PRODUCTION OF ISS/ISE PACKAGE
PHASTAR was contracted to assist a global pharmaceutical company with their integrated summary of safety and efficacy for a regulatory submission. The work started with assisting the sponsor in defining an integration strategy for approximately 20 phase I studies, six phase II studies and their corresponding extension as well as three phase III studies and their long-term follow-up study. It involved defining a set of relevant analyses sets and reporting periods for both safety and efficacy analyses, ahead of writing up the analysis plans for the phase II pooled analyses, and phase II & III pooled analyses.
From a programming perspective, work started with a review of SDTM datasets provided by another vendor and the building of a pooled reporting database. The integration of those datasets was carried out at the ADaM level, writing pooled ADaM datasets using the individual study ADaMs. Adverse events, concomitant medications and medical history had variables recoded so that dictionaries were consistently used across all studies. Adverse events of special interest were re-defined across all studies. Coded variables had been coded to CDISC controlled terminology, but we checked that this was the case and corrected any discrepancies.
Since many of the studies had differing follow-up times, adverse event data was generally reported after adjustments for exposure time (i.e. using exposure-adjusted event rates measured in patient-years). A discussion with the sponsor was held to ensure that we had the correct definition of exposure-adjusted event rates, with the appropriate numerator and denominator. We noticed that exposure had been defined differently across the different studies, with treatment gaps handled inconsistently. We had to re-derive the exposure information and check against the individual studies that our derivations were correct. Safety analyses were planned around summaries and bar charts of exposure-adjusted event rates, along with a range of other graphical displays such as prevalence plots and cumulative incidence plots.
Laboratory units were generally inconsistent across studies. We had to re-derive lab results in standardized units according to sponsor standards.
Efficacy analyses focused on reporting long-term efficacy results for each study separately. We reported a variety of efficacy measures, and had to ensure that the results from the individual studies matched the results that we had produced. Time was dedicated to ensuring that our results matched the previously reported study results.