Hazard ratio, and other stat stuff

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I have written about hazard ratio in the context of Provectus's pivotal Phase 3 trial. For example, see:

• June 2012, Pivotal MM Phase 3 Trial Design: Study Size Dramatically Reduced, 

• October 2012, $PVCT.OB Presents Final Phase 2 Melanoma Data At ESMO 2012, 

• June 2014, Trial Math: Meeting the Primary Endpoint, Pt. 1, and

• July 2014, 2014 Annual CEO Letter (pt. 1).

Hazard ratio ("HR") is "[a] measure of how often a particular event happens in one group compared to how often it happens in another group, over time." In the context of a clinical trial in oncology, hazard ratios often are used "...as the preferred method to assess efficacy," and "...offered as evidence of treatment success when comparing new drugs or combinations with established therapies" (n.b. hazard ratios, however, have "...very limited value unless accompanied by a number that quantifies the magnitude of benefit in time").

The projected hazard ratio of Provectus' upcoming pivotal Phase 3 trial (a registration study) for locally advanced cutaneous melanoma is unknown.

Assumption: Let's assume this number is 0.545 or thereabouts, which derives from past Phase 3 trial design information publicly provided by the company. See below from 2013:

Click to enlarge. Provectus corporate presentation, March 15, 2013

This figure of 0.545 could be traced back further, such as to 2012:

Click to enlarge. June 2012 blog post Pivotal MM Phase 3 Trial Design: Study Size Dramatically Reduced.

Note: While the above company slides are from 2012-2013, Eric presented preliminary metastatic melanoma Phase 2 trial results at SMR 2010, and final results at ESMO 2012.

Wikipedia notes about hazard ratio: "If the analogy of a race is applied, the hazard ratio is equivalent to the odds that an individual in the group with the higher hazard reaches the end of the race first. The probability of being first can be derived from the odds, which is the probability of being first divided by the probability of not being first: HR = P/(1 − P); P = HR/(1 + HR)."

In the case of Provectus' pivotal trial, and using the race analogy above, race entrant number 1 is PV-10 (the trial's treatment arm), and entrant number 2 is chemotherapy (the comparator or control arm). Hazard ratio, or HR, is the probability of PV-10 being first — an event or hazard (i.e., progression of disease) occurring in the treatment arm before it occurs in the control one.

Calculation: The probability of PV-10 being first is 0.545 / (1 + 0.545), or ~35%.

Another way of putting it, "...hazard ratio compares two treatments. If the hazard ratio is 2.0, then the rate of [events or hazards] in one treatment group is twice the rate in the other group." In the case of Provectus' pivotal trial, if the projected hazard ratio is 0.545, the rate of events or hazards in PV-10 treatment arm is projected to be about half the rate in the chemotherapy control arm.

Progression-free survival for chemotherapy (dacarbazine ["DTIC"] or temozolomide ["TMZ"] in Provectus' Phase 3 trial) is approximately 2-3 months (e.g., Middleton et al. (2000), Patel et al. (2011) [see footnote 13], Hauschild et al. (2012) [see reference 1], etc.). According to Eric, "[t]he performance of DTIC and TMZ are well documented and generally yield a normal distribution of events (for example, refer to Middleton et al.)."

Assumption: Let's assume most patients in the company's Phase 3 trial's chemotherapy comparator or control arm have their disease progress after 2-3 months (about 8-13 weeks). PFS assessments will be made every 12 weeks (i.e., t = 12 weeks, 24 weeks, etc.) up to 18 months.

Provectus observed (see the ESMO 2012 poster) Stage 3 patients in the company's Phase 2 trial achieved PFS of 9.7+ months (mean) as measured by modified RECIST (9.8 months (mean) on the ESMO 2014 poster). Eric reported PFS as measured by RECIST 1.1 (according to Peter), which is the approach or convention by which tumor progression will be measured in the Phase 3 trial, on ClinicalTrials.gov as 3.7 months (median). PFS was measured for 12 months (or 52 weeks).

Eric has not disclosed PFS for the subset of patients in the Phase 2 trial who had all of their disease treated. This all disease treated subgroup formed the basis of Provectus' denied breakthrough therapy designation application), and the Phase 3 trial solely will comprise these patients. Stage 3 patients as a group appear to have achieved a 37% complete response ("CR") and an objective response rate ("ORR") of 63%, while all disease treated Stage 3 patients achieved 50% and 71%, respectively (an improvement of 35% and 13%, respectively). See original data, and 95% confidence intervals on the ESMO 2014 poster.

Assumption: Let's assume the Phase 3 trial's PFS for PV-10 is at least 3.7 months (as reported for all Stage 3 patients from the Phase 2 trial). Or perhaps it is higher, like 4.2 months (13% above 3.7) or 5.0 months (35% above 3.7). Or perhaps it is much higher, like there is no event because there is no progression because (i) all of their disease is treated with PV-10 and (ii) PV-10 will be injected until the tumors achieve CR (or progress, and thus an event or hazard occurs).

So, at the first assessment period of 12 weeks:

• Most if not all patients receiving chemotherapy would have progressed: 2-3 months ~< 12 weeks, and

• Most if not all patients receiving PV-10 would have not: 3.7 to 4.2-5.0 to never > 12 weeks.

Assumption: Let's assume the probability of chemo patients progressing after 12 weeks is 80-90%, and the probability of PV-10 patients progressing after 12 weeks is 0-10%.

Calculation: The actual hazard ratio of the Phase 3 trial — the probability of an event in the PV-10 treatment arm divided by the probability of an event in the chemotherapy control arm — may range from 0 (0% / 90%: not going to happen) to 0.13 (10% / 80%).

A projected trial hazard ratio of 0.545 and an 80-90% probability of progression in the control arm would imply a 44-49% probability of progression in the PV-10 treatment arm. Provectus likely expects the actual hazard ratio (on the order of .13'ish) to handily beat the projected hazard ratio (of 0.545).

Provectus' focus may not be on whether the Phase 3 trial outcome is successful, but rather on how many enrolled and treated patients (and their presumed successful outcomes) are needed for the outcome to reach clinical (statistical) significance as quickly as possible.

2014 Annual CEO Letter (pt. 1)

On Tuesday Provectus management published their annual CEO letter.

SUFFICIENT CAPITAL ON HAND 

Our financial position and corporate governance are such that we expect to continue to meet the relevant listing requirements of NYSE MKT. We believe our efforts to obtain regulatory clarity will be helpful to facilitate such transactions with potential partners. Additionally, the existing and forthcoming clinical and nonclinical mechanism of action data for both PV-10 and PH-10 are expected to further aid in both regulatory clarity and transactions with potential partners. The Company's current cash position is sufficient to meet our obligations. In addition, management is returning $8.96 million to the Company as a result of the previously announced settlement of a shareholder derivative lawsuit (subject to a 2:1 credit to the executives, such that total actual repayment by the executives may be $1.12 million per executive) and further enhanced our strength by management's recent exercise of options. In total, we have adequate funds to operate without a further injection of capital through mid-2015.

The relevant verbiage of the paragraph, "[i]n total, we have adequate funds to operate without a further injection of capital through mid-2015," is inartful when one (or two, both Peter and Eric) previously said the company has adequate capital to reach the point of an interim data readout of the Phase 3 trial for unresected locally advanced cutaneous melanoma. "Previously" would refer to the conference calls (e.g., May 23rd, June 3rd, June 19th), yet we have the above from the July 8th CEO letter. If we take Eric's previous comment Provectus would have interim data as early as 15 months after the Phase 3 study starts accruing patients, and previous guidance of a 3Q14 trial commencement (say, September 2014), data would (could) be available five quarters later starting in 4Q15 (say, November 2015).

Quarterly cash burn has trended downward, and the company projects a go forward, 12-month annual expense run rate (not including Phase 3 trial expenses) of $10 million (an average of $2.5 million a quarter), which would include salaries, overhead, PV-10 and PH-10 mechanism of action study costs, liver study costs (expanded Phase 1), FDA regulatory affair consulting costs, etc.

Click to enlarge.

Without consideration of the melanoma Phase 3 trial, the projected cash balance should look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 4Q15 timeframe (potential fund raising would occur before that so the threshold is not met of course).

Click to enlarge.

Now, layering on potential expenses related to the Phase 3 trial -- e.g., per patients costs of $25-50K, pay-as-you-go CRO expenses, enrollment of about 12 patients per month, a September 2014 start to enrollment -- the company would approach BDO' threshold (the purple colored lines below are Phase 3 trial adjusted cash balance scenarios) in 3Q15 timeframe.

Click to enlarge.

With a 210-patient study (N), 105 progressions (i.e., 50%) [P] are required to occur before the data are examined by the independent data monitoring committee. The study would be deemed a success if the necessary differential occurred in the events between the two arms. The greenish line above tabulates cumulative patients enrolled; consider 1 progression event occurrence per patient and 1 progression for every 2 patients accrued/enrolled/treated. An interim readout (interim meaning half of the patients) would require half of the above mentioned progressions (P1 would equal about 53), which would suggest accrual/enrollment/treatment of about 103 patients (N1).

When Eric said interim data would be available as early as 15 months after the study started accruing, I think he meant interim data on N=210 (I could be wrong of course), and not N1=103:

• Assume about 12 patients are enrolled per month (about 36 per quarter), which comes from a 210 patient figure and an accrual/enrollment period of 18 months (210 ÷ 18 = 11.67),
• Assume all patients irrespective of arm would progress, and
• 105 progressions requires 105 patients accrued, which would take about 9 months (105 ÷ 11.67 = 9).

If there is a non-normal distribution of events (e.g., a substantial fraction of patients in one arm are not progressing within the projected timeframe) or an unexpected distribution of events (e.g., patients in one arm are faring much better than predicted), the time to accumulate the necessary number of events could be delayed. To address this possibility I imagine Eric would have designed the study to trigger a review of the data upon the first of (i) accumulating the necessary number of events or (ii) reaching a prescribed period of time after which said events would be expected (e.g., two or three times the predicted progression free survival ("PFS") for the last patient in the PV-10 arm).

Predicted PFS for the PV-10 arm would derive from the projected hazard ratio ("HR") of the Phase 3 trial, which we do not know; however:

• Assume the projected HR is 0.545 (from the 180-patient, SPA-designed Phase 3 trial), or 0.6-0.65 (if the HR inched upward to reflect the increased number of patients). See my Trial Math: Meeting the Primary Endpoint, Pt. 1 blog post,
• Assume a projected comparator (DTIC) PFS of 1.5 months,
• Calculate a projected PV-10 trial PFS of 2-3 months (1.5 ÷ 0.545 = 3, rounded, or 1.5 ÷ 0.636 = 2, rounded) and
• Calculate a prescribed period of time after which the necessary number of events would be expected of 6 months (PFS of 3 months × 2 = 6, or PFS of 2 months × 3 = 6).

15 months, for N, then should comprise 9 months of accrual time and 6 months of time as the prescribed period after which the necessary number of events would be expected.

N1, however, might suggest a 10.5 month period (three-and-a-half quarters). Assuming a 3Q14 trial commencement (i.e., September 2014), such data could be available starting in 3Q15 (say, July 2015).

Click to enlarge.

Understanding that the above is a rough analysis, that there are ranges to every figures used (i.e., give or take, plus or minus), and that folks can have different starting points and assumptions, I think one could make a reasonable argument Provectus may have enough money to provide an interim readout (N1) without a further injection of capital.

$PVCT.OB Presents Final Phase 2 Melanoma Data At ESMO 2012

Provectus issued a PR yesterday describing final MM Phase 2 data, providing a copy of the ESMO 2012 poster and describing design parameters of the pivotal MM Phase 3 trial for which the company is seeking an SPA from the FDA.

Phase 2 data. The final MM data was first presented by Dr. Agarwala in Munich on June 22 at At 2nd European Post-Chicago Melanoma Meeting 2012. See the PR here. There some slight differences from the data presented in Vienna on October 1 that may be gleaned from comparing the two PRs. These appear negligible or immaterial:

• An Objective Response Rate of 51% (v. 50% in Munich) in subjects' target lesions (25% Complete Response and 26% Partial Response [v. 25%]);
• 69% disease control (v. 70%) in these lesions (combined Complete, Partial and Stable Response subjects); and
• Stage III subjects experienced a substantially higher target lesion response rate (60% OR [v. 58%] and 79% [v. 81%] disease control) versus Stage IV subjects (22% and 33%, respectively);
• Analysis of temporal data showed that Stage III subjects also experienced significantly greater mean Progression Free Survival (PFS) of at least 9.7 [v. 9.6] months, versus 3.1 months for Stage IV subjects (median PFS for Stage III subjects was not reached during the 12-month study interval).

What appeared new (in contrast to the Munich presentation was overall survival.

Overall, the Phase 2 data was very strong, particularly for Stage III subjects, who will be the patient population for the Phase 3 trial. It was striking to net out those subjects experiencing early progression prior to the week 8 assessment who were then classified as non‐evaluable (NEV): 66% OR -- two-thirds of subjects -- and 88% disease control -- nearly 9 in 10 subjects, assuming my process and math is correct. The PFS curve is very similar when netting out NEV, although it does improve.

What is even more striking is the expectation the Phase 3 trial will improve further -- Phase 2 bested Phase 1, and now Phase 3 is expected to best Phase 2 -- since Phase 3 investigators will be able to treat all lesions.

The finalization of this data bodes well for its long-awaited publication in The Lancet in 2012.

ESMO poster. The poster itself had a few other useful nuggets. First, the Australian combination therapy study of intralesional PV-10 plus radiotherapy by Foote et al. had enrolled 7 patients as of July. The recent rumor of a double digit number of patients enrolled in the trial makes sense.

Second, the start of the human MOA study by Moffitt was imminent as of the submission of the poster.

Phase 3 trial design. I had thought Dr. Agarwala's Munich presentation had contained the final design. I was incorrect. I am led to believe there is no more negotiating or discussion with the FDA on the trial design, which makes sense. The Vienna PR goes into great detail about the design parameters, as contrasted with the Munich PR, which did not mention any meaningful aspect of the trial design.

The second quote attributed to Eric in the trial design section of the PR is telling. In particular: "This study is designed to demonstrate delay or avoidance of progression of melanoma from a locoregional disease to a life-threatening systemic stage." PV-10 treats disease so well, there will be much less Stage IV disease. Melanoma will not spread to visceral organs because the drug would have stopped it before it does.

There would appear to be no doubt the Phase 3 trial will hit is primary endpoint of PFS. If Provectus hits the same PFS in Phase 3 as the company did in Phase 2, the endpoint is reached. The contemplated hazard ratio dictates almost 6 months PFS for PV-10 versus just less than 3 months for DTIC/TMZ.

The 4-week clinical response assessment (in addition to the 12-week full response assessment) is interesting new design parameter. It is an excellent way for Provectus to measure how effective PV-10 is versus DTIC/TMZ as the study progresses (i.e., a very clear picture of trial success as early as 1Q13 or 2Q13).