"they said comeback with a placebo trial. It. Provide it works compared to placebo"
"what's more msb knew this and decided they knew better. And surprise surprise....."
"sorry do you have unequivocal proof that FDA said yes to single arm?"
Above are comments from the poster @tubbyguts and below is my take:
I've found sometimes it makes more sense if you turn the whole thing on its head. Perhaps this situation has arisen because Ryoncil works so well and doctors know it. They've been using it in the EAP for a decade. Cause and effect are easiest to see in severe acute inflammation of the gut. Unlike chronic GI inflammation which waxes and wanes, acute is a constant. Inflammation begets more inflammation. Spontaneous remissions do not occur. A stimulated response is therefore obvious.
You can see this even in EEN. It kicks in within 24 hours. Pain is gone. Inflammatory markers come right down, within a certain time-frame. EEN is usually delivered via naso-gastric tube (Seattle CH is now experimenting with mixing up their own smoothies) so it would be a challenge to run a RCT against a placebo, but considering its safety profile, this therapy is recommended first-line in pediatric CD now in Europe and becoming more popular in the US. It delivers superior mucosal healing to steroids (visual evidence of consistently superior results.) It's a very difficult therapy to do and there's a high relapse rate once stopped, but my point is that everyone knows it works (not so much how.) Would the FDA view this as just a whole lot of anecdotes?
In ICU there are biomarkers predicting non survival; everything is weighed, measured, monitored around the clock. I listened to the KOLs and I liked the sound of them. I didn't need to be told Dr Prockop was a KOL. I could tell that because she had to make it very clear that even mild GvHD wasn't beneficial to patients with non malignant conditions. Based on experience of rux in three patients they wouldn't be participating a clinical trial. Look how on the mark that was. That was before Reach2 results were published. I don't know specifics, so I'm just going on what I know of doctors in acute medicine in general, but do you think it might be difficult to get them to give a placebo against a safe therapy they know works, maybe already using in adults, in a condition with such a high death rate for SR? Why must it be that MSB is being tricksy?
I once asked a transplant doctor how doctors could know if it was the MSCs that worked. Could it be an effect from a drug given earlier which might have kicked in? My suggestion was politely but unequivocally rejected out of hand. The rule in aGvHD is that when a patient is not responding adequately to a therapy, whatever you add the subsequent effect (ie. recovery) is attributed to that. Also if I recall right, during the conference call on the p3 trial, Dr Skerrett said the children weren't given anything else because investigators had to know it was the cells.
There's strong evidence that the FDA did say yes to a single-arm trial. That evidence is approval of ruxolitinib for the same indication. Please can you explain to me how the FDA, with its supposed exacting standards, approved a tablet when the greatest challenge in aGvHD comes from uncontrollable diarrhea? I believe the FDA did change its mind about Ryoncil because I saw the set up, the narrative constructed that rux approval was good news for us because of the similar design of trials.
What happened to data from EAP and Temcell being allowed to support our application? Did the FDA change its mind on this too? An article was posted here early last year that said the FDA would be going more on RCTs than real-world data. That was a big red flag to me that they were intending to move the goal posts. I was so sure of this I ripped into them accusing them of having blood on their hands. I actually felt a bit ashamed after ODAC vote.
My background is in languages and I've long been interested in how we're trained to think in a superficial way. I see it in medical journals too. It's all about association, the one case that informs them all. Does it then go something like this...?
The FDA wanting to go more on RCTs is understandable in light of Reach2 in rux showing no difference in survival, which now calls into question the claim of outstanding results in real world study of rux in severe gut and skin, a bizarre and perplexing study, that imo couldn't have impressed any doctor familiar with GvHD.
Does Ryoncil and similar product Temcell years of real-world data count for nothing now? What about data from patients treated with MSCs for acute GvHD maybe not going on to develop chronic GvHD? Chronic GvHD of skin and lung is a huge problem and great cost burden. There's been denial of lung GvHD but it's very common and I note Bronchiolitis Obliterans starting to be mentioned in studies in GvHD in just the last year or so.
Severe acute GvHD is a condition in its own right, with its own unique challenges, and the argument that rux is already approved for other conditions is totally irrelevant. The FACT is that a drug with well known adverse effects was approved and a safe agent was not approved on the same basis.
IF MSB knew, as you confidently assert, the requirement of the FDA for a RCT, but decided they knew better then perhaps they were thinking the FDA wouldn't insist on an unprecedented and awful thing in a therapy targeting grades C/D, with an extraordinarily high death rate for SR GI and lower GI survival can be as low as 5%. A condition where doctors know the importance of the window in which to act. If there's been a precedent of RCTs in acute GvHD, why would editorial say Reach2 was "finally" a successful RCT in GvHD?
MSB has agreed agreed to run a RCT in adults. When a RCT in high-risk adults against RUX was first proposed, I just couldn't see how it would be ethical to give anyone this drug in a condition with an extraordinarily high death rate, especially in the light of Reach2 results.
Maybe the trial will be against steroids? Even that imo could be psychologically difficult for doctors if they know how well Ryoncil works and knowing the fact of the poor job steroids do in GI GvHD. Reach2 had a crossover, which is not advised, but Zeiser et al say investigators wouldn't have agreed otherwise. And this is for a drug with well known bad side effects. Our cells respond to signals of peak inflammation. Even if you have a crossover, you've already reduced the patient's chance of responding to the cells.
As the situation is NOW, a requirement for a RCT prior to approval for children would be the most disingenuous and heinous thing I ever heard but post approval, perhaps this will be the catalyst to get our cells ahead of an inadequate therapy. Steroids are harmful to MSCs.
I was hoping ARDS trial would spare GvHD patients from a RCT with a placebo but then the WHO and their steroids screwed over our trial. Even so, I hope there's enough data from the first half of the trial to put to rest the phoney 'batch inconsistency' narrative.
A RCT that meets a primary endpoint is the gold standard, the proof the FDA requires that a therapy works. How's that working in the real world? I guess the answer to that would have to be: It depends what you mean by 'works'. I'm researching for a piece on this and finding so much criticism in journals that RCTs have become an academic exercise that has little bearing on the real world. There's great distortion of results amplified in literature discussing the trials.
According to the editorial in the NEJ, Reach2 is "finally a successful RCT in GvHD". It met its primary endpoint of overall response at 28 days. Author says:
"Some data was apparently not greater with ruxolitinib than with the control therapy”
The not so great data was there was no difference in overall survival!
Reach2 met its primary endpoint so it can still be given to patients who are in ICU passing litres of diarrhea. I know this is happening right now from social media in at least one patient. This drug can still be given to patients with grades C/D GI GvHD and also very young children, even though the dose hasn't been established. I've come across recent studies in rux in very young children.
Every so often we get a litany of depressing MSB failures posted here, which is on first reading overwhelming. It almost seems a miracle that MSB has managed to keep trundling along, but when you look into it and think about it, the failures can all be attributed to one or two simple things. Take the LVAD trial, for example, that critics here were saying didn't bode well for CHF results. The failed primary endpoint (which MSB didn't choose) was mainly because of cohort being younger patients and faulty LVAD devices, patients becoming too frightened to turn them off. As for other 'failed' trials, in the light of knowing now that cells should be used early for best effect, it all makes sense; we should consider what the cells have achieved in spite of being put in an environment where they're given a hard time. How more real world can you get?
I take the criticism of choice of primary endpoints and sometimes poor communications, but MSB got the hard stuff right, the things that matter. Because of FDA rigid adherence to the rule of primary endpoint, we could be years away from getting CHF and CBP on the market. I accept that could well be the case, but at the same time it's important to look at the context, the state of disaster that exists in GvHD, CHF, CBP and the pressure doctors are under. This has been going on for a long time but there's a risk in not approving in the light of awareness of being able to do something about the situation.
Anyway, I'm going take my own advice and the current FDA should not be discredited by association with any of its predecessors. All I hope is that the new people will have some common sense. I watched a YT interview where Prof Kurtzberg said MSCs are not drugs and need their own set of rules. It was a simple thing to say that I thought I understood at the time but I never really got it. Not like I do now.
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