Stem Cell Therapy
Safety
Adverse Events (AEs)
All clinical intervention studies have the potential to cause adverse events. In clinical studies on stem cell therapy safety and tolerability is often determined by assessing changes in vital signs, laboratory tests, physical examination, questionnaires, imaging studies and reported side effects, also known as adverse events (AEs). An AE as is defined by the FDA as “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.” AEs are classified depending on their seriousness, severity, expectedness and relatedness to the treatment. General categories include, serious or non-serious; expected or unexpected; not treatment related, possibly treatment related, and treatment related. A grading system of AEs has been developed and is used to report severity of AEs. Most clinical trials often report only grade 3-5 AEs as these are most concerning. There are 5 grades; Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening or disabling, Grade 5 is death. Grades 4 and 5 are considered to be serious adverse events (SAEs). An SAE is defined as “any untoward medical occurrence that at any dose results in death, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or congenial anomaly or birth defect.”
Reported Cases of Adverse Events
In 2018 Bauer et al (https://doi.org/10.1002/sctm.17-0282) presented a review of 35 cases describing acute or chronic complications or death after stem cell therapy. They used Google scholar and PubMed search engines and identified 19 cases from scientific literature and 16 cases from media reports. The type of stem cell and derived tissue used in these reports was diverse. Twelve cases involved adipose derived stem cells and one case involved umbilical cord blood which are both commonly used in research due to a large number of studies demonstrating safety. The remaining cases involved stem cells rarely used in research including animal based stem cells, fetal neural stem cells, olfactory mucosal stem cells, and olfactory ensheathing fetal cells.
Of the 35 reported cases, serious adverse events (SAEs) were mostly neoplastic (tumor forming), neurologic, cardiovascular, vision loss, infections, or febrile illness; 5 cases involved neoplastic complications, 4 cases involved neurologic complications, 7 involved cardiovascular complications, 3 involved vision loss (All from BioHeart Int.), 6 involved infectious complications, 2 involved febrile illness, and 2 involved autoimmune reaction. The remaining cases were not adequately described.
Of these 35 cases, only 5 cases were from the United States with three cited in scientific literature resulting in blindness after stem cells were injected into the eye. All three cases of blindness involved stem cells from BioHeart Inc which halted eye injections after FDA warning letters and ensuing court cases.
A 2019 Washington Post article (https://www.washingtonpost.com/national/health-science/miraculous-stem-cell-therapy-has-sickened-people-in-five-states/2019/02/26/c04b23a4-3539-11e9-854a-7a14d7fec96a_story.html) reported recent adverse events (AEs) from stem cells therapy in at least 17 people after receiving umbilical cord derived stem cells between 2018 and 2019. Most of these cases were local or systemic bacterial infection. After receiving numerous reports of AEs, the CDC launched an investigation and determined the infections were probably due to contaminated stem cell products after they found bacteria in a number of unopened vials obtained from the clinics where AEs were reported.
The reports presented by Bauer et al and the Washington Post raises concern regarding the potential AEs of stem cell therapy and are important to be aware of. However, these reports only highlight relatively rare adverse events and do not reflect the safety and tolerability reported by most clinical trials.
The safety and tolerability of stem cell therapy has been clearly demonstrated in numerous studies involving large numbers of patients treated for various different conditions. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.
Please see Safety Research Archive for a list of recent clinical studies demonstrating the safety of stem cell therapy in various common conditions.
Adverse Events
- All clinical intervention studies have the potential to cause adverse events.
- In clinical studies on stem cell therapy safety and tolerability is often determined by assessing changes in vital signs, laboratory tests, physical examination, questionnaires, imaging studies and reported side effects, also known as adverse events (AEs).
- An AE as is defined by the FDA as “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 - AEs are classified depending on their seriousness, severity, expectedness and relatedness to the treatment. General categories include, serious or non-serious; expected or unexpected; not treatment related, possibly treatment related, and treatment related.
- A grading system of AEs has been developed and is used to report severity of AEs. Most clinical trials often report only grade 3-5 AEs as these are most concerning. There are 5 grades; Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening or disabling, Grade 5 is death.
- Grades 4 and 5 are considered to be serious adverse events (SAEs). An SAE is defined as “any untoward medical occurrence that at any dose results in death, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or congenial anomaly or birth defect”.
https://www.nbt.nhs.uk/research-innovation/running-your-study/safety-reporting/classification-adverse-events
Safety of Stem Cell Therapy
- The safety and tolerability of stem cell therapy has been clearly demonstrated in numerous studies involving large numbers of patients treated for various different conditions. Common conditions include heart disease such as cardiomyopathy, heart attack, stroke, orthopedic conditions such as osteoarthritis, autoimmune diseases such as lupus and neurological conditions such as multiple sclerosis, autism, cerebral palsy and many more.
- Factors that affect safety and tolerability include individual patient’s health, source of allogenic stem cell products, stem cell dose, frequency of treatment and method of administration (IE. Injections into the eye, brain and spinal cord are higher risk for adverse events compared to intravenous or local joint injections). For more information on the safety of stem cell therapy, please see our “Safety Research Archive” [INSERT HYPERLINK].
- Non-serious and non-severe adverse events reported in the literature include headache, local injection site irritation, pain and swelling, fever, and others which have been documented to be short lived and typically did not require additional treatment. Infection is a serious complication and is always a risk with any type of injection therapy. Sterility of stem cells and stem cell products is of the upmost importance to eliminate risk of infection. Furthermore by using universal administration safety protocols risk of infection due to administration is significantly minimized, if not eliminated. Serious short or long term adverse reactions to stem cell therapy such as blindness, cancer, blot clots, stroke, death, etc., have been reported in published studies and in the media, but are exceedingly rare.
Reported Cases of Adverse Events
- In 2018 Bauer et al presented a review of 35 cases describing acute or chronic complications or death after stem cell therapy. They used google scholar and pubmed search engines and identified 19 cases from scientific literature and 16 cases from media reports. The type of stem cell and derived tissue used in these reports was diverse. Twelve cases involved adipose derived stem cells and one case involved umbilical cord blood which are both commonly used in research due to a large number of studies demonstrating safety. The remaining cases involved stem cells rarely used in research including animal based stem cells, fetal neural stem cells, olfactory mucosal stem cells, and olfactory ensheathing fetal cells.
- Of the 35 cases, SAEs were mostly neoplastic (tumor forming), neurologic, cardiovascular, vision loss, infections, or febrile illness; 5 cases involved neoplastic complications, 4 cases involved neurologic complications, 7 involved cardiovascular complications, 3 involved vision loss (All from BioHeart Int.), 6 involved infectious complications, 2 involved febrile illness, and 2 involved autoimmune reaction. The remaining cases were not adequately described.
- Of the 35 cases, only 5 cases were from the United States with three cited in scientific literature resulting in blindness after stem cells were injected into the eye. All three cases of blindness involved stem cells from BioHeart Inc which halted eye injections after FDA warning letters and ensuing court cases.(INSERT: Citation/link to article)
- A 2019 Washington Post article reported recent adverse events from stem cells therapy in at least 17 people after receiving umbilical cord derived stem cells between 2018 and 2019. Most of these cases were local or systemic bacterial infection. After receiving numerous reports of AEs, the CDC launched an investigation and determined the infections were probably due to contaminated stem cell products after they found bacteria in a number of unopened vials obtained from the clinics where AEs were reported.
- “This investigation highlights the serious potential risks to patients of stem cell therapies administered for unapproved and unproven uses other than hematopoietic or immunologic reconstitution.” (INSERT: Citation/link to article)
- The reports presented by Bauer et al and the Washington Post raises concern regarding the potential AEs of stem cell therapy and are important to be aware of. However, these reports only highlight adverse events and do not reflect the safety and tolerability reported by most clinical trials.
- Please see “Safety Research Archive” for a list of recent clinical studies demonstrating the safety of stem cell therapy in various common conditions.
Safety Research Archive
The purpose of the “Safety Research Archive” is to highlight recent clinical studies demonstrating the safety of stem cell therapy in a format that is quick and easy to review. More detailed summaries of these studies can be found in our Efficacy Research Archive.
OSTEOARTHRITIS: SAFETY OF INTRA-ARTICULAR STEM CELL THERAPY IN OSTEOARTHRITIS
- In 2015 Centeno et al conducted a multicenter analysis of 2372 patients who received bone marrow derived stem cell therapy for various orthopedic conditions. The therapy was deemed safe and well tolerated due to observed low rates of reported adverse events and substantially lower rates of serious or treatment related adverse events. (INSERT: Citation/link to article)
- A 2019 randomized controlled trial by Freitag et al involving 30 participants with knee osteoarthritis treated with adipose derived mesenchymal stem cells revealed no serious adverse events during 12 month follow up. Only two participants reported severe pain and swelling at injection site. They concluded that “Autologous ADMSC therapy appears to be a safe and effective therapy for knee osteoarthritis and may have the potential to prevent disease progression.” (INSERT: Citation/link to article)
- In a 2019 double blind, randomized, self-controlled trial, by Hong et al observed no severe adverse events during 12 month follow up in 16 participants with knee OA treated with adipose derived stem cells (Stromal Vascular Fraction). Six participants reported pain and swelling at injection site. They concluded that “The results of this study suggest that autologous adipose-derived SVF treatment is safe and can effectively relief pain, improve function, and repair cartilage defects in patients with knee osteoarthritis”. (INSERT: Citation/link to article )
- A 2019 double blind, randomized controlled trial by Lee et al also showed no serious adverse events during 6 month follow up in 24 participants with knee osteoarthritis treated with adipose derived mesenchymal stem cells. Treatment related AEs were reported in eight participants; 6 joint pain and 2 joint swelling. They concluded that “An intra-articular injection of autologous AD-MSCs provided satisfactory functional improvement and pain relief for patients with knee osteoarthritis in the outpatient setting, without causing adverse events at 6 months’ follow-up” (INSERT: Citation/link to article)
- In 2019 Matas et al conducted a triple blind, randomized trial of 29 participants with knee osteoarthritis treated with umbilical cord mesenchymal stem cells and observed no serious AEs during 12 month follow up. Common treatment related AEs included acute synovitis, joint pain and swelling. They concluded that “Repeated UC‐MSC treatment is safe and superior to active comparator in knee OA at 1‐year follow‐up” (INSERT: Citation/link to article)
- In 2017 Bansal et al conducted a preliminary clinical study of adipose derived stromal vascular fraction stem cells and PRP in 10 patients with knee osteoarthritis and observed no serious AEs during the 24 month follow up. One participant reported pain and swelling at harvest site and one participant developed acute synovitits. They concluded that “The procedure demonstrated a strong safety profile with no severe adverse events or complications reported” (INSERT: Citation/link to article)
CARDIOVASCUALR CONDITIONS AND SAFETY OF INTRAVENOUS STEM CELL THERAPY
- In 2019 Jayaraj et al conducted a systematic review with meta-analysis of 6 randomized, controlled trials involving 526 patients with advanced heart failure to assess safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They found no difference in risk for all-cause mortality between treatment and control groups, and most trials reported no or did not report treatment related complications such as arrhythmia, stroke or heart attack. Jayaraji et al concluded that the safety results from this review correlate well with previous meta-analysis. “The safety analysis indicates no increased risk of mortality in patients with advanced heart failure” (INSERT: Citation/link to article)
- In 2018 Lalu et al conducted a systematic review of 23 studies involving 1,148 patients with acute heart attack or ischemic heart failure to assess the safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They observed no association between stem cells and acute AEs in all 23 studies and no difference in risk of mortalities between treatment and control groups. They concluded that “Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe.” (INSERT: Citation/link to article)
- In 2017 Bartolucci et al conducted a double blind, randomized, placebo-controlled trial to evaluate safety and efficacy of IV umbilical cord derived mesenchymal stem cells in 30 patients with chronic heart failure. They observed no acute treatment related AEs, no significant differences in AEs between placebo and treatment group and no significant abnormalities in laboratory tests during the 12 month follow up. They concluded that “Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment.” (INSERT: Citation/link to article)
- In 2016 Nguyen et al conducted a systematic review of 29 randomized, controlled trials involving 2817 patients with heart failure and ischemic heart disease. Stem cell derived tissue used and route of delivery was not uniform among studies. No SAEs after intracoronary or IV stem cells in acute heart attack and ischemic heart disease. Two studies using skeletal myoblast cells reported acute arrhythmias. They concluded that “Safe delivery of cells has been demonstrated in both preclinical and clinical trials”. (INSERT: Citation/link to article)
- A 2016 systematic review by Fisher et al of 38 studies involving 1907 patients with ischemic heart disease and congestive heart failure demonstrated safety of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They found SAEs during mapping or injection procedure were infrequent, early postoperative SAEs were rare and AEs associated with bone marrow aspiration were rare. (INSERT: Citation/link to article)
- In a small 2016 study to assess safety and efficacy of IV umbilical cord derived mesenchymal stem cells in patients with systolic heart failure, Fang et al observed no complications, AEs or SAEs during the 12 month follow up. No cases of distal coronary artery occlusion, acute cardiac dysfunction and ventricular arrhythmia occurred. (INSERT: Citation/link to article)
STROKE AND SAFETY OF INTRAVENOUS STEM CELL THERAPY
- In 2019 Vahidy et al demonstrated the safety of intravenous bone marrow derived mononuclear stem cells in the treatment of 25 patients with acute ischemic stroke. All patients successfully completed the study intervention and no treatment related SAEs were observed in the 12 month follow up. Of 31 treatment related AEs 28 were grade 1 (mild) and ten of the 31 were due to harvest procedure. They concluded that “Bone marrow harvest and infusion of MNCs is safe and feasible in patients with acute ischemic stroke.” (INSERT: Citation/link to article )
- In 2019 Levy et al assessed safety and preliminary efficacy of IV bone marrow derived stem cells in 36 patients with chronic stroke. Treatment was deemed safe based on serial examinations, ECG, laboratory tests, imaging studies and reported of AEs. 15 SAEs were reported and none were ‘possibly’, ‘probably’ or ‘related’ to treatment. Two Grade 1 AEs were ‘possibly related’ to treatment and included urinary tract infection and irritation at IV site. They concluded that “Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe”. (INSERT: Citation/link to article)
- In 2018 Laskowitz et al assessed the safety and feasibility of IV umbilical cord blood in 10 adult patients with acute ischemic stroke. Of 113 reported AEs, 112 were classified as “unrelated to treatment” to treatment. They concluded that this therapy was safe and well tolerated in these patients. They concluded that “Data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke”. (INSERT: Citation/link to article)
- In 2018 Xue et al conducted a systematic review including 23 studies with 1,279 patients with ischemic stroke. Stem cell derived tissue used and route of delivery was not uniform among studies. No SAEs were reported in the follow up period which ranged from 1 to 60 months. The most common AEs were headache and fever which resolved within 24 hr without treatment. They concluded that “MSC therapy is safe and effective in treating ischemic stroke” (INSERT: Citation/link to article)
