The FDA Response

The Agency's letter to Provectus has the look and feel of two different sets of views.

Key for me to the FDA's response regarding the Agency's denial of the company's breakthrough therapy designation ("BTD") application include:

"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." {Bold emphasis is mine} 

There seems to be clear recognition by the FDA of the applicability of local/intralesional agent PV-10 for the treatment of locally advanced cutaneous melanoma, which the Agency deemed a serious or life-threatening disease or condition. That is substantive recognition.

"The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." {Bold emphasis is mine} 

The FDA also seems to have recognized the drug works, notably in malignant melanoma. Again, that is substantive recognition.

Yet, in both letter sentences above, and here's where the divergence of opinion appears to manifest itself, the FDA qualified their positive recognitions of PV-10 by noting preliminary clinical data submitted by Provectus in seeking BTD did not demonstrate substantial improvement over existing therapies in one or more clinically significant endpoints, which they identify below as pain, infection and significant bleeding.

"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." {Bold and bold underlined emphasis is mine} 

The FDA's choice of the word paucity is interesting and, I believe, nuanced: the presence of something only in small or insufficient quantities or amounts.

The Agency recognized the applicability of PV-10 to treat locally advanced cutaneous melanoma (which it also deemed a serious or life-threatening disease or condition). It recognized the drug worked. The FDA, however, said Provectus did not provide enough data -- from the 54 patient sub-group where all disease was followed and the 28 patient sub-group where all disease was treated -- regarding symptom control (e.g., pain, infection or significant bleeding) to warrant BTD. BTD's generalized two-fold criteria are (i) a serious condition and (ii) preliminary clinical evidence of substantial improvement over available therapy on a clinically significant endpoint(s). Robust complete response (which Eric believed was tantamount to symptom control) and some pain data from the aforementioned subgroups was not enough to establish the correlation between complete response and symptom control.

While the amount of data did not meet the FDA's threshold for BTD, the Agency agreed Provectus submitted appropriate data (albeit in small or insufficient quantities or amounts).

The company's metastatic melanoma Phase 2 trial data did not have as much information on pain, infection and significant bleeding as the FDA desired. This only was established at Provectus' December 16, 2013 meeting with the Agency:

"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)."

Nothing we know today is any less positive than what we knew on Thursday. PV-10 works, and the Agency acknowledged it in writing. What we do know, however, is that BTD, at the moment, is not the appropriate program for the drug due to insufficient (not enough) data on pain, infection or significant bleeding.

What we need to know is what's next for PV-10's clinical development program to provide this data to the FDA. It would appear the FDA recognizes the company and drug can provide it.