A few comments,
"And if the Outcome for DEX is significantly better in the best Outcome category the patients must come from the number 2 category since there are few patients in the lower categories. So the fact that the total number in the top two categories hasn’t significantly changed is more an artifact of the GOS score tops out too soon and is too coarse. "
from the Neuroinvestment website, this supports your conclusion of the GOS "good outcome" category" being rather blunt
2)With the easiest to understand measure--death--providing positive but uninspiring support for HU211, the next digestible measure is that of recovered functionality--"good outcome"-the percentage of patients resuming normal function at 3 mos, and 6 mos. This is a generous category, it includes anyone who can hold a job outside of a sheltered workshop setting. At 3 months after the injury, 40% of HU211 patients had a good outcome, compared to 17% of the placebo group (a trend, p=.10) However, at 6 months, the contrast was 45% vs 37% (p=.3) One might think that the placebo group catches up, that the drug accelerates recovery but does not change the ultimate endpoint. However, we suspect that a more finetuned assessment instrument, one which does not incorporate such a large range of function and dysfunction into the 'good outcome' category, might show that the drug group did continue to improve compared to placebo from 3-6 months, more than these figures would indicate.
"2) I saw something on the boards that indicated that only 1% of the patients had died in the phase III. That would be bad because it would indicate either the standard of care has improved making DEX’s job a lot harder, or the patients are healthier in the Phase III and that exacerbates the GOS ceiling effect. I can find no confirmation of this 1% mortality, and Pharmos does indicate that 1% of the patients were lost to follow up. I suspect the poster, who I could not find with any more credible posts, has confused “1% lost” with “1% dead”."
I believe the intent of Pharmos was to limit the # of patients that would die regardless of treatment. The goal was to find patients that would most likely demonstrate ICP problems, yet still be able to survive. With that being said we do know that with 621 patients enrolled, 36.7% or 230 patients fell in the 1-3 GOSE category. So, some patients have died.
"4) Stratified results in Phase III. I still don’t understand the FDA well enough, but I think that if the overall numbers are positive that they will give approval regardless of stratification – although they might modify the label in some way. Not worried by that scenario. As for overall numbers shy of stat sig, but a stratified subgroup is stat sig, I suspect Pharmos will have to run another test. This is a moderate worry to me, but that is why it is priced for phase ii and not phase iii."
The million dollar word being used is "covariate analysis". Basically, what they are doing is adjusting the probability of a good outcome based on some factors we know and others we don't.
The following is from a discussion I had with IR about the issue.
"To illustrate the concept, consider one very important prognostic
factor, age. Ones ability to recover from head trauma declines with
increasing age. All other things being equal, a 20 year old patient
with
the same injury as a 60 year old patient would have a much better
chance
of recovery. Let's assume that these two patients are entered into the
trial with the 20 year old receiving placebo and the 60 year old
receiving the drug. At the end of 6 months both patients are judged to
have achieved the top level of the GOSE. Under the former method of
analysis, the conclusion would have to be that the drug had no effect
because both patients achieved the same Good Outcome. However, with the
amended method of analysis, in this illustration a different conclusion
is obtained. Because of his age, the 60 year old may be assigned to a
band where he is expected to have only a 30% chance of achieving the
top
GOSE level. On the other hand, the 20 year old may be assigned to a
band
such that he would have a 90% chance of achieving the top GOSE level.
With this analysis, one would recognize the positive effect of the drug
on the patient receiving it.
The example is meant only to illustrate the concept. When several
prognostic factors are imputed for all 861 enrollees, we believe that
the methodology will provide a more realistic and powerful analysis."
What is interesting imo is that this is first time that the FDA has agreed to do something like this and it was agreed to after the trial started. Sometime this Spring I believe. Some of the other variables, that I know of are other organ injuries and possibly time to treatment. With the ABIC and the EBIC behind this trial, there are some big people involved with this trial.
jonmarin |
