scholarly journals Comparison of futility monitoring guidelines using completed phase III oncology trials

2016 ◽  
Vol 14 (1) ◽  
pp. 48-58 ◽  
Author(s):  
Qiang Zhang ◽  
Boris Freidlin ◽  
Edward L Korn ◽  
Susan Halabi ◽  
Sumithra Mandrekar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Alternative Hypothesis ◽  
Phase Iii ◽  
Interim Result ◽  
Type I ◽  
Conditional Power ◽  
Phase Iii Clinical Trials ◽  
The Impact ◽  
Analytical Approaches

Background: Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. Purpose: We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. Methods: We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. Results: For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. Conclusion: The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

Analytical Approaches for the BOAC SNP Panel Association with Progression Free Survival in Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2715-2715
Author(s):  
Brian G. Van Ness ◽  
Christine Ramos ◽  
Vipin Kumar ◽  
Michael Steinbach ◽  
Brian GM Durie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Expression Profiles ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Support Vector ◽  
Type I ◽  
Free Survival ◽  
Snp Panel ◽  
Analytical Approaches

Abstract The Bank On A Cure (BOAC) has established DNA banks from multiple cooperative and institutional clinical trials, and platforms for examining the association of genetic variations (SNPs) with disease risk and outcomes in myeloma. We have previously described the development and content of a novel custom SNP panel that contains 3,404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. Although survival certainly varies according to tumor heterogeneity (ie. chromosomal abnormalities, gene expression variations) germline variations that influence the microenvironment, drug distribution, drug transport and metabolism, may also have an association with event free survival outcomes. To explore SNP associations with progression free survival (PFS) we compared the BOAC SNP profiles of short term PFS (less than 1 year, n=70) versus long term PFS (greater than 3 years, n=73) in two phase III clinical trials (ECOG E9487 and SWOG S9321). A variety of analytical approaches was undertaken including univariate rank ordering, recursive partitioning, and support vector machine learning tools (SVM). Each of these approaches has advantages and limitations in dealing with type I false positive errors as well as sensitivity and specificity. We included subset validation approaches and randomization of classes to address how robust and predictive different approaches were. From our analysis we conclude germline genomic variations do have an impact on progression free survival, with a subset of SNPs from the panel reaching 76% predictive association and hazard ratios of PFS of 9.6 (CI 4.5, 20.5), p&lt;0.001, using SVM analysis. Based on univariate approaches, we find the most significant variations associated with PFS differences were genes that could be functionally categorized as pharmacologic. The presentation will focus on the analytical approaches, and refinements necessary to assure predictive value compared to random associations. Notwithstanding the clear importance of tumor cell variations in genetic deregulation, we conclude that various functions within the bone marrow and drug response likely interplay as a complex influence on disease progression, response, and survival. This suggests combining gene expression profiles of the tumors with germline SNP profiles may provide more accurate prognosis. These combined analytical approaches are currently being developed with BOAC data bases, and examples will be discussed.

A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 129-129
Author(s):  
Raman Tatla ◽  
Denis Landaverde ◽  
Charles Victor ◽  
David Miles ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Clinical Endpoints ◽  
Phase Iii Clinical Trials ◽  
The Impact

129 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's funcitonal abilities has led to an emphasis of incorporating quality of life (QoL) measures into clinical trials. The main objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QOL as an endpoint, in addition to conventional efficacy endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, evaluating systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p=0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in the QoL endpoint; of not, instruments of varying validity were utilized. There needs to be a greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

A phase II trial design with direct assignment option for initial marker validation.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
Sumithra J. Mandrekar ◽  
Ming-Wen An ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Type I Error ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Phase Iii ◽  
Type I ◽  
Design Strategies ◽  
Number Of Patients ◽  
The Impact

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (<1.8%) and minimal increase in T1ER (<2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was <1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.

Comparison of four sequential methods allowing for early stopping of comparative clinical trials

2000 ◽  
Vol 98 (5) ◽  
pp. 569-578 ◽  
Author(s):  
Véronique SEBILLE ◽  
Eric BELLISSANT
Keyword(s):  
Sample Size ◽  
Alternative Hypothesis ◽  
Phase Iii ◽  
Ratio Test ◽  
Type I ◽  
Early Stopping ◽  
Sample Number ◽  
Sequential Methods ◽  
Number Of Patients ◽  
Sequential Tests

Phase III trials aim to assess whether a new treatment has superior efficacy than a standard treatment. Sequential methods, such as the sequential probability ratio test (SPRT), the triangular test (TT) and so-called one-parameter boundaries (OPB), now allow early stopping of such trials, both in the case of efficacy (alternative hypothesis; H1) and in the case of lack of efficacy (null hypothesis; H0). We compared the statistical properties of the SPRT and the TT, and of OPB with Pocock (OPBΔ = 0.5) and O'Brien and Fleming (OPBΔ = 0) type boundaries, in the setting of one-sided comparative trials with normal response. We studied the type I error (α), power (1-β), average sample number (ASN) and 90th percentile (P90) of the number of patients required to reach a conclusion using simulations. The four tests were also compared with the corresponding single-stage design (SSD). All sequential tests display α and 1-β close to nominal values and, as compared with SSD, allow important decreases in ASN: for example, -48%, -42%, -40% and -31% under H0 and H1 for SPRT, TT, OPBΔ = 0.5 and OPBΔ = 0 respectively. For situations between H0 and H1, ASNs of all sequential tests were still smaller than the sample size required by SSD, with the TT displaying the largest decrease (-25%). The P90s of the TT and OPBΔ = 0 under H0 and H1 were smaller than the P90s of the SPRT and OPBΔ = 0.5, which were similar to the sample size required by SSD. If all sequential tests display approximately similar features, the TT is the most appealing regarding decreases in sample size, especially for situations between H0 and H1.

P4-004: Planning Dose Escalation in Phase III Clinical Trials May Prevent Underpowered Trials and Mitigate the Increase in Sample Size or Duration of Adaptive Trials

2016 ◽  
Vol 12 ◽  
pp. P1015-P1015
Author(s):  
Guoqiao Wang ◽  
Eric McDade ◽  
Randall Bateman ◽  
Jason Hassenstab ◽  
Martin R. Farlow ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Dose Escalation ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Adaptive Trials

A review of clinical endpoints and use of quality of life outcomes in phase III metastatic breast cancer clinical trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16547-e16547
Author(s):  
Raman Tatla ◽  
Denis Landaverde ◽  
Charles Victor ◽  
David Miles ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Clinical Endpoints ◽  
Phase Iii Clinical Trials ◽  
The Impact

e16547 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with therapy used to relieve disease symptoms, minimize treatment effects and prolong survival. The impact of disease and treatment on patients has led to an emphasis of quality of life (QoL) measures in clinical trials. This study’s primary objective is to evaluate phase III clinical trials in MBC, and assess the inclusion of QoL as an endpoint. Methods: A PubMed search was conducted to identify phase III clinical trials published from Jan 1990 to Aug 2011, which evaluated systemic therapy in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a focus on progression-based (PB), overall survival (OS), and QoL endpoints. The instrument(s) used to evaluate QoL were also noted (if applicable). Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. 14 instruments were identified as QoL tools among the studies, with EORTC QLQ-C30 and FACT-B accounting for 54.7% of the instruments used. While the inclusion of QoL was not related to the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as an endpoint (p=0.016). Stratification by treatment arm found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management, only one-third of identified phase III clinical trials included its assessment. Half of these trials showed no statistically significant differences in QoL endpoint; of note, instruments of varying validity were utilized. There needs to be greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

2001 ◽  
Vol 120 (5) ◽  
pp. A284-A284
Author(s):  
B NAULT ◽  
S SUE ◽  
J HEGGLAND ◽  
S GOHARI ◽  
G LIGOZIO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Irritable Bowel Syndrome ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Irritable Bowel ◽  
Rome I
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