Ryoncil: ODAC/FDA Meeting Discussion, page-465

Steven R Bauer – Fifth Speaker

FDA product characterization

TLDR: Bauer says "your methods do not show MOA", "link between TNFR1 and MOA not demonstrated"

- Raised questions regarding product quality and effectiveness – “how can we know that the next batch has the same activity as the batches used in the clinical trial?”

- Outlined three methods to answer the above question: product testing, source control, process control.

- The focus of today is “product testing”. Which focuses on “quality attributes”.

- QAs defined: They are a molecular or other characteristic of the product that is selected for its ability to help indicate the quality of the product.

- “we also identified critical quality attributes or NCQA which consist of the physical chemical biological or microbiological property that should be within an appropriate limited range for distribution to assure the desired product”

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- “These characteristics overlap considerably with characteristics the scientific literature and stakeholder community have developed has consistence markers and properties that define MSCs”

Above : CQAs put forward by MSB – FDA has highlighted those targeted for discussion.

“A biological license application may be approved on the basis of the demonstration that the biological product that the subject of the application is safe, pure, and potent.”

“specific ability or capacity of the product as indicated by appropriate laboratory tests by adequately controlled data obtained through the administration of the product in the manner intended to affect the given results.”

“cellular products such as Remestemcel-L the mechanisms of action may be very complex.”

Due to products biological complexity, multiple complimentary assays have been used:

“The potency proposed by the applicant is based on reasonable proposal for mechanism of action”

On MSB trials:

“The applicant states that Remestemcel-L has [ Indiscernible ] mechanism of action that counteract inflammatory is a cease associated with steroid refractory acute graft-versus- host disease.”

“Th ere was no placebo control for comparison”

“As you've heard earlier the applicant is proposing that there is a positive relationship between [ Indiscernible ] and overall survival but here is why we do not agree with that conclusion”

“The BLA presented data with clinical outcomes but some limitations of the data were not discussed in the applicant briefing document.”

“And the BLA the applicant presented data outcomes with the laws used to treat individual patients there”

“the clinical trial that provides the primary evidence of the effectiveness.”

“There was no association between survival on day 100 and that mean TNFR1 levels and the lot study 01.”

“There is no association between day 28 overall response.”

“The primary outcome of study 001 and the mean TNFR1 in the lots used in 001.”

“Using pool data from three clinical studies the applicant found a statistically significant association between Remestemcel-L TNFR1 and survival.

“No Clear relationship between TNFR1 levels and proposed MOA”

“Therefore any efficacy Remestemcel-L in treating the disease is not sufficient to demonstrate the products mechanism of action”

“We developed functional qualitative bioassays for MSC based on the biological function shown here to induce differentiation and immunomodulation and anti-inflammatory angiogenesis.”

“These methods are sufficiently sensitive and reproducible so we can detect differences and activity and [ Indiscernible ] from different batches and different lengths of time and tissue culture and passaging.

“They (these methods) were similar used by the applicant”

Spent another 20 minutes outlining highly in-depth assay methods, then said that the FDA did not expect stakeholders/applicants to use these highly in-depth methods, but wanted to show that they were possible (?? Wow.)

Conclusion:

“This raises the concern that potency tests forRemestemcel-L may not detect differences between batches or what the applicant calls drugproduct lot since they do not correlate with chemical effectiveness”