This pivotal adaptive study involved multiple endpoint analyses and primary analyses in two different populations, which added complexity to the analysis plan. An interim analysis was set up to test the study’s futility and included conditions for possible sample size re-estimation. The conditional power at the interim analysis exceeded the range where the sample size required re-estimation.
The services provided included data management and biostatistics for multiple projects, such as the pivotal phase III and a pooled analysis for the ISS. The team took over biostatistics from another CRO, amending the protocol and incorporating adaptive and statistical analysis components. The protocol was amended a few times throughout the study to adjust for major study design changes and interim analysis strategy components and study changes were incorporated into the final SAP.
Challenges faced during Phase III execution
- Adaptive components were added early in the trial, but they were not originally included in the design, which presented challenges to the sponsor and biostatisticians.
- The original design had two populations as part of the primary analysis, which required testing in the overall and the defined sub-population. The sub-population was made up of those with a gene deficiency. The analysis of the sub-population was eventually dropped from the analysis.
- An adaptive interim analysis was conducted for futility and sample size reassessment, which presented some challenges to the sponsor.
- The standard of care (SOC) changed during the trial due to the uptake of a newly approved drug in the market and population, which presented a significant challenge to the sponsor.
- Changes were made to the protocol, randomization, EDC, and SAP, which required amending.
- ISS-related challenges included, determining which trials to include in the pooled data due to the breadth of product/indication history, as well as data which had to be upconverted to CDISC format from one of the earlier trials in the program.
Solutions implemented to overcome project challenges
- The protocol, randomization, EDC, and SAP were amended for study design and adaptive components, which helped to streamline the biostatistical complexity.
- The sponsor worked with the team to adjust the study design and adaptive components after removal of the sub-population analysis component, which helped to simplify the analysis.
- The biostatistics group provided expertise to plan and execute the adaptive component. The sample size did not require re-estimation, and futility was a non-issue. Therefore, the trial proceeded.
- To address the ISS-related challenges, an integration plan was prepared and details sent to the FDA for approval and feedback. The FDA feedback was beneficial to Precision and the sponsor to focus only on the appropriate data needed to be pooled and converted to support the ISS package.
- Due to the disruption in the SOC, the trial and sponsor had to pivot via DSMB and Precision support to determine recommendations to bring the trial to a successful completion.
- Based on DSMB feedback, the sponsor decided to wrap up the trial based on the data already available instead of prolonging and disrupting the project due to changes in the patient population’s standard of care.
- The DSMB continued to review survival and safety as patients were followed up for one year. Overall, the team worked collaboratively to overcome the challenges and bring the project to a successful conclusion.
Outcomes delivered
Collaboration between the Precision for Medicine team and the sponsor was integral in overcoming the myriad challenges faced throughout the study and through submission. The team worked collaboratively to amend the protocol, EDC, and SAP for adaptive components, simplify the analysis, and address the changes in standard of care. The adaptive component was executed successfully, and the trial proceeded without needing a larger sample size.
Ultimately, the sponsor decided to wrap up the trial based on the data already available, and the DSMB continued to review survival and safety as patients were followed up for one year. The team’s solid work led to a successful conclusion of the project, and Precision for Medicine was awarded another Phase III study for the same compound in a different indication.
