Stopping one of two sister trials early for futility – subgroup selection

Authors: Patricia Glomb, Dr. Birgit Gaschler-Markefski

In most therapeutic areas of pharmaceutical research – including Oncology – at least two well-conducted confirmatory trials are required for the submission and approval of new drug applications. Despite being increasing in size, duration and costs, the success rate of phase III registration trials remains very low. This is particularly true for Oncology. Stopping a clinical trial early that is very unlikely to be successful can therefore reduce substantial recourses, save time and effort. For that reason an interim analysis for futility is often implemented at a pre-specified point in time. A futility analysis is typically conducted by an Independent Data Monitoring Committee (IDMC) and causes a trial to be terminated if evidence shows that the results at the end of the trial are likely to be negative. Conducting two confirmatory Phase III sister-trials in parallel for both of which a futility analysis is planned, the scenario can arise where based on the interim results one trial will emerge promising but the other considered futile. Although set up in parallel, due to different recruitment rates and other trial specific behaviour the interim analysis of one trial can become due only several months after the futility analysis of the first trial was conducted. Given the futility analysis of the first trial is positive (results indicate that the new treatment is very likely to beat the control) but the futility analysis of the second trial is negative (results indicate that the new treatment is unlikely to beat the control), several questions arise while making an overall judgement on the substance’s effect:

a)     At the time of the later conducted futility analysis of the second trial, how should the information from the first non-futile trial be taken into account?

b)     Which methods and additional information can be used in order to confirm the futility decision of the second trial?

c)     Can a subgroup of patients who are more likely to benefit from the treatment be identified?

We aim to investigate these questions within the framework of typical phase III oncology trials. While in oncology overall survival (OS) remains the key endpoint with the greatest relevance to patients, progression-free survival (PFS) is more and more taking the leading role as a surrogate end point for OS and is being used as the preferred primary efficacy in clinical trials. Being the primary endpoint PFS also provides the basis for interim futility decisions. For our case studies we will present the methodologies used at the pre-planned futility analyses and also consider the three-state modelling in order to make use of the dependence between the primary endpoint PFS and the key-secondary endpoint OS.  In the light of the promising first trial, the negative futility result of the second trial raises the question whether there is a sub-group of patients who are more likely to benefit from the treatment than others. We will present the exploratory approach applied in our case studies, including the identification of a potential subgroup in the data of the futile study and its internal and external validation using the information from the first non-futile trial.