 Research article
 Open Access
 Published:
Reformulating Gehan’s design as a flexible twostage singlearm trial
BMC Medical Research Methodology volume 19, Article number: 22 (2019)
Abstract
Background
Gehan’s twostage design was historically the design of choice for phase II oncology trials. One of the reasons it is less frequently used today is that it does not allow for a formal test of treatment efficacy, and therefore does not control conventional typeI and typeII errorrates.
Methods
We describe how recently developed methodology for flexible twostage singlearm trials can be used to incorporate the hypothesis test commonly associated with phase II trials in to Gehan’s design. We additionally detail how this hypothesis test can be optimised in order to maximise its power, and describe how the second stage sample sizes can be chosen to more readily provide the operating characteristics that were originally envisioned by Gehan. Finally, we contrast our modified Gehan designs to Simon’s designs, based on two examples motivated by real clinical trials.
Results
Gehan’s original designs are often greatly under or overpowered when compared to typeII errorrates typically used in phase II. However, we demonstrate that the control parameters of his design can be chosen to resolve this problem. With this, though, the modified Gehan designs have operating characteristics similar to the more familiar Simon designs.
Conclusions
The trial design settings in which Gehan’s design will be preferable over Simon’s designs are likely limited. Provided the second stage sample sizes are chosen carefully, however, one scenario of potential utility is when the trial’s primary goal is to ascertain the treatment response rate to a certain precision.
Background
Phase II oncology clinical trials are commonly carried out via nonrandomized singlearm designs. In particular, Gehan’s twostage singlearm design was perhaps the first design ever forwarded for phase II oncology trials [1]. In it, stage one is conducted to ascertain whether the regimen under study displays enough anticancer activity to justify further investigation, with this decision based upon whether at least one tumour response is observed amongst a small number of patients. Following the observation of at least one response, stage two is then constructed to try and ensure that the true response rate can be estimated to a certain precision.
Whilst Gehan’s design was once commonly utilised [2], it was later replaced as the typical approach to phase II trial conduct by two twostage group sequential designs offered by Simon [3]. Importantly, the parameters of Simon’s designs are those which, amongst the parameter combinations that control the operating characteristics of a particular hypothesis test, minimise the expected sample size under a nominated uninteresting response rate, or minimise the trial’s maximal possible sample size. The simplicity of Simon’s designs, and their efficiency at weeding out inactive agents, has led to their evident sustained popularity [4–6].
Moreover, the fact that Simon’s designs are still commonly utilised has meant that developing methodology for their extension remains an active area of research. Several recent such presentations have focused upon a socalled flexible twostage design framework that allows, in particular, the second stage sample size to be dependent on the number of responses observed in stage one [7–11]. Interestingly, these flexible designs therefore have parallels with Gehan’s once popular design, which also specifies the stagetwo sample sizes in a response adaptive manner.
Ultimately, Gehan’s design fell out of common use because, unlike Simon’s designs, it provides no means of formally testing whether a regimen’s observed response rate is sufficiently large to warrant its further development [2]. That is, it affords no method for controlling a study’s typeI errorrate or power to a desired level. Indeed, the latest available figures on phase II oncology trials suggest Gehan’s approach is now used infrequently in comparison to Simon’s designs. Specifically, LangrandEscure et al. (2017) [6] reviewed phase II clinical trials published in three top oncology journals between 2010 and 2015. They identified only six studies that utilised Gehan’s design. However, on our further inspection, only three of these articles cited Gehan’s paper. Therefore, to more accurately quantify how often Gehan’s design has been employed in recent years, we carried out a narrative literature review, ultimately finding evidence that Gehan’s design is being used more regularly than previous reviews suggest.
Specifically, we surveyed the 200 articles, according to Google Scholar, which have cited Gehan’s 1961 paper since January 1 2008. Additionally, we reviewed the 1872 articles on PubMed Central, with a publication date later than January 1 2008, that contained “Gehan" in any field. We found 52 papers that stated they had utilised either Gehan’s methodology, or a modified version of it, with many in high impact oncology journals. Further details of how this survey was conducted are provided in Additional files 1 and 2. Moreover, two of the articles found by LangrandEscure et al. (2017) [6] were not identified in our search. Consequently, it is possible that substantially more published trials have utilised Gehan’s design in recent years than our narrative review suggests. And, of course, there may well be numerous unpublished trials that have utilised his approach, given that many studies remain unpublished [12], and as it has been argued previously, singlearm trials may be more susceptible to nonpublication than their randomised counterparts because their small sample size leads to a perception that they have less intrinsic value [13].
Therefore, methods that improve Gehan’s original design, and provide further evidence on its statistical characteristics, are of value to the trials community. Here, our focus is on providing such methodology. Significantly, we describe how techniques for flexible twostage singlearm trials can be used to incorporate hypothesis testing in to Gehan’s design. We further expound on how this test can be optimised in order to maximise its power. Following this, we describe modified approaches to specifying the secondstage sample sizes in Gehan’s design, in order to permit the design’s desired operating characteristics to be more commonly attained.
The primary motivation for our work is then to utilise our results to be able to present a thorough comparison of our modified versions of Gehan’s design to Simon’s designs. We achieve this based on two real trial examples, and discuss important considerations around the power of the designs, along with the precision to which they can estimate the response rate on trial conclusion. We conclude with a discussion of the potential scenarios in which our enhanced versions of Gehan’s design could be useful within the context of developing a novel treatment regime.
Methods
Gehan’s design
We proceed by first formally describing Gehan’s design. As noted, Gehan proposed a twostage approach in which a regimen’s performance is judged according to the number of patients who experience a tumour response. Thus, denoting the outcome for patient i by X_{i}, Gehan’s framework supposes that X_{i}∼Bern(π), for response rate π∈[0,1]. A response rate, π_{1}∈(0,1], is specified so as to warrant the further investigation of the regimen. Then, the sample size required in stage one, \(n_{1}\in \mathbb {N}^{+}\), is chosen based on \(S_{1} = {\sum \nolimits }_{i=1}^{n_{1}}X_{i} \sim Bin(n_{1},\pi)\), using a rejection probability β_{1}∈(0,1), as
where b(s∣m,π)=^{m}C_{s}π^{s}(1−π)^{m−s} is the probability mass function of a Bin(m,π) random variable. Thus, n_{1} is chosen such that if the response rate is at least π_{1}, then the probability of observing no responses is less than or equal to β_{1}.
Then, if the observed value of S_{1},s_{1}, is equal to zero, the study is stopped for futility. Otherwise, Gehan suggested that the sample size for stage two, \(n_{2}\in \mathbb {N}\), be chosen to allow the true response rate to be estimated to a certain precision. Explicitly, an interim estimate of the response rate, \(\hat {\pi }\in [0,1]\), is specified based on the first stage data. We then choose n_{2} as
Here, \(\sqrt {\hat {\pi }(1  \hat {\pi })/(n_{1}+n_{2})}\) is an estimate of the standard error of the response rate at the end of stage two. Thus, Gehan proposed that this estimate be controlled to some maximal value γ∈(0,1]. Note that the above allows for n_{2}=0, signifying that the desired precision is met at the end of stage one.
Observing that the above calculation is heavily dependent upon \(\hat {\pi }\), Gehan advised that a conservative value be specified via the upper 75th percent confidence limit for π, based on the stage one data. He did not describe precisely how this confidence interval should be computed, but the designs that were subsequently presented suggest that a Waldbased confidence interval was utilised, giving for any s_{1} and n_{1}
This proposal remains a potentially reasonable one if our desire is to approximately provide a certain level of precision in the estimate of the response rate at the end of stage two. However, this specification of \(\hat {\pi }\), based on an argument for conservatism, can be improved upon without a significant increase in computational or statistical complexity. Specifically, given the typically small nature of n_{1}, a confidence limit based on a confidence interval determination procedure that is not reliant on asymptotic theory could be utilised. Moreover, Eq. (2) will be maximised, for any \(n_{1}+n_{2}\in \mathbb {N}^{+}\), when \(\hat {\pi }=0.5\). Therefore, using the upper confidence limit when s_{1}/n_{1}≥0.5 is actually less conservative than the simple maximum likelihood estimate s_{1}/n_{1}. Such a possibility was an unlikely one in the 1960s but may not be unreasonable in certain disease settings today. Consequently, choosing ClopperPearson [14] as the approach to confidence interval specification, these considerations could lead to the following proposal for \(\hat {\pi }\), rather than that given in Eq. (3)
for \(\hat {\Pi } = \{Q_{\text {Beta}}(0.125, s_{1}, n_{1}  s + 1),Q_{\text {Beta}}(0.875, s_{1} + 1, n_{1}  s_{1}),s_{1}/n_{1}\}\). Here, Q_{Beta}(p,a,b) is the pth quantile of a Beta distribution with shape parameters a and b. That is, \(\hat {\pi }\) could be specified as either its maximum likelihood estimate s_{1}/n_{1}, or its lower or upper 75th percent confidence limits using ClopperPearson, according to which is closest to 0.5 (the elements in \(\hat {\pi }\)).
In this paper, we consider both of these methods for specifying \(\hat {\pi }\). We refer to Gehan’s original approach based on Eq. (3) as the ‘original’, and our proposal in Eq. (4), as the ‘conservative’ method. Note that in the above we retain use of the 75% confidence interval. However, intervals for other coverages could readily be employed.
The above completes the description of our approach to specifying Gehan’s design. Notably, Gehan provided a table of designs for several combinations of π_{1},β_{1}, and γ. We will return later to consider the power of these designs following the inclusion of a hypothesis test.
Incorporating and optimising a hypothesis test
To resolve one of the principal limitations of Gehan’s design framework, we now describe how we can modify his approach to include the hypothesis test typically associated with phase II oncology trials. Precisely, we test the following null hypothesis
where π_{0}∈(0,π_{1}). As usual, we will desire to control the typeI errorrate under H_{0} to some α∈(0,1). Note that here, π_{0} is an uninteresting or null response rate that would make the regimen of no further interest. Typically, this is specified based on the historical response rate for the current standard of care.
Now, the methodology of the previous section allows us to prescribe values for n_{1}, and n_{2} for each s_{1}∈{0,…,n_{1}}, which we will signify from here by n_{2}(s_{1}). Such notation is common in the flexible and adaptive twostage singlearm trial literature [7–9], and indeed we can readily view Gehan’s design as a type of flexible twostage design. For, whilst these articles have generally sought to determine values n_{2}(s_{1}) that minimise some function of the trial’s (expected) required sample size, as is evident, Gehan’s framework simply prescribes an alternative approach to specifying the second stage sample sizes based on the first stage data.
Importantly, the literature on flexibly designing twostage singlearm trials is facilitated by the concept of a discrete conditional error function (DCEF), as formalised by Englert and Keiser (2012) [7]. A DCEF consists of values D(s_{1})∈[0,1] for s_{1}∈{0,…,n_{1}}. Using these values, if D(s_{1})=0 the trial is terminated at the end of the first stage for futility (H_{0} is not rejected). Similarly, if D(s_{1})=1 the trial is terminated at the end of stage one for efficacy (H_{0} is rejected). Otherwise, for those s_{1} such that D(s_{1})∈(0,1), the trial continues to the end of stage two, and rejects H_{0} if the second stage pvalue, p_{2}, is sufficiently small. Formally, H_{0} is rejected when
where \(S_{2} = {\sum \nolimits }_{i=n_{1}+1}^{n_{1}+n_{2}(s_{1})} X_{i} \sim Bin\{n_{2}(s_{1}), \pi \}\), and B(s∣m,π) is the cumulative distribution function of a Bin(m,π) variable. Then, the test is controlled to level α provided that
It is this concept of a DCEF that allows us to incorporate a hypothesis test in to Gehan’s design. Our task is simply to choose values for the D(s_{1}) such that Eq. (6) holds: any such set of values, in combination with the testing rules described, allows us to include a formal test of the hypothesis given in Eq. (5), and be assured that the typeI errorrate is controlled to the desired level.
In practice, there will be many such sets of values that will conform to the above requirement, and therefore a method is necessitated for choosing between them. To achieve this in a logical manner, we can specify an optimality criteria of interest. As noted above, the previous articles in this domain have focused on methods for optimally choosing the D(s_{1}) to minimise some function of the trial’s expected sample size. In fact, in Englert and Keiser (2013) [8] and Shan et al. (2016) [9], each D(s_{1}) is directly associated with a value for n_{2}(s_{1}). That is, n_{2} is dependent on s_{1} through the value of D(s_{1}). Thus, their optimisation procedures also determine the second stage sample sizes.
In our setting, Gehan’s precision requirement is instead responsible for the specification of the n_{2}(s_{1}). Consequently, we cannot use considerations around the expected sample size to optimise the D(s_{1}). Therefore, we propose here to instead maximise the power of the resulting hypothesis test. To this end, note that the probability we reject H_{0} for any π∈[0,1] is given by
where P_{2} denotes the random value of the second stage pvalue, the distribution of which is dependent upon π and n_{2}(s_{1}) [8]. Then, it is P(π_{1}) that we use as our optimality criteria.
The final key consideration is to carefully specify the restrictions that are placed upon the D(s_{1}). Here, the following are used

1
D(0)<D(1)<⋯<D(n_{1}). This restriction is logical in that the probability we will reject H_{0} should increase as the number of responses observed at interim does.

2
D(s_{1})∈{0,1−B[n_{2}(s_{1})−1∣,n_{2}(s_{1}),π_{0}],…,1−B[0∣,n_{2}(s_{1}),π_{0}],1}. This restriction corresponds to the fact that we need not treat the D(s_{1}) as continuous parameters, as for each s_{1} there are a finite number of possible pvalues that can be observed at the end of stage two; specifically those specified in the set here.

3
D(s_{1})∈{0,1} if n_{2}(s_{1})=0. If n_{2}(s_{1})=0 the trial is stopped at the end of stage one. To ensure that a decision is always made in our testing framework, we must therefore have that H_{0} is either rejected (D(s_{1})=1) or not rejected (D(s_{1})=0) at this point. A caveat of this restriction is that we must have D(0)=0, as D(0)=1 would imply a typeI errorrate of one given Restriction 1.

4
D(s_{1})∉{0,1} if n_{2}(s_{1})>0. If n_{2}(s_{1})>0 then the trial progresses to stage two. In this case, D(s_{1}) should not equal 0 or 1 as it is not logical for a decision on the trial’s outcome to be certain before the second stage commences.
Thus, our problem is reduced to maximising Eq. (7) over an n_{1}dimensional discrete search space. Unfortunately, this will in general still leave an extremely large number of possible choices for the D(s_{1}). Fortunately, Englert and Keiser (2013) [8] have demonstrated how this problem can be resolved using the branchandbound algorithm to efficiently and exhaustively search over the possible designs. Briefly, this algorithm works by recursively defining the D(s_{1}) for s_{1}∈{0,…,n_{1}} through repeated branching steps that split the optimisation problem in to further and further subproblems. Within this recursion, the bounding step systematically discards subproblems that cannot lead to the optimal design. Here, this corresponds to those subproblems which either cannot control the typeI errorrate to the desired level α, or cannot increase the trial’s power relative to that of the best design identified thus far. More precisely, after s branching steps, when D(s_{1}) has been specified for s_{1}∈{0,…,s}, the minimal possible typeI errorrate of a design for any potential choices of D(s_{1}) for s_{1}∈{s+1,…,n_{1}}, is given by
and the maximal possible power will be
We can therefore discard all subproblems when α_{min}>α or P_{max}<P_{current}, where P_{current} is the largest power of the designs considered so far. It is this bounding step that allows for the efficient consideration of all possible designs, as we are able to avoid the computational cost of evaluating many sets of D(s_{1}) that could not possibly be optimal.
Note that one small caveat to the above considerations is that a design may not exist that is capable of controlling the typeI errorrate to α. Explicitly, the most conservative possible design would take for s_{1}∈{1,…,n_{1}}
Thus the minimal possible typeI errorrate is P(π_{0}) with the above values of the D(s_{1}), and therefore if this is greater than α no DCEF exists which attains the desired typeI errorrate. However, later, we perform a large search over what are likely to be common choices for α,γ,π_{0}, and π_{1}, and demonstrate that this is likely to rarely occur in practice, at least when using the conservative approach to specifying \(\hat {\pi }\) in f_{G}.
This describes our complete approach to optimising a test of the hypotheses given in Eq. (5) within Gehan’s design. A program to execute our search procedure in R is available in the singlearm package [15].
Alternative methods for specifying the second stage sample sizes
Later, we will observe that Gehan’s design determination procedure, even with our conservative method for specifying \(\hat {\pi }\) at the end of stage one, would routinely be expected not to provide the desired level of precision in the estimate of the response rate at the end of stage two. For this reason, we here detail several alternative methods that could be used to specify the second stage sample sizes.
First, suppose that n_{1} is specified as the solution of Eq. (1). Then, a general framework for specifying n_{2}, for any s_{1}, can be prescribed by allocating it as the solution of the following problem
Here, f is a function that evaluates the suitability of a candidate n_{2}, for a given vector of (decision guiding) parameters θ. In Gehan’s original proposal
It is a consequence of that fact that f_{G} provides only an estimate of the true standard error that the desired precision may not be achieved at the end of the trial. One way to resolve this issue would be to specify f via a function L(s_{1},s_{2},n_{1},n_{2}), which prescribes the length of the confidence interval for π at the end of the trial, given the number of responses observed in stages one and two. Then, n_{2} could be determined using
That is, n_{2} could be chosen to ensure that, no matter the value of s_{2}, half of the confidence interval width is always constrained to Φ^{−1}(1−α/2)γ. The factor Φ^{−1}(1−α/2) arises here to correspond to Gehan’s original precision requirement, which aims to ensure a Wald confidence interval for π at the end of stage two has length 2Φ^{−1}(1−α/2)γ (i.e., so that the designs aim to achieve the same precision requirement).
In practice, such an approach may lead in certain circumstances to undesirably large values of the n_{2}(s_{1}). An intermediate option might be to make use of an interim estimate of π, as well as a function L(s_{1},s_{2},n_{1},n_{2}). Then, half the expected length of the final confidence interval could be constrained to γ, when the true response rate is \(\hat {\pi }\), by taking
In this paper, we will consider the operating characteristics of designs determined using f_{G},f_{L}, and f_{EL} for the specification of the second stage sample sizes, considering the utility of both Eqs. (3) and (4) for the value of \(\hat {\pi }\) in f_{EL}. Furthermore, we utilise ClopperPearson for L(s_{1},s_{2},n_{1},n_{2}) in the above equations, giving
Design comparison
In what follows, we assess the power of Gehan’s original designs for the majority of parameters considered in Table II of his paper. We motivate a more in depth examination of the performance of our modified and optimised designs using design parameters based on two real clinical trials.
Firstly, DupuisGirod et al. (2012) [16] presented the results of a phase II study to test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of hereditary hemorrhagic telangiectasia. Gehan’s design was employed, with β_{1}=0.1,π_{1}=0.3, and γ=0.1. We will consider designs for α=0.05, when π_{0}=π_{1}−0.15=0.15.
In Additional file 1 we also present results corresponding to Lorenzen et al. (2008) [17], who investigated the tumour response rate to neoadjuvant continuous infusion of weekly 5fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in patients with locally advanced oesophageal squamous cell carcinoma. This trial also used Gehan’s design, but for β_{1}=0.05,π_{1}=0.5, and γ=0.1. In this case, we consider designs for α=0.1, with π_{0}=π_{1}−0.2=0.3.
In both cases, we denote the Simon designs as having stagewise group sizes n_{1} and n_{2}, and futility boundaries f_{1} and f_{2} (that is, stage two is commended if s_{1}>f_{1}, and H_{0} rejected only when s_{1}+s_{2}>f_{2}). Then, for these designs, we have
In our assessments, we repeatedly examine several different statistical quantities in order to compare the performance of the designs. In all instances, we calculate these quantities using exact calculations, without recourse to simulation, by employing exhaustive calculations over possible trial outcomes.
Firstly, we will examine the expected sample size (ESS) required by the various designs. Therefore, note that we can compute this for any π∈[0,1] using
We also compare the expected length of the 100(1−α)% confidence intervals at the end of the trials, conditional on not stopping for futility in stage one. That is, conditional on S_{1}>f_{1}, where for the Gehan designs we take \(f_{1}=\text{argmax}_{s_{1}\in \{0,\dots,n_{1}\}}\{D(s_{1})=0\}\). We compute this, for any π∈[0,1], as
We will refer to this as the conditional expected length (CEL). We focus on the CEL, rather than the unconditional expected length of the confidence interval across all possible values of s_{1}, for two reasons. Firstly, because Gehan’s designs is constructed to try and provide a certain precision at the end of stage two. And secondly, as analysis of this kind is arguably more important when a trial has not been stopped early for futility [18].
Adaptive twostage designs require specialised methodology for confidence interval construction, and therefore when computing the CEL, we utilise for L(s_{1},s_{2},n_{1},n_{2}) the exact ClopperPearson type confidence interval, based on an ordering of the sample space induced by the optimal compatible estimator, described by Kunzmann and Keiser (2018) [11]. Our reason for utilising such confidence intervals for computing the CEL, but not when evaluating f_{L} and f_{EL}, is as follows: the adjusted confidence intervals of Kunzmann and Keiser (2018) [11] are only defined given the n_{2}(s_{1}). Thus after accounting for the complexity of their calculation, this means that they cannot be used in a computationally efficient to choose the n_{2}(s_{1}).
Furthermore, note that by the above we are utilising the same type of confidence interval construction procedure for both the Gehan and Simon designs, in order to make our comparisons fair. Finally, unfortunately no closed form expressions are available for such L. However, they can be computed using available software [11]. We have stored all our required confidence intervals in.csv files contained within Additional file 5, and provided the Julia code for their determination in Additional file 4.
When comparing the various Gehan designs to each other, we will also consider EL(π∣S_{1}=s_{1}), the conditional expected confidence interval lengths for each possible value of s_{1}>0, given by
Note that code to recreate our design evaluations and reproduce each of the tables and figures is provided in Additional file 3.
Results
Power of Gehan’s design
First, we present the optimal values of the D(s_{1}), along with the corresponding typeI errorrate, power, and values of ESS(π_{0}) and ESS(π_{1}), for several of the parameter combinations given in Table II of Gehan (1961) [1]. Explicitly, these correspond to (β_{1},γ,π_{1})∈{0.05,0.1}×{0.05,0.1}×{0.2,0.25,0.3} with α=0.05. Our results are provided in Table 1 for both the original and conservative methods for specifying \(\hat {\pi }\) at the end of stage one, in Gehan’s original f_{G} for specifying the second stage sample sizes. In Additional file 1, we present further results for many other possible parameter combinations.
From Table 1, we observe that in all instances our search procedure returns values for the D(s_{1}) that imply a typeI errorrate of less than α=0.05. Moreover, the corresponding power of the designs ranges between 0.073 and 0.948. Thus, as was noted earlier, in no instance is the optimization procedure unable to find a design confirming to the desired level of typeI error control. However, there are instances in which the discrete nature of the test only permits a design with P(π_{0})≪α, which in turn results in some small values of P(π_{1}). Nonetheless, it is clear that the power of Gehan’s designs is heavily dependent upon the choice of the design parameters.
In addition, note that the power of the design when using the conservative method for specifying \(\hat {\pi }\) is always larger than that for the original method. This is a consequence of the fact that the conservative method, as was discussed, results in larger values for the n_{2}(s_{1}). This is evidently at a cost to the trials ESS under π_{0} and π_{1}, however.
Comparison to Simon’s designs
We now focus on design for our motivating scenario based on DupuisGirod et al. (2012) [16]. In this case, our optimal version of Gehan’s design using the original method for constructing \(\hat {\pi }\), for use with f_{G}, has n_{1}=7 and
Similarly, using f_{G} with our conservative method for constructing \(\hat {\pi }\)
Thus, the power of these modified Gehan designs is less than that we would generally desire in a phase II trial. Whilst for the former design this is in part due to the conservativeness of the test, even the conservative approach for constructing \(\hat {\pi }\), which has larger second stage sample sizes, and attains a typeI errorrate close to the desired level, still only has power of 0.572. It is thus clear that neither method is capable of providing a reasonable amount of power for π_{0}=π_{1}−0.15. It is therefore useful to describe how this can be achieved, and also informative to examine the performance of the designs when they have a more typical level of power.
Explicitly, to achieve this for either method, we can treat γ as a parameter and identify a γ∈(0,1) that provides, say, 80% power. It is important to realise that such a search must be conducted carefully, as the discrete nature of the design means P(π_{1}) may not be monotonic in γ. A simple option is to search for the maximal γ such that P(π_{1}) is above the desired level. This is logical because the ESS will monotonically decrease in γ, as increasing γ has no effect on the design other than to monotonically decrease the n_{2}(s_{1}).
Performing this search for the original method, we find that γ=0.0658 gives a design with n_{1}=7 and
Whilst for the conservative approach, γ=0.0686 results in a design with n_{1}=7 and
It is now highly informative to ask whether these optimised Gehan designs offer advantageous performance over Simon’s popular designs. Thus, next, we contrast the performance of these designs to the nulloptimal and minimax Simon design’s when β=0.2. Precisely, these are
Thus the maximal sample size of both of the Gehan designs listed above is larger than that for both Simon designs. We further investigate the likely required sample size of these four designs through their ESS curves, which are provided in Fig. 1 for π∈[0,1]. We can see that the ESS of the Gehan designs is lower when π is close to zero; a result of their smaller first stage sample size. Similarly, the ability of the Gehan designs to lower their second stage sample size when s_{1} is large means that they return to having lower ESSs when π is large; this is particularly true for the design utilising the original approach to specifying \(\hat {\pi }\). However, for a large range of arguably more realistic values of π, given the values of π_{0} and π_{1}, the ESS of the Simon designs is smaller.
A final important question is whether the Gehan designs more readily estimate π to a certain precision, in contrast to that afforded by Simon’s designs. To this end, in Fig. 2 we compare the CEL curves of the four designs. We consider only π∈(0,1), as π∈{0,1} can result in strange results as the outcome of the designs is deterministic.
What we observe largely corresponds, as one would expect, to the findings in Fig. 2. That is, for the majority of values of π the design which has the largest ESS, has the smallest CEL value. In particular, for Gehan’s design with the original approach to specifying \(\hat {\pi }\), when π is large, the ESS of this design being much smaller results in its CEL being substantially larger. Overall, it is clear that Simon’s designs, and the Gehan design with the conservative approach, have similar values for the CEL across a wide range of response rates.
Gehan designs with modified second stage sample sizes
A further consequence of Fig. 2 is that the confidence intervals determined at the end of the Gehan designs evidently must in certain cases have length substantially greater than the implicitly desired 2Φ^{−1}(1−α/2)γ based on Wald confidence intervals (which is, e.g., equal to 0.26 to 2 dp for the design using Gehan’s original approach to specifying \(\hat {\pi }\)).
We now conclude our results by investigating this further for the originally desired precision in the DupuisGirod et al. (2012) trial, γ=0.1. Firstly, we determined the optimised Gehan design based on f_{L} to be
In addition, that based on f_{EL} with the original approach to specifying \(\hat {\pi }\) was identified as
And finally, that for f_{EL} with our conservative approach to specifying \(\hat {\pi }\) as
As we would expect, as the most conservative approach, the required second stage sample sizes are largest for f_{L}. Observe that for the conservative approach, relative to f_{G}, using f_{EL} increases the stage two sample sizes for most s_{1}, but decreases it for s_{1}=7.
We then present the CEL curves of the final 95% exact ClopperPearson type confidence intervals for the five designs (based on the considered combinations of function f with the original and conservative methods), for s_{1}∈{1,…,n_{1}}, in Fig. 3.
Gehan’s original design aimed to provide a (Wald) confidence interval with approximate length of 2γΦ^{−1}(1−α/2)=0.39 to 2 dp. It is evident that Gehan’s original design (f_{G}, Original) would often be expected to provide ClopperPearson type confidence intervals of length much larger than that desired. Moreover, we can see that utilising f_{EL} rather than f_{G} with the conservative approach improves performance for several values, but not all, of the s_{1}.
Finally, using f_{L} guarantees that the final confidence interval has a CEL below that desired for all s_{1}. So to do f_{G} and f_{EL} when paired with the conservative approach to specifying \(\hat {\pi }\). In this case, where these designs require only a small increase to the second stage sample sizes (one that is arguably achievable given the maximal possible required sample size of Gehan’s original design), they should almost certainly be preferred.
Discussion
Gehan’s design was once regularly used in phase II oncology trials. It did not, however, include a formal test of a regimen’s efficacy. Consequently, as the number of effective anticancer agents began to increase, and a higher standard of evidence was necessitated for a treatment to proceed to further testing, it fell out of habitual employment. Nonetheless, as was discussed, Gehan’s design is still utilised in practice. Thus methodology to improve upon Gehan’s original framework, and to describe the potential advantages of the modified approach compared to more commonly utilised designs, is therefore of value to the trials community. Here, we provided such work, describing the first methodology by which the hypothesis test typically associated with singlearm phase II trials can be incorporated in to Gehan’s design. We further went on to describe how this test can be optimised in order to maximise its power, and then presented a statistical evaluation of our modified Gehan designs.
It is valuable to note how our research builds upon previous findings. Several studies have identified that a major problem with Gehan’s design is that the probability stage two is commenced is typically high [19, 20], with this true even when the response rate is below that which we hope to observe. Here, we have provided the additional result that the power of Gehan’s originally presented designs varies widely for a null response rate of π_{0}=π_{1}−0.15 (Table 1). This suggests that many studies that have used Gehan’s design may have not had a strong probability to reliably identify efficacious treatments. In contrast, when the required precision γ was set to 0.05, some of the designs had power far higher than that which would typically be desired in a phase II trial.
We noted earlier that several of the designs in Table 1 have typeI errorrates substantially smaller than the permitted level. This is a consequence of the discrete nature of the design. In Additional file 1, via a large search over potential design parameters, we provide evidence that it is unlikely a reliable rule for when this will occur can be described. However, we argue that it would be expected to occur more often for larger values of γ and π_{1}, when the second stage sample sizes are small. For, in this case, the number of permissible DCEFs will also be small, and the possibility that one will utilise the entire allowed typeI error will be reduced. A possible solution to this problem might be to relax the monotonicity requirements on the DCEF. However, as noted, this should in general be avoided. An ad hoc, but more acceptable solution, might be to artificially increase the values of the n_{2}(s_{1}) beyond those required by the precision requirements. This will increase the number of potential DCEFs, potentially permitting one which will more exhaustively utilise the allowed typeI error.
The fact that the power of Gehan’s original designs is not well calibrated may not be surprising, as it was not constructed to provide a certain power, but to estimate a response rate to within a certain precision. What is particularly troubling therefore is our presentations in Figs. 2 and 3, which demonstrated that typically the confidence interval width at the end of stage two would not be that which was desired. It is for this reason that we described how one can calculate the stage two sample sizes in an alternative manner to allow for more precise estimation at the end of the trial.
For our motivating example presented in this article, and that discussed in Additional file 1, we again identified potential issues with the power of Gehan’s designs for the utilised value of γ. For this reason, we advised that choosing γ carefully is particularly important, and described how a numerical search could be performed to identify the value of γ that provides the desired power.
The problem with this, however, is that once we modified the Gehan designs to have 80% power, on contrasting their performance to Simon’s designs, it was clear that Gehan’s designs often offered little advantage in terms of their statistical operating characteristics. Gehan’s designs tended to require fewer patients on average for extreme values of the response rate, but for arguably more realistic interim values of π, Simon’s designs were often more efficient (Fig. 1 and Additional file 1: Figure A5). Additionally, in Fig. 2 we observed few possible values of π for which the CEL of the Gehan designs was smaller than Simon’s designs. Though contrastingly, for the second scenario, in Additional file 1: Figure A6 it can be seen that Gehan’s designs would be expected to more accurately estimate the response rate at the end of stage tow.
The evident similar performance of the designs should perhaps not surprise us, as for the same typeI and typeII errorrates, the Gehan design’s parameters are similar to those of a nonoptimal version of a twostage group sequential design. This suggests that, for particular required errorrates, Gehan’s framework may have little utility for estimating the response rate π efficiently.
This begs the important question as to when Gehan’s designs could be useful, particularly when we take in to consideration the grater volume of theoretical results and software that is available pertaining to Simon’s designs. Firstly, in rare disease settings the fact that Simon’s designs may often have smaller ESSs makes them advantageous over Gehan’s design. It may in particular be anticipated that Gehan’s design would be useful when there are few available efficacious therapies for the disease under study, and thus any observed level of response would signify interest in proceeding to stage two. That is to say, when the value of π_{0} is small. For, this was in part Gehan’s motivation for the construction of his design. However, in this case, we could choose a nonoptimal group sequential design with a small value of f_{1}. We elaborate on this in Additional file 1. Consequently, we feel it is unlikely that Gehan’s design would regularly be preferable in such a setting.
Note that in order to attempt to address aforementioned issues around the interim stopping rule in Gehan’s design being too relaxed, an extension to Gehan’s framework to make it more applicable to trials with high response rates has been presented [21]. We might hope a modification of this form may improve how the operating characteristics of Gehan’s design fair in comparison to Simon’s designs. However, in Additional file 1 we describe how a particular logical modification to the stage one stopping rule in Gehan’s design would be unlikely to result in improved statistical performance. Consequently, we believe it is also unlikely Gehan’s design will be preferable in situations where the response rate is anticipated to be large.
As we observed in Fig. 2, Gehan’s design is likely to have better performance in terms of the length of the final confidence interval when the response rate is much smaller than π_{0} and π_{1}. However, this is simply a result of its increased requisite sample size. Furthermore, if π_{0} is known accurately based on reliable historical data, we would hope that this would be a rare occurrence. Ultimately, we feel that there is one principal situation in which Gehan’s designs may be particularly useful: when the primary goal of a trial is to estimate the response rate to a desired level of precision, and many patients are available to enroll in the study. This may occur perhaps when the regimen under investigation is a novel singleagent, in a more common cancer type. It was for this reason that we described design based on the functions f_{L} and f_{EL}. With these, Gehan’s framework then provides a direct way to ensure that the response rate can be estimated precisely at the end of stage two. As, to guarantee the same precision with a twostage group sequential design, a large search would need to be conducted over the possible design parameters to identify combinations that would lead to precise estimation on trial completion, across all possible true response rates. That is, the principal advantage in this setting would be computational. For, it may well be the case, as was evident for the example design utilising f_{L} in the previous section, that the required second stage sample sizes are constant for all s_{1}, meaning the Gehan design functions in a similar manner to a groupsequential design. Of course, one should note that designs which provide such precise final estimates could require significantly increased sample sizes to those typically associated with singlearm phase II trials.
A useful compromise between the two competing designs could be to prospectively plan to use a flexible twostage design [7]. With this, at the interim analysis, the remainder of the trial could then be specified in a group sequential design style, to retain the simplicity of Simon’s original designs. Alternatively, investigators could based on the interim data decide to take a Gehan like approach and complete stage two to achieve a precise final estimate of the response rate.
Conclusions
We can readily incorporate a hypothesis test in to Gehan’s twostage design, resolving one of its primary limitations. However, trialists should think carefully about using this design in practice, as Simon’s designs may often have advantageous or comparable performance in terms of their required sample size and the precision to which they will be able to estimate the response rate.
Abbreviations
 CEL:

Conditional expected length
 DCEF:

Discrete conditional error function
 ESS:

Expected sample size
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Funding
This work was supported by the Medical Research Council [grant number MC_UU_00002/3 to APM and MJG]. The funding body had no role in the design of the study, nor in the collection, analysis, and interpretation of data, or in writing the manuscript.
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MJG conceived the idea for the article. MJG and APM wrote the computer code required to acquire the results. MJG wrote the initial draft of the manuscript, which APM helped revise. Both authors read and approved the final manuscript.
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Additional files
Additional file 1
Survey of studies utilising Gehan’s design and Design comparison based on Lorenzen et al. (2008). Details of how the survey to evaluate the number of studies that have utilised Gehan’s design was conducted are provided. In addition, an additional comparison of the performance of Gehan’s and Simon’s designs is given, based on the trial reported in Lorenzen et al. (2008) [17]. (PDF 181 kb)
Additional file 2
Survey results. An.xlsx file containing the results of the survey described in the Introduction and in Additional file 1. (XLSX 482 kb)
Additional file 3
R code. R code to determine the designs discussed in the manuscript and additional files, and reproduce each of the tables and figures. (R 36.6 kb)
Additional file 4
Julia code. Julia code to determine the confidence intervals for the designs discussed in the manuscript and additional files. (JL 11.7 kb)
Additional file 5
Confidence intervals. A.zip file containing.csv files that store the confidence intervals for the designs discussed in the manuscript and additional files. (ZIP 27.6 kb)
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Grayling, M.J., Mander, A.P. Reformulating Gehan’s design as a flexible twostage singlearm trial. BMC Med Res Methodol 19, 22 (2019). https://doi.org/10.1186/s1287401906592
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Keywords
 Adaptive
 Binary
 Group sequential
 Onesample
 Phase II
 Singlearm