New Drug Approval
FDA's Consideration of Evidence from Certain Clinical Trials Gao ID: GAO-10-798 July 30, 2010Before approving a new drug, the Food and Drug Administration (FDA)--an agency of the Department of Health and Human Services (HHS)--assesses a drug's effectiveness. To do so, it examines information contained in a new drug application (NDA), including data from clinical trials in humans. Several types of trials may be used to gather this evidence. For example, superiority trials may show that a new drug is more effective than an active control--a drug known to be effective. Non-inferiority trials aim to demonstrate that the difference between the effectiveness of a new drug and an active control is small--small enough to show that the new drug is also effective. Drugs approved on this basis may provide important benefits, such as improved safety. Because non-inferiority trials are difficult to design and interpret, they have received attention within the research community and FDA. FDA has issued guidance on these trials. GAO was asked to examine FDA's use of non-inferiority trial evidence. This report (1) identifies NDAs for new molecular entities--potentially innovative new drugs not FDA-approved in any form--that included evidence from non-inferiority trials, (2) examines the characteristics of these trials, and (3) describes FDA's guidance on these trials. GAO reviewed NDAs submitted to FDA between fiscal year 2002 (the first full year that FDA documentation was available electronically) and fiscal year 2009 (the last full year of submissions), examined FDA's guidance, and interviewed agency officials.
Evidence from non-inferiority trials was included in about one-quarter, or 43, of the 175 NDAs for new molecular entities that were submitted to FDA for review from fiscal years 2002 through 2009. Many of these applications were for antimicrobial drugs, such as those treating bacterial, viral, and fungal infections. As of December 31, 2009, FDA approved 18 of the 43 NDAs on the basis of evidence from non-inferiority trials. Of the remaining 25 NDAs, FDA approved 11 based on other evidence, such as proof that the new drug was more effective than a placebo (no treatment), and decided not to approve 14. The non-inferiority trials included in these NDAs varied with respect to their characteristics. FDA generally requires sponsors to provide evidence of a drug's effectiveness as shown in more than one trial. For the 18 NDAs that were approved based on evidence from non-inferiority trials, the number of non-inferiority trials used to provide primary support for approval ranged from one to four, with an average of 2 such trials per NDA. Half of these applications included non-inferiority trials that tested the effectiveness of the new drug against more than one active control. The non-inferiority margins--the maximum clinically acceptable extent to which the new drug can be less effective than the active control and still show evidence of an effect--ranged from 5 to 20 percent among trials that supported approval. Among the other 25, FDA identified nine NDAs that included poorly designed non-inferiority trials which did not provide primary evidence for approval. Some of these problems included an inappropriate selection of an active control and an improper calculation of a non-inferiority margin. FDA notified sponsors of its concerns with the poorly designed trials prior to the sponsors' submissions of all NDAs that included such trials. In March 2010 FDA issued draft guidance which focused solely on the use of non-inferiority trials. This guidance presents detailed and comprehensive recommendations on how non-inferiority trials may be used to provide evidence of a drug's effectiveness. For example, it provides advice on how to select an active control and how to set the non-inferiority margin, as well as how to interpret the trials. This guidance offers broad, generally applicable recommendations to supplement indication-specific guidance documents that FDA had previously issued. These indication-specific guidance documents include FDA's advice on many issues related to the development of drugs for particular indications, some of which are related to the use of non-inferiority trials. GAO's review of FDA's guidance showed that the agency has become more conservative in allowing evidence from non-inferiority trials to demonstrate a drug's effectiveness. First, FDA has limited the indications for which these trials may be used. Second, the agency has also become more rigorous in its review of evidence from non-inferiority trials. We sent a draft of this report to HHS for review. HHS provided us with technical comments, which we incorporated as appropriate.
GAO-10-798, New Drug Approval: FDA's Consideration of Evidence from Certain Clinical Trials
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Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
July 2010:
New Drug Approval:
FDA's Consideration of Evidence from Certain Clinical Trials:
GAO-10-798:
GAO Highlights:
Highlights of GAO-10-798, a report to congressional requesters.
Why GAO Did This Study:
Before approving a new drug, the Food and Drug Administration (FDA)”an
agency of the Department of Health and Human Services (HHS)”assesses a
drug‘s effectiveness. To do so, it examines information contained in a
new drug application (NDA), including data from clinical trials in
humans. Several types of trials may be used to gather this evidence.
For example, superiority trials may show that a new drug is more
effective than an active control”a drug known to be effective. Non-
inferiority trials aim to demonstrate that the difference between the
effectiveness of a new drug and an active control is small”small
enough to show that the new drug is also effective. Drugs approved on
this basis may provide important benefits, such as improved safety.
Because non-inferiority trials are difficult to design and interpret,
they have received attention within the research community and FDA.
FDA has issued guidance on these trials. GAO was asked to examine FDA‘
s use of non-inferiority trial evidence. This report (1) identifies
NDAs for new molecular entities”potentially innovative new drugs not
FDA-approved in any form”that included evidence from non-inferiority
trials, (2) examines the characteristics of these trials, and (3)
describes FDA‘s guidance on these trials. GAO reviewed NDAs submitted
to FDA between fiscal year 2002 (the first full year that FDA
documentation was available electronically) and fiscal year 2009 (the
last full year of submissions), examined FDA‘s guidance, and
interviewed agency officials.
What GAO Found:
Evidence from non-inferiority trials was included in about one-
quarter, or 43, of the 175 NDAs for new molecular entities that were
submitted to FDA for review from fiscal years 2002 through 2009. Many
of these applications were for antimicrobial drugs, such as those
treating bacterial, viral, and fungal infections. As of December 31,
2009, FDA approved 18 of the 43 NDAs on the basis of evidence from non-
inferiority trials. Of the remaining 25 NDAs, FDA approved 11 based on
other evidence, such as proof that the new drug was more effective
than a placebo (no treatment), and decided not to approve 14.
The non-inferiority trials included in these NDAs varied with respect
to their characteristics. FDA generally requires sponsors to provide
evidence of a drug‘s effectiveness as shown in more than one trial.
For the 18 NDAs that were approved based on evidence from non-
inferiority trials, the number of non-inferiority trials used to
provide primary support for approval ranged from one to four, with an
average of 2 such trials per NDA. Half of these applications included
non-inferiority trials that tested the effectiveness of the new drug
against more than one active control. The non-inferiority margins”the
maximum clinically acceptable extent to which the new drug can be less
effective than the active control and still show evidence of an effect”
ranged from 5 to 20 percent among trials that supported approval.
Among the other 25, FDA identified nine NDAs that included poorly
designed non-inferiority trials which did not provide primary evidence
for approval. Some of these problems included an inappropriate
selection of an active control and an improper calculation of a non-
inferiority margin. FDA notified sponsors of its concerns with the
poorly designed trials prior to the sponsors‘ submissions of all NDAs
that included such trials.
In March 2010 FDA issued draft guidance which focused solely on the
use of non-inferiority trials. This guidance presents detailed and
comprehensive recommendations on how non-inferiority trials may be
used to provide evidence of a drug‘s effectiveness. For example, it
provides advice on how to select an active control and how to set the
non-inferiority margin, as well as how to interpret the trials. This
guidance offers broad, generally applicable recommendations to
supplement indication-specific guidance documents that FDA had
previously issued. These indication-specific guidance documents
include FDA‘s advice on many issues related to the development of
drugs for particular indications, some of which are related to the use
of non-inferiority trials. GAO‘s review of FDA‘s guidance showed that
the agency has become more conservative in allowing evidence from non-
inferiority trials to demonstrate a drug‘s effectiveness. First, FDA
has limited the indications for which these trials may be used.
Second, the agency has also become more rigorous in its review of
evidence from non-inferiority trials.
We sent a draft of this report to HHS for review. HHS provided us with
technical comments, which we incorporated as appropriate.
View [hyperlink, http://www.gao.gov/products/GAO-10-798] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
One-Quarter of NDAs Included Evidence from Non-Inferiority Trials and
FDA Approved a Majority of These Applications:
Non-Inferiority Trial Characteristics Varied and Not All Such Trials
Provided Primary Evidence for the Approval of NDAs:
FDA Has Issued Detailed and Comprehensive Guidance on the Use of Non-
Inferiority Trials to Establish the Effectiveness of New Drugs:
Agency Comments:
Appendix I: New Drug Applications Approved on the Basis of Evidence
from Non-Inferiority Trials:
Appendix II: FDA Guidance Documents Issued with Information on the Use
of Non-Inferiority Trials:
Appendix III: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: NDAs Submitted from Fiscal Years 2002 through 2009 with
Evidence from at Least One Non-Inferiority Trial, by Drug Type:
Table 2: Characteristics of Non-Inferiority Trials for 18 NDAs
Submitted for FDA Review from Fiscal Years 2002 through 2009 and
Approved on the Basis of Primary Evidence from Non-Inferiority Trials:
Table 3: Summary of FDA Guidance Regarding the Use of Non-Inferiority
Trials for Particular Indications:
Table 4: NDAs Submitted for FDA Review from Fiscal Years 2002 through
2009 Where the Basis of Approval Included Primary Evidence from Non-
Inferiority Trials:
Table 5: FDA-Issued Guidance Including Recommendations on the Use of
Non-Inferiority Trials, January 2002 through June 2010:
Figures:
Figure 1: Examples of Clinical Trials Demonstrating Non-Inferiority
Compared to Those Showing Inferiority and Superiority:
Figure 2: NDAs Submitted from Fiscal Years 2002 through 2009 with
Evidence from at Least One Non-Inferiority Trial:
Figure 3: Approval Status of 43 NDAs Submitted from Fiscal Years 2002
through 2009 with Evidence from Non-Inferiority Trials:
Abbreviations:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
HIV: human immunodeficiency virus:
NDA: new drug application:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
July 30, 2010:
Congressional Requesters:
Testing new drugs on human volunteers is an essential step in the drug
development process. These tests, known as clinical trials, are
instrumental in determining whether a drug is safe and effective.
Their purpose is to measure the effect of a new drug separately from
other influences, such as a spontaneous change in the course of a
disease. Before a new drug can be marketed in the United States, the
drug's sponsor--typically a manufacturer--must submit a new drug
application (NDA) to the Food and Drug Administration (FDA) for
approval. The agency will only approve the NDA if it determines that
the drug is safe and effective for its intended use. To make this
determination, FDA reviews the results of clinical trials that
sponsors submit as part of their NDAs.
Sponsors must provide evidence of a drug's effectiveness based on
adequate and well-controlled trials.[Footnote 1] Several different
types of trials may be used to gather this evidence. Some clinical
trials are designed to test whether a new drug is more effective than
a placebo or no treatment at all. However, in some instances it would
be unethical to offer a placebo or withhold treatment because it would
deprive human volunteers of an available treatment known to prevent
death, irreversible injury, or other serious harm. In such instances,
a clinical trial may be conducted to measure the effect of a new drug
compared to an active control--a drug already known to be effective.
For example, a superiority trial could be conducted to show that a new
drug is more effective than an active control. Another type of
clinical trial, a non-inferiority trial, is intended to establish that
the difference in the effectiveness of a new drug and an active
control is small. Non-inferiority trials that demonstrate a small
difference in the effectiveness of the two drugs may be able to
support a conclusion that the new drug is effective because the
effectiveness of the active control is known.
FDA considers the use of non-inferiority trials to be acceptable in
certain circumstances and has approved drugs on the basis of evidence
from such trials. Although non-inferiority trials may prove that new
drugs are no more effective than the active controls they are compared
to, new drugs approved on the basis of non-inferiority may provide
patients with other important benefits, such as improved safety, fewer
drug-to-drug interactions, convenience of administration, or a lower
cost.
However, non-inferiority trials are more complicated to design and
their results are more difficult to interpret than other types of
clinical trials. For example, in interpreting the results of non-
inferiority trials, sponsors not only must examine the difference in
the effectiveness of the two drugs as measured in the non-inferiority
trial, they must also assess whether the active control proved to be
as effective as expected. If the active control did not demonstrate
its expected effect in the trial, results showing the similarity of
the two drugs are meaningless. As a result of these and other issues,
non-inferiority trials have received attention within the research
community and FDA. To assist sponsors in appropriately using non-
inferiority trials to establish a drug's effectiveness, FDA has issued
written guidance conveying the agency's understanding of non-
inferiority trials and how such trials may be used to support a drug's
approval.
You asked us to review FDA's use of evidence from non-inferiority
trials to establish a drug's effectiveness and support approval. In
this report, we (1) identify the type and status of drug applications
submitted for FDA review that included evidence from non-inferiority
trials; (2) examine the characteristics of non-inferiority trials FDA
considered in making approval decisions; and (3) describe FDA's
guidance for establishing a drug's effectiveness on the basis of non-
inferiority trials.
To identify the type and status of drug applications submitted to FDA
for review that included evidence from non-inferiority trials, we
limited our scope to a subset of drugs. FDA officials told us that the
majority of non-inferiority trials for drugs listed in NDAs were for
new molecular entities--potentially innovative drugs containing active
ingredients that have never been approved for marketing in the United
States in any form. We therefore examined FDA data on the 223 NDAs for
new molecular entities that were submitted to FDA during the last 8
years--fiscal years 2002 through 2009 (October 1, 2001, through
September 30, 2009).[Footnote 2] Fiscal year 2002 was the first full
year that records documenting FDA's review of NDAs were available in
electronic format, and so we did not include prior years in our scope.
Fiscal year 2009 was the last full year for which data was available
at the time we requested data from FDA and so we excluded NDAs
submitted to FDA after that period. We limited our scope to
prescription drugs intended to prevent or treat diseases or other
medical conditions. We excluded 18 NDAs for nonprescription drugs,
drugs used to aid in diagnosing diseases, or drugs aiding in the
absorption of other drugs. We further limited our scope to those NDAs
for which FDA had completed its review by December 31, 2009--excluding
30 NDAs that were either withdrawn or pending review as of that date.
These two limitations excluded 48 of the 223 NDAs from our review and
we conducted our analysis on the remaining 175 NDAs for new molecular
entities.[Footnote 3] As our analysis was limited to a subset of all
NDAs received by FDA, the results of our review may not be
generalizable to other types of applications.
To determine whether NDAs within our scope included evidence from non-
inferiority trials, we examined documents summarizing the results of
clinical trials that we obtained from FDA's Web site[Footnote 4] (for
approved NDAs) and from agency officials (for NDAs not approved as of
December 31, 2009). Specifically, we reviewed FDA's statistical and
medical reviews to determine whether the application included a non-
inferiority trial. For those NDAs with at least one non-inferiority
trial, we determined whether FDA considered data from these trials as
pivotal--that is, providing the primary evidence of effectiveness to
support the NDA.[Footnote 5] Because FDA could not readily identify
the NDAs that it had received that included evidence from non-
inferiority trials, we submitted the results of our analysis to FDA.
We asked agency officials to confirm that we had correctly identified
the NDAs that included evidence from non-inferiority trials--including
those that were approved primarily based on this evidence, approved
based on other primary evidence, or that had not been approved as of
December 31, 2009.
To examine the characteristics of non-inferiority trials FDA
considered in making approval decisions, we analyzed FDA's statistical
and medical reviews for those drugs that included evidence from at
least one non-inferiority trial in their NDAs. For those drugs FDA
ultimately approved based on evidence from non-inferiority trials, we
gathered descriptive information about the non-inferiority trials that
FDA considered. In particular, we determined the number of non-
inferiority trials conducted to support each application, identified
the active controls used in these trials, and reviewed whether and how
each trial supported the conclusion that the drug was effective. We
also reviewed whether the characteristics of the non-inferiority
trials providing primary evidence for approval revealed evidence of
biocreep. Biocreep refers to a concern that successive generations of
drugs approved based on non-inferiority trials, with the active
control changing in each new generation, could lead to the adoption of
decreasingly effective drugs, culminating in the approval of drugs
that are no more effective than a placebo. We examined how FDA
assessed the effectiveness of the active controls used in non-
inferiority trials to ensure that comparisons to these drugs were
appropriate--particularly where successive generations of non-
inferiority trials occurred. We also reviewed FDA's correspondence
with sponsors about their non-inferiority trials to analyze the
information FDA communicated with sponsors before, during, and after
their clinical trials. We gathered information on the concerns FDA
identified and communicated with sponsors regarding their non-
inferiority trials and determined when FDA notified sponsors about
these issues.
To describe FDA's guidance for establishing drug effectiveness on the
basis of non-inferiority trials, we reviewed guidance FDA issued from
January 2002 through June 2010 that was related to the design of such
trials. From these published guidance documents we gathered FDA's
recommendations on how to use non-inferiority trials to support the
effectiveness of new drugs. We interviewed FDA officials to obtain
contextual information regarding their issuance of this guidance. We
also interviewed experts, such as biostatisticians and physician
specialists, including those affiliated with the Infectious Diseases
Society of America and the American Society of Clinical Oncology, to
obtain their perspectives regarding the content and clarity of FDA's
guidance. We did not assess the extent to which sponsors' non-
inferiority trials or FDA's approval decisions on applications that
included evidence from these types of trials comported with agency
guidance.
We conducted this performance audit from July 2009 to July 2010 in
accordance with generally accepted government auditing standards.
Those standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings and conclusions based on our audit objectives. We believe
that the evidence obtained provides a reasonable basis for our
findings and conclusions based on our audit objectives.
Background:
FDA, an agency within the Department of Health and Human Services
(HHS), is responsible for overseeing the safety and effectiveness of
drugs marketed within the United States. These responsibilities begin
before a product is brought to the market, and include reviewing drug
sponsors' proposals for conducting clinical trials, providing advice
and publishing guidance regarding these trials, as well as reviewing
applications for new drugs.
The Use of Non-Inferiority Trials in Obtaining Evidence of a Drug's
Effectiveness:
Once a drug sponsor identifies a promising chemical compound it
believes to be capable of curing or treating diseases, the sponsor may
decide to conduct clinical trials on humans to gather the evidence
necessary to demonstrate to FDA that the drug is safe and effective
for its intended use. Before beginning clinical trials in the United
States, a sponsor generally must submit an investigational new drug
application to FDA for review.[Footnote 6] This application provides
FDA with extensive information about the drug, including safety and
manufacturing information, and outlines the sponsor's plans for
clinical trials, which gradually introduce new drugs to increasingly
larger numbers of patients.[Footnote 7] FDA assesses the information
in the application--which is later included as part of the NDA--to
ensure that the drug is reasonably safe to begin studying in humans.
[Footnote 8]
Sponsors may use these clinical trials to gather evidence of a drug's
safety and effectiveness. In general, FDA requires sponsors to submit
the results of more than one clinical trial demonstrating
effectiveness in order to provide substantial evidence that a drug is
effective for the intended indication and population.[Footnote 9] FDA
has issued regulations and guidance that provide industry with
information to properly design, conduct, and interpret these trials.
For example, in 1985 FDA substantially revised its regulations
including the provision addressing the characteristics of adequate and
well-controlled trials and the types of controlled trials that can be
used to gather evidence of a new drug's effectiveness.[Footnote 10]
Sponsors may use trials of varying designs to obtain evidence of a
drug's effectiveness. One type of clinical trial is a non-inferiority
trial. The objective of a non-inferiority trial is to show that any
difference in the effectiveness of two drugs is small enough to allow
a conclusion that the new drug is also effective, but not
substantially less effective than the active control. To conduct a non-
inferiority trial, sponsors must make many decisions regarding how the
trial will measure the new drug's effectiveness. For example, they
must select the trial's primary endpoint, the principal measure used
to determine a drug's effectiveness. The primary endpoint may be a
clinical endpoint--a direct measure of how a patient feels, functions,
or survives--or, in some cases, a surrogate endpoint--a laboratory
measure or physical sign used as a substitute for a clinical endpoint
that reasonably predicts a clinical benefit.[Footnote 11] Sponsors
must also determine when to measure the trial's endpoint--for example,
are patients cured within 7, 14, or 30 days after starting treatment--
in addition to determining the number and type of patients to be
enrolled in each trial.
Sponsors conducting non-inferiority trials must also make decisions to
account for the new drug's comparison to the active control. Sponsors
must identify an available treatment for use as an active control in
the non-inferiority trial.[Footnote 12] They must then use evidence of
the active control's effectiveness as shown in prior clinical trials
to estimate the effect that the active control will have in the
planned non-inferiority trial, adjusting for any differences between
the prior and planned trials. Using this estimate, sponsors determine
the trial's non-inferiority margin--the maximum clinically acceptable
extent to which the new drug can be less effective than the active
control and still show evidence of an effect. FDA considers the
selection of a margin to be the single greatest challenge in
designing, conducting, and interpreting non-inferiority trials. Its
calculation is not only dependent on a string of other decisions
related to the trial--for example, the data collected on the active
control's effectiveness in other trials--but also includes the
application of clinical judgment to determine the maximum amount of
effectiveness that could be lost without having a substantial impact
on the drug's effectiveness. If a non-inferiority margin is
incorrectly calculated and is set too large, a drug that is not
effective may appear to be effective; if the margin is too small, an
effective drug may appear to be ineffective.
In a non-inferiority trial, patients are randomly assigned to receive
either the new drug or an active control. After the trial, the sponsor
identifies the observed effect of each drug in the trial, and
calculates the observed difference in the drugs' effectiveness. The
actual difference in the drugs' effectiveness in the entire population
could be greater or less than what is observed in the trial. For that
reason, sponsors calculate a confidence interval around the observed
difference in effectiveness between the new drug and active control
drug. The confidence interval provides a range of values for the
difference in effectiveness within which the true difference is likely
to be found.
The confidence interval around the observed difference in
effectiveness is used to determine if the new drug is non-inferior to
the active control. It is compared to the non-inferiority margin--the
maximum clinically acceptable extent to which the new drug can be less
effective than the active control. If the confidence interval is
within the non-inferiority margin, and the sponsor provides adequate
evidence that the active control demonstrated its expected effect in
the trial, the new drug may be deemed non-inferior to the active
control.[Footnote 13] A new drug can be non-inferior to an active
control even if the estimated difference in effectiveness and its
confidence interval lies entirely below zero, meaning that the active
control drug is more effective than the new drug, but by an irrelevant
amount. However, if the confidence interval shows that the effect of
the drug could be below the margin--even if the observed effect of the
drug was within the margin--the drug would not have shown an effect,
and is therefore considered inferior. In addition, if the confidence
interval lies entirely above zero--demonstrating that the new drug is
more effective than the active control--the drug can be considered
superior. (See figure 1.)
Figure 1: Examples of Clinical Trials Demonstrating Non-Inferiority
Compared to Those Showing Inferiority and Superiority:
[Refer to PDF for image: illustration]
The illustration depicts clinical trials with the following
information:
Difference in effectiveness (new drug effectiveness minus active
control drug effectiveness);
Confidence interval for the difference.
The trials are shown plotted against the following plot line:
Active control drug more effective;
-X%;
0% difference in effectiveness;
New drug more effective.
Clinical trial A:
Difference in effectiveness: Inferior.
Clinical trial B:
Difference in effectiveness: Inferior.
Clinical trial C:
Difference in effectiveness: Non-inferior.
Clinical trial D:
Difference in effectiveness: Non-inferior.
Clinical trial E:
Difference in effectiveness: Non-inferior.
Clinical trial F:
Difference in effectiveness: Superior.
Clinical trial G:
Difference in effectiveness: Superior.
Source: GAO.
[End of figure]
Since issuing regulations that address the elements of adequate and
well-controlled trials, FDA has also periodically issued guidance
documents to provide updates on the agency's current thinking on a
range of topics. These guidance documents encompass broad issues such
as statistical principles for use in clinical trials and how to select
an appropriate control, whereas others are more focused and serve to
consolidate relevant recommendations on the development of drugs
treating a particular indication.
In addition to disseminating guidance on non-inferiority trials, FDA
provides specific advice regarding the design of clinical trials at
the request of sponsors. For example, sponsors may ask FDA to review
and provide advice on a trial's proposed active control, non-
inferiority margin, or endpoint before the given trial has begun.
After the conclusion of their clinical trials, sponsors may consult
with FDA regarding the interpretation of trial results or to discuss
the information the agency would expect to see submitted in an NDA.
FDA's advice and recommendations to sponsors are considered advisory;
sponsors are not required to implement any of the agency's
suggestions.[Footnote 14]
If sponsors believe they have successfully demonstrated a new drug's
safety and effectiveness, they may submit an NDA to FDA for review.
The NDA contains information about the safety and effectiveness of the
drug as demonstrated in clinical trials and other research, such as
studies in animals. Once the agency receives an NDA, the application
is reviewed by one of FDA's medical review divisions, depending on the
indication the drug has been proposed to treat. If FDA determines that
the drug is safe and effective for its intended use--that its clinical
benefits outweigh its potential health risks--and that other
requirements are met, it will approve the application. After approving
a new drug, FDA's responsibilities continue as it is charged with
monitoring the safety, effectiveness, and promotion of approved drugs.
FDA executes these responsibilities in the same manner regardless of
whether drugs were approved on the basis of evidence from non-
inferiority trials.
Issues Unique to Non-Inferiority Trials:
Non-inferiority trials present unique issues in measuring the
effectiveness of new drugs. For example, the use of these trials can
raise uncertainties about the true effectiveness of new drugs because
non-inferiority trials cannot measure this directly. Instead, these
trials measure the effectiveness of the new drug relative to the
active control, and sponsors must assess whether the active control
can be considered to be as effective in the non-inferiority trial as
was expected based on past experience. Using data from the non-
inferiority trial and from prior trials measuring the effectiveness of
the active control, the effectiveness of the new drug is estimated--
but not ever fully known. In addition, non-inferiority trials are more
prone to certain biases than superiority trials. For example, if
patients in a superiority trial do not take the new drug as directed,
this poor compliance will dilute the measured effectiveness of the new
drug, making it less likely that the trial will successfully
demonstrate superiority. In a non-inferiority trial, however, poor
compliance by patients taking the active control drug can have a
different effect. It can reduce the difference in the measured
effectiveness between the new drug and the active control, making the
treatments appear more similar than they might otherwise be. As such,
poor compliance in a non-inferiority trial can increase the likelihood
that an ineffective drug is concluded to be effective.
The use of non-inferiority trials over time also raises concerns about
the potential for "biocreep" to occur. This term is used to describe
the concern that successive generations of drugs approved based on non-
inferiority trials, with the active control changing in each new
generation, could lead to the adoption of decreasingly effective drugs
and ultimately to the approval of drugs that are no more effective
than a placebo. Non-inferiority trials that are poorly designed are
especially prone to biocreep. The selection of inappropriate active
controls--that is, drugs that are not known to be consistently
effective, or drugs that were themselves approved on the basis of non-
inferiority trials--could lead to biocreep.
Even if successive generations of non-inferiority trials are conducted
and each trial is itself well-designed, biocreep may still occur
because placebo controls are not included in these trials. Non-
inferiority trials are only able to measure the effectiveness of the
new drug relative to the active control, not a placebo. As a result,
the true effectiveness of any of the new drugs, compared to a placebo,
is not measured. Without this metric, it is impossible to determine
the extent to which the effectiveness of the new drug is similar to
that of a placebo and whether biocreep has occurred.
FDA has acknowledged some concerns over the uncertainties inherent in
non-inferiority trials and the potential these trials create for
biocreep. For example, FDA stated in a 1992 guidance document that, in
order to avoid biocreep, sponsors should consult with the agency
regarding the active controls they were considering for their
trials.[Footnote 15] In other guidance documents, FDA has also
encouraged sponsors to consult with the agency regarding their planned
non-inferiority trials.
One-Quarter of NDAs Included Evidence from Non-Inferiority Trials and
FDA Approved a Majority of These Applications:
One-quarter of NDAs submitted to FDA for review from fiscal years 2002
through 2009 included evidence from non-inferiority trials, and many
of these applications were for antimicrobial drugs. FDA approved a
majority of the applications that included evidence from these trials.
One-Quarter of NDAs, Many for Antimicrobial Drugs, Included Evidence
from Non-Inferiority Trials:
Forty-three, or one-quarter, of the 175 NDAs we reviewed that were
submitted to FDA from fiscal years 2002 through 2009 included evidence
from at least one non-inferiority trial. The number of NDAs with
evidence from non-inferiority trials varied from year to year and
generally declined from fiscal years 2002 through 2009. On average,
FDA received five NDAs each year that included evidence from non-
inferiority trials. (See figure 2.)
Figure 2: NDAs Submitted from Fiscal Years 2002 through 2009 with
Evidence from at Least One Non-Inferiority Trial:
[Refer to PDF for image: vertical bar graph and pie-chart]
175 NDAs:
Applications including evidence from non-inferiority trials: 43;
All other applications: 132.
43 NDAs Including Evidence from Non-Inferiority Trials:
FDA received an average of 5 NDAs each year.
Fiscal year of submission: 2002;
Number of NDAs: 9.
Fiscal year of submission: 2003;
Number of NDAs: 9.
Fiscal year of submission: 2004;
Number of NDAs: 2.
Fiscal year of submission: 2005;
Number of NDAs: 6.
Fiscal year of submission: 2006;
Number of NDAs: 5.
Fiscal year of submission: 2007;
Number of NDAs: 4.
Fiscal year of submission: 2008;
Number of NDAs: 7.
Fiscal year of submission: 2009;
Number of NDAs: 1.
Source: GAO analysis of FDA documents.
Note: Our review was limited to NDAs for new molecular entities.
[End of figure]
About half of the 43 NDAs submitted with evidence from at least one
non-inferiority trial--or 22--were for antimicrobial drugs,[Footnote
16] such as those that treat bacterial, viral, or fungal infections.
The remaining portion of NDAs submitted with evidence from these
trials represented a variety of drug types. (See table 1.)
Table 1: NDAs Submitted from Fiscal Years 2002 through 2009 with
Evidence from at Least One Non-Inferiority Trial, by Drug Type:
Antimicrobial drugs:
Drug Type: Antibacterial drugs;
Number: 10;
Percentage: 23%.
Drug Type: Antiviral drugs;
Number: 5;
Percentage: 12%.
Drug Type: Antifungal drugs;
Number: 3;
Percentage: 7%.
Drug Type: Other antimicrobial drugs;
Number: 4;
Percentage: 9%.
Antimicrobial drugs subtotal:
Number: 22;
Percentage: 51%.
Other drug types:
Drug Type: Metabolism and endocrinology drugs;
Number: 5;
Percentage: 12%.
Drug Type: Ophthalmology drugs;
Number: 3;
Percentage: 7%.
Drug Type: Analgesia drugs;
Number: 2;
Percentage: 5%.
Drug Type: Hematology drugs;
Number: 2;
Percentage: 5%.
Drug Type: Pulmonary drugs;
Number: 2;
Percentage: 5%.
Drug Type: Cardiovascular and renal drugs;
Number: 2;
Percentage: 5%.
Drug Type: Gastroenterology drugs;
Number: 1;
Percentage: 2%.
Drug Type: Psychiatry drugs;
Number: 1;
Percentage: 2%.
Drug Type: Reproductive drugs;
Number: 1;
Percentage: 2%.
Drug Type: Rheumatology drugs;
Number: 1;
Percentage: 2%.
Drug Type: Transplant drugs;
Number: 1;
Percentage: 2%.
Other drug types subtotal:
Number: 21;
Percentage: 49%.
Drug Type: Total;
Number: 43;
Percentage: 100%.
Source: GAO analysis of FDA documents.
Note: Our review was limited to NDAs for new molecular entities.
[End of table]
FDA Approved a Majority of NDAs That Included Evidence from Non-
Inferiority Trials:
FDA approved 29 of the 43 NDAs submitted for review from fiscal years
2002 through 2009 that included evidence from at least one non-
inferiority trial. Most NDAs--18 of the 29--were approved based on
evidence from pivotal non-inferiority trials.[Footnote 17] FDA
approved the remaining 11 applications based on other evidence, such
as the superiority of the new drug compared to a placebo or an active
control. As of December 31, 2009, FDA had decided not to approve 14
applications that included evidence from non-inferiority trials. (See
figure 3.)
Figure 3: Approval Status of 43 NDAs Submitted from Fiscal Years 2002
through 2009 with Evidence from Non-Inferiority Trials:
[Refer to PDF for image: pie-chart]
Approved based on primary evidence from non-inferiority trials: 18;
Approved based on other primary evidence: 11;
Reviewed but not approved: 14.
Source: GAO analysis of FDA documents.
Notes: Our review was limited to NDAs for new molecular entities.
Approval status is as of December 31, 2009.
[End of figure]
Many NDAs including evidence from non-inferiority trials were for
antimicrobial drugs, and the majority of approvals based on this
evidence were also for these types of drugs. Two-thirds, or 12 of the
18, NDAs approved on the basis of non-inferiority trials were for
antimicrobial drugs.[Footnote 18] The remaining one-third of NDAs
approved on the basis of non-inferiority trials were for various other
types of drugs, including those treating diabetes and chemotherapy-
induced nausea and vomiting. See appendix I for a list of all 18 NDAs
approved based on evidence from non-inferiority trials, including
fiscal year of approval, drug type, and approved indication.
Non-Inferiority Trial Characteristics Varied and Not All Such Trials
Provided Primary Evidence for the Approval of NDAs:
Characteristics varied among the non-inferiority trials providing
primary evidence to support FDA's approval of 18 NDAs. Some other
applications also included non-inferiority trials that FDA identified
as being poorly designed; these trials did not provide primary
evidence for approval.
Characteristics Varied Among the Non-Inferiority Trials That Provided
Primary Evidence for Approval of 18 NDAs:
Characteristics varied among the non-inferiority trials that provided
primary evidence for the approval of the 18 NDAs. FDA relied on
primary evidence from multiple pivotal non-inferiority trials to
support the approval of most of these applications. The number of
pivotal non-inferiority trials used as primary evidence for these 18
NDAs ranged from one to four, with an average of two pivotal non-
inferiority trials supporting the approval of each application. In
addition to including evidence from pivotal non-inferiority trials,
five applications included evidence from other types of pivotal
trials; for example, trials demonstrating superiority to a placebo or
active control drug. Thirteen of the 18 applications included only
pivotal non-inferiority trials in their applications. Of these
applications, FDA approved four based on evidence from a single
pivotal non-inferiority trial.
Two-thirds, or 12, of the 18 NDAs included trials that measured drug
effectiveness using a surrogate, rather than a clinical, primary
endpoint in at least one of their pivotal trials.[Footnote 19]
Although FDA generally prefers that drug sponsors demonstrate the
effectiveness of a new drug by showing its impact on a clinical
endpoint, in certain cases, it will consider a surrogate endpoint if
it determines it is a reasonable substitute. However, all experts we
interviewed who commented on this topic noted that the approval of
drugs on the basis of both non-inferiority trials and surrogate
endpoints increases uncertainty in the drugs' true effectiveness.
Half of the 18 NDAs FDA approved on the basis of non-inferiority
trials tested the effectiveness of the new drug against more than one
active control. A majority of the active controls used in non-
inferiority trials were FDA-approved for the indication. However,
three applications included evidence from non-inferiority trials that
used one active control that was not FDA-approved for the indication.
For example, in fiscal year 2003, FDA approved Cubicin for the
treatment of complicated skin and skin structure infections on the
basis of evidence from two pivotal non-inferiority trials that used a
total of five different active control drugs. While three of these
active control drugs were FDA-approved to treat this indication, two
were not.[Footnote 20] In addition, some of the active controls used
in non-inferiority trials were themselves approved on the basis of
evidence from other trials that compared the drug to another active
control.[Footnote 21] However, FDA reviewed the selection of nearly
all of the active controls used in the pivotal non-inferiority trials
that supported the approval of the 18 NDAs, and found the active
controls appropriate for use in these trials.[Footnote 22] FDA
officials also told us that if a new drug was approved on the basis of
evidence from non-inferiority trials, the active control used in these
trials would most likely also be used in subsequent trials, except in
cases where the newer drug proved to be superior to the active
control.[Footnote 23]
The margins used for most of the 18 NDAs approved on the basis of
evidence from non-inferiority trials ranged from 5 to 20 percent, with
the most commonly used margin being 10 percent.[Footnote 24] That is,
for trials using a 10 percent non-inferiority margin, the new drug
could be estimated to be up to 10 percent less effective than the
active control. However, the observed difference in the effectiveness
of the new drug and active control, as measured in the clinical
trials, would be less than 10 percent.
At the time of its review of the NDAs, FDA agreed with the non-
inferiority margins set for all of the pivotal trials submitted for
the majority of drugs approved on the basis of evidence from non-
inferiority trials.[Footnote 25] All of the pivotal trials submitted
for these drugs--that is, those where FDA agreed with the margin--
demonstrated that the new drug was non-inferior to the active control
drug as measured on the primary endpoint, with one exception.[Footnote
26] These trials showed that the confidence interval for the
difference in the drugs' effectiveness was within the non-inferiority
margin.
FDA did not agree with the non-inferiority margins set for pivotal
trials submitted with three applications, though the agency approved
these drugs based on evidence from these trials. For two drugs, Exjade
and Reyataz, FDA stated that the proposed margins could not be used to
measure the drugs' effectiveness. FDA conducted additional analyses of
data from pivotal trials submitted in these drugs' applications which
showed that the drugs were superior to a placebo. For the third drug,
Noxafil, FDA did not agree with the sponsor's proposed justification
of the margin for one trial, although this trial showed the difference
in the drugs' effectiveness to be less than the disputed margin.
* FDA approved Exjade in fiscal year 2006 to treat chronic iron
overload in certain patients receiving blood transfusions. Exjade's
NDA included evidence from one pivotal non-inferiority trial that had
an objective of showing that Exjade lowered iron levels to a similar
extent as the active control. Upon reviewing the application, FDA
disagreed with the non-inferiority margin proposed for this trial. FDA
analyzed data from the trial which showed that Exjade was effective in
lowering patients' iron levels despite ongoing blood transfusions
(which typically result in increased iron levels), particularly among
those patients who began the trial with very high iron levels. FDA
approved Exjade on the basis of this evidence, which showed that the
drug would have been more effective than a placebo. In addition, FDA
officials noted that Exjade presented a valuable alternative in the
treatment of this indication.[Footnote 27]
* FDA approved Reyataz in fiscal year 2003 for the treatment of human
immunodeficiency virus (HIV) infection. Reyataz's NDA included
evidence from two pivotal non-inferiority trials, including one in
patients that were naïve to HIV treatment and one in patients that had
experience receiving HIV treatment. FDA agreed with the margin
proposed for the trial conducted in the treatment-naïve population,
which was successful in demonstrating that Reyataz was non-inferior to
its active control. However, FDA disagreed with the margin proposed
for the trial conducted in the treatment-experienced population.
Agency officials analyzed data from this trial which showed that
Reyataz was effective in treatment-experienced patients, and this
effect was greater than what would have been expected with a placebo.
FDA approved Reyataz to treat HIV infection on the basis of this
evidence, as well as other pivotal evidence of effectiveness in the
treatment-naïve population. In addition, FDA officials noted that
Reyataz presented an alternative to HIV-infected patients that were
not responding to available HIV treatments.
* FDA approved Noxafil in fiscal year 2006 for the prevention of
invasive Aspergillus and Candida infections in certain patients on the
basis of evidence from two pivotal trials. In its review of this NDA,
FDA noted that the sponsor had not adequately explained the relevance
of the proposed 15 percent non-inferiority margin. One of these trials
demonstrated that Noxafil was superior to its active control, and the
other trial demonstrated that the drug was at most three percent less
effective than the active control. FDA approved this drug on the basis
of this evidence of effectiveness.
Table 2 provides a summary of the characteristics of non-inferiority
trials for the 18 NDAs we identified as approved on the basis of
evidence from non-inferiority trials.
Table 2: Characteristics of Non-Inferiority Trials for 18 NDAs
Submitted for FDA Review from Fiscal Years 2002 through 2009 and
Approved on the Basis of Primary Evidence from Non-Inferiority Trials:
Drug name: Alinia;
Number of pivotal non-inferiority trials: 1;
Type of primary endpoint(s): clinical;
Number of active controls: 1[A];
Non-inferiority margin(s): 20%.
Drug name: Aloxi;
Number of pivotal non-inferiority trials: 3;
Type of primary endpoint(s): clinical;
Number of active controls: 2;
Non-inferiority margin(s): 15%.
Drug name: Apidra;
Number of pivotal non-inferiority trials: 3;
Type of primary endpoint(s): surrogate;
Number of active controls: 2;
Non-inferiority margin(s): 0.4%[B].
Drug name: Cubicin;
Number of pivotal non-inferiority trials: 2;
Type of primary endpoint(s): clinical;
Number of active controls: 5[A];
Non-inferiority margin(s): 10%.
Drug name: Doribax;
Number of pivotal non-inferiority trials: 3[C];
Type of primary endpoint(s): clinical and surrogate;
Number of active controls: 2;
Non-inferiority margin(s): 10% and 15%.
Drug name: Eraxis;
Number of pivotal non-inferiority trials: 2;
Type of primary endpoint(s): clinical and surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 10% and 20%.
Drug name: Exjade;
Number of pivotal non-inferiority trials: 1;
Type of primary endpoint(s): surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 15%.
Drug name: Levemir;
Number of pivotal non-inferiority trials: 3;
Type of primary endpoint(s): surrogate;
Number of active controls: 2;
Non-inferiority margin(s): 0.4%[B].
Drug name: Livalo;
Number of pivotal non-inferiority trials: 4[C];
Type of primary endpoint(s): surrogate;
Number of active controls: 3;
Non-inferiority margin(s): 6%[D].
Drug name: Mycamine;
Number of pivotal non-inferiority trials: 2;
Type of primary endpoint(s): clinical and surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 10%.
Drug name: Noxafil;
Number of pivotal non-inferiority trials: 1[C];
Type of primary endpoint(s): clinical;
Number of active controls: 1;
Non-inferiority margin(s): 15%.
Drug name: Pylera;
Number of pivotal non-inferiority trials: 1;
Type of primary endpoint(s): surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 15%.
Drug name: Reyataz;
Number of pivotal non-inferiority trials: 2;
Type of primary endpoint(s): surrogate;
Number of active controls: 2;
Non-inferiority margin(s): 10%[E].
Drug name: Tindamax;
Number of pivotal non-inferiority trials: 4[C];
Type of primary endpoint(s): surrogate;
Number of active controls: 2[A];
Non-inferiority margin(s): 5%.
Drug name: Tygacil;
Number of pivotal non-inferiority trials: 4;
Type of primary endpoint(s): clinical;
Number of active controls: 3;
Non-inferiority margin(s): 10%.
Drug name: Tyzeka;
Number of pivotal non-inferiority trials: 1;
Type of primary endpoint(s): surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 15%.
Drug name: Uloric;
Number of pivotal non-inferiority trials: 1[C];
Type of primary endpoint(s): surrogate;
Number of active controls: 1;
Non-inferiority margin(s): 10%.
Drug name: Vibativ;
Number of pivotal non-inferiority trials: 2;
Type of primary endpoint(s): clinical;
Number of active controls: 1;
Non-inferiority margin(s): 10%.
Source: GAO analysis of FDA documents.
Notes: This list reflects NDAs for new molecular entities that FDA
approved as of December 31, 2009. NDAs that included more than one non-
inferiority trial may have each used different endpoints and different
margins. Unless otherwise noted, all active controls were FDA-approved
for the indication, and all margins represent the maximum acceptable
difference in the portion of patients achieving a successful outcome.
[A] At least one active control was not FDA approved for the
indication.
[B] The non-inferiority margin for this NDA represents the maximum
acceptable difference in blood sugar levels.
[C] The NDA also included data from at least one other pivotal
clinical trial that was not a non-inferiority trial; for example, a
superiority trial.
[D] The non-inferiority margin for this NDA represents the maximum
acceptable difference in cholesterol levels.
[E] In addition to the margin listed, this NDA included primary
evidence from another pivotal trial that set a margin of .5 log
copies/mL, representing the maximum acceptable difference in HIV viral
load levels.
[End of table]
We found that FDA reviewed the characteristics of the non-inferiority
trials supporting the approval of the 18 NDAs to ensure that the drugs
it approved were more effective than a placebo. FDA's review therefore
minimized the potential for biocreep. Similarly, our examination of
the trials' characteristics also revealed no evidence of biocreep.
Some Non-Inferiority Trials Were Poorly Designed and Did Not Provide
Primary Evidence for Approval:
While non-inferiority trials provided primary evidence of
effectiveness to support the approval of 18 NDAs, other non-
inferiority trials were poorly designed and did not provide such
evidence. Of the other 25 NDAs that included evidence from non-
inferiority trials, FDA identified 9 applications that included poorly
designed non-inferiority trials.[Footnote 28] These trials were unable
to accurately measure the new drugs' effectiveness and did not provide
primary evidence for the approval of these drugs.[Footnote 29] Some of
the concerns FDA identified with sponsors' non-inferiority trials were:
* inappropriate use of non-inferiority trials for the indication being
treated,
* inappropriate selection of an active control, including cases where
the drug was not FDA-approved or the sponsor did not provide an
adequate justification, and:
* improper calculation or justification of the non-inferiority margin.
FDA informed sponsors of its concerns with all of these applications'
non-inferiority trials prior to the sponsors' submission of the NDAs.
Specifically, FDA notified the sponsors between 1 month and 94 months
before submission, with an average of about 30 months prior to
submission. With the exception of one application, FDA notified all
sponsors at least 6 months prior to submission.
* For example, FDA advised one sponsor before the sponsor began its
non-inferiority trials--24 months prior to submitting its NDA--that
the agency did not consider it appropriate to use non-inferiority
trials to support the approval of the drug for the indication being
sought--treatment of schizophrenia. FDA reiterated this position on
another occasion prior to the NDA submission. FDA did not consider the
results of this trial to provide primary evidence to support its
approval decision. The agency ultimately approved the drug based on
evidence that the drug was superior to placebo as demonstrated in
several other trials.
* In another case, a sponsor conducted the non-inferiority trial
outside of the U.S. and had not requested FDA's input while planning
or conducting the trial. The sponsor requested a meeting with FDA to
discuss its planned NDA. During this meeting, which occurred 1 month
before FDA received the NDA, the agency learned of the sponsor's non-
inferiority trial and communicated its concerns regarding the design
of the trial. FDA did not consider the results of this non-inferiority
trial in its approval decision, but ultimately approved the drug based
on evidence of superiority to placebo as demonstrated in another trial.
FDA Has Issued Detailed and Comprehensive Guidance on the Use of Non-
Inferiority Trials to Establish the Effectiveness of New Drugs:
In March 2010, FDA issued draft guidance on non-inferiority trials
that provides detailed recommendations on using these trials to
provide evidence of a new drug's effectiveness. This March 2010 draft
guidance offers broader and more comprehensive information to
supplement other indication-specific guidance documents the agency
previously issued.
FDA's March 2010 Draft Guidance Provides Detailed Recommendations on
the Use of Non-Inferiority Trials in Establishing the Effectiveness of
New Drugs:
In March 2010, FDA issued new draft guidance on non-inferiority trials
that provides detailed recommendations on how these trials may be used
to establish the effectiveness of new drugs.[Footnote 30] Although FDA
had previously issued guidance documents that included information
regarding the use of non-inferiority trials for certain indications,
this March 2010 guidance is the first focused solely on the use of non-
inferiority trials. It explains the key principles involved in using a
non-inferiority trial to demonstrate the effectiveness of a drug and
provides detailed recommendations for such trials, including how to
select an active control and how to set the non-inferiority margin
(that is, determining the maximum clinically acceptable extent to
which the new drug can be less effective than the active control),
among other things. The March 2010 guidance also explains why the
agency considers its recommendations appropriate, offers answers to
frequently asked questions, and lists detailed examples to illustrate
some common challenges in designing and interpreting non-inferiority
trials.
FDA officials told us that they developed the March 2010 guidance on
non-inferiority trials because it was clear to them that these trials
were not well understood. The concepts elaborated on in the March 2010
guidance are not new, however. They have been part of FDA's
considerations since at least 1985 when the agency substantially
revised NDA regulations to include a provision describing the
characteristics of adequate and well-controlled trials. These concepts
have also been addressed, in part, in other agency guidance documents.
However, FDA officials saw the need for more detailed guidance as they
noticed many errors, especially related to the selection of a non-
inferiority margin, in sponsors' execution of these trials. FDA
officials also expect that the use of non-inferiority trials will rise
as more drugs become available to prevent death or serious illness and
the use of placebos may become unethical.
FDA's March 2010 guidance explains when non-inferiority trials may be
used to establish a drug's effectiveness. The guidance states that
these trials are generally used when an available treatment is known
to provide an important benefit--for example, the prevention of death
or irreversible harm. In these cases, it would be considered unethical
to use a placebo in a clinical trial. The guidance also states that
non-inferiority trials may only be used when they are capable of
measuring the effect of the new drug in the study--that is, when the
active control is able to consistently demonstrate its expected effect
in the non-inferiority trial.[Footnote 31] FDA's March 2010 guidance
explains that non-inferiority trials may not be able to demonstrate
the effectiveness of drugs treating certain indications because not
all drugs have a consistent effect in treating these indications.
[Footnote 32] The guidance also offers suggestions for other types of
trials that may be useful in demonstrating a drug's effectiveness in
cases where a non-inferiority trial is unable to provide evidence of
effectiveness.
The March 2010 guidance provides detailed recommendations on how to
select an active control. For example, when more than one potential
active control exists, the guidance recommends that the most effective
drug be chosen as the active control. In addition, the frequently
asked questions section also clarifies that the active control does
not need to be FDA-approved for the indication. However, FDA officials
we interviewed stated that active controls used in non-inferiority
trials are usually FDA-approved. If the active control is not FDA-
approved, FDA asks sponsors to provide evidence of the active
control's effectiveness.
FDA's March 2010 guidance also offers detailed advice on a range of
other topics related to the use and interpretation of non-inferiority
trials. For example, it suggests two methodologies that can be used to
set the margin, offers step-by-step instructions on how to use each of
these approaches, and addresses the role of clinical judgment in
determining the margin. It also explains how to adjust the margin to
account for some of the uncertainties related to non-inferiority
trials, such as differences between the planned non-inferiority trial
and prior trials that measured the effectiveness of the active
control. The guidance offers advice on how to determine the proper
number and type of patients to enroll in the trial, and how to select
an endpoint. For example, the guidance states that the endpoint should
be "one for which there is a good basis for knowing the effect of the
active control."
Most of the experts we interviewed who reviewed FDA's March 2010
guidance told us that they thought the recommendations it included
were clear and detailed, and addressed the key principles involved in
conducting non-inferiority trials. Some experts noted that the
guidance's frequently asked questions and examples were useful in
illustrating the key principles described in the document, and said
that FDA's recommendations would help sponsors appropriately use these
trials to prove a drug's effectiveness.
While experts we interviewed who reviewed FDA's March 2010 guidance
noted that it addressed key principles, most identified additional
technical issues that they would have liked this guidance to have
addressed. For example, the March 2010 guidance does not address how
the use of a surrogate endpoint impacts the design and interpretation
of a non-inferiority trial. FDA officials told us that the guidance
applies to non-inferiority trials that use surrogate endpoints.
However, some experts we interviewed noted that such trials are
difficult to design and interpret; therefore, additional guidance on
this topic may be helpful. Since the non-inferiority margin represents
the maximum clinically acceptable extent to which the new drug can be
less effective than the active control, experts told us that sponsors
would need to translate the drug's effect on a surrogate endpoint into
its expected effect on a clinical endpoint in order to calculate the
non-inferiority margin and interpret the trials' results. Some experts
also noted that the guidance does not include enough detailed
instructions on how to estimate the effect of the active control in
the non-inferiority trial. Finally, some experts who reviewed FDA's
March 2010 guidance told us that they wished the guidance more
emphatically stated that non-inferiority trials should only be used as
a last resort when seeking drug approval.
FDA's March 2010 Draft Guidance Provides Broader and More
Comprehensive Recommendations to Supplement Previously Issued
Indication-Specific Guidance Documents:
FDA's March 2010 draft guidance provides broader and more
comprehensive information about the use of non-inferiority trials,
supplementing other indication-specific guidance documents the agency
had already issued. The objective and content of these two types of
guidance documents differ. The March 2010 guidance offers
comprehensive information on one topic, non-inferiority trials, that
may be generally applied for all drugs using these trials. In
contrast, FDA's indication-specific guidance documents present
recommendations on many topics--including trial design--for
consideration in developing drugs to treat a particular indication or
set of indications. Some of these indication-specific documents
provide recommendations on how to use non-inferiority trials for that
particular indication; for example, by suggesting a specific margin or
a specific endpoint. However, unlike FDA's March 2010 guidance, not
all indication-specific guidance documents include information on all
of the key principles involved in using a non-inferiority trial to
establish a drug's effectiveness. In addition, these indication-
specific guidance documents do not include the same level of detail on
the key principles that is in the March 2010 guidance. For example,
several of FDA's indication-specific guidance documents state that
sponsors should justify their selection of non-inferiority margins in
their NDAs. However, in these documents FDA does not elaborate on the
methods sponsors could use to select or justify the margins. In
contrast, the March 2010 non-inferiority guidance provides detailed
instructions on how to calculate the margin.
FDA's indication-specific guidance documents provide sponsors with
additional clarity on when non-inferiority trials may be used to
establish the effectiveness of drugs treating a particular indication.
From January 2002 through June 2010, FDA issued 17 guidance documents
that state the agency's position regarding the use of non-inferiority
trials in demonstrating the effectiveness of drugs treating certain
indications. In these indication-specific guidance documents, FDA
stated that non-inferiority trials may be able to demonstrate the
effectiveness of drugs treating eight indications, including those for
HIV, cancer, diabetes mellitus, and certain severe infections. During
the same period, FDA also issued nine indication-specific guidance
documents which state that non-inferiority trials may not be able to
demonstrate the effectiveness of drugs treating other indications--
including some less severe infections such as sinusitis and acute
bacterial otitis media (ear infections)--because the agency has been
unable to identify available drugs that have a consistent effect and
could serve as active controls in non-inferiority trials. (See table
3.) Appendix II identifies the guidance documents FDA has issued with
information on the use of non-inferiority trials from January 2002
through June 2010, including indication-specific documents as well as
the March 2010 draft guidance on non-inferiority trials.
Table 3: Summary of FDA Guidance Regarding the Use of Non-Inferiority
Trials for Particular Indications:
Indications for which non-inferiority trials may be able to
demonstrate a new drug's effectiveness (guidance issuance date):
1. HIV (Oct. 2002);
2. Gingivitis (June 2005);
3. Cancer (May 2007);
4. Malaria (June 2007);
5. Certain infections[A] (Oct. 2007);
6. Diabetes mellitus (Feb. 2008);
7. Community-acquired bacterial pneumonia (Mar. 2009);
8. Helicobacter pylori (Oct. 2009).
Indications for which non-inferiority trials may not be able to
demonstrate a new drug's effectiveness (guidance issuance date):
1. Complications arising from the smallpox vaccine with vaccina virus
(Mar. 2004);
2. Sinusitis treated with non-antibiotic drugs (Nov. 2006);
3. Acute bacterial sinusitis (Oct. 2007);
4. Chronic obstructive pulmonary disease (Nov. 2007);
5. Acute bacterial otitis media (Jan. 2008);
6. Acute bacterial exacerbations of chronic bronchitis in patients
with chronic obstructive pulmonary disease (Aug. 2008);
7. Influenza (Feb. 2009);
8. Systemic lupus erythematosus (June 2010);
9. Lupus nephritis caused by systemic lupus erythematosus (June 2010).
Source: GAO analysis of FDA documents.
[A] FDA's guidance noted that non-inferiority trials may be able to
provide evidence of effectiveness for drugs treating some, but not all
infections.
[End of table]
Our review of FDA's indication-specific guidance showed that the
agency has become more conservative in allowing evidence from non-
inferiority trials to demonstrate the effectiveness of new drugs.
First, FDA has revised its view regarding when non-inferiority trials
may be used. Prior to 2007, for example, FDA had approved drugs
treating several less severe infections--including acute bacterial
sinusitis, acute bacterial otitis media, and acute bacterial
exacerbations of chronic bronchitis--on the basis of evidence from non-
inferiority trials.[Footnote 33] Experts we interviewed noted that
these infections can often be resolved without treatment--and thus it
is difficult to estimate the effect that an active control drug would
have in a non-inferiority trial. In 2007 and 2008, FDA issued several
guidance documents stating that non-inferiority trials may not be able
to demonstrate the effectiveness of drugs treating these indications.
Second, FDA has become more rigorous in its review of evidence from
non-inferiority trials. For example, prior to 2001, FDA's guidance on
the development of anti-infective drugs had not advised sponsors to
scientifically calculate or justify their selected non-inferiority
margins--a step that FDA's March 2010 guidance recommends.
Agency Comments:
We provided a draft of this report to HHS for review. We received
technical comments from HHS, which we incorporated as appropriate.
As agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
from the report date. At that time, we will send copies to the
Commissioner of FDA and appropriate congressional committees. The
report also will be available at no charge on the GAO Web site at
[hyperlink, http://www.gao.gov].
If you or your staff have any questions about this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for
our Offices of Congressional Relations and Public Affairs may be found
on the last page of this report. GAO staff who made major
contributions to this report are listed in appendix III.
Signed by:
Marcia Crosse Director, Health Care:
List of Requesters:
The Honorable Charles E. Grassley:
Ranking Member:
Committee on Finance:
United States Senate:
The Honorable Henry A. Waxman:
Chairman:
The Honorable John D. Dingell:
Chairman Emeritus:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Bart Stupak:
Chairman:
Subcommittee on Oversight and Investigations:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Edward J. Markey:
House of Representatives:
[End of section]
Appendix I: New Drug Applications Approved on the Basis of Evidence
from Non-Inferiority Trials:
The Food and Drug Administration (FDA) approved 18 new drug
applications (NDA) that were submitted from fiscal year 2002 through
fiscal year 2009 on the basis of evidence from non-inferiority trials.
The majority of these were antimicrobial drugs, such as those that
treat bacterial, viral, and fungal infections. (See table 4.)
Table 4: NDAs Submitted for FDA Review from Fiscal Years 2002 through
2009 Where the Basis of Approval Included Primary Evidence from Non-
Inferiority Trials:
Drug name (active ingredient): Alinia (nitazoxanide);
NDA number: 21498;
Fiscal year of approval: 2003;
Drug type: Antimicrobial;
Approved indication: Treatment of diarrhea caused by the pathogen
Giardia lamblia[A].
Drug name (active ingredient): Aloxi (palonosetron hydrochloride);
NDA number: 21372;
Fiscal year of approval: 2003;
Drug type: Gastroenterology;
Approved indication: Prevention of acute nausea and vomiting
associated with initial and repeated courses of moderately and highly
emetogenic cancer chemotherapy[B].
Drug name (active ingredient): Cubicin (daptomycin);
NDA number: 21572;
Fiscal year of approval: 2003;
Drug type: Antimicrobial;
Approved indication: Treatment of complicated skin and skin structure
infections caused by susceptible isolates of gram-positive
microorganisms.
Drug name (active ingredient): Reyataz (atazanavir sulfate);
NDA number: 21567;
Fiscal year of approval: 2003;
Drug type: Antimicrobial;
Approved indication: Treatment of human immunodeficiency virus-1
infection.
Drug name (active ingredient): Apidra (insulin glulisine);
NDA number: 21629;
Fiscal year of approval: 2004;
Drug type: Metabolism and endocrinology;
Approved indication: Treatment of diabetes mellitus in adult patients.
Drug name (active ingredient): Tindamax (tinidazole);
NDA number: 21618;
Fiscal year of approval: 2004;
Drug type: Antimicrobial;
Approved indication: Treatment of trichomoniasis.
Drug name (active ingredient): Levemir (insulin detemir);
NDA number: 21536;
Fiscal year of approval: 2005;
Drug type: Metabolism and endocrinology;
Approved indication: Treatment of diabetes mellitus in adult patients.
Drug name (active ingredient): Mycamine (micafungin sodium);
NDA number: 21506;
Fiscal year of approval: 2005;
Drug type: Antimicrobial;
Approved indication: Prevention of Candida infections in patients
undergoing hematopoietic stem cell transplantation.
Drug name (active ingredient): Tygacil (tigecycline);
NDA number: 21821;
Fiscal year of approval: 2005;
Drug type: Antimicrobial;
Approved indication: Treatment of complicated skin and skin structure
infections and complicated intra-abdominal infections.
Drug name (active ingredient): Eraxis (anidulafungin);
NDA number: 21632;
Fiscal year of approval: 2006;
Drug type: Antimicrobial;
Approved indication: Treatment of esophageal candidiasis.
Drug name (active ingredient): Exjade (deferasirox);
NDA number: 21882;
Fiscal year of approval: 2006;
Drug type: Hematology;
Approved indication: Treatment of chronic iron overload due to blood
transfusions in patients 2 years of age and older.
Drug name (active ingredient): Noxafil (posaconazole);
NDA number: 22003;
Fiscal year of approval: 2006;
Drug type: Antimicrobial;
Approved indication: Prevention of invasive Aspergillus and Candida
infections in patients, 13 years of age and older, who are at high
risk of developing these infections.
Drug name (active ingredient): Pylera (biskalcitrate, metronidazole,
and tetracycline hydrochloride);
NDA number: 50786;
Fiscal year of approval: 2006;
Drug type: Antimicrobial;
Approved indication: Treatment of patients with Helicobacter pylori
infection and duodenal ulcer disease.
Drug name (active ingredient): Tyzeka (telbivudine);
NDA number: 22011;
Fiscal year of approval: 2007;
Drug type: Antimicrobial;
Approved indication: Treatment of chronic hepatitis B in certain
populations of adults.
Drug name (active ingredient): Doribax (doripenem);
NDA number: 22106;
Fiscal year of approval: 2008;
Drug type: Antimicrobial;
Approved indication: Treatment of complicated intra-abdominal
infections and complicated urinary tract infections caused by certain
microorganisms.
Drug name (active ingredient): Livalo (pitavastatin);
NDA number: 22363;
Fiscal year of approval: 2009;
Drug type: Metabolism and endocrinology;
Approved indication: Treatment of primary hyperlipidemia and mixed
dyslipidemia.
Drug name (active ingredient): Uloric (febuxostat);
NDA number: 21856;
Fiscal year of approval: 2009;
Drug type: Rheumatology;
Approved indication: Treatment of hyperuricemia in patients with gout.
Drug name (active ingredient): Vibativ (telavancin);
NDA number: 22110;
Fiscal year of approval: 2009;
Drug type: Antimicrobial;
Approved indication: Treatment of complicated skin and skin structure
infections caused by susceptible gram-positive bacteria in adults.
Source: GAO analysis of FDA data.
Note: Our review was limited to NDAs for new molecular entities.
[A] As part of the same NDA, Alinia was approved for the treatment of
diarrhea caused by the pathogen Cryptosporidium parvum based on
evidence from two pivotal placebo-controlled trials.
[B] As part of the same NDA, Aloxi was approved for the treatment of
delayed nausea and vomiting associated with initial and repeated
courses of moderately emetogenic cancer chemotherapy based on evidence
of superiority to an active control in the same trial.
[End of table]
[End of section]
Appendix II: FDA Guidance Documents Issued with Information on the Use
of Non-Inferiority Trials:
From January 2002 through June 2010, FDA issued 17 indication-specific
guidance documents that included information about non-inferiority
trials, and one guidance document that included broad recommendations
regarding the use of non-inferiority trials.
Table 5: FDA-Issued Guidance Including Recommendations on the Use of
Non-Inferiority Trials, January 2002 through June 2010:
Guidance title: Guidance for Industry, Antiretroviral Drugs Using
Plasma HIV RNA Measurements--Clinical Considerations for Accelerated
and Traditional Approval;
Issuance month and year: October 2002.
Guidance title: Guidance for Industry, Vaccinia Virus--Developing
Drugs to Mitigate Complications from Smallpox Vaccination;
Issuance month and year: March 2004.
Guidance title: Guidance for Industry, Gingivitis: Development and
Evaluation of Drugs for Treatment or Prevention;
Issuance month and year: June 2005.
Guidance title: Guidance for Industry, Sinusitis: Designing Clinical
Development Programs of Nonantimicrobial Drugs for Treatment;
Issuance month and year: November 2006.
Guidance title: Guidance for Industry, Clinical Trial Endpoints for
the Approval of Cancer Drugs and Biologics;
Issuance month and year: May 2007.
Guidance title: Guidance for Industry, Malaria: Developing Drug and
Nonvaccine Biological Products for Treatment and Prophylaxis;
Issuance month and year: June 2007.
Guidance title: Guidance for Industry, Acute Bacterial Sinusitis:
Developing Drugs for Treatment;
Issuance month and year: October 2007.
Guidance title: Guidance for Industry, Antibacterial Drug Products:
Use of Noninferiority Studies to Support Approval;
Issuance month and year: October 2007.
Guidance title: Guidance for Industry, Chronic Obstructive Pulmonary
Disease: Developing Drugs for Treatment;
Issuance month and year: November 2007.
Guidance title: Guidance for Industry, Acute Bacterial Otitis Media:
Developing Drugs for Treatment;
Issuance month and year: January 2008.
Guidance title: Guidance for Industry, Diabetes Mellitus: Developing
Drugs and Therapeutic Biologics for Treatment and Prevention;
Issuance month and year: February 2008.
Guidance title: Guidance for Industry, Acute Bacterial Exacerbations
of Chronic Bronchitis in Patients with Chronic Obstructive Pulmonary
Disease: Developing Antimicrobial Drugs for Treatment;
Issuance month and year: August 2008.
Guidance title: Guidance for Industry, Influenza: Developing Drugs for
Treatment and/or Prophylaxis;
Issuance month and year: February 2009.
Guidance title: Guidance for Industry, Community-Acquired Bacterial
Pneumonia: Developing Drugs for Treatment;
Issuance month and year: March 2009.
Guidance title: Guidance for Industry, Helicobacter pylori-Associated
Duodenal Ulcer Disease in Adults: Developing Drugs for Treatment;
Issuance month and year: October 2009.
Guidance title: Guidance for Industry, Non-Inferiority Clinical Trials;
Issuance month and year: March 2010.
Guidance title: Guidance for Industry, Lupus Nephritis Caused By
Systemic Lupus Erythematosus--Developing Medical Products for
Treatment;
Issuance month and year: June 2010.
Guidance title: Guidance for Industry, Systemic Lupus Erythematosus--
Developing Medical Products for Treatment (previously issued in March
2005 as Guidance for Industry, Systemic Lupus Erythematosus--
Developing Drugs for Treatment);
Issuance month and year: June 2010.
Source: FDA documents.
[End of table]
[End of section]
Appendix III: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
In addition to the contact named above, Geri Redican-Bigott, Assistant
Director; Kathleen Diamond; Carolyn Garvey; Cathy Hamann; Julian
Klazkin; Kaitlin McConnell; and Patricia Roy made key contributions to
this report.
[End of section]
Footnotes:
[1] 21 U.S.C. § 355(d), 21 C.F.R. § 314.126 (2009).
[2] NDAs for new molecular entities represented about 25 percent of
all NDAs submitted during this period.
[3] Unless otherwise noted, we use the term NDA throughout this report
to refer to NDAs for new molecular entities.
[4] We obtained these materials between July 2009 and January 2010
from FDA's Web site, [hyperlink,
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/].
[5] Alternatively, FDA may determine that other clinical trials
provide support for the overall application, but do not provide the
primary evidence of effectiveness.
[6] 21 C.F.R. § 312.20 (2009). Sponsors conducting clinical trials
outside the United States are not required to submit data to, or
consult with, FDA prior to or during the trials, although they may
choose to do so at any time.
[7] 21 C.F.R. § 312.23 (2009).
[8] FDA will allow clinical trials to proceed as long as the
participants are not exposed to an unreasonable and significant risk
of illness or injury, and that other requirements are met. 21 C.F.R. §
312.42(b) (2009).
[9] FDA does not require sponsors to show that a drug is more
effective than other available treatments, although such evidence may
be used to support a drug's approval.
[10] 21 C.F.R. § 314.126 (2009).
[11] For example, demonstrating that a drug can lower blood pressure
may be used as a surrogate endpoint to predict whether the drug is
effective in preventing strokes. A drug sponsor can demonstrate the
effect of a new drug on a surrogate endpoint based on smaller and
shorter trials than would be required to prove the drug's
effectiveness on a clinical endpoint. For additional information on
the use of surrogate endpoints in the drug approval process, see GAO,
New Drug Approval: FDA Needs to Enhance Its Oversight of Drugs
Approved on the Basis of Surrogate Endpoints, GAO-09-866 (Washington,
D.C.: Sept. 23, 2009).
[12] According to FDA officials, the active controls used in non-
inferiority trials are generally FDA-approved for that particular
indication and population. However, sponsors may use active control
drugs that are not FDA-approved; for example, when clinical trials
take place outside the United States. In such cases, FDA asks sponsors
to provide, as part of their NDA, evidence of the active control's
effect in treating the indication and population as studied in
adequate and well-controlled trials.
[13] Non-inferiority trials that show a small difference between a new
drug and an active control do not necessarily demonstrate that the new
drug is effective--it could also mean that neither was effective in
the trial; evidence that the active control drug was effective in the
trial is therefore critical.
[14] 21 C.F.R. § 312.41(c) (2009).
[15] Food and Drug Administration, Guidance For Industry: Clinical
Development and Labeling of Anti-infective Drug Products (Rockville,
Md.: Oct. 26, 1992).
[16] Seventy-six percent of all NDAs for antimicrobial drugs included
evidence from at least one non-inferiority trial.
[17] The 18 NDAs that FDA approved on the basis of evidence from
pivotal non-inferiority trials represent a small share, about 14
percent, of the total number of NDAs FDA approved during this period--
125. These 18 approvals also reflect a 42 percent approval rate for
all NDA applications submitted with evidence from non-inferiority
trials from fiscal years 2002 through 2009, lower than the respective
approval rate--71 percent--for all NDA applications submitted during
this period.
[18] These 12 approvals reflect 50 percent of all NDAs for
antimicrobial drugs that were approved during this time frame.
[19] For example, in 2004 FDA approved the drug Apidra for the
treatment of diabetes mellitus in adult patients based on evidence of
effectiveness on a surrogate endpoint as measured in three pivotal non-
inferiority trials. Through the use of a blood test, the drug's
sponsor demonstrated that Apidra reduced patients' hemoglobin A1c--a
measure of blood sugar levels. This surrogate endpoint was used as an
alternative to measuring clinical endpoints of diabetes-related
morbidity, such as eye or kidney disease.
[20] One of the two unapproved active control drugs was similar to an
FDA-approved drug; both had the same active ingredient but used
different formulations and routes of administration.
[21] For some of these drugs, we were unable to distinguish between
trials demonstrating superiority and non-inferiority to active
controls because FDA has not always included evidence of its
statistical testing--for example, confidence intervals--in its review
documentation.
[22] We could not determine whether FDA reviewed two active controls
that were used in pivotal non-inferiority trials supporting two NDAs.
Both NDAs were approved based on evidence from multiple pivotal non-
inferiority trials, and each included one other active control which
FDA reviewed.
[23] In its review documentation, FDA identified and acknowledged that
one of the drugs it approved on the basis of evidence from a non-
inferiority trial would be inappropriate to use as an active control
drug in future trials. This type of identification and acknowledgment
reduces the potential for biocreep to occur in the future.
[24] Fourteen of the 18 NDAs FDA approved included non-inferiority
trials that measured the effectiveness of the new drug and active
control drugs with a success rate representing the portion of patients
achieving a successful outcome for the relevant indication. Trials for
3 of the 18 NDAs did not measure effectiveness this way; these trials
measured effectiveness as a percentage change in outcome, for example,
the percentage change in cholesterol or blood sugar, and therefore the
non-inferiority margins used for these drugs are not directly
comparable. In addition, the one remaining NDA included evidence from
two non-inferiority trials that measured the effect of the new drug in
both ways, measuring with a success rate in one trial and a percentage
change in outcome in another trial.
[25] We did not assess whether FDA's agreement with these margins was
appropriate.
[26] One pivotal trial for Livalo--a drug FDA approved in fiscal year
2009 for the treatment of patients with high cholesterol--was
unsuccessful in demonstrating non-inferiority to its active control in
one patient group. However, this drug's application also included the
results from four other pivotal trials which tested the drug in
different patient groups using three different active controls. One of
these four trials showed that Livalo was superior to its active
control, and three trials demonstrated that the drug was non-inferior
to the trials' respective active controls. FDA approved the drug based
on the collective evidence of effectiveness as demonstrated in all
five trials.
[27] Exjade presented an opportunity for increased convenience in
administration and a potential for increased compliance with
treatment. Exjade is available in a once-daily tablet. Previously, the
only other available treatment was an infusion administered between 8
and 24 hours per day.
[28] The remaining 16 NDAs also included evidence from non-inferiority
trials but were either approved on the basis of other primary
evidence, or were not approved as of December 31, 2009. Some of these
trials were unsuccessful in demonstrating non-inferiority to an active
control or had demonstrated superiority to an active control or
placebo. Other applications provided evidence of effectiveness through
non-inferiority trials but FDA had not approved the drug due to other
concerns, such as safety.
[29] As of December 31, 2009, FDA had approved seven of these
applications based on other evidence, such as superiority to placebo
or active control. It decided not to approve the remaining two drugs.
[30] See Food and Drug Administration, Guidance for Industry: Non-
Inferiority Clinical Trials (Silver Spring, Md.: Mar. 1, 2010). FDA
guidance documents reflect the agency's current thinking on a topic.
Such documents include non-binding recommendations and do not
establish legally enforceable requirements. FDA solicited comments
from the public on this draft guidance through June 1, 2010, and
received comments from 13 interested parties as of that date. Agency
officials told us that they plan to review these comments and issue a
final version of the guidance, although they were unsure of when this
guidance would be issued in final form.
[31] FDA recommends that the active control consistently demonstrate
its expected effect because non-inferiority trials are only able to
measure the new drug's effectiveness relative to the active control.
If the active control did not demonstrate its expected effect in the
non-inferiority trial, the results of the trial may not be able to
support the conclusion that the new drug is effective.
[32] For example, drugs treating depression and anxiety often fail to
consistently demonstrate effectiveness compared to placebo. Therefore,
the agency considers non-inferiority trials incapable of providing
evidence of effectiveness to support the approval of new drugs
treating these indications.
[33] For example, FDA approved Factive in fiscal year 2003 for the
treatment of acute bacterial exacerbations of chronic bronchitis on
the basis of evidence from non-inferiority trials. FDA also approved
Ketek in fiscal year 2004 for the treatment of acute bacterial
sinusitis, acute bacterial exacerbations of chronic bronchitis, and
community acquired pneumonia (of mild to moderate severity) on the
basis of evidence from non-inferiority trials. However, in fiscal year
2007 FDA removed two indications--acute bacterial sinusitis and acute
bacterial exacerbations of chronic bronchitis--from Ketek's labeling
as a result of concerns related to the product's safety. The NDAs for
both of these drugs were submitted for review prior to fiscal year
2002 and were therefore not included within our scope.
[End of section]
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