Replies to post #5456 on Dendreon Corp fka DNDNQ

[poorgradstudent]

One thing that has me wondering:

This trial started by enrolling G<7. So now that they are reducing the events at the analyses, do they run the risk of biasing the events more towards this population and, therefore, having the populations that "event" on both arms being relatively unbalanced?

[rancherho]

From the errata of the Advisory Committee Briefing Materials:
"Page 6, Section 1.2 Analysis plan, 1st paragraph, line 6: change the text “an O.Brien-Fleming adjusting” to be “the Haybittle-Peto method” according to the corrections the sponsor provided for their original submission."http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03b.htm

From what I remember reading, both of these approaches for allocating alpha are quite conservative. Since the alpha for the interim would have been set when the 9902b protocol was changed, a conservative allocation might have remained for the interim. This might have made the interim a real reach even if the number of events was relatively high (say 240 interim, 360 final), The real issue might then be a realization that given a small chance of making it on the interim, everything will ride on making it on the final.

This further suggests that rumors about the FDA accepting a p value of 0.05 at the interim were wishful thinking by DNDN and some analysts, obviously serving to support the market cap and ability to raise funds given the recurring optimism of so many biotech investors.

The other very real factor is the CEGE projection that its final look at the results of their 625 patient Vital 1 trial in asymptomatic AIPC is projected to occur in 2H09, and possibly the 600 patient Vital 2 trial in symptomatic AIPC as well. If either is successful, CEGE would probably still require an additional 6 months to prepare a BLA, which DNDN has already largely done with 9902b amendments to follow. The bottom line is that there could be real competition from the get go, although there would technically be nothing except possible reimbursement issues, to preclude a patient from usung both Provenge and GVAX if the FDA approves both. DNDN cannot, however, risk seeing CEGE's GVAX enter the market first, especially if they sign up a strong marketing partner. This could be a very prudent time for DNDN to also revisit the partnership issue. JMHO.

[ocyanblue]

Clark -

Rancherho pointed out a while back that DNDN used Haybittle-Peto for interim alpha allocation in D9901. That might remain the same for the original IMPACT SPA. In that case, regardless of how many interims or when, the interim alpha remains a constant at .01.

On the other hand, they could have changed the alpha spending function to O'Brien-Fleming. This is "a big assumption". But, if true, the effect of lowering the final trigger and raising the interim one at the same time is to increase the information fraction (interim/final). In turn, this would raise the nominal alpha for the interim look without affecting that of the final too much. For example, according to OBF, if the interim is 230 and the final is 304, then the interim alpha would be .02 while the final alpha remains at .044. Although the sum of the alphas is larger than .05, this does not violate the preservation of the family alpha since the two analysis share the same set of events in the interim.

If we focus only on the data, lowering the final trigger will hurt the final p value since the 56 events taken out are the longer lasting events. So this move would make sense only if they see a substantial benefit in making the interim better. The PR was vague but its use of the term "alpha spending function" instead "alpha value" would make the above scenario not too tenuous.

If, as you thought, that this was all about finance and the alpha spending function remains Haybittle-Peto or whatever not OBF, then all doors are open. Let's see what they say tomorrow before deciding what is what.