Applications of Bayesian statistical methodology to clinical trial design: A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis

Claire L. Smith, Yan Jin, Eyas Raddad, Terry A. McNearney, Xiao Ni, David Monteith, Roger Brown, Mark A. Deeg, Thomas J Schnitzer

Research output: Contribution to journalArticle

Abstract

Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14-mm improvement and ≤1% risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.

Original languageEnglish (US)
Pages (from-to)39-53
Number of pages15
JournalPharmaceutical Statistics
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Osteoarthritis
Medical Futility
Knee Osteoarthritis
Interim Analysis
Clinical Trials
Methodology
Treatment Effects
Bayesian Approach
Drugs
Dose Finding
Bayes Theorem
Analgesics
Celecoxib
Placebos
Dose-response
Literature Review
Pain
Therapeutics
Therapy
Efficacy

ASJC Scopus subject areas

  • Statistics and Probability
  • Pharmacology
  • Pharmacology (medical)

Cite this

Smith, Claire L. ; Jin, Yan ; Raddad, Eyas ; McNearney, Terry A. ; Ni, Xiao ; Monteith, David ; Brown, Roger ; Deeg, Mark A. ; Schnitzer, Thomas J. / Applications of Bayesian statistical methodology to clinical trial design : A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis. In: Pharmaceutical Statistics. 2019 ; Vol. 18, No. 1. pp. 39-53.
@article{6fec4b2adc5c447a850fe6e7be53c504,
title = "Applications of Bayesian statistical methodology to clinical trial design: A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis",
abstract = "Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85{\%} power to detect a 14-mm improvement and ≤1{\%} risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.",
author = "Smith, {Claire L.} and Yan Jin and Eyas Raddad and McNearney, {Terry A.} and Xiao Ni and David Monteith and Roger Brown and Deeg, {Mark A.} and Schnitzer, {Thomas J}",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/pst.1906",
language = "English (US)",
volume = "18",
pages = "39--53",
journal = "Pharmaceutical Statistics",
issn = "1539-1604",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

Applications of Bayesian statistical methodology to clinical trial design : A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis. / Smith, Claire L.; Jin, Yan; Raddad, Eyas; McNearney, Terry A.; Ni, Xiao; Monteith, David; Brown, Roger; Deeg, Mark A.; Schnitzer, Thomas J.

In: Pharmaceutical Statistics, Vol. 18, No. 1, 01.01.2019, p. 39-53.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Applications of Bayesian statistical methodology to clinical trial design

T2 - A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis

AU - Smith, Claire L.

AU - Jin, Yan

AU - Raddad, Eyas

AU - McNearney, Terry A.

AU - Ni, Xiao

AU - Monteith, David

AU - Brown, Roger

AU - Deeg, Mark A.

AU - Schnitzer, Thomas J

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14-mm improvement and ≤1% risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.

AB - Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14-mm improvement and ≤1% risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.

UR - http://www.scopus.com/inward/record.url?scp=85055104676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055104676&partnerID=8YFLogxK

U2 - 10.1002/pst.1906

DO - 10.1002/pst.1906

M3 - Article

VL - 18

SP - 39

EP - 53

JO - Pharmaceutical Statistics

JF - Pharmaceutical Statistics

SN - 1539-1604

IS - 1

ER -