The Untrigger

Updated below: 8/15/16.

I have written a lot about the so-called clinical trial math of Provectus' ongoing pivotal Phase 3 study entitled PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma (official title). The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD discussed some of this math on Provectus' August 10th 2Q16 business update conference call.

Eric said the number (not the percentage) of disease progression events required to trigger the interim and full study analyses were 81 and 162, respectively. I discussed this as item 5. Clinical trial math under Quick: 2Q16 (August 9, 2016) on the blog's Current News page.

It was helpful and insightful, but disappointing, to hear Eric say the trial does not have a scheduled assessment (a prescribed time trigger):

"So, when we began designing the study several years ago, we looked at the issue of how to schedule an interim assessment. And while that was a rather uncommon idea, we looked at that very carefully. We even had discussions with FDA on that topic. And they were adamant that they were strongly opposed to any sort of effort to schedule an interim assessment. Our hypothesis at the time was that, for example, because the interim assessment and the final assessment are based on a number of progressions, they're modeled using standard statistical models. If there was a longer progression-free survival in the PV-10 arm than expected, there would not be the required number of progressions in that arm to add up to the required number of events."

As such, as I hear and read it, one should consider that there only is one trigger (a prescribed event trigger), stated on the trial's CT.gov page as "[a]n interim assessment of efficacy and safety will be performed by the IRC when 50% of the events required for the primary endpoint have occurred." As a number, rather than a percentage, this figure is 81.

Eric said on the call that "one of our crown jewels is our study protocols because they represent everything that we've invested in the company up to the point that that protocol is issued." He certainly is reluctant to show his jewels if he doesn't have to (although it is possible he may fondle them from time to time). He "teased" two sections of the Phase 3 trial protocol. First, section 4.9 (with my underlined emphasis):

"An interim assessment of efficacy and safety will be performed when the IRC--that's Independent Root [sp] Committee--will be performed by the IRC when 50 percent of the events required for the primary endpoint, that is 81 disease progressions as defined in the study protocol, have occurred. And so, that explains to you that there's a set number. It's designed at the beginning of the study, and that's the point when that number of progressions have occurred."

Second, section 4.10 (with my underlined emphasis):

"It doesn't matter if they're all in the PV-10 arm, if they're all in the comparator arm, which isn't possibly because there aren't enough patients in the comparator arm. We have to have enough progressions to hit that metric. Now, we had hoped, as I said, to have some sort of a mechanism in the study that would allow that to be triggered early if, for example, we're going along and we're not seeing progressions as we expected. And so, while we worked on that with the agency, as I said, they're adamant that that was not appropriate for a pivotal study. So, what we managed to compromise on was that in Section 4.10, which is captioned "Study Duration", that subjects will be monitored until survival--for survival until death, loss to follow up, withdrawal of consent, or study termination by the sponsor."

Rather than hash out or re-hash my work/writing about prescribed event and time triggers, the number of patients needed to be enrolled to hit 81 events, etc., I'd like to state (speculate) the following -- [I believe] there is a trigger Eric does not want to explicitly speak about or affirm, which could/would be an imbalance in the number of events between the treatment and control arms, which could/would cause a statistical and ethical dilemma for the study's IRC. What would an imbalance look like or comprise? In the extreme, or potentially actually, there would be no events in the PV-10 treatment arm, and events of whatever frequency or magnitude in the chemotherapy/oncolytic virus control arm. Takeaway: The pivotal trial does not have to reach 81 events for the interim analysis to be triggered.

In his own special way I believe Eric said this on the call (with my underlined emphasis):

"And so, we are able to monitor at the terminal end of the study, and if the clinical trial data monitoring committee determines that it's in the best interest to end the study, it could end before we had all of the progression events occurring. I doubt that'll happen. It will be a very unusual circumstance, but it would probably be positive for the drug because it would suggest that a large number of patients weren't progressing because of the majority of the patients in a two-to-one randomized study are from the PV-10 arm, and that probably would imply that the PV-10 patients weren't progressing. 

But, this is all speculation."

The statistical dilemma is having a treatment arm with no or very few events, and a control arm with many, many more (like 0 and 15, or 0 and 20). The ethical dilemma is a treatment arm that works and works very, very well (i.e., no disease progression), and a control arm that demonstrates what everyone already predicted (i.e., everybody progresses).

The question then would be, "how many events in total and across the two arms would be required for the IRC to recognize an imbalance, and thus trigger the interim analysis?" Twenty events in the control arm (and none in the treatment arm)? Thirty? A two-to-one study randomization then would suggest enrollment and treatment of 60 patients. Or 90.

Math, math, math.

Updated (8/15/16): My projection for enrollment in the pivotal melanoma Phase 3 trial is below (having adjusted only for 5 months of no enrollment as a result of the major amendment related to Amgen's intralesional (IL) drug Imlygic, and also differentiating enrollment rates between medical and surgical oncology sites). The study may generate enough events to highlight the imbalance between the two arms in 1Q16, where the idea is that most-to-all of the control arm patients generate events, and few-to-none of the treatment arm ones do.

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What proportion of events in each arm ("proportion"), and what number of events in each arm ("sample size") gets you to a sufficiently low p-value?

If 75-100% of the control arm generate events, and 0-25% of the treatment do too, who you got?! Using this calculator, which is a simple analysis, and may even be simplistic, may require upwards of 30 patients; however, this may be too low.

E.g., Sample 1: Proportion of Control Arm Events (Number of events generated in the control arm ÷ Number of control arm patients); Sample 2: Proportion of Treatment Arm Events (Number of events generated in the treatment arm ÷ Number of treatment arm patients)

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PV-10, Phase 3, Provectus: Almost [but not quite] there

Almost there (image source)

Provectus issued press release Provectus Biopharmaceuticals Met with FDA on Operational Aspects of PV-10 Phase 3 Melanoma Study today, with the byline FDA allows Provectus to go forward on Phase 3, and filed an associated 8-K.

Previously, on December 22, 2014, the company issued press release Provectus Biopharmaceuticals to Meet with FDA on Operational Aspects of PV-10 Phase 3 Melanoma Study with Aim to Maximize Speed of Enrollment regarding its Type C meeting with the FDA.

I imagine management's talking points are:

• Provectus met with the FDA,

• Eric has effectively managed his/the company's interactions with the Agency,

• The FDA allowed Provectus to move forward with the company's Phase 3 trial, and

• There are no more changes to the trial design.

My additional takeaways include:

1. While we're continuing to see and read about the making of more sausage, Eric continues to make progress towards kicking-off the company's Phase 3 trial. This meeting result should enable Provectus to commence patient enrollment and treatment following completion of various/certain procedural trial-related items. The Phase 3 trial after all is a registration study that successful completion of which should lead to drug approval.

2. We'll need to see the final version of and thus the changes in the trial protocol posted on ClinicalTrials.gov to draw what (if any) conclusions about how much (if anything) Eric was able to positively change of the trial's operational aspects. If he did effectively manage the FDA, he should have got a lot of what he wanted.

3. I imagine the elapsed time between the dates of the meeting (January 29th) and today's press release (February 9th) primarily if not exclusively comprised waiting for the Agency to confirm in writing Eric's understanding of the meeting's results.

4. Eric was being Eric in issuing a useful but overall poorly written press release from a stock market perspective. He approves (and also may write or mostly write), I believe, all releases related to Provectus' clinical development program. His statement in the PR, among other things, that "[t]he outcome of the review does not affect the fundamental design of the study nor the patient population, but does affect certain details concerning some secondary end points and statistical analysis matters, such as the treatment of missing data" (underlined emphasis is mine) is his way of communicating, I believe, that he endeavored to cover as many of his trial bases as he could, in this case as an example discussing with the FDA a potential scenario in which data is missing from the trial, and how to handle such a situation from among other things a data reporting and analysis perspective. Eric is a process- and detail-oriented (i.e., anal retentive) individual, a character trait I value in his clinical development program role and given his responsibilities, albeit taken in the context of his inexperience entering the role and his experience set now.

5. Although Eric has repeatedly missed timelines and deadlines he has set for himself (and thus Provectus) and despite prior expectations for an earlier start to this trial that repeatedly changed — 3Q 2014 in June at ASCO, 4Q 2014 in September at ESMO, 4Q via the corporate website presentation prior to the December 22nd press release, 1Q 2015 via an updated version of the presentation in January and potentially imputed from today's press release — the 6-month delay from 3Q14 to 1Q15 on the front-end (pre-Phase 3 trial start) may save time and improve outcome on the back-end (drug approval).

6.  I find it hard to believe there were no discussions related to PV-10's label, which would be finalized or put into place should the trial be successful. Eric being Eric, however, means his press release would not discuss the topic because the label was in-process; that is, publicly discussing the label before the trial had an outcome would be premature.

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.

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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).

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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.

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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).

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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.

Trial Math: Meeting the Primary Endpoint, Pt. 2

We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug. -- Provectus' Eric Wachter, June 19th conference call

In my blog post Trial Math: Meeting the Primary Endpoint, Pt. 1 I noted DTIC's PFS is likely to be around 1.5 to 2 months for the stage of patient being recruited for the trial's comparator arm. The performance of systemic chemotherapies DTIC and TMZ are well documented, and generally yield a normal distribution of events (e.g., Middleton et al.). I also noted that in Provectus' metastatic melanoma Phase 2 trial the median PFS for Stage III patients (similar to those who would be enrolled in the Phase 3 trial) was at least 9.7 months (median PFS for Stage III subjects was not reached during the 12-month study interval), and the mean PFS of the all disease treated subgroup of the Phase 2 trial was 9.8 months. So, 9.7-9.8 months for PV-10 PFS > 1.5-2 months for DTIC/TMZ PFS.

That is all well and good, but for Provectus' upcoming Phase 3 trial to meet its primary endpoint of progress free survival ("PFS"), the confidence interval ("CI") for response in the PV-10 (test) arm cannot overlap the CI for response of the DTIC/TMZ (comparator) arm. The trial's power is 90%, and statistics are two-sided with an alpha of 0.05, which means there is a 5% chance the true response is above or below a 90% CI.

Information about DTIC/TMZ PFS figures abound for applicable patient populations, together with 95% CIs. These intervals can be converted or adjusted to present 90% CIs (applicable to the Phase 3 trial design).

Provectus provided durable objective response  ("DOR") data for the all disease treated subgroup from its Phase 2 trial on its ASCO 2014 poster.

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DOR, or durable response rate, is complete response ("CR") plus partial response ("PR") that is durable, and is measured in months. PFS is essentially CR + PR + SD (stable disease), in that the disease does not progress or become "PD" (progressive disease). I say SD because shrinkage is neither sufficient to qualify for PR nor a sufficient increase to qualify for PD. As such, PFS ultimately will be a greater figure than DOR. I utilized the CI for PV-10 DOR as a guide to estimate the CI for PV-10 PFS. Comparison of 95% and 90% CIs for DTIC and PV-10 are below.

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Neither PV-10's actual Phase 2 DOR nor estimated Phase 3 PFS CI overlap DTIC CIs. While the bottom DOR intervals are within spitting distance of the top DTIC intervals, there is substantial daylight between the PFS endpoint bottom intervals and the top DTIC ones. This would suggest the likelihood of the Phase 3 trial meeting its primary endpoint of PFS.

Trial Math: Meeting the Primary Endpoint, Pt. 1

We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug. -- Provectus' Eric Wachter, June 19th conference call

There are important aspects of Provectus' upcoming pivotal Phase 3 trial for unresected locally advanced cutaneous melanoma to consider and assess, including but not limited the design itself, total trial cost and cost per patient, likelihood of success at completion, and likelihood of success at or by the interim assessment. The trial design is discussed on Provectus' ASCO 2014 poster (bottom right hand corner). Could the trial be successful, and if so why (or why not)? Could it be stopped early, and if so when and why (or why not)? How much could the trial cost?

The sample size (N) of the pivotal trial is estimated at 210 patients and randomized two-to-one (2:1). There would be 140 patients in the PV-10 arm and 70 patients in the comparator/systemic chemotherapy (DTIC [dacarbazine]/TMZ [temozolomide]) arm. The trial's primary endpoint is progression free survival ("PFS"). The study assumes the null or base hypothesis of the two arms having the same response -- that is, PFS for both PV-10 and the systemic chemotherapy (DTIC/TMZ, or DTIC for short) would be the same. The trial is powered to detect the alternate hypothesis or outcome of the PV-10 and DTIC arms having different responses -- that is PFS for PV-10 would be different from PFS for DTIC.

The alternative hypothesis or difference in response -- this difference in PFS between patients in the PV-10 arm versus those in the control or comparator (DTIC) arm -- may be expressed as a hazard ratio ("HR"), which essentially is the ratio of the response (PFS) of the control arm divided by the response (PFS) of the PV-10 arm. The smaller the HR, the larger the effect size (or impact of investigational drug), and thus the more clinically relevant the observed difference between the two arms is.

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In the example above, for this pivotal trial, a target DTIC PFS of 1.5 months and a predicted HR of 0.545 would lead to a predicted PV-10 PFS of 2.8 months -- that is, assuming a target control arm PFS of 1.5 months and using a set HR of 0.545, the goal of the trial would be for patients in the PV-10 to demonstrate a PFS of at least 2.8 months.

DTIC and TMZ are well known systemic chemotherapies (the former is administered intravenously, the latter is a pill). Their performance is well documented. For example, refer to Middleton et al., where median PFS was 1.9 months for TMZ and 1.5 months for DTIC. There are various other randomized control trials and studies utilizing DTIC/TMZ as control arms (in similar settings to Provectus' pivotal trial), and PFS may be as high as 2 months (so x above might be 3.7 months). Thus far the pivotal Phase 3 trial's HR is not known. I'm using the HR from 2012/2013 when Eric was discussing a Phase 3 trial design under a sought after special protocol assessment with the FDA (see below). The target HR for the current trial may be higher or lower, but I doubt it is materially different.

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

In Provectus' metastatic melanoma Phase 2 trial, median PFS for Stage III patients (similar to those who would be enrolled in the pivotal Phase 3 trial) was at least 9.7 months (median PFS for Stage III subjects was not reached during the 12-month study interval) (see below).

Click to enlarge. Immuno-chemoablation of metastatic melanoma with intralesional rose bengal, October 2012

Another way of looking at potential PV-10 PFS in the pivotal Phase 3 trial is considering the mean PFS of the all disease treated subgroup of the Phase 2 trial (see below).

Click to enlarge. Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, September 2013

9.7-9.8 months for PV-10 PFS > 2-3.7 months for PV-10 PFS "predicted" > 1.5-2 months for DTIC/TMZ PFS.

Historical PV-10 PFSs may be indicative of potential pivotal trial success because the figures are substantially greater than the possible or likely DTIC PFS; however, the above analysis is very rough and not the lease bit "loose." Additionally, trial success is achieved when the PV-10 arm's confidence interval ("CI") for response -- the CI for PV-10's PFS -- does not overlap or cross DTIC's CI for response -- the CI for DTIC's PFS. Nevertheless, the large difference between PV-10's possible pivotal trial's PFS and DTIC's may present a large enough cushion between the two figures, and the potential for trial success when the time comes.

Perhaps this is what Eric might have meant, in part, when he said "[w]e firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome" on the June 19th conference call.