NorthWest Biotherapeutics Inc (NWBO)

[dennisdave]

To answer my own question I dont think NWBO is waiting for this guidance, nor should they, to come into effect officially at all for the reasons SOS previously already outlined in his blog of Jan 16 2020

https://smithonstocks.com/northwest-biotherapeutics-why-i-believe-there-is-a-high-probability-for-approval-of-dcvax-l-nwbo-buy-0-21/

Proposed New Guidelines Are Very Positive for DCVax-L

This report is focused on comparing the blinded results of the DCVax-L trial with the results from the phase 3 trial that led to the approval of Novocure’s medical device Optune in nGBM. However, it is important to juxtapose this with proposed guidelines from the FDA advising companies on what type of trial design and clinical data will now be acceptable to the FDA in considering regulatory approval. On December 19, 2019 the FDA released for comment proposed guidelines called Demonstrating the Substantial Evidence of Effectiveness for Human Drug and Biological Products. Here is the link.

Aggressive short sellers of NWBO have claimed that the FDA will not approve DCVax-L because of flaws in the trial design. They reference the general agency guideline that approval should be based on two well controlled phase 3 trials which compare a new drug to placebo or effective therapy. Because Northwest executed only one phase 3 trial, the shorts argue that NWBO will have to do a second confirmatory trial. This would be devastating. The new guidelines dismiss this argument. They state that in the case of life threatening diseases with unmet medical need like nGBM that the FDA will consider one well controlled trial as adequate for approval.

Actually, this is already how the FDA is currently operating. It has become common for the FDA to approve drugs on the basis of just one trial. Optune was approved on the basis of just one phase 3 trial. The CAR-T drugs Kymriah and Yescarta were approved for r/r DLBCL on the basis of open label, phase 2 trials that enrolled 115 and 112 patients respectively. Interestingly, the endpoint of these two trials was objective response rate (tumor shrinkage). At the time of approval, there was no meaningful data on survival. The phase 3 trial of DCVax-L initially enrolled 232 patients on DCVax-L plus SOC and very importantly, there is strong data on survival as the last patient was enrolled over four years ago. It is a much more meaningful data base than that which led to the approval of Kynmriah and Yescarta. The mOS of r/r DLBCL before the CAR-T drugs was about eight months and the mOS of nGBM with SOC is about 19 to 20 months. Both would seem to meet the FDA definition of life threatening, highly aggressive cancers. We can easily dismiss the short sellers’ contention that having only one phase 3 trial of DCVax-L is inadequate for approval.

The short sellers also argue that the FDA will not approve DCVax-L because it does not have a large enough SOC group against which to compare results for DCVax-L plus SOC. As previously discussed, the trial allowed patients who progressed on SOC to then receive DCVax-L. As a result, only about 30 patients in the trial received just SOC and never received DCVax-L. This compares to about 99 patients who initially received SOC. The short argument is that this small sample of SOC patients will result in a p value much higher than the p≤0.05 generally required for approval. However, the proposed guidelines state that in the case of a life threatening disease like nGBM, FDA will consider historical results from other trials. In this report, I have identified six trials in which 1,608 patients were given just SOC. The mOS in these patients fell in a tight range of 19 to 20 months. The proposed guidelines indicate that NWBO can statistically compare DCVax-L plus SOC results in the phase 3 trial to these historical results. This is huge.

Looking down the road, this new willingness to accept historical controls also augurs well for future trial of DCVax-L in other solid tumors. The FDA also says that if mechanism of action has been established as hopefully will be the case in nGBM, that it will take this into account as trials are done to expand the label into other indications; i.e. other solid tumors. This could result in the approval of DCVax-L for numerous other solid tumors on the basis of small phase 2 trials like those that led to the approval of Kymriah and Yescarta. This is equally huge.