The study had 3 unknowns: 1. Rate of surgical failure of TURBT 2. Efficacy of Apaziquone to treat surgical failure 3. Rate of spontaneous new cancers. Apaziquone could have been 100% successful in treatment of surgical failure with minimal side effects; but still failed. For example:the failure rate of TURBT might have been low; say 8% The efficacy of Apaziquone might have been perfect, 100%. The rate of spontaneous new cancers in 2 years might have been 20%. This would result in following numbers. Apaziquone group hour 1: 32 residual tumors. Day 1 after treatment: 0 residual tumors. 2 years: 80 cancers Apaziquone total:80 Control group 32 treatment failures + 80 spontaneous new cancers =112 80 vs 112 might have p >.05 Combined 2 studies: 160 vs 224 p<.05 So if can show that Apaziquone has excellent efficacy and minimal side effects; FDA might consider approval. On the other hand, Apaziquone might have failed due to poor efficay. Data shows that Apaziquone would have past if different study design. If end point was 21 months instead of 24 months, might have been statistically significant. If combined two studies would have been statistically significant. From reported results can't determine if Apaziquone is an excellent drug with excellent efficacy and minimal side effects or if Apaziquone is a very mediocre drug. What is 100% certain is that the study design was very poor. They should have done a study which measured only what Apaziquone was trying to do: treatment of failed TURBT; not a study with 3 moving parts. It also appears Raj didn't have a good idea of (a) percent of failure of TURBT and (c) spontaneous development of new cancers. My guess is the failure of phase III study was due to major blunder by Raj in the study design, rather than problems with Apaziquone.
Should have been multi-instillation, so the focus is on that study now? years away but Apaziquone is not dead, and maybe they can still find something worthy in this study, Raj said they should meet with the FDA in a few weeks on the CC.
Single instillation would have met SPA if combined 1600 patient study or shorter study. If study 1 year would have met SPA and probably 18 months, maybe 21 months. Many Urologists don't use Mitomycin C because they figure that the rate of surgical treatment failure is low and most of recurrent cancers due to spontaneous new cancers, not treatment failure. Looks like these Urologist who don't use Mitomycin C are correct. Big problem with study is surgical treatment failure rate is probably less than 10% for these low grade cancers. Therefore, not much for Apaziquone to work on and the big number for spontaneous new cancers obscured Apaziquone effect. Problem with literature, there was probably a lot of unsuccessful studies that people did not bother to report. Investigators sometimes only report the successful studies, not the ones that fail.
That is the major points of short sellers that small drug companies cut coners with PII trials and have poor PIII designs based on questionable PII results. There ae still more than 50% FDA may approve A on the combined results. Last and this years many small companies PIII failures sure prove they are right 99% right.