The 2 stage design incorporates an early termination point, which allows the investigator to discontinue patient accrual if a desired endpoint has not been achieved in the first stage of the trial. Twostage designs optimal under the alternative hypothesis. They developed theoretical expressions for the power, nominal size, average sample size, and probability of early termination of the combined procedure. Flemings two stage design this program generates flemings fleming, 1982 two stage designs for phase ii single arm clinical trials that are admissible similar to jung et al. Umbrella trials, conversely, are prospective clinical trials that test multiple targeted interventions for a single disease based on predictive biomarkers or other predictive patient risk factors. We propose an adaptive twostage design which allows the sample size at the second stage to depend on the results at the first stage. Optimal twostage designs for phase ii clinical trials richard simon, phd biometric research branch, national cancer institute, bethesda, maryland abstract.
This important property has been extensively studied in traditional onestage study settings e. Simon s design and extensions simon r, optimal twostage designs for phase ii clinical trials, controlled clinical trials, 1989, 10, 1 10. A major concern is whether or not clinical trials should achieve statistical significance on all of the multiple primary endpoints i. At the completion of the first stage, an interim analysis is made to determine if the second stage should be conducted. Clinical trial design and data analysis functions rdrr. If there are no responses to therapy, the study will be terminated. Optimal twostage designs in phaseii clinical trials. Lack of efficacy unacceptable toxicity need good historical control data multistage designs frequentist gehan 2stage simon 2stage optimal simon 2stage minimax fleming 1stage gehan. Phase ii clinical trials determine whether a drug or regimen has sufficient activity against disease to warrant more extensive study and development. Randomized phase ii trial as an internal pilot to test response rates in standard clinical trial designs, the sample size is determined by the power at a given. The simon s two stage design is a commonly used phase ii design. Twostage markerstratified clinical trial design in the presence of biomarker misclassification. Activity of vemurafenib vem with or without cetuximab ctx in colorectal. A hybrid geometric phase iiiii clinical trial design.
Simon 2stage design and the likelihood method, dan ayers, vanderbilt university software in action 4. The early stopping rule is based on a criteria determined more quickly than that for efficacy. Adaptive design, admissible design, efficacy, futility, minimax design, simons design background in phase ii clinical trials, a ne w treatment or a new therapy. Optimal twostage designs for phase ii clinical trials richard simon, controlled clinical trials 10. Clinical trials using talazoparib national cancer institute. Planned versus attained design in phase ii clinical trials. The design two stages the design could have more than two stages, but less practical and not used enroll n. The study will be conducted using a simon 2 stage minimax design. Clinical trials using capmatinib national cancer institute. A hybrid geometric phase iiiii clinical trial design based on treatment failure time and toxicity peter f. Usual methodology of cancer phase ii trials consists in testing the null hypothesis 0 versus 1. Onestage design used when timedependent endpoints are considered early stopping rules usually incorporated for. A study proceeds to the second stage unless the null hypothesis, that the true tumour response rate is below some specified value, is already accepted at the end of stage one. In a twostage design, the patients are divided into two groups or stages.
Clinical trial design elizabeth ness, rn, ms nurse consultant education center for cancer research, nci agenda types of clinical trials clinical trial design general principles and terminology phase i iii clinical trial designs. The panel focused on master protocols, which include umbrella. Twostageintroduction clinfun april, 2018 title clinical trial design and data analysis functions version 1. Suppose that n patients are treated by the experimental therapy of a singlearm phase ii clinical trial. Lynn henry kelly kidwell topics may include, but are not limited to. For phase ii trials, it has functions to calculate sample size, effect size, and power based on fishers exact test, the operating characteristics of a twostage boundary, optimal and minimax 2stage phase ii designs given by richard simon, the exact 1stage phase ii design and can compute a stopping rule and its operating characteristics for. Optimal fixed two stage designs, where the sample size at each stage is fixed in advance, were proposed by simon when the primary outcome is a binary response. Clinical trials look at new ways to prevent, detect, or treat disease. The design approach considered here is to specify the parameters p0,pl,c. Establishment of a reliable mechanism to ensure patient registration prior to treatment is of fundamental importance for all clinical trials. This program generates simons optimal twostage designs simon, 1989 and admissible designs from jung et al. Simon 2stage optimal simon 2stage minimax fleming 1stage. Twostageintroduction stage designs are commonly used in phase ii clinical trials especially in cancer clinical trials.
Further discussion of the design and some concluding remarks are given in section 5. Seshan description utilities to make your clinical collaborations easier if not fun. Nov 22, 2016 optimal two stage designs for phase ii clinical trials richard simon, controlled clinical trials 10. The clinical trials on this list are studying talazoparib. A twostage design for choosing among several experimental treatments and a control in clinical trials, biometrics, 45, 537547. A sequential twostage dose escalation study to evaluate. Optimal twostage designs for phase ii clinical trials. The primary objective of a phase ii clinical trial of a new drug or regimen is to. An evaluation of a simon 2stage phase ii clinical trial. Nov 28, 2016 the trial aims to assess the activity of multiple drugs used in mutationspecific baskets mutations, amplifications, or translocations, regardless of tumor origin, using a single stage design for each biomarkerdefined subgroup ie, mutationspecific basket. Pdf minimax and admissible adaptive twostage designs in. Package clinfun april, 2018 title clinical trial design and data analysis functions version 1. The 2018 accelerating anticancer agent development aaadv workshop assembled a panel of experts for an indepth discussion session to present challenges with novel clinical trial designs. Ncis basic information about clinical trials explains the types and phases of trials and how they are carried out.
A novel statistical tool for differential expression analysis of nanostring ncounter data, chi wang, university of kentucky 3. References a practical guide to designing phase ii. In a two stage design, the patients are divided into two groups or stages. Exact p values for simons twostage designs in clinical. Demographic and clinical variables for the study patients will be summarized using descriptive statistics mean, standard deviation, median, interquartile. Feb 25, 2010 the simon two stage optimal design is often used for phase ii cancer clinical trials. Simon 2 stage design and the likelihood method, dan ayers, vanderbilt university software in action 4. The primary objective of a phase ii clinical trial of a new drug or regimen is to determine whether it has. The simon twostage optimal design is often used for phase ii cancer clinical trials. The 2stage design incorporates an early termination point, which allows the investigator to discontinue patient accrual if a desired endpoint has not been achieved in the first stage of the trial. Operating characteristics of a simon twostage phase ii.
For patient i 1, n, let t i denote the survival time with a survival function st pt i. This lecture covers a very special form of phase ii clinical trials. Introduction the literature on adaptive clinical trial design has focused on samplesize reestimation, changing the plan for interim analyses, or modifying randomization weights chow and chang 2007, muller and schafer 2001, rosenberger and lachin 1993, karrison, huo, and chappell 2003, and kim et al. Alternative trial designs titecrm for phase i for example 3. The simons two stage design is a commonly used phase ii design. In phase ii clinical trial, randomized design is proposed to establish the sample size for the study to obtain the treatment with greatest response rate for further phase iii study. Phase ii clinical trials with timetoevent endpoints. At the conclusion of the clinical trial, the regimen will be declared active or inactive.
Clinical trials are research studies that involve people. Simon 1989 proposed two criteria minimax and optimal for selecting sample sizes and critical values for these two stage designs. Anderson cancer center, houston, tx, usa b department of pediatrics, tufts medical center, boston, ma, usa article info article history. Example simons design dichotomous outcome usually in phase ii trial suppose that we want to test h0. Optimal fixed twostage designs, where the sample size at each stage is fixed in advance, were proposed by simon when the primary outcome is a binary response. The trial aims to assess the activity of multiple drugs used in mutationspecific baskets mutations, amplifications, or translocations, regardless of tumor origin, using a single stage design for each biomarkerdefined subgroup ie, mutationspecific basket. A small group of patients are enrolled in the first stage. For phase ii trials, it has functions to calculate sample size, effect size, and power based on fishers exact test, the operating characteristics of a two stage boundary, optimal and minimax 2 stage phase ii designs given by richard simon, the exact 1 stage phase ii design and can compute a stopping rule and its operating characteristics for. Exact p values for simons twostage designs in clinical trials. Bayesian twostage designs for phase ii clinical trials. Randomization helps ensure that patients are centrally registered before treatment starts.
Jung sh, lee t, kim km, george sl, admissible twostage designs for phase ii cancer clinical trials, statistics in medicine, 2004, 23, 561 569. The primary objective of a phase ii clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant. Jan 28, 20 for the phase 2 study the simon s optimal two stage design will be employed to test the null hypothesis that response rate rr equals to 10% versus the alternative that rr equals to 30%. Sequential design of phase iiiii cancer trials tze leung lai 1.
All trials on the list are supported by nci ncis basic information about clinical trials explains the types and phases of trials and how they are carried out. Simons twostage design and the admissible twostage design have been commonly used in practice for singlearm phase ii clinical trials when the primary endpoint is binary. It contains functions for designing studies such as simon. Hyman et al, abst 2533, asco 2014 braf v 600m vemurafenib simon 2stage design objective responses. Introduction for ethical, scientific and economic reasons, clinical trials are often repeatedly. Simon s two stage design and the admissible two stage design have been commonly used in practice for singlearm phase ii clinical trials when the primary endpoint is binary. May 30, 2014 however, at the design stage of a clinical trial, we usually know the expected accrual for the trial, rather than the accrual period. Calculates optimal and minimax 2stage phase ii designs given by richard simon ph2simon. The primary objective of a phase 11 clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant more extensive development. At the conclusion of the clinical trial, the regimen will be. Vebasket, a simon 2stage adaptive design, phase ii. Jun 16, 2016 this important property has been extensively studied in traditional onestage study settings e.
If there is at least 1 response an additional 7 evaluable subjects will be accrued. We propose an adaptive two stage design which allows the sample size at the second stage to depend on the results at the first stage. This design employs different endpoints to assess early stopping and efficacy. Ray and rai expanded the concept to allow for continuous toxicity monitoring during a phase ii clinical trial based on the simon 2 stage design.
An overview of precision oncology basket and umbrella. Background clinical trials often employ two or more primary endpoints. These include dynamically stratified randomization, optimal 2 stage phase 2 clinical trial designs, accelerated titration phase 1 designs, stochastic curtailment for futility monitoring, tests of qualitative treatment by covariate interactions, predictive biomarker based enrichment designs, adaptive. The panel focused on master protocols, which include.
An evaluation of bias in 2 stage residual inclusion survival models, fei wan, university of arkansas 2. For the phase 2 study the simons optimal twostage design will be employed to test the null hypothesis that response rate rr equals to 10% versus the alternative that rr equals to 30%. Ray and rai expanded the concept to allow for continuous toxicity monitoring during a phase ii clinical trial based on the simon 2stage design. For example, the first line in table 1 corresponds to a design with p0 0. For background information see the book by green, benedetti and crowley. Keywords group sequential design, clinical trials, twostage design, efficiency 1.