optimal_multiarm: Optimal phase II/III drug development planning for multi-arm...

In Sterniii3/drugdevelopR: Utility-Based Optimal Phase II/III Drug Development Planning

Optimal phase II/III drug development planning for multi-arm programs with time-to-event endpoint

Description

The function optimal_multiarm of the drugdevelopR package enables planning of multi-arm phase II/III drug development programs with optimal sample size allocation and go/no-go decision rules (Preussler et. al, 2019) for time-to-event endpoints. So far, only three-arm trials with two treatments and one control are supported. The assumed true treatment effects are assumed fixed (planning is also possible via user-friendly R Shiny App: multiarm). Fast computing is enabled by parallel programming.

Usage

optimal_multiarm(
  hr1,
  hr2,
  ec,
  n2min,
  n2max,
  stepn2,
  hrgomin,
  hrgomax,
  stephrgo,
  alpha,
  beta,
  c2,
  c3,
  c02,
  c03,
  K = Inf,
  N = Inf,
  S = -Inf,
  steps1 = 1,
  stepm1 = 0.95,
  stepl1 = 0.85,
  b1,
  b2,
  b3,
  strategy,
  num_cl = 1
)

Arguments

hr1	assumed true treatment effect on HR scale for treatment 1
hr2	assumed true treatment effect on HR scale for treatment 2
ec	control arm event rate for phase II and III
n2min	minimal total sample size in phase II, must be divisible by 3
n2max	maximal total sample size in phase II, must be divisible by 3
stepn2	stepsize for the optimization over n2, must be divisible by 3
hrgomin	minimal threshold value for the go/no-go decision rule
hrgomax	maximal threshold value for the go/no-go decision rule
stephrgo	step size for the optimization over HRgo
alpha	one-sided significance level/family-wise error rate
beta	type-II error rate for any pair, i.e. 1 - beta is the (any-pair) power for calculation of the number of events for phase III
c2	variable per-patient cost for phase II
c3	variable per-patient cost for phase III
c02	fixed cost for phase II
c03	fixed cost for phase III
K	constraint on the costs of the program, default: Inf, e.g. no constraint
N	constraint on the total expected sample size of the program, default: Inf, e.g. no constraint
S	constraint on the expected probability of a successful program, default: -Inf, e.g. no constraint
steps1	lower boundary for effect size category "small" in HR scale, default: 1
stepm1	lower boundary for effect size category "medium" in HR scale = upper boundary for effect size category "small" in HR scale, default: 0.95
stepl1	lower boundary for effect size category "large" in HR scale = upper boundary for effect size category "medium" in HR scale, default: 0.85
b1	expected gain for effect size category "small"
b2	expected gain for effect size category "medium"
b3	expected gain for effect size category "large"
strategy	choose strategy: 1 (only the best promising candidate), 2 (all promising candidates) or 3 (both strategies)
num_cl	number of clusters used for parallel computing, default: 1

Value

The output of the function is a data.frame object containing the optimization results:

Strategy

Strategy, 1: "only best promising" or 2: "all promising"

u

maximal expected utility under the optimization constraints, i.e. the expected utility of the optimal sample size and threshold value

HRgo

optimal threshold value for the decision rule to go to phase III

d2

optimal total number of events for phase II

d3

total expected number of events for phase III; rounded to next natural number

d

total expected number of events in the program; d = d2 + d3

n2

total sample size for phase II; rounded to the next even natural number

n3

total sample size for phase III; rounded to the next even natural number

n

total sample size in the program; n = n2 + n3

K

maximal costs of the program (i.e. the cost constraint, if it is set or the sum K2+K3 if no cost constraint is set)

pgo

probability to go to phase III

sProg

probability of a successful program

sProg2

probability of a successful program with two arms in phase III

sProg3

probability of a successful program with three arms in phase III

K2

expected costs for phase II

K3

expected costs for phase III

and further input parameters. Taking cat(comment()) of the data frame lists the used optimization sequences, start and finish date of the optimization procedure.

References

Preussler, S., Kirchner, M., Goette, H., Kieser, M. (2019). Optimal Designs for Multi-Arm Phase II/III Drug Development Programs. Submitted to peer-review journal.

IQWiG (2016). Allgemeine Methoden. Version 5.0, 10.07.2016, Technical Report. Available at https://www.iqwig.de/ueber-uns/methoden/methodenpapier/, assessed last 15.05.19.

Examples

# Activate progress bar (optional)
## Not run: progressr::handlers(global = TRUE)
# Optimize

optimal_multiarm(hr1 = 0.75, hr2 = 0.80,    # define assumed true HRs 
  ec = 0.6,                                          # control arm event rate
  n2min = 30, n2max = 90, stepn2 = 6,                # define optimization set for n2
  hrgomin = 0.7, hrgomax = 0.9, stephrgo = 0.05,     # define optimization set for HRgo
  alpha = 0.025, beta = 0.1,                         # drug development planning parameters
  c2 = 0.75, c3 = 1, c02 = 100, c03 = 150,           # fixed/variable costs for phase II/III
  K = Inf, N = Inf, S = -Inf,                        # set constraints
  steps1 = 1,                                        # define lower boundary for "small"
  stepm1 = 0.95,                                     # "medium"
  stepl1 = 0.85,                                     # and "large" effect size categories
  b1 = 1000, b2 = 2000, b3 = 3000,                   # define expected benefit 
  strategy = 1,                                      # choose strategy: 1, 2 or 3
  num_cl = 1)                                        # number of cores for parallelized computing 
  

Sterniii3/drugdevelopR documentation built on Jan. 26, 2024, 6:17 a.m.