Trial Math: Meeting the Primary Endpoint, Pt. 2

We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug. -- Provectus' Eric Wachter, June 19th conference call

In my blog post Trial Math: Meeting the Primary Endpoint, Pt. 1 I noted DTIC's PFS is likely to be around 1.5 to 2 months for the stage of patient being recruited for the trial's comparator arm. The performance of systemic chemotherapies DTIC and TMZ are well documented, and generally yield a normal distribution of events (e.g., Middleton et al.). I also noted that in Provectus' metastatic melanoma Phase 2 trial the median PFS for Stage III patients (similar to those who would be enrolled in the Phase 3 trial) was at least 9.7 months (median PFS for Stage III subjects was not reached during the 12-month study interval), and the mean PFS of the all disease treated subgroup of the Phase 2 trial was 9.8 months. So, 9.7-9.8 months for PV-10 PFS > 1.5-2 months for DTIC/TMZ PFS.

That is all well and good, but for Provectus' upcoming Phase 3 trial to meet its primary endpoint of progress free survival ("PFS"), the confidence interval ("CI") for response in the PV-10 (test) arm cannot overlap the CI for response of the DTIC/TMZ (comparator) arm. The trial's power is 90%, and statistics are two-sided with an alpha of 0.05, which means there is a 5% chance the true response is above or below a 90% CI.

Information about DTIC/TMZ PFS figures abound for applicable patient populations, together with 95% CIs. These intervals can be converted or adjusted to present 90% CIs (applicable to the Phase 3 trial design).

Provectus provided durable objective response  ("DOR") data for the all disease treated subgroup from its Phase 2 trial on its ASCO 2014 poster.

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DOR, or durable response rate, is complete response ("CR") plus partial response ("PR") that is durable, and is measured in months. PFS is essentially CR + PR + SD (stable disease), in that the disease does not progress or become "PD" (progressive disease). I say SD because shrinkage is neither sufficient to qualify for PR nor a sufficient increase to qualify for PD. As such, PFS ultimately will be a greater figure than DOR. I utilized the CI for PV-10 DOR as a guide to estimate the CI for PV-10 PFS. Comparison of 95% and 90% CIs for DTIC and PV-10 are below.

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Neither PV-10's actual Phase 2 DOR nor estimated Phase 3 PFS CI overlap DTIC CIs. While the bottom DOR intervals are within spitting distance of the top DTIC intervals, there is substantial daylight between the PFS endpoint bottom intervals and the top DTIC ones. This would suggest the likelihood of the Phase 3 trial meeting its primary endpoint of PFS.