FDA Review Times (Testimony, 05/02/96, GAO/T-PEMD-96-9).

GAO examined the Food and Drug Administration's (FDA) drug review and
approval times, focusing on: (1) whether the timeliness of new drug
reviews and approvals has changed; and (2) how approval times in the
United States compare with those in the United Kingdom (UK). GAO found
that: (1) new drug applications (NDA) are moving more quickly through
the review and approval process; (2) the time taken for NDA approvals
has decreased from 33 months in 1987 to 19 months in 1992; (3) the
priority FDA assigns to NDA and the experience of application sponsors
affect the timeliness of NDA decisions; (4) FDA assigns priority status
to those applications expected to provide greater therapeutic relief;
(5) NDA are approved 10 months faster than standard applications; (6)
FDA made timely decisions on 67 percent of NDA between 1987 and 1993;
(7) the on-time percentage for NDA is relatively stable and varies
between a low of 62 percent to a high of 72 percent; (8) there is little
relationship between the time FDA takes to reach a final decision and
whether or not it meets a specific action deadline; (9) sponsors account
for 20 percent of the time in NDA approval; (10) UK approval times are
similar to the United States' and average 56 working days; (11) UK
granted licenses for applications representing 32 new active substances
during the 12-month period examined; and (13) it is too early to
determine whether the European Union's new method of drug approval will
ensure more efficient review while ensuring product safety.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  T-PEMD-96-9
     TITLE:  FDA Review Times
      DATE:  05/02/96
   SUBJECT:  Drugs
             Foreign governments
             Pharmacological research
             Product safety
             Consumer protection
             Regulatory agencies
             Food and drug law
             Pharmaceutical industry
             Safety regulation
             Product performance evaluation
IDENTIFIER:  European Union
             United Kingdom
             
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Cover
================================================================ COVER


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

GAO/T-PEMD-96-9

GAO/PEMD-96-9T

FDA Review Times

(973821)


Abbreviations
=============================================================== ABBREV

  CSM - Committee on the Safety of Medicines
  FDA - Food and Drug Administration
  MCA - Medicines Control Agency
  NDA - New drug application
  NME - New molecular entity
  EU - European Union

============================================================ Chapter 0

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. 

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. 


--------------------
\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). 


   BACKGROUND
---------------------------------------------------------- Chapter 0:1

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. 


   METHODOLOGY
---------------------------------------------------------- Chapter 0:2

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. 


--------------------
\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. 


   RESULTS IN BRIEF
---------------------------------------------------------- Chapter 0:3

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 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
---------------------------------------------------------- Chapter 0:4

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-
                                       94\a


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
--------------------------------------------------------------------------------
\a Final 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. 

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


--------------------
\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. 


      HOW LONG DOES THE REVIEW
      PROCESS TAKE? 
-------------------------------------------------------- Chapter 0:4.1

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


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 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

                                          Months until      Percent of
                                           half of all   NDAs approved
                                             NDAs were       within 24
Year of submission                            approved          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 faster
than standard applications and that applications from the most
experienced sponsors are approved 4 months faster than applications
from less experienced sponsors. 


--------------------
\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. 

\7 Fifty-eight percent of the NDAs submitted in 1988 and 1991 were
approved--the years with the greatest proportion of approvals. 


      PROCESS MEASURES OF TIME
-------------------------------------------------------- Chapter 0:4.2

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 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.)


--------------------
\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. 

\10 We excluded the 1994 data. 

\11 In 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. 

\12 Our calculations of sponsor time were conservative, tending to
underestimate, rather than overestimate, the proportion of review
time accounted for by the sponsors of NDAs. 


      APPROVAL TIMES IN THE UNITED
      KINGDOM
-------------------------------------------------------- Chapter 0:4.3

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. 

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. 


--------------------
\13 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. 

\14 From the bimonthly newsletter of the Medicines Control Agency,
The MAIL, November-December 1994. 

\15 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. 


   SUMMARY
---------------------------------------------------------- Chapter 0:5

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 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. 


-------------------------------------------------------- Chapter 0:5.1

This concludes my statement, Mr.  Chairman.  I will be happy to
answer any questions that you or Members of the Committee may have. 


ATTACHMENT 1
=========================================================== Appendix 1

   Figure 1:  Months Between
   Submission and Approval of
   Drugs

   (See figure in printed
   edition.)

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


ATTACHMENT 2
=========================================================== Appendix 2

   Figure 2:  FDA and Sponsor
   Times for Approved NDAs

   (See figure in printed
   edition.)


*** End of document. ***