NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

Fox,

Some of your posts were in reply to Hodge or others, but seemed reference to me, so I'll just mention them all briefly. I have decided to cap myself at 15 posts per day (and I'm sure to the relief of many on here lol, by becoming a basic member again), hence my late response.

You have missed the point. This change that you suggest, that is dropping the placebo, is a formal change that would have to be announced and it has not. Given the German agreement, there should be a change to the ongoing trial. Why have we not received information.

No one is dropping the placebo from this trial in any way. Otherwise I would agree. Part of the confusion here is with how the 2:1 is broken up by site. It is not an even distribution but entirely random. It would not be unethical for one of the US sites to be entirely placebo or treatment, for example. What matters is the overall total ratio being preserved at 2:1. Therefore, there has been no change in this due to HE in Germany, and thus no change to protocol, and thus no information on this disseminated to the public.

It makes no sense that Germans would continue in the trial with the placebo being dropped. That would mean that placebos would have to be made up in the US.

The simplest route is to drop the European contribution to the trial completely and expand to 310 the total in the US. To PY, I believe that this board had concluded forever that 70 would be enrolled from Europe. If that is part of the protocol for the PIII as part of the two continent strategy, then it a major change in protocol that will need to be announced. Why has it not?

Or the UK. Or other sites in preparation and about to open perhaps elsewhere in Europe (the 10-K makes this an open possibility). It seems you and others are assuming this is a massive number. Enrollment is estimated to complete by "late summer." We are most likely well over 200 enrolled now, and perhaps over 260 according to my tentative estimates (they do not stop enrolling while waiting for German and UK sites to open--remember, these sites are just as much about being in operation post approval as they are about enrolling in this trial). There may only need to be a further 60-100 patients left total, meaning 20-33 placebo patients. Given all of the sites, some let's say 10-20 coming from Germany on the treatment side post HE approval, there would still be a 1.5:1 ratio elsewhere. That is not unethical, especially given crossover protocol everywhere, and given there are no viable treatments out there.

Further, they cannot "drop the European contribution to the trial completely" as you say, for various reasons. They are seeking approval by the EMA. And also there are already a number of patients enrolled at King's College. What would you suggest they do with them? Throw the data away?

As far as 70 in Europe, again, there is no protocol change necessary when a company decides, for whatever reason, to increase enrollment at one location and decrease it (or drop it altogether if none have enrolled) at another location. All that matters is that 312 enroll.

That statement is not a way around a non-significant predesignated P value. The surrogate endpoint would have to hit significance.

Actually, yes it is. The verification of surrogate benefit is quite loose, and dependent upon multiple possible measurements. AA does not have to be based on statistically significant findings (p-value < 0.05), and often is not. You are speaking of full approval. That is the goal of a post approval (post AA) confirmatory trial. Often that is done in another indication altogether, as it still requires a placebo arm, and of course, who would register for a trial where the same treatment is already approved? There is one way around the need for a post-approval confirmatory trial, and that is through the quote longusa dug up. In effect, the interim look is used as the basis for approval, while the data that accumulates during the time it takes to assemble the information, submit it to FDA, and the time for FDA response, can be used AS that post-approval confirmatory trial. Currently that could be as many as 15-20 additional events worth of time (sorry to talk so crudely about human beings). Read the section on AA here in detail (you will see how loose the basis can be for approval), and also consider the Breakthrough Therapy section while thinking about DCVax Direct: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

There is another aspect. Different populations respond to treatments in different ways. So, it would be nuts to think FDA would allow a disproportion number of treated patients coming from one geographic region and more placebos from another. This point is really not worthy of discussion.

Oh, but fox, they already have (how many US sites vs European sites?). Besides you are forgetting we have two major regulatory bodies involved here. And the reach of the EMA actually exceeds that of the FDA. But no, there is no real basis for saying that certain geographic locations would affect treated patients any more than another.

You say that keeping the CEO out of the loop with discussions with FDA happens all the time. I need one example where a CEO has given a public talk and appeared clueless on this issue only later to reveal that personal at the company have been engaged in talks all along. Future Linda quote: "Gee I just did not know". Never in my life have I heard of such a situation. What a CEO would say is that I cannot comment on any potential or ongoing discussion with FDA--that you hear all the time. Even fire-walled, the CEO would know that the process is occurring.

Yes, it certainly does. CEOs and other staff that come in direct contact with patients, or must convey important information to the public, or must negotiate financing are certainly ALL kept blinded to the data and possible ongoing negotiations. Of course, not all can be, as the sponsor is often involved. Hence the need for firewalled employees. Now, of course, she knew this was all part of the trial design (as did we, if we read up on the Company enough). She knows what a delay like this most likely means. However, she maintains the stance that the DMC recommendation is "outstanding," which keeps her and the trial safe. If absolutely cornered, she would most likely say she too is waiting to hear a recommendation, and will inform the public as soon as the Company receives it. This balance is very important and necessary in these situations. Anything that can jeopardize the trial (and bringing a CEO into discussions and thereby the FDA minutes certainly could) should be avoided at all cost. I will put the onus on you: find for me an example in which the CEO of a bio tech company during a blinded trial was in talks with the FDA concerning AA, having been unblinded to trial data (obviously detailed discussions about the surrogate endpoint(s) seen in the trial would be had), while engaging the public at conferences and procuring financing deals.

Finally, I'm excited for where things are going. I believe we are coming to a head here, and that's the main point. Our investment is blooming, and patients are that much closer to finally receiving some sort of viable alternative to the impotent available treatments for GBM.