I think there is a very subtle – nuanced argument to be made here for approval now for children with a RCT in adults post approval.
Look at what has driven the FDAs requirement for an additional trial. Three things (from the Ad Com meeting).
First. “As discussed this morning, the mechanism of action of remestemcel-L is unclear, and it has been difficult to identify product characteristics that correlate with efficacy outcomes in GVHD. In this setting where the scientific basis of activities are uncertain, we rely heavily on the clinical trial results to provide persuasive evidence of efficacy.”
Second. “The efficacy data for remestemcel-L come primarily from MSB-GVHD001,single-arm study in pediatric patients with steroid-refractory acute GVHD. The primary efficacy endpoint was day 28 overall response rate. The results from the study were statistically significant, however, due to the limitations of the study design, we have concerns regarding the interpretability and persuasiveness of those results.”
What the FDA are saying is that when you don’t know how something works, clinical trial evidence has to do heavier lifting. But because of limitations of the single arm trial this evidence is not capable of doing the heavy lifting.
MSB claim to have better established the link between product characteristics and outcomes (from the in vitro potency assay – EAP 275) and so therefore in theory this takes some of the pressure off the clinical trial evidence. At the same time, the Ad Com 9:1 vote shows that the independent experts didn’t share the FDA concerns about the interpretability and persuasiveness of the trial results.
So it is the synergy between these two things. A better understanding and evidence for the scientific basis of activities leading to less reliance on the single arm trial evidence while at same time there is a positive re-evaluation of the persuasiveness of the trial results stemming from the 9:1 vote.
The fly in the ointment is the third driver for an additional trial - the totality of the evidence. This includes the two previous failed RCTS along with all the other failed trials for the product are a big drag on approval. As the FDA point out:
“However, the results of Protocols 265 and 280, the two randomized trials, did not provide evidence of a treatment effect for remestemcel in acute GVHD even when we analyzed using the efficacy endpoint of day 28 ORR. In fact, treatment effect has not been identified in any of the previous clinical trials conducted in various disease entities, including type 1 diabetes mellitus, Crohn's disease, myocardial infarction, or severe chronic obstructive pulmonary disease.”
MSB of-course argue that the product has been improved. But this heads you straight to the FDA’s current position – great, demonstrate the improved product in a RCT.
The final little issue is the politics. To some degree by agreeing to the Ad Com meeting the FDA are implicitly agreeing to take part in a process. There is no argument that a RCT in adults should take place – everybody thinks this should happen. The difference between MSB and the FDA is whether this is post child approval.
MSB are most likely not bluffing that without child approval there will be no adult trial. One interpretation of the 9:1 vote is that there was strong support from the experts that there was sufficient strength from the totality of the evidence to warrant an additional trial. There would be disappointment this wasn’t going to happen. So it possible the scales might be finely balanced … and if FDA can see this approval within a wider context MSB might get lucky.
On the other hand, the FDA position is entrenched and long standing. From their perspective if MSB had just got on and done the adult trial when they first suggested it (way back during the rolling BLA) the whole issue would have been long resolved.
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