This is where I think you may be wrong, @JB1975. Unlike small molecule drugs, ATMPs (advanced therapy medicinal products) including CGT (cellular and gene therapies) products are harder to standardise in manufacturing for obvious reasons, and potency testing is a much bigger deal for precisely that reason. At the heart of the current actions being undertaken by the company is the most important and outstanding CMC issue which the FDA have identified in the first CRL and the company is trying to resolve, not so much an efficacy issue anymore, as Dr. Krause was at pains to emphasise in one conference call last year after the surprise CRL (and I don’t think it is spin, with the long term data in the resubmission corroborating the ODAC expert 9-1 opinion in 2020 and probably being weighed almost as heavily as the pivotal trial data in the FDA thinking, given the FDA’s own use of and advocacy for real world evidence). This is why the company has cited the relevant FDA regulation and emphasised the issue of standardisation needing to be addressed in its public release accompanying the CRL. With the subsequent Type A meeting to discuss the CRL having been attended alongside the company by people from the BMT-CTN, the well regarded keeper of real world clinical trial evidence, the weight given to the long term data would, I imagine, have been given a further boost compared with that which went into the drafting of the second CRL in August.
For the purpose of approval any drug product obviously needs to have the intended effect, but it is more of a manufacturing or quality control/assurance issue that is being tested or considered by the FDA in the latest CRL ie. where the assay (or testing method) is administered before the product is given to the patient. This helps resolve something that I, too, could not wrap my mind around previously, and that is, how the reverse engineering could or would work with the trial over a long time ago. Ideally the product should still match clinical outcome but apart from being performed before it is released, the test may be needed for in-storage quality control, as well as demonstration of process and product comparability before and after process and material changes. Hence, the requirements for the assay(s) to be robust and reliable, stability-indicating and able to differentiate between target and degraded product. I believe it is in the latter contexts, that the CRL can be taken as what some describe as a “soft rejection”.
Then I went back to the work and substantial investment that, since 2020, the company has put into developing a matrix approach to the assay. I think it was @Phaedrus who mentioned that this enhanced assay has been shown in large part to the FDA ie. not in full, and I have also read recently SI’s mention that the company can revert to the old potency assay in use during the pivotal trial. I have been trying to understand the context and reconcile the two. I remember quite distinctly Dr. Rose saying on one of the calls early in 202, shortly after he became the CMO, that the potency assay “has problems”. In retrospect, I think he was referring to that which has now been identified as a stability issue with the potency test, specifically with the reagent, itself (as opposed to the cells - this is public). @Phaedrus has said in one recent post that it had taken the company almost 18 months to track down the source of the instability of the reagent but that the issue has, it seems only recently, been addressed - unfortunately it was not before the resubmission in early 2023. Perhaps this explains why the company started developing the (likely more expensive but) enhanced assay* but now, in order to address the FDA’s concern of a lack of an effective potency assay during the trial, SI is talking about the old approach again - I am guessing because they have resolved the issue with the test reagent. If in the company’s view, both assays work, then it should have a good chance of being able to produce consistency results in “comparability” studies in their “parallel strategy” because it opens up the possibility of (i) having a last shot at near term approval for kids’ GVHD by addressing the quality or standard of the trial product and (ii) paving the way for the current inventory to be used in the adults’ GVHD trial. I have done some research and now understand what they are trying to use to get the extra data, at a high level, to be a “bridging” analytical method. It is something that is normally used in the context of manufacturing changes to ensure that batches after the changes are still usable despite the changes, and it normally applies to already licensed products. However, the concept seems now to be used by the company with the potency assay, in order to show that the commercial inventory is the same as the trial product, and can be used either to launch the kids’ product, or to be used in the adult trial. (This is where Dr. Krause has no doubt been adding a lot of value, and if you have been following my thinking so far, perhaps the reason why he has participated in the capital raising recently.) They are attempting to link the product (likely to be retained samples) when the old assay was in use during the trial (to directly tackle the FDA’s issue with the lack of an effective product potency assay or test during the clinical trial, now that they have found the source of the problem) to the current inventory they initially prepared for commercial release using the enhanced assay and pending the approval they were betting on but did not come in August 2023.
If they succeed in producing data that are useful, they would have shown not only that the product is standardised and ready to go commercially, but also that the potency assay, so central to ATMPs, is good to use.
The main reason, as I see it, for going down the adult trial, is a commercial one, as SI explained before. Previously, I got a sense that the company was reluctant to target Inctye**, the manufacturer of Rux, directly. Unless they feel they have a fair chance to gain approval for children, they won’t have started thinking about activating this pre-conceived strategy of going for the adult market as well. If, however, the FDA knocked back the potency data they are working on, pursuing a parallel strategy has the advantage of building further on (some may say, not having to write off) the value of the kids’ GVHD work. The trouble is, you can’t really say these things out loud as you have just been knocked back a second time and you may sound foolhardy, and it is quite hard to articulate such difficult tradeoffs. Yes one may gain greater assurance of the MoA or insights into a slightly different MoA in adults than in kids, but I don’t believe that is the main point about pursuing an adult trial.
@Pfeiffer1982 mentioned that the FDA does not validate potency assays. However, they must be in place for commercial production and most guidelines recommend those to be used already for testing of the product before pivotal clinical studies, so that correlation of the potency test results with clinical efficacy can be explored. With the lesson from the kids’ trial learnt, I believe the company was pushing for the FDA to endorse the enhanced potency assay at the Type A meeting so they could push on with the trial. I am guessing that was a big reason why the BTM-CTN people were there @Wilba32 . Like MSB, the people have been involved in a couple of failed GVHD trials, so they must have learnt something.
*For the uninitiated, the enhanced approach had already been discussed by SI during the 2020 ODAC meeting, but I believed only developed during the COVID period and after the first CRL, with whatever scraps of regulatory guidance the company managed to wrest from the FDA during what would have been a very difficult period.
**Novartis provided financing to kickstart ruxolitinib’s development, and contributed Novartis's global reach and marketing expertise. The agreement formalizing their collaboration established separate sales territories: Incyte was to sell ruxolitinib in the United States, and Novartis everywhere else. The parties agreed to pay each other royalties based on sales in their respective domains and to cooperate on the development of new uses for ruxolitinib. But this fruitful collaboration turned sour in 2019, when Incyte unilaterally decided that it was entitled to reduce its royalty payments to Novartis by 50%, as a result of the loss of some of its regulatory protections for the drug in the United States.
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