Replies to post #232390 on NorthWest Biotherapeutics Inc (NWBO)

[sukus]

Those whose tumors progressed in 2015 was in better condition as time passed. They were curious why and investigated what the root causes. It turned out the tumors were dying which confirmed the immunotherapy works but it just took time to develop to mount an attack and defense system inside the body.

FDA briefed by many doctors worldwide including scientists from BMY reviewed the data and understood what is going on. This lifted the hold. Imo..

[exwannabe]

and so the FDA forced the screening halt to ensure no one new (except those in the pipeline for which vaccines were already made) entered the trial, why then would the FDA lift the screening halt in Feb 2017?

They lifted the hold when NWBO changed the trial to no longer plan on enrolling patients.

How could the FDA not accept NWBO's decision on to resolve the issue when NWBO did exactly when the FDA had been forcing? And when NWBO responded with the enrollment termination, the FDA had by law to either lift the hold or explain why the Spinsor's response did not address the FDA concern.

[meirluc]

If what you suggest were the case, that an official IA took place in the summer of 2015, and as a result, the DMC gave an official recommendation that the trial be halted for futility, and the company refused to comply with the recommendation... and so the FDA forced the screening halt to ensure no one new (except those in the pipeline for which vaccines were already made) entered the trial, why then would the FDA lift the screening halt in Feb 2017?

Considering what was coming down the pipe after 8/15, the screening halt was a ridiculous mistake.

What was probably not known in 2015 was that this P3 is a tale of 2 trials, 2 mOS and most probably 2 mPFS.

And here is the evidence. The official mOs of the entire trial is 23.1 months and while I doubt that this 50% survival rate still stands, it can be used as a baseline to highlight the differences between the first 223 patients and the last 108. If considered separately, the mOS and 36 months survival figures of the two contingents is qualitatively different.

At 3/17 of the last 108 enrolled, 46 were dead, 40 survivors were on trial 18-24 months and 22 survivors were on trial 24-30 months. I estimate that because the survivors at 18-24 months outnumbered the survivors at 24-30 months by about 2:1, the combined average time on trial for the 62 survivors (40+22) was about 22 months.

First question: If 62 of the 108 are still alive at an average of 22 months, how long will it take for an additional 8 to event because with 8 additional patients eventing and 54 surviving that time will represent the mOS of the 108. We know that of the 62 alive at 22 months, 42 became post 36 months survivors and 20 did not make it. A loss of 20 patients between 22 and 36 months represents a total loss of 1.43 patients/month. If during that time 1.43 patients event each month, it would probably take about 5 months to lose 8 patients. Adding 5 to 22 months, gives us an estimated 27 months mOS for the last contingent of 108 patients. Since the first contingent of 223 patients has a little over double the number of the last contingent of 108, I estimate that the 223 patient contingent has an mOS of about 21 months. Between the two contingents, the average mOS would be about 23 months. As I understand it, the mOS is based on the first 50% (165) events. However, irregardless of the changes by the end of the trial, it seems to me that an mOS difference of 6 months (or there abouts) between the first contingent of 223 and the last 108 may be close to reality.

It is therefore not surprising that the contingent of 108 had 42 post 36 months survivors whereas the first 223 patients included only 49 such patients. If at 27 months 54 of the 108 were alive and 42 of the 54 reached 36 months alive, this is a loss of only 22% (12 of 62 patients) and over the 9 months period (27-36 months) represents a monthly loss of about 2.5%.

The earlier group of 223 patients had presumably 50%=111 patients alive at the estimated mOS of 21 months. This group lost 62 of the 111 patients over the 15 months (21-36 months) and ended up with only 49 post 36 months survivors. This is a loss of 55.9% of the 111 patients and over the 15 months (21-36 months) represents a monthly loss of 3.7%. This is much higher than the 2.5% monthly loss of the last 108.

THE TAKE AWAY:
1. From the get go the last 108 were the stars in this trial.
2. While I don't know the reason for this phenomenal improvement during the last 1/3 of the trial, I can't attribute it to pure chance (luck).
3. I don't see any valid reason for the hold and given the tremendous improvement after 8/15, if indeed a 2015 call for futility was a reality, it was totally unwarranted. JMO.

[AVII77]

If what you suggest were the case, that an official IA took place in the summer of 2015, and as a result, the DMC gave an official recommendation that the trial be halted for futility, and the company refused to comply with the recommendation... and so the FDA forced the screening halt to ensure no one new (except those in the pipeline for which vaccines were already made) entered the trial, why then would the FDA lift the screening halt in Feb 2017?

For the same reason the FDA lifted the partial hold on Cel-Sci after futility: because the sponsor agreed to not enroll additional patients.

Senti, how would you feel if someone you loved and was stricken by a deadly disease was told they could contribute to science by participating in a trial testing if Drug X improved PFS ...... after the trialists know they have a low liklihood of answering that question.

Don't you think that's a detail a patient considering participating in a trial should know?