@Zenox, I think it's a reasonable question and I'll give my humble opinion. We're operating with limited information as to the contents of the last CRL, but the fact that the Type A meeting is to discuss adults, not children, is a strong indicator the FDA wants an RCT. As we discussed above, in orphan indications that FDA may wave the requirement for two large phase 3 RCT's if a medication shows "extraordinary statistical significance" even in an open-label study. Looking at slide 13 from the February presentation, the Company reported p-values of .01 for both ORR and OS when patients with a MAP score above 0.29 are treated open-label with rem-L and compared to MAGIC controls. That's certainly in the range of "extraordinary" but... the number of treated rem-L patients in that category was only 11 (OS) or 12 (ORR) . By my calculation the mortality p-value is .011. With Yates correction (which I believe FDA uses) it's .038, which is well above .01. The solution would be to treat more patients... open-label and get the same rates of response/survival. That's apparently not what the meeting is about. FDA wants RCT data, perhaps because of confounding variables that you mention... I believe there are many... starting with the medications these patients receive.
Except for the lucky few with an identical twin or stored cord blood, these patients are receiving allogenic transplants that don't exactly match... so that's one important variable right there - the amount of mismatch plus the prophylactic immune-suppressant anti-rejection regimen they receive prior to the transplant. Both of those factors might influence the course of subsequent GvHD and response to treatment. If acute GvHD develops, IV steroids are given... on top of the prophylaxis regimen. Other immune modifying medications may also be given during primary therapy, another variable. If patients don't respond to steroids they are deemed to have "steroid resistant" aGvHD at which point a variety of medications and treatments may be tried off-label. The list of immune-modifying medications for these patients is surprisingly long: Anti-thymocyte globulin, methotrexate, even higher doses of steroids, tacrolimus, mycophenolate mofetil, daclizumab (now off US market), anti-IL2R, cyclosporine, sirolimus, infliximab, etanercept, Psoralen-UVA radiation, Extra-Corporeal Photophoresis, muromomab-CD3, humanized anti-Tac Antibody, ABX-CBL IgM mAb, Visilizumab, Pentostatin and of course ruxolitinib, which is the only one on the list specifically FDA-approved for steroid-resistant cases. This may be why some studies refer to "Best Available Therapy" rather than "Standard of Care". SoC is poorly defined in this illness.
So, yes, even though mortality rates may be high... the treatment of patients is complex, heterogeneous and evolving... hopefully improving. Using historical controls it may be a challenge to find a comparable group for for comparison. I suspect in that setting the FDA is requesting RCT data and that's why the company is moving to adults. Other opinions welcome.
Someone asked why I invested in this... well, I was swayed by the MAP data though I regret not having analyzed it more thoroughly. Slide 13 is a bit misleading. The p-value applies to a study of only 11 or 12 patients with high scores who received rem-L,. And another conclusion one may draw from the slide is that mortality persists and rem-L has no apparent benefit when the MAP score is below 0.29... a factor the company should have pointed to, imo. I was swayed by ongoing sales in Japan, the manufacturing inspection, the testimonies at ODAC, and... the proposition of the CEO that the right way to proceed was via the "well-established" dispute resolution pathway he had chosen. I also felt the climate at the FDA could not be better with Marks-Califf and the Kurtzburg-Duke connections. The fact that dispute resolution did not succeed in Mesoblast's favor, and that SI is now switching to adults, suggests the FDA bureaucrats must have a pretty good case when the say more (controlled) data are needed. Even sympathetic upper echelons of the Agency sided with them. It's now evident that childhood SR-aGvHD should never have been advanced as a first or lead indication for rem-L... and the first CRL should never have been disputed. Major mistakes.
@DV, It's going to take more than your raving to change my mind. Meanwhile, let's play fair. Just because I say I don't know something on a fine point of analysis because it hasn't been tested in an experiment, doesn't mean I'm "wrong". In fact you don't know either because no one knows. Your debate tactics are below even your tiny online stature.
Wishing everyone a pleasant weekend in the land down under. Left-e
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