1 / 38

Issues in the Analysis of Failure Time Data

Current Issues in Failure Time Studies. Unrecognized heterogeneityBivariate estimation of safety and efficacyDependent interval censoringDependent truncation. Unrecognized Heterogeneity. Highly relevant as genetic discoveries are and are not being madeKnown to undermine the power of clinical tr

lieu
Download Presentation

Issues in the Analysis of Failure Time Data

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. Issues in the Analysis of Failure Time Data Rebecca Betensky Harvard School of Public Health FDA/Industry Statistical Workshop September 19, 2003

    2. Current Issues in Failure Time Studies Unrecognized heterogeneity Bivariate estimation of safety and efficacy Dependent interval censoring Dependent truncation

    3. Unrecognized Heterogeneity Highly relevant as genetic discoveries are and are not being made Known to undermine the power of clinical trials Calls for adaptive designs

    4. Background Histologic diagnosis is principal eligibility criterion for clinical trials in oncology. Based on assumption that cancers that seem histologically identical constitute a single disease. This notion is false; cancers of single histologic type often respond differently to treatment, likely due to biologic differences.

    5. In neuro-oncology, at least 3 genetic subtypes of anaplastic oligodendroglioma have been identified (1pLOH, TP53 mutation). These clinically distinct subtypes are indistinguishable microscopically. Identification of molecular subtypes and the use of molecular signatures to direct treatment is becoming part of clinical practice in neuro-oncology.

    6. If molecular heterogeneity implies that only some patients in a clinical trial will respond to treatment, important implications for the design and interpretations of clinical trials.

    7. North American and European Intergroup trials comparing chemo+RT versus RT for patients with AO nearing completion. Trials were designed prior to discovery of 3 clinically distinct genetic subtypes: 1pLOH: good response and survival 1p intact, no TP53 mutation: poor response and survival 1p intact, TP53 mutation: intermediate response and survival

    8. Proportions of these genetic subtypes differ across cohorts; in uncontrolled Phase II studies proportion of 1pLOH is 90%, versus 60% among all newly diagnosed cases. Leads to unrealistic design assumptions for Phase III trials.

    9. Investigators now question whether these trials might have been under-powered due to this unrecognized heterogeneity. Both consortia collected tumor tissue on all randomized cases; post hoc clinical molecular correlative studies will be feasible and may enhance interpretation.

    10. In Statistical Terms The investigators assume that the data follow a simple proportional hazards model: However, the data really follow a different proportional hazards model:

More Related