My conversation this morning with Hodag regarding a post of JerryC this morning on iVillage:
Jerryc:
presentation slides?
See page 19 labeled "External Controls for nGBM"
I have a ton of experience in stats, but not medical stats, so I'd welcome other voices.
There are 5 comparator trials. There are a number of gaps in data, so a few items are clearly meaningless. Both IDH-1 and Res. Disease only have data from one other paper, so let's ignore those.
KPS score has data from 4 of 5 papers. nwbo's trial is 5% higher than the comparators. You would expect the nwbo patients to do better.
MGMT methylation data is present for all 5 comparators, with an average of 32%. nwbo data is 39%. Again, favorable for the nwbo population.
Tumor resection data is present for 4 of the 5 comparators. The 3 earlier trials are in the range of 54% to 59% complete resection. The one small recent paper shows 74%. Seems like a trend in improved surgical techniques, which correlates with favorable outcomes. Overall, the comparator group has 57% total resection versus 63% for nwbo.
All three of these data points are tilted in nwbo's favor, so this is far from apples to apples.
If this leaps out at me as a stats-competent non-medical person, I assume that any regulator would want to see an analysis to see how much is explained by those factors alone.
Hodag:
Jerry, you can't look at raw numbers and draw a conclusion. You need to look at the averages plus and minus their error ranges to see if they overlap. This is done for you on slide 31 where it shows the hazard ratios. Hazard ratios show the relative risk of being treated with Drug A or Drug B.
The way to read this chart is that if the length of the horizontal line overlaps the vertical dashed line (where the ratio is 1), then the measured benefit is within the range of likely error and, given the way the comparator group was cobbled together, if the horizontal line even comes close to the vertical, that factor will probably not be significant either. 5 of 6 measures cross or come very close to the vertical line, which means that those 5 measures have approximately the same risk between DCVax and the comparator group.
So, what are those results? Two factors (minimal residual disease and MGMT unmethylated) clearly intersect the vertical, meaning that the result is not significant with a 95% CI. Three more lines (Age >65, Age < 65, and MGMT methylated) are essentially intersecting the vertical with values of 0.99, 0.98, and 1.00, respectively). Those would be a hard sell to FDA in an approval setting absent a confirmatory trial.
The final factor, significant residual disease, shows a benefit for DCVax (midpoint estimate 0.65 with a range of 0.48-0.87, that is clearly different from 1.00). That benefit could be due to the immunomodulation provided by the vaccine, a better surgical debulking of the tumor, or a combination of the two.
In the final analysis, does DCVax provide an incremental benefit over the comparator group? Probably it does, but the benefit is marginal. Do these results present a case for having the drug approved as is? Probably not. Can this drug still be approved following a confirmatory trial or a combination trial? Plausibly yes, but that extends the approval date by at least 3-4 years and requires additional clinical work.
Note that while these results are not enough for FDA or EMA approval, but they may be helpful to marketing in countries (like Germany) where no marketing license is required for autologous therapies. Whether the marketing claims this data support are adequate to have an economically sustainable business is a different question.
Me:
You seem very knowledgeable but once again why cannot you see the forest for the trees. Yes you did see some one-off points (a few trees--the HR 0.99, 0.98, and 1.00 from the three charts you interested) but forget the forests (the general, clear separations of curves--overwhelmingly more representative HR 0.63, 0.78, 0.74 respectively).
Note: the reference here are data of those patients who were treated with the best of care or standard of care. Not because an one-off point which is within the calculating error or even it's true, the FDA would be too scared to do its job.
BTW, FDA would look at the whole picture besides HR and p-values which clearly show efficaciousness, but various other factors: some will come when the publication is released, some like "failed" PFS which in the eye of any un-biased, knowledgeable person and FDA is a clear sign of DCVax-L is working, and the other clear and beautiful separation of DCVax-L for rGBM compared with control with HR 0.58 and P-value <0.001.
One other "forest": Over the past 17 years there have not been any trials but DCVax-L trial which has showed significant improvement in patients OS in nGBM, and over the past 27 years there have been no any trials but DCVax-L trial which has showed significant improvement in patients OS in rGBM.
So you want to delay this vaccine to get approved, and add many more years to the unnecessary human suffering? Or you want a big pharm of your association or not to take over this company cheap?
Disclaimer: I am a long-term investor holding well over seven-figure of NWBO shares. Just on the day of presentation on 10May 2022, I added well over six-figure of shares, with first batch in the range of $1.2-$1.3, and the second larger batch in the range of $0.3-$0.4. Part of the purchase was funded by my selling of about 10% of my holding days before the presentation. I am once again top my holding.
Hodag:
Dan, I am looking at the forest and from the FDA's perspective there are a couple of giant redwoods standing between NWBO and approval. I have taken multiple products through regulatory processes in the US, Europe, and elsewhere, and I know what kind of things the agencies ask about and what statistical arguments they accept, and which draw all manner of skepticism. I have gone into more than one regulatory meeting with better stats than these and left those meetings battered, bruised, and bleeding. In particular, the level of scrutiny the regulators apply when applying for permission to conduct a trial is orders of magnitude less than what they do when a company applies for a full marketing authorization.
If you are so confident that NWBO has a slam-dunk approval decision waiting based on this data, then by all means invest your life savings. This is still a free country.
Me:
I love free country, and believe the collective wisdom (more) than any individual ones.
Look at what setting we are in. For nGBM, let alone rGBM a merely 2-month or 1.5-month of improvement in OS in the past had got drugs approved, which happened decade or if not decades ago.
It's simple do you believe DCVax-L is safe, does it demonstrate some officiousness for the indication concerned.
Guess, the first is a check, the second I say yes and of course you say no.
After all, it's RAs which will make the decision.
My investment is based on I do believe DCVax-L will get approved, at least in other countries if not in US, for at least nGBM or rGBM.
If that happens, a floodgate is open for other good things to follow.
thank you for your comments. Not intended to offend anyone else in this board, you are the only one I read when I come to this board from time to time.
