"Why did it take four years...to arrive at this point?"

Eric's discussion on the May 23rd conference call of the history of the company's regulatory interactions with the FDA since the end of Provectus' metastatic melanoma Phase 2 trial about four years ago to arrive at this point is informative and useful. I edited the transcript to remove "so," "um" and "uh," and made a few other minor verbiage changes to make the material more readable. Bold emphasis of dates below is mine.

Why did it take four years from the end of phase two study to arrive at this point? 

I think it is good to start back in May of 2010 when the last patient completed the phase two study. Shortly before that point, we held our first type A meeting with the Agency. That was in April of that year when we had interim data from the first 40 patients in the study.  And what was interesting to me as the study progressed, we had interim analyses scheduled at N equals 20 patients, N equals 40 patients, and then a final analysis when the total of 80 intent to treat patients, or ITT population was enrolled. And by the time we got to N equals 40 patients, the numbers were looking better than what we had seen in phase one, which we expected based on a more aggressive treatment of the patients, despite the fact that we had, uh, a larger number of stage four patients in the patient population. I'll comment that as we finally matured the data to N equals 80 patients, the response metrics remained roughly the same over time. And at this time in April of 2010, the melanoma landscape was beginning to change very rapidly with ipilimumab and vemurafenib approvals approaching on the horizon. This meeting established that what we proposed at the time for phase three study in patients with a patient population and end point similar to studies underway at that time under special protocol assessment for two other investigational intralesional therapies for melanoma would not be appropriate going forward. 

The Agency told us that they did not like our proposed patient population nor our end points, and also cast tremendous amount of doubt on the relevance of the drug in melanoma, a disease that they noted was systemically malignant and would be difficult to treat with a local therapy. 

We matured the data from the phase two study further and held a second meeting finally in March of 2011 after completing our initial analysis of data from the full 80 patient data set from the phase two study. We went into the meeting with proposed end points and patient population modified based on guidance from the first meeting. That study design was proposed to evaluate response in patients with, uh, Stage IIIB to IVM1A disease. These are patients with cutaneous or nodal disease, uh, and where all disease would be accessible by intralesional injection. In addition, we tightened the definition of dermal response that we had proposed, uh, in that first meeting in light of the Agency's advice. At this meeting, the Agency made it clear that a time to event end point would be required and expressed concern about our proposed modifications to RECIST that we felt were relevant to treatment of local recurrence. 

We met with our advisors further and finally scheduled and held a third type B meeting in October of 2011. At that meeting, we proposed modified end points in the patient population, once again based on prior guidance. This study was proposed to evaluate response in patients with cutaneous or subcutaneous recurrent or metastatic melanoma. Okay. That's a lot to digest, the cutaneous or subcutaneous recurrent metastatic melanoma that had no active nodal or visceral disease. These were patients, for example, with a history of nodal disease that had undergone nodal resection and would be candidates because their nodal disease had been surgically removed. They had no active nodal disease, similarly a case for patients that might have had limited lung mets, for example, that had been successfully treated somehow surgically, radiation, or some other therapy. Progression free survival versus DTIC was proposed for our RCT. We proposed a time to event end point in a randomized controlled trial. The Agency at that point expressed continued concern about enrolling patients with any history of visceral disease based on the concern I mentioned earlier, that there was inadequate support for use of PV-10 intralesionally in patients with systemic disease, so local therapy for patients with systemic disease. They also expressed concern about our proposed effect size, which we were willing to address. At the conclusion of the meeting, we agreed to develop a revised RCT design in patients with no history of visceral disease and no active nodal disease, and to submit this for SPA. 

Now in light of our discussions in the second and third meetings with a lead medical reviewer concerning adequacy of support for potential distant effects of PV-10 ablation, which we had noticed in our so-called bystander effect in cutaneous lesions, untreated cutaneous lesions in phase one and in phase two testing, and in a limited number of patients with visceral mets at enrollment in the phase two study. Some of them showed regression of their untreated visceral mets over the study interval in a fashion similar to some other drugs that were being developed for melanoma at the time. 

We realized we needed to get the story straight on this systemic effect before we could have significant traction with regulators in the U.S. and presumably abroad.

We began a dialogue with researchers from Moffitt Cancer Center early in 2011. Between the the second and third meeting that by the end of that year evolved into formal non-clinical studies on the cellular basis underlying the bystander effect. And eventually, it matured into the translational medicine study that's began in early 2013 that we are expected to hear results on June 2nd [2014] at ASCO. Data from these projects were reported starting in March 2012 at the Society for Surgical Oncology annual meeting in 2013 at the Society for Immunotherapy with Cancer annual meeting, and at the 2013 and 2014 annual meetings in the American Association for Cancer Research. As I mentioned, additional clinical data from this effort is expected to be presented by the Moffitt team next week at ASCO. 

We believed at this time we started, and we continue to believe now, that this aspect of the PV[-10] story may be crucial to obtaining regulatory approval. 

During this period, we also convened several advisory boards comprised of investigators and key opinion leaders to work on design of the promised RCT. We met privately with a number of these experts and other similar experts to discuss the challenges of designing a RCT that could be balanced in terms of level of intervention between the PV-10 arm and the comparator arm appropriate for patients principally with Stage IIIB and IIIC disease, and it would not suffer unacceptably low accrual or high dropout from the comparator arm. As the melanoma landscape continued to evolve, this proved to be a difficult challenge. Over the same period, we worked on modernization of our PV-10 supply chain, uh, as evidenced by a recently issued U.S. patent September of 2013 covering methods for manufacturing Rose bengal to modern quality standards. I think absent this work, it is unlikely that early investigation drug product was used up to that time could have been qualified for phase three use, and certainly not for support of an NDA. As we announced when the patent issued last fall, a drug product appropriate for such phase three use has now been manufactured. 

Finally, by October of 2013, we had become sufficiently frustrated by the difficulties posed by design of a study based on the third type [B] meeting and the discussions leading up to that third type [B] meeting, and also encouraged with the emerging immunologic mechanism data, such that we requested an additional meeting with the Agency in the fall of 2013. That request was granted. And the type C meeting was held in December of that year. At that meeting, we provided an overview of PV-10 data in melanoma from both phase one and phase two melanoma studies from our expanded access protocol, which now has enrolled over 100 patients, uh, from our hepatic tumor study, from an investigator-initiated study of PV-10, followed by radiation therapy for treatment of melanoma, and from the afore-mentioned Moffitt study. This data included an exploratory subgroup analysis presented earlier that year at the European Cancer Conference and included response metrics for patients having all or substantially all other baseline disease treated with PV-10. 

We also presented a straw man outline for Breakthrough Therapy Designation request and asked for advice on such requests. To our surprise, in the meeting the Agency focused on the [ECC] 2013 subgroup analyses and clinical response evidenced in these patients via clinical photography. We had a lengthy discussion regarding patients with locally advanced cutaneous melanoma, the need for therapies for these patients, and the types of end points appropriate for demonstration of clinical benefit. Based on our positive impression and discussions from the meeting in the meeting minutes released a month later, we prepared and submitted our Breakthrough Designation application in March [2014]. 

I warned you there was a long road, a difficult, complicated story. And what it shows is that as our understanding of PV-10 has matured over time and as the melanoma landscape has evolved over time, our interaction with the Agency has improved over time in that we now are in a position that the Agency has helped us to define indications that they believe our drug shows potential value and have helped us to define types of end points that are vastly different than perhaps progression-free survival in the proposed phase three randomized control trial from the third type [B] meeting, which would have used DTIC as a comparator. It's impossible to run that study [under] the current climate. We wouldn't enroll patients with the appropriate, uh, extent of disease burden. Yes, I can understand the feeling that maybe we're the clever student in class that doesn't listen to the advice of the teacher. But I would prefer to think that we've been working with the Agency to understand what proved to be a very difficult challenge. We're taking a new class of agent. And there's superficial similarities to other investigational drugs currently under phase three investigation or recently under phase three investigation. But those similarities are superficial at best. The effect of the drug immediately via its primary ablation is very different than other drugs that have been developed. The secondary immunologic response that appears to occur in a large fraction of patients, as evidenced by the data coming out of Moffitt, is very different than what has been shown in the past. And understanding what patients might benefit in a clinical trial setting has been complicated. I think we have very good guidance now from the agency in terms of types of patients to look at types of end points to use. And I hope that we'll be able to convince all people that are watching this story that we're definitely listening to the teacher. 

And so, in the meeting in December [2013], the Agency said, to paraphrase, hey, we like this ablative effect that you're showing in these patients with disease confined to the skin. But can you show us that that also improves symptoms that we've heard are important in melanoma, pain, bleeding, infection, for example. That would be a winning combination.