Analysing and reporting limited data to demonstrate cardiovascular safety in a rare disease study

The sponsor, a small biotech, had received orphan drug status from the Food and Drug
Administration (FDA) for a potential rare disease treatment. The sponsor was developing a bile acid drug and sought ICON’s help analysing ECG data that has already been collected during a clinical trial within the patient population. Almost all drug approvals must include evidence of the drug’s effect on ventricular repolarisation as part of the FDA’s cardiac safety requirements. Usually this data is collected in an intensive manner from more than 20 subjects. The collection schema is standardised so that comparisons can be made at each timepoint. The data is then compiled into a Cardiovascular Safety Report (CVSR) which is crucial for FDA drug approval.

This was an unusual study for an extremely rare disease. To date only 100 patients have
been diagnosed with it worldwide. There were only 12 patients in this study, few of whom were treatment naïve. In larger studies patients are screened and randomised, with standardised dosing and ECG timepoints. Within this small study cohort however there were variabilities around screening, dosing and timepoints. Patients had triplicate ECGs collected at screening visits and a further six collected at post-dose timepoints. Some subjects had taken the drug before their screening visits while others took it after screening. Dosing at the study sites was also inconsistent across the post-screening visits.

Drawing from extensive experience supporting over 1,125 cardiac safety trials, ICON
reviewed the data and identified four different dosing patterns. Data was analysed by
both timepoint, and categorical analysis by dosing pattern. The data showed that there
were no cardiac safety issues associated with the bile acid treatment. Based on a strong
understanding of the FDA requirements, ICON decided on the best approach to present
the findings in the cardiovascular safety report. Additional data displays showing trending values were also included given the small number of patient participants.

The FDA accepted the cardiovascular safety report for the ECG requirement, even with
the acknowledged data limitations. The sponsor’s treatment was subsequently approved, giving patients with this rare disease access to a new treatment option.