Equivalence trials

Most clinical trials are superiority trials and they are usually conducted
to show that a new treatment is better than another or to the placebo
It is increasingly more difficult to develop new therapies with higher
efficacy than the standard of care.
In some cases it may be necessary to show that a new drug is
comparable or not inferior to an existing one, with the difference being
within a predefined range. Such studies are called equivalence studies
Unlike a placebo control trial, establishing equivalence of the
therapies does not imply that either of them are effective. Therefore
the investigator needs to establish equivalence to a therapy that has
been proven to be superior to placebo.
Statistical methods for the analysis of equivalence studies require only
simple modifications to the traditional hypotheses testing framework

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Equivalence trials

Why are equivalence trials needed?

There might be changes developed in the chemical composition of a
drug and it is of interest whether the change in formulation does not
change the efficacy of the drug
The patents for the existing drug are expiring, creating the
opportunity to develop generic alternatives.

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Terminology

The term active control trial refers to all studies in which the
control treatment is an established treatment with a known degree of
effectiveness
If the intent is to show that the differences between control and study
treatments are not large in either direction, the trial is called an
equivalence trial
In many active control trials the principal comparison is one-sided, the
objective being to demonstrate that the study treatment is at least
not substantially worse than the control treatment. Such trials are
termed non-inferiority trials (they are also called sufficiency trials)

J Siegel, Equivalence and Noninferiority trials, American Heart Journal,

139(4):166170
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Equivalence trials

Successful equivalence trials cannot prove that drug effects are

identical
Successful non-inferiority trials do not establish the absence of any
inferiority between therapies.
Both types of trials seek to reject the possibility that differences in
treatment effects equal or exceed a preset limit or margin.

J Siegel, Equivalence and Noninferiority trials, American Heart Journal,

139(4):166170
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Types of equivalence trials

Clinical equivalence: Equivalence based on clinical outcomes such

as death, heart attack
Bioequivalence: Uses a pharmacokinetic (PK) approach, comparing
the parameters from plasma or blood concentration

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Designs issues in equivalence trials

The active control treatment must have been shown conclusively to

be effective
The active control must be used with the dose and formulation
proven effective
The studies that demonstrated benefit of active control versus
placebo must be sufficiently recent to make sure no medical advances
or other changes have occured
The evidence that demonstrated the benefits of the active control
must be available
The response variable used in the new trial must be sensitive to the
postulated effects of the active control
The design for equivalence trials can be either parallel or crossover
The crossover design is usually more efficient

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Designs issues in equivalence trials

It cannot be shown that two therapies are identical

If the intervention falls sufficiently close to the active control as
defined by some predefined margins, the new intervention is claimed
to be the same as the active control (in an equivalence trial) or no
worse than the control (in a noninferiority trial)

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Specifying the hypotheses in equivalence and noninferiority
trials

The Null hypothesis is the opposite of the research hypothesis and is

what the investigator hopes to disprove
The Alternative hypothesis is what the study aims to show
We want to minimize the type I error (i.e. incorrectly rejecting the
null hypothesis)
The probability of occurrence of a type I error is called the
significance level of the test and it is usually denoted by
The value for is usually set at 0.05 or lower.

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Specifying the hypotheses in equivalence and noninferiority
trials

T : rate of outcome with the new therapy

AC : rate of outcome with the active control therapy
Smaller rates mean better efficacy

Equivalence Noninferiority
Statistical test Two sided One sided
Null hypothesis H0 : T AC or H0 : T AC M
T AC
Alternative hypothesis HA : < T AC < HA : T AC < M

is the amount of worse effect of the new treatment compared to active control
that was chosen as tolerable
M is the prespecified maximum allowable limit of difference in outcome rates
between the new treatment and the active control
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Equivalence trial

In an equivalence trial the null hypothesis (HA ) implies that the new
and active control treatments have differing outcome rates, while the
alternative hypothesis implies that the new treatment is statistically
similar in outcome rates to the active control, within a predefined
range (, )
Example equivalence trial:
(, ) = (1%, 1%) ; by medical expert opinion, it is agreed that an
absolute reduction of event rates within 1% of the active control
treatment is acceptable to determine that the new treatment has an
equivalent efficacy to the active control
Results: 90%CI for T AC =(0.7%, 0.7%);
Conclusion: Since (0.7%, 0.7%) is included in (1%, 1%),
equivalence can be established between the new treatment and the
active control

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Equivalence trial

In an equivalence trial the null hypothesis (H0 ) implies that the new
and active control treatments have differing outcome rates, while the
alternative hypothesis implies that the new treatment is statistically
similar in outcome rates to the active control, within a predefined
range (, )
Example equivalence trial:
(, ) = (1%, 1%) ; by medical expert opinion, it is agreed that an
absolute reduction of event rates within 1% of the active control
treatment is acceptable to determine that the new treatment has an
equivalent efficacy to the active control
Results: 90%CI for T AC =(3%, 3%);
Conclusion: Equivalence cannot be established between the new
treatment and the active control

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Noninferiority trial

In an noninferiority trial the null hypothesis (H0 ) implies that the new
treatment is inferior to the active control, while the alternative
hypothesis implies that the new treatment is clinically noninferior to
the active control treatment within the predefined allowable range M
of clinical significance

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Procedure for testing equivalence

The most widely used approach to test equivalence is the two

one-sided test (TOST) procedure (DJ Schuirmann, 1987)
Using TOST, equivalence is established at the significance level if a
(1 2)100% confidence interval for the difference in efficacy is
contained within the interval (, )

DJ Schuirmann. A comparison of the two one-sided tests procedure and the power
approach for assessing equivalence of average bioavailability. J Pharmacokin Biopharm.
1987;15:657680
E Walker and A. S. Nowaki. Understanding Equivalence and Noninferiority Testing.
J Gen Intern Med. 2011 Feb; 26(2): 192196
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