Well, I have nothing much better to do at the moment, and I'm genuinely interested given the short timeline and millions of dollars that are at stake. Watch me rip apart the latest Lassman Law vs Mesoblast FDA petition Supplement.
" This submission addresses new regulatory developments regarding the BLA for RYONCIL and provides further scientific support
for the arguments in the Citizen Petition that the data submitted in the BLA to establish
effectiveness – including data submitted in Mesoblast’s most recent filing – fails to meet the
rigorous standards necessary to qualify as “substantial evidence” of effectiveness under the Public
Health Service Act (“PHS Act”) and Food and Drug Administration (“FDA”) policies.
Accordingly, approving RYONCIL based upon this inadequate data set not only threatens
to expose pediatric patients suffering from SR-aGVHD to an unproven and potentially ineffective
treatment, but also could impede many eligible pediatric patients from using Jakafi (ruxolitinib),
the only medication approved by FDA for treatment of SR-aGVHD in pediatric patients 12 years
and older. Because of the serious and progressive nature of SR-aGVHD, even minor delays in
effective treatment pose a serious public health concern. "
A. Factual Background ( supposedly - I will only include all the mistakes that Lassman made )RYONCIL previously has been studied for a number of other indications, including;
chronic obstructive pulmonary disease (“COPD”), ( WRONG link Different Drug - Prochymal™ NOT Ryoncil )
acute coronary syndrome (“ACS”), - No record of Mesoblast treating this condition in Clinical Trials.gov
Diabetes Mellitus Type I (“DMT1”), ( WRONG link Different Drug - Prochymal™ NOT Ryoncil )
Crohn’s Disease, ( WRONG link Different Drug - Prochymal™ NOT Ryoncil )
but none of these development programs appear to have been successful. ( For the other drug, that is not going for approval Prochymal™ - and what is the relevance here? Why not talk about the trials and EAP that included mostly Ryoncil ? )
Likewise, RYONCIL was studied in a
Phase 3, randomized clinical trial for the treatment of SR-aGVHD in adult and pediatric patients,
but the study was unsuccessful and did not meet the primary endpoint for demonstrating the
effectiveness of RYONCIL. ( Partly correct, and some Ryoncil was used, and some Prochymal™ was used. The Ryoncil that was used on children in this first trial, provided the first piece of evidence that Ryoncil did indeed work on Children - which lead to the children only trial and FDA granting the children only EAP )
Mesoblast conducted a single-arm, open-label, non-randomized trial
of RYONCIL in a limited number of pediatric patients with SR-aGVHD. ( Just like the FDA agreed we should, and just like Ruxolitinib did, only Mesoblast used more children, and the patients in Mesoblasts trial were sicker than the patients in the Ruxolitinib trial. )“the FDA recommended that Mesoblast conduct at
least one additional randomized, controlled study in adults and/or children to provide further
evidence of the effectiveness of remestemcel-L for SR-aGVHD.”
B. Mesoblast Continues to Fail to Provide “Substantial Evidence” of ( FDA asked for further evidence, not substantial evidence ) Effectiveness in Treating SR-aGVHD in Pediatric Patients
As discussed in the July 20, 2020, Citizen Petition, a demonstration of efficacy must
account for many factors. Most importantly, it requires robust clinical data using a design that
minimizes bias and distinguishes the effect of the test drug from other influences. In remestemcelL’s case, reliance on a single-arm, historically controlled trial as the primary evidence of efficacy
is inappropriate because, among other things:
(1) remestemcel-L’s mechanism of action is poorly defined; ( No, It is clearly defined, but it is more complex than defined )
(2) prior, concurrently-controlled clinical trials have failed to support efficacy in a broad
aGVHD population, and there is little reason to believe remestemcel-L would perform
significantly better in pediatric patients alone; and ( But previous trials in pediatric patients only, and the pediatric EAP, and the pediatric GVHD001 trial have all performed significantly better than BAT - What is the relevance of referencing adult results, when the label is for children and adults and children have differing immune systems )
(3) Mesoblast’s use of a historical control in its
pivotal single-arm efficacy trial is problematic. ( Was it problematic for Ruxolitinib, which was approved ? )
"FDA identified the need for further scientific rationale to demonstrate the relationship of potency measurements to the
product’s biologic activity.”
New Information Confirms That Remestemcel-L’s Historical Control Cohort Is Severely Confounded ( What new information )
The Citizen Petition explained in detail why the historical control cohort relied upon by
Mesoblast is severely confounded. Among other things, the Citizen Petition exposed significant
problems with Mesoblast’s use of a 45% historical OR rate to assess efficacy, which Mesoblast
claimed is supported by “historical age and disease severity-adjusted published findings and
internal data showing an approximate 45% day 28 OR rate for aGVHD patients treated with
steroids, second-line systemic agents, and supportive symptom management.”6 However, the
Citizen Petition demonstrated that the references cited by Mesoblast do not appear to support its
historical control.
For example, the only study conducted solely in pediatric patients – the 2019
MacMillan article – appears to show a day 28 OR rate of 65%, which is 20 percentage points
higher than Mesoblast’s preferred historical control rate of 45%.8 ( Why don't we write the rest of what was written in the Macmillan article. 28 Day response rate for Minnesota High Risk was only 48%, 28 Day response rate for Grade 4 was only 43%, 28 day response for grade 3 was only 59 %, now ask yourself, had Macmillan had the same ratio as mesoblast - 88% Grade C/D..... Clearly the Macmillan severity grade adjusted response rate will be closer to 50%. Macmillan only had 14 grade 4 patients in his trial.)
This raised significant questions about whether Mesoblast’s historical control is biased and/or whether the results of the single-arm
study overestimate the efficacy of remestemcel-L, as is often seen with historically controlled,
non-randomized, single-arm studies. ( Actually this raises serious questions of does the author have any clue at all what might actually be involved in creating a disease severity adjusted control rate. For a start, Mesoblast had 88% Grade D, and Macmillan only had 22% Grade 3/4, So obviously to anyone with 1/4 of a brain, the publised Macmillan overall trial response rate cannot be used if it is 22% grade 3/4, and would need to have sub group analysis performed to figure out what the response rate would have been if 88% were grade 3/4 ...... Obviously )
Now that Mesoblast apparently has decided to resubmit its BLA without conducting any
additional randomized, controlled clinical trials, Petitioner has identified additional information
that raises further concerns about Mesoblast’s reliance on a single clinical trial with historical
controls. ( What additional information? ) Specifically, a review of the literature for second-line treatment in pediatric aGVHD
patients has been conducted and finds eleven (11) clinical trials and prospective and retrospective
studies that show a wide range of overall response rates, ranging from 34 to 100% (citations
provided in Appendix). The mean across the studies is 67.7% and the sample size weighted average
is 65.2%. Given the wide range of ORs (18.6% standard deviation), it is not possible to predict
how a control population would behave until there is a true control population, one that should be
established in a prospective, randomized, concurrently controlled clinical study. ( Yet - Ruxilitinib did exactly this in their approval single arm open label trial. The mixture of OR's that have been provided by the author - none of which have been disease severity-adjusted are unable to be compared with Mesoblasts' disease severity-adjusted Control rate. If the author wanted to get serious he would have provided disease severity-adjusted Control rates to directly compare - but chose not to probably realizing they are indeed close to Mesoblast's calculated historical control rate.
The data provided by the author does not have any P values provided, and that is because most of the P values are a joke, and the Grade of GVHD is also not considered at all - which is a must
100% response..... In a trial with 3 people !
Ruxolitinib 87.5%.. In a trial with 8 people !
Ruxolitinib 87%. .. In a trial with 5 people !
Here is an idea..... write to the CIBMTR registery and ask them for the Overall response for the entire pediatric database with 88% Grade C/D..... Oh wait, Mesoblast has already done that ! )
Mesoblast Has Made No Efforts to Conduct a Randomized, Controlled
Study In Adults and/or Children to Provide Further Evidence of the
Effectiveness of Remestemcel-L for SR-aGVHD ( I have to agree here- they have not since the requirement was provide further evidence, and they have in mortality and potency linked to survival. What a complete waste of time and lives another phase3 trial would have been when patients who have no treatment option could have been saved recieving ryoncil, are instead poisoned recieving ruxilitinib with no benefit observed in overall survival at all for Ruxolitinib)
In fact, the only “new” data generated by Mesoblast have been additional post hoc analyses
of the single-arm trial ( Well we know that is a blatant lie, because the company did not even have 2 year, 3 year or 4 year survival data, or adequate prochymal to ryoncil comparisons, or eap275 analysis at all included in the original BLA, the new data is really new data, only created in the year 2022, unavailable in 2021 )
On October 3, 2022, Mesoblast announced it had submitted “substantial new information
on clinical and potency assay items” to FDA to address the deficiencies identified in the Agency’s
CRL.5 Although Mesoblast states that the new information was submitted to its IND file “as
guided by FDA,” it appears that this filing is intended to constitute a resubmission of the BLA in
accordance with 21 C.F.R. § 601.3(b)(1) ( What a clanger this is, we know for a fact the BLA was not submitted in October 2022, becase it's public knowledge MSB submitted it in 2023 and FDA accepted the resubmission in 2023 )
“externally controlled trial should generally be considered only when prior belief in the superiority of the test
therapy
to all available alternative is so strong that alternative designs appear unacceptable ….”
FDA, Guidance for Industry: Choice of Control Group and Related Issues in Clinical Trials (ICH
E10), p. 28 (May 2001). In this case, especially given the string of failed prospective, concurrently
controlled clinical trials in GVHD and other diseases, there is no objective evidence to support a
“prior belief in the superiority of [remestemcel-L] to all available alternatives.”
( So, the 50% 4 year survival, which is superior to all other available therapies, BAT, and even Ruxolitinib , and the CIBMTR database , would justify a single arm as suitable then , particularly with no approved therapy )
That's enough, I think there is nothing that is valid really covered by the letter, that we don't allready know is factually incorrect, or we now know MSB has addressed, and so the moan is now invalid. Thoughts if anyone see's anything as actually valid ? Whytee you cannot say the entire letter and everything in it is valid - that just makes you also invalid 
(20min delay)