Really good to see your post since you are able to put together so many details over time in a logical way.
There do seem to be a few things that stand out from the development course which have hindered progress.
All along its been harder to do paediatric studies because there are fewer affected children than adults. Osiris started out by doing an inclusive RCT. It was the involvement of Dr Kurtzberg though as an investigator that upended the studies. She apparently decided either from anecdotal experience or post hoc analysis or because it aligned with some other work she was doing that MSCs were more effective in children than adults, that children responded better than adults. So even though the initial trial didn't demonstrate efficacy she was instrumental in the design of future trials so that children involved would all recieve MSCs (but potentially were denied alternative treatments that she considered less effective or had side effects she didn't like).
On the plus side perhaps she could use her position and influence to facilitate the trials and probably persuade other clinicians to participate and follow her lead. She was also able to declare randomized trials "unethical" to ensure the children in the trials would only receive Remestemcel. All of these things would be attractive to a sponsor. On the negative side, it would potentially introduce bias and confounding variables that would make the trials less reliable and muddy the waters for regualtors trying to evaluate the results. For Dr Kurtzberg she could continue to treat children with her favoured Remestemcel and publish papers.
Osiris tries to get approval in the USA, Australia, NZ and Canada. They have developmental programs for Remestemcel involvimg diabetes, heart, knee injuries, back injuries aGVHD, inflammatory bowel disease. The Australian TGA doesn't like the trial evidence and wants an RCT to prove efficacy. Canada doesn't like the trial evidence but grants conditional approval. Some of the regulatory Board participants have used MSCs and think they could be efficacious, but a new and better trial is obligatory as part of the conditions. It isn't done. The FDA takes the same view as the TGA. Osiris is roundly criticised in the media for delays in informing investors and spinning the Remestemcel (Prochymal) story. When the results of the second failed trial comes out and approvals are denied the share price tanks. Along comes SI and sees an opportunity for a ready made kit development program at a cheap price. He picks it up for a $50m deposit and another $50m if it can be commercialised. Along the way he manages to get around $50m for himself during the share shuffle and partnership deals with TEVA.
Now old Silver Tongue goes to the market and raises some pretty good capital for trials for the "new treatment paradigm" and attracts some partners willing to pony up funds for trials. Retail investors are enthralled by stemcells which can cure everything and grow new body parts, Mesoblast is on everyones lips. The price rockets to $20 and the BoD reaps the rewards, holders are getting rich without a single MSC being sold. Share chat forums are playing "guess the price when" and e-gurus are calculating how much the company will make after 5 years of operations and what the share price will be. Bell Potter is flashing "BUY" to their clients. Initial phase 2 trials for Knee Meniscal injuries, Intervertrbral Disc injuries, Congestive Heart Failure are failures or equivocal but post hoc analyses are spun by SI as successful and with a few tweaks march straight on to phase 3. Covid comes along and SI sees the opportunity to do a trial for ARDS and manages to attract Novartis as a"billion dollar" partner. Despite the trial being stopped because of futility, it's billed as a success because sub group analysis turns up a group that statistically performed slightly better than controls. After a year of trying to access the data or studying the results, Novartis walks away saying that the didn't see anything worthy of further research. SI says he doesn't understand why.
The FDA doesn't like the BLA for Study001 for aGVHD and in an effort to be fair convenes an ODAC meeting to guage efficacy. It vote 8:2 with a voting member changing their vote making it 9:1 in favour of efficacy, but quite a lot of members are equivocal or voting on the basis that it might work but seems safe. A member remarks that the evidence they are voting on is basically a line up of anecdotes. SI asserts that there is no longer any claim that children respond better, the problem was that the manufacturing process was inconsistent so potency was varaiable and they have fixed it. But in the end the senior officials at the FDA rule that there are too many deficiencies in the trial and totality of the evidence to endorse Remestemcel for aGVHD. They issue a CRL which includes things that need to be addressed such as a satisfactory potency assay with some kind of correlation with a mechanism of action and a new trial with better quality evidence.
Meantime the Japanese regulator changes their laws to allow medicines that are proven safe but without proven efficacy to be sold in Japan . SI tells shareolders it's a perfect way for Mesoblast to gain commercial access to the Japanes market without having to prove they work. They do a deal with Temcell which is worth $8m a year in royalties.
So after 3 years and a resubmitted BLA the FDA has once again issued a CRL but the progress is that the FDA has accepted the potency assay and SI has accepted he should do a better controlled trial in adults.
You are saying that the right thing to do is a smaller cheaper exploratory study in adults with propensity matched controls to see if everything works as Mesoblast claims. The new manufacturing process with consistent potency, the better potency assay that aligns with the proposed mechanism of action and the better response and survival outcomes. If it's successful then move on to a new phase 3 pivotal trial in adults which would lead to approval in adults and children.
(20min delay)