Replies to post #511968 on NorthWest Biotherapeutics Inc (NWBO)

[hoffmann6383]

LOL, first sentence is inconsistent with current science. Didn't read past that point.

[biosectinvestor]

They had no idea if PFS had failed. It was blinded. They chose to go with OS because they knew they would have virtually no placebo arm and it is difficult to argue with people surviving longer. That’s just an obvious thing.

They also knew there was a pseudoprogression issue early on, so it made sense to pick a more reliable and real measure rather than a proxy for survival. PFS is not a REAL measure. It is a PROXY for survival. Do you and the other shorts understand the word PROXY? It’s a hoped for alternative proximate measure for survival, but frequently it does not actually predict any increase in survival. The FDA’s primary goal for ALL of these trials is survival. PFS is acceptable on the ASSUMPTION that it is a proxy for survival in cases especially to accelerate trials, which could not be done in this case, for the above stated reasons.

However, where they have accelerated approvals they usually require a follow-up study. That is why they re-reviewed many of the PFS based approvals for immunotherapies just last year, and canceled some and allowed some to persist, despite their not extending survival. But the question that was most important to the FDA was whether those trials that were approved on an accelerated basis because they used PFS actually created a REAL benefit, which is extended or an increase in ongoing survival.

Try to understand their priorities.

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Perhaps the better word is Surrogate Endpoint. PFS is a surrogate endpoint in most trials for improvement in survival. I have posted before in another long post how PFS can actually mislead and in fact patients have no increased survival and the appearance of improvement can be, with immunotherapies particularly, illusory.

But here’s a quickly referenced paper that addresses some of the points I was making.

https://www.nature.com/articles/s41416-020-0805-y

“Abstract
Background
Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology. Validation of PFS as a surrogate must be done for each indication and each intervention. We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics.

Methods
We conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation).

Results
We identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy.

Conclusions
Although most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.”

See also, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690300/

OS is a real and firm and conference endpoint. Shorts like to pretend that you’d data dredge to get to OS numbers. This notion is bogus. You data dredge for surrogates and argue before you can prove survival, that these other surrogates suggest an OS benefit without running a trial as long as possible to prove survival actually is improved. Then you get approval and hope it sticks.

That is the opposite of what happened with DCVax-L. They ran the trial out to this lengthy degree to get actual survival data. Period. No data dredging is possible to price SURVIVAL. In this context you have actual beating hearts, as people say. Something most other studies can’t show because they were approved based on a surrogate for survival. That includes Optune.