Almost There

When the minutes arrive, what will they say/what will happen? As I wrote yesterday, in meetings such as the one Provectus publicized it had with the FDA on December 16th, the Agency and sponsor reach a consensus during the meeting. The sponsor subsequently waits until the FDA had codified the consensus reached (i.e., has memorialized and sent final meeting minutes) before the sponsor communicates the outcome to the public. There may be (and usually are) collaborative interactions between the Agency and sponsor prior to finalization of the minutes. I think Provectus is in the same situation. I also wrote I further believe the pathway may either be a one- or two-step process, both providing discernible timelines from the drug's approval and commercialization.

Management noted in Wednesday's 8-K filing they "...took the opportunity to provide input into the documentation of meeting minute notes." I believe this input refers to data and statistical analysis related to the topic of tumor destruction (and more broadly locoregional disease control) upon injection of PV-10 into patient lesions. Recall Provectus' European Cancer Congress ("ECC") 2013 poster presentation (poster here, press release here). While the trial was a typical or traditional patient study, Provectus also collected (categorized) data on a per lesion basis. One might almost think of the trial as a "lesion study," where although N was the number of patients or subjects, n was the number of lesions. I believe about or more than a 1,000 lesions were treated and/or observed, of which 491 were treated as target lesions. Among these 491 lesions, 53% achieved complete response ("CR"), 5% partial response ("PR") and 12% stable disease ("SD"). 70% locoregional disease control (CR+PR+SD).

Pieces of Craig's two quotes in the ECC 2013 press release are quite relevant (see my bold underlined emphasis below):

• "The researchers concluded that PV-10 has a unique immuno-chemoablative profile that offers significant potential due to several important attributes. First, its safety and efficacy compare favorably with existing and emerging therapies. Second, its safety profile makes it an attractive candidate as a combination strategy for treatment of advanced disease. And finally, it provides a powerful combination of rapid reduction of tumor burden with induction of tumor-specific immune response that can achieve rapid disease control in refractory patients with locally advanced melanoma."
• "Melanoma patients and their caregivers experience profound discouragement upon recurrence of the serious skin manifestations of this disease. The investigators on this study describe the effect of PV-10 as "rapid, durable response" but as the photographs have documented, many of the PV-10 treated tumors almost appear to have never been present. PV-10 was only injected intermittently, when tumors were present during the first 16 weeks of the study, in stark contrast to typical clinical studies where treatment is given until either resistance is engendered or patients experience unacceptable toxicity. We are gratified that response to PV-10 was demonstrated consistently across all study centers, with minimal intervention in patients refractory to multiple prior treatments. PV-10’s unique mechanism of action, alone or in combination with existing or emerging therapy, has the potential to shift the paradigm in oncology, where an intermittent intervention can dramatically reduce disease burden and may prod the immune system into preventing or arresting the formation of life threatening metastases."

Locoregional disease control via PV-10: The company appears to have successfully demonstrated to the FDA that the drug can provide rapid disease control and induce the immune system to delay, reverse or prevent progression of regional disease to distant metastatic disease. That is the key: Delay, reverse or prevent progression of regional disease to distant metastatic disease.

Eric, whose responsibilities at Provectus include biostatistics, may have worked with the FDA to provide or isolate data from the company's metastatic melanoma Phase 2 trial to support statistical significance or relevance of locoregional disease control at a lesion level (not merely at a patient level). p-values, for example, previously have been provided by the company for N (i.e., subjects) in past presentations. p-values, which I use for illustrative purposes (I don't know what specific statistical parameter(s) the Agency would require), for lesions have not. If the FDA recognized new endpoints (tumor- or symptom-based) were appropriate and necessary for PV-10, Eric, following the December 16th meeting, could have recasted already collected and locked data as such for the Agency to consider. If this work indeed was the "input" Provectus took the opportunity to provide, and if accepted by the FDA, then it's not unreasonable for an approval pathway potentially to follow.

Now consider the changes to the website presentation, which was updated today. It seems to me management is saying exactly that: an approval pathway, currently being collaboratively developed with the Agency, should follow.

Click to enlarge the figure.

BTD and/or AA. The approval pathway could be a one- or two-step process, both providing discernible timelines from the drug's approval and commercialization. One-step suggests either regular approval (what I term outright approval on the blog) or accelerated approval ("AA") with the post-marketing requirement ("PMR") of a confirmatory study employing what may be a new symptom-based endpoint appropriate to the local agent. Two-step could be, first, receiving breakthrough therapy designation, and second, after a little time has elapsed to permit further collaboration, receiving regular approval, or obtaining AA with the PMR above, or having to conduct a small bridging study (i.e., a study permitting international citizenry to be among the patient population, now utilizing the new endpoint) prior to then receiving regular approval. If management can achieve agreement with the FDA for regular approval or AA, the next step probably would be for Provectus to submit an NDA filing. The next Provectus PR should herald the approval pathway of the drug.