NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

It's been awhile, but I wanted to review this video more closely. It's very interesting to listen to, and I think his discussion about Project Orbis is especially relevant, as you pointed out, seeing as hopefully sometime in the coming months, Northwest will submit their applications to the various regulatory agencies, and that pathway may prove a means to help speed things up.

Anyhow, regarding Rick Pazdur's speech as it pertained to the randomized trials and cross-overs, it certainly does sound as if he's describing the DCVax-L trial exactly as it was designed. In fact, it's uncanny how closely his description mirrors our trial, but I suppose there are probably other many other trials out there that offered the cross over option as well, although I'm not sure there are very many in oncology.

In the 1980s, after the discussions with the Oncology Advisory Committee, or ODAC, FDA determined that the approval of drugs should be based on improvements in overall survival due to the perception that most oncology drugs at that time had marginal to modest activity with very marked toxicity.

Let’s jump to the new millennium. With the advent of targeted therapies, it became apparent that a reevaluation of the dogma that overall survival was the only acceptable endpoint, that needed simply to be reevaluated.

First, for drugs demonstrating unprecedented response rates in early clinical trials in cancer with few therapeutic options for patients, the ability to randomize patients to either a drug with a markedly improved durable response rate versus a toxic marginally effective drug simply was not feasible… and was of questionable value to either society or scientifically. *Equipoise, a concept in randomization that is inherent in this concept of randomization simply did not exist in many situations.

If a randomized study is conducted in these situations, investigators and patients request a cross over to the investigational drug at the time of progression in those drugs that demonstrated early and forensic (?) activity.

So this request for cross over at the time of disease progression probably represents that true equipoise did not exist in the randomization process. This cross over may confound the demonstration of an improvement in overall survival because patients are basically receiving in both arms the same therapy, albeit, in different sequences.

A demonstration of overall survival may also not be practical in cancers with long, natural histories, due to our advances, or simply due to the long natural history of the disease.

*Equipoise: Clinical equipoise is the assumption that there is not one 'better' intervention present (for either the control or experimental group) during the design of a randomized controlled trial (RCT). A true state of equipoise exists when one has no good basis for a choice between two or more care options.

Clinical equipoise allows investigators to continue a trial until they have enough statistical evidence to convince other experts of the validity of their results, without a loss of ethical integrity on the part of the investigators.