Limited support is provided for 2-sample design with a normally distributed random variable as the outcome. Users are encouraged to look at guidance such as in Jennison and Turnbull (2000). We provide a tool where for a large sample case where a reasonable estimate of standard deviation is available, a reasonable sample size can be computed based straightforward distribution theory outlined below.

The overall sample size notation used for **gsDesign**
is to consider a standardized effect size parameter which is referred to
as \(\theta\) in Jennison and Turnbull (2000). We begin with the
2-sample normal problem where we assume a possibly different standard
deviation in each treatment group. For \(j =
1, 2\), we let \(X_{j, i}\),
\(i = 1, 2, \ldots n_j\) represent
independent and identically distributed observations following a normal
distribution with mean \(\mu_j\) and
standard deviation \(\sigma_j\). The
natural parameter for comparing the two distributions is

\[\delta = \mu_2 - \mu_1\]

and we wish to test if \(\delta >
0\) in a one-sided testing scenario to test for superiority of
treatment 2 over treatment 1. We could also consider testing, say, \(\delta > \delta_0\) for a
non-inferiority scenario with \(\delta_0<0\) or **super
superiority** if \(\delta_0>0\). While normally a t-test
would be used for this, for large sample sizes this would be nearly
equivalent to a Z-test defined by:

\[Z=\frac{\bar X_2 - \bar X_1-\delta_0}{\sqrt{\sigma^2_2/n_2 + \sigma_1^2/n_1}}\approx \frac{\bar X_2 - \bar X_1}{\sqrt{s^2_2/n_2 + s_1^2/n_1}}=t\] where \(\bar X_j\) is the sample mean and \(s_j^2\) is the sample variance for group \(j=1,2\). The far right hand side of this is Welch’s t-test. For our examples we use this \(t\)-test and show that the sample size computation based on the \(Z\)-test above works well for the chosen problems.

Thus, \(n_2=rn/(1+r)\), \(n_1=n/(1+r)\) and when \(r=1\) we have \(n_1=n_2=n/2\). Now that we have completed needed notation, those not interested in the theory behind the sample size and power calculation used may skip the rest of this section.

We let \[\sigma^2=(1+r)(\sigma_1^2+\sigma_2^2/r)\] and define \[ \theta= (\delta -\delta_0)/\sigma.\] Under the given assumptions, \[Z \sim \text{Normal}\left(\sqrt n\theta,1\right).\] Under the null hypothesis that \(\delta=\delta_0\), we have \(Z\sim \text{Normal}(0,1)\). Thus, regardless of \(n\) we have \[P_0[Z\ge \Phi^{-1}(1-\alpha)]=\alpha.\] Under the alternate hypothesis that \(\delta=\delta_1\) and we denote a corresponding \(\theta_1\). We define the type II error \(\beta\) and power \(1-\beta\) by

\[ \begin{align} 1-\beta =& P_1[Z\ge \Phi^{-1}(1-\alpha)]\\ =& P[Z-\sqrt n\theta_1\ge \Phi^{-1}(1-\alpha)-\sqrt n\theta_1]\\ =&\Phi(\Phi^{-1}(1-\alpha)-\sqrt n\theta_1)). \end{align}\]

If the power \(1-\beta\) is fixed, we can invert this formula to compute sample size with:

\[n= \left(\frac{\Phi^{-1}(1-\beta)+\Phi^{-1}(1-\alpha)}{\theta_1}\right)^2.\]

For 2-sided testing, we simply substitute \(\alpha/2\) for \(\alpha\) in the above two formulas.

We consider two examples to check the above formulas
vs. `nNormal()`

. We then confirm that the approximation is
working well by simulating and confirming that the power and Type I
error approximations are useful. Finally, we provide a simple group
sequential design example.

We consider an example with \(\sigma_2=1.25\), \(\sigma_1=1.6\), \(\delta=0.8\) and \(\delta_0=0\). We let the sample size ratio
be 2 experimental group observations per control observation. We compute
sample size with `nNormal()`

assuming one-sided Type I error
\(\alpha=0.025\) and 90% power (\(1-\beta=0.9\)).

Checking using the sample size formula above, we have:

```
<- 2
r <- sqrt((1 + r) * (1.6^2 + 1.25^2 / r))
sigma <- 0.8 / sigma
theta qnorm(.9) + qnorm(.975)) / theta)^2
((#> [1] 164.5684
```

Now, assume we let the sample size be 200 and compute power under the same scenario.

```
nNormal(delta1 = 0.8, sd = 1.6, sd2 = 1.25, alpha = 0.025, n = 200, ratio = 2)
#> [1] 0.9466825
```

From the power formula above, we duplicate this with:

```
<- pnorm(qnorm(.975) - sqrt(200) * theta, lower.tail = FALSE)
pwr
pwr#> [1] 0.9466825
```

If we want to plot power for a variety of sample sizes, we can input
`n`

as a vector:

```
<- 100:200
n <- nNormal(delta1 = 0.8, sd = 1.6, sd2 = 1.25, alpha = 0.025, n = n, ratio = 2)
pwrn plot(n, pwrn, type = "l")
```

Alternatively, you could fix sample size at 200 and plot power under different treatment effect assumptions:

```
<- seq(.5, 1, .025)
delta1 <- nNormal(delta1 = delta1, sd = 1.6, sd2 = 1.25, alpha = 0.025, n = 200, ratio = 2)
pwrdelta1 plot(delta1, pwrdelta1, type = "l")
```

Rather than simulate individual observations, we will take advantage of the fact that for \(j=1,2\)

\[\bar X_j\sim \text{Normal}(\mu_j,\sigma_j^2/n_j)\]

and

\[(n_j-1)s_j^2/\sigma_j^2=\sum_{i=1}^{n_j} (X_{ij}-\bar X_j)/\sigma^2 \sim \chi ^2_{n_j-1}\]

are independent. Thus, we can simulate trial power with \(n=200\) 1 million times with a t-statistic with unequal variances quickly as follows under the alternate hypothesis:

```
<- 1000000
nsim <- 0.8
delta <- 1.6
sd1 <- 1.25
sd2 <- 67
n1 <- 133
n2 <- rnorm(n = nsim, mean = delta, sd = sd1 / sqrt(n1)) -
deltahat rnorm(n = nsim, mean = 0, sd = sd2 / sqrt(n2))
<- sqrt(
s ^2 * rchisq(n = nsim, df = n1 - 1) / (n1 - 1) / n1 +
sd1^2 * rchisq(n = nsim, df = n2 - 1) / (n2 - 1) / n2
sd2
)<- deltahat / s
z mean(z >= qnorm(.975))
#> [1] 0.946229
```

The standard error for this simulation power calculation is approximately

```
sqrt(pwr * (1 - pwr) / nsim)
#> [1] 0.0002246659
```

suggesting we should be within less than about 0.001 if the actual power, which suggests the normal power approximation is reasonable for this scenario.

Now we derive a group sequential design under the above scenario. We will largely use default parameters and show two methods. For the first, we plug in the fixed sample size above as follows:

```
<- gsDesign(
d k = 2,
n.fix = nNormal(delta1 = 0.8, sd = 1.6, sd2 = 1.25, alpha = 0.025, beta = .1, ratio = 2),
delta1 = 0.8
)%>%
d gsBoundSummary(deltaname = "Mean difference") %>%
kable(row.names = FALSE)
```

Analysis | Value | Efficacy | Futility |
---|---|---|---|

IA 1: 50% | Z | 2.7500 | 0.4122 |

N: 86 | p (1-sided) | 0.0030 | 0.3401 |

~Mean difference at bound | 0.9399 | 0.1409 | |

P(Cross) if Mean difference=0 | 0.0030 | 0.6599 | |

P(Cross) if Mean difference=0.8 | 0.3412 | 0.0269 | |

Final | Z | 1.9811 | 1.9811 |

N: 172 | p (1-sided) | 0.0238 | 0.0238 |

~Mean difference at bound | 0.4788 | 0.4788 | |

P(Cross) if Mean difference=0 | 0.0239 | 0.9761 | |

P(Cross) if Mean difference=0.8 | 0.9000 | 0.1000 |

A textual summary of the design is given by:

`cat(summary(d))`

Asymmetric two-sided group sequential design with non-binding futility bound, 2 analyses, sample size 172, 90 percent power, 2.5 percent (1-sided) Type I error. Efficacy bounds derived using a Hwang-Shih-DeCani spending function with gamma = -4. Futility bounds derived using a Hwang-Shih-DeCani spending function with gamma = -2.

We can get the same answer by plugging in the standardized effect size we computed above:

```
gsDesign(
k = 2,
delta = theta,
delta1 = 0.8
%>%
) gsBoundSummary(deltaname = "Mean difference") %>%
kable(row.names = FALSE)
```

Analysis | Value | Efficacy | Futility |
---|---|---|---|

IA 1: 50% | Z | 2.7500 | 0.4122 |

N: 86 | p (1-sided) | 0.0030 | 0.3401 |

~Mean difference at bound | 0.9399 | 0.1409 | |

P(Cross) if Mean difference=0 | 0.0030 | 0.6599 | |

P(Cross) if Mean difference=0.8 | 0.3412 | 0.0269 | |

Final | Z | 1.9811 | 1.9811 |

N: 172 | p (1-sided) | 0.0238 | 0.0238 |

~Mean difference at bound | 0.4788 | 0.4788 | |

P(Cross) if Mean difference=0 | 0.0239 | 0.9761 | |

P(Cross) if Mean difference=0.8 | 0.9000 | 0.1000 |

We leave it to the reader to verify the properties of the above design using simulation as in the fixed design example.

Jennison, Christopher, and Bruce W. Turnbull. 2000. *Group Sequential
Methods with Applications to Clinical Trials*. Boca Raton, FL:
Chapman; Hall/CRC.