Ann: Long-Term Survival for Acute GvHD Treatment with Remestemcel, page-141

Its rude not respond at all. Although much of this might be old ground and this forum is repetitive enough.

Your question:

“Do you suppose that the FDA said to MSB this time around…hey you need to do a new double blinded placebo controlled RCT…but MSB decided to go against this advise, increase the risk of them not receiving an approval in the future, and simply go for an “easier” option that suits them…and hope that the FDA won’t mind and grant them an approval?”

Yes, the easier option every time.

MSB have been advised twice now to conduct an adult randomised controlled trial. First during the rolling BLA and then when they received the CRL.

MSB are steadfastly refusing to do the adult trial unless they receive approval for children first. The FDA position to MSB is first fix the potency assays and CMC issues then do an adult randomised control trial. If the results are good then they will talk about approval for children.

Go back to 2010. After the two failed GVHD trial Osiris tried to argue for approval on the basis of a survival benefit. The FDA were unswayed – Osiris were told to conduct another trial.

By this stage the product had clocked up numerous trial failure, Osiris gave up on it and sold it cheaply to MSB.

Why did MSB purchase it? Because a post-hoc sub-group analysis had shown a survival benefit for children.

MSB’s cleverness was to get the FDA to agree to a single arm trial in children (for ethical / logistical reasons) which sidestepped the FDAs insistence to Osiris for another randomised controlled trial.

But there was a big catch. While the FDA briefing notes make it clear that a single arm trial could in theory support approval the FDA insist the design needed to be reviewed by them before being conducted.

The reason for the FDA review was to enable the FDA to build in some tough design hurdles. And the reason for that was that the trial had to do some very heavy lifting.

The MOA was poorly understood which puts greater weight on the clinical trial evidence. But more importantly the single arm trial had to overcome the compellingly negative evidence from the numerous previous Osiris failed randomised control trials. The “totality of evidence” argument.

In other words, the FDA never intended the concession for the single arm trial to be a free kick.

Wires got crossed. MSB believed they had agreement with the FDA about the crucial hypothetical control estimate. In November 2017 the then CMO claimed:

“Hi, Mark. Thanks for your questions. So your first question regarding the FDA, sounds like the expectations with the FDA in terms of defining success, we did negotiate with the FDA on the assumptions we used to design this trial. And the hypothesis we generated that would provide a comparative expected response from a hypothetical control population. So we have reached agreement with the FDA on what success would look like in the trial.”

The FDA dispute there was any such agreement. And MSBs method used to generate the hypothetical control rate was rejected; it lacked rigour. And from there it was all downhill. The rejected MAGIC study where MSB had failed to test any pre-specified hypothesis and this error wasn’t picked up because MSB hadn’t submitted the SAP for review.

At every point MSB has taken the easier option. Despite the 9-1 ODAC vote, MSB are now in the exact position as Orisis in 2010; being required to do an adult randomised controlled trial. MSB say how about an observational cohort study for OS. The easier option; a continuation of the thinking that has got MSB where they are today.