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.

Keywords: ClinicalTrials.gov; dose; intravenous; mesenchymal stromal cell.

Figure 1

Number of new mesenchymal stem cell (MSC) clinical trials registered in each year at http://ClinicalTrials.gov divided by clinical phase (A). B, Data in (A) represented in a graph of the 3 phases plotted separately

Figure 2

Number of trials using MSCs from different sources divided by phase. A, UC and placenta derived MSC are only allogenic. Autologous MSC were derived mainly from BM and adipose tissue with small numbers from other sources including dental pulp, gingiva, oral mucosa, perinatal tissue, peripheral blood, skin, menstrual blood, and stromal vascular fraction designated as other. B, Number of new MSC autologous and allogenic trials in each year. BM, bone marrow; MSC, mesenchymal stem cell; UC, umbilical cord

Figure 3

Number of clinical trials using proprietary MSC and involving companies. A, Graph of number of new trials using proprietary (blue) and non‐proprietary (white) MSC shown for four major sources. Small number of additional trials using MSC from dental pulp, oral mucosa, menstrual blood, and stromal vascular fraction have been included in the category called other. B, Number of new trials recorded in each year conducted by, or sponsored by, companies with all sources of MSCs. BM, bone marrow; MSC, mesenchymal stem cell; UC, umbilical cord

Figure 4

Mesenchymal stem cell (MSC) clinical trials by disease category subdivided by phase. The 14 disease categories shown account for >90% of the trials in our database. The remaining trials were defined as other

Figure 5

Routes of MSC administration in clinical trials subdivided by phases and dosing. A, Trials were divided into the 8 most commonly used routes with the remaining routes defined as other. Intravenous (IV) is by far the largest group. Intra‐cardiac (IC), intra‐articular (IAT), intra‐muscular (IM), intra‐osseous (IO), intra‐thecal (IT), intra‐arterial (IA). Implant includes MSC embedded in biological matrices or synthetic materials. B, Doses of MSC using different routes of administration in clinical trials using Box‐and‐Whisker plot showing the average (dot), median (horizontal line), 10th to 90th percentile whiskers, and 25th to 75th percentile boxes (*P < .05, **P < .02, ****P < .005). C, Disorders are divided by frequencies of different routes of MSC delivery