On the precipice of…

There, in Knoxville, Tennessee, they stand on the precipice of...what? "What" at this point depends entirely on the FDA, and what the Agency has to say about the regulatory pathway(s) to approval for PV-10.

It would seem reasonable to think all of the parties, Provectus and the respective interested license and/or acquisition partners, are (and have been) waiting for regulatory clarity before transacting. Yes, I am looking forward to a December outcome for clarity, good, bad or indifferent ("bad" and "indifferent," mind you, are relative in nature).

Management may have asked, along the way or at some singular point in time, for "everything," which would include outright or accelerated approval ("OA" or "AA"), breakthrough therapy designation ("BTD"), and a special protocol assessment (an "SPA" for a pivotal Phase 3 trial randomized control trial, or "RCT"). But, Provectus, through self-described collaborative discussions about regulatory pathways to approval with Agency staff based on pre-clinical and clinical trial data generated by both the company and Moffitt Cancer Center ("Moffitt"), may have asked for "something," OA or AA, and/or BTD (i.e., BTD and OA/AA, or BTD), where asking for an SPA is or recently has been OBE because of current clinical data ("OBE:" overcome by events, where a situation changes so rapidly that previously proposed courses of action are no longer relevant).

It would seem there is a key upcoming FDA "event" (e.g., call, meeting, panel, discussion, etc.) for Provectus, but I don't know what one would call it in Agency vernacular. The company of course is past end-of-Phase 2 meetings ("EOP2"), which ended with the third meeting highlighted in the January 18, 2012 press release. In that PR management said they received guidance from FDA to submit its Phase 3 protocol for review (either via standard review or a request for SPA), guidance that was in response to their request of a final EOP2 meeting to achieve consensus on the design of a planned pivotal Phase 3 RCT of PV-10 for metastatic melanoma ("MM"); according to Provectus the FDA indicated that additional EOP2 meetings were not required. In a November 4, 2013 Knoxnews.com article Peter was quoted as "We're talking to the FDA about what's the appropriate path to move forward." In an article appearing in the November/December 2013 issue of Oncology News on the final analysis of PV-10 Phase 2 melanoma study data presented at the European Cancer Congress ("ECC") 2013 meeting, PV-10 continues to show robust effect in cutaneous Stage III-IV melanoma, management was said to believe "...they now have sufficient information to seek regulatory approval." There is the line of thought, too, the company submitted an application for BTD for PV-10 for melanoma. And, I don't recall prior Provectus-related chatter describing prior FDA interactions as structurally key. I don't recall management asking for anything of the FDA in the past in the manner they're asking (or have asked) for something now.

So, whatever this event is or is called, it would seem regulatory clarity, of one sort or the other, should be the outcome. The population seems to be divided into at least two categories: Population {1} ("Pop 1"): Patients refractory to treatment, and Population {2, ..., n} ("Pop n"): For now, in combination with other therapies (e.g., ipilimumab, vemurafenib, nivolumab, etc.).

A. Outright or Accelerated Approval for Pop 1. A direct ask, the data and precedent (such as pertuzumab, read here, here and here) would suggest are very supportive of OA. In the event OA is not granted and A is, one might imagine the FDA asking for a confirmatory study or maybe just additional confirmatory data.

B. Breakthrough Therapy Designation for Pop 1 and Pop n: A broader ask (and, I think but maybe wrong, a concurrent one), the breadth of data would suggest greater use of PV-10 for melanoma. The flexibility of the BTD program might provide the FDA group considering Provectus' asks, the Division of Oncology Products 2 ("DOP2"), with several options for Pop 1: OA, AA with a confirmatory study or additional confirmatory data, a single arm Phase 3 trial, or wait for more Moffitt clinical data while having granted BTD to PV-10. The single arm trial would recognize the inappropriateness (i.e., ethicalness given efficacy) of running an RCT for the drug based on the breadth and depth of clinical data generated to date, and medical key opinion leader ("KOL") and community support. In addition to Pop 1, the FDA could elaborate on the use of PV-10 for Pop n, now or thereafter, by articulating further studies for the drug.

C. Breakthrough Therapy Designation for Melanoma: Probably the least specific in terms of drug approval or other regulatory clarity, the Agency could recognize PV-10 with BTD, not release the drug yet, and wait on a clarity decision or decisions pending more data from/for current and/or other trials.

I found Adam Feuerstein's 2014 FDA Drug Approval Decision Calendar article useful to speculate about the timing of a supposed key FDA event date for Provectus. Feuerstein compiled his calendar using company reports, his own research and the services of BioMedTracker.com. Peter supposedly is traveling to China and Europe next week (the week of December 2nd), and which may bleed over into the following week (the week of December 9th). The week of December 23rd, with Christmas, would seem like a "dead" week (Feuerstein identifies the 20th as the last event date before the holidays). It's possible the week of December 30th could contain a Provectus date; however, Feuerstein's earliest date that week is January 3rd, which is in the new year (2014), and management continues to guide that regulatory clarity will arrive before the end of the year (2013).

The above, in my view, leaves late-week of December 9th (following Peter's return from travel) and the week of December 16th. Giddy up!

History? Dees, Scott and Wachter. An established multi-disciplinary team of inventors (a virologist, a chemical engineer and a chemist, with working and overlapping knowledges of the others' fields of expertise) arrive at this point: No local therapy has been approved for the treatment of cancer. PV-10's potential for broad applicability to solid tumor cancer appears vast. The drug and the company require an FDA decision; here's hoping it's very, very clear.

History? Culpepper. Leading the monetization of the drug and company seems relatively easy to Peter compared to the team's journey to arrive at the precipice of regulatory clarity, and possibly history. I do understand his view, because I cannot imagine or comprehend their struggle to overcome tradition, bias, skepticism, opposition and lack of understanding. The innovation of the drug requires a comparable monetization outcome; here's hoping it's very, very easy.