Replies to post #3628 on Dendreon Corp fka DNDNQ

[walldiver]

9902B Q & A:

Q: What factors led to the relatively poor results of 9902A?

A: Main reason was strong # of bone metastases factor favoring the placebo arm...secondary reason was smaller trial size.

Q: Why should the results of 9902B look much more like 9901 than 9902A at the interim and final?

A: One of the stratification factors in 9902B will be # of bone metastases...this and the much larger size of the trial should help balance out the likelihood of a higher % of placebo crossovers.

Q: Could the results of a few patients sway the results one way or the other if we roughly mirrored the combined 9901 and 9902A results?

A: This would be more possible at the interim look, which probably will occur around the 180-death point...and yes, there is a possibility of this happening if the results of the Provenge arm are moderately successful.

Q: How might the relatively sicker patient population affect the results?

A: It's hard to say...I think a bigger factor could be how balanced the followup Taxotere usage is.

Q: How might slow ramp up on enrollment of 9902B affect the results at the interim and final for an event given trial?

A: There will be a greater effect at the interim look. There will be a lot more censored patients who are more recent enrollees, and this will be a confounding factor.

Q: How do long-term survivors factor into the results of an event driven trial?

A: This is one of the most promising factors for the Provenge arm. In 9901/9902A, the 36-month survivors had to be censored at the 36-month point. In other words, the Provenge arm got no p-value bonus beyond 36 months for Mr. Garcia, who is a 7-year survivor. In 9901, we know that 28/82 survived 36 months, and that eight more deaths were reported in the BLA for those 36-month survivors. Does that mean that 20/82 were alive at the time of the panel meeting? Possibly, but it may just mean that we lost contact with the other 19 besides Mr. Garcia.

[iwfal]

How much of the shortfall in log rank p-value and HR is attributable to smaller size?

Very little. Trial size was only a small contributor.

The two biggest 'known' contributors were probably sicker population and imbalance. But there is probably something else going on as well - the imbalance probably isn't as severe as the published CR would lead one to believe.

If 9902B mirrors the combined 9901/9902A results, what might the results of 9902B using the SPA prespecified cox analysis look like at the interim and final?

My guess is that it is stat sig - but just barely. The reason that it is just barely is the effect that Ego brought up - the HR at less than 2 years is pretty low even with exactly the same patient pop as in 9901/2a. Remember that 9901/2a was p=0.011 at everyone 3 years. 02b will be only a few more deaths - but probably more than 50% of them will be at less than 2 years since randomization. So ...

[ocyanblue]

<What factors led to the relatively poor results of 9902A? How much of the shortfall in log rank p-value and HR is attributable to smaller size? trial imbalances favoring placebo, etc>

If the trial was run well, the small size would have had relatively little effect on the results while the sicker population and imbalances such as bone mets counted for more. However, a large factor might have been that there were more patients in D9902a than in D9901 who did not get full treatment (around 15% vs 5%). Per the patient distribution decision tree in the stat review, there was even one patient on the treatment arm of D9902a who did not get treated! Because of that, the small trial size might have played a larger role due to a reverse cross-over situation where a significant number patients on the treatment arm were acting like placebos. That might have had some effect on the poor TTP result in D9902a too.

<Why should the results of 9902B look much more like 9901 than 9902A at the interim and final?>

The larger enrollment number will make the trial more balanced across prognostic factors, both the ones accounted for and the ones unknown (the latter is really what people refer to when they say that a large trial is more robust than a small trial - we don't always know everything, e.g., genetic variations, etc.). In addition, stratifying on bone mets and Gleason scores should help. Last, per the CD54 data, the early enrollees on the treatment arm were compliant and hopefully the recent ones would be too due to better published trial data. So there should be less of the reverse cross-over issue above.