banter and General Discussion, page-4736

Yer right , as though you have no idea of the company or the trial that I was referring too despite holding shares in it . CYP cohort B shows a clinicl response at 3 days

Honestly, I didn't know. The details that had caught your attention about CYP, the 3 days, hadn't caught mine. This happens sometimes even when people do a lot of research (or think they do) they don't see things the same as other people. Which is why its good to exchange views. I notice pfeifer1982 who'd I'd regard as one of the more detailed readers of CYP also asked about this point. I liked the manner in which you answered his question and the manner in which he asked it of you.

.Now as I asked you yesterday and the day before.

You have a child that has a bad blood test. Data suggest about a 20% chance of survival . Decision is made for Remestemcell-L to be administered as the product has been deemed safe and the child has more than 3 times the chance of long term survival . I should see a response within 3 days and blood test will confirm that response at 7 days , that will confirm that my patient is very likely to survive long term.

Okay, I can understand your scenario better now that I understand where your "I should see a response within 3 days" is coming from. (Having read you reply to pfeifer) That was a complete mystery to me before. Because although I hold CYP, you'd seen something in a CYP related report I hadn't seen.

Would you not think to take action ,report and demand another batch of Remestemcell-L if a response was inadequate?

Putting myself in the hypothetical situation of the doctor and assuming I made the decision as the treating physician to administer remestemcel because I'd investigated and deemed it safe (an easy assumption to make) and that I believed I'd see a response within 3 days (an assumption I'm not completely comfortable with - but I'll play along) and that blood tests will conform that response at 7 days (I think serum levels data here is pretty good - so I'm pretty ok with assuming that), so I'll go along with holding a reasonable belief that my patient might very likely survive long term given the givens.

But if I've just found out one batch of remestemcel-l seems inadequate because my patient hasn't responded whether I report (to who would I report?) and demand (to who would I demand?) another batch of remestemcel might be something I'd do.

In the situation you've placed me time seems to be of the essence for my patient. Having, in the situation you've placed me some reason to doubt the batch of remestemcel I've administered why would I not doubt other batches as well? How can I know as a physician what went into what batch or how long it will take MSB to get me product from a lot that will better than what I just used? Isn't it likely that the other doses of remestemcel I'd have available to me where I'm working are from the same batch so wouldn't I have to do a lot of waiting and hoping and chasing through the company perhaps to try to get a better batch whilst all the while having to deal with people who'd be saying well nothing works in every patient maybe your patients is just one of the unlucky ones.

As that hypothetical physician I think I really don't want to have to go back to the manufacturer and try to get another dose I think I'm pretty much focused on my patient so I might be more inclined to try something else - perhaps something off label and having had one treatment from the manufacturer not work I'm not inclined to want to muck about with that manufacturer again if I can find alternatives. Would I think about going back to the manufacturer and asking for another batch. Maybe, in your scenario I had a lot of confidence in the product previously, so probably I'd follow up eventually in some form, but at the time my focus is on my patient and I don't think my patient has a lot of time to wait.

I've tried to answer your question. But I think you have more faith in remestemcel than I do. And more faith especially in seeing something at three days (based on what you read about CYP cells in cohort B that I hadn't read - which is a more homogeneous product - all from one donor) than I do. Please don't misunderstand I'm not saying CYP is better - if MSB can show good evidence that their product coming from different donors nonetheless is potent - I don't see that it matters for effectiveness. The potency test (once its established as being a true potency test) is the test of effectiveness.


Now we may not agree that MSCs provide rapid response or that our therapy even works.,

Noted.

it should not be a concern to the FDA as the Dr would be concerned if he had not observed a clinical response at day 3 and a blood test would be taken at day 7 to confirm ether a negative or a positive outcome.

The Dr taking a blood test at day 7 and getting good info from that I grant you.

The reasons for the FDA concern over potency assays have gone from been significant at time of the ODAC meeting to now a fairly minimal concern.

DO YOU AGREE?

No - but I'm not miles away from agreeing either - you constructed a good hypothetical. I think your post deserves its great analysis ticks more than most posts that get them in my opinion because you really are analyzing and inviting analysis.

But the FDA's concerns over potency assays which we both acknowledge were significant at the time of the ODAC meeting are in my opinion on the evidence I've seen still going to be a significant concern.

You are relying on the FDA accepting a lot of new evidence as being persuasive. For instance you are relying on the FDA giving a lot of credit to serum related biomarkers like Reg3alpha and ST2 and Magic Biomarker Scores. And although that hasn't happened yet and although I think that stuff is pretty persuasive myself its not something that can be completely banked on. The folk with the intellectual property to the Magic Biomarker Score stuff haven't registered their biomarker with the FDA so far as I know. They hadn't last I looked.

But I'd give a pretty high probability that the FDA will come down MSBs way (or really the MAGIC Biomarkers IP holders way) on serum biomarkers. Maybe 90 percent or better. Only because that's about how good I think the biomarker stuff is independently of anything to do with MSB or remestemcel. And that 90% isn't a calculation I can justify its just my personal intuitive sense.

But on the general area of potency assays as measured by potency tests I cannot give you or MSB credit for stuff I haven't seen demonstrated. I'm sure the FDA won't give you credit for stuff you don't demonstrate to them either.

Otherperspective's post might persuade me more when I process it further. That MSB's data can be better than I've been giving it credit for being. Because under the Protocol 275 Supplemental Tables (not in his post but in the original - which his post with its sourcing (yah for sourcing)) is a reference to "P values based on a Cochrane-Mantel-Haenszel (CMH) test" which I checked out. And that test is specifically about dealing with confounding variables in your data.

Dachopper's post on statistics is interesting to me because although he frustratingly doesn't show any working but shoves it all back on me to do he isn't actually wrong. When I actually did some work myself trying to work out the p value of 18/25 versus 13/27 (the 28 day comparison) I actually get a p-value that is significant (under 0.04) when MSB doesn't they get (0.08). So I'm not a stats expert but I think I'm impartial whereas I think MSB are not impartial but probably are better at stats then me and so I see them reporting their own result as not being significant (they would have loved to have been able to report significance but they don't) yet when I try to work out on their numbers I do see those numbers of theirs as being significant.