight categories

of NDAs fell considerably (from 33 to 18 months, or 45 percent, for all NDAs,

or from 33 to 19 months, or 42 percent for approved NDAs). In addition, the

reductions in time came for NDAs submitted throughout the period of our

study. This finding is consistent with FDA’s statements that review time has

decreased in recent years.

Alternative presentations of the data demonstrate the same result. For

example, table 4 shows that the number of months that passed before half

of all submissions were approved declined from 58 months for NDAs

submitted in 1987 to 33 months for 1992 submissions. Since just 56 percent

of the NDAs submitted between 1987 and 1992 were approved, this measure

captures the approval period for almost all the approvals that will

ultimately be granted.8

 Similarly, table 4 shows that the proportion of

submitted NDAs that were approved within 2 years increased from

23 percent for NDAs submitted in 1987 to 39 percent for NDAs submitted in

1992.

7

The only FDA decision that is truly “final” is the decision to approve the NDA. All other decisions

allow the sponsor to continue to pursue an approval decision. For example, even if FDA sends a

not-approvable letter, the sponsor can address the concerns listed in that letter and resubmit the NDA.

Therefore, whenever we use the term “final decision” in this report, it means the status of the

application as of May 16, 1995.

8

Fifty-eight percent of the NDAs submitted in 1988 and 1991 were approved, the years with the greatest

proportion of approvals (see appendix VI).

Page 7 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

Table 4: Two Alternative Measures of

Review Time for NDAs Submitted

1987-92

Year of submission

Months until half of all

NDAs were approved

Percent of NDAs

approved within 24

months

1987 58 23%

1988 52 27

1989 41 31

1990 47 29

1991 30 36

1992 33 39

Closer examination of the individual NDAs shows that they differed

considerably in how long it took before a final decision was made. Some

NDAs were approved within a few months (the shortest was 2 months);

others took years (the slowest was 96 months). The variation was similar

among applications that were not approved. Some were withdrawn on the

day they were submitted. The longest outstanding application was 92

months old.

This considerable variation raises the question of what differentiates one

NDA from the next: Do some factors predict the time it will take to reach a

final decision? When we tested potential explanatory variables, we found

that the priority FDA assigned to an application and the sponsor’s

experience in submitting NDAs were statistically significant predictors of

how long review and approval took. (See appendix IV.) More specifically,

controlling for the effects of the other explanatory variables in the model,

our regression analysis found that priority NDA applications are approved

10 months faster than standard applications and that applications from the

most experienced sponsors are approved 4 months faster than

applications from less experienced sponsors.

Process Measures of Time The interval between first submission and final decision indicates how

long the public must wait for drugs after sponsors believe they have

assembled all the evidence to support an approval decision. Alternative

measures provide insight into what happens to an NDA before FDA approves

it. One such measure is the extent to which FDA is “on time” in making

decisions. We examined both the degree to which FDA was on time and the

factors that influenced whether it made its decisions on time. The criteria

for “on time” performance that we used in this analysis were established

Page 8 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

under the Prescription Drug User Fee Act of 1992.9 Although on-time

performance may be seen as one indicator of FDA’s efficiency, it is

important to note that FDA is not required to meet these criteria until 1997.10

Of all the decisions FDA made on the NDAs submitted between 1987 and

1993, 67 percent were on time. Simpler decisions (for example, refusals to

file) were made on time more often than relatively complex decisions (for

example, priority applications in which the first decision was an approval).

Overall, the on-time percentage remained relatively stable, varying

between a low of 62 percent for NDAs submitted in 1992 and a high of

72 percent for NDAs submitted in 1987.11 In sharp contrast to the decline in

overall time between submission and final decision shown in table 3, this

stability shows that there is little relationship between the time FDA takes

to reach a final decision and whether or not it meets its deadlines for

specific actions.12

Another process measure of review time is based on where responsibility

lies for different parts of the process—with FDA for the intervals during

which it acts on an application, or with the sponsor, for the intervals

during which FDA waits for the sponsor to provide additional information

or to resubmit the application. Figure 2 shows how their relative times

were distributed for approved NDAs submitted between 1987 and 1992.

9

Upon receipt of an NDA, FDA has 60 days to determine whether the application will be filed or

refused. If the application is filed, under the performance goals referenced in the Prescription Drug

User Fee Act, FDA is to perform a complete review of the entire application and issue an approval

letter, approvable letter, or not-approvable letter within 6 months for priority applications and within

12 months for standard applications. In accordance with the act, FDA intends to fully implement these

goals by the end of fiscal year 1997.

10Our calculations of FDA’s on-time performance were conservative, tending to underestimate, rather

than overestimate, the proportion of FDA’s actions that have been on time (see appendix II).

11See appendix II. We excluded the rates for the 1994 cohort from this analysis.

12In commenting on a draft of this report, FDA maintained that our on-time analysis underestimates the

extent to which its performance has improved. See appendix II for FDA’s comments and our response.

Page 9 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

Figure 2: FDA and Sponsor Times for

Approved NDAs Submitted 1987-92 Months

0

6

12

18

24

30

36

1987 1988 1989 1990 1991 1992

Year of submission

Total time

FDA time

Sponsor time

As can be seen from the figure, sponsors accounted for approximately

20 percent of the time in the NDA phase for applications that FDA

approved.13 Importantly, the time for both sponsors and FDA diminished for

NDAs submitted between 1987 and 1992.

Approval Times in the

United Kingdom

Regulatory processes similar to FDA’s have been mentioned as models for

reforming FDA. The one most often mentioned is the United Kingdom’s.

Proponents of FDA reform have argued that the British counterpart to the

FDA, the Medicines Control Agency, performs reviews of equivalent quality

and does so significantly more quickly.

Comparisons between the Medicines Control Agency and FDA are difficult

because the workload, approval criteria, and review procedures followed

by the agency may not be exactly the same as FDA’s and because its reports

cover a slightly different period than FDA’s. However, the most recent data

13Our calculations of sponsor time were conservative, tending to underestimate, rather than

overestimate, the proportion of review time accounted for by the sponsors of NDAs (see appendix I).

Page 10 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

show that overall approval times are actually somewhat longer in the

United Kingdom than they are in this country. For the 12-month period

ending September 30, 1994, the Medicines Control Agency reported that

the median approval time for applications that were apparently equivalent

to NMEs was 30 months. The average time was 24 months. The fastest

approval was granted in about 4 months, the slowest in 62 months.

According to FDA, the median approval time for NMEs approved in the

United States in calendar year 1994 was 18 months, the average about 20

months. The fastest FDA approval took about 6 months and the slowest

about 40 months. (See appendix VII for a fuller comparison.)

Conclusion and

Implications

Aside from shedding light on the central issue of time, the data we

assembled provide some interesting but rarely mentioned facts about FDA’s

drug review and approval process. First, nearly half the NDAs submitted to

FDA are not approved for marketing. The 44 percent of NDAs that were not

approved in our sample either were not judged by FDA to be safe and

effective or were not pursued by their sponsors. Second, the percentage of

NDAs for drugs that are viewed by FDA as offering an important therapeutic

advance is relatively small. As we pointed out in table 1, only 17 percent of

all NDAs were given priority status. Third, our data on drug review and

approval show that approximately one fifth of the time in that process

comprises activities for which sponsors are responsible.

With respect to time, NDAs are moving more quickly through the drug

review and approval process. Whether this improvement is because of

actions by FDA or the pharmaceutical industry or some other factors is an

issue that is beyond the scope of this report. However, the consistency of

all our results supports the conclusion that the reduction in time is real

and not an artifact of how time is measured. Further, the magnitude of the

reduction—more than 40 percent—should be considered in the ongoing

discussions of the need to change the NDA review process or the agency in

order to speed the availability of drugs to patients.

Agency Comments FDA officials reviewed a draft of this report and discussed their comments

with us. They generally agreed with our analytic methods and findings.

However, they expressed concerns about some aspects of our analysis of

FDA’s on-time performance. These comments, and our responses to them,

appear in appendix II. FDA also provided a number of specific technical

comments that have been incorporated into the report where appropriate.

Page 11 GAO/PEMD-96-1 FDA Review Time for Drugs
B-266023 

As we agreed with your offices, we plan no further distribution of this

report until 30 days from its date of issue, unless you publicly announce its

contents earlier. We will then send copies to the Secretary of Health and

Human Services, the Commissioner of Food and Drugs, and to others who

are interested. We will also make copies available to others upon request.

If you have any questions regarding our report, please call me at

(202) 512-2900 or George Silberman, Assistant Director, at (202) 512-5885.

Joseph F. Delfico

Acting Assistant Comptroller General

Page 12 GAO/PEMD-96-1 FDA Review Time for Drugs
Page 13 GAO/PEMD-96-1 FDA Review Time for Drugs
Contents

Letter 1

Appendix I 

Data and

Methodology

18

The Data We Examined 18

The Variables We Analyzed 19

Methodology 21

Appendix II 

Alternative Measures

of Time

23

Starting Points for Calculations of Time 23

On-Time Performance 23

Agency Comments and Our Response 24

Alternative Measures of Total Review Time 25

Appendix III 

Intermediate

Outcomes From FDA’s

Review Process

28

First Actions 28

Cycles 29

Amendments 30

Appendix IV 

Regression Analyses

for Review Time

32

Appendix V 

Regression Analysis

for Approval

35

Appendix VI 

Censoring Bias

38

Appendix VII 

Approval Times in the

United Kingdom

40

Page 14 GAO/PEMD-96-1 FDA Review Time for Drugs
Contents

Appendix VIII 

Major Contributors to

This Report

42

Related GAO Products 44

Tables Table 1: Number of NDAs Submitted 1987-94 5

Table 2: Final Status of NDAs Submitted 1987-92 6

Table 3: Average Number of Months From Initial NDA

Submission to Final Decision for NDAs submitted 1987-92

7

Table 4: Two Alternative Measures of Review Time for NDAs

Submitted 1987-92

8

Table II.1: Actions Taken on Time by FDA for NDAs Submitted

1987-94

24

Table II.2: Average and Median Months to Approval for NDAs

Submitted 1987-92

25

Table II.3: Average NDA Approval Times in Months, 1987-94 26

Table II.4: Percent of NDAs Approved 1987-94 With Approval

Times Greater Than 4 Years

27

Table III.1: First Actions on NDAs Submitted 1987-94 28

Table III.2: Review Cycles for NDAs Submitted 1987-92 29

Table III.3: Major Amendments for NDAs Submitted 1987-92 30

Table IV.1: For Approved New Drug Applications, Regression

Analysis Predicting Number of Months From First Submission to

Approvala

33

Table IV.2: For New Drug Applications Not Approved, Regression

Analysis Predicting Number of Months From First Submission to

Date of Final Action

34

Table V.1: Logistic Regression Analysis Predicting NDA Approval 36

Table VI.1: Final Status for NDAs Submitted by Year of

Submission 1987-94

38

Table VI.2: Percent of NDAs Approved Quickly, 1987-92 and

1993-94

39

Figures Figure 1: Months Between Submission and Approval for NDAs

Submitted 1987-92

4

Figure 2: FDA and Sponsor Times for Approved NDAs Submitted

1987-92

10

Page 15 GAO/PEMD-96-1 FDA Review Time for Drugs
Contents

Abbreviations

CSM Committee on the Safety of Medicines

FDA Food and Drug Administration

GAO U.S. General Accounting Office

MCA Medicines Control Agency

NDA New drug application

NME New molecular entity

Page 16 GAO/PEMD-96-1 FDA Review Time for Drugs
Page 17 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix I 

Data and Methodology

The Data We

Examined

At our request, FDA provided detailed information about all new drug

applications, totaling 905, initially submitted between January 1, 1987, and

December 31, 1994. This included the contents and date of all FDA

decisions and all major communications between FDA and the NDA

sponsors through May 16, 1995. The variables we used in our analysis are

described in the next section.

Our choice of this time period has important implications for the analysis

of drug review time. First, we started with 1987 because that was the first

full year following a major change in FDA’s drug review procedures. We do

not believe that examining new drug applications from before 1987 would

shed any light on FDA’s current activities. Second, most reports of drug

approval times, including those published by FDA, measure time for drugs

approved during a particular period, regardless of when they were

submitted. Some approved drugs may have been submitted much earlier.

By limiting our analysis to new drug applications submitted (but not

necessarily approved) in 1987 and later, we have limited the maximum

value of review time. However, we do not believe that this has significantly

biased our findings, since relatively few drugs win approval after

exceptionally long review periods. (Appendix VI describes the outcomes

of the review process as a function of year of approval in our sample.)

While we were unable to independently verify the accuracy of all the data

FDA provided, we did undertake a number of validation procedures to

ensure the quality of the data. First, we performed extensive checks of the

internal consistency of the databases FDA provided. In several cases, we

uncovered discrepancies in the level of detail for different categories of

drugs and between the information contained in one data file and that

contained in another file. We resolved all these inconsistencies with FDA.

Second, we compared the information in the data files with published

sources where possible. For approved drugs, many reports (by FDA and by

others) list the names, submission dates, and approval dates. We were able

to resolve with FDA the few inconsistencies we discovered through this

method. However, it is important to note that we were unable to do this

for nonapproved drugs because there are no published reports on them.

Third, for an earlier report, we had already obtained documentation for all

NDAs for NMEs submitted in 1989.1 We compared those documents with the

1

U.S. General Accounting Office, FDA User Fees: Current Measures Not Sufficient for Evaluating

Effect on Public Health, GAO/PEMD-94-26 (Washington, D.C.: July 1994).

Page 18 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix I 

Data and Methodology

data FDA provided us for this report, and we were able to resolve all

apparent inconsistencies.

The Variables We

Analyzed

This section describes the variables we used in our analyses. Our

definitions of the variables do not necessarily agree with FDA’s practice.

FDA provided some of the variables directly to us; we computed others

from the data FDA provided and from other sources.2

Drug Characteristics Priority drugs. Those that FDA determines to represent a significant

therapeutic advance, either offering important therapeutic gains (such as

the first treatment for a condition) or reducing adverse reactions.

Nonpriority, or standard, drugs offer no therapeutic advantage over other

drugs already on the market.

New molecular entities. Drugs with molecular structures that have not

previously been approved for marketing in this country, either as a

separate drug or as part of a combination product. Drugs that are not NMEs

are from one of six categories defined by FDA: a new ester or salt, a new

dosage form or formulation of a previously approved compound, a new

combination of previously approved compounds, a new manufacturer of a

previously approved drug, a new indication for an already approved drug,

or drugs already marketed but without an approved NDA (that is, drugs first

marketed before FDA began reviewing NDAs).

Submissions to the Review

Process

Initial submission. The first submission of the application to FDA.

Resubmission. After a sponsor has withdrawn an application or FDA has

refused it for filing, sponsors can resubmit it.

Major amendments. Substantial submissions of new information by the

sponsor to FDA, either of the sponsor’s own volition or in response to an

FDA query.

Results of the Review

Process

Refusal to file. After FDA receives a new drug application, the agency first

determines if the application is sufficiently complete to allow a substantive

review. If not, FDA can refuse to file it. Since the implementation of user

2

For more information about the drug approval process, drug characteristics, and measurement of

time, see FDA User Fees, esp. pp. 4-10 and app. I.

Page 19 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix I 

Data and Methodology

fees in 1993, applications must be rejected if the sponsor has failed to pay

the appropriate fee to FDA. These applications are categorized as

“unacceptable for filing,” not refusal to file.

Approval. If FDA is satisfied that a drug is safe and effective, it approves the

drug for marketing for its intended use as described in the label.

Approvable. FDA determines that a drug is approvable if there is substantial

evidence that it is safe and effective, but the sponsor must either supply

additional information or agree to some limiting conditions before FDA

grants final approval.

Not approvable. If FDA determines that the evidence submitted by the

sponsor to show that the drug is safe and effective is insufficient, the

agency notifies the sponsor that the drug is not approvable.

Withdrawal. The sponsor of an NDA may withdraw it at any time for any

reason.

Final status. We examined the data file for each NDA to see if the drug had

ever been approved. If not, we searched the file for the last event that was

a withdrawal, not approvable, approvable, or a refusal to file, and we

identified that event as the application’s final status. However, since FDA

never definitively rejects applications, some whose final status is other

than approval may ultimately be approved. (See appendix III.)

Drug Review Time Year of submission. The calendar year in which an application is first

submitted to FDA.

Review time. The period between the date of the initial submission of an

NDA, even if FDA refuses to file it, and the date of the application’s final

status in the data file. For approved drugs, review time is the period

between the initial submission and the date of approval.

FDA time and sponsor time. For some of the analyses, we divided the total

review time into time that is FDA’s responsibility and time that is the

sponsor’s responsibility. FDA time consists of periods that begin when the

agency has the information it has requested from the sponsor for that

stage of the review and that end when FDA issues a judgment of refusal to

file, approval, approvable, or not approvable or the application is

Page 20 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix I 

Data and Methodology

withdrawn.3 Sponsor time consists of periods when FDA is waiting for the

sponsor to provide additional information or to resubmit the application.

FDA time and sponsor time are complementary and together sum to total

review time.

Review cycles. Each period of FDA time is one review cycle.

FDA’s on-time performance. The Prescription Drug User Fee Act of 1992

established specific performance goals for each review cycle.4

 The agency

must issue refusals to file within 60 days of submission and must reach all

other decisions for priority drugs within 6 months and for standard drugs

within 12 months. We applied these guidelines retroactively to identify

actions as either on time or not on time for each review cycle for NDAs

submitted between 1987 and 1994.

Sponsor Characteristics Experience. We divided the sponsoring pharmaceutical companies into

four groups, based on their activities between 1987 and 1994. We defined

the most experienced companies as those that submitted 9 or more NDAs

to FDA during this period (that is, at least one per year). Those that

submitted between 5 and 8 NDAs in that period made up the

middle-experience group. The two least experienced groups submitted 4

or fewer NDAs. We further divided the least experienced companies into

one group with affiliations with other companies that sponsored NDAs

during this period and another group without such affiliations. Affiliation

meant that another sponsoring company had a significant ownership stake

in the sponsor of the NDA. We identified affiliations by reviewing business

and financial directories.

Methodology Most of our statistical analyses consist simply of listing average review

times, or the number of NDAs with a particular characteristic, separately by

year of submission or by the outcome of review. However, we also

conducted two regression analyses, one to identify variables related to the

3

The beginning of a period of FDA time is clear when the NDA is first submitted or resubmitted after a

withdrawal or refusal to file. It is less obvious when the sponsor submits amendments in response to

approvable or not-approvable letters, because sponsors frequently submit several amendments on

different dates. We chose to use the date of the first amendment as starting a period of FDA time, even

though FDA may not have all the information it needs to continue the review at that point. Our

procedure maximizes FDA time and minimizes sponsor time. An alternative method is to start a period

of FDA time when the last amendment before the next FDA action is received, letting FDA review the

earlier amendments during a period of sponsor time. That procedure minimizes FDA time and

maximizes sponsor time.

4

See FDA User Fees, esp. pp. 21-22.

Page 21 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix I 

Data and Methodology

length of the review process and another to identify factors related to drug

approval. (See appendixes IV and V.) This allowed us to isolate the effects

of one variable (for example, drug priority) while statistically holding

constant the other predictor variables (for example, year of submission

and the experience of the sponsoring company). All our statements about

statistical significance are based on the results of the regressions, which

answer the question: If there were no differences among these NDAs

except, for example, drug priority, does drug priority influence the

chances of approval?

We performed our work in accordance with generally accepted

government auditing standards.

Page 22 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix II 

Alternative Measures of Time

The key statistics presented in this report are the average times to final

decisions for NDAs submitted in consecutive calendar years from 1987

onward. Previous reports on time have presented other results, sometimes

relying on slightly different measures of time, sometimes reporting other

statistics (medians rather than averages), and usually constructing cohorts

based on the years in which the NDAs were approved rather than the years

in which they were submitted. In the sections that follow, we place our

work in the context of other studies of drug review and approval time by

examining the differences in approach.

Starting Points for

Calculations of Time

In our study, review time begins with the first submission of the NDA to

FDA. In FDA’s statistical reports, it starts the clock with the submission of

an “accepted” NDA. The two measures would provide similar results if the

NDA were accepted on the first submission or, if FDA refused to file it, the

sponsor never resubmitted the application. However, in any situation in

which FDA refused to file the NDA and the sponsor eventually resubmitted

it, our measure of review time would be longer by the interval between the

first submission and the date of an accepted submission. Approximately 1

in 10 NDAs (9.4 percent) fall into this category. The average time to

resubmission for these applications was a little less than 2 months (1.7

months). Therefore, our review times are slightly longer on average than

those reported by FDA.

On-Time Performance Another approach to time measurement is to be less concerned with how

long the process took than with whether it was completed within a

specified period. FDA takes this approach when it reports the extent to

which the agency meets its user fee performance goals as referenced in

the Prescription Drug User Fee Act. Data on our measure of on-time

performance appear in the body of this report. Table II.1 shows an annual

breakdown of “on time” performance.1

1

See appendix I for a discussion of our coding of an action as on time.

Page 23 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix II 

Alternative Measures of Time

Table II.1: Actions Taken on Time by

FDA for NDAs Submitted 1987-94a

Year of submission

Number of

NDAs

Number of

actions

Percent taken

“on time”

1987 142 304 72%

1988 129 251 68

1989 117 206 67

1990 99 179 62

1991 110 188 63

1992 103 161 65

1993 87 116 72

1994 118 67 94

aActions taken as of May 16, 1995.

As can be seen from table II.1, the percentages have changed little over the

years.2

 Interestingly, this is in contrast to the reduction in total review time

(the entire interval between submission and approval) during this period.

Seemingly, FDA has managed to reduce the overall time even though it has

not increased the proportion of specific actions taken on time.3

Agency Comments

and Our Response

In commenting on a draft of this report, FDA officials agreed with our

general conclusions but made two points regarding our analysis of on-time

performance.

First, FDA emphasized that the 6- and 12-months guidelines used in our

analysis were not in effect during the years we studied and that FDA is not

required to meet them until 1997.

Second, while FDA believes that its review cycle on-time performance may

not have improved, the agency cautioned that the nature of its actions has

changed with the initiation of the user fee program, particularly for

not-approvable letters. Prior to the initiation of user fees, not-approvable

letters were not necessarily a complete listing of all the deficiencies in the

2

The data for 1994 are biased by the small number and type of decisions that had been made for those

NDAs by the time we collected our data.

3

The assumptions we used to calculate on-time performance served to minimize the proportion of FDA

actions that met the standard. First, as we described in appendix I, we started each period of FDA time

with the submission of the first amendment after the last FDA action, not the submission of the last

amendment. Second, we did not extend the deadline by 3 months if major amendments were filed

close to the original due date, as allowed in some circumstances under user fees. We reported that

67 percent of FDA’s actions are on time. Choosing assumptions that are the most favorable to FDA

(starting the clock with the last submitted amendment and extending the deadline by 3 months in

every case) would increase this figure to 78 percent.

Page 24 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix II 

Alternative Measures of Time

NDA. For example, FDA may have sent one not-approvable letter when the

review of one section of the NDA was complete and additional

not-approvable letters as other sections of the review were completed.

After user fees, FDA is required to take complete actions, so a

not-approvable letter must contain all the deficiencies FDA identifies. In

other words, FDA must now complete more work to satisfy a post-user fee

deadline than it had to before user fees were introduced.

We agree with FDA’s first point. FDA’s second point argues for caution in

making comparisons of on-time performance between different years. We

agree that changes in procedure would invalidate such comparisons. For

that reason, we did not use this measure as an indicator of whether the

overall timeliness of the drug approval process had improved. Rather, we

included the trends in on-time performance in the report in order to be

comprehensive in presenting all measures of time that others had

reported.

Alternative Measures

of Total Review Time

Average Times Compared

to Median Times

Throughout this report, we have reported the average times for NDA

review. An alternative is to report the median review time, the time for the

50th percentile application. In this case, medians reduce the influence of

drugs with unusually long review periods and are therefore usually

somewhat lower than average review times. Table II.2 lists the average and

median approval times for the drugs we examined by year of submission.

While the median values are generally slightly lower, they show the same

pattern of consistent decrease as the average values.

Table II.2: Average and Median Months

to Approval for NDAs Submitted

1987-92

Year of

submission Average Median

1987 33.3 29.1

1988 30.1 26.7

1989 25.5 23.4

1990 25.1 23.1

1991 21.1 21.3

1992 19.2 18.7

Page 25 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix II 

Alternative Measures of Time

Year of Submission

Compared to Year of

Approval

FDA and others frequently report time statistics for NDAs that group the

applications by the year in which they were approved rather than the year

in which they were submitted. To some extent, this reflects FDA’s general

orientation away from publishing data on submissions (given that much of

that information is proprietary until they are approved). Table II.3

compares the average approval times we computed using year of

submission with the average approval times FDA computed using year of

decision. The discussion that follows the table indicates why grouping

NDAs by year of submission is preferable for our purpose.

Table II.3: Average NDA Approval

Times in Months, 1987-94

Year

By year of

submissiona

By year of

approvalb

1987 33.3 29.0

1988 30.1 28.9

1989 25.5 30.9

1990 25.1 30.0

1991 21.1 28.5

1992 19.2 32.6

1993 c 33.1

1994 c 25.5

aCalculated by GAO.

bReported by FDA.

cWe do not present values for these years because they may be biased as a result of the

censoring problem discussed in appendix VI.

Table II.3 shows an obvious difference between the decrease in approval

times when NDAs are grouped by year of submission and the stability when

they are grouped by year of approval. This difference arises because

grouping by year of approval incorporates into the calculation whatever

backlog of NDAs existed at FDA. For example, several NDAs submitted in

1987 that had very lengthy 5-year reviews would increase the average

review time in 1987 for year-of-submission statistics but would add to the

average review time in 1992 for year-of-approval figures.

Thus, whenever the possibility of a backlog exists, basing time on year of

approval is a less appropriate way to measure current practice because it

incorporates the older applications. In contrast, time based on year of

submission eliminates the confounding effects of the backlog and,

Page 26 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix II 

Alternative Measures of Time

therefore, is the preferable measure for assessing the current performance

of the agency.

In 1987, the first year in our study, FDA had a considerable backlog of NDAs

submitted in 1986 and earlier and that backlog affected times throughout

nearly the entire period of our study. This can be seen from table II.4.

Table II.4: Percent of NDAs Approved

1987-94 With Approval Times Greater

Than 4 Years Year of approval Total NDAs approved

Percent approved in more

than 4 years

1987 68 15%

1988 67 15

1989 87 20

1990 64 16

1991 63 16

1992 91 23

1993 70 24

1994 62 10

Source: Adapted from FDA statistics.

As the table shows, a considerable proportion of the approvals in every

year except for 1994 were for older NDAs that had been under review for a

long time. The first years in which FDA seemed to make progress in

reducing the backlog were 1992 and 1993, when larger percentages of

older applications were approved. This progress was reflected in the

smaller percentage of older NDAs that were approved in 1994 and in the

sharp drop in times measured by year of approval between 1993 and 1994

(see table II.3). The decrease from 33 to 26 months indicates that the

backlog may have finally passed through the system.

Page 27 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix III 

Intermediate Outcomes From FDA’s Review

Process

In this appendix, we present data on what happens to the NDAs as they

move through the review process, focusing on three kinds of activities:

first actions, review cycles, and major amendments.

First Actions Table III.1 shows the first action taken on NDAs submitted in each

successive year. It can be seen that approval is the initial decision for

relatively few NDAs.

Table III.1: First Actions on NDAs

Submitted 1987-94 Year of submission

First action 1987 1988 1989 1990 1991 1992 1993 1994

Percent of first actions on

submissionsa

Refusal to file 16% 10% 6% 13% 24% 27% 18% 11%

Withdrawal 13 18 17 15 8 13 8 4

Not approvable 46 41 37 34 32 19 20 10

Approvable 12 13 19 19 16 22 15 4

Approval 13 18 21 18 19 17 17 4

No first actionb 0 0 0 0 1 1 11 52

Total 100% 100% 100% 99% 100% 99% 89% 86%

Total number

of submissions 142 129 117 99 110 103 87 118

aPercentages may not total 100 because of rounding. Percentages for 1993 and 1994 do not total

100 because NDAs found “unacceptable for filing” because of failure to pay user fees are not

included in the table.

bAs of May 16, 1995.

Given that approximately 55 percent of all NDAs are ultimately approved,

the data in table III.1 also show that such “negative” decisions as refusal to

file, not approvable, and withdrawal are not necessarily fatal to an

application. Of the 110 NDAs submitted from 1987 to 1992 that FDA initially

refused to file, 35 (32 percent) were ultimately approved. Similarly,

43 percent of the NDAs that had a not-approvable first action were

ultimately approved, and 27 percent of the withdrawals were resubmitted

and approved. Overall, 43 percent of the 390 drugs submitted from 1987 to

1992 that were approved were refused, withdrawn, or found not

approvable at some point on their way to approval.

Page 28 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix III 

Intermediate Outcomes From FDA’s Review

Process

Cycles FDA reports the review cycles that an NDA goes through in its yearly

Statistical Reports. A cycle starts with the submission or resubmission of

an NDA and ends with the withdrawal of the NDA, a refusal to file decision,

or an approval, approvable, or not-approvable letter. Each new cycle starts

the review clock anew. Table III.2 shows the number of cycles for various

types of NDAs.

Table III.2: Review Cycles for NDAs

Submitted 1987-92

Average

Number of cycles

Type of NDA 1 2 3 ≥4 Total

Approved

only

Approveda 32% 41% 19% 9% 2.1 b

Not approved 64 22 11 3 1.5 b

Priority 52 38 7 4 1.6 1.7

Standard 45 31 17 7 1.9 2.2

NME 54 38 7 2 1.6 1.7

Non-NME 43 30 18 9 2.0 2.3

Year of submission

1987 32 35 25 8 2.1 2.4

1988 47 29 15 10 1.9 2.2

1989 51 30 14 5 1.8 2.0

1990 48 34 9 8 1.8 2.1

1991 49 34 14 4 1.7 2.0

1992 55 33 11 1 1.6 1.9

All 46 33 15 6 1.8 2.1

aPercentages may not total 100 because of rounding.

bNot applicable.

As can be seen from table III.2, some types of NDAs are more likely to go

through multiple review cycles than others. Approved NDAs go through

more cycles on average than applications that get dropped along the way;

priority NDAs go through fewer cycles on average than standard NDAs; and,

similarly, NMEs go through fewer cycles on average than non-NMEs. The

number of cycles for both approved NDAs and all NDAs has decreased for

submissions since 1987. This decrease is consistent with the decrease in

time to final decisions.

Page 29 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix III 

Intermediate Outcomes From FDA’s Review

Process

Amendments FDA has questions about almost all NDAs and requires sponsors to submit

additional data in response to those questions. The sponsors submit these

data in the form of amendments. Relatively small amounts of data (for

example, clarification of a point or correction of a value) are classified as

minor amendments, and relatively large amounts of data (for example, a

reanalysis or results of an additional study) are classified as major

amendments.

Table III.3: Major Amendments for

NDAs Submitted 1987-92

Average

Number of major amendments

Type of NDA 0 1-5 6-10 ≥11 Total

Approved

only

Approveda 12% 73% 12% 3% 3.5 b

Not approved 45 49 5 1 1.7 b

Priority 23 57 17 3 3.3 3.5

Standard 28 63 7 2 2.6 3.5

NME 20 59 15 5 3.8 4.6

Non-NME 29 63 6 1 2.3 3.0

Year of submission

1987 25 63 8 4 2.9 4.3

1988 20 71 6 2 2.7 3.1

1989 25 59 15 1 3.1 3.8

1990 31 54 10 5 2.9 4.4

1991 34 55 9 2 2.5 2.9

1992 27 69 4 0 2.0 2.3

All 27 62 9 2 2.7 3.5

aPercentages may not total 100 because of rounding.

bNot applicable.

Table III.3 shows the number of amendments for different types of NDAs.

As expected, NDAs that are pursued through to approval have more major

amendments on the average than NDAs that drop out of the process. NDAs

for priority drugs and for NMEs required more amending on average than

applications for standard drugs and non-NMEs. As with the data on cycles,

table III.3 shows a decrease in the number of amendments for submissions

since 1987.

These data, along with those in table III.1 showing a steady decrease in the

numbers of not approvables and in table III.2 showing fewer cycles,

Page 30 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix III 

Intermediate Outcomes From FDA’s Review

Process

suggest that the drug review and approval process is getting “cleaner.”

This change may result from different applications submitted by the

sponsors of new drugs, different FDA review procedures, or both. Without

additional study, it is not possible to identify the reasons for this.

However, all three sets of data (on first action, cycles, and major

amendments) are consistent with a quicker review process.

Page 31 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix IV 

Regression Analyses for Review Time

We conducted two regression analyses predicting review time, one for

approved new drug applications and the other for applications that were

not approved. As table IV.1 shows, we found that the length of time until

approval was significantly affected by three factors—year of submission,

drug priority, and sponsor experience. Applications submitted in later

years were approved much faster than earlier applications (for example,

11 months quicker in 1992 than in 1987). Drug applications given

therapeutic priority by FDA were approved nearly 10 months faster than

standard drugs. Applications from sponsors that submitted many NDAs

were approved more quickly than applications from relatively

inexperienced sponsors (for example, applications from the most

experienced sponsors were approved 4 months faster than those from

inexperienced sponsors that were not affiliated with other sponsoring

companies).

Page 32 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix IV 

Regression Analyses for Review Time

Table IV.1: For Approved New Drug

Applications, Regression Analysis

Predicting Number of Months From

First Submission to Approvala

Variableb Coefficientc T-valued

Probability

levele

Sample

mean

Year of submission

(vs. 1987)

1988 –2.44 –1.08 .28 .19

1989 –6.92 –2.95 .01 .17

1990 –6.54 –2.60 .01 .14

1991 –11.19 –4.76 .01 .16

1992 –11.39 –4.54 .01 .14

Priority drugs

(vs. standard) –9.89 –4.97 .01 .23

New molecular entity

(vs. not) .38 .22 .82 .32

Sponsor experience

(vs. inexperienced,

unaffiliated)

Inexperienced, affiliated –6.47 –1.99 .05 .07

Mid-experienced –4.14 –1.58 .12 .12

Most experienced –4.38 –2.22 .03 .65

Constant 38.25

aFor applications first submitted from 1987 to 1992, N = 390, and R-squared = 0.24. The mean

review time is 26.36 months.

bThe list of predictor variables also included categorical variables for the FDA reviewing divisions.

We did not report those coefficients here because they cannot readily be interpreted; the

chemical and therapeutic content and complexities of new drugs are strongly correlated with the

reviewing divisions, making it impossible for us to distinguish the effects of drug variations from

those that are attributable to the internal operations of the divisions. However, it is important to

note that the coefficients reported in the table are statistically independent of the effects of the

reviewing division.

cCoefficients are from an ordinary least-squares regression analysis with the SAS-PC software

package. The coefficient indicates the change in review time relative to that of the group left out.

For example, the coefficient of –2.44 for applications submitted in 1988 means that those

applications were approved nearly 2-1/2 times faster than applications submitted in 1987, the

group left out.

dThe T-values test the statistical significance of the coefficients.

eProbability level refers to the chances that the coefficient equals zero in the population. By

convention, coefficients with a probability level less than or equal to 5 percent (0.05) are regarded

as statistically significant. In this table, 0.01 indicates a probability level less than or equal to 0.01.

In contrast, for drugs that were not approved, the only significant factor

was year of submission. Applications submitted in later years were acted

on more quickly than those submitted earlier (see table IV.2). Neither

therapeutic priority nor the experience of the sponsor affected review

Page 33 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix IV 

Regression Analyses for Review Time

time. It is important to reiterate that FDA does not definitively reject

applications it does not approve. Therefore, FDA may take further action on

some of the applications in this analysis.

Table IV.2: For New Drug Applications

Not Approved, Regression Analysis

Predicting Number of Months From

First Submission to Date of Final

Actiona

Variableb Coefficientc T-valued

Probability

levele

Sample

mean

Year of submission (vs. 1987)

1988 .98 .27 .79 .18

1989 –10.13 –2.67 .01 .17

1990 –12.83 –3.32 .01 .15

1991 –11.90 –3.01 .01 .15

1992 –15.87 –4.14 .01 .16

Priority drugs

(vs. standard) 2.79 .71 .48 .09

New molecular entity (vs. not) 1.90 .68 .50 .22

Sponsor experience (vs.

inexperienced, unaffiliated)

Inexperienced, affiliated 7.10 1.51 .13 .07

Mid-experienced 2.01 .53 .59 .14

Most experienced 4.00 1.53 .13 .48

Constant 34.70

aFor applications first submitted from 1987 to 1992, N = 308, and R-squared = 0.16. Mean review

time is 24.93 months.

bThe list of predictor variables also included categorical variables for the FDA reviewing divisions.

We did not report those coefficients here because they cannot readily be interpreted; the

chemical and therapeutic content and complexities of new drugs are strongly correlated with the

reviewing divisions, making it impossible for us to distinguish effects from drug variations from

those that are attributable to the internal operations of the divisions. However, it is important to

note that the coefficients reported in the table are statistically independent of the effects of the

reviewing division.

cCoefficients are from an ordinary least-squares regression analysis with the SAS-PC software

package. The coefficient indicates the change in review time relative to that of the group left out.

For example, the coefficient of 0.98 for applications submitted in 1988 means that those

applications were acted on nearly 1 month slower than applications submitted in 1987, the group

left out.

dThe T-values test the statistical significance of the coefficients.

eProbability level refers to the chances that the coefficient equals zero in the population. By

convention, coefficients with a probability level less than or equal to 5 percent (0.05) are regarded

as statistically significant. In this table, 0.01 indicates a probability level less than or equal to 0.01.

Page 34 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix V 

Regression Analysis for Approval

Table V.1 presents the results of a logistic regression analysis predicting

NDA approval. The outcome variable is dichotomous: “1” indicates that the

drug has been approved, “0” that it has not been approved. Fifty-six

percent of the NDAs were approved. The data set for the regression

consists of the 698 drugs first submitted between 1987 and 1992 that had

final status values as of May 16, 1995 (two applications were pending).

Page 35 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix V 

Regression Analysis for Approval

Table V.1: Logistic Regression

Analysis Predicting NDA Approval

Variablea Coefficientb Odds ratioc Chi-squared

Probability

levele

Sample

mean

Year of

submission

(vs. 1987)

1988 .06 1.07 .06 .81 .18

1989 -.18 .84 .43 .51 .17

1990 -.30 .74 1.07 .30 .14

1991 .01 1.01 .01 .98 .16

1992 -.46 .63 2.62 .11 .15

Priority drug 

(vs. standard) 1.30 3.68 23.98 .01 .17

New molecular

entity (vs. not) .27 1.30 1.70 .19 .28

Sponsor

experience (vs.

inexperienced,

unaffiliated)

Inexperienced,

affiliated .49 1.63 1.83 .18 .07

Midexperienced .60 1.81 4.03 .04 .13

Most

experienced 1.10 3.01 28.21 .01 .57

Constant -.49

aThe list of predictor variables also included categorical variables for the FDA reviewing divisions.

We did not report those coefficients here because they are not readily interpretable; the chemical

and therapeutic content and complexities of new drugs are strongly correlated with the reviewing

divisions, making it impossible for us to distinguish effects from drug variations from those that

are attributable to the internal operations of the divisions. However, it is important to note that the

coefficients reported in the table are statistically independent of the effects of the reviewing

division.

bCoefficients are from a logistic regression analysis with the SAS-PC software package.

cThe odds ratio is the exponentiated coefficient (ecoefficient). The odds ratio indicates the change in

the odds of approval relative to that of the group left out. For example, the approval odds for

applications submitted in 1988 are 1.07 greater than those for applications submitted in 1987, the

group left out.

dThe chi-square values test the statistical significance of the coefficients.

eProbability level refers to the chances that the coefficient equals zero in the population. By

convention, coefficients with a probability level less than or equal to 5 percent (0.05) are regarded

as statistically significant. In this table, 0.01 indicates a probability level less than or equal to 0.01.

Page 36 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix V 

Regression Analysis for Approval

The regression uncovered two statistically significant factors—drug

priority and sponsor experience. Priority drugs were approved at nearly

four times the rate of nonpriority drugs. Applications from sponsors that

submitted many NDAs during this period were approved more often than

applications from relatively inexperienced sponsors (applications from the

most experienced sponsors were approved three times more often than

applications from inexperienced sponsors that were not affiliated with

other sponsoring companies; applications from companies with mid-levels

of experience were approved nearly twice as often).

Page 37 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VI 

Censoring Bias

As mentioned in appendix II, basing our selection of NDAs for analysis on

the year of submission has one significant advantage over the more

traditional approach of examining NDAs by year of approval. That is, our

approach avoids the contamination of the averages by whatever backlog

exists. However, relying on year of submission can introduce another form

of bias in that averages for approval time computed from all the 1993 and

1994 cohorts incorporate only a highly selective group of NDAs from those

2 years.

As table VI.1 shows, the final status distribution for NDAs submitted in 1993

and 1994 is radically different from that for NDAs submitted earlier. Clearly,

this is because many of the applications had not had time to “mature” by

the time we collected our data. While more than 50 percent of NDAs

submitted in every year from 1987 to 1992 were approved by May 1995,

comparatively few of the NDAs submitted in 1993 and 1994 had been

approved. Most importantly, the only NDAs from 1993 and 1994 that were

approved were those that had been approved relatively quickly. As a

result, the average approval time for NDAs submitted in 1987-92 is 26.4

months, while the average time for approved NDAs submitted in 1993 and

1994 is 12.6 months. Because of this bias, we excluded NDAs submitted

after 1992 whenever we examined final status.

Table VI.1: Final Status for NDAs

Submitted by Year of Submission

1987-94a

Year of submission

Final status 1987 1988 1989 1990 1991 1992 1993 1994

Approved 56% 58% 56% 54% 58% 52% 33% 5%

Withdrawn 21 26 22 25 11 18 11 6

Refused to file 7 3 3 3 12 9 11 13

Approvable 1 2 2 3 5 5 7 4

Not approvable 14 12 17 15 13 16 23 11

Pending 0 0 0 0 1 1 11 51

aFinal status as of May 16, 1995. Percentages may not total 100 because of rounding.

Percentages for 1993 and 1994 do not total 100 because NDAs found “unacceptable for filing”

because user fees were not paid are not included in the table.

However, we included NDAs from 1991 and 1992 because we found no

evidence that including these years risks exposure to the censoring bias

found in 1993 and 1994. As table VI.1 shows, the approval rates for 1991

and 1992 are equivalent to those from earlier years. That is, almost all the

NDAs from 1991 and 1992 for which approval ultimately would be expected

Page 38 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VI 

Censoring Bias

have already been approved by FDA. Approval times for those years are not

likely to increase much.

The question that remains is whether the trend in decreasing time that we

observed for submissions between 1987 and 1992 continued for 1993 and

1994 submissions. That question cannot be answered definitively until the

1993 and 1994 cohorts have had time to mature. However, preliminary

evidence suggests that the trend continues. Table VI.2 compares the

percentage of all applications submitted before 1993 that were approved

quickly to the same percentage for NDAs submitted in 1993 and 1994.

Table VI.2: Percent of NDAs Approved

Quickly, 1987-92 and 1993-94 Time between acceptance of NDA and approval 1987-92 1993-94

Within 6 months 1% 2%

Within 9 months 4 5

Within 12 months 8 9

As table VI.2 shows, approximately the same percentages of NDAs were

approved quickly both before and after 1992. From this evidence, we have

no reason to suspect that the trend of speedier drug approval for 1987-92

submissions was reversed for 1993-94 submissions.

Page 39 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VII 

Approval Times in the United Kingdom

The United Kingdom’s equivalent of FDA is the Medicines Control Agency

(MCA). MCA publishes information similar to that contained in FDA’s

statistical reports, including data on workload (number and type of

submissions) and time (how long it takes to review applications). MCA’s

1994-95 annual report indicates that the assessment of an application for a

new active substance (the apparent equivalent of what FDA terms a new

molecular entity) took an average of 56 working days. This figure stands in

sharp contrast to FDA’s reports that show an average approval time of 20

months for applications for NMEs approved in 1994. No doubt, the sharp

contrast in these two averages is one factor creating the impression that

approval times are much shorter in the United Kingdom than they are in

this country.

However, closer examination of the data in MCA’s annual report shows that

they should be compared to our data on FDA with caution. Most

importantly, the drug review process in the United Kingdom is very

different from that in the United States. In the United Kingdom, MCA’s

assessment is only the first step in a multistage process of drug review and

approval. All applications for new active substances are also automatically

referred to a government body called the Committee on the Safety of

Medicines (CSM). CSM’s expert subcommittees also assess the application,

and these assessments, along with those from MCA, are provided to CSM.

CSM then provides advice to the Licensing Authority, which actually grants

or denies the product license. However, the rate of rejection of

applications or requests for modifications or additional information is very

high (99 percent for applications submitted 1987-89), although many of

these issues are minor and quickly resolved. Applications with remaining

unresolved issues then go through a formal appeals process that may

involve additional work on the part of the applicant, reassessment by MCA

or CSM, and, in rare cases, the involvement of another body called the

Medicines Commission. Thus, the total time until the license is actually

granted is considerably longer than the period of initial assessment by MCA.

In contrast, the time FDA reports includes all the steps between an

accepted NDA and the final decision on it.

When one examines total time for both processes, the United Kingdom

does not appear to be dramatically faster than the United States. One

recent study compared approval times for 11 drugs that were approved in

both countries during the period 1986-92. The median time in the United

States (about 23 months) was 15 percent longer than the median time in

Page 40 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VII 

Approval Times in the United Kingdom

the United Kingdom (20 months).1 The most recent data from MCA show

that overall approval times are actually somewhat longer than that.2

 These

data indicate that MCA granted licenses for applications representing 32

new active substances during the 12-month period ending September 30,

1994. The median time for granting a license was 30 months and the

average was 24 months. The fastest license was granted in about 4 months,

the slowest in 62 months.3

FDA’s data for the calendar year ending December 31, 1994, indicate that

the agency approved a total of 22 new molecular entities. The median

approval time was 18 months, average approval time about 20 months. The

fastest approval reported by FDA took about 6 months and the slowest

about 40 months.

Thus, the most recent data show that approval times for NMEs are actually

shorter in the United States. In addition, a broader perspective shows that

approval processes in many industrialized nations may be converging.4

Approval times over the past 10 years for France, Germany, Japan, the

United Kingdom, and the United States all seem to be moving toward the

2-year point. The trend in the United States (which had lengthy times

throughout the mid-1980s) has been toward more rapid times, whereas the

process has been getting slower in some of the other (originally faster)

countries.

1

C. Harvey et al., “A Comparison of the Review of a Cohort of NCEs by Four National Regulatory

Authorities,” Journal of Pharmaceutical Medicine, 3 (1993), 65-75.

2

From the bimonthly newsletter of the Medicines Control Agency, The MAIL, November-December

1994.

3

An additional complication is that MCA was starting to make the conversion to a European-wide drug

review process during this period, meaning that the times MCA reported for 1994 may not be typical.

4

Neal McAuslane, “A Comparison of Regulatory Review Times in Europe, Japan, and the United

States,” presented at the 31st Annual Meeting of the Drug Information Association, Orlando, Florida,

June 26, 1995.

Page 41 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VIII 

Major Contributors to This Report

This report was prepared by Martin T. Gahart, Michele Orza, George

Silberman, and Richard Weston of the Program Evaluation and

Methodology Division.

Page 42 GAO/PEMD-96-1 FDA Review Time for Drugs
Appendix VIII 

Major Contributors to This Report

Page 43 GAO/PEMD-96-1 FDA Review Time for Drugs
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