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Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials.

ABSTRACT: Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal treatment effects in compliers, these methods do not apply to a common class of trials where a) the primary objective compares survival curves, b) it is inconceivable to assign participants to be adherent and event-free before adherence is measured, and c) the exclusion restriction assumption fails to hold. HIV vaccine efficacy trials including the recent RV144 trial exemplify this class, because many primary endpoints (e.g., HIV infections) occur before adherence is measured, and nonadherent subjects who receive some of the planned immunizations may be partially protected. Therefore, we develop methods for assessing per-protocol treatment efficacy for this problem class, considering three causal estimands of interest. Because these estimands are not identifiable from the observable data, we develop nonparametric bounds and semiparametric sensitivity analysis methods that yield estimated ignorance and uncertainty intervals. The methods are applied to RV144.

SUBMITTER: Gilbert PB

PROVIDER: S-EPMC3811958 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials.

Gilbert Peter B PB Shepherd Bryan E BE Hudgens Michael G MG

Journal of the American Statistical Association 20130101 503

Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal trea ...[more]

PMID: 24187408

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Project description:BACKGROUND:The per-protocol effect is the effect that would have been observed in a randomized trial had everybody followed the protocol. Though obtaining a valid point estimate for the per-protocol effect requires assumptions that are unverifiable and often implausible, lower and upper bounds for the per-protocol effect may be estimated under more plausible assumptions. Strategies for obtaining bounds, known as "partial identification" methods, are especially promising in randomized trials. RESULTS:We estimated bounds for the per-protocol effect of colorectal cancer screening in the Norwegian Colorectal Cancer Prevention trial, a randomized trial of one-time sigmoidoscopy screening in 98,792 men and women aged 50-64 years. The screening was not available to the control arm, while approximately two thirds of individuals in the treatment arm attended the screening. Study outcomes included colorectal cancer incidence and mortality over 10 years of follow-up. Without any assumptions, the data alone provide little information about the size of the effect. Under the assumption that randomization had no effect on the outcome except through screening, a point estimate for the risk under no screening and bounds for the risk under screening are achievable. Thus, the 10-year risk difference for colorectal cancer was estimated to be at least -0.6 % but less than 37.0 %. Bounds for the risk difference for colorectal cancer mortality (-0.2 to 37.4 %) and all-cause mortality (-5.1 to 32.6 %) had similar widths. These bounds appear helpful in quantifying the maximum possible effectiveness, but cannot rule out harm. By making further assumptions about the effect in the subpopulation who would not attend screening regardless of their randomization arm, narrower bounds can be achieved. CONCLUSIONS:Bounding the per-protocol effect under several sets of assumptions illuminates our reliance on unverifiable assumptions, highlights the range of effect sizes we are most confident in, and can sometimes demonstrate whether to expect certain subpopulations to receive more benefit or harm than others. TRIAL REGISTRATION:Clinicaltrials.gov identifier NCT00119912 (registered 6 July 2005).

Project description:ObjectiveAcupuncture has been used by rehabilitation specialists as an adjunctive treatment for the symptomatic treatment of rheumatoid arthritis (RA). This meta-analysis aims to evaluate the efficacy of acupuncture in treating patients with RA.MethodsA comprehensive search was conducted in CBM, CNKI, PubMed, CENTRAL, Web of Science, and Embase from their inception up to March 2022. All randomized controlled trials (RCTs) without the language restriction, concerning the patients with RA treated with acupuncture, were included. Two reviewers independently assessed the risk of bias with the Cochrane Risk of Bias Assessment tool. Weight mean difference (MD) and 95% CI were calculated, and data were pooled with random effects model.ResultsA total of eleven RCTs involving 796 patients with RA met the established inclusion criteria. This systematic review indicated the efficacy of acupuncture as an adjunctive treatment for patients with RA. Invasive acupuncture could reduce significantly in pain (MD = -1.00, 95% CI: -1.96 to -0.05, P=0.040), health assessment questionnaire (HAQ, MD = -0.20, 95% CI: -0.30 to -0.11, P < 0.001), physician global assessment (PhGA, MD = -0.98, 95% CI: -1.23 to -0.72, P < 0.001), tender joint count (TJC, MD = -1.24, 95% CI: -2.11 to -0.37, P=0.005), C-reactive protein (CRP, MD = -1.81, 95% CI: -3.32 to -0.29, P=0.019), and erythrocyte sedimentation rate (ESR, MD = -3.03, 95% CI: -5.80 to -0.26, P=0.032), while compared to control group. Laser acupuncture could reduce HAQ (MD = -0.15, 95% CI: -0.28 to -0.01, P=0.034), the RA quality of life questionnaire (RAQoL, MD = -2.32, 95% CI: -4.40 to -0.25, P=0.028), CRP (MD = -35.24, 95% CI: -36.49 to -33.99, P < 0.001), and interleukin-6 (IL-6, MD = -29.63, 95% CI: -49.34 to -9.92, P=0.003), while compared to control group. No adverse events associated with acupuncture were reported.ConclusionAvailable evidence suggests that acupuncture is beneficial for relieving pain and ameliorating quality of life and health index in patients with RA; thereby, it should be available as an adjunctive nonpharmacological treatment in rehabilitation programmes.

Dataset Information

Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials.

Publications

Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials.

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