Over $2buck hit, page-11

The study that you are quoting was conducted between 2006-2009. MSB and SI are arguing that they have modified the manufacture to enhance the content of specific bio-markers when producing Remestemcel-L, they argue that these changes have been instrumental in increasing efficacy as demonstrated in their more recent (2018) single-arm AGVHD tests on children.

Examining the actual results the study you cite:
"Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated."

The first issue is that it didn't meet the primary goal for the intended population of that study which was a durable complete response - i.e. the patient is effectively symptom free after 180 days that was markedly different (35% compared to 30%) to normal treatment (i.e. steroids) - children below the age of 12 do not tolerate the steroid treatment hence there is no treatment for them.

So in many ways this study, while negative, doesn't actually apply to the case targeted by the MSB BLA, i.e. children.
When post hoc analysis was performed on the study data, they found that there was actually a benefit - i.e. overall response (OR) - being complete or partial response showed statistically significant improvement for the MSC arm, 29% versus 5% - so those treated had slightly better outcomes - but still died or were very sick after 180 days. Interestingly pediatric patients - exactly the group that the actual BLA was for - showed a much stronger response - 64% versus 23%. In addition the treatment was deemed very safe and well tolerated by all groups.

So the FDA has decided that a study was adverse because it didn't meet its overall goals, despite it actually being trialled across a different population to that being addressed in the BLA and despite the study actually producing a very positive result for pediatric patients.

While I can see where some of the unease from the FDA comes from in studies like this (particularly since it it double-blinded placebo controlled), I think it isn't actually that informative for pediatric cases, since it does seem to strongly indicate a significantly different (and beneficial) response from pediatric patients compared to adults. In addition, the fact that the results for children improved markedly showed that Remestemcel-L produced the same outcome for children that steroids produce for adults, which again is the area that the BLA is addressing.

I think the FDA stats handling here isn't great and it's an area that MSB and SI might want to attack.

The logic being:

• It is likely that overall numbers in the trial were heavily biased towards adults.
• The results show little difference between MSC treated and normally treated patients.
• However the adults are being treated by " second-line therapy according to institutional standards" which for adults is steroids and for children it is NOTHING
• Pediatric responses were markedly better than those of adults - so one can conclude that Adult+steroids is roughly equivalent to Adult+steroids+MSC and that this would dominate the stats. But clearly children+MSC is markedly better than the results of no steroid treatment for children.
• The study did not compare Adult+MSC versus Adult with no steroids, which might reveal that the two treatments are addressing the same mechanism of action in dealing with this disease and hence the reason why there was little statistical difference in the outcomes.