United States General Accounting Office

GAO Testimony

Before the Subcommittee on Health and Environment,

Committee on Commerce, House of Representatives

For Release on Delivery

Expected at

10:00 a.m. EST

Thursday

May 2, 1996

FDA REVIEW TIMES

Statement of Mary R. Hamilton, Ph.D.

Director of Program Evaluation

in Human Services Areas

Program Evaluation and Methodology Division

G O A

years

1921 - 1996

GAO/T-PEMD-96-9

Mr. Chairman and Members of the Committee:

In October 1995, GAO issued a report on the Food and Drug

Administration’s (FDA’s) drug review and approval times.1

 It is a pleasure

to appear before this Committee today to present our principal findings

from that report. My testimony today focuses on two questions that have

received considerable attention in recent months:

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

changed in recent years?

• How do approval times in the United States compare to approval times in

the United Kingdom?

In sum, our conclusions are that new drug applications (NDAs) are moving

more quickly through the review and approval process and that the

amount of time to obtain an approval is approximately the same in this

country and in the United Kingdom.

In addition to our work on drug review times, we have also published

reports on review times for medical devices and on the approach to

medical product review in Europe.2

Briefly, our work on FDA review times for medical device applications

showed that they varied widely from one year to the next. For all types of

applications, the median review time increased dramatically in either 1992

or 1993 and then began to decrease. Whether the downturn will continue

will only become clear as data for additional years become available.

Our examination of the new systems implemented by the European Union

(EU) in 1995 for drug and medical device review showed that some aspects

of the new systems are seemingly quite distinct from FDA’s approach to

medical product review, and there is great optimism within the European

Community about their prospects. However, at this time, it is still too early

to know whether the approach the EU has adopted will result in more

efficient review while ensuring product safety.

1

U.S. General Accounting Office, FDA Drug Approval: Review Time Has Decreased in Recent Years,

GAO/PEMD-96-1 (Washington, D.C.: October 1995).

2

U.S. General Accounting Office, Medical Devices: FDA Review Time, GAO/PEMD-96-2 (Washington,

D.C.: October 1995); Medical Device Regulation: Too Early to Assess European System’s Value as

Model for FDA, GAO/HEHS-96-65 (Washington, D.C.: March 1996); and European Union Drug

Approval: Overview of New European Medicines Evaluation Agency and Approval Process,

GAO/HEHS-96-71 (Washington, D.C.: April 1996).

Page 1 GAO/T-PEMD-96-9 FDA Review Times
Let me turn now to the focus of my testimony today—FDA drug review.

First, let me describe FDA’s review and approval process and give an

overview of our methodology in studying that process.

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

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

that seems to hold promise, preclinical animal studies are typically

conducted to see how it 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 has been submitted

to FDA. As the clinical trials progress through several phases aimed at

establishing safety and efficacy, the manufacturer develops the processes

that will be 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 a new drug

application 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 the agency

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 a new drug

application, it decides whether to approve the drug on the basis of the

information in the application and any supplemental information it has

requested from the sponsoring firm. 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, however, of withdrawing the

application at any time.

Page 2 GAO/T-PEMD-96-9 FDA Review Times
Methodology For each NDA submitted between 1987 and 1994 (a total of 905), 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 16, 1995. To ensure that the data were

valid, we independently checked them against values in published reports

and other sources.

We computed time by measuring the interval between all significant

events. 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.” 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 1992.3

 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.4

We focused primarily on the NDA review phase—the final critical step for

bringing a drug to market. We have only begun to look intensively at the

lengthier process of a sponsor’s initial exploration and clinical testing, and

we did not study the phase that follows a drug’s approval, during which

additional studies can be conducted and 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. 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 (on display) shows, the overall decrease in

3

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.

4

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/T-PEMD-96-9 FDA Review Times
approval times was achieved through gradual reductions in time for the

applications submitted in each successive year. (See attachment 1.)

The priority that 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

time to be approved than do standard applications (those for which there

is no 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.

The data available on drug review time for FDA and the counterpart agency

in the United Kingdom are limited, but they show that times are not faster

in the U.K.

Our Analysis As mentioned above, 905 new drug applications were submitted to FDA in

the years 1987-94. Of these, approximately one in five (17 percent) were

for priority drugs. The other NDAs were for drugs that FDA considered to

offer little therapeutic benefit beyond that already available to patients.

Because much of the current discussion has been on how long it takes to

obtain approval for an NDA, the fact that many NDAs do not ultimately get

approved can easily be missed. Table 1 shows the final status of those

NDAs as of May 1995.

Table 1: Final Status for NDAs Submitted, 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 we did not include in the table those

NDAs that were found “unacceptable for filing” because user fees were not paid.

Page 4 GAO/T-PEMD-96-9 FDA Review Times
As can be seen from the table, a relatively large percentage of 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. Truly innovative

drugs (known as new molecular entities, or NMEs) were approved at a

higher rate than non-NMEs (64 percent to 52 percent), and priority drugs

were approved more often than standard drugs (76 percent to 52 percent).

This shows that whether an NDA is or is not ultimately approved is an

important question, as is how long approval takes.5

How Long Does the

Review Process Take?

Table 2 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

were approved and those that were not.6

 The table also distinguishes

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

molecular entities, priority applications, and standard applications.

Table 2: Average Number of Months From Initial NDA Submission to Final Decision, 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 NDA

categories fell considerably (45 percent for all NDAs and 42 percent for

approved applications). In addition, the reductions in time came for NDAs

5

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.

6

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

nonapprovable 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, we mean the status of the

application as of May 16, 1995.

Page 5 GAO/T-PEMD-96-9 FDA Review Times
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 3 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 approvals that are ever likely to

be granted.7

 Similarly, table 3 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.

Table 3: Two Alternative Measures of

Review Time 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). Among applications that

were not approved, the variation was similar. 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. 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

7

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

greatest proportion of approvals.

Page 6 GAO/T-PEMD-96-9 FDA Review Times
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 on a new drug

application 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 (using criteria established under the

Prescription Drug User Fee Act).8

 We examined both the degree to which

FDA was on time and the factors that influenced whether it made its

decisions on time.9

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 1987.10 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.11

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

8

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 nonapprovable 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.

9

Our 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. In addition, our criteria for

determining whether the agency was “on time” were based on the performance goals contained in the

Prescription Drug User Fee Act of 1992.

10We excluded the 1994 data.

11In commenting on our October 1995 report on review time, FDA maintained that our on-time analysis

underestimates the extent to which its performance has improved.

Page 7 GAO/T-PEMD-96-9 FDA Review Times
or to resubmit the application. Figure 2 (on display) shows how the

relative times were distributed for approved NDAs submitted between 1987

and 1992. Sponsors accounted for approximately 20 percent of the time in

the NDA phase for applications that FDA approved.12 Importantly, the time

for both sponsors and FDA diminished for NDAs submitted between 1987

and 1992. (See attachment 2.)

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. In the United

Kingdom, MCA’s assessment is only the first step in the process of drug

review and approval. All applications for new active substances are also

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

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

and then send these assessments, along with those from MCA, to the full

committee. CSM then makes a recommendation to the Licensing Authority,

which is the government body that actually grants or denies the product

license. Moreover, because the rate of rejection of applications or requests

for modifications or additional information is very high (99 percent for

applications submitted 1987-89), many applications go through an appeals

process that may involve additional work on the part of the applicant,

reassessment by MCA or CSM, and 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 that FDA reports includes all the steps between an

accepted NDA and the final decision on it.

12Our calculations of sponsor time were conservative, tending to underestimate, rather than

overestimate, the proportion of review time accounted for by the sponsors of NDAs.

Page 8 GAO/T-PEMD-96-9 FDA Review Times
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

the United Kingdom (20 months).13 The most recent data from MCA show

that overall approval times are actually somewhat longer than that.14

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.

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.15

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.

Summary In sum, the data we have presented show that NDAs are moving more

quickly through the drug review and approval process and that the amount

of time to obtain an approval is approximately the same in this country

and in the United Kingdom. Whether the improvement in FDA time is

because of actions that the agency or the pharmaceutical industry has

13C. 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.

14From the bimonthly newsletter of the Medicines Control Agency, The MAIL, November-December

1994.

15Neal 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 9 GAO/T-PEMD-96-9 FDA Review Times
taken or because of some other factors is an issue that was beyond the

scope of our study. 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) and the relative similarity of review times internationally

should both be considered in the ongoing discussions of whether it is

necessary to change the NDA review process or the agency in order to

speed the availability of drugs to patients.

This concludes my statement, Mr. Chairman. I will be happy to answer any

questions that you or Members of the Committee may have.

Page 10 GAO/T-PEMD-96-9 FDA Review Times
Page 11 GAO/T-PEMD-96-9 FDA Review Times
Attachment 1

Figure 1: Months Between Submission

and Approval of Drugs Months

0

6

12

18

24

30

36

1987 1988 1989 1990 1991 1992

Year of submission

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

Page 12 GAO/T-PEMD-96-9 FDA Review Times
Attachment 2

Figure 2: FDA and Sponsor Times for

Approved NDAs Months

0

6

12

18

24

30

36

1987 1988 1989 1990 1991 1992

Year of submission

Total time

FDA time

Sponsor time

(973821) Page 13 GAO/T-PEMD-96-9 FDA Review Times
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