Pfizer clarification and IVUS notes
To reinforce what I wrote on Pfizer, I said I expect the trial to show statistical significance P<0.05. Clinical significance will be a matter of debate. I believe the risks are such that whichever way one is positioned on Pfizer when the data finally arrive, one must protect against a significantly high chance of a tail event.
As to IVUS, I am lucky enough to have worked closely with a private company who produced the coils used by Dr. Nissen in the ESPR trials. IVUS is an invasive intravascular procedure whose readings are HIGHLY sensitive to the speed with which the device is withdrawn, the exact starting location, and the exact ending location. For those who were paying very close attention to the 2003 ESPR trial that made a household name out of Dr. Nissen, the trial was as much about seeing concordance between IVUS measurements as it was about the dramatic results seen from the drug. Prior to this trial, the gold standard in clinical practice and for regulatory purposes was an external ultrasound technique.
In every demonstration of IVUS I know of, measurements are best regarded as cardiologist-specific. I believe Dr. Nissen would agree to a point, amending my assertion to say that his team at Cleveland Clinic shows a particularly high degree of concordance. That claim is the basis for his salesmanship of his clinic as a centralized IVUS adjudicator (a point referenced in an article posted here in the last few weeks).
If Pfizer randomizes by surgeon/cardiologist (as in ZymoGenetics' rhThrombin pivotal trial), then the point is probably moot. If they have some sort of centralized IVUS center where a limited number of cardiologists perform the IVUS (akin to centralized radiography adjudication in oncology trials), then it also might be a moot point. I suppose a third way would be to have more than one cardiologist take a reading, but because it is an invasive procedure and there are health risks (dislodging plaque, infection, etc.) I would very much doubt that was the measurement protocol.
Any IVUS-based approach that does not use one of the first two approaches should be looked at with at least as much skepticism as investigator determinations of objective responses in oncology trials. Whether the community will be skeptical (if appropriate) of IVUS in terms of the torcetrapib trial is an unknown since science doesn't always drive behavior.
Happy Holidays,
David Miller
BSR, LLC
One or more BSR staff members owned a long position in ZGEN at the time this was written. See the Disclosures page on our web site for more detail.
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