https://www.fda.gov/regulatory-information/search-fda-guidance-do...

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/benefit-risk-assessment-new-drug-and-biological-products

The final step in the FDA process is a benefit risk assessment.

The risks that would be relevant in considering AA od Revascor for end stage HF LVAD patients should be very low, given their state of disease.

The trial was discussed in a webcast or dial-in call at the end of 2018, which Dr. Rose took part in as a director and expert cardiologist in LVAD. He would have performed many LVAD implantations and in fact he led the REMATCH trial that started the LVAD industry as noted in the latest announcement by the company on the completion of placement and issuance of new shares to Dr. Rose, currently company CMO.

I am not sure the recording is still on the company website but I distinctly remember Dr. Rose describing the reduction in GI bleeding, a major cause of death in patients with LVAD, as significant. Could this be considered a surrogate endpoint in an AA? I suspect it can be. Dr. Rose absolutely can be trusted for knowing what he was talking about, and I suggest he would have been instrumental in convincing the FDA of sufficient benefits being present in coming to its “reasonable likelihood” of an AA conclusion for this HF LVAD indication post the recent meeting with the company in late February, as seen in the recent announcement.

Not sure how easy it is to recruit these end stage patients, but I also recall the primary results were influenced by blood clots caused by the LVAD implantation, not the use of the cells. The use of the cells actually improve the survival of these patients with LVADs who would otherwise have died from GI bleeding, in much the same way these improve the size of the left ventricle in the common heart procedure for young kids with HLHS. This is where the coming meeting on HLHS also becomes interesting.

My point is, increasingly one comes to the realisation that these are complicated, severe diseases that the company has been investigating, where trials may not present prima facie success in primary endpoints but where, nevertheless, post hoc analysis in subgroups, especially if they are pre-determined ones, can be of huge importance in FDA benefit-risk assessments when it comes to approval. See below 2023 guidance by the FDA on how it does benefit-risk assessments in drug approvals, which is much more nuanced than just looking at primary endpohttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/benefit-risk-assessment-new-drug-and-biological-productsints.