Trends in mesenchymal stem cell clinical trials 2004-2018: Is efficacy optimal in a narrow dose range?

Abstract The number of clinical trials using mesenchymal stem cells (MSCs) has increased since 2008, but this trend slowed in the past several years and dropped precipitously in 2018. Previous reports have analyzed MSC clinical trials by disease, phase, cell source, country of origin, and trial initiation date, all of which can be downloaded directly from ClinicalTrials.gov. We have extended analyses to a larger group of 914 MSC trials reported through 2018. To search for potential factors that may influence the design of new trials, we extracted data on routes of administration and dosing from individual ClinicalTrials.gov records as this information cannot be downloaded directly from the database. Intravenous (IV) injection is the most common, least invasive and most reproducible method, accounting for 43% of all trials. The median dose for IV delivery is 100 million MSCs/patient/dose. Analysis of all trials using IV injection that reported positive outcomes indicated minimal effective doses (MEDs) ranging from 70 to 190 million MSCs/patient/dose in 14/16 trials with the other two trials administering much higher doses of at least 900 million cells. Dose-response data showing differential efficacy for improved outcomes were reported in only four trials, which indicated a narrower MED range of 100-150 million MSCs/patient with lower and higher IV doses being less effective. The results suggest that it may be critical to determine MEDs in early trials before proceeding with large clinical trials. Lessons learned Initially, the number of trials increased, then leveled off several years ago and dropped dramatically in 2018. Many of the doses of cells being delivered may not be maximally effective because they are too low or high in some trials. It is important to test for efficacy as well as safety in early trials. Significance statementThe significance of this study is that critical numbers of cells may need to be used for the most effective stem cell therapies. The results suggest a range of minimally effective cell doses for intravenous injection, which is the method used in almost half of all therapies. Increasing doses are usually tested for safety, and the highest tolerated dose is often used in a clinical trial. Studies need to measure initial efficacy along with safety to use the most effective doses rather than the safest doses tolerated, which might be an overdose. Too many or few cells are not optimal.