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Biovest Misleading in BioVaxID Data


Don't get the wrong idea about this drug trial.


I wasn't too surprised when my cautionary comments on Biovest (BVTI) and Accentia Biopharma's (ABPI) description of their BioVaxID press release generated several e-mails and comments – most of which were not too complimentary. Those of us who are fans of active immunotherapies tend to be a passionate group.

Most of the less complimentary e-mails centered on my comments about the missing first six months of the Kaplan-Meier curves shown by the company:

"If you had dug a little deeper in your research you would have discovered there is a legitimate reason that Biovest begins measuring patient responses six months after randomization is completed. This is because, in between the point of randomization and the point the vaccine is administered, there is a scheduled six month rest period."

If you scroll to page 25 of one of Biovest's presentations, you'll see what the poster is talking about.

The problem is the slide is misleading and the company might well be misleading investors if the comment above is an accurate representation of what it's saying. By FDA rule and biostatistical convention, monitoring of patient responses starts the moment a patient is randomized into a trial. In this BioVaxID trial, that happens at the big yellow arrow on that slide (after a complete response to prior therapy is confirmed).

The graphic Biovest uses is misleading. While it does call out the point of randomization, they don't split the arms until after the vaccine is administered. That's not how the statistics of this trial will be interpreted by the FDA, and I seriously doubt that's how the statistical analysis of this trial is described in the statistical analysis plan on file at the FDA.

This makes the Kaplan-Meier curves shown in the company's press release completely incorrect. There will be patient events in the six month "immune system rest" period. That means the curves will not start at 100% as indicated in the press release. They will start lower.

There is a legitimate question as to whether this makes a difference. That's why I didn't say the trial would certainly fail. Because the two arms are likely to drop together during that six month resting interval, however, it will make it harder for the overall trial to become statistically significant. If I were a betting man, I would bet that's what the DSMB saw – that the data looked interesting only after the resting period and manufacturing failures were excluded.

Unfortunately, this FDA is unlikely to let this perfectly logical way of looking at this trial slide. For those who have been following along, you know that the FDA – particularly the oncology division – does not operate by logic. They operate by strict and unforgiving interpretations of the rules of biostatistics – patient needs be damned. This is sad and deplorable, but they control the rules and investors must recognize this.

"So why did Biovest shift the curves," one of the commentators on the original article asked. Two reasons:

1. The company believes it can convince the FDA to interpret its trial this way (it's wrong).

2. It is spinning a failed trial so they can raise money and/or keep their jobs.

The two aren't mutually exclusive, of course, but the first gives them the benefit of the doubt that they aren't purposefully trying to obfuscate the data and snow investors. If you are invested, or thinking of investing, in these companies you must demand to see the curves from the point of randomization and including all patients enrolled in the trial (something called an Intent To Treat (ITT) analysis) because that's what the FDA will be looking at for their decision. Anything else – curves that shift six months or that exclude manufacturing failures – will provide you with unreliable information.
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