MSC 2013: Standardization and nomenclature debate

by Alexey Bersenev on August 22, 2013 · 4 comments

in consensus, mesenchymal

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MSC 2013 conference just finished in Cleveland. It was great meeting! The most interesting discussion from the second day of conference was about standards and nomenclature of MSCs. Expert’s panel included Arnold Caplan (Case Western, conference director), Mahendra Rao (NIH) and Paul Simmons (Mesoblast).

Mahenrda Rao started discussion from expressing a position of NIH/ FDA on the issue of MSC standards. FDA views every MSC product, which derived from different source and different tissue, cultured under different conditions, underwent different processing as a distinct drug. So, if we will apply this to every submission, the number of products will be much greater than a number of applications for small molecules or/and chemical drugs submitted to the agency. This is a fundamental problem. Obviously, FDA considers it as a very important issue. He said that FDA/ NIH needs a consensus from professional MSC community. If we will get a good proposal, NIH will be very supportive to finalize and distribute the standard.

Rao said that we need some kind of common standard characterization data – he called it a “ruler” (metrics), which everyone can use as a reference to measure a minimal criteria of MSC identity and quality. He compared this ruler with a fluorescent beads calibration in FACS machine – everyone accept it universally as a quality control. With recent MSC characterization paper, FDA has started to create such ruler. However, Caplan thinks that we can not apply a ruler for MSC-based cell products. He compared it to a “X-mas tree”, which we can “decorate” in terms of targeted therapy and desired MSC function. “We need to help FDA to build X-mas tree, not a ruler” – he said. One comment from the audience made discussion even hotter. A commenter (who used to work for FDA) said that realization of idea of multi-dimentional ruler will take 1-2 decades. He thinks that FDA won’t listen different groups but will base its decisions on a data from few products on market. So, there was no defined opinion and consensus on it. Nonetheless, if some kind of ruler will be applied, multiple parameters should be accounted, such as: origin (source, tissue), species, sex, age, culture conditions, population doubling (instead of passage), composition of final product and other.

Caplan highlighted differences between industry and academia approaches. He said that criteria for academic and for commercial cell products could be different: “Bone marrow MSC were a gold standard for the industry, but they are not!” He believes that all differently derived MSC should be assayed under different specific conditions. He thinks that approach, where all CD markers were described many years ago, “screwed up of whole industry”. Caplan is very much in favor of industry: “From bench to bedside is wrong way, we need to go from bench to business to bedside”. He pointed out, that FDA has a huge amount information about MSC from industry, but it’s not public. We all can greatly benefit from this information, because “industry guys” are the leaders in establishing release criteria and potency assays. So he “plead for FDA transparency”.

The whole issue of standardization is very confusing for the MSC community, so it’s hard to come with consensus. Some questions from audience were: “what nomenclature should we use in papers to satisfy reviewers?” and “when standards will be created?”. I asked a panel about how to move forward – consolidate the efforts and propose a standards draft. Unfortunately, I didn’t get clear answer. Rao mentioned that there are mechanisms at place (ISCT Committee, National Institute of Standards…), but we are moving too slow. He thinks that we need stakeholders meetings for brainstorm and consensus. One of such public meetings actually scheduled for October 7 at FDA.

Simmons highlighted the importance of potency assays in MSC characterization. He thinks that potency is a “black box” and its significance is hugely underestimated. He said that markers are causing a big problem, because they are frequently irrelevant. As some other speakers, he pointed out that in vitro assays are not predictive of in vivo function. He said that assays should probably be defined based on MSC source. We know it for bone marrow MSC (for example – formation of ossicles in vivo), but we don’t know what to use for adipose or placental MSCs.

Overall, this discussion was very interesting, but not very satisfying. Everybody is acknowledging the necessity of standardization and use the same terms, everybody knows how hard it is, but nobody has a solution on how to come up with a consensus and fix the problem.

{ 4 comments… read them below or add one }

Owen August 22, 2013 at 1:03 pm

Great piece on how much a mess the current standardisation on MSCs is.

It’s hard to see how can move forward if can’t even come to some sort of conclusion on how to define MSCs. Like you mentioned the surface marker characterisation (albeit easy) paradigm is ineffective, with fibroblasts & perivascualr cells showing similar marker expression, gene expression and to some extent tri-lineage differentiation.

The X-mas tree model sounds good, although a horrible metaphor. It’s a shame that this might be unprobable due to the inflexibility of the FDA. As a product I think MSCs will to be defined according to their intended use. ie. biological release assays for MSCs used in GvHD, is going to be different than those for CLI, or cardiac indications. However, it is complicated by the undefined mechanism of action of MSC.

‘multiple parameters should be accounted, such as: origin (source, tissue), species, sex, age, culture conditions, population doubling (instead of passage), composition of final product and other’
This is great to prove standardisation.

It’s frustrating that after doing my PhD for 4 years using MSCs, I can’t confident define an MSC, more so describe what it isnt!

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Claudia Zylberberg August 23, 2013 at 9:29 am

This reminds me that we are in the biologics sector where things are not necessarily defined The same is true for plasma derived products like Factor VIII, or many other such as simply as FBS where each lot has a different composition, and we don’t know why they perform differently. We need to learn to live with the limitations of this raw material and work with what we have: potency related with MOA(mechanism of action) and biomarkers that synergistically can narrow the scope. Until the tools are ready to assist in the transition to a more “defined” strategy, all stakeholders have to follow this path closely. The most important factor will be to translate this to the industry for a validated and release criteria.

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SammyJo Wilkinson February 9, 2014 at 5:56 pm

Here is Arnold Caplan et al. follow on the his presentation reported on above. Giving the scientific context of what is known as of today on safety/effectiveness of MSCs, ant their characterization.
“Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine”
http://www.nature.com/emm/journal/v45/n11/pdf/emm201394a.pdf

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Rodeghiero Francesco July 12, 2014 at 6:29 am

Very interesting debate! In the lack of a standard how can we compare outcome results of academic clinical trials? Standardization is a must not only for companies.

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