Administration of these living cells involves thawingout the...

Administration of these living cells involves thawingout the final container under hopefully controlled conditions in the clinicalsetting (hopefully, but in practice problematical). The FDA will want tounderstand how the parameters measured before the cells were frozen (as therelease criteria) relate to what is actually administered to the patient afterthe cells go through a freeze cycle (presumably well controlled via themanufacturing protocol) and a subsequent thaw cycle (less well controlled).

Hopefully, MSB has collected data relevant to thecharacteristics of the cells as administered - if not then it is another potential misstep in alitany of missteps!

Inresponse to above: Just for the benefit of the HC community, drugproduct release tests required by the FDA for cell therapies like ours includetests for safety and tests for effectiveness. The tests for effectivenessusually include cell number (dose), cell viability, identity, and potency. Alsomanufacturers must deliver a stable product so when ‘thawed’ the product attributes/parametersmatch the release criteria measured prior to ‘freezing’. In other words, the ‘freezing’and subsequent ‘thawing’ does not alter the viability, safety and potency ofthe product.

Obviously manufacturers of both allogenic (e.g. Rem-L) orautologous stem cell therapies (e.g. CAR-T therapy Khymriah) cannot conducttheir final release test at the hospital once the product is delivered fresh orthawed, so the FDA requires manufacturers to undergo a ‘stability-indicating’testing programs and subsequently follow cGMP protocols to ensure the integrityof the product from initial product manufacture to the patients’ bedside. A ‘stability-indicating’program to assess the stability characteristics ‘challenges/tests’ the drug productin conditions similar to being used in clinical trials and for subsequentmarketing, e.g. storage, shipping, consistent ‘thawing’… I also acknowledgethat Mesoblast has been able to ship product successfully during the COVID-19pandemic, no small feat. In other words, it is not a requirement to individuallyre-test each product after ‘thawing’ in the hospital setting prior toadministration/infusion (for clinical trials or thereafter).

@Techinvestor I am confident Mesoblast have conducted anddocumented ‘stability testing’ as this would have formed part of the original BLAsubmission; as well as documented SOPs regarding storage and transport ofproduct (e.g. cells cryopreserved between -60 to -150 degrees, designatedshipping containers that include real-time temperature, education andinstructions for how to ‘thaw’ etc). In addition it is a requirement manufacturersmust conduct stability testing in all phases of the IND trials (and I have seenno evidence/statement that the FDA have said we have not complied with thisrequirement). Furthermore use of the product past the duration of the trial(e.g. compassionate care usage) requires the manufacturer to verify thestability throughout the relevant time period, one reason why there needs to bereserve samples maintained even past the expiration date. Another reason I believeMesoblast has done the required ‘stability testing’.

I will cut Mesoblast some slack regarding the time to get thepotency assays right because potency assays for cell products are some of themost difficult assays to develop (hopefully widening the economic MOAT). Why? Firstit requires knowledge of how the therapy works or the MOA (and it seems theremight be multiple mechanisms of action to add to the complexity/uncertainty).Second, this may make potency assays prone to high degrees of variability. Soin short this takes some time to pin down (and ideally needs to be done ‘right’.Maybe it was Dr Krause that nudged Mesoblast to pursue a new method of potencyvalidation? Maybe he has insider knowledge how other autologous cell therapiesconfirm potency? He would definitely have insight to how the FDA thinks aboutcertain therapies, maybe the angle of T-cell regulation (could be as simple asa marker for T cell purity, ratios – we will soon find out) is the path ofleast resistance to assist approval?

I am glad Mesoblast are taking the time to optimise therelease protocol/potency tests (albeit not knowing the details of tests,discussions) before approval, as it would be very cumbersome, costly anddisruptive to address any such issues post-approval.

Finally I just want to highlight again that in some cases (ethicsone reason) the FDA may accept single arm trials compared to historicalcontrols with documented reports of how past patients have progressed with thedisease or condition in question. Found a statistic in a course I completedrecently (a bit dated but gives the gist) that for the 31 breakthroughtherapies approved between 2013 to 2016, about ½ were approved on the basis ofsingle arm trials or trials without any concurrent control.

Let’s hope Mesoblast has done enough to satisfy the FDA thistime round.