Unproven regenerative medical products have led to infections, disabilities, and deaths

Stem cell products and other regenerative therapies have significant potential to treat traumatic injuries and serious diseases. Although some have earned approval from the Food and Drug Administration, most have not, and many of these unapproved interventions have led to life-threatening infections, chronic pain, and even death.

More than 700 clinics in the U.S. offer unapproved stem cell and regenerative medicine interventions (SCRIs) for conditions such as Alzheimer’s disease, muscular dystrophy, autism, spinal cord injuries, and, most recently, COVID-19. The products made and sold by these businesses typically use cells from the patient’s own body or from donated amniotic fluid, placental tissue, or umbilical cord blood, among other birth-derived cells and tissues. FDA has given manufacturers and marketers of SCRIs until May 31, 2021, to come into compliance with the agency’s regulations governing human cell and tissue products, including submitting those products for FDA review when necessary.

FDA uses reports of adverse events—undesirable patient experiences associated with the use of medical treatments—to help identify potentially dangerous products meriting further investigation. However, adverse events associated with any medical product are generally underreported, and providers of unapproved treatments are particularly unlikely to report patient harm to regulators or disclose such cases through public reporting— making it more difficult for the agency to prioritize its enforcement actions, and also leading policymakers and the public to underestimate the risks of these interventions.

To create a clearer picture of the risks that these interventions pose and underscore the need for increased FDA oversight, The Pew Charitable Trusts gathered reports of adverse events (AEs) linked to unapproved SCRIs administered outside of clinical trials. In total, we identified reports of 360 people who had AEs that occurred between 2004 and September 2020, including:

• 334 cases documented in peer-reviewed journals, government and news media reports, and other literature.
• 5 cases reported in FDA’s adverse event reporting system (known as FAERS), a public database of reports submitted to the agency.
•  21 cases described in consumer reviews of stem cell businesses posted to Google, Yelp, and Facebook.

Pew’s findings reinforce the need for increased FDA enforcement action against businesses that manufacture and market these unapproved—and, in many cases, unproven—products. (See Appendix A for definitions of key terms.) They also underscore how more frequent and thorough reporting of AEs by consumers and clinicians, and the FDA’s use of social media data, could allow the agency to more quickly identify businesses that are putting patients’ health at risk and target its limited oversight resources more effectively. More broadly, the findings highlight the importance of FDA oversight in ensuring that regenerative products on the market are safe and effective. The agency should move quickly to enforce its regulations governing human cell and tissue products for businesses that fail to comply by FDA’s May 31 deadline, and regulators should not hesitate to seek legal injunctions and mandate product recalls when necessary.

Adverse events related to unapproved SCRIs continue to be reported in the literature

Most of the adverse events identified in this research (334, or 93%) came from the literature, which included peer-reviewed articles, media reports, and government publications. This literature review built upon previous Pew research published in 2019, which identified 69 reports of harm, including lifelong disabilities and death, dating as early as 2004. For this latest round of research, which covered literature published between November 2019 and January 2021, the team identified an additional 265 cases of harm related to these products, bringing the total number of AEs to 334 and the total number of subsequent deaths to 20. The majority of the new cases added to the updated list (242) were published in January 2021 as part of a prospective study of patient medical records drawn from a single insurance company database—complete with information on the type of treatment and complications—to identify AEs associated with unapproved SCRIs. 

Many of the AEs identified involved serious bacterial infection, including at least two cases of septicemia, a life-threatening blood infection. Others included serious and even lifelong disabilities such as partial or complete blindness (9); paraplegia (1); pulmonary embolism (6); cardiac arrest (5); tumors, lesions, or other growths (16); and organ damage or failure in several cases that resulted in death. Many of these AEs required hospitalization (104) and caused acute or worsening pain (55). The most common type of interventions linked to these AEs were autologous (that is, the stem cells were obtained from the patient’s body) or donor stem cells administered by injection into the eye, spine, hip, shoulder, or knee.

The prevalence of infection among the adverse events is likely due to several factors. In some cases, the infections can originate from the products themselves, which may not have been processed in compliance with good manufacturing practice. In one case, for example, FDA issued a warning to a California-based stem cell company for selling unapproved stem cell products that were manufactured without proper safety measures, including a failure to properly screen for communicable diseases such as HIV and hepatitis B and C, and failure to have a system in place to prevent contamination. At least 13 people were hospitalized due to serious bacterial infection after receiving contaminated stem cell products manufactured by the company and then distributed to various clinics in Texas, Arizona, Kansas, and Florida. Most recently, FDA sent a letter to a company, based in Las Vegas, warning of unsafe manufacturing practices after the company’s stem cell product caused multiple serious AEs in patients in Nebraska.

In other cases, the infections may have been due to unsafe injection practices on the part of the product distributor. The literature review identified several types of administration practices—direct injections, surgical transplantations, and IV infusions; it’s unclear whether any of these methods of administration are safe or, alternately, if they may have contributed to an adverse event. The risks of infection or other serious complications are likely higher in cases in which the person administering the product has limited training in treating that patient’s disease or condition, a fact that was acknowledged by FDA and highlighted by the Federation of State Medical Boards in a 2016 policy statement on stem cell interventions. Likewise, a 2019 study of 166 stem cell companies found that nine did not have a physician on staff, and that only half of the remaining 157 businesses employed a physician with formal training that matched the conditions they claimed to treat. The problem was more acute when it came to clinics that used stem cells to treat nonorthopedic conditions: Only 13 companies (19%) employed physicians operating within the scope of their training.

These adverse events highlight many of the risks of unapproved SCRIs, and are particularly concerning given that unapproved SCRIs not only haven’t been shown to offer definitive benefits, but are also likely entirely paid for by the patient, at a cost often totaling thousands of dollars. Use of unapproved SCRIs may also lead patients to delay seeking approved and evidence-based medical treatments under the false hope that stem cell therapies will cure them or improve their condition; a delay in proper medical care poses the additional risk of their condition worsening.

Finally, given that more than 70% of new identified AE reports came from a single prospective study of SCRIs, the findings from the literature also underscore the fundamental importance of evaluating SCRIs in clinical trials that are designed to systematically assess their risks and benefits compared with the standard of care. Although case studies are very helpful to the medical and public health community in identifying potential harms associated with a treatment, it is only through rigorous studies that regulators and clinicians can fully understand which SCRIs are beneficial and which are useless or harmful.

FDA’s database of adverse events captures some reports linked to unapproved SCRIs

FDA collects reports of AEs associated with drug and therapeutic biologic products in its adverse event reporting system (FAERS) through reports submitted to a public database known as MedWatch. This database includes mandatory reports from manufacturers and other organizations that are involved in drug supply and distribution, as well as voluntary reports from health care providers, patients, and consumers. The system serves as an important oversight tool for the agency; FDA staff routinely monitor the system to detect signs that a medical product may be causing harm. When such a safety signal is detected, FDA may follow up to determine if further action is required to protect public health. This follow-up can take the form of public health alerts, consumer
advisories, or other regulatory actions where necessary.

However, businesses that make or sell unapproved SCRIs are unlikely to report adverse events associated with their products to FDA, either because they do not know that they should or because they are evading oversight. Therefore, any adverse events related to unapproved SCRIs in the FAERS database are likely to have been reported voluntarily by physicians who may be treating complications that arise from these treatments, or from consumers themselves. And these voluntary reports are more likely to be incomplete compared with submissions from mandatory reporters, which may limit the agency’s ability to identify the source of the harm and take action. For instance, if a report does not include information on the type of stem cell intervention used or the condition that was being treated, it is more challenging to determine if that report is associated with an unapproved product.

Pew conducted a search of the database from November 1997 to March 2020 to better understand if AEs linked to unapproved products are being reported in FAERS. An initial keyword search of the FAERS database yielded 673 unique results. Of those, the 495 submitted by mandatory reporters—e.g., manufacturers with approved products—were excluded. The remaining 178 reports, which were submitted by voluntary reporters, included 118 that were deemed incomplete because they didn’t meet the criteria for inclusion—that is, they didn’t include information on the type of stem cell intervention used or the condition that was being treated—leaving 60 reports that could be considered “complete.” Of those 60, a further 55 were excluded because they appeared related to an approved use—resulting in a final count of five reports that appear to be associated with unapproved SCRIs. Among the five reports, death was listed as an outcome in one case, and hospitalization or life-threatening reaction to treatment in three. Types of AEs listed in the five reports included bacterial infection, severe immune reaction and inflammatory response, and heart attack. Importantly, though: Even for the five cases that met the inclusion criteria, there is no mechanism to verify the information provided. A report can indicate a correlation between the product and the AE but cannot establish causation.

But because this final number of five reports reflects only complete, nonduplicative, voluntary reports, it is likely an undercount. Some of the reports that were excluded from the final count—because they didn’t include the condition being treated by a stem cell therapy (there are approved uses for such interventions) or list the type of stem cell therapy—may have been related to unapproved products.

FDA acknowledged the problem of underreporting in a recent article in JAMA and encouraged patients and their providers to more thoroughly report AEs.¹⁵ Improved reporting would allow the agency to target enforcement activities more effectively and reinforce the case for tighter regulation of this market. As awareness of the harm grows, fewer patients may be willing to undergo these treatments in the first place.

Reviews on social media sites underscore that adverse events are underreported

Many consumers and patients use social media platforms to share their experiences with medical treatments, including SCRIs, which means that these sites can be a potential resource for identifying self-reported cases of AEs. Social media posts may be more expansive than the information included in the FAERS database, and include important contextual information related to the event, such as the location where the intervention occurred and additional details describing the patient’s experience. However, as with FAERS, consumer-generated reviews and testimonials can only identify a correlation, not causation. Additionally, these posts may still lack important information, such as the specific type of stem cell intervention received.

FDA has acknowledged that social media monitoring for AEs may have the potential for faster safety signal detection and may include important information that otherwise may not be available through FAERS. To test this hypothesis, Pew analyzed all patient reviews of businesses offering unapproved SCRIs posted before September 2020 across three websites: Google, Yelp, and Facebook. This analysis identified 21 reviews describing AEs that appeared to be directly linked to unapproved SCRIs. Most of these reviews (17) identify the adverse event as pain—including new or worsening pain that in some cases is described as “extreme” and “excruciating.” Other AEs mentioned in the reviews include infection, inflammation, allergic reactions (8), and loss of mobility and function in limbs (9). Three of the reviews were linked with a business that has been the target of FDA regulatory action in the past.

The analysis also identified 67 reviews describing concerns about the quality of care received. These reviews did not have adequate information to conclude that an AE was directly associated with an unapproved product, but they described other negative experiences, including patients not receiving adequate care during or after the procedure (30) or delaying evidence-based medical treatments because they pursued unproven SCRIs (31).

Consumers’ Online Reviews Illustrate Serious Risks and Complications

Select comments from adverse experiences with unapproved regenerative products
“Day 5 after my stem cell in my lumbar spine, I woke up in the most severe pain on my life. I couldn’t walk and was bed ridden for 8 weeks.” – Reviewer on Google, 2020

“I have a worse time walking and sleeping, which isn’t good because of the pain, something that wasn’t happening before the (stem cell) shot.” – Reviewer on Facebook, 2020

“I contracted an infection which required 6 days of hospitalization, 2 emergency surgeries, 6 weeks of IV antibiotics and 6 months of oral antibiotics.” – Reviewer on Google, 2019

“The procedure was very painful but initially there was some improvement then deterioration back to my original condition. One year later my knees are the same as before and my shoulder which had been getting better before the injections is now worse than when I went in. I am seriously wondering about the ethics and efficacy of this experience and practice.” – Reviewer on Google, 2019

“I chose to try stem cell and blood platelet therapy for my hip with worn cartilage. … I did have significant relief for a few months after the joint injection. But the pain soon returned. The MRIs taken before and after the injection looked identical. There was no cartilage regrowth. The temporary relief was simply a result of the fluid injection. I then opted for an anterior entry hip replacement.” – Reviewer on Yelp, 2016

Although Pew’s research primarily focused on the physical harms associated with these SCRI interventions, the research also identified cases of patients reporting emotional and financial harms, which raises significant concerns and highlights that the harms associated with unproven SCRIs are not restricted to physical injuries. At least 87 reviews included complaints about the financial cost of these treatments, including reviews that describe spending money on treatments that did not work (45) or were painful to undergo or recover from (29). Because these procedures are typically not covered by insurance, patients are likely paying out of pocket or turning to crowdfunding sites to pay for care that is unlikely to benefit them.

In line with other studies that analyzed social media data for AE reports, Pew’s social media analysis did not reveal many new serious or life-threatening AEs. This finding is reassuring as well as unsurprising: If an AE is life-threatening or otherwise serious, the treating physician may report the case to FDA or another regulator or seek to publish case studies about it. However, the data collected from these reviews provides a window into how stem cell businesses operate and may be useful to FDA and other regulators or oversight bodies with jurisdiction over medical or business practices.

And it’s worth noting that not all the reviews left on the social media sites were reports of negative experiences from undergoing SCRIs; many, in fact, were positive. This finding correlates with other perception studies that report on patients’ positive experiences with these interventions. Pew’s analysis excluded 94 positive reviews that were not already eliminated in our initial search.

However, a little more than a third of the positive reviews (35) were posted within a few months—and in some cases, within a few days—after a patient received the treatment, and reports of positive outcomes shortly after receiving an SCRI do not necessarily indicate treatment efficacy. Not only do such reports leave open the possibility that AEs (or concerns that the treatments did not work as promised) may have emerged later, but they also may be a result of other procedures done before or after receiving the treatment or continued evidence- based treatments, such as physical rehabilitation therapy. For example, one reviewer described experiencing “significant relief” for a few months after receiving an SCRI but associated it with the cushioning effects of the fluid injection they received rather than the effects of stem cells. Another reviewer described “noticeable improvement” six weeks post-treatment with continued rehabilitation therapy but described new symptoms and admitted that the procedure “did not work” one year after receiving the SCRI.

Stem cell businesses routinely use these testimonials to promote their unproven therapies. But as with the negative reviews evaluated as part of the research, it’s difficult to assess the validity of these positive reviews. Some researchers suggest that specific blogs, social media sites, and other venues and platforms run or produced by clinics likely control the patient narrative and thus provide only posts with a positive outlook or portrayal of SCRIs —omitting negative reports. (Pew identified at least two negative reviews describing AEs that users reposted after they were deleted the first time.) Through this and other techniques—such as publishing results of quality-of-life surveys filled out by patients who receive treatments— businesses create a misleading picture of the safety and efficacy of SCRIs.

For these reasons, the research likely did not capture all AEs associated with these businesses. Additionally, the analysis was limited to only English-language posts on three social media websites. The analysis also did not capture any businesses that may not exist under the same name or in the same location as they did when patients complained about them. These factors highlight the challenges facing FDA and other regulators that attempt to use social media to track businesses that offer unapproved treatments to patients.

And although Pew’s search focused primarily on stem cell products, the social media analysis also identified AE reports associated with platelet-rich plasma (PRP), which has been marketed as a regenerative intervention for various ailments, including orthopedic conditions and hair loss. PRP does not contain stem cells, and FDA does not consider it a cell- or tissue-based product. The therapy involves injecting patients with a concentrated dose of their own platelets—a type of blood cell that contains growth factors and plays an important role in the body’s natural wound-healing process—to stimulate tissue regeneration in the targeted area. Blood drawn from the patient is run through a centrifuge to create a concentrated sample that contains high levels of platelets, then injected back into the patient. The more than 1,000 clinical studies investigating the effects of PRP that are listed in clinicaltrials.gov, a large registry of clinical trials maintained by the U.S. National Library of Medicine, have not yet demonstrated definitive efficacy in treating particular conditions or diseases. However, clinics continue to market this therapy to patients for a range of indications.

Of the 21 AEs that Pew identified, seven were associated with PRP therapy. An additional 23 reviews associated with PRP therapy either described pain during the procedure or complained about its ineffectiveness (16), resulting in a delay in receiving proper medical treatment, such as surgery or physical therapy (10).

Next steps for FDA and other stakeholders

This research aimed to systematically collect and analyze AE data about unapproved SCRIs from multiple sources and better characterize the risks of these interventions. Although it’s impossible to know the true rate of AEs associated with unapproved SCRIs, it’s clear from the cases that are reported that these procedures can cause serious and sometimes life-threatening harm, and that more should be done to protect patients.

These findings also highlight the need for strong FDA oversight, and help to underscore why the agency needs to fully implement its regulatory framework and significantly expand the scope of its enforcement activities against all businesses offering unapproved and unproven SCRIs. Hundreds of businesses continue to operate under the agency’s current policy of enforcement discretion, which was due to end in November 2020 but was extended to May 2021 due to the coronavirus pandemic. FDA announced in April 2021 that it would not extend this period any further, which is an encouraging development. It should now move quickly to enforce its regulations and bring the industry into compliance. The agency also needs adequate resources to do so.

Because it is difficult to know the extent of the problems occurring from these procedures, FDA should work to improve reporting systems and consider alternative approaches to identifying adverse events. It should encourage more reporting of adverse events through MedWatch, the database it uses to collect such reports; such improved AE reporting will help the agency better target its limited resources toward those businesses engaging in risky practices that may be harming patients. The agency should consider updating the instructions for patients in the MedWatch online reporting system to facilitate easier and more complete reporting of AEs related to unapproved SCRIs—such as information on where patients receive these interventions. Targeted public awareness campaigns could also help boost knowledge of FAERS and encourage broader use of it.

As previously mentioned, FDA has acknowledged that, despite variability in the quality of reports submitted, social media monitoring for AEs has the potential for faster safety signal detection. The agency should consider analyzing social media sites for AEs associated with unapproved SCRIs. Given the widespread underreporting of these AEs, data collected from online sources could potentially supplement data from traditional sources, such as FAERS, to create a more thorough understanding of the scope and type of harm associated with these products. A 2018 FDA white paper describes the agency’s plans to adopt new and innovative data mining methods or tools to monitor social media data for signals of AEs associated with FDA-regulated medical products. Tracking potential safety signals in this manner could provide new opportunities for the agency to gather more real-world evidence of harm.

Other Stakeholders Can Help Safeguard Public Health

Alongside enforcement by FDA, federal and state policymakers, medical licensing authorities, and other stakeholders can take steps to help protect patients from unapproved products. Opportunities include legal action by federal and state agencies, such as the Federal Trade Commission and state attorneys general offices; state legislation to tighten regulation of clinics; better oversight by state medical boards; and individual private action against clinics. Scientific and professional organizations can also take steps to improve both patient and provider education about unapproved SCRIs and increase awareness about their risks. Finally, companies that manage online platforms could do more to limit the spread of misinformation, and prevent clinics from advertising their products on their platforms.

Conclusion

As FDA’s enforcement discretion period draws to a close, the agency should maintain pressure on businesses offering unapproved products and ensure that patients are protected from SCRIs that have caused harm or have the potential to cause harm. Encouraging patients and clinicians to report AEs and devising effective strategies to collect more real-world evidence of harm can help the agency in its efforts to curb the growth of this unregulated market and ensure that the regenerative medicine field develops into one that clinicians and patients can trust and safely access.