I think the team on this board has teased this out really well and I believe has hit upon the highly probable cause of the highly probable open issue. Please think about this:
- if enrollment is complete or very close, which I think has been deemed probable
- if FDA has required the crossover (most likely assuming a fairly robust primary metric measurement of PFS)
- phase 3 is intended to be a confirmatory phase but since the field of cancer is so complex and the biologic underpinning knowledge is constantly evolving, and, since the trials consume such long periods of time that there are new learnings in most cancer trials, all for the advancement of the field
- if the results are appearing to be significantly positive (most difficult patients in parallel study showing 40% at 36 mos OS vs SOC of 25% at 24 mos, though open label)
The new, more proactive FDA in this field has some latitude. We know there needs to be a primary metric that can be used to measure success since the FDA has many competing companies to service and has to be careful to be objective and science based in decision making. This is critical to their mission, though se secondary to patient safety, which is a long way to being proven a non-issue with DCVax, which makes the analysis so much simpler for them. In this case the backup of immune response would serve well if PFS is convoluted, given current msmt tools for GBM and new learning about the course of the therapy (meaning short term tumor inflammation during resolution). And, the FDA can incorporate clinical investigators' inputs, which presumably will be quite positive in this study, as clinical evidence to support the apparent results. And, the FDA can have the data un-blinded for their eyes only and not the company's. This will show them limited insights into the results to date, but, another r piece of the picture.
I do not see any way the FDA would want to wait for OS, given what they must be piecing together. The problem is that every step of the analysis takes more time to collect, analyze, report and discuss, and, across multiple regulatory bodies. This is a major undertaking for a tiny company. But, they cannot partner until they have the leverage of the first major breakthrough, which they must attain on their own.
And, the FDA will not require another trial if safety is proven and if the results are apparently very positive. So, it is up to the scientists and the limits of the current tools. But, FDA must have an objective metric to use. If PFS is clouded in the short term (short term is the reason to use PFS), immune response, supported by clinical testimony and a partial statistical data package from the study (today's more accepted statistical tools are more powerful, though again they take more time), should provide what is needed for at least conditional approval (AA). The secondary endpt of OS will statistically strengthen with every successful month of each initially actively treated patient experiencing extended life vs SOC (not the control, which is an ethically correct FDA imposed msmt challenge). Worst case is there is a need for more time to allow the trial to generate more data, utilizing more OS data in particular, but, the agency would not want the trial to extend beyond its current natural life, knowing what they are most likely now believing. And, if at all possible, they will not want the trial to have to continue to its natural life, which will consume another year, but, they do have limitations. I feel very good about where this is and what it can do, and, hope for everyone's sake from patients to investors to owners to the regulatory bodies, that the supporting scientists and clinical investigators can rally sufficient data and information to give the FDA the support they need to progress this asap to market. Who on this board would not want to be in LP's shoes, working to objectively prove, within the constraints of our clinical system, what has been evolving beneath her nose. I believe she and her small staff is frustrated but more-so is confident and feeling good about what they will bring to patients shortly, we just have to wait unfortunately. I lost a neighbor and friend to GBM a few years ago, and his path was just under 24 mos from diagnosis to passing, and, his QOL was very difficult. This therapy will hopefully change that for many to come.
