NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Administrative Process as it Relates to "Long Tail" Development.

(I titled this post and edited it due to "sticky" status. Please use this version.)

Each site will likely freeze for a short time while that site's trial review entity approves and implements the trial changes, as NW noted in the PR: LongUSA

The trial enhancements will also have to go through Institutional Review Board (IRB) review and approval at each of the clinical trial sites. There are currently over 50 trial sites in operation in the US and a number of sites in operation in the UK and Germany. There will also be certain other requirements for implementation of the changes, modified documentation and procedures. NWBO PR

Here is a very basic reason I surmise the administrative pause noted above will result in further beneficial trial maturation followed by a shift to fast enrollment in Germany.

Recall the original 33 patient group. Their long tail certainly had time to mature in the treatment arm. Look at the next 207 patients enrolled between March 2011 and March 2014. If you think about those 207 patients as a group, like you thought about the first 33, the 207 group gets time to mature on its own while the administrative freeze takes place. (The group of 33 had a very long time to mature due to the 2008 recession.)

So look at the patient groups again.

33 Group -- Long tail maturity assured by first interim analysis at 148 events (caveat is what random patient subgroups fell in to this group). This is due to very long maturation time.

207 Group -- Confidence in Long Tail effect moderate to high. This is due to moderately long maturation time.

108 enrolled from about January 2015 to August 2015. Long tail effect in this group almost nonexistent by first interim analysis. This is due to short maturation time. However, enlargement of the overall trial to 348 eventually reduces the chance of any subgroup artificially impairing the trial by random chance.

IMHO, here is what I speculate is a very likely scenario.

We hit 66 events in December 2013. We will likely hit 110 about New Years 2015. At this point, events from the group of 240 enrollees will start to slow due to the long tail effect, plus the pool of people who have not evented becomes smaller. The European clinics (and administrative steps) will be ready at this point, and the final push for approximately 108 more patients will happen very quickly. (I can't remember which article I read it in, and I have not been able to locate it again, but the author stated once German enrollment begins, it should outpace prior U.S. rates.)

Over the course of enrollment of 108 patients, this last group will supply several more events, for the first interim analysis, on the short side of median from the placebo group. There will also be a handful (but just a handful) of non-responders from the treatment group also on the short side of median. Those events, plus a few more from the relatively mature 207 group, will likely bump us up to 148 events by June 2015. (Pyrr's ongoing work was taken into consideration here).

NWBO does not immediately announce the event threshold was met. The DMC conducts a 60-90 day review and recommends an early halt. NWBO takes long enough to consider the halt that Europe completes enrollment by Halloween 2015. The halt is announced approximately November 1, 2015. (The completion of enrollment prior to halt is likely very important for statistical reasons as well as post-trial confirmation purposes for the FDA.)

(If the halt is not recommended at the 1st interim event, than the final group of 108 will need time to mature as well, because the likelihood would be that the first 240 had a disproportionate number of people whose white blood cell count (CD4) was severely and possibly irrevocably damaged by radiation. If this was the case, the additional 108 patients will need time to mature and contribute their long tail effect. By that time, the number enrolled is extremely likely to prevent any random chance that too high of a percentage of the subgroup will artificially interfere with the trial.)

Meanwhile, the psPD group data added to the expanded access protocol (unblinded), plus all the other excluded subgroup results should be released from time to time. Also, we will likely receive data results from the UCLA alternative L phase 2 trial by the end of this year. Recently Dr. Liau's assistant, under supervision from Dr. Liau, conducted a phase 2 study on Direct, and while I assume it was very small, I expect to hear more about the already encouraging conclusions. http://sttp.healthsciences.ucla.edu/abstract/sttp-abstract-current?abstract_id=2455

This scenario is simply my humble opinion. Obviously it is an approximation.