Case In Point
Overcoming Critical ISE and ISS Challenges on the Path to FDA Approval for an Oncology Biologic
About Client
A long-standing sponsor, developing a biologic therapy to reduce chemotherapy-induced febrile neutropenia, began to prepare a Biologics License Application (BLA) during Phase III.
In preparing the Integrated Summary of Efficacy (ISE) and the Integrated Summary of Safety (ISS), Everest overcame three significant regulatory and statistical challenges to support a successful regulatory submission.
Challenge
Each clinical study differed substantially in design: dose formulation, primary objectives, background chemotherapy regimen, control groups, and patient populations, making a traditional pooled ISE scientifically inappropriate. The sponsor needed a regulatory strategy that would satisfy FDA statutory requirements while accurately representing the clinical evidence.
Because the studies enrolled breast cancer patients, the study population was entirely female and lacked sufficient racial diversity to support standard demographic subgroup analyses, which is typically expected by the FDA.
In addition, and due to the work of Everest’s meticulous programming team, a critical data mapping issue from the lab vendor was detected that affected the primary efficacy endpoint in multiple studies. Had the error remained, it would have likely compromised the integrity of the BLA and jeopardized the entire submission.
Solution
Everest developed a comprehensive strategy that addressed each challenge while maintaining the scientific integrity of the submission.
Everest collaborated with the sponsor and regulatory consultants to develop a parallel structure ISE strategy rather than forcing a pooled efficacy analysis that combined data from heterogenous studies together. Each pivotal study was analyzed using identical methods for common endpoints but reported independently, preserving the integrity of each trial while enabling consistent comparisons across studies. Everest presented the strategy during a pre-BLA meeting with the FDA and the agency accepted it.
Everest developed regulatory justifications for an alternative analytical approach where subgroup analyses could not be completed. This approach was also discussed during the pre-BLA meeting and accepted by FDA.
After identifying the mapping issue, Everest partnered with the sponsor to remediate the affected data, complete all analyses, amend those Clinical Study Reports, and update Module 2 and 5 documents before submission. Although the remediation delayed the submission, it prevented a much greater regulatory risk had the issue been identified during FDA review.
Results
Everest successfully delivered the ISE, as well as the ISS, with the work of Everest’s statistics, statistical programming, medical writing, and regulatory submission services required for the sponsor’s BLA. The FDA approved the therapeutic, and it is on the market today. In addition, Everest subsequently supported the client through its submission to EMA, and ultimately, the therapeutic gained EU approval, as well.
