DNDN / Mouton:
>On the first point, consider Mr. X, who enrolled one month ago. He does not know whether he received treatment or placebo. Maybe he suspects it was placebo as he did not any fever. He wants to quit and enter CU, where he has a 100% chance of receiving treatment, not a less than 2/3rds chance of treatment (recall his suspicion he in the placebo arm) to be followed by a crossover, which he views as too little, too late.<
If he hasn't progressed, then who is going to refer him to the CU program? I would think it is a minority of cancer patients that try to start another regimen at a time when their disease isn't progressing. How many doctors would truly support this, especially when their patient is going to eventually get provenge anyways (provided he hasn't already). What motivates the doctor to advocate another therapy to a patient that is clinically stable?
I do think that this type of hyper-aware patient that tries to completely game the clinical trial system is the exception. I would bet it is about as prevalent as a patient progressing off the provenge arm and then getting another experimental therapy that truly does benefit him.
In other words, I think these patients are few, they and their doctors have little incentive to take additional action in the absence of clinical indications of disease progression, and their subsequent actions have equal chance of positively or negatively affecting the trial.
>And if the answer to Mr. X is tough, if you quit the trial you get nothing from us, then the company is discriminating against men who have entered their trial. Maybe that can be done, but it feels "wrong." If the answer to Mr. X is OK, then isn't there a strong incentive to leave the trial? Again, as time passes and men progress and crossover, that incentive strongly diminishes.<
Once a patient is in a trial, it falls into the ITT analysis and it is up to the company to make sure that their trial is robustly designed to handle crossovers and other such eventualities.
But again, there is little incentive for a patient that hasn't clinically progressed to go seek alternative therapy, so I don't see the overwhelming desire to leave the trial in the absence of clinical progression. Especially when they are guaranteed provenge if and when they show progression.
>Let's say that the FDA believes given the totality of the evidence, the "true" p-value is .04. I.e., a 96% chance the results were not due to chance. I think they have a strong interest in confirming this result and reducing the chance of a type I error as much as possible. Why are the considerations materially different than those that obtain where approval is based on a surrogate endpoint followed by a phase IV study? (I understand the REGULATORY framework is different).<
Provided I understand you... it's different because a surrogate for survival is a surrogate, survival is survival; the correlation between a surrogate and survival has to be tested. Why does a finding of survival, if true and reliable, need to be confirmed?
So if a drug gets on the market because of its effect on a surrogate, then it is reasonable to provide a framework to allow the sponsor to test survival. But if a drug is getting on the market because the FDA says it increases survival, then what sense does it make to test that survival again? Did it improve survival in the disease or didn't it? If it did, then no duplication of the trial would be necessary.
In thinking about this further, given the minor difference between the 01 / 02A population and the 02B population, if the FDA approves then they have to shut 02B down because it becomes an unethical trial. FDA approval would mean that indicated patients taking provenge should expect a survival benefit, so there is no logical reason to test it again. If the FDA approves and gives DNDN the requirement of a successful 02B to keep it on the market, then the FDA are saying that the survival benefit in the BLA package is not reliable.
>As to waiting till 2010, that is what they said at the panel presentation, and they also said that the SPA provides for termination upon 350 or 360 deaths (I don't recall which of those is the number, but it one of them).<
I agree that was the company's timeline. I just wonder if it foreshadows an attempt by DNDN to change the primary analysis of 02B.
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