Abstract
Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3245-3258 |
| Number of pages | 14 |
| Journal | Statistics in Medicine |
| Volume | 35 |
| Issue number | 19 |
| DOIs | |
| State | Published - Aug 30 2016 |
Fingerprint
Keywords
- benefit and risk
- phase III design strategy
- randomized controlled trial
- rare cancer
- simulation
ASJC Scopus subject areas
- Epidemiology
- Statistics and Probability
Cite this
New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon : a simulation study. / Bayar, Mohamed Amine; Le Teuff, Gwénaël; Michiels, Stefan; Sargent, Daniel J.; Le Deley, Marie Cécile.
In: Statistics in Medicine, Vol. 35, No. 19, 30.08.2016, p. 3245-3258.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon
T2 - a simulation study
AU - Bayar, Mohamed Amine
AU - Le Teuff, Gwénaël
AU - Michiels, Stefan
AU - Sargent, Daniel J.
AU - Le Deley, Marie Cécile
PY - 2016/8/30
Y1 - 2016/8/30
N2 - Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases.
AB - Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases.
KW - benefit and risk
KW - phase III design strategy
KW - randomized controlled trial
KW - rare cancer
KW - simulation
UR - http://www.scopus.com/inward/record.url?scp=84977654753&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84977654753&partnerID=8YFLogxK
U2 - 10.1002/sim.6942
DO - 10.1002/sim.6942
M3 - Article
C2 - 27027783
AN - SCOPUS:84977654753
VL - 35
SP - 3245
EP - 3258
JO - Statistics in Medicine
JF - Statistics in Medicine
SN - 0277-6715
IS - 19
ER -