After the COVID-19 pandemic started clinical trials quickly sprouted up to test various kinds of cell therapy for COVID-19 including stem cells. The most common rationale for this approach is to suppress damaging overactive immune responses.
Trials of cell therapy for COVID-19 including stem cells
I’ve written quite a lot about these cellular medicine and stem cell trials over the past 16 months or so. That link will also take you to some guest posts on the topic and other COVID info.
Many of these trials seemed small and not designed to test efficacy. I was concerned about some of the exuberance about the idea of cells for COVID-19 in the media and even by politicians.
There weren’t any comprehensive analyses of these trials. How much potential do these trials have overall?
My talented UC Davis student Mina Kim and I started a study last summer in this area. The goal was to try to predict the rigor and impact that these new trials might have.
Our work was just published Friday in the journal Regenerative Medicine. You can see a figure from the paper on the geographic distribution of the cell therapy for COVID-19 trials above.
The trial landscape
This paper, entitled, “Anticipated impact of stem cell and other cellular medicine clinical trials for COVID-19″ came to a number of interesting conclusions.
One hypothesis was disproven, but that led to another surprising conclusion.
A concern I’ve had in following the flood of dozens of cell therapy trials for COVID-19 was that rigor might be sacrificed in many of these trials. After all, the horrible consequences of the pandemic put pressure to move potential therapies forward quickly. So one hypothesis I had was that COVID-19-related cell therapy trials might have lower anticipated rigor than other cell therapy trials unrelated to the pandemic.
However, in our study we found in a general sense that the landscape of cellular medicine trials for COVID-19 was not predicted to be less rigorous than those unrelated to COVID-19.
If anything these COVID-19 trials seemed to have more use of three trial design features that we mainly focused on: randomization, at least double-blinding, and use of placebo controls.
I was surprised.
The interpretation is a bit complicated though because our controls for comparisons were challenging to choose and develop. We ended up using a broad set of cellular therapies unrelated to COVID-19 as one control. I wanted a second control group that was more specific so we focused on cellular therapies for arthritis.
The surprise was that COVID-19 trials, despite the understandable pandemic pressure, were predicted to have the potential to end up having more impact than the no-specific-disease and arthritis control groups.
Few cell therapy for COVID-19 trials use the 3 design features overall
Notably, relatively few of the COVID-19 cellular therapy trials themselves used all three rigor-associated design features. It’s just that the general (no one specific disease) and arthritis groups of cellular therapy trials used these design features even less.
Part of what may be going on here is that the cell therapy field is relatively new. As a result it has loads of early trials that naturally have less use of placebo controls and such.
With this in mind, in addition to the overall analysis, we also compared COVID-19 and control trials paired by like phase (e.g. Phase 1 to Phase 1, Phase 2 to Phase 2, etc.). In this apples-to-apples comparison, the general trends held up.
Again, this was an important analysis because the phase of a trial or group of trials strongly influences the use of randomization, at least double blinding, and use of placebo controls.
Stem cells for COVID-19 trials often jumped ahead of Phase 1
It was also interesting that despite the new nature of the pandemic, relatively few of the stem cells for COVID-19 trials were Phase 1 or earlier. This may be in part because of past trial data supporting the general safety of the most commonly used type of cell, mesenchymal stem/stromal cells (MSCs). However, at the start of the pandemic there were very little relevant data on use of MSCs for any disease relevant to COVID-19.
Using MSCs for COVID-19 likely poses unique risks. Still, it seems regulators were okay with trials often jumping ahead to later phases for COVID-19.
Later trials should tend to have more rigor-associated design features.
The size of trials also bears on their power. Most COVID-19 cellular therapy trials were relatively small, with around 40-something participants. This was about the same size on average as cellular therapy trials in general focusing on no particular disease.
Cell therapy trials for arthritis were on average about three-fold bigger. This may reflect the fact that the idea of cell therapies for arthritis has been around much longer. There is also a large population of people with arthritis who can readily enroll. While there are a vast number of COVID-19 patients at any one time, enrolling them in trials is complicated by issues like their contagious state.
Small trials make it difficult to come to conclusions from their data. For instance, a small cord trial out of University of Miami for COVID-19 presented seemingly somewhat encouraging findings, but it was so small that the baseline characteristics of the control and interventional groups were too different. If there’s real potential there, it’ll have to be defined in the upcoming larger follow up study.
Another even newer trial pub that seems fairly rigorous on face value (even if very small) just came out in Stem Cells Translational Medicine. It reports some possible benefit, but I’m still trying to assess the meaning there. There wasn’t much data on the baseline characteristics of the groups.
Of the 79 interventional cellular therapy trials that we found on the US and China clinical trials registries, most are not going to tell us much of anything about efficacy. They just weren’t designed to do that. They don’t have the power.
It’s important then for all of us including the sponsors to use caution in discussing possible efficacy in this area. There’s a long road ahead for this line of research to get to clear conclusions.
If cellular therapies are effective for treating COVID-19, this could be very impactful as it’s going to take many years to vaccinate a large proportion of the world’s population. At the same time, these therapies will have risks. For instance, infusions of MSCs could make COVID-19 patients sicker by overshooting and suppressing immune responses too much.
Very strong data is needed to inform any clinical applications here.
Since in our new paper we looked at two main databases, Clinicaltrials.gov and the Chinese registry, in theory it might also be possible to compare trials from these 2 databases. However, the Chinese registry search tool functions somewhat differently so we have to be cautious in making comparisons. We couldn’t always use the exact same search terms. Still, it seemed like there might be some meaningful differences. Check out the paper for that.
There’s another final more general lesson from this study. Predicting in advance the anticipated rigor or impact of groups of somewhat diverse clinical trials is very challenging. However, I think it’s valuable and worth the effort. Predictions can then be checked in future years for accuracy, multiplying the impact of such research. This can then also lead to refinement of predictive tools.
It’ll be interesting to follow up and see the actual data that the trials produce in the future on cell therapy for COVID-19 trials.
In terms of the pandemic, is cell therapy for COVID-19 going to make a meaningful difference? Are one or more such approaches going to get formal drug approval? We need more data to be able to make such a prediction confidently, but I’m still leaning skeptical. Only a handful of these trials struck me as having the potential to yield concrete results on efficacy.