Friday, January 13, 2012

Attention Stats Gurus - Is it Possible ThermoDox Hit its PFS Endpoint at the Interim?

I won't even try to act like I am a statistics guru, but I want to bounce a particular journal article off my blog viewers to read. I received an email from another fellow shareholder (whose name I will not disclose) who directly influenced me to send Celsion CEO Michael Tardugno one of the several questions I recently posed to management:

It's clear from the recent CEO letter that the "no statistical penalty" verbiage from the interim PR was changed to "de minimis". I take this as reinforcing that the alpha penalty is negligible. Is the alpha spent on the next interim any less than the normal Lan-Demets because the company is able to "buy back" the alpha spent on the previous interim and redistribute it the new interim?

So, why, might you ask, would the DMC recommend the trial to continue even if the PFS data was strong? There could be many reasons:
  1. An early unblinding may have muddied the waters in China, as recall, the company continues to enroll patients in the HEAT trial in China such that a sufficient number of patients are enrolled to meet SFDA filing requirements. 
  2. PFS may have been strong, but there may not have been a well defined OS trend established. (though one could argue PFS and OS are strongly correlated)
  3. Unblinding does present some problems in terms of OS as well, since patients in the control arm who have recurred (but remain eligible for RFA per inclusion/exclusion criteria of the trial), would be given ThermoDox. This could ultimately impact the confirmatory OS results upon realization of 372 events.
  4. More generally, the DMC could not justify an early unblinding due to the risk-benefit profile established at the time, which would include number 2 above certainly.
Anyways, the point is there may have been a myriad of reasons why the DMC may have used their judgment to recommend the HEAT trial continue even though PFS may have been strong. And for the record, even if a 2nd interim analysis is done, many of the same issues above may still apply (although I would imagine China would be fully enrolled by then).

The shareholder in question who I referred to above, by the way, was particularly intrigued by the CEO's comments in the initial press release that there would be "no statistical penalty" (later revised to "de minimis" penalty in the CEO letter) if a 2nd look was conducted after having received approval from the FDA via a SPA modification to do so. 

I can't stress enough...the company was extremely conservative before the interim analysis in ensuring that the trial, in it's entirely, be conducted to the highest of standards, which includes not "tampering" with the original SPA. That tune has completely changed, and I would imagine that as of right now, they are in discussion with the FDA to do just that.

The paper below (Note the name of the author, Lan, as in "Lan DeMets") strikes at this precise issue in question. I want to emphasize that I am by no means asserting this is indeed what happened during the interim analysis. We don't know, and the company is only going off of what the DMC has recommended to them.


Sunday, January 1, 2012

Some Great New Year's Reading, Quick Thoughts on ABLATE

What a better way to start the new year than with more reading materials? :-)

In all seriousness, I continue to add journals to the links at the top of my blog, and I recently came across some fantastic reads that span a few different areas of interest. A couple of these articles really dive into the "nitty gritty" of thermal ablation, and in particular, draw upon the potential synergies seen with adjuvant therapies in the "sub-lethal zone" of ablation. I have also posted a very recent review of locoregional treatments in general for HCC, and have included some articles to get your interest brewing in the ABLATE trial Celsion recently initiated, focusing on the role of RFA for colorectal liver mets.

On the topic of CRLM, just keep in mind that while the population of patients with colorectal cancer is significant, and about 40-50% of them get liver mets at some point in their prognosis, it is confined liver mets (~25-30% of all patients, see the second to last reference below) where local treatment, such as RFA or surgery, would be used (this is reflected in the ABLATE trial protocol as well). This, of course, has implications for the "treatable" CRLM population with ThermoDox, impacting market potential estimates. Going even further, around 25% of that 30% are now treatable with surgery, so that leaves a little over 20% of patients that could receive some form of local treatment for colorectal liver mets (TACE, RFA, PEI, etc.), excluding surgery. Still, the numbers are significant from a market potential perspective for ThermoDox. Even if we say Celsion captures 10% at peak share capture, in the US alone, that is ~15,000 patients. Those numbers are even more important since the CRLM incidence primarily comes from the Western world, where Celsion is likely to have a more aggressive pricing strategy as well.

In regards to the ABLATE trial, I anxiously await news from the company in terms of a "first patient treated" press release, as I believe this should be imminent (in fact, this should have happened before end of 2011).

Chem Physics Lipids- (in press) Synergy Lipo Thermal Ablation 2011.pdf

Surg Oncol Clin- Basic Research in Thermal Ablation 2011.pdf

Can Treat Rev- Locoregional radiological Tx for HCC Which When How 2012.pdf

J Surg Onc- RFA of CRLM Dec 2010.pdf

J Surg Onc- Tx of CRLM Role of lap. RFA, Micr 2010.pdf

Cancer Control- Resection of CRLM Current Perspectives Jan 2006.pdf

Cancer Control- RFA of Liver Metastases Jan 2006.pdf

Int. J Surg Onc- Colorectal Liver Mets Review- Dec 2010.pdf (Added 1/2/12)

Enjoy the articles. I look forward to a busy 2012 for Celsion.