"This determination is based on the paucity of data..."

Updated 11/16/14: See A Bridging Study to an NDA (November 16, 2014) on the blog's News page.

Copyright of (presumably) the Knoxville News Sentinel.

January 24, 2014 (December 16, 2013). On January 24th, following their December 16th Type C meeting with the FDA, Provectus issued press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes in which the company highlighted the indication being sought (and patient population being targeted) as locally advanced cutaneous melanoma.

Provectus also discussed guidance from the FDA during the meeting:

• The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding), (1)

• The Agency agreed to work with Provectus to quantify symptom control in this patient population, and

• In reference to discussions on the potential for breakthrough therapy designation, "FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions."

Provectus wrote in the PR, constructing a quote for/from Craig:

• "We are very pleased that the path to initial approval in the U.S. is now clear and PV-10 can be available to help patients in a more condensed time frame than if the Agency required an overall survival endpoint in a large randomized Phase 3 study." (2)

Finally, the company wrote, again via a quote from Craig:

• "The Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This would allow more frequent dosing than was permitted in the Phase 2 study, presumably akin to the dosing schedule currently used to treat nearly 100 patients under our expanded access protocol, and allow symptomatic endpoints to be prospectively correlated with objective response criteria."

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May 23, 2014 (May 16). On May 23rd, following the FDA's May 16th denial of Provectus' breakthrough therapy designation ("BTD") application, Provectus issued press release Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation saying:

• Via a quote from the FDA's BTD denial letter: "We have reviewed your request and while we have determined that treatment of 'locally advanced cutaneous melanoma' meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." 

• Via a quote from Craig: "We are very happy that the Agency recognized that locally advanced cutaneous melanoma is a serious condition and consider that a win for melanoma patients. We believe that elimination of these patients' tumors is clinically relevant, but as we alluded to in our January 24, 2014 press release regarding our Type C meeting of December 16, 2013, a focused bridging study appears to be necessary to conclusively establish a link between complete response and symptom-based endpoints."

Additionally, the Agency letter also said:

• This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease. (3) The information provided on durability of response is also of unclear clinical significance given the modifications to RECIST.

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May 23, 2014. On the conference call convened to discuss the company's go forward approach in the wake of BTD denial, Eric said (edited from the call's transcript to remove sos and uhs):

The longer version of my answer is that definitely we were very encouraged by the guidance that we received from the Agency in that meeting.

That being said, I described myself recently as being a professional worrier. Maybe that’s good for someone who is responsible for clinical development in a small company. But I was worried about being able to conclusively demonstrate a correlation between this high level of objective response, and I’ll use that loosely. What I mean by that is objectively observable response, uh, evidenced by complete responses in patients. 

All of their disease is gone after PV-10 injections in 50 percent of those patients versus what I knew was very thin data concerning the types of symptoms that the Agency was suggesting should be shown, uh, improvement in. 

And we did our best with that study. Looked at, as I mentioned earlier, pain data, and we were able to draw some supporting evidence to show that there is definitely a trend in pain data that matches the trend in objectively observed response of tumors. 

The Quality of Life EORTC-QL2-C30 instrument, this 30-question questionnaire that’s principally designed for patients with late stage systemic disease maybe that are taking toxic chemotherapy, I had great concerns that that was not going to be valuable because we had already shown in the full analysis for [unintelligible] patients in studies that there were no clear trends evident other that the patients didn’t get worse and that proved to be correct. 

There was nothing that we could extract from that particular instrument. It was a measured risk submitting the application. (4) But again as I mentioned earlier, our logic seemed clearer that if we were making the patients' tumors disappear in 50 percent of the patients that was a very large effect size, and that was tantamount to making any symptoms that they might have been suffering from the tumor burden disappear. (5)

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November 13, 2014. Provectus issued press release Provectus Biopharmaceuticals' Protocol for Phase 3 Study Of PV-10 As Treatment for Melanoma Now Available Online to highlight the publication of its trial protocol on www.clinicaltrials.gov. The primary endpoint ("EP") is:

• Progression-free survival ("PFS") -- a loco-regional disease-oriented EP.

The secondary EPs are:

• Complete response rate ("CRR") -- a loco-regional disease-oriented EP,
• Duration of complete response -- a loco-regional disease-oriented EP,
• Change in total symptom score from baseline using the patient reported Skindex-16 instrument* -- a patient-reported outcome ("PRO"),
• Overall survival ("OS") -- a distant disease-oriented EP, and
• Number of participants with adverse events -- loco-regional & distant disease-oriented EP.

Among other aspects of the trial, there was the following cross-over provision:

• Subjects in the comparator arm who have completed at least 1 cycle of dacarbazine or temozolomide and who meet the study protocol definition of disease progression but do not have evidence of distant cutaneous, subcutaneous, active nodal or visceral metastases will be eligible to enter the crossover portion of the study and receive PV-10.

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January. In January, and just prior to BTD denial, there would have been excitement at Provectus about the potential prospect of an expedited approval path for PV-10. Setting aside the speed of traveling along the path, the issue at hand would have been the path itself. There was agreement on the suitable patient population of PV-10: locally advanced cutaneous melanoma.

The January 24th PR's sentence above (2) implied no Phase 3 trial with OS as a primary EP. Locally advanced melanoma patients have a lengthy life expectancy that makes OS problematic as a primary EP. In addition, National Comprehensive Cancer Network ("NCCN") guidelines indicate "clinical trial" as the preferred treatment option for these patients.

But, the clinical significance of objective response (i.e., complete responders + partial responders) still was unclear to the FDA for these patients, stated in PR's sentence above (1). Since Provectus is attempting to establish new regulatory precedent in melanoma, the PR describes the Agency as advising the company to show them how to establish a link between observable response (such as objective response) and clinically significant change in patients (i.e., reduction of suffering, etc).

The BTD application would have attempted to link observable response metrics to clearly evident symptomatic benefit in sufficient patients to demonstrate preliminary evidence. These patients were the sub-group of 28 who had all of their disease treated in the Phase 2 trial (e.g., see PV-10 delivers greatest effects when all lesions are injected).

Although management thought their available data was compelling at the time, and hoped it also would prove compelling to the FDA as part of a BTD application, they understood further study (i.e., a so-called [but undefined] bridging study) may have been needed (i.e., collected at some point in the future) to provide sufficient evidence to support granting of BTD. Such a study would have served to support BTD, validate EPs to be used in any subsequent pivotal study, and provide crucial supportive safety and efficacy data for a new drug application ("NDA").

Management thus calculated their existing sub-group data may prove sufficiently compelling to the Agency to warrant granting BTD, which if achieved would have afforded Provectus the opportunity to comprehensively and quickly review the PV-10 melanoma development program with senior Agency staff to design efficient clinical demonstration of efficacy.

May. A partially skeptical FDA (from the seemingly multiple personalities of the BTD denial letter) said the subgroup data was not sufficiently compelling, and asked for more data.

Eric said on the conference call it was a measured risk. See May 23rd conference call transcript sentence above (4). His rationale was PV-10 making tumors disappear was tantamount to making patient suffering disappear. See May 23rd conference call transcript sentence above (4).

Shortly after the decision was communicated by Provectus, a shareholder with whom I regularly collaborate on this project conveyed feedback he had sought on the letter from folks who routinely interact with Agency staff on oncology matters. Their (these folks') view was not to read too much into the BTD denial letter, and that the FDA merely was asking for more information (data). The company had the right data, but not enough of it. See the May 16th BTD denial letter sentence above (3).

November. Several aspects of the protocol suggest an interesting [to me] description of Provectus' pivotal Phase 3 trial. These are:

• The use of systemic chemotherapy (intravenous dacarbazine or oral temozolomide) as the trial's comparator. As I noted above, NCCN guidelines indicate "clinical trial" as the preferred treatment option for patients with locally advanced cutaneous melanoma, and not systemic chemotherapy,

• The above mentioned cross-over set-up that permits switching after only one 28-day (4-week) chemotherapy cycle (and study protocol definition of disease progression, as well as no evidence of distant disease). The first EP assessment period is 12 weeks (4 weeks for the adverse event EP),

• The anticipation that many (perhaps all) patients in the chemotherapy control arm would not develop distant disease after one cycle, and

• The confounding of the OS EP, the so-called gold standard of distant disease-oriented EPs, due to crossover. Crossover would have an impact on the measurement of OS, but not PFS, CRR, duration of CR, patient-reported outcomes or adverse events. I have no doubt Eric knows it is unlikely there would be a statistically significant difference in the two arms** given the study size, as the Phase 3 trial does not appear to be powered for survival because there is no way to estimate what any difference might be (in light of crossover). In addition, the trial's patient population comprises Stage III patients with expected lengthy OS.

The above might allow one to describe Provectus' upcoming pivotal Phase 3 randomized control trial for locally advanced cutaneous melanoma as a "single-arm study" collecting more of the right data about PV-10 for the FDA.

As such, I think the trial may be much shorter in duration than expected, and provide the necessary supportive safety and efficacy data for a PV-10 NDA filing.


* The Skindex-16 health-related quality of life questionnaire was utilized in clinical trial work for basal cell carcinoma-approved vismodegib.

** There should be marginal survival benefit between or no statistically difference in the two arms, because the control arm would start out as patients receiving chemotherapy and then transform into the arm of patients who started out on chemotherapy and then switched over to PV-10. Thus, there likely would not be much difference in survival of (i) patients initially receiving PV-10 and (ii) patients receiving, say, 1 cycle or month of chemotherapy and then PV-10. It may be possible, however, to analyze the data for OS by modelling the absence of crossover through rank-preserving structural failure time (see Pfizer, sunitinib, gastrointestinal stromal tumours).