# Simulate Correlated Progression-Free Survival and Overall Survival Using a Gumbel Copula

Progression-free survival (PFS) and overall survival (OS) are common time-to-event endpoints in oncology trials. Because progression or death defines a PFS event, simulated trial data should always satisfy \(\mbox{PFS} \leq \mbox{OS}\). At the same time, the two endpoints are often highly correlated, so independent marginal simulation is usually not appropriate.

This vignette describes the copula-based generator implemented in `TrialSimulator::CorrelatedPfsAndOs2()`. The function is intended for simulation settings where the user wants to specify three interpretable quantities:

- the marginal median PFS,
- the marginal median OS,
- Kendall’s tau between the observed, uncensored PFS and OS times.

The method uses a Gumbel survival copula for a latent time to progression (TTP) and OS, and then defines

\[ \mbox{PFS} = \min(\mbox{TTP}, \mbox{OS}). \]

This construction guarantees \(\mbox{PFS} \leq \mbox{OS}\) for every simulated patient. It also keeps both marginal PFS and OS exponential, so the inputs can be specified directly through their medians.

This is a useful distinction from the illness-death model in `TrialSimulator::CorrelatedPfsAndOs3()`. The illness-death model gives a clinically interpretable transition structure, but OS generated from that model can have a time-varying hazard ratio between treatment arms. Therefore, if OS will be analyzed using a proportional hazards Cox model and the simulation should be consistent with that analysis model, the copula-based method described here is often more appropriate.

## Model

Let \(X\) denote latent TTP and let \(Y\) denote OS. The model assumes exponential marginal survival functions

\[ \Pr(X > x) = \exp(-\lambda_X x), \qquad \Pr(Y > y) = \exp(-\lambda_Y y), \]

and a Gumbel–Hougaard survival copula

\[ \Pr(X > x, Y > y) = \exp\left[ -\left\{(\lambda_X x)^\theta + (\lambda_Y y)^\theta\right\}^{1/\theta} \right], \qquad \theta \geq 1. \]

The observed PFS time is

\[ P = \min(X, Y). \]

Under this model, OS is exponential with rate \(\lambda_Y\). PFS is also exponential, with survival function

\[ \Pr(P > t) = \Pr(X > t, Y > t) = \exp\left[ -\left\{(\lambda_X^\theta + \lambda_Y^\theta)t^\theta\right\}^{1/\theta} \right] = \exp(-\lambda_P t), \]

where

\[ \lambda_P = \left(\lambda_X^\theta + \lambda_Y^\theta\right)^{1/\theta}. \]

Therefore, if the target medians are \(m_P\) for PFS and \(m_Y\) for OS,

\[ \lambda_P = \frac{\log(2)}{m_P}, \qquad \lambda_Y = \frac{\log(2)}{m_Y}. \]

For a candidate value of \(\theta\), the latent TTP rate is then

\[ \lambda_X = \left(\lambda_P^\theta - \lambda_Y^\theta\right)^{1/\theta}. \]

This requires \(m_P < m_Y\), as expected for PFS and OS.

## Choosing the Copula Parameter

For the Gumbel copula, Kendall’s tau between latent TTP and OS is

\[ \tau(X,Y) = 1 - \frac{1}{\theta}. \]

However, `CorrelatedPfsAndOs2()` asks for Kendall’s tau between the observed, uncensored endpoints \(P=\min(X,Y)\) and \(Y\), not between latent TTP and OS. These are not the same quantity. The formula below is derived in the appendix. Under the model above,

\[ \tau(P,Y) = 1 - \frac{1}{\theta} \left[ 1 - \left(\frac{m_P}{m_Y}\right)^\theta \right]. \]

Equivalently, writing \(\tau_X = \tau(X,Y)\) and \(\theta = 1/(1-\tau_X)\),

\[ \tau(P,Y) = 1 - (1-\tau_X) \left[ 1 - \left(\frac{m_P}{m_Y}\right)^{1/(1-\tau_X)} \right]. \]

`CorrelatedPfsAndOs2()` solves this equation numerically for the latent Kendall’s tau \(\tau_X\), converts it to \(\theta\), and then simulates from the Gumbel copula.

For any finite \(\theta\), \(\tau(P,Y)\) is larger than \(\tau(X,Y)\):

\[ \tau(P,Y)-\tau(X,Y) = \frac{1}{\theta} \left(\frac{m_P}{m_Y}\right)^\theta > 0. \]

Intuitively, even if latent TTP and OS have a weaker association, observed PFS contains deaths by construction, which increases the association between observed PFS and OS.

The requested value of \(\tau(P,Y)\) has a lower bound. When \(\theta=1\), TTP and OS are independent, but PFS still contains OS deaths through the definition \(P=\min(X,Y)\). In this limiting case,

\[ \tau(P,Y) = \frac{m_P}{m_Y}. \]

Thus, for fixed medians \(m_P\) and \(m_Y\), `CorrelatedPfsAndOs2()` can only target

\[ \frac{m_P}{m_Y} \leq \tau(P,Y) < 1. \]

If the requested Kendall’s tau is too small for the two medians, the function stops with an error.

## Example

Suppose we want to simulate PFS with median 5 months and OS with median 11 months, targeting Kendall’s tau of 0.6 between observed, uncensored PFS and OS times.

    pfs_and_os <- endpoint(name = c('pfs', 'os'),
                           type = c('tte', 'tte'),
                           generator = CorrelatedPfsAndOs2,
                           median_pfs = 5,
                           median_os = 11,
                           kendall = 0.6,
                           pfs_name = 'pfs',
                           os_name = 'os')

    pfs_and_os

For verification only, we can call the generator directly. This is not the recommended way to use `TrialSimulator` for simulation studies; in practice, the generator should usually be supplied to `endpoint()` and used inside the trial simulation workflow. Direct calls are helpful here because they let us check the marginal medians, the observed Kendall’s tau, and the ordering \(\mbox{PFS} \leq \mbox{OS}\) before adding enrollment, censoring, treatment arms, and analyses.

    set.seed(123)
    dat <- CorrelatedPfsAndOs2(n = 10000,
                               median_pfs = 5,
                               median_os = 11,
                               kendall = 0.6)

    head(dat, 2)
    #>        pfs       os pfs_event os_event
    #> 1 6.534539 6.534539         1        1
    #> 2 3.116476 3.116476         1        1

The simulation should approximately recover the requested medians and Kendall’s tau between observed, uncensored PFS and OS times.

    with(dat, median(pfs))
    #> [1] 5.013457
    with(dat, median(os))
    #> [1] 11.35727
    with(dat, cor(pfs, os, method = 'kendall'))
    #> [1] 0.6068072
    with(dat, all(pfs <= os))
    #> [1] TRUE

Because this generator returns event indicators equal to 1 for both endpoints, censoring and staggered enrollment should be handled by the broader trial simulation workflow rather than by this endpoint generator.

## Practical Guidance

This generator is most useful when the simulation objective is to specify marginal PFS and OS medians and a rank-based association between the two observed endpoints. Kendall’s tau is often more stable and interpretable than Pearson correlation for skewed time-to-event variables, and it is directly connected to the Gumbel copula parameter.

There are still modeling assumptions to keep in mind:

- PFS and OS are both marginally exponential.
- Dependence is induced through a Gumbel survival copula on latent TTP and OS.
- The Gumbel copula only allows non-negative dependence.
- The requested Kendall’s tau is for observed PFS and OS event times before censoring is applied.
- The attainable Kendall’s tau between observed PFS and OS is constrained by the PFS/OS median ratio.

For simulations that require transition-specific hazards or a mechanistic disease process, the illness-death model implemented in `TrialSimulator::CorrelatedPfsAndOs3()` may be more appropriate. For simulations where the main requirement is a direct medians-plus-Kendall’s-tau specification, especially when OS will be analyzed under a proportional hazards Cox model, `CorrelatedPfsAndOs2()` provides a compact alternative.

## Appendix: Kendall’s Tau for Observed PFS and OS

This appendix gives the derivation behind the formula used in `CorrelatedPfsAndOs2()`.

Let \(X\) and \(Y\) be nonnegative random variables with exponential margins

\[ X \sim \operatorname{Exp}(\lambda_X), \qquad Y \sim \operatorname{Exp}(\lambda_Y), \]

and joint survival function

\[ S_{X,Y}(x,y) = \Pr(X>x, Y>y) = \exp\left[ -\left\{(\lambda_X x)^\theta + (\lambda_Y y)^\theta\right\}^{1/\theta} \right], \qquad \theta \ge 1. \]

Define \(P=\min(X,Y)\). We want Kendall’s tau between \(P\) and \(Y\).

Standardize the margins by setting

\[ A=\lambda_X X, \qquad B=\lambda_Y Y. \]

Then the joint survival function of \((A,B)\) is

\[ \Pr(A>a, B>b) = \exp\left\{-(a^\theta+b^\theta)^{1/\theta}\right\}. \]

Use the polar-type transformation

\[ R=(A^\theta+B^\theta)^{1/\theta}, \qquad W=\frac{A^\theta}{A^\theta+B^\theta}. \]

A Jacobian calculation gives the joint density

\[ f_{R,W}(r,w)=\frac{1}{\theta} e^{-r}(r+\theta-1), \qquad r>0,\; 0<w<1. \]

Thus, \(R\) and \(W\) are independent and \(W \sim \operatorname{Unif}(0,1)\). The inverse transformation is

\[ A = R W^{1/\theta}, \qquad B = R(1-W)^{1/\theta}. \]

Let

\[ a=\lambda_X^\theta, \qquad b=\lambda_Y^\theta, \qquad c=\frac{a}{a+b}, \qquad d=\frac{b}{a+b}. \]

The event \(X \le Y\) is equivalent to \(W \le c\):

\[ X \le Y \iff \frac{A}{\lambda_X} \le \frac{B}{\lambda_Y} \iff W \le c, \]

so

\[ P= \begin{cases} X, & W \le c,\\ Y, & W > c. \end{cases} \]

Using the survival-copula representation of Kendall’s tau,

\[ \tau(P,Y)=4E\{S_{P,Y}(P,Y)\}-1. \]

When \(W \le c\), \(P=X\) and

\[ S_{P,Y}(P,Y)=S_{X,Y}(X,Y)=e^{-R}. \]

When \(W>c\), \(P=Y\). Since

\[ S_{P,Y}(y,y)=\Pr(P>y,Y>y)=\Pr(X>y,Y>y), \]

we have, using \(Y=B/\lambda_Y=R(1-W)^{1/\theta}/\lambda_Y\),

\[ S_{P,Y}(Y,Y) = \exp\left[ -R\left(\frac{1-W}{d}\right)^{1/\theta} \right]. \]

Therefore,

\[ E\{S_{P,Y}(P,Y)\} = E\{e^{-R}\mathbf 1(W\le c)\} + E\left[ e^{-R((1-W)/d)^{1/\theta}} \mathbf 1(W>c) \right]. \]

By independence of \(R\) and \(W\),

\[ E\{S_{P,Y}(P,Y)\} = cL_R(1) + \int_c^1 L_R\left\{\left(\frac{1-w}{d}\right)^{1/\theta}\right\} dw, \]

where \(L_R(s)=E(e^{-sR})\). From the density of \(R\),

\[ L_R(s) = \frac{1}{\theta} \int_0^\infty e^{-(1+s)r}(r+\theta-1)\,dr = \frac{\theta+(\theta-1)s}{\theta(1+s)^2}. \]

In particular,

\[ L_R(1)=\frac{2\theta-1}{4\theta}. \]

For the integral term, use the substitution

\[ t=\left(\frac{1-w}{d}\right)^{1/\theta}, \qquad dw=-d\theta t^{\theta-1}dt. \]

Then

\[ \int_c^1 L_R\left\{\left(\frac{1-w}{d}\right)^{1/\theta}\right\} dw = d\theta\int_0^1 t^{\theta-1}L_R(t)\,dt. \]

Substituting \(L_R(t)\) gives

\[ d\int_0^1 \frac{\theta t^{\theta-1}+(\theta-1)t^\theta}{(1+t)^2} dt. \]

Because

\[ \frac{d}{dt}\left(\frac{t^\theta}{1+t}\right) = \frac{\theta t^{\theta-1}+(\theta-1)t^\theta}{(1+t)^2}, \]

the integral is

\[ d\left[\frac{t^\theta}{1+t}\right]_0^1 = \frac{d}{2}. \]

Thus,

\[ E\{S_{P,Y}(P,Y)\} = c\frac{2\theta-1}{4\theta}+\frac{d}{2} = \frac{2\theta-1+d}{4\theta}, \]

using \(c+d=1\). Finally,

\[ \tau(P,Y) = 4E\{S_{P,Y}(P,Y)\}-1 = \frac{\theta-1+d}{\theta} = 1-\frac{1}{\theta} \left( \frac{\lambda_X^\theta}{\lambda_X^\theta+\lambda_Y^\theta} \right). \]

Since \(P\) has rate

\[ \lambda_P = \left(\lambda_X^\theta+\lambda_Y^\theta\right)^{1/\theta}, \]

this can also be written as

\[ \tau(P,Y) = 1-\frac{1}{\theta} \left( \frac{\lambda_X^\theta}{\lambda_P^\theta} \right) = 1-\frac{1}{\theta} \left[ 1-\left(\frac{\lambda_Y}{\lambda_P}\right)^\theta \right]. \]

Because \(\lambda_Y/\lambda_P = m_P/m_Y\), the formula used by `CorrelatedPfsAndOs2()` is

\[ \tau(P,Y) = 1-\frac{1}{\theta} \left[ 1-\left(\frac{m_P}{m_Y}\right)^\theta \right]. \]