PV-10 v. Standard of Care

Among several aspects of the Provectus story I detailed in my post Expect More, one was the evolution of the parameters of the pivotal Phase 3 Randomized Controlled Trial ("RCT") for the company's lead indication, metastatic melanoma ("MM").

The last change, until somewhat recently, was made to the "Planned Phase 3 Trial" slide in June 2012, when Dr. Agarwala presented some new and final MM Phase 2 trial data at the 2nd European Post-Chicago Melanoma Meeting 2012, Interdisciplinary Global Conference on Developing New Treatments for Melanoma, which as was prelude to ESMO 2012. At that time, when discussing the consensus Phase 3 trial path, Provectus presented a trial endpoint of PFS, which it previously had noted; however, the trial's patient population had been reduced from 250-300 to 180, and refined from Stage III-IV-M1a to Stage IIIB-IIIC.

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The above slide has been included in the company's corporate presentation on the website under Press Center, Press Kit. PV-10 would be compared to systemic chemotherapy (dacarbazine or "DTIC," or temozolomide or "TMZ"). DTIC is normally administered by intravenous infusion. TMZ is the pill version of DTIC. From March:

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Management, in particular Craig and Eric, have long tussled with what they consider the ethical dilemma presented by running any RCT involving PV-10. Even though the main reason for using the RCT design is a scientific one, that society is likely to suffer as a direct result of avoiding such high quality evidence, there is no true comparator to PV-10 in terms of a drug that also is rose or pink colored, and injected intralesionally (into a lesion) or intratumorally (into a tumor).

The skeptic could argue the RCT, "the gold standard for a clinical trial," is necessary to truly establish PV-10's efficacy and effectiveness within the desired patient population. After all, these promising intralesional agents BioVex's OncoVex, later Amgen's talimogene laherparepvec or T-vec, and Vical's Allovectin-7 struggled to meet its primary endpoint and Allovectin-7 did not in their respect RCTs. Interestingly, and "supporting" the skeptic's position, while T-vec was compared to subcutaneous granulocyte-macrophage colony-stimulating factor ("GM-CSF"), Allovectin-7 was compared to DTIC and TMZ. The ethicist might counter that without a true comparator, at a minimum in terms of color and delivery route, there indeed is an ethical issue with providing a clearly insufficient comparator like DTIC or TMZ whose limitations and lack of efficacy are fully known.

A "trial parameter" changed during the summer, after the 8th World Congress of Melanoma (which was held in conjunction with the World Meeting of Melanoma Centers, the Post-Chicago Melanoma Meeting 2013 and the 9th Congress of the European Association of Dermato-Oncology) from July 17-20 in Hamburg, Germany. This change then was communicated via the website presentation, the version from November:

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No longer PV-10 vs. Dacarbazine or Temozolomide, but then/now PV-10 versus Standard of Care.

Consider the NCCN Guidelines for treating melanoma, what is the standard of care for Stage IIIB-C patients, let alone those refractory to treatment?

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There are standard treatment options for Stage 3 patients, and treatment options for patients with recurrent melanoma.

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I don't see standard of care: "Treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. Also called best practice, standard medical care, and standard therapy."

Did the FDA conclude comparing PV-10 to something required a different perspective than historical thinking or practice?

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Why did the company change this parameter? I cannot find the standard of care for the treatment of Stage 3B-C patients as supported by the company's MM Phase 2 clinical trial data (i.e., patients refractory to multiple treatments like surgery, chemotherapy, immunotherapy, radiotherapy, investigational agents, and amputation). Is "PV-10 versus Standard of Care" an homage to the reality there is no standard of care?

Attendees at Provectus' annual shareholders meeting at the end of June, which preceded the changes to the "trial parameter," observed notable changes in the attitudes of company principals. Clearing this hurdle, challenge or regulatory discussion point of how to compare PV-10, or perhaps how to think about PV-10, could have been considered by management to be a very notable achievement in their pursuit of the approval of PV-10.