Biostatisticians propose use of 'adaptive' study designs to maximise success of clinical trials

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  • Author: Andy Grieve
  • Date: 25 Feb 2013

Since 1948 and the publication of the MRC trial of streptomycin for the treatment of tuberculosis designed by Sir Austin Bradford-Hill the gold-standard for clinical trials has been the double–blind randomised and controlled clinical trial. A trait of such trials is that they are static in that the key elements driving the design - the significance level, the primary endpoint, the primary hypothesis, the type of test and test statistic, and the sample size based on a specified effect size and required power - are specified in advance and do not change. The trial is then run, the outcomes for patients observed, estimates of parameters determined, p-value(s) for specified hypothesis (es) computed and a conclusion drawn.

thumbnail image: Biostatisticians propose use of 'adaptive' study designs to maximise success of clinical trials

An obvious problem with this approach is that the planning of such trials is based on a fixed set of assumptions. For example, assumptions are made about the likely effect size, the variability for continuous variables and the control rate for binary data and each of these is either subject to uncertainty, or at the time of planning unknown. Incorrect choices for these parameters can lead to trials which are under-powered or over-powered, and both of these outcomes are ethically questionable and undesirable.

Since the millennium biostatisticians, particularly in pharmaceutical R&D, but more recently in non-pharmaceutical medical research, have investigated the benefits and practical feasibility of utilising adaptive designs to increase the chance of a positive outcome and to increase efficiency. Adaptive trials employ methodologies that allow study sponsors to monitor the data being gathered during the course of a trial with the objective of implementing a pre-planned adaptation to maximize the success of the trial.

Perhaps the simplest adaptive designs utilise interim analyses, long associated with group sequential trials, to test the assumptions of trials and to make decisions about their future conduct. For example at an interim if the patient-to-patient variability is much larger than anticipated at the planning stage, the sample size can be increased to ensure that the trial has the desired power. Conversely if the estimated effect size at the interim is non-existent or much smaller than required then the trial can be stopped for so-called futility. The benefits of a wholesale introduction of these techniques across a pharmaceutical company’s portfolio are clear since the chance of success will be increased when appropriate or a development can be stopped early if that is the appropriate decision. Both of these measures will increase the overall return on investment across a portfolio. A number of large pharmaceutical companies have implemented such strategies with considerable savings.

A second area for consideration is in phase II dose-response studies. In adaptive dose-finding studies the post promising doses are followed with ineffective doses being dropped. These designs allow a wider range of doses to be investigated without unduly increasing the number of patients studied.

More recently the ability to identify clinically meaningful biomarkers has allowed researchers to focus on patient sub-populations with potentially greater treatment effect. Instead of being limited to enrolling patients from such an enriched population an adaptive approach enables a data-driven selection of one or more pre-specified subpopulations in an interim analysis and the confirmatory proof of efficacy in the selected subset at the end of the trial.

The use of many of these designs is being considered outside of the pharmaceutical industry. The WHO has shown an interest in their use in vaccine trials and in diseases such as tuberculosis, HVC and malaria. There is hope that adaptive strategies will play a role in developing treatments for diseases such as Alzheimers with its increasing burden of morbidity and mortality. Research into these areas will join with on-going research in adaptive trials in early phase drug development which have been around for 30 years and which can improve the determination of safe dose of new drugs for the later phases of drug development.

To hear more on adaptive designs, we recommend you attend Adaptive Designs in Clinical Trials in London on 7th & 9th April (be sure to mention Wiley to claim £100 discount).

Andy Grieve is the Senior Vice President Clinical Trial Methodology, Aptiv Solutions (and former President of the Royal Statistical Society).

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