Ryoncil: ODAC/FDA Meeting Discussion, page-1078

Dr Baird - Fifth Speaker (FDA)

“FDA did not discover differences from what the applicants have shown in their safety review and therefore product safety will not be included in our discussion.”

Issue #1 Trial Design

TLDR: FDAdid not like that there was no placebo, acknowledges there is not much data on the issue, then goes on to discuss how using the only data available is a limitation because it is limited.

- Lack of randomization

- Lack of blinding

- Ideally the rate would be based on expected day 28 ORR inpatients untreated or treated with a standard of care comparator.

- However, the ideal approach was not employed by the applicant.

- I nstead for study 001, the hypothesis was determined as well.

- It was 55% based on the rate observed and for the stem cell treated pediatric subgroup of 280.

- This is problematic because it was determined not by comparable external control but rather by data generated from previous studies with the same product at different patient population than that to be studied in 001 and that these patients were treated with additional salvage therapy for steroid were factory.

- FDA acknowledges there is a lack of data available for pediatric for untreatabledisease

- Limitations for determining NULL Rate ofstudy (45% control): subgroup analysis / also included adult patients, small sample, additional salvage therapies, patients were not randomized by age, data from literature limited, studies included small sample sizes, varied endpoints etc.

Issue #2 Evidence of effectiveness

Single trial requirements: FDA frequently requires more than one trial to establish efficacy and effectiveness guidance, it states the reliance on a single trial to establish and effectiveness will generally be limited to situations in which the trial has demonstrated a clinically meaningful effect on a potentially serious outcome and confirmation of the results in a second trial would be practically or ethically impossible.

Due to being unhappy with the setting of null, it is not possible to determine effectiveness. E.g. due to FDA not trusting 45% as base rate of survival, then the

Study 275 and 280 allowed other salvage treatments, whereas study 001 only allowed Remestemcel-L

“difficult to make any conclusion from the data due to differing methods in three studies”

Literally, 001 had the best results and only used Remestemcel-L.. ?

Discusses difference in variability in success from three previous studies 275, 280, and 001, which ranged from ~50% - 70% (70% in 001) (didshe listen at all to grossman? He just explained that 001 was based on anoptimised msc product)

“FDA may require an additional trial to support the effectivenessof pediatric steroid refractory. And if so, what recommendations would theboard recommend for the trial?”