CEO Itescu needs to go, page-821

Hi @LeftYahoo,

your questions appear inter-woven. So I'll try to address them chronologically.

It's difficult to speculate about what may have occurred between the FDA and MSB in the follow-up to the 2020 ODAC meeting. No doubt there were numerous meetings, and it may be that a quasi-randomised trial(s) of adults was discussed with the FDA at that time. Personally, I think it unlikely it was considered necessary at any earlier time given the history of SAT approvals in rare oncology disease, the orphan drug designation for paediatric treatment and FDA's award of priority review to Remestemcel-l for paediatric SR-aGVHD. Then, the further exchanges between MSB and the FDA leading up to the 2023 CRL are still confidential, so it's difficult to do other than speculate about what may have been discussed, which I find unproductive. Lets not do that.

First, you asked why the FDA would "no longer require a randomized trial". If that question can be asked now, it can of course also be asked as of October 2020.

The short answer is that FDA never did.

The longer answer, of course, lies partly in the question, as the text of Mesoblast Ltd's notice said only that the FDA " recommended " that Mesoblast conduct at least one additional randomized, controlled "study". It seems that the only real focus that's left for you and me is any perceived need for " randomization ". I believe a vital clue here is the linked purpose in MSB's 2020 announcement i.e. that the study was to provide " further evidence of the effectiveness" of remestemcel-L for SR-aGVHD. Provided that objective was met to the FDA's satisfaction, I don't believe randomization (as a feature of any study protocol(s)) was ever mandatory, or even ultimately necessary in the FDA's eyes, even in 2020. I see the term 'RCT' as a form of short-hand used by many when their real meaning is 'adequate and well-controlled'. We can discuss in a separate thread the pros and cons of RCTs & how the FDA's position on the acceptability of 'adequate and well-controlled' RWE for the purpose of establishing efficacy has evolved in the past 5 years. But I feel an important thing here is that word 'evolve'. In my mind, the critical matter will always be whether the totality of the evidence tendered to the FDA adequately addresses all significant risks - cue the biostatisticians.

So to answer your real question long-windedly, the reason the FDA did from 2020 onwards no longer request 'randomisation' as part of the process of acquiring evidence to put before it, is because - despite the confidentiality of those processes - FDA must have satisfied itself on the design of the study processes tendered to it by MSB that it could possibly have as a totality an 'adequate and well-controlled' body of evidence of efficacy from those studies & it was reasonable to expect that evidence would be complementary.

Second, one reason why the externally controlled, non-randomized, no-placebo-involved trial which I believe is likely to be put forward now couldn't have been "just performed in children" as a " small, quick, targeted, non-randomized, externally controlled study " back in 2020/ 2021 is that the data available to Mesoblast Ltd at that time to select an appropriate external control didn't include CIBMTR's 4-yr GVHD-001 obervational cohort survival outcome study (see https://tandem.confex.com/tandem/2023/meetingapp.cgi/Paper/22430). You'll recall the FDA had problems with consistent external controls in this disease - see Dr Sung's comments at ODAC. Neither did the data available in 2020 include the other key potency & CQA validation study results on %IL2-Rα inhibition presented by Dr Kurtzberg at TANDEM in February 2023 i.e. " The Immunomodulatory Activity of Remestemcel-L on T Cell Activation in Vitro is a Direct Measure of Product Potency and Correlates with Clinical Outcomes in Pediatric Patients with Steroid-Refractory Acute Gvhd" (see https://tandem.confex.com/tandem/2023/meetingapp.cgi/Paper/22428). This shouldn't surprise us - recall that CEO Itescu stated across the table, about the use of IL2-Rα as a CQA, at ODAC during the AM Session with Dr Robey (p. 131), " we are able to demonstrate that there is a clear correlation between a second potency assay, IL-2 receptor inhibition in vitro and the reduction over a 28-day period in activated CD4 T cells as defined by expression of IL-2 receptor in HLA VF, a direct significant correlation. That therefore allows us to validate this as a potency assay. ", so MSB was even then looking forward to the ability to do that & to then, if necessary, turn what it labelled its' qualitative bioassay into the primary bioassay - but it was looking forward.

Without those 2023 announced studies, there would be no 'demonstrated' basis of the revised focus of the MOA i.e. focussing (at least for registration purposes) on the role of T Cell proliferation. That rationale would be needed to inform the selection of external control. Also, it may have been hard for MSB to demonstrate the natural course of SR-aGVHD disease under current SOC, & it would have been impossible for MSB, for example only, to demonstrate to the FDA's satisfaction a degree of correlation with the MOA of %IL2-Rα inhibition as a CQA or to then construct and validate a potency assay demonstrating to the FDA an adequate analytical assay was in place prior to the conduct of the study.

And lastly, as to why the suggested non-randomised, interventional study could not be "just performed in children" now, i.e. post the August 2, 2023 CRL, this question can be viewed from a number of different angles, and perhaps it can be just performed in children but it shouldn't or even just needn't in all the circumstances (which we're not privy to). You describe this as a "new angle". I don't see it that way. Consider e.g.

- the consistency angle - you already noted that in 2020 the FDA mentioned that the 'further evidence' for children could come either from adults or children. So, the FDA apparently even in 2020 were prepared to extrapolate from adult outcomes to likely paediatric outcomes. We shouldn't be surprised here either - because that's exactly what Dr Przepiorka said FDA were happy to do for ruxolitinib in her FDA Approval Summary article: link here : the good doctor said " The Study 271 population did not include children. On the basis of the biology of GVHD and mechanism of action of ruxolitinib, the efficacy of ruxolitinib for pediatric patients with this indication can be extrapolated from the adult experience. The safety of ruxolitinib is described in labeling down to age 2 years. However, at the recommended dose for treatment of aGVHD, the lowest available formulation and strength of ruxolitinib (5 mg tablets) limits use to patients comparable in size to adults." Shouldn't MSB have the benefit of the same extrapolative process? ;

- the pragmatic angle - studying adults arguably allows for speedier recruitment & earlier commencement (& therefore completion) of any study, assuming sufficient numbers of these patients will be available to power an appropriate study based on the research collaborators' expectations of patient avaiability at the time of study commencement;

- the marketing angle - access to two markets for the price of one, seems like sound microeconomics to many;

- the admin process angle - it may be that, in the final analysis, the FDA isn't focussed on the age of the patient population at all by now & is really only interested in a limited aspect i.e. the admin desirability of a prospective confirmatory controlled dataset. One could argue it simply wants to see validated processes of manufacture, Type 1 error risk minimised in a 'good enough' trial structure, SAP methodology formulation (including external control identification & null hypothesis validation) in proper order, etc all demonstrably in place and run through in order from start to finish pre-study, so that FDA biostatisticians can at last agree the counterfactuals ensure there are no significant confounders in the 'targeted group' & then accept the (assumed) prospective confirmatory controlled dataset and tick the boxes they have left to tick for a first-in-class product.

There is also, as I see it, likely to be a higher level of understanding between MSB and the FDA at this point in time right now as to how far apart they really are. Witness the comments by CEO Itescu that the FDA offered MSB the option of providing controlled data from adults or children, with an expectation it will satisfy approvals for both. I'm not aware that has been put forward by the FDA previously.

I expect they are closer than they ever have been on MOA and CMC processes, despite embryonic stem cells being confused with everything, despite the FDA seeing the 'horrific' vision of stem cell butchers flogging unregulated therapies, despite COVID-19 pandemic disruption and cancellation of everything you can think of, and despite the Dr Christian Hinrichs of this world. Given that likelihood IMO, it may seem reasonable to tailor the proposed study to kill as many birds as possible with the one stone.

Food for thought. Just idle speculation on my part.
Cheers
GLTAH


PS: As an afterthought on the issue of "randomisation", as a practical example of hypocrisy IMO, consider that while Dr Christian Hinrichs, the expert from the National Cancer Institute was telling the August 2020 ODAC and the FDA that RCTs were a standard they needed to uphold because " I voted no. The reason why is that I think that we need to continue to make regulatory decisions about drugs based on rigorous high-quality science, and I think that this single-arm study that was performed did not represent that, and it's not compelling..." , the National Cancer Institute's Pediatrics Division received approval from the FDA in April 2020 for marketing of Koselugo (selumetinib) for pediatric patients, 2 years of age and older on the basis of " The recommendation to approve selumetinib is based on results from a single trial, entitled, “A Phase I/II Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor Selumetinib (AZD6244; HYD Sulfate) in Children with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)” (SPRINT), specifically from Phase II, Stratum 1 of the trial. SPRINT was an open-label, single arm, multi-center trial conducted by the National Cancer Institute (NCI) Pediatric Oncology Branch (POB). Fifty pediatric patients with NF1 and PNrelated morbidity were enrolled. The major efficacy outcome measure for the trial was overall response rate (ORR), or the percentage of patients with complete response (defined as PN volume confirmed at a subsequent tumor assessment within 3-6 months). The results from SPRINT Phase II Stratum 1 demonstrated an overall response rate (ORR) per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria of 66% (95% CI: 51, 79) based upon NCI central review, and 44% (95% CI: 30, 59) based upon independent central review (ICR). Among the 33 responding patients included in the NCI assessment, the median duration of response (DOR) was not reached while 82% of patients had a DOR of at least 12 months ". (see https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-neurofibromatosis-type-1-symptomatic-inoperable-plexiform-neurofibromas )

That's what we're dealing with here.