In another thread I encouraged shareholders/investors to do some research to come up with at least three good reasons why the FDA would issue a CRL (either type 1 - 2 month extension or type 2 CRL resubmit your BLA). Because once you do this, it will give you a much more realistic view and understanding of the level of risk you are taking on this coming week.
I do not want to share all the reasons I came up with, as I encourage independent research.
But one of the strongest reasons I feel the FDA would issue a CRL is around manufacturing, specifically CQA's and how MSB can ensure batch-to-batch consistency.
Why I think this is a potential source of a CRL is because I have seen many other NDA's being issued CRL's for manufacturing issues. Whilst efficacy and safety are ticked off, manufacturing has been a reason that the FDA has citied as a stand-alone issue that requires addressing before product approval.
Having said that, the examples I came across were not for a disease as deadly as SR aGVHD in the pediatric population where the mortality rate is approx 80% and where no other approved treatment is available.
But the elephant in the room at the ODAC meeting (AM session), was that the panel members didn't really answer the questions the FDA had posed.. and in turn did not really answer or provide the FDA with anything useful that they didn't already know.
The entire morning session was really a Q&A from panel members to Silviu on how the CQA's identified by MSB ensure product quality and what MSB propose to address the FDA concerns in future. I am sure the FDA were hoping the panel members would be advising the FDA on what MSB could or should be doing, or at least provide a view as to the ability to rely on the CQA's identified by MSB.
The general consensus from the panel members, MSB and the FDA in it's closing remarks of the AM session .. is that what MSB have on hand, is state-of-the-art and it is extremely complex. More on this later.
The key issue the FDA has is that for a product to be approved, the FDA requires MSB to demonstrate that remestemcel-l is safe, pure and potent. The FDA understands the challenges in doing this with biologics, but does provide guidance as to what the FDA is willing to accept. The way I look at it, the path taken by MSB has two distinct elements:
a) One of these is the use of potency assays based on a reasonable hypotheses about the mechanism of action (MOA). The FDA allows a matrix approach, which relies on at least one quantitative bioassay and one qualitative bioassay, which together are sufficiently related to the proposed MOA.
b) As for other assays for quality attributes, potency assays used under these conditions must be sufficiently robust in terms of reproducibility and as indicators of product quality and product stability.
While the FDA has raised concerns that MSB were not able to demonstrate through their pivotal clinical trial data that the potency assays directly correlate with the reasonable hypotheses about the MOA. From my understanding, it is actually not a requirement for this to be demonstrated. In fact, this suggested pathway is supposed to be an accepted alternative for treatments such as MSCs where it is particularly challenging to demonstrate this in vivo (in humans/living organisms). So while it is a nice to have, I believe this is a nice to have and 'gold standard' that the FDA would like to see MSB or other sponsors achieve at some stage... but at this stage, it doesn't appear to be a requirement.
So I want to highlight that I believe the FDA's main concern is with b). Specifically that they believe the potency assays used are not sufficiently robust in terms of indicators of product quality.
In my view, the FDA may has grounds to issue a CRL if they believe MSB does not yet have potency assays that are sufficient indicators of product quality. That is, the FDA is not confident that MSB can ensure the next batch of remestemcel-l is as potent as the batch used in the phase 3 pivotal trial.
The FDA acknowledges that MSB have submitted a lot of analyses as shown in MSB's presentations at the ODAC. None of these have changed the FDA's mind, and the panel members didn't give the FDA anything useful to alleviate their concern.
So for me, if the FDA is going to approve remestemcel-l next week.. they will have to come to a compromise or solution with MSB with post-approval.
If there is a CRL issued next week, I'm going to hazard a guess that this is probably one of the reasons for it (ideally a type 1 CRL where non-clinical analysis is required, or they are still working on how to implement post approval measures to address this issue).
So in light of this, why do I think they will still approve remestemcel-l next week?
The panel members, MSB and the FDA all acknowledge this is state-of-the-art technology and what MSB have is simply the best data available with nobody else able to provide any further insight into what else could be done to resolve the FDA's concerns.. other than through the generation of more data and measuring more CQA's and further validating the current CQA's indicator of product quality;
More data can be generated in two ways, either through more clinical trials, real-life data or a combination of the two. The FDA can take a hard stance on this and demand MSB provide more clinical data to ensure product quality... this is a possibility, and my thinking on this is as follows.
What the FDA is weighing up here is the benefit of approving a safe and effective product that will save children's lives, versus the risk of patients getting a product that is safe but not effective. So does the FDA approve a product that is likely to save many lives that have no other alternative treatment, risking that there is a chance some patients may not get an effective treatment and die. Because the alternative is that they reject the product and order more trials, and condemn many children to death by not allowing them access to this life saving treatment.
For me, time is of the essence here and time really does equate to lives being saved. If this treatment was for pain management or another ailment that did not have such a high mortality rate, then the FDA's chance of rejecting the treatment on these grounds would be significantly higher. But pediatric SR-aGVHD is in dire need for a safe and effective treatment... and for this reason, I believe the FDA will take a pragmatic approach to this and not deprive patients an effective and safe treatment.
Furthermore, MSB admitted on several occasions that they don't have all the answers and there is still a lot to learn. But what they do have is a commitment to excellence in science and clinical outcomes and they are in this to advance and improve the technology over time. To this, the FDA can get more data through a confirmatory trial and real-world post-approval data. There is a mechanism in place whereby the FDA can approve the product and require post-approval studies/trials, which in my view will satisfy the FDA's concerns raised on product quality. This in my view is a WIN / WIN situation... families are given access to this life saving treatment and children's lives are saved IMMEDIATELY. That's a WIN.
The FDA get's their data... and if the data is bad, they cancel the approval.. and if its good, then no lives were lost unnecessarily. WIN.
Would be great to see what other's think on this, and hopefully you can share your thoughts on other reasons why the FDA may issue a CRL.
(20min delay)