Statistical software for improved Phase I clinical trial design and better data utilization.
- Uses isotonic design for improved accuracy of Maximum Tolerated Dose (MTD) estimation and statistical strength.
- Incorporates Normalized Equivalent Toxicity Score (NETS) as a more detailed and comprehensive measure of toxic events.
The cost of conducting and implementing clinical trials continues to rise. Between 2008 and 2011, the Phase I per-patient clinical trial costs increased 46% on average. Across all clinical trial phases, the average increase for this same time period was 70%. There is a growing need for strategies and tools to decrease the costs associated with clinical trials and increase efficiency. One strategy for increasing cost efficiency is to design more efficient clinical trials.
Current Phase I clinical trial designs are grouped as two categories (ruled based and model based). The ruled based designs, such as the 3+3 design, have the advantages of simplicity and robustness, but low accuracy of MTD. Use of an incorrect MTD in further Phase II/III clinical trials can lead to delays in time to approval or even overall failure of the drug. The model based designs, such as the continuous reassessment method, have improved accuracy of MTD, but depend heavily on a reliable model for dose toxicity relationship which may not be available for new drug first on human being. Isotonic design is a semi-parametric design which only assumes a generally accepted monotonically increasing dose toxicity relationship. Using an isotonic design, dosage adjustments are made across all patient cohorts with isotonic regression, giving the advantage of both enhanced statistical strength (simplicity and robustness) and accurate MTD recommendations.
The majority of cancer Phase I trials treat the toxicity response of patient as a binary (yes/no) type indicator of DLT although patient usually has multiple toxicities, even multiple DLTs. This approach limits the utilization of all data as a lot of valuable toxicity information is discarded. The NETS system is an alternative method for fully utilizing all toxic events. The NETS system treats toxicity response as a quasi-continuous variable, gathers all toxicity information, differentiates toxic events into multiple levels according to their grades, determines a more accurate MTD, and increases trial efficiency.
Emory researchers have developed a novel statistical design called Isotonic Design using Normalized Equivalent Toxicity Score (ID-NETS). It combines isotonic design with NETS system to conduct more efficient, accurate, and higher quality clinical trials. This novel design has been shown to yield more accurate estimations of MTD and increase the efficiency of the Phase I trial by fully utilizing all toxicities. Using ID-NETS can also decrease the time to approval for new drug by providing more accurate MTD with optimal therapeutic effect for Phase II/III trials and shortening Phase I clinical trials with less patients and no dosing-related waiting delays. ID-NETS©TM is the only software available to facilitate designing and conducting a Phase I clinical trial with ID-NETS which can fully utilize toxicity data and improve MTD accuracy in Phase I clinical trial. This software has two functions: (1) Calculating the recommended next dose level from completed data; and (2) Performing simulation to obtain the operating characteristics of a trial designed with ID-NETS. The software is currently available on Emory’s website for download.