What are the main concerns of the FDA:
1. Cell therapies are highly complex products so chemistry, manufacturing and control issues can be particularly challenging. Hence to approve the product Mesoblast must be able to ensure that every lot has the same safety and efficacy as those seen in the trials. This was raised at the last meeting and the Prof. dealt with this quite succinctly ensuring that manufacturing process are aimed at enabling commercial scale production with reproducibility and batch to batch consistency. Mesoblast has also improved its technology and its products are more potent than when they first started.The FDA has to understand that as this is cutting edge technology, the company works towards continuous improvement and their products will get get better.
2. The FDA has substantial concern regarding the application. the biggest concern to do with uncertainties about the therapy's mechanism of action, potential viability in an off the shelf therapy and the lack of randomised control trial (RCT). In this respect Dr Kutzberg has given a very strong case for Mesoblast "Kurtzberg said she has been using remestemcel-L for more than a decade with good results. Because of that experience and the positive results she’s seen with the therapy, Kurtzberg argued against requiring a controlled study, saying she and other clinicians wouldn’t risk putting their young patients into a control arm when remestemcel-L works so well. She pointed out that without the therapy, the survival rate for children with GVHD who don’t respond to steroids is 35%.Given Kurtzberg’s remarks, panelist Mark Walters, director of blood and marrow transplantation at the University of California San Francisco, questioned the feasibility of requiring Mesoblast to conduct an RCT. Such a study would be ethical, Walters said, but it wouldn’t be practical because the already established belief in the therapy’s efficacy would create a barrier to getting trial participation.Mesoblast’s product has been in development for more than 15 years and has been available through compassionate use. Although previous trials in adult populations failed to meet their endpoint, no safety signals were sounded. That left the FDA questioning the efficacy that was revealed in the latest study – a single-arm trial that showed a 70% overall response rate at day 28 and overall survival of 74% at day 100.The response rate far exceeded the 45% null hypothesis Mesoblast set based on historic controls. However, the FDA questioned the null hypothesis and the lack of a control in the trial. It also brought up the past failures, even though Mesoblast pointed out the previous trials were conducted with an earlier iteration of the therapy. Since then, it has optimised its processes, increasing the potency of the product."
Based on the above the FDA will have to have an iron tight case to not allow the use of Ryoncil as a cure for GVHD in pediatric patients.
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