Replies to post #141005 on Biotech Values

[biomaven0]

FDA shenanigans - Abiraterone

I'm not understanding what you are getting at here. Why is it strange for the FDA to ask for an updated interim analysis?

Peter

[DewDiligence]

Two comments on JNJ’s Zytiga trial you posted about:

1. The interim OS analysis was evidently dispositive in JNJ’s opinion insofar as the PR on the interim analysis (from Oct 2010) stated categorically that JNJ intended to submit marketing applications for Zytiga in all major jurisdictions.

2. The FDA may have been more willing than usual to bar crossovers within the confines of the phase-3 trial because JNJ was on the verge of opening an expanded access program for Zytiga.

[hirogen]

I'll add some dates to your timeline from the FDA medical review document.
8/20/10 DMC recommends study unblinding - "The protocol pre-specified interim analysis showed an overall survival benefit with abiraterone. The IDMC recommended unblinding of the study and crossing over of patients initially assigned on placebo. FDA
concurred with the proposals."
8/26/10 Amendment 3 to SPA to allow unblinding and allow placebo to crossover
9/09/10 JNJ issues PR on study unblinding and allowing placebo crossover
9/20/10 Data cut off for final analysis

That the FDA requested updated survival data doesn't seem so troubling to me given that trigger occurred at 67% info fraction and median follow up was only 12.8 months at the interim cutoff. I think the question here is what took the DMC so long to analyze and make the recommendation from the Jan interim trigger. My suspicion is that the "I"DMC was not so independent from JNJ. Delaying the time to crossover also gave JNJ valuable data on when Zytiga's effect would dissipate - and the p value decimal place did move a couple of places to the right despite the higher number of events. Hence, imo JNJ's decision to allow crossover of 302 after the interim despite OS not being stat sig (which apparently the FDA does not have a problem allowing crossover and did not have a problem with in 301 upon notification).

p.s. I also will note that 301 used standard OBF with standard boundaries ;-)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf

http://www.investor.jnj.com/releaseDetail.cfm?releaseid=506329

[biomaven0]

a) Jan 2010 (see dates in FDA Statistical Review): Pre-planned interim occurs for OS - Zytiga is VERY stat sig (<0.0001 when alpha was 0.0141).

b) Sept 2010: Final OS analysis for OS (kinda immaterial - but very stat sig)

c) Oct 2010: First J&J PR that they hit the interim (and thus x-over is allowed - but note PR is silent on the fact that they hit that interim 9 months ago).

By my reading the interim analysis did not occur in Jan 2010, but only in August 2010. I don't know why the delay between the cut-off date and the interim analysis date, but it's not something you can blame the FDA for. Given the long lag, an updated OS analysis before crossover seems quite reasonable - no reason to throw away potentially very informative data.

Study COU-AA-301 had a pre-planned interim superiority analysis of OS after occurrence of 534 deaths (67% information) with the O’Brien-Fleming type I error spending function for alpha adjustment (alpha for the interim analysis = 0.0124; alpha for the final analysis = 0.0462).
The IDMC reviewed the OS interim analysis of 552 deaths in August 2010. The nominal significance level for the interim analysis with 552 deaths was 0.0141 (two-sided) using the O’Brien-Fleming spending function. Given an observed p-value of <0.0001, the IDMC concluded that the prespecified efficacy boundary had been crossed and there was a significant OS improvement in favor of abiraterone acetate treatment. The IDMC recommended that the blinded portion of the study be terminated. The study COU-AA-301 was then amended (Amendment #3) to allow subjects in the placebo group to receive abiraterone acetate treatment.