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Stem cell merchandise and other regenerative therapies have important potential to treat traumatic accidents and critical diseases. Although some have earned approval from the Food and Drug Administration, most have not, and plenty of of these unapproved interventions have led to life-threatening infections, chronic ache, and even death.1

Greater than seven hundred clinics within the U.S. supply unapproved stem cell and regenerative drugs interventions (SCRIs) for circumstances comparable to Alzheimer’s illness, muscular dystrophy, autism, spinal cord accidents, and, most just lately, COVID-19.2 The merchandise made and sold by these businesses sometimes use cells from the patient’s personal physique or from donated amniotic fluid, placental tissue, or umbilical cord blood, amongst different birth-derived cells and tissues. FDA has given manufacturers and entrepreneurs of SCRIs until May 31, 2021, to come into compliance with the agency’s laws governing human cell and tissue merchandise, together with submitting those products for FDA evaluation when necessary.3

FDA uses stories of adversarial events-undesirable affected person experiences related to the usage of medical remedies-to help identify doubtlessly dangerous products meriting additional investigation. However, adverse events associated with any medical product are generally underreported, and suppliers of unapproved therapies are significantly unlikely to report patient harm to regulators or disclose such cases through public reporting- making it tougher for the company to prioritize its enforcement actions, and also main policymakers and the public to underestimate the risks of those 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 reviews of opposed events (AEs) linked to unapproved SCRIs administered outdoors of clinical trials. In whole, we recognized reviews of 360 people who had AEs that occurred between 2004 and September 2020, including:

- 334 cases documented in peer-reviewed journals, authorities and news media reports, and different literature.- 5 instances reported in FDA’s hostile occasion reporting system (known as FAERS), a public database of stories submitted to the agency.- 21 instances described in consumer critiques of stem cell businesses posted to Google, Yelp, and Facebook.

Pew’s findings reinforce the need for increased FDA enforcement action in opposition to businesses that manufacture and market these unapproved-and, in lots of circumstances, unproven-merchandise. (See Appendix A for definitions of key terms.) Additionally they underscore how more frequent and thorough reporting of AEs by customers and clinicians, and the FDA’s use of social media knowledge, might allow the agency to extra shortly establish businesses that are placing patients’ health in danger and goal its limited oversight resources extra effectively. More broadly, the findings spotlight the importance of FDA oversight in guaranteeing that regenerative merchandise available on the market are protected and effective. The agency should move shortly to implement its regulations governing human cell and tissue products for businesses that fail to conform by FDA’s May 31 deadline, and regulators shouldn't hesitate to seek authorized injunctions and mandate product recalls when vital.

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

Many of the opposed events identified on this analysis (334, or 93%) got here from the literature, which included peer-reviewed articles, media studies, and authorities publications. This literature evaluation built upon earlier Pew research printed in 2019, which recognized sixty nine experiences of hurt, together with lifelong disabilities and dying, relationship as early as 2004. For this latest round of analysis, which covered literature revealed between November 2019 and January 2021, the team recognized an additional 265 circumstances of hurt related to those products, bringing the total number of AEs to 334 and the overall number of subsequent deaths to 20. The majority of the brand new cases added to the up to date record (242) were published in January 2021 as a part of a prospective examine of patient medical records drawn from a single insurance coverage company database-full with information on the kind of therapy and complications-to identify AEs related to unapproved SCRIs.Four (See Appendix B for a full listing of AEs related to unapproved SCRIs and an outline of the methodology for the literature assessment.)

Many of the AEs identified involved severe bacterial infection, including not less than two instances of septicemia, a life-threatening blood infection. Others included severe and even lifelong disabilities similar to 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 circumstances that resulted in dying. Many of those AEs required hospitalization (104) and prompted acute or worsening pain (55). The most common kind of interventions linked to those AEs were autologous (that is, the stem cells had been obtained from the patient’s physique) or donor stem cells administered by injection into the eye, spine, hip, shoulder, or knee.

The prevalence of infection among the adverse occasions is probably going on account of several components. In some circumstances, the infections can originate from the merchandise themselves, which can not have been processed in compliance with good manufacturing apply. In one case, for instance, FDA issued a warning to a California-based mostly stem cell company for selling unapproved stem cell merchandise that were manufactured without proper security measures, including a failure to correctly display screen for communicable diseases resembling HIV and hepatitis B and C, and failure to have a system in place to prevent contamination.5 A minimum of thirteen folks had been hospitalized due to severe bacterial infection after receiving contaminated stem cell products manufactured by the corporate after which distributed to numerous clinics in Texas, Arizona, Kansas, and Florida.6 Most just lately, FDA sent a letter to an organization, based mostly in Las Vegas, warning of unsafe manufacturing practices after the company’s stem cell product brought about a number of critical AEs in patients in Nebraska.7

In different circumstances, the infections could have been due to unsafe injection practices on the part of the product distributor. The literature evaluate identified a number of sorts of administration practices-direct injections, surgical transplantations, and IV infusions; it’s unclear whether or not any of those methods of administration are protected or, alternately, if they could have contributed to an hostile event. The dangers of infection or other severe complications are probably greater in circumstances during which the individual administering the product has limited coaching in treating that patient’s disease or situation, a proven fact that was acknowledged by FDA and highlighted by the Federation of State Medical Boards in a 2016 coverage statement on stem cell interventions.Eight Likewise, a 2019 examine of 166 stem cell firms discovered that 9 didn't have a physician on staff, and that solely half of the remaining 157 companies employed a physician with formal training that matched the situations they claimed to deal with. The problem was more acute when it came to clinics that used stem cells to deal with nonorthopedic conditions: Only 13 companies (19%) employed physicians operating inside the scope of their coaching.9

These hostile events spotlight most of the dangers of unapproved SCRIs, and are notably concerning given that unapproved SCRIs not solely haven’t been proven to supply definitive advantages, but are also seemingly completely paid for by the affected person, at a value usually totaling thousands of dollars.10 Use of unapproved SCRIs can also lead patients to delay searching for accredited and proof-based medical therapies below the false hope that stem cell therapies will cure them or enhance their situation; a delay in proper medical care poses the extra danger of their situation worsening.

Finally, given that more than 70% of recent identified AE reviews came from a single potential examine of SCRIs,11 the findings from the literature additionally underscore the basic importance of evaluating SCRIs in clinical trials which are designed to systematically assess their risks and advantages compared with the usual of care. Although case research are very useful to the medical and public well being group in figuring out potential harms associated with a therapy, it is just by way of rigorous research that regulators and clinicians can absolutely understand which SCRIs are helpful and that are useless or harmful.

FDA’s database of hostile events captures some experiences linked to unapproved SCRIs

FDA collects stories of AEs related to drug and therapeutic biologic merchandise in its opposed event reporting system (FAERS) through experiences submitted to a public database known as MedWatch.12 This database contains mandatory reports from manufacturers and different organizations which might be concerned in drug provide and distribution, as well as voluntary studies from well being care suppliers, patients, and consumers.Thirteen The system serves as an essential oversight software for the agency; FDA employees routinely monitor the system to detect signs that a medical product may be inflicting harm. When such a safety sign is detected, FDA might comply with up to determine if further action is required to guard public well being. This follow-up can take the form of public health alerts, client advisories, or other regulatory actions the place mandatory.

However, companies that make or sell unapproved SCRIs are unlikely to report opposed occasions associated with their merchandise to FDA, both as a result of they have no idea that they need to or because they are evading oversight. Therefore, any antagonistic events associated to unapproved SCRIs within the FAERS database are more likely to have been reported voluntarily by physicians who may be treating complications that come up from these remedies, or from consumers themselves.14 And these voluntary stories are more likely to be incomplete compared with submissions from mandatory reporters, which can limit the agency’s capability to identify the source of the harm and take motion. For example, if a report does not embrace information on the kind of stem cell intervention used or the condition that was being handled, it is extra difficult to find out if that report is associated with an unapproved product.

Pew carried out a search of the database from November 1997 to March 2020 to better understand if AEs linked to unapproved merchandise are being reported in FAERS. (See Appendix C for a full description of the methodology.) An preliminary keyword search of the FAERS database yielded 673 unique outcomes. Of those, the 495 submitted by obligatory reporters-e.g., manufacturers with authorized products-have been excluded. The remaining 178 stories, which had been submitted by voluntary reporters, included 118 that have been deemed incomplete because they didn’t meet the factors for inclusion-that is, they didn’t embrace info on the kind of stem cell intervention used or the situation that was being treated-leaving 60 reviews that may very well be considered "complete." Of these 60, an extra 55 have been excluded as a result of they appeared related to an accredited use-resulting in a closing count of five reports that look like related to unapproved SCRIs. Among the many five reports, demise was listed as an outcome in one case, and hospitalization or life-threatening response to therapy in three. Sorts of AEs listed within the five reviews included bacterial infection, severe immune response and inflammatory response, and heart assault. (See Appendix Table C.1 for additional details on these experiences.) Importantly, though: Even for the five circumstances that met the inclusion standards, there isn't a mechanism to confirm the knowledge offered. A report can point out a correlation between the product and the AE however can not establish causation.

But because this last variety of 5 reviews displays solely full, nonduplicative, voluntary reviews, it is likely an undercount. A few of the studies that have been excluded from the ultimate depend-because they didn’t embody the condition being treated by a stem cell therapy (there are permitted uses for such interventions) or listing the type of stem cell therapy-might have been related to unapproved merchandise.

FDA acknowledged the problem of underreporting in a latest article in JAMA and encouraged patients and their suppliers to more thoroughly report AEs.15 Improved reporting would allow the agency to focus on enforcement activities more successfully and reinforce the case for tighter regulation of this market. As awareness of the harm grows, fewer patients could also be prepared to endure these remedies in the first place.

Reviews on social media websites underscore that hostile events are underreported

Many customers and patients use social media platforms to share their experiences with medical remedies, together with SCRIs, which implies that these sites might be a potential useful resource for figuring out self-reported cases of AEs.16 Social media posts could also be extra expansive than the data included within the FAERS database, and include necessary contextual data related to the event, comparable to the placement the place the intervention occurred and additional particulars describing the patient’s expertise. However, as with FAERS, shopper-generated opinions and testimonials can solely establish a correlation, not causation. Additionally, these posts may still lack important info, corresponding to the particular kind of stem cell intervention acquired.

FDA has acknowledged that social media monitoring for AEs could have the potential for faster security signal detection and will include important data that otherwise may not be obtainable by way of FAERS.17 To check this hypothesis, Pew analyzed all affected person critiques of companies offering unapproved SCRIs posted earlier than September 2020 throughout three web sites: Google, Yelp, and Facebook. (See Appendix D for a full description of the methodology and an inventory of keywords.) This analysis identified 21 critiques describing AEs that appeared to be immediately linked to unapproved SCRIs. (See Appendix Table D.1 for a full checklist of AEs that had been identified.) Most of those reviews (17) identify the adverse occasion as pain-together with new or worsening pain that in some instances is described as "extreme" and "excruciating." Other AEs talked about in the opinions embrace infection, inflammation, allergic reactions (8), and loss of mobility and function in limbs (9). Three of the opinions have been linked with a business that has been the target of FDA regulatory action previously.18

The evaluation additionally identified 67 evaluations describing concerns about the standard of care acquired. These opinions did not have adequate information to conclude that an AE was instantly related to an unapproved product, but they described different unfavourable experiences, together with patients not receiving adequate care throughout or after the procedure (30) or delaying evidence-based mostly medical remedies as a result of they pursued unproven SCRIs (31).

Consumers’ Online Reviews Illustrate Serious Risks and Complications

Select feedback from antagonistic experiences with unapproved regenerative merchandise "Day 5 after my stem cell in my lumbar spine, I woke up in the most severe ache on my life. I couldn’t walk and was bed ridden for 8 weeks." - Reviewer on Google, 2020

"I have a worse time strolling and sleeping, which isn’t good due to the pain, something that wasn’t happening earlier than 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 enchancment then deterioration back to my authentic condition. One year later my knees are the same as before and my shoulder which had been getting higher earlier than the injections is now worse than once i went in. I'm severely wondering about the ethics and efficacy of this expertise and practice." - Reviewer on Google, 2019

"I selected to attempt stem cell and blood platelet therapy for my hip with worn cartilage. … I did have significant relief for a number of months after the joint injection. However the pain soon returned. The MRIs taken earlier than and after the injection looked an identical. There was no cartilage regrowth. The non permanent relief was merely a result of the fluid injection. I then opted for an anterior entry hip substitute." - Reviewer on Yelp, 2016

Although Pew’s analysis primarily targeted on the physical harms associated with these SCRI interventions, the research also recognized circumstances of patients reporting emotional and financial harms, which raises significant considerations and highlights that the harms associated with unproven SCRIs are usually not restricted to bodily accidents. At the very least 87 critiques included complaints in regards to the financial value of these remedies, including evaluations that describe spending cash on therapies that didn't work (45) or have been painful to endure or recuperate from (29). Because these procedures are usually not coated by insurance, patients are likely paying out of pocket or turning to crowdfunding websites to pay for care that's unlikely to learn them.19

In line with different studies that analyzed social media knowledge for AE studies, Pew’s social media evaluation did not reveal many new critical or life-threatening AEs.20 This discovering is reassuring as well as unsurprising: If an AE is life-threatening or in any other case severe, the treating physician may report the case to FDA or one other regulator or search to publish case research about it. However, the info collected from these evaluations provides a window into how stem cell businesses operate and could also be useful to FDA and different regulators or oversight our bodies with jurisdiction over medical or enterprise practices.

And it’s value noting that not all of the reviews left on the social media websites were reports of negative experiences from undergoing SCRIs; many, in fact, were constructive. This finding correlates with different notion research that report on patients’ constructive experiences with these interventions.21 Pew’s analysis excluded ninety four constructive opinions that were not already eliminated in our preliminary search.

However, somewhat more than a 3rd of the optimistic evaluations (35) have been posted inside just a few months-and in some circumstances, within just a few days-after a patient acquired the treatment, and stories of constructive outcomes shortly after receiving an SCRI do not essentially indicate therapy efficacy.22 Not solely do such reports leave open the likelihood that AEs (or considerations that the treatments did not work as promised) might have emerged later, but they also could also be a result of different procedures accomplished before or after receiving the remedy or continued proof- primarily based treatments, reminiscent of physical rehabilitation therapy. For instance, one reviewer described experiencing "significant relief" for just a few months after receiving an SCRI but associated it with the cushioning results of the fluid injection they obtained relatively than the consequences of stem cells. Another reviewer described "noticeable improvement" six weeks submit-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.23 But as with the damaging evaluations evaluated as a part of the analysis, it’s troublesome to assess the validity of these constructive critiques. Some researchers suggest that specific blogs, social media sites, and different venues and platforms run or produced by clinics seemingly management the patient narrative and thus present only posts with a optimistic outlook or portrayal of SCRIs -omitting destructive reports.24 (Pew identified at the very least two adverse evaluations describing AEs that customers reposted after they were deleted the first time.) Through this and different methods-reminiscent of publishing outcomes of high quality-of-life surveys filled out by patients who obtain treatments- businesses create a deceptive image of the safety and efficacy of SCRIs.25

For these reasons, the research possible didn't seize all AEs related to these companies. Additionally, the evaluation was limited to solely English-language posts on three social media websites. The evaluation additionally didn't capture any businesses that will not exist beneath the identical identify or in the identical location as they did when patients complained about them. These elements spotlight the challenges going through FDA and different regulators that attempt to make use of social media to trace businesses that offer unapproved therapies to patients.

And though Pew’s search centered totally on stem cell merchandise, the social media analysis also identified AE reports related to platelet-rich plasma (PRP), which has been marketed as a regenerative intervention for numerous ailments, together with orthopedic circumstances and hair loss.26 PRP doesn't contain stem cells, and FDA does not consider it a cell- or tissue-based product. The therapy includes injecting patients with a concentrated dose of their own platelets-a type of blood cell that contains growth components and plays an important role within the body’s natural wound-healing course of-to stimulate tissue regeneration within the targeted space. Blood drawn from the patient is run via a centrifuge to create a concentrated sample that incorporates high levels of platelets, then injected back into the affected person. The greater than 1,000 clinical studies investigating the consequences of PRP which are listed in clinicaltrials.gov, a big registry of clinical trials maintained by the U.S. National Library of Medicine,27 haven't yet demonstrated definitive efficacy in treating specific circumstances or diseases.28 However, clinics continue to market this therapy to patients for a variety of indications.29

Of the 21 AEs that Pew recognized, seven were related to PRP therapy. (See Appendix Table D.1 for an inventory of AEs related to PRP). A further 23 opinions related to PRP therapy either described pain during the procedure or complained about its ineffectiveness (16), leading to a delay in receiving correct medical treatment, reminiscent of surgical procedure or bodily therapy (10).

Next steps for FDA and other stakeholders

This research aimed to systematically acquire and analyze AE data about unapproved SCRIs from multiple sources and higher characterize the dangers of these interventions. Although it’s inconceivable to know the true price of AEs related to unapproved SCRIs, it’s clear from the cases which might be reported that these procedures may cause severe and typically life-threatening hurt, and that more must be done to guard patients.

These findings additionally highlight the necessity for robust FDA oversight, and help to underscore why the agency wants to fully implement its regulatory framework and considerably expand the scope of its enforcement actions in opposition to all companies offering unapproved and unproven SCRIs. Hundreds of businesses continue to function underneath the agency’s present policy of enforcement discretion, which was due to end in November 2020 however was extended to May 2021 because of the coronavirus pandemic. FDA announced in April 2021 that it would not lengthen this period any further, which is an encouraging growth. It should now move shortly to implement its regulations and bring the industry into compliance. The agency also needs enough sources to take action.

Because it is tough to know the extent of the issues occurring from these procedures, FDA should work to enhance reporting techniques and consider various approaches to identifying opposed events. It should encourage extra reporting of adverse occasions by MedWatch, the database it uses to gather such experiences; such improved AE reporting will assist the company better target its restricted resources towards these companies participating in dangerous practices that could be harming patients. The agency should consider updating the instructions for patients in the MedWatch online reporting system to facilitate simpler and extra full reporting of AEs related to unapproved SCRIs-akin to info on where patients obtain these interventions. Targeted public awareness campaigns may also assist enhance knowledge of FAERS and encourage broader use of it.

As beforehand talked about, FDA has acknowledged that, despite variability in the standard of stories submitted, social media monitoring for AEs has the potential for faster safety sign detection.30 The company ought to consider analyzing social media websites for AEs associated with unapproved SCRIs. Given the widespread underreporting of these AEs, knowledge collected from online sources might potentially supplement information from traditional sources, such as FAERS, to create a more thorough understanding of the scope and sort of hurt associated with these merchandise. A 2018 FDA white paper describes the agency’s plans to adopt new and revolutionary information mining strategies or instruments to monitor social media data for indicators of AEs related to FDA-regulated medical products.31 Tracking potential security indicators on this manner might provide new opportunities for the company to gather extra real-world proof of harm.

Other Stakeholders Can assist Safeguard Public Health

Alongside enforcement by FDA, federal and state policymakers, medical licensing authorities, and other stakeholders can take steps to assist protect patients from unapproved merchandise. Opportunities embrace authorized motion by federal and state agencies, such because the Federal Trade Commission and state attorneys common places of work; state laws to tighten regulation of clinics; higher oversight by state medical boards; and individual non-public motion towards clinics. Scientific and skilled organizations may also take steps to improve both patient and supplier training about unapproved SCRIs and increase awareness about their dangers. Finally, firms that manage online platforms might do more to limit the unfold of misinformation, and prevent clinics from advertising their products on their platforms.

As FDA’s enforcement discretion period draws to a close, the company should maintain strain on companies providing unapproved merchandise and make sure that patients are protected from SCRIs that have triggered harm or have the potential to cause hurt. Encouraging patients and clinicians to report AEs and devising efficient methods to gather more real-world evidence of hurt can help the agency in its efforts to curb the expansion of this unregulated market and make sure that the regenerative medicine subject develops into one that clinicians and patients can trust and safely entry.

Endnotes

1. G. Bauer, M. Elsallab, and M. Abou-El-Enein, "Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions," Stem Cells Translational Medicine (July 31, 2018), https://doi.org/10.1002/sctm.17-0282.2. L. Turner, "The U.S. Direct-to-Consumer Marketplace for Autologous Stem Cell Interventions," Perspectives in Biology and Medicine 61, no. 1 (2018): 7-24, https://muse.jhu.edu/article/694817; B. Schrotenboer, "Stem Cell Companies Sell Hope with Unproven Medicine for COVID-19," USA Today, last modified June 23, 2020, June 22, 2020, https://www.usatoday.com/story/money/enterprise/2020/06/22/stem-cell-firms-selling-hope-unproven-therapies-covid-19/5348246002/.3. The Pew Charitable Trusts, "FDA’s Framework for Regulating Regenerative Medicine Will Improve Oversight," Oct. 17, 2019, https://www.pewtrusts.org/en/analysis-and-analysis/reviews/2019/10/17/fdas-framework-for-regulating-regenerative-medicine-will-enhance-oversight.4. J.W. Pritchett, "The Debit Side of Stem Cell Joint Injections: A Prospective Cohort Study," Current Orthopaedic Practice 32, no. 2 (2021): 1-6, https://journals.lww.com/c-orthopaedicpractice/Abstract/2021/03000/The_debit_facet_of_stem_cell_joint_injections__a.3.aspx.5. K. Watson, program division director, Office of Biological Products Operations, U.S. Food and Drug Administration, letter to Edwin N. Pinos, president, Genetech, Inc., "Warning Letter OBPO 19-03," Nov. 29, 2018, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/genetech-inc-561808-11292018; K. Watson, Program Division Director, Office of Biological Products Operations - Division 2, U.S. Food & Drug Administration, letter to Roya Panah, president/chief executive officer, Liveyon Labs Inc., "Warning Letter OBPO 20-588399," Dec. 5, 2019, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/liveyon-labs-inc-588399-12052019; K.T. Watson, program division director, Office of Biological Products Operations - Division 2, U.S Food and Drug Administration, letter to Travis H. Bird, chief government officer, EUCYT Laboratories LLC, "Warning Letter #OBPO 20-603498," June 4, 2020, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/eucyt-laboratories-llc-607182-06042020.6. D. Grady, "12 People Hospitalized With Infections From Stem Cell Shots," The brand new York Times, Dec. 20, 2018, https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html; A. Marso, "KC Woman Got E. Coli Infection From Stem Cell Treatment at JoCo Clinic, Lawsuit Says," The Kansas City Star, Aug. 23, 2019, https://www.kansascity.com/information/business/health-care/article234306097.html.7. U.S. Food and Drug Administration, "Public Safety Notification on Exosome Products," Dec. 6, 2019, https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification-exosome-merchandise; Watson, letter.8. Federation of State Medical Boards, "Position Statement on Practice Drift," information launch, April 2016, https://www.fsmb.org/siteassets/advocacy/policies/position-statement-on-practice-drift.pdf; U.S. Food and Drug Administration, "Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use: Guidance for Industry and Food and Drug Administration Staff" (2020), https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585403.pdf.9. W. Fu et al., "Characteristics and Scope of coaching of Clinicians Participating within the U.S. Direct-to-Consumer Marketplace for Unproven Stem Cell Interventions," Journal of the American Medical Association 321, no. 24 (2019): 2463-64, https://jamanetwork.com/journals/jama/fullarticle/2736545.10. P. Knoepfler, "Update on Stem Cell Treatment Cost for 2018 from Ongoing Poll," The Niche (blog), Knoepfler Lab Stem Cell Blog, April 15, 2018, https://ipscell.com/2018/04/replace-on-stem-cell-therapy-cost-for-2018-from-ongoing-poll.11. Pritchett, "The Debit Side."12. U.S. Food and Drug Administration, "FDA Adverse Event Reporting System (FAERS) Public Dashboard," final modified Oct. 29, 2020, https://www.fda.gov/medication/questions-and-answers-fdas-antagonistic-occasion-reporting-system-faers/fda-antagonistic-event-reporting-system-faers-public-dashboard.13. U.S. Food and Drug Administration, "Reporting Serious Problems to FDA," last modified May 22, 2018, https://www.fda.gov/security/medwatch-fda-security-information-and-opposed-event-reporting-program/reporting-critical-problems-fda#:~:textual content=Industry%20 (Mandatory),process%2C%20review%2C%20and%20archive.14. Pritchett, "The Debit Side."15. P. Marks and S. Hahn, "Identifying the Risks of Unproven Regenerative Medicine Therapies," Journal of the American Medical Association 324, no. Three (2020): 241-42, https://jamanetwork.com/journals/jama/article-summary/2767586.16. S. Golder, G. Norman, and Y.K. Loke, "Systematic Review on the Prevalence, Frequency and Comparative Value of Adverse Events Data in Social Media," British Journal of Clinical Pharmacology 80, no. Four (2015): 878-88, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594731/; J. Snyder and L. Turner, "Crowdfunding for Stem Cell-Based Interventions to Treat Neurologic Diseases and Injuries," Contemporary Issues 93, no. 6 (2019), https://n.neurology.org/content material/93/6/252.17. H.J. Duggirala, senior epidemiologist, Center for Veterinary Medicine, "FDA Perspectives on Social Media for Postmarket Safety Monitoring," Nov. 15, 2018, https://www.fda.gov/media/122897/download.18. D. Grady and R. Abelson, "Stem Cell Treatments Flourish With Little Evidence That They Work," The brand new York Times, May 13, 2019, https://www.nytimes.com/2019/05/13/well being/stem-cells-fda.html.19. J. Snyder, L. Turner, and V.A. Crooks, "Crowdfunding for Unproven Stem Cell-Based Interventions," Journal of the American Medical Association 319, no. 18 (2018): 1935-36, http://doi.org/10.1001/jama.2018.3057; Snyder and Turner, "Crowdfunding for Stem Cell-Based Interventions to Treat Neurologic Diseases and Injuries."20. Golder, Norman, and Loke, "Systematic Review."21. B. Hawke et al., "How to Peddle Hope: An Analysis of YouTube Patient Testimonials of Unproven Stem Cell Treatments," Stem Cell Reports 12, no. 6 (2019): 1186-89, https://www.ncbi.nlm.nih.gov/pubmed/31189092; A. Petersen, K. Seear, and M. Munsie, "Therapeutic Journeys: The Hopeful Travails of Stem Cell Tourists," Sociology of Health and Illness 36, no. 5 (2014): 670-85, https://doi.org/10.1111/1467-9566.1209222. Pritchett, "The Debit Side."23. J. Interlandi, "The Trouble With Stem Cell Therapy," Consumer Reports, Jan. 11, 2018, https://www.consumerreports.org/medical-treatments-procedures/trouble-with-stem-cell-therapy/.24. C. Rachul, "‘What Have I Got to Lose?’: An Analysis of Stem Cell Therapy Patients’ Blogs," Health Law Review 20, no. 1 (2011); Hawke et al., "How to Peddle Hope."25. W. Wan and L. McGinley, "Clinic Pitches Unproven Treatments to Desperate Patients, With Tips on Raising the Cash," The Washington Post, Dec. 1, 2019, https://www.washingtonpost.com/national/well being-science/clinic-pitches-unproven-therapies-to-desperate-patients-with-tips-on-elevating-the-cash/2019/12/01/fe94cfcc-d3c6-11e8-8c22-fa2ef74bd6d6_story.html; J. Interlandi, "The Trouble with Stem Cell Therapy."26. S. Giordano, M. Romeo, and P. Lankinen, "Platelet-Rich Plasma for Androgenetic Alopecia: Does It Work? Evidence From Meta Analysis," Journal of Cosmetic Dermatology 16, no. 3 (2017): 374-81, https://pubmed.ncbi.nlm.nih.gov/28296142/; N. Hussain, H. Johal, and M. Bhandari, "An Evidence-Based Evaluation on the use of Platelet Rich Plasma in Orthopedics-A Review of the Literature," SICOT-J three (2017): 57, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632954/.27. ClinicalTrials.gov, "Platelet-Rich Plasma or PRP," U.S. National Library of Medicine, accessed Jan. 25, 2021, https://clinicaltrials.gov/ct2/outcomes?cond=&term=platelet-wealthy+plasma+OR+PRP&cntry=&state=&metropolis=&dist=.28. I.A. Jones, R.C. Togashi, and C. Thomas Vangsness, Jr., "The Economics and Regulation of PRP in the Evolving Field of Orthopedic Biologics," Current Reviews in Musculoskeletal Medicine 11, no. Four (2018): 558-65, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220002/; P. Knoepfler, "What Is PRP Injection & Is It Worth It?," The Niche, accessed Jan. 25, 2021, https://ipscell.com/2020/05/affected person-qa-3-what-is-prp-is-it-worth-trying/.29. Knoepfler, "What Is PRP Injection & Is It Worth It?"30. Duggirala, "FDA Perspectives on Social Media for Postmarket Safety Monitoring."31. U.S. Food & Drug Administration, "Data Mining at FDA-White Paper," final modified Aug. 20, 2018, https://www.fda.gov/science-research/data-mining/data-mining-fda-white-paper.
Appendix A

Definitions of key terms

Adverse event: Any undesirable experience related to using a medical product in a affected person.

Serious hostile occasion: An adverse occasion is considered critical when the patient final result is demise or entails a life-threatening incident or hospitalization, causes incapacity or permanent harm or required intervention to stop everlasting impairment or harm, causes congenital anomaly/start defect, or other critical important medical events that may require medical or surgical intervention to prevent certainly one of the opposite outcomes (e.g., severe allergic reactions, seizures, or convulsions).

Regenerative medication: This time period covers a variety of treatments intended to repair or substitute damaged cells, tissues, or organs. These treatments include cell therapies, bioengineered tissue products, and gene therapies.32

Unproven therapies/interventions: Therapies or interventions that lack definitive, high-high quality clinical proof of security and efficacy. The phrases "unproven therapies" and "unapproved therapies" are often used

interchangeably. However, the main focus of Pew’s research is to spotlight antagonistic occasions associated with "unapproved therapies" which will even be unproven.

Unapproved therapies/interventions: Therapies or interventions that haven't been reviewed by FDA for safety, effectiveness, or high quality or potency.

Appendix B

Literature Review Methodology

Pew analyzed peer-reviewed publications in educational journals and grey literature, including authorities publications, media experiences, case histories, and legal documents, to determine AEs related to unapproved SCRIs from November 2019 by means of January 2021 to update a beforehand revealed record of AEs.

Pew staff conducted nonsystematic searches utilizing the key phrases "stem cell," "regenerative remedy/ therapy," "exosome," and "platelet rich plasma (PRP) remedies," sometimes together with "adverse occasion," "complication," "infection," "inflammation," "swelling," "pain," "cancer," "lesion," or "tumor." Using these

keywords, Pew searched available publications on the web, together with databases akin to Google Scholar, PubMed, and Ebsco, for articles published in main medical journals; the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report; FDA website; and major newspaper websites, including The brand new York Times and The Washington Post, in addition to native newspapers in regions with massive numbers of stem cell clinics, similar to Florida, Texas, and California.

Articles that directly referred to an AE in the title were reviewed for any dialogue of AE exterior of clinical trials or accepted therapies. Articles with normal discussions of the use of these treatments have been examined for dialogue of AEs, as had been their references. AEs showing to be related to an unapproved SCRI were included in Table B.1.

Limitations: The variety of AEs documented in Table B.1 doubtless does not reflect the true variety of reported AEs related to unapproved SCRIs. This result's because our examine was not designed to be a systematic evaluate and subsequently might not have captured all available publications on the net. Additionally, many cases of AEs reported in scientific publications and the media don't embrace complete or mandatory information to attract a correlation between the kind of intervention and the AE. Therefore, instances that did not meet the minimum situations for the occasion to be thought of a confirmed case of AE caused by an unapproved SCRI were excluded from the final count.

Table B.1

Adverse Events Associated with Unapproved Stem Cell and Regenerative Interventions

Note: All AEs included in this desk are associated with unapproved regenerative medication products, although the regulatory status for specific products cannot be individually verified-some SCRIs included on this examine might not require FDA approval to be administered to patients.

1. B.H. Dobkin, A. Curt, and J. Guest, "Cellular Transplants in China: Observational Study From the biggest Human Experiment in Chronic Spinal Cord Injury," Neurorehabilitation Neural Repair 20, no. 1 (2006): 5-13, http://dx.doi.org/10.1177/1545968305284675.2. Pelocytosis means elevated cell depend.3. Reaction to antibodies in the recipient blood.4. N. Amariglio et al., "Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient," PLOS Medicine 6, no. 2 (2009): e1000029, https://www.ncbi.nlm.nih.gov/pubmed/19226183.5. Ibid. Ataxia telangiectasia is a rare disorder characterized by degeneration of the mind region that controls movement and speech.6. N.A. Kishk, N.T. Abokrysha, and H. Gabr, "Possible Induction of Acute Disseminated Encephalomyelitis (ADEM)-Like Demyelinating Illness by Intrathecal Mesenchymal Stem Cell Injection," Journal of Clinical Neuroscience 20 (2013): 312-13, https://www.sciencedirect. com/science/article/pii/S096758681200330X.7. D. Thirabanjasak et al., "Angiomyeloproliferative Lesions Following Autologous Stem Cell Therapy," Journal of the American Society of Nephrology 21, no. 7 (2010): 1218-22, https://doi.org/10.1681/ASN.2009111156.8. F. Jabr, "In the Flesh: The Embedded Dangers of Untested Stem Cell Cosmetics," Scientific American, Dec. 17, 2012, https://stemcellscosts.com/ https://www. scientificamerican.com/article/stem-cell-cosmetics.9. C. MacGregor, A. Petersen, and M. Munsie, "Stem Cell Tourism: Selling Hope Through Unproven Stem Cell Treatments-Lessons From the X-Cell Center Controversy," EuroStemCell, accessed Feb. 22, 2019, https://www.eurostemcell.org/stem-cell-tourism-selling-hope- through-unproven-stem-cell-remedies-lessons-x-cell-middle; R. Mendick, "Stem Cell Clinic That ‘Preyed on the Vulnerable,’" The Telegraph, April 8, 2012, https://www.telegraph.co.uk/news/well being/information/9192157/Stem-cell-clinic-that-preyed-on-the-susceptible.html.10. "Bonita Springs Stem Cell Doctor Grekos Loses Two More Rounds in Court," Naples Daily News, Sept. 1, 2014, http://archive.naplesnews. com/news/local/bonita-springs-stem-cell-physician-grekos-loses-two-more-rounds-in-court docket-ep-589350147-337085341.html.11. Ibid.; C. Gentry and the Associated Press, "FDA: Florida Stem Cell Clinic Violates Law," Health News Florida, Feb. 8, 2016, http://health. wusf.usf.edu/publish/fda-florida-stem-cell-clinic-violates-legislation.12. L. Turner, "Medical Malpractice Lawsuit Following Death for Stem Cell Recipient," Health in the global Village, Nov. 27, 2012,, http://www. healthintheglobalvillage.com/medical-malpractice-lawsuit-following-dying-of-stem-cell-recipient.13. W. Kremer, "Paolo Macchiarini: A Surgeon’s Downfall," BBC, Sept. 10, 2016, https://www.bbc.com/news/magazine-37311038; J. Rasko and C. Power, "Dr Con Man: The Rise and Fall of a star Scientist Who Fooled Almost Everyone," The Guardian, Sept. 1, 2017, https:// www.theguardian.com/science/2017/sep/01/paolo-macchiarini-scientist-surgeon-rise-and-fall.14. J. W. Pritchett, "The Debit Side of Stem Cell Joint Injections: A Prospective Cohort Study," Current Orthopaedic Practice 32, no. 2 (2021): 1-6, https://journals.lww.com/c-orthopaedicpractice/Abstract/2021/03000/The_debit_aspect_of_stem_cell_joint_injections a.3.aspx. Most reviews on this table are drawn from single case reviews. However, this knowledge is drawn from a cohort examine that recognized long-time period complications from unapproved stem cell injections utilizing knowledge collected from medical information held by a single insurer.15. A brief fall in blood pressure caused by overactivity of the vagus nerve.16. Temporary lack of consciousness attributable to a fall in blood pressure.17. T. Ikka et al., "Recent Court Ruling in Japan Exemplifies Another Layer of Regulation for Regenerative Therapy," Cell Stem Cell 17, no. 5 (2015): 507-08, https://doi.org/10.1016/j.stem.2015.10.008.18. R. Hurst et al., "Inflammatory Hypertrophic Cauda Equina Following Intrathecal Neural Stem Cell Injection," Muscle and Nerve, 48, no. 5 (2013): 831-835, https://doi.org/10.1002/mus.23920.19. J.W. Jung, "Familial Occurrence of Pulmonary Embolism After Intravenous, Adipose Tissue-Derived Stem Cell Therapy," Yonsei Medical Journal 54, no. 5 (2013): 1293-96, http://dx.doi.org/10.3349/ymj.2013.54.5.1293.20. S. Hobbs, "Florida Takes Away License of Doctor With Troubled Past," The Sun Sentinel, Nov. 17, 2017, https://www.solar-sentinel.com/ well being/fl-physician-self-discipline-kantzler-20171117-story.html; Florida Department of Health, Amended Administrative Complaint, Department of Health v. Mark G. Kantzler, Case No. 2013-10663 (filed July 13, 2015).21. Coroners Court New South Wales, "Inquest Into the Death of Sheila Drysdale" (2016), http://www.coroners.justice.nsw.gov.au/ Documents/Findings%20Drysdale.pdf.22. S. K. Rhea et al., "Cluster of Staphylococcus Aureus Septic Arthritis Cases After Intra-Articular Injection of Autologous Platelet-Rich Plasma-North Carolina 2013," Proceedings of Epidemic Intelligence Services Annual Conference, 2014, https://www.cdc.gov/eis/ downloads/2014-EIS-Conference.pdf.23. M.P. Robyn et al., "Q Fever Outbreak Among Travelers to Germany Who Received Live Cell Therapy-United States and Canada, 2014," MorbidityandMortalityWeeklyReport,Oct. 2, 2015, https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6438a3.htm.24. Live cell therapy, or contemporary cell therapy, is the observe of injecting processed cells from organs or fetuses of nonhuman animals into human recipients.25. A. Rollins, "Beware Stem Cell Doctors Trading on Hope," Australian Medicine 26, no. 15 (2014): 24, https://search.informit.org/doi/ abs/10.3316/ielapa.561644836270530; M. Davey, "Stem Cell Therapies: Medical Experts Call for Strict International Rules," The Guardian, July 6, 2017, https://www.theguardian.com/science/2017/jul/06/stem-cell-therapies-medical-experts-call-for-strict- international-guidelines; N. Bodchenski and A. Brown, "Brisbane Woman Dies Undergoing Russian Stem Cell Treatment," The Queensland Times, July 28, 2014, https://www.qt.com.au/information/brisbane-girl-dies-undergoing-russian-stem-cell-t/2331189/.26. A. J. Rong et al., "Vision Loss Secondary to Autologous Adipose Stem Cell Injections: A Rising Problem," JAMA Ophthalmology 136, no. 1 (2018), https://jamanetwork.com/journals/jamaophthalmology/article-summary/2664084.27. United States v. California Stem Cell Treatment Center Inc., Cell Surgical Network Corp., Elliot B. Lander, M.D., and Mark Berman, M.D., No. 5:18-CV-1005 (U.S. District Court for the Central District of California, May 9, 2018), https://www.courtlistener.com/ docket/6550705/1/united-states-v-california-stem-cell-treatment-heart-inc.28. K.M. Perkins et al., "Notes From the sphere: Infections After Receipt of Bacterially Contaminated Umbilical Cord Blood-Derived Stem Cell Products for Aside from Hematopoietic or Immunologic Reconstitution-United States, 2018," Morbidity and Mortality Weekly Report, Dec. 21, 2018, https://www.cdc.gov/mmwr/volumes/67/wr/mm6750a5.htm?s_cid=mm6750a5_w#T1_down; W. Wan and L. McGinley, "‘Miraculous’ Stem Cell Therapy Has Sickened People in Five States," The Washington Post, Feb. 27, 2019, https://www.washingtonpost. com/nationwide/well being-science/miraculous-stem-cell-therapy-has-sickened-people-in-five-states/2019/02/26/c04b23a4-3539-11e9- 854a-7a14d7fec96a_story.html; Andy Marso, "KC Woman Got E. coli Infection From Stem Cell Treatment at JoCo Clinic, Lawsuit Says," The Kansas City Star, Aug. 23, 2019, https://www.kansascity.com/information/business/health-care/article234306097.html.29. Wan and McGinley, "’Miraculous’ Stem Cell Therapy."30. L. McGinley and W. Wan, "This Clinic’s Experimental Stem Cell Treatment Blinded Patients. Four Years Later, the federal government Remains to be Trying to Shut It Down," The Washington Post, April 3, 2019, https://www.washingtonpost.com/national/health-science/ this-clinics-experimental-stem-cell-therapy-blinded-patients-four-years-later-the-authorities-is-nonetheless-making an attempt-to-shut-it- down/2019/04/03/432d6d04-ff2f-11e8-83c0-b06139e540e5_story.html.31. Ž. Večerić-Haler et al., "Multiorgan Failure With Fatal Outcome After Stem Cell Tourism," European Journal of Medical Research 26, no. 5 (2021), https://doi.org/10.1186/s40001-020-00477-4.32. Nebraska Department of Health and Human Services, Health Alert Network Advisory, "Risk Associated with Unapproved Products Derived From Stem Cells, Placenta and Umbilical Cord Blood," Dec. 6, 2019, http://dhhs.ne.gov/han%20Documents/ADVISORY12062019.pdf; K. Fiore, "Serious Illnesses in Nebraska Tied to Exosome Therapy," MedPage Today, Dec. 16, 2019, https://www. medpagetoday.com/infectiousdisease/publichealth/83928.33. Y.J. Alderazi, S.W. Coons, and K. Chapman, "Catastrophic Demyelinating Encephalomyelitis After Intrathecal and Intravenous Stem Cell Transplantation in a Patient With Multiple Sclerosis," Journal of Child Neurology 27, no. 5 (2012): 632-35, https://www.ncbi.nlm.nih.gov/ pubmed/22156784.34. Demyelinating encephalomyelitis is a widespread assault of inflammation within the spinal cord and brain that damages the protective masking of nerve fibers. See National Institutes of Neurological Disorders and Stroke, "Acute Disseminated Encephalomyelitis Information Page," accessed Dec. 11, 2018, https://www.ninds.nih.gov/Disorders/All-Disorders/Acute-Disseminated-Encephalomyelitis- Information-Page.35. A.L. Berkowitz et al., "Glioproliferative Lesion of the Spinal Cord as a Complication of ‘Stem-Cell Tourism,’" New England Journal of Medicine 375 (2016): 196-8, http://dx.doi.org/10.1056/NEJMc1600188.36. M. Dobke et al., "Necrotizing Metachronous Facial Ulcerations After ‘Stem Cell Face Lift,’" Annals of Plastic Surgery 70, no. 4 (2013): 392- 96, http://dx.doi.org/10.1097/SAP.0b013e31827a7d7d.37. Necrosis is the death of most or the entire cells in a tissue or organ.38. B.J. Dlouhy et al., "Autograft-Derived Spinal Cord Mass Following Olfactory Mucosal Cell Transplantation in a Spinal Cord Injury Patient," Journal of Neurosurgery Spine 21, no. 4 (2014): 618-22, https://doi.org/10.3171/2014.5.SPINE13992.39. C. F. Woodworth et al., "Intramedullary Cervical Spinal Mass After Stem Cell Transplantation Using an Olfactory Mucosal Cell Autograft," CMAJ191, no. 27 (July 8, 2019): E761 https://www.cmaj.ca/content/191/27/E761.40. C. Wilson, "Stem Cell Treatment Causes Nasal Growth in Woman’s Back," New Scientist, July 8, 2014, https://www.newscientist.com/ article/dn25859-stem-cell-remedy-causes-nasal-growth-in-womans-back/#.U8nhAoBdWdw.41. A.E. Kuriyan et al., "Vision Loss After Intravitreal Injection of Autologous ‘Stem Cells’ for AMD," New England Journal of Medicine 376 (2017): 1047-53, http://dx.doi.org/10.1056/NEJMoa1609583.42. P. Pytel et al., "Ventricular Fibrillation Following Autologous Intramyocardial Cell Therapy for Inherited Cardiomyopathy," Cardiovascular Pathology 19, no. 2 (2010): e33-36, https://doi.org/10.1016/j.carpath.2008.09.004.43. T. Sheldon, "Dutch Clinic Is Ordered to Stop Giving Stem Cell Therapy," The BMJ 333, no. 7572 (2006): 770, https://doi.org/10.1136/bmj.333.7572.770-a.44. J. Lee, "South Korean Company Cleared in Deaths Following Stem Cell Therapy," CNN, Dec. 14, 2010, http://edition.cnn.com/2010/ WORLD/asiapcf/12/14/south.korea.stem.cell/index.html.45. T.E. Lyn, "China ‘Stem Cell Therapies’ Offer Heartbreak for many," Reuters, Sept. 21, 2011, https://www.reuters.com/article/us-stemcell- scams/china-stem-cell-therapies-offer-heartbreak-for-many-idUSTRE78K18120110921.46. "Stem Cell Rip-Off," Newsweek, Nov. 7, 2004, http://www.newsweek.com/stem-cell-rip-124481.47. A. Olmedo-Reneaum et al., "Rogue ‘Stem Cell Clinic’ Results in Mycobacterium abscessus Infection," The Lancet 393 (March 2, 2019): 918 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30299-5/fulltext.48. L. Curwen, "The Risks Behind the Hype of Stem-Cell Treatments," BBC Radio 4, Jan. 7, 2020, https://www.bbc.com/news/ well being-51006333; Care Quality Commission, Inspection Report: The Regenerative Clinic (2019) https://www.cqc.org.uk/ location/1-5447933570/reports.49. M. T. Giordana et al., "Neuropathology of Olfactory Ensheathing Cell Transplantation into the Brain of Two Amyotrophic Lateral Sclerosis (ALS) Patients," Brain Pathology 20 (2010): 730-737, https://pubmed.ncbi.nlm.nih.gov/19919605/.50. S. S. Saraf et al., "Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived ‘Stem Cells’ in a Patient With Exudative Macular Degeneration," Ophthalmic Surgery, Lasers and Imaging Retina 48, no. 9 (2017): 772-775, https://doi.org/10.3928/23258160- 20170829-16.51. J. Taliaferro et al., "Cash-Based Stem-Cell Clinics, The Modern day Snake Oil Salesman? A Report of Two Cases of Patients Harmed by Intra-Articular Stem Cell Injections," JBJS Case Connector 9, no. 4 (October-December 2019): e0363, http://dx.doi.org/10.2106/JBJS. CC.19.00363.52. K. T. Khine et al., "Chronic Retinal Detachment and Neovascular Glaucoma After Intravitreal Stem Cell Injection for Usher Syndrome," AmericanJournalofOphthalmologyCaseReports18 (2020): 100647, https://doi.org/10.1016/j.ajoc.2020.100647.53. K. Boudreault et al., "Complication of Autologous Stem Cell Transplantation in Retinitis Pigmentosa," JAMA Ophthalmology 134, no. 6 (June 2016), https://doi.org/10.1001/jamaophthalmol.2016.0803.54. B. A. Kendall et al., "Disseminated Mycobacterial Infection After International Medical Tourism," Open Forum Infectious Diseases, OFID Brief Report 2, no. 2 (2015), https://doi.org/10.1093/ofid/ofv054.55. J. Y. Kim et al., "Epiretinal Membrane Formation After Intravitreal Autologous Stem Cell Implantation in a Retinitis Pigmentosa Patient," RetinalCases&BriefReports11, no. 3: 227-231, (July 2017), https://doi.org/10.1097/icb.0000000000000327.56. R. Rahangdale et al., "Glioneuronal Growth of Spinal Cord Following Intrathecal Stem Cell Transplant," Neurology 90, no. 15 Supplement (April 10, 2018), http://n.neurology.org/content material/90/15_Supplement/P4.164.57. A. A. Madhavan et al., "Polyclonal Lymphocytic Infiltrate With Arachnoiditis Resulting From Intrathecal Stem Cell Transplantation," The Neuroradiology Journal 3, no. 2(Feb. 3, 2020): 174-178, https://doi.org/10.1177/1971400920902451.58. E. H. Leung et al., "Retinal Detachment After Subretinal Stem Cell Transplantation," Ophthalmic Surgery, Lasers and Imaging Retina 47, no. 6 (2016): 600-601 https://doi.org/10.3928/23258160-20160601-16.59. G. Bauer et al., "Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell- Based Interventions," Stem Cells Translational Medicine 7, no. 9 (2018): 1-10, www.StemCellsTM.com; H. Butzkueven, "Commentary on ‘Possible Induction of Acute Disseminated Encephalomyelitis (ADEM)-Like demyelinating Illness by Intrathecal Mesenchymal Stem Cell Injection,’" Journal of Clinical Neuroscience 20 (2013): 312-31, https://doi.org/10.1016/j.jocn.2012.06.003.60. E. Nasli-Esfahani et al., "Transitional Meningioma After Fetal Liver-Derived Cell Suspension Allotransplant," Experimental and Clinical Transplantation 15, no. 2 (2017):231-234, https://pubmed.ncbi.nlm.nih.gov/26788941/.

Appendix C

FAERS Review Methodology

Pew contracted with an exterior provider with experience in pharmacovigilance platforms such as the FDA Adverse Event Reporting System (FAERS) to review the type and frequency of AEs reported into the database. The contractor reviewed FAERS data for the interval November 1997-March 2020. Original datasets containing uncooked knowledge were downloaded from FDA’s web site. A proprietary cleaning protocol was utilized to enhance user understanding of the information, and the following key phrases and combination of keywords have been used to conduct a search of the database: "stem cell (or equivalent)," "umbilical," "hematopoietic," "progenitor," "marrow," "cord," "blood," "hESC-RPE (human embryonic stem cell-derived retinal pigment epithelial cells)," "HSC835" and "regen."

Through a series of identification and filtration methods, 19 complete, nonduplicative, voluntary experiences that appeared to be associated to unapproved SCRIs had been recognized. These distinctive case experiences had been additional reviewed by a pediatric oncologist to verify that they had been prone to be related to an unapproved SCRI. An additional 14 case reports had been removed after figuring out that that they had been most more likely to be associated with an accredited

product, resulting in a ultimate count of five unique case reviews that have been moderately expected to be associated with unapproved SCRIs. The flow chart beneath illustrates how this info was obtained.

Table C.1

Adverse Event Reports Related to Unapproved SCRIs Identified in FAERS

apheresis services†

marker elevated, nodal rhythm, put up-procedural complication, post- procedural fever, procedural complication, procedural hypotension, tachycardia, ventricular fibrillation

* The original raw information in FAERS listed the therapy as: HPC-A W2333090900158-four 3.29E6 CD34+KG.

† Apheresis is a process that separates blood into its parts after which selectively removes or redirects sure blood components back into the affected person. Apheresis can be utilized to collect stem cells from blood.

Note: The original FAERS knowledge reflected on this desk may be incomplete and some of it could lack clarification; solely the data for which enough data was out there has been adapted to enhance readability and comprehension.

Appendix D

Social Media Scrape Methodology

Pew contracted with an exterior data science research agency, Codex, to conduct an internet scrape of patient critiques and testimonials posted on Facebook public pages, Yelp, and Google to assemble AE data related to unapproved SCRIs. Codex used the Selenium framework to automate a Chrome browser and switch web content material into structured data.

Using an inventory of key phrases supplied by Pew, Codex used the Python programming language to develop a customized code to scrape evaluations of companies that market unapproved SCRIs. The names and locations of businesses had been offered by Leigh Turner, a bioethics professor who tracks stem cell businesses and printed an earlier model of the database in 2018. The checklist of therapy and AE keywords was tailored from Turner’s paper on the U.S. direct-to-client stem cell market.33

Treatment/therapy key phrases:

- Stem cell or regenerative therapy/remedy for: aging, arthritis, autism, COPD, diabetes, knees, ache, paralysis/paraplegia, erectile dysfunction, Alzheimer’s, dementia, COVID-19/coronavirus.- Adipose/fat/fat-derived stem cell therapy/therapy/adipose-derived stem cells (ADSC).- Amyotrophic lateral sclerosis (ALS) stem cell therapy/therapy.- Multiple sclerosis (MS) stem cell therapy/treatment.- Amniotic stem cell therapy/remedy/umbilical/perinatal cord blood/placenta-derived stem cells/human embryonic stem cells.- Sports stem cell therapy/therapy.- Stem cell injections/infusions in: knee, spinal cord, eye, mind.- Stromal vascular fraction stem cell therapy/treatment.- Exosome therapy/therapy.- Platelet-wealthy plasma (PRP) therapy/treatment.- Mesenchymal stem cells (MSCs).- Bone marrow-derived stem cells.- Fetal neural stem cells (fNSC).- Hematopoietic stem cells.- Live cell/recent cell therapy.- Tennis elbow.- Thinning/balding hair/hair loss.- Plantar fasciitis.

Adverse occasions key phrases:

- Sick.- Sore.- Pneumonia (cough, problem breathing).- Meningitis (stiff neck, headache).- Vomiting (throw up, puke).- Gastrointestinal bleeding (blood in stool or abdominal pain).- Fever.- Pain.- Headache.- Bonelike development.- Brain tumors/tumors within the mind.- Brain hemorrhage (brain bleed, uncontrollable bleeding, ruptured blood vessel).- Spinal tumors/tumors in the spine.- Inflammation/acute inflammation/redness/swelling/pain/tenderness of: brain, spinal cord, kidney, liver, adrenal gland, knee.- Lesions/spotting or injury in: kidney, liver, adrenal gland, spinal cord.- Stroke.- Cardiac arrest/heart assault (lack of coronary heart perform/lack of oxygen to coronary heart).- Hospitalization/admitted to hospital/taken to the hospital/ER.- Coma.- Death.- Infection.- Abscess/blister/pus/redness/swelling.- Pulmonary embolism/blood clot within the lungs.- Bleeding/blood loss.- Paralysis/paraplegia/spinal damage or disease.- Urinary incontinence/involuntary urine leak/loss of bladder control.- Blindness/loss of vision/flashes of mild/light sensitivity/retinal detachment.

The contractor performed a preliminary search using these keywords and supplied a 10% sample of the info to Pew to make sure that the script was pulling the correct knowledge for evaluation earlier than proceeding with your entire scrape. Additional therapy keywords such as PRP were added as a result of critiques describing this therapy have been organically recognized throughout this preliminary search.

The customized script was used by an experienced scraper to assemble evaluate textual content, date of writing, star scores, and hyperlinks to the original review location from all of the critiques yielded by each of those searches. Where attainable, the reviewer broke search terms into element parts to capture their diversified use in pure language. For instance, the reviewer searched for the word fragment "inflam" to establish reviews that use the words "inflamed," "inflammation," and "inflammatory." To counteract words that generated too many false positives, the reviewer offered the Python script with variations on the identical term, reminiscent of "went blind," "go blind," and "blindness." The info was then saved to a Python data frame and exported as an Excel file.

Natural language processing was then applied to the dataset to extract reviews that mentioned each stem cell treatments and antagonistic occasions and to establish critiques with constructive and adverse sentiment. However, the standard sentiment analysis utilizing Python’s VADER library (which is typically thought-about best-in-class for social media information) carried out poorly. It's because many reviewers post lengthy discussion of pain and suffering earlier than seeking treatment, and then state that stem cell therapy cured them, leading the VADER library to code the sentiment in these critiques as unfavorable.

To counteract this situation, Codex referred to the consumer-provided star ratings as a fallback and coded all reviews with fewer than four of five stars as potentially negative. A hybrid dataset was created using star opinions when potential and sentiment solely when the user didn't provide a numerical score. This method subsetting the information

performed relatively effectively, although it nonetheless pulled some false positive reviews that had been manually highlighted by the contractor. Reports that have been confirmed to be false positives have been people who describe pretreatment pain or use keywords in an unexpected context. These have been excluded from the ultimate count that was submitted to Pew.

A complete of 328 critiques have been submitted to Pew for handbook coding. Of those, 106 opinions had been identified on Facebook, a hundred and one on Google, and 121 on Yelp. These evaluations have been additional categorized into three fundamental buckets:

Yes = reviews that point out opposed occasions showing to be associated with an unapproved SCRI. These reviews can embody phrase