If the FDA was consistent in its criteria for Ryconcil as a treatment for GvHD, one only has to look at their own material to see the approval of Ruxolitinib (Incyte Corp.) was on a single-arm study with poorer results than Ryconcil. One might ask how that got approved if Ryconcil is rejected:
"At the present time, ruxolitinib is the only product FDA approved for the treatment of SRaGVHD. The approval of Ruxolitinib in May 2019 was based on Study INCB18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD treated with ruxolitinib monotherapy. The primary endpoint of the study was Day-28 ORR. The statistical analysis plan indicated that a positive result is concluded if the lower limit of the 95% CI of the ORR was above the prespecified threshold of 40%.The Day-28 ORR was 57.1% (95% CI: 42.2–71.2), the median duration of response was 0.5 months (95% CI: 0.3–2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable).
FDA frequently requires a randomized trial to support traditional approval. FDA has considered single-arm trials to support a marketing approval in instances where there are no available therapies that would be considered standard of care, where the effect of response is presumed to be attributable to the investigational product. FDA concluded for ruxolitinib that since the disease is life-threatening, there were no approved therapies, there was no optimal therapy of aGVHD identified, the efficacy endpoint was objective, the activity of the drug was established in other diseases that shared similar pathophysiology as with aGVHD, and there was a substantial safety database, a single-arm trial as the sole basis of efficacy would be acceptable. Further, the Day-28 ORR of 57.1% with a lower 95% CI bound excluding 40% with durability was considered clinically meaningful for patients with SR-aGVHD. Lastly, due to the fact that the lowest available strength of ruxolitinib precluded safe treatment in infants and children, the indication was limited to patients 12 years and older."
In MSB's Protocol 275 single arm study, the 28-day ORR was 69%. Now the FDA ideally wanted MSB to do a fully randomized controlled study in adults (its ethically okay to let control group adults die in control groups, but Physicians draw the line at children) but given it had better results in a similar single armed study than Ruxolitinib, that "no safety signal of concern was identified in the studies of remestemcel-L" and its been used in Japan since 2016, one might conclude it holds as much merit for approval as US company's Ruxolitinib.
There's been lots of discussion of MSB's null hypothesis on HC (and the FDA obviously riases whether its statistically acceptable), but one has to wonder again why Ruxolitinib used a 40% lower threshold on its trials? Whilst the way MSB got there does seem a little crude, the Mount Sinai data does seem to vindicate its use.
It does seem the FDA is pre-disposed to rejecting MSB from some of its language:
"The null hypothesis for MSB-GVHD001 is not based on data from a historical control population. In the absence of data from appropriate historical controls, FDA is unable to agree that the proposed null hypothesis is acceptable".
"Given the absence of appropriate concurrent or historical controls, MSB-GVHD001 does not appear to be an adequate and well-controlled study. Thus, the trial as designed may not be sufficient to provide primary evidence of effectiveness to support a marketing application".
But if I was MSB I'd have a very good grasp of Ruxolitinib's trial parameters, citing how it was approved on similar basis. I am not confident MSB will get the nod from the FDA, but if they don't does the above not point to inconsistency?
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