Doc:
FWIW, here is my opinion. NWBO has a legitimate concern on P-value particularly as it pertains to separation between the cross-over/placebo and Tx arms OS. The bottom line is that even those with late vaccinations have received some benefit despite the fact that very few second resections were done. This is particularly noteworthy and when coupled with the extremely flexible FDA guidelines might permit approval for recurrent GBM as well which is a large market in and of itself. If approved just for nGBM, the vaccine can still be prescribed by physicians off label. Hence if the data shows that cross over patients benefitted even by later vaccination, this would instil confidence in physicians in prescribing for rGBM. This view is supported by LL that "it seems everyone is living longer" and by Dr. Ashkan's plea that the vaccine should be "available to all patients".
It should be noted that the FDA did NOT require NWBO to have a cross-over arm. It was NWBO that included the cross-over arm in its trial protocol. NWBO discussed this with the FDA and told them that it would be more difficult to recruit patients in the trial absent a cross-over capability. The FDA agreed with this and agreed that NWBO have this cross-over function in the trial.
Although the trial has yet to be unblinded, out of an abundance of caution, NWBO wanted the FDA to take note that even IF an overall trial failed to achieve the specified end points, but certain significant and identified sub-groups did demonstrate efficacy and positive safety characteristics, then as to such sub-groups there should not be a requirement to restart another trial but have a conditional approval predicated upon a "phase IV" protocol. NWBO has significant sub-groups that may cover 50% or more of the nGBM spectrum: these are M+ and MES. With respect to M+MES, the vaccine is particularly efficacious due to two pathways--methylation which interferes with the cellular repair mechanism and immunogenicity which involves a greater threshold of T-cells upon which to build and a less immunosuppressive micro-tumour environment allowing more time for T cell infiltration and destruction. With respect to un-methylated MES, it is still very immunogenic and while more aggressive than its methylated counterpart, the vaccine is also significantly efficacious as was hinted at in the JTM article where the overall blended delta for M- was about 7 months. This would include M-MES and other un-methylated molecular sub-groups with much less efficacy masking the rather dramatic efficacy upon un-methylated MES which is the most aggressive of all molecular sub-groups and where the Tx arm could be significantly longer.
There have been extensive discussions with the FDA on all this. The FDA did provide comments with respect to NWBO's SAP. P values and sub-group issues are not de novo issues raised for the first time by NWBO, or for that matter, anyone else. These are important issues and NWBO felt that, although the FDA was well aware and even in agreement, it was important to go "public" with these recommendations and have some specific rather than just overall generic flexibility in the guidelines. The role of p-values and sub-groups and their applications should be important considerations in flexibly considering therapeutic approvals.
NWBO deals with these foregoing issues rather extensively in its SAP upon which the FDA has provided its comments.
NWBO is pioneering trial and regulatory policy with respect to immunological trials The old evaluative criteria more appropriate for surgery, radiation and chemo need to give way to much more up to date evaluative criteria. The FDA guidelines and, indeed, relatively recent approvals demonstrate a paradigm shift in the way that regulatory agencies view novel therapies and should go about evaluating and approving them. NWBO's trial will be a treasure trove of data and the most extensive of any GBM trial.
Accordingly, when viewed in this light, the letter does not imply desperation and trial failure. Rather, it represents a reasoned approach to recognising novel therapies which could revolutionise the way medicine is practiced. And....the letter echoes what the regulatory agencies have already begun to recognise.
I believe the letter is a harbinger of things to come. NWBO has broken its silence with respect to the FDA. And it has done so through the opportunity to publicly submit comments to the FDA guidelines. JMHO.
