R/SimPhase123.R

In Phase123: Simulating and Conducting Phase 123 Trials

#' Simulates replications of the phase123 and phase 12-3 trials.
#'
#' This function simulates replications of the phase123 and phase 12-3 trials and returns a list containing the doses chosen, decisions made (1=A(x) better, 0= futility, -1=C better)
#' @param Dose Vector of standardized doses considered in the trial.
#' @param NET Maximum sample size of the phase 12 trial.
#' @param NF Number of patients to assign deterministic doses prior to adaptive randomization.
#' @param Hypermeans Prior Means for the Eff-Tox design of length 6.
#' @param Hypervars Prior Variances for the Eff-Tox design of length 6.
#' @param betaA True linear term for the rate or mean parameter (beta_1,exp(beta_E),-exp(beta_T),beta_2,beta_0) for agent A.
#' @param Family Time to event distribution. Options include: Exponential, Gamma, Weibull, Lognormal.
#' @param alpha Shape parameter or standard deviation of a lognormal distribution.
#' @param Nmax Maximum number of patients to enroll in phase 3.
#' @param Accrue Accrual rate for patients in the phase 3 portion of the trial.
#' @param Accrue12 Accrual rate for patients in the phase 12 portion of the trial.
#' @param Time12 Time window for phase 12.
#' @param Twait Waiting time in between phase 12 and phase 3.
#' @param NLookSwitch Number of patient events to determine if we re-optimize doses for A.
#' @param NLook Vector of information criteria for making interim looks.
#' @param Sup Vector of superiority boundaries.
#' @param Fut Vector of futility boundaries.
#' @param PE True efficacy dose-toxicity vector.
#' @param PT True toxicity dose-toxicity vector.
#' @param DoseStart Starting dose of the phase 12 trial.
#' @param Contour Vector containing 4 entries used to make the desireability function. Contour[1] contains a desired toxicity probability given efficacy, Countour[2] contains a desired efficacy probability given toxicity, and (Contour[3],Contour[4]) is an equally desireable pair of efficacy and toxicity probabilities that are non-zero or one.
#' @param PiLim Vector of length two with PiLim[1] containing the acceptable lower limit on efficacy probability and PiLim[2] containing the acceptable upper limit on toxicity probability.
#' @param ProbLim Vector of length two with ProbLim[1] containing the probability cutoff for acceptable efficacy probability and ProbLim[2] containing the probability cutoff for acceptable toxicity probability.
#' @param cohort Size of each patient cohort.
#' @param ProbC Probability of efficacy and toxicity for the control therapy.
#' @param betaC Linear term for efficacy, toxicity and beta_0 for the control groupar term for efficacy, toxicity and beta_0 for the control group.
#' @param nSims Number of simulations to run for the phase 123 and conventional design.
#' @importFrom  stats sd
#' @import survival
#' @references
#' [1] Chapple and Thall (2018).A Hybrid Phase I-II/III Clinical Trial Design Allowing Dose Re-Optimization in Phase III. Biometrics. In Press,
#' @examples
#'  ##We need to specify Phase 12,
#'###Phase 3 trial paramters,
#'##the additional phase 123 parameters and simulation parameters
#'#This is scenario 3 for the exponetial case
#'##the additional phase 123 parameters and simulation parameters
#' ###########PHASE12 Parameters ##################
#' DoseStart=1
#'##True Efficacy and Toxicity Probabilities
#'PT = c(.05,.08,.1,.15,.2)
#'PE=c(.2,.25,.35,.4,.55)
#'##Raw Dose Levels considered
#'Dose = c(1,2,3,3.5,5)
#'#Max Sample Size
#'NET=30
#'##Number of patients before randomization
#'NF=15
#'##Cohort size
#'cohort=3
#'##Hypermeans for Eff-Tox
#'Hypermeans = c(.022,3.45,0,-4.23,3.1,0)
#'Hypervars = c(2.6761, 2.6852, .2, 3.1304, 3.1165, 1)
#'Hypervars=Hypervars^2
#'##Contour Vector
#'Contour = c(.35, .75,.7,.4)
#'##Acceptability Criteria
#'PiLim = c(.3,.4)
#'ProbLim=c(.1,.1)
#'##Phase 12 accrual rate
#'Accrue12=5
#'###How long is the time window in phase 12?
#'Time12=1
#'##########PHASE3 Parameters####################
#'Nmax=500
#'##Number of patient events for interim looks
#'NLook = c(200,300,400)
#'##Superiority Boundaries
#'Sup = c(2.96, 2.53,1.99)
#'##Futility Boundaries (0 means no futility decision)
#'Fut = c(0,1.001,0)
#'##Average accrual rate for phase III
#'Accrue = 10
#'###########Phase123 Parameters###########
#'###Number of patient events to re-optimize doses
#'NLookSwitch=50
#' ##Time in between phase 12 and phase 3
#' Twait=1
#' #########Simulation Parameters######
#'###Family of Distributions
#'Family="Gamma"
#'###Shape parameter, Not needed for Exponential
#'alpha=1
#'###True Beta vector (beta_1,exp(beta_E),-exp(beta_T),beta_2,beta_0)
#'betaA = c(.1, .3, -1,-1,3.6)
#'##True beta vector for (exp(beta_E),-exp(beta_T),beta_C)  of the control treatment
#'betaC=c(.3,-1,log(24/1.035111))
#'##True efficacy and toxicity probability for control group
#'ProbC = c(.3,.1)
#'##Number of simulations to run
#'nSims=1
#'##Run Simulations
#'Results=SimPhase123(DoseStart,Dose,PE,PT,Hypermeans,Hypervars,Contour,
#'                  PiLim,ProbLim,NET,NF,Accrue12,Time12,cohort,betaA,ProbC,betaC,
#'                 Family,alpha,Nmax,Accrue,Twait,NLookSwitch,NLook,Sup,Fut,nSims)
#' @export
SimPhase123=function(DoseStart,Dose,PE,PT,Hypermeans,Hypervars,Contour,PiLim,ProbLim,NET,NF,Accrue12,Time12,cohort,betaA,ProbC,betaC,Family,alpha,Nmax,Accrue,Twait,NLookSwitch,NLook,Sup,Fut,nSims){


  Doselog = log(Dose)-mean(log(Dose))

  Dose1=(Dose-mean(Dose))/sd(Dose)


PH123=matrix(rep(NA,4*nSims),nrow=nSims)
PH12=matrix(rep(NA,4*nSims),nrow=nSims)

B=2000


  for(h in 1:nSims){

    if(h%%100==0){
      cat(h, "Simulations Finished

          ")

    }


Phase12 = RunAdaptiveEffToxTrial(DoseStart,Doselog, Hypermeans,  Hypervars,  Contour, PiLim, ProbLim,  cohort, NET,  NF, B, 1, PE, PT )

Opt=Phase12[[1]][1]

Phase12=Phase12[[3]]

Phase12[,1]=Phase12[,1]+1


ACC1=cumsum(rexp(NET,Accrue12))
Grab = rep(NA,NET/cohort)
for(m in 1:length(Grab)){Grab[m]=ACC1[m*3]}
for(m in 1:length(Grab)){ACC1[((m-1)*cohort+1):((m-1)*cohort+cohort)]=rep(Grab[m],cohort)}
Phase12 = cbind(Phase12,ACC1)




Z=SimPhase3(Dose1,Phase12,PE,PT,Hypermeans,Hypervars,betaA,ProbC,betaC,Family,alpha,Nmax,Opt,Accrue,Time12,Twait,NLookSwitch,NLook,Sup,Fut)


Z123=Z[[1]]
Z12=Z[[2]]

PH123[h,]=Z123
PH12[h,]=Z12

}


Z=as.list(c(0,0))
Z[[1]]=PH123
Z[[2]]=PH12




return(Z)


}