New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon: a simulation study

Mohamed Amine Bayar, Gwénaël Le Teuff, Stefan Michiels, Daniel J. Sargent, Marie Cécile Le Deley

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3245-3258
Number of pages14
JournalStatistics in Medicine
Volume35
Issue number19
DOIs
StatePublished - Aug 30 2016

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Randomized Controlled Trial
Rare Diseases
Horizon
Randomized Controlled Trials
Simulation Study
Evaluation
Survival
Research
Hazard Rate
Sample Size
Treatment Effects
Therapeutics
Series
Randomized Clinical Trial
Prognosis
Parameter Design
Baseline
Maximise

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 journalArticle

Bayar, Mohamed Amine ; Le Teuff, Gwénaël ; Michiels, Stefan ; Sargent, Daniel J. ; Le Deley, Marie Cécile. / New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon : a simulation study. In: Statistics in Medicine. 2016 ; Vol. 35, No. 19. pp. 3245-3258.
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