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Taking the long view: how to design a series of Phase III trials to maximize cumulative therapeutic benefit.

ABSTRACT: Traditional clinical trial designs strive to definitively establish the superiority of an experimental treatment, which results in risk-adverse criteria and large sample sizes. Increasingly, common cancers are recognized as consisting of small subsets with specific aberrations for targeted therapy, making large trials infeasible.To compare the performance of different trial design strategies over a long-term research horizon.We simulated a series of two-treatment superiority trials over 15 years using different design parameters. Trial parameters examined included the number of positive trials to establish superiority (one-trial vs. two-trial rule), ? level (2.5%-50%), and the number of trials in the 15-year period, K (thus, trial sample size). The design parameters were evaluated for different disease scenarios, accrual rates, and distributions of treatment effect. Metrics used included the overall survival gain at a 15-year horizon measured by the hazard ratio (HR), year 15 versus year 0. We also computed the expected total survival benefit and the risk of selecting as new standard of care at year 15 a treatment inferior to the initial control treatment, P(detrimental effect).Expected survival benefits over the 15-year horizon were maximized when more (smaller) trials were conducted than recommended under traditional criteria, using the criterion of one positive trial (vs. two), and relaxing the ? value from 2.5% to 20%. Reducing the sample size and relaxing the ? value also increased the likelihood of selecting an inferior treatment at the end. The impact of ? and K on the survival benefit depended on the specific disease scenario and accrual rate: greater gains for relaxing ? in diseases with good outcome and/or low accrual rates and greater gains for increasing K for diseases with poor outcomes. Trials with smaller sample size did not perform well when using stringent (standard) level of evidence. For each disease scenario and accrual rate studied, the optimal design, defined as the design that the maximized expected total survival benefit while constraining P(detrimental effect) < 2.5%, specified ? = 20% or 10%, and a sample size considerably smaller than that recommended by the traditional designs. The results were consistent under different assumed distributions for treatment effect.The simulations assumed no toxicity issues and did not consider interim analyses.It is worthwhile to consider a design paradigm that seeks to maximize the expected survival benefit across a series of trials, over a longer research horizon. In today's environment of constrained, biomarker-selected populations, our results indicate that smaller sample sizes and larger ? values lead to greater long-term survival gains compared to traditional large trials designed to meet stringent criteria with a low efficacy bar.

SUBMITTER: Deley MC

PROVIDER: S-EPMC3904223 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo describe telephone interview completion rates among 12-month cardiac arrest survivors enrolled in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials, identify key characteristics of the completed follow-up interviews at both 3- and 12-month postcardiac arrest, and describe strategies implemented to promote follow-up.SettingCentralized telephone follow-up interviews.DesignRetrospective report of data collected for Therapeutic Hypothermia after Pediatric Cardiac Arrest trials, and summary of strategies used to maximize follow-up completion.PatientsTwelve-month survivors (n = 251) from 39 Therapeutic Hypothermia after Pediatric Cardiac Arrest PICU sites in the United States, Canada, and United Kingdom.InterventionsNot applicable.Measurements and main resultsThe 3- and 12-month telephone interviews included completion of the Vineland Adaptive Behavior Scales, Second Edition. Vineland Adaptive Behavior Scales, Second Edition data were available on 96% of 3-month survivors (242/251) and 95% of 12-month survivors (239/251) with no differences in demographics between those with and without completed Vineland Adaptive Behavior Scales, Second Edition. At 12 months, a substantial minority of interviews were completed with caregivers other than parents (10%), after calls attempts were made on 6 or more days (18%), and during evenings/weekends (17%). Strategies included emphasizing the relationship between study teams and participants, ongoing communication between study team members across sites, promoting site engagement during the study's final year, and withholding payment for work associated with the primary outcome until work had been completed.ConclusionsIt is feasible to use telephone follow-up interviews to successfully collect detailed neurobehavioral outcome about children following pediatric cardiac arrest. Future studies should consider availability of the telephone interviewer to conduct calls at times convenient for families, using a range of respondents, ongoing engagement with site teams, and site payment related to primary outcome completion.

Project description:BackgroundMonoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials?MethodsWe included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL).ResultsOverall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations.ConclusionsFremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice.Trial registrationClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

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Taking the long view: how to design a series of Phase III trials to maximize cumulative therapeutic benefit.

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