Ann: Remestemcel-L FDA Fast Track Designation for COVID-19 ARDS, page-367

Well@Southoz

I had to give my thoughts on the subject. The FDA also refused to accept the findings of the Magic Consortium which verified all the data against their own contemporaneous database. They are acknowledged as the world leaders in this particular ailment ...they undertook a specific review of every single case....and wait for it , the FDA criticised their work as well....

“In Mesoblast’s open-label Phase 3 trial of remestemcel-L in 55 children with SR-aGVHD, 89% of whom had Grade C/D disease, the primary endpoint of Day 28 Overall Response in those exposed to remestemcel-L was achieved in 70% and Day 100 survival was 75%. These outcomes were superior to those from a cohort of 30 pediatric patients with SR-aGVHD from the MAGIC consortium matched for inclusion criteria and disease severity (80% Grade C/D). In the MAGIC controls, Day 28 Overall Response was 43% and Day 100 survival was 57%.Mesoblast Chief Medical Officer Dr Fred Grossman said: “We are pleased to have submitted to the FDA clinical efficacy and safety data for remestemcel-L, as well as comparative clinical outcome data from contemporaneous controls. We are working closely with the FDA to make our cellular medicine available and improve outcomes in children with this devastating condition.”


https://www.globenewswire.com/news-release/2020/05/25/2038051/0/en/Clinical-Outcomes-Using-RYONCIL-remestemcel-L-in-Children-and-Adults-With-Severe-Inflammatory-Graft-Versus-Host-Disease-Published-in-Three-Articles-in-Biology-of-Blood-and-Marrow-T.html

https://labs.icahn.mssm.edu/ferraralab/meet-the-principal-investigator/

So just to be clear...you state that the FDA decided the trial was not “adequate and well controlled” based around the null hypothesis applied and you think that it is a cut and dried case.... and yet the FDA’s own observations about the null hypothesis were partly discredited (their own comparatives had inaccuracies because they included multiple treatments results ) at the same meeting because of some of the data they used. Mesoblast knew that in the short time they had to present, that ripping apart the regulators comments would not be constructive. Most of the practitioners on the ODAC committee gave the FDA argument short shift when they realised that our trial had done the opposite of “cherry picking”. IF, Mesoblast had been cherry picking patients (look at the patient severity of the Jakafi trial if you want to compare null hypotheses ) why did they have the confidence to enrol the most severe grades ?

Perhaps you can explain how a greater null hypothesis should have been used when 89% of the patients had Grade C/D sr aGVHD ? Are you familiar with mortality rates for this grouping of patients. The FDA observation was clearly absurd unless you wanted to rebase the calculations in the extreme, by no more than 2-3%. For goodness sake, 49% of the patients were Grade D !!!
Just so you can do some homework...try asking the FDA if there was a change of key personnel at CEBR, from when the trial design was agreed and the Phase 3 trial was conducted ...to when we started our submission. I think you will find the answer enlightening .

THEN, if you have time. Look at the Jakafi phase 3 trial results. Look at the treatments chosen as best available therapy ....look at the changes made to their trial midway through...look at the percentage of Grade 2 less severe skin patients and look at the null hypothesis applied to their trial. Then tell me that that was an adequate well designed trial. So long as the “ trial investigator” sanctions it...apparently its OK. The latter trial was actually found to have complied with the FDA requirements... enough said . They have approved Jakafi for use for 12-18 age group and yet I have found no evidence from researching their results that they ever improved upon the underlying standard of care. Indeed please show me how , with efficacy of only approx 41-43% in virtually all Grade C/D categories and a whole heap of nasty side effects, that this treatment is a patch on Ryoncil. I am sorry but little children are dying as arguably the pedantic mantras of a few select individuals have held sway . It disgusts me..,..and it should disgust you. Please dont tell me that your post was “simply” pointing out the facts...because you dont know all the facts...just the briefing pack disclosures . The expert practitioners did not agree with the “current team” at CEBR. They did not simply judge efficacy as you say.....because efficacy is calculated AROUND A BASELINENULLHYPOTHESIS. It was not ignored as an issue.
If you research the rules for accelerated approval you should conclude that the primary and secondary endpoints used were fit for purpose. If you think that Mesoblast designed a trial that the FDA objected to at the outset....I would say i disagree totally with you.

Lastly, if you are familiar with oncology approvals you will know that many orphan designations have been approved using single arm trials , subject to a confirmatory trial bring conducted post approval . Mesoblast were not cutting corners ...there was no best available therapy to use at the time. I refuse to criticise a company for saving the lives of sick children ,especially as we have heard testimony from leading practitioners that the trial design this particular team at CEBR wanted was deemed unethical by most practitioners. Maybe we should ask the leading smartar$e in the CEBR team to administer the placebo to the babies and tell the parents afterwards that it was entirely necessary for their protocols .

How does the FDA expect anyone to develop therapies for orphan indications for a few hundred children with 15 years of trials and no certainty of success at the end of it. Steroid refractory acute GVHD is an UNMET need. The rules are there to be opined on. There is flexibility in how they are interpreted. We just were in the wrong place at the wrong time with the wrong kind of people. Same as the legal system . You often see the same cases taken to a less experienced judge who makes the wrong judgement and then subsequently, BASED ON THE SAME RULES, the judgement is overturned in favour of the plaintiff. Just tell me....WHO ARE THE BAD GUYS HERE ?

I dont mean to make this post personal in any way. I am just so angry and seeing what in my opinion is the legalised slaughtering of young children . You can call me an old softy if you like. OP



Please do not rely on the facts or opinions expressed in the above post when making an investment decision. Nothing in the statement above should be construed as alleging any form of malpractice or non compliance with the rules . The sad thing, is that the rules have been interpreted in a way inconsistent with past cases of approval for adult and chronic sr aGVHD..something that members of ODAC were well aware of at the time they cast their votes. Remember they had read all the relevant documents and found in favour of Ryoncil receiving approval.