NorthWest Biotherapeutics Inc (NWBO)

[MI Dendream]

Diver, I agree generally with your sentiments, but your premise about the halt is not at all clear to me.

However, I think it's very clear to anyone who's followed NWBO and this trial and all the crazy things that have happened in the past 4 years that PFS and the idea of pseudoprogression from DCVax treatment (not from SOC) may have caused an issue.

Here are some of my issues with this idea of pseudo-progression wreaking havoc and leading to a halt. Given a fixed number of patients (say 330), then 1:1 randomization (165 per arm) is significantly more powerful than 2:1 (220 vs 110). Likewise 2.3:1(232 vs 99) is weaker than 2:1. Why would a company that is concerned about failure agree to weaken their trial? Why would FDA allow patients to risk experiencing an unknown adverse event from therapy if they felt current evidence suggested a lack of efficacy? Why would either cap enrollment below fully enrolled and thus also weaken power for OS endpoint if data was trending towards a negative outcome for PFS?

The company has stated that no efficacy peek occurred at that time. Generally, a futility analysis is performed on blinded data. There is a range within the measured outcome which informs the company that the study has likely failed, succeeded already, or should be continued. Often if the later is the case, companies will boost their chances by altering the protocol and adding more patients....hmmm.

Also, Early Access Programs are FDA approved and reserved for drug candidates where FDA/EMEA believe efficacy is highly likely or already proven. In my experience, these are only initiated prior to approval, but after NDA filing. Why would FDA allow at least 110 EAP patients if they questioned efficacy?...hmmm.

In my personal experience, outcome adjudication is performed by a panel of experts not otherwise involved in the trial. The adjudication process ran concurrently with the trial on an ongoing quarterly basis. At least 2 of the panel of 3 needed to agree to overrule the investigators decision. At the end of study, both the adjusted and unadjusted analysis were performed and submitted to FDA. Arguments over which data set more accurately reflect true outcome occurred during the label negotiations. In my area, this could go either way, trial by trial, and was sometimes inconsistent with prior drug studies in the same field.

Finally, the impact that pseudprogression would have, if adjustment leads to a huge difference in PFS outcome, on what is possibly a dual primary end point (OS), had already occurred If adjudication has not been performed in real time. Therefore, the possible benefit adjudication would provide to PFS is counterbalanced by a negative impact on OS. I just don’t believe the issue is that big of a problem.

An alternative explanation is that PFS was already positive and could be discerned originally on blinded dat (for example 110 events divided nearly evenly between to arms despit a 2:1 randomization). In this case, if a company were to choose to continue the trial towards another endpoint, FDA would insist on silence to preserve the blind amongst investigators and subjects.

MI Dendream