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.


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