What are some of your thoughts in regards to finalizing the SAP's?
I imagine they are already finalized, since usually you need to have a good idea of your statistical analysis before you start. Things can change, but hopefully they have a good team that can get this done in a timely manner.
Do you feel enough time has gone by that NWBO may have already submitted these to the 4 Regulatory Agencies?
Probably, but I don't have a crystal ball.
Do you think that NWBO may have already received revised SAP approval from any/all 4 RAs?
(see above)
What main revisions do you believe NWBO might be incorporating in these revised SAPs?
How to deal with pseudoprogression appropriately. (see below)
How to statistically interpret PFS events & pseudoprogression?
They would have to have a solid definition of pseudoprogression that can be confirmed as true pseudoprogression (which is hard to do and can be subjective). Up to 50% of patients may show signs of this after RT+TMZ. This is also influenced by MGMT methylation status. Tests like fMRI can be helpful if there is a question. Ultimately, there are physicians all across the study making independent judgements on if a patient truly progressed or not. This can be a form of bias in the study (and in reality cannot be controlled for unless they have a good definition to follow). Most likely those that were officially determined to have pseudoprogressed would have to be excluded from PFS as an "event", since it's not real progression.
Surgery with/without dyes (5 ALA)?
White blood cells counts?
Other factors?
I don't know much about surgery or anything about dyes, so I won't comment on that. I know TMZ can affect blood counts since it is an alkylating agent, but I'm not sure how this would confound results (unless it is somehow affecting DCVax's ability to mount an immune response). Other factors would be any potential confounder that was not accounted for. This could even be just better treatment delivery over the past 10 years (better surgeries, better radiation delivery, better TMZ management) that has just allowed standard of care to work better. Time is a huge issue in long cohort studies as medicine gets better. This could be controlled for in the statistical analysis by having something like "year of surgery " as a surrogate in multivariate analysis. They also need to make sure participants are stratified by something like modified RPA (recursive partitioning analysis, which is basically a performance status for gliomas and glioblastomas are III-VI). If a patient is already a poor performer, they need to be analyzed as a separate group.
What is your current expected timeframe for topline/data lock? From the PR it appears this will not be announced at ASCO ... are you thinking perhaps within weeks, or perhaps towards year-end?
I have no idea. I can only go by what little information they give. Anything else is just reading tea leaves.
Statistics: which of the trial results do you believe might have improved compared to their most recent blinded results disclosed?
I'm hoping to see survival improvement. This is one of those disease sites where we hang on improvements in survival by weeks. The first thing I thought when I saw Linda Liau's presentation was "how is this possible?" Even unblinded the survival is striking. The fact that it is a cross-over trial makes me suspect that it has to do with the interventional treatment (but if the big fat confounder is better standard of care delivery over the past 10 years or so, we have a problem).
Do you think that Primary Endpoint (PFS) might still come through OK? Or that the long tail of OS will need to "save the day/trial"?
It still could be fine, but good statistical analysis to control for any measurable confounders (pseudoprogression) would be really needed. "Statistical hand waving" as one of my attendings in residency once said. The long tail could be important, but I have no way of telling at this point. If we unblind and everyone did well no matter the intervention, the long tail does not matter.
Once unblinded, where do you figure the OS results might wind up for:
Treatment Group (early DCVax)? No idea, but I'm really excited to find out.
Placebo Group (no DCVax versus Late DCVax)? Where standard of care has been in the past (Class III 4 yr OS ~28% and MS ~21 months).
Or they could be nearly the same! And that's sad...
Assuming approval of DCVax-L, which country/RA do you believe might grant approval first?
I'm not an expert in international health policy or geopolitics, so you guess is as good as mine.
Research is a lot of blood, sweat, tears and hope. Many times it doesn't work out and it's heartbreaking. That's all a part of the scientific process of making us better understand the world we live in. Yes, making some money would be nice. But adding even a few months of survival to this disease would be life changing for anyone who is facing this diagnosis.
