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Encyclopedia of Biopharmaceutical Statistics


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Active Control Trials


George Y. H. Chi a; Gang Chen a; Mark Rothmann a; Ning Li a a Division of Biometrics I/OB/OPaSS/CDER/FDA, U.S. Food and Drug Administration, Rockville, Maryland, U.S.A. Online Publication Date: 23 April 2003

To cite this Section Chi, George Y. H., Chen, Gang, Rothmann, Mark and Li, Ning(2003)'Active Control Trials',Encyclopedia of

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Active Control Trials


George Y. H. Chi Gang Chen Mark Rothmann Ning Li
U.S. Food and Drug Administration, Rockville, Maryland, U.S.A.

INTRODUCTION An active control is an intervention, such as a drug, a therapy, or a medical device, whose effectiveness has previously been established. Active controls have been used in trials with or without a placebo. For clinical drug trials with a placebo, active controls usually play a secondary role with respect to demonstrating the effect of a new treatment. In placebo control trials involving psychotropic agents (Leber[1,2]), active controls are intended for the purpose of verifying the assay sensitivity of the trial, i.e., the ability of the trial to demonstrate an effective drug to be effective (ICH-E10[3]). In this article, an active control trial refers specifically to a trial with an effective intervention or treatment as the control, without the presence of a placebo. Active control trials often arise when the objective of a trial is to investigate the effect of the new treatment on mortality or serious morbidity outcome for patients with certain serious diseases. For obvious ethical reason, when there are available known effective treatments for the disease, one should use one of these active treatments instead of a placebo as the control (Declaration of Helsinki[4]). In the interest of clarity and without much loss in generality, the concepts and issues will be discussed here within the framework of a blinded, parallel, randomized trial comparing the survival experience of a new treatment, T, to a single active control, C, in treating patients with certain serious diseases.

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perimenter then concludes that the new treatment is equivalent or noninferior to the active control. However, this reasoning is fallacious because in a superiority trial, failing to reject the null hypothesis of inferiority or no difference does not imply that the null hypothesis is true. If there is any interest to show that the new treatment is equivalent or noninferior to the active control, then the hypothesis should reflect the desired equivalency or noninferiority. Unless the new treatment represents a significant therapeutic advance, in general, it would be difficult for the new treatment to show superiority to the active control. This naturally leads to an interest in demonstrating the effectiveness of a new treatment through an active control noninferiority (or equivalence, in a two-sided version) trial. One may refer to Temple[5] for a discussion of some of the problems involved in the interpretation of active control trials. This article will clarify some of these concepts and the assumptions behind an active control trial. HYPOTHESES OF AN ACTIVE CONTROL TRIAL Let the true hazard ratio of T relative to C be denoted by HR(T/C), and let hr(T/C) denote its estimator. Let P denote the reference placebo, and HR(P/C) and hr(P/C) denote the corresponding hazard ratios. Superiority Hypotheses If there is reason to believe that the new treatment, T, represents a true therapeutic advance and one wishes to demonstrate the superiority of T over C, then the null and alternative hypotheses are simply, H0 : HRT =C  1 vs: Ha : HRT =C < 1

OBJECTIVE OF AN ACTIVE CONTROL TRIAL The primary objective of an active control trial is to demonstrate the effectiveness of a new treatment, T. To show that a new treatment, T, is effective, traditionally, it is required to demonstrate that T is superior to C, the active control. This is analogous to a placebo control trial where the new treatment, T , has to demonstrate superiority to the placebo. It often happens that upon failing to demonstrate superiority in such a trial, the exEncyclopedia of Biopharmaceutical Statistics DOI: 10.1081/E-EBS 120007377 Copyright D 2003 by Marcel Dekker, Inc. All rights reserved.

In terms of log hazard, these hypotheses may be stated as, H0 : log HRT =C  0 vs: Ha : log HRT=C < 0
1 9

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Active Control Trials

Fig. 1

Control effect, treatment effect, and margin d.

The null hypothesis in Eq. 1 may be tested by the following test statistic.
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t0 log hr T =C=SElog hr T =C

where d > 0 is a fixed noninferiority margin (this d is different from the d above). The null hypothesis in Eq. 3 may be tested by the following test statistic. t0 d log hr T =C d=SElog hr T =C
4

where SE stands for standard error. The null hypothesis in Eq. 1 is rejected if t0 < 1.96 (Walds test), or equivalently, if log hr(T/C) + 1.96SE[log hr(T/C)] < 0, at the one-sided 2.5% significance level. As in a placebo control trial, in an active control superiority trial, there is only one parameter that will be tested. In the case here, this parameter is the log-hazard ratio, log HR(T/C), of the new treatment relative to the control. However, if the new treatment is only as effective as the control, then the null hypothesis in Eq. 1 is unlikely to be rejected. One may not conclude that the new treatment is noninferior (or equivalent) to the control upon failing to reject this null hypothesis. Noninferiority Hypotheses with a Fixed d Margin When the new treatment is thought to be as effective as the control and the objective of the trial is to demonstrate the effectiveness of this new treatment by showing that it is noninferior to the control, then the null and alternative hypotheses may be stated as follows: H0 : HRT =C  1 d Ha : HRT =C < 1 d where d > 0 is a fixed noninferiority margin (Blackwelder[6]). Again, in terms of log hazard, these hypotheses may be stated as follows: H0 : log HRT =C  d Ha : log HRT =C < d vs:
3

vs:

The null hypothesis in Eq. 3 is rejected if t0(d) < 1.96, or equivalently, if log hr(T/C) + 1.96SE[log hr(T/ C)] < d, at the one-sided 2.5% significance level. One may then conclude that the new treatment is noninferior to the active control within this fixed margin d. The question is how should this d margin be defined? If the margin d is arbitrarily selected, then the rejection of the null hypothesis in Eq. 3 may actually lead to the conclusion that a new treatment is noninferior to the control when, in reality, it is worse than a placebo. This can easily be seen from the following scenario. Assume that in the current trial, the true hazard ratio is known and is given by HR(P/C). If the margin d is specified so that it is greater than the effect of the control, i.e., d > log HR(P/ C), then the rejection of the null hypothesis in Eq. 3 does not rule out the possibility that the new treatment can be worse than the placebo, i.e., log HR(P/C) < log HR(T/ C). This is easily seen from the following diagrams. From Fig. 1, it is clear that, in general, in an active control trial, one should not specify the margin d to be an arbitrarily fixed number. In particular, one should avoid specifying a d margin that is greater than the effect of the control. How can this be accomplished? If the true hazard ratio, HR(P/C), is known, then this can be done easily by defining the d margin to be a fraction of the control effect, e.g., d = 1/2 log HR(P/C). However, the true control effect is never known even if there were a placebo present in the current trial. The true control effect can only be estimated. When there is a placebo in the current trial, then the true control effect may be estimated by log hr(P/C). When there is no placebo in the current trial, the true control effect needs to be estimated from historical data. In either case, one can

Active Control Trials

11

only provide at best a probability statement regarding the likelihood of d < log HR(P/C)). For example, if the true control effect, log HR(P/C), can be estimated from the historical data by the lower limit of the 95% confidence interval (CI) of the control effect, then the d margin defined as a fixed number equal to half of this estimate of the control effect, i.e., d 1=2 flog hr P=C 1:96SElog hr P=C g
5

provides a high probability that d < log HR(P/C). The test of the null hypothesis in Eq. 3 by t0(d), where d is defined as in Eq. 5, has been called the two 95% CItesting procedure. That is, the null hypothesis in Eq. 3 is rejected if log hr T =C 1:96SElog hr T =C
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< 1=2floghr P=C 1:96SElog hr P=Cg

A somewhat similar two 90% CI-testing procedure has been used in thrombolytic trials (White[7]). Note that this d in Eq. 5 is not truly a fixed number because it is defined in terms of the observed historical data. Thus, treating d as a fixed number in the hypotheses in Eq. 3 is not exactly correct. It is argued that although the two 95% CI-testing procedure offers a high probability that d < log HR (P/C), it may be conservative because the true control effect, log HR(P/C), may be very much underestimated by the lower limit of the 95% CI of the control effect. On the other hand, using the point estimate, hr(P/C), in the estimate of the true control effect may lead to a margin d that is larger than the true control effect with relatively high probability. That is, if one defines d 1=2 log hr P=C
7

high probability, one must define d as a certain fraction, 0 < f0 < 1, of the control effect, log HR(P/C), which is unknown and needs to be estimated with data from historical placebo control trials. The idea of considering retention of a certain fraction of the control effect has been discussed in Hauck and Anderson,[8] Holmgren,[9] Koch and Tangen,[10] and Rothmann et al.[11] When the noninferiority hypothesis is formulated in terms of a fraction of control effect to be retained, it provides several advantages. First, with the specification of f0, one does not need to prespecify a d margin. Secondly, the fraction of control effect to be retained can be specified according to the trial objective. For instance, if the current trial objective is to demonstrate that the new treatment is noninferior to the active control, then the fraction specified should be closer to 1. If the current trial objective is to demonstrate that the new treatment is simply effective, then the fraction specified may be relatively smaller. Thirdly, the type I error can be controlled at the desired level under certain assumptions. The definition of the fraction, f, of control effect retained by the new treatment is simply, f log HRP=C log HRT =C = log HRP=C
8

where the active control is assumed to be effective, i.e., log HR(P/C) > 0, in the current trial. The noninferiority hypotheses may be stated as follows. H0 : f  f0 vs: Ha : f > f0
9

where f0 is the desired fraction of active control effect to be retained by the new treatment. Upon substituting the expression for f in Eqs. 8 into 9 and after some algebra, the null and alternative hypotheses in Eq. 9 can be restated as, H0 : log HRT =C  1 f0 log HRP=C vs: Ha : log HRT =C < 1 f0 log HRP=C
10

Testing the null hypothesis in Eq. 3 with the statistic t0(d), where d is defined by Eq. 7, is equivalent to an asymmetric two CI-testing procedure where the control effect, log HR(P/C), is estimated by the point estimate, log hr(P/C), which can be thought of as the lower limit of the 0% CI of the control effect. These issues will have a more satisfactory explanation when one reformulates the null and alternative hypotheses as discussed below. Noninferiority Hypotheses with Fraction of Control Effect Retained From the above discussion, it is clear that for the margin d to satisfy the condition that d < log HR(P/C) with

The alternative hypothesis of interest in Eq. 10 can be interpreted as a desire to rule out a loss of more than (1 f0) of the control effect. The fraction f0 reflects, in a sense, the level of evidence one may demand of the new treatment. For example, when f0 = 1, i.e., requiring 100% retention of the control effect, the hypotheses in Eq. 10 become the superiority hypotheses in Eq. 1. When f0 = 0, i.e., requiring 0% retention of the control effect, the hypotheses in Eq. 10 become indirect comparisons to the reference placebo. Comparing to Eq. 3, one may view the expression (1 f0) log HR(P/C) in Eq. 10 as the d margin although,

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Active Control Trials

here, (1 f0) log HR(P/C) is not a prespecified number. It involves the true control effect, log HR(P/C), which is unknown. In the two 95% CI-testing procedure, the expression (1 f0) log HR(P/C) in Eq. 10 is replaced by the estimate (Eq. 5), and the whole expression is considered as a fixed d margin. In contrast to a superiority trial, in an active control noninferiority trial, the hypotheses in Eq. 10 involve two parameters: the hazard ratios HR(T/C) and HR(P/C). Recognizing the fact that log HR(P/C) is an unknown parameter, the following statistic T is proposed for testing the null hypothesis in Eq. 10. T log hr T =C 1 f0 log hr P=C= q fSE2log hr T =C SE2 1 f0 log hr P=Cg
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One rejects H0 at the one-sided 2.5% significance level if t < 1.96. From the triangle inequality, one can easily deduce that q q fSE2 log hr T =C g fSE2 1 f0 log hr P=C g q  fSE2 log hr T =C SE2 1 f0 log hr P=C g
13

11

T is asymptotically normal and has good convergence property (Rothmann et al.[11]). One can reject H0 at the one-sided 2.5% significance level if T < 1.96. An application of this method can be found in Li et al.[12] As in an active control trial, there is no concurrent placebo, one cannot estimate the control effect, log HR(P/C), from the current trial. In Eq. 11, the estimate, log hr(P/C), needs to be estimated with data from historical placebo control trials. For this to be valid, one has to assume that the current control effect has not changed over time or, if it has changed, how much it has been reduced. For example, one may assume that the current control effect is a fraction, y, of the historical control effect. Thus, in Eq. 11, one may include a fraction, y, in front of the estimate of the control effect, log hr(P/C), which is based on the data from historical placebo control trials. Without loss in generality, the discussion below will assume that y = 1. Relationship Between the Fixed d-Margin Hypotheses and Fraction Retention Hypotheses The test of the fixed d-margin null hypothesis in Eq. 3 using the statistics t0(d) with d defined by Eq. 5 is equivalent to the two 95% CI-testing procedure (Eq. 6). It can easily be shown to be equivalent to using the following statistic t to test the fraction retention null hypothesis in Eq. 10: t flog hr T =C 1 f0 log hr P=C g q = fSE2 log hr T =Cg q fSE2 1 f0 log hr P=C g

and, hence, it follows that T < t, whenever the common numerator of both T and t, log hr(T/C) (1 f0) log hr(P/C), is negative. Therefore, the null hypothesis H0 in Eq. 10 will be rejected by T whenever it is rejected by t at the same critical value, say, 1.96. This implies that relative to testing the null hypothesis in Eq. 10, the statistic t is deflating the type I error. The test of the fixed d-margin null hypothesis in Eq. 4 using the statistic t0(d) with d defined by Eq. 7 based on the point estimate, log hr(P/C), is a special case of an asymmetric two CI-testing procedure. It is easily seen to be equivalent to using the following statistic t* to test the null hypothesis in Eq. 10: t* flog hr T =C 1 f0 log hr P=C g= q SE2 flog hr T =Cg
14

12

Once again, note that t* < T < t whenever the common numerator of t*, T and t, log hr(T/C) (1 f0) log hr(P/C) is negative. Thus, in testing the null hypothesis in Eq. 10 at the same critical value of 1.96, the statistic t* inflates the type I error. Thus, the statistic T protects against the conservatism of t and the liberalism of t* relative to testing the fraction retention null hypothesis in Eq. 10. It is shown that for time to event endpoints, the statistic t deflates the type I error from 0.025 to as low as approximately 0.0028, while t* can inflate the type I error to as much as 0.50 (Rothmann et al.[11]). It is of interest to point out that these test statistics can be shown to correspond conditionally to two CI-testing procedures, where the control effect is estimated by the lower limit of a 100(1 g)% CI, 0 < g < 1. The test statistic t* corresponds to g = 1, t corresponds to g = 0.05, and T corresponds to some g = gT, where 0.05 < gT < 1. This provides an intuitive explanation as to why the test statistic T protects against the conservatism of t and the liberalism of t*. For time to event endpoints, such as survival, one may obtain an approximate estimate of gT at the design stage.

Active Control Trials

13

Some Remarks The definition of the fraction, f, of control effect to be retained by the new treatment can also be stated in terms of hazard ratios as follows. fh HRP=C HRT =C =HRP=C 1
15

where the active control is assumed to be effective, i.e., HR(P/C) 1 > 0, in the current trial. The noninferiority hypotheses may be stated as follows. H0 : fh  f0 vs: Ha : fh > f0
16

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where f0 is the desired fraction of active control effect to be retained by the new treatment. Upon substituting the expression for fh in Eqs. 15 into 16 and after some algebra, the null and alternative hypotheses in Eq. 16 can be restated as, H0 : HRT =C  1 1 fh HRP=C 1 vs: Ha : HRT =C < 1 1 fh HRP=C 1
17

When 0 < f < 1, it can be shown easily that f < fh < 1. Thus, if the noninferiority null hypothesis in Eq. 10 is rejected, then it follows that the null hypothesis in Eq. 16 is rejected for the same value of f0. Also, a test statistic for those hypotheses in Eq. 16 analogous to Eq. 14 can be constructed. An application of such a test statistic can be found in Ref. [13].

ICH-E10 document on the Choice of Control[3] introduces and discusses this concept in some detail. It essentially involves the quality of a trial including various aspects of trial design, conduct, and analysis. The third assumption is that the control effect in the current trial is either the same as or is some fraction of the historical control effect, and that there are placebo control historical trials on the basis of which the control effect and its variability can be reasonably assessed. In this regard, issues with regard to quality, reliability, publication, and selection biases of these historical trials are of major concern and need to be dealt with. One should strive to make the current trial as similar as possible to the historical trials. If the active control effect has been diminished for one reason or another, then one need to be able to specify this reduction fraction. The fourth assumption is that the trial is free of bias. Active control trial has potential for bias toward the null without having the trial unblinded. Strict standard operating procedures should be in place. As all of these assumptions cannot be truly verified, the validity of an active control trial is always subject to question. Therefore, active control trials should be considered only when it is truly unethical to use a placebo. Some Design Considerations As there is no placebo in the current active control trial, the control effect needs to be estimated from historical trial data. The questions one should address are: What historical placebo control trials are available? Which collection of historical trials will be used to provide the estimate of the control effect? What kind of analysis will be used to provide this estimate? How reliable is the estimate of the historical control effect? Although the control effect may be assessed by using data from historical randomized placebo-controlled studies, the current control effect may be different because of changes in patient population, standard care, medical practice, etc. One should design the current trial to be as similar as possible to the historical placebo control trials used in estimating the historical control effect. Important factors that may influence the trial outcome should be identified and may include regional, gender, ethnic, patient characteristics. Standard of care differences may affect trial outcome. The current trial should also be as similar as possible to the historical trials with respect to these factors. Some adjustment of the historical control effect may be necessary by either replacing the control effect, log HR(P/C), in the hypotheses in Eq. 10 by y log HR(P/C), where 0 < y < 1, or by adjusting using a mathematical model for population and study differences. One should be clear about the primary objective of the active control trial. Should the objective be to demonstrate superiority of the new treatment to the control,

PLANNING FOR AN ACTIVE CONTROL TRIAL The following are some important issues to be considered when contemplating an active control trial. Validity of Active Control Trials In order to have a valid statistical inference for an active control trial, several key assumptions have to be reasonably satisfied. The first assumption is that in the current trial setting, the active control is effective. Generally, this assumption is unverifiable. If this assumption is not true, then, for a superiority trial, one may only conclude that the new treatment is effective, but not that it is superior to the control. For a noninferiority trial, it may lead to the approval of a new treatment that is actually worse than a placebo. If possible, one should consider special design features and other concurrent trials that may provide evidence that the active control is effective. The second assumption is that the current trial has assay sensitivity. Assay sensitivity is defined as the ability of a trial to show an effective treatment to be effective. The

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noninferiority to the control, or simply effectiveness of T1.1 the new treatment? Each of these objectives requires a T1.2 different hypothesis. For demonstration of noninferiority, one needs to specify a fraction, f0, of the control effect T1.3 to be retained. The specification of this fraction depends T1.4 on the trial objective. If the active control is highly T1.5 effective, then there may be no legitimate reason to T1.6 consider a new treatment that is inferior to this control. In T1.7 this case, one may require f0 to be closer to 1. However, if the new treatment offers some important benefits that are not available from the active control, such as a better toxicity profile, then f0 may be specified somewhat smaller. In the latter case, one may only conclude that the new treatment is effective, but not noninferior to the control. The actual value of f0 may also depend not only on types of therapies, diseases, and endpoints but also on the distributional properties of the estimated control effect as well. The conservatism of the two 95% CI-testing procedure does not take into account any of the concerns regarding the validity of the active control trial, nor the confidence one has regarding the estimate of the control effect. At the design stage of an active control trial, such concerns and lack of confidence may be reflected in the values specified for various design parameters. The design parameters include the fraction, f0, of control effect to be retained and the fraction, y, of the historical control effect to be reduced. The specification of these design parameters should also take into consideration how the control effect estimate is calculated and the resultant sample-size requirement. Once f0 and y have been specified, one can calculate the sample size required for testing the noninferiority null hypothesis in Eq. 10. Sample-Size Determination The sample size required for testing the null hypothesis in Eq. 10 at a given significance level can be calculated as follows. The calculation depends on an appropriate assessment of the control effect. As mentioned before, using the statistic T to test the null hypothesis in Eq. 10 is conditionally equivalent to an asymmetric two CI-testing procedure, where the control effect is estimated by the lower limit of a 100(1 gT)% CI. The value of this gT is not known ahead of time. However, for time to event endpoint, this gT can be approximately calculated at design stage based on the prespecified number of events at stopping time (the final analysis) and the significance level used in the test of the null hypothesis in Eq. 10. In practice, the control effect sometimes cannot be assessed reliably either because there is insufficient historical data or the control effect may have changed over time. In such cases, the sample-size calculation should be based on a conservatively estimated control

Table 1 HR(T/C) 1 0.95 0.90 0.85 0.80

Number of events needed for 80% power Number of events 4801 1505 750 446 291 Cutoff 1.0842 1.0976 1.1044 1.1085 1.1114

effect, e.g., using the lower limit of the 95% or even 99% CI. In oncology, we require, as stopping rules for time to event endpoints, prespecified fixed number of events. A lower bound and approximation for the asymptotic standard error of p log hr(T/C) for a 1:1 randomization is given by 2= n, where n denotes the prespecified total number of events at stopping. The use of this lower bound for the standard error at the design stage allows us to algebraically equate the use of a test statistic with a prespecified two CI procedure. Consider the case where a = 0.025, b = 0.2, f0 = 0.5, y = 1, log hr(P/C) = 0.234, and SE[log hr(P/C)] = 0.075. Table 1 gives the number of events needed for various alternatives for HR(T/C) and the corresponding noninferiority cutoffs for the upper limit of the 95% CI for log HR(T/C). The cutoff is defined as d = (1 f0){log hr(P/C) c(1 g)SE[log hr(P/C)]}, where c(1 g) is the solution to the equation, p 2= n c1g 1 f0 SElog hr P=C=1:96 q f4=n 1 f0 2 SE2 log hr P=Cg and the number of events needed at stopping is given by n where n solves p 2F1 1 b= n 1 f0 log hr P=C log HRT =C F1 a q f4=n 1 f0 2 SE2 log hr P=C g

CONCLUSION Active control noninferiority trials should be considered on a case-by-case basis. We need to have assurance that the active control effect exists in the current patient population. We need to assess whether the current effect size, if it exists, has diminished. We should have multiple historical randomized placebo-controlled studies that show relatively consistent results. An active control

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noninferiority trial may be prone to bias toward no difference. Careful attention should be paid to the conduct and analysis of such a study. In the design of a noninferiority trial, we believe that the hypothesis with a percent retention of the control effect is more appropriate formulation. Hypotheses with any type of fixed margin, regardless of arbitrary margin or margin calculated based on the control effect, are, in general, problematic. The hypothesis with a fixed percent retention should be formulated in the study design. The randomized active control trial should be well monitored and conducted. After the study is done and all efficacy data are collected, the conclusion whether the new treatment is effective should be based on testing protocol-specified hypothesis under an appropriate significance level. In some oncology diseases, the response rate may be used as a surrogate to assess the efficacy of the new treatment. In this case, hypotheses with a fixed margin may be used in the design of an active control trial because one may believe that tumor responses can be attributed to the treatment only.

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DISCLAIMER The views expressed in this article are those of the authors and not necessarily those of the U.S. Food and Drug Administration.

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