In the year 2013

In Provectus' annual CEO letter published May 2013, management wrote under Regulatory Progress:

"Provectus is finalizing details for submission of a pivotal Phase 3 randomized controlled trial ("RCT") of PV-10 for metastatic melanoma, suitable for Special Protocol Assessment ("SPA"), to the Food and Drug Administration ("FDA"). While preparation for submission of our SPA has taken longer than expected, it is crucial to remember that oncology presents a moving playing field. Fine tuning of the study design is expected to mitigate clinical efficacy risk, optimize patient accrual, and increase FDA's confidence that the study design and protocol will ensure the best possible outcome for our pivotal trial. We have every reason to believe this key milestone will be achieved in 2013."

"Provectus is also considering applying for the new Breakthrough Therapy Designation for PV-10 to treat melanoma. This new regulatory pathway was announced with the passage of The Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. A breakthrough therapy designation conveys all of the fast track program features as well as more intensive FDA guidance on an efficient drug development program. However, because this program is relatively new, the potential impact of receiving such designation is still unclear, but could be pivotal in achieving an accelerated path for approval of PV-10."

It now appears Provectus has made its [final] submission of a pivotal Phase 3 RCT of PV-10 for metastatic melanoma ("MM"), suitable for SPA, to the FDA, and also submitted its application for BTD for PV-10 to treat melanoma.

Based on connecting some dots, the submission date very likely was after October 1st. Below is a table of CDER BTD requests from October 1-25, where I think Provectus' request is one of the eight the Agency received during this period:

The recent partial federal government shutdown ran from October 1-16, with operations resuming October 17th. Assuming Provectus hears within 60 days of submission of its BTD request, and adjusting for a delay of about half-a-month related to the shutdown (there might be an adjustment for when the FDA actually received the application itself), we should learn about this outcome around or before mid-December.

Updated 11/1/13: The next six weeks, maybe sooner or potentially later, may provide a fuller picture of the regulatory clarity path management has hoed the last several years and the final step(s) or finish line. I'm still foggy about how and the process by which management is requesting exactly whatever they're requesting.

The SPA is a step on the way to approval, albeit no guarantee of such upon completion. Accelerated approval ("AA") and outright approval ("OA") are steps too (but closer to being actual destinations). Fast Track, BTD and Priority Review, while designations, are processes that speed access to new important therapies by leading to subsequent steps. A good, recent article on BTD is FDA Speeds Things Up: Breakthrough Therapy Designation Is Changing How the Agency Operates (October 1, 2013, Genetic Engineering & Biotechnology News). Some of the article's quotes are striking:

• "...the designation’s greatest value was that it prompted an “all-hands-on-deck” mentality at CDER."
• "...the breakthrough designation can rely on preliminary clinical evidence demonstrating substantial improvement on a significant clinical endpoint, while the fast-track could be based on nonclinical data such as the drug’s mechanism of action."
• "Under breakthrough designation, he said, “everything is on the table” for discussion in order to move the process along as quickly as possible. Communications that might typically take weeks and months take minutes under the breakthrough pathway."

BTD and the SPA are two independent regulatory pathways, so it makes sense management has been cultivating multiple options (including pursuit of approval via AA). I'm not clear, however, if AA is another independent pathway or an outcome of BTD in this case. The Agency notes "...a drug that has received a breakthrough therapy designation or a fast track designation can be eligible for the accelerated approval pathway, if the relevant criteria are met."

Setting aside the parallel pursuit of the SPA, it would seem several outcomes are possible if BTD is awarded: the SPA (and a "full" Phase 3 trial), a modified version of the Phase 3 trial under the SPA, AA or OA.

What's the ask? Whether directly or unrelated to the BTD application, the first ask very likely is AA, or potentially OA, for Stage IIIb-IIIc melanoma patients refractory to treatment on the basis and strength of Provectus' multi-thousand page final MM Phase 2 clinical study report and Moffitt's PLoS paper Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer: compelling clinical data showing PV-10 can forestall the onset of metastatic disease, and the elucidation of PV-10's mechanism of action (and systemic benefit). The second ask, or perhaps the "other side of the coin" of the first ask, should be, of course, BTD.