Cell Therapy News/Articles, page-15050

The aGVHD trial was completed on 19 April, 2018
ASX announcement:

The Phase 3 primary endpoint was successfully met
• The primary endpoint of Day 28 overall response rate to remestemcel-L treatment was
69%, a statistically significant increase compared to the protocol-defined historical control rate of 45% (p=0.0003)

2019 Annual Report, Nov 2019

In addition, the FDA or other regulatory agencies may find the data from our clinical studies insufficient to support marketing approval. For example, our Phase 3 study for remestemcel-L, which met the primary clinical endpoint with statistical significance, was conducted as a single-arm study due to the seriousness of the condition, the rapid clinical deterioration of affected patients, the mounting literature suggesting a meaningful treatment effect, and the position in the medical community that a randomized controlled trial was neither feasible nor ethical in this patient population. While we intend to provide the FDA with comparator outcomes from control subjects, it is possible that the FDA may not find the data sufficient for approval. In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

2020 Annual Report. NOVEMBER 2020
https://investorsmedia.mesoblast.com/static-files/2c149f66-1a72-462c-a266-a9e07e7b58fc

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For example, our Phase 3 study for RYONCIL, which met the primary clinical endpoint
with statistical significance, was conducted as a single-arm study due to the seriousness of the condition, the rapid clinical deterioration of affected patients, the mounting literature suggesting a meaningful treatment effect, and the position in the medical community that a randomized controlled trial was neither feasible nor ethical in this patient population. While we have provided the FDA with comparator outcomes from control subjects, it is possible that the FDA may not find the data sufficient for approval. In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

More than a year after the trial was completed, MSB admitted the trial didn't have adequate "controls" despite the original statements to investors that the trial had a "protocol defined historical control rate". When the FDA asked where this control rate came from, it turned out that it was derived by working backwards from the results of the trial and it suddenly became a "hypothetical control rate", and the FDA didn't find this to be acceptable. So MSB "intended" to provide the FDA with comparator controls 18 months AFTER the trial had finished.

THAT was the number one problem with the trial, related to the methodology and it's one reason why the FDA "recommended" that Mesoblast do another trial at least on adults.

You can't provide "controls" for a trial that was already completed years before... LoL

In the years that have gone by MSB hasn't made any attempt to even start another trial and clings to a hope that they can arm twist the FDA into accepting the results of a less than adequate trial by resubmitting the BLA. IMO the FDA will still want a properly conducted randomised controlled trial at least in adults.