“Time’s up,” said the Food and Drug Administration (FDA). A three-and-a-half-year grace period during which companies manufacturing and providing regenerative medicine procedures were instructed to get their operations in line with new, clarified rules announced in 2017, ended May 31, 2021. Those procedures had previously fallen into a gray area of regulation because they rely on harvesting live stem cells or related products rather than traditionally manufactured drugs to repair damaged tissues and organs. Starting June 1, the agency expects all such companies to be in compliance or risk a variety of enforcement actions from warning letters to pursuing criminal prosecution.
For many years, the regenerative medicine industry operated with limited FDA oversight. The field exploded in the 2010s, with nearly a thousand clinics popping up throughout the US. In 2017, the FDA announced stricter, clearer regulations for those treatments. Knowing that a multibillion-dollar industry already existed and wanting to support research and innovation in what most researchers believe is a promising field of medicine, the agency didn’t penalize all clinics that weren’t following the rules. Instead, the FDA offered a grace period, during which companies could file regulatory paperwork and design trials in line with the agency’s requirements.
Streamlining the Approval Process
Traditional clinical trials can take years and sometimes even decades to complete, so the FDA has offered several types of expedited approval pathways for therapies expected to provide valuable treatment to patients who have few options. In 2016, it created the Regenerative Medicine Advance Therapy Designation (RMAT) as a part of the 21st Century Cures Act. If the FDA grants the designation to a treatment, the researchers conducting its trials get special support from the agency that can streamline the approval process. The company may be permitted to submit real world data and patient registries in lieu of data from a standard clinical trial, in which some patients are randomized to receive a placebo, to be considered for approval.
But in June 2019, Ned Sharpless, the acting FDA commissioner, announced that the agency had received far fewer approval requests — RMAT or otherwise — than it had anticipated during the grace period. “We’re more than halfway through the enforcement discretion period, and the pace of progress of those offering these human cells, tissues and cellular and tissue-based products, including stem cell treatments, to come into compliance with the requirements has been slower than expected. It’s possible some stakeholders have questions about the requirements or the length of the process,” he said in a statement announcing the Tissue Reference Group’s Rapid Inquiry Program (TRIP). Essentially, companies that were unsure which level of regulation their products required could have submitted a request to the Tissue Regerence Group, which would answer within three days, outlining the steps needed to meet the FDA’s requirements for compliance. That program ended on March 31, 2021.
The FDA Cracks Down on Risky Procedures
While the FDA offered to help companies willing to seek regulatory approval, the agency continued to penalize those companies it believes are conducting the riskiest procedures and making the boldest claims, which had fallen outside of even the previous, cloudier regulations.
For instance, Vibrant Health Care received a warning letter from the FDA in November 2020, after marketing umbilical-cord-derived stem cell treatments designed to boost the immune system and protect patients against COVID-19.
A banner on the company’s homepage now reads: “Vibrant Health Care does not offer any products or treatments that can mitigate, prevent, treat, diagnose or cure COVID-19. If you are experiencing COVID 19 symptoms, please contact your primary care physician or local hospital.”
The letter also cited patient testimonials on the website that claimed that Vibrant’s treatments had cured their asthma overnight, for example, or led to other dramatic improvements. The testimonials page no longer includes references to specific treatments other than Botox. Instead, patients make broad statements like, “Dr. Farrell has been keeping me functional for many years. She always finds some way to alleviate my pain.”
An FDA spokesperson told MedShadow in an email, “Clinics currently offering products outside of FDA’s review process are taking advantage of patients and flouting federal statutes and FDA regulations. This ultimately puts at risk the very patients that these clinics claim to want to help, by either delaying treatment with legitimate and scientifically sound treatment options, or worse, posing harm to patients.”
Need for Thorough Clinical Trials
While some providers are working to get their products in line with FDA recommendations, others continue to claim that their products should not be subject to FDA review. Some companies may be toeing a fine line, registering clinical trials as a way to offer treatments to patients, but not designing those trials in ways that are likely to bring the therapies to market.
A search for “stem cell” and “COVID” on clinicaltrials.gov, a government website that lists clinical trial information, yields over 100 results. It could be a sign that researchers are working on new therapies and developing them through traditional clinical trial pathways sanctioned by the FDA. But, trials listed here are not always what they seem and the listings are subject to limited oversight. Thousands of trials registered on clinicaltrials.gov are not completed and the results never published. It’s possible that some companies don’t intend to send their results to the FDA for review and instead have set up sham trials for the appearance of legitimacy.
Leigh Turner, PhD, a bioethicist at the University of Minnesota published an analysis in 2017 that found 18 US-based clinical trials testing stem cells listed on clinicaltrials.gov required the patients to pay for their own treatments. In most clinical trials, patients are responsible for little to none of the cost of treatment or are paid a stipend and compensated for some travel costs to and from the medical facility. Moreover, Wired reported that patients paid $5,000 to $15,000 per treatment, a fact that was not disclosed in any of the clinicaltrials.gov listings themselves. None of the 18 studies were randomized or blinded, conditions usually required in studies intended for FDA review, because they minimize bias in results.
In 2019, Google banned advertisements for treatments that “have no established biomedical or scientific basis.” The company’s announcement also stated, “The new policy also includes treatments that are rooted in basic scientific findings and preliminary clinical experience, but currently have insufficient formal clinical testing to justify widespread clinical use.” Some companies, Turner suggests in his article, may be using clinicaltrials.gov as an advertising tool to recruit patients willing to pay for the treatments, without conducting scientifically sound trials.
Concerns Regarding ‘Right to Try’
[Disclosure: The MedShadow Foundation advocated against the Right to Try Act.]
Even if you might benefit from an experimental drug, you might not be eligible for a trial. Maybe you’re not the right age, you’ve been prescribed drugs in the past or have a comorbidity that interferes with the treatment being tested. Those conditions could cloud the data for scientists, even if the treatment is still helpful to you. For these situations, the FDA created the Expanded Access Pathway.
“The expanded access pathway has been around for a long time. It tries to acknowledge that there may be circumstances where it’s justifiable to provide access to investigational new drugs outside of a clinical trial context,” says Turner. “But with the expanded access route, there is a fair degree of oversight.”
The FDA evaluates each application for a patient who has exhausted other options to receive a drug through the expanded access pathway. According to a 2017 study, initiating the process requires paperwork that takes about 45 minutes to fill out. On average, the FDA issues a decision within four days. In emergency situations, it usually responds in less than 24 hours. The overwhelming majority of requests are approved, though about 11% require adjustments like a change in dosing or an informed consent form before approval.
The Right to Try Act allows patients, physicians and sponsors to bypass this FDA review. “It really means that decision-making devolves onto patients, their physicians and a sponsor,” says Turner. “If everyone is being careful and cautious and doing everything they can to be compliant, it may be an approach that works in an acceptable fashion.”
When Congress passed the Right to Try act in 2018, Matthew Feshbach, who had previously run a company that provided stem cell treatments in the Bahamas, saw an opportunity to return to the US and open Ambrose Cell Therapy, which now offers stem cell treatments for patients with a wide range of diseases who have exhausted conventional therapeutic options.
On the company’s website, the tagline under the Ambrose Cell Therapy logo reads “your right to try,” and the site has a page dedicated to explaining the legislation. The company uses a system made by another company, Cytori Therapeutics, to process cells collected from a patient’s fat and reintroduce them into the patient’s body. The system has been tested for safety in nine Phase I and Phase II trials, but Ambrose is not currently pursuing any clinical trials of the treatment to bring it to market for specific diseases under FDA approval. Rather, the company is offering the stem cell treatment exclusively on a Right to Try basis. Feshbach says, “There are very few large-scale clinical trials that have been done with adult stem cells. They usually don’t make it past Phase II, primarily because of funding.” Additionally, he says, he is “not a big believer in randomized controlled trials, because in the real world, [treatments] don’t work out the way they did in a trial.”
He explains that there is a growing body of peer-reviewed literature to support the cells that Ambrose uses (and encourages patients to ask for such literature when searching for stem cell treatment options). The company is collecting data on patients and plans to publish a series of case reports.
Turner worries that the offering treatment in this context is “never going to bring a safe and efficacious stem cell product to market. It’s a way of sitting out there for years, [technically] complying with regulations.”
A Look at Costs
Prices for different products and procedures aren’t readily available, and Feshbach declined to discuss the cost of care at Ambrose. A 2017 study showed that the average price quoted to a patient seeking stem cell injections for osteoarthritis in the knee is about $5,000. It’s important to review all costs you can expect before beginning treatment, especially considering that, in most cases, insurance won’t cover it.
During our conversation, Turner also mentions that there is a line in the Right to Try act that seemed to suggest that companies, like Ambrose Cell Therapy, couldn’t profit solely from offering treatments on a Right to Try basis. He admitted that while it had caught his eye, he wasn’t yet positive if he was interpreting the law accurately.
The Right to Try states that eligible investigational drugs must be in compliance with 312.6, 312.7 and 312.8 d (1). Of Title 21 Code of Federal Regulations. 312.8d states that, “A sponsor may recover only the direct costs of making its investigational drug available.”
To investigate, I reached out to a retired biotech executive who was involved with several expanded access requests, which are also required to conform to 312.8d, prior to the approval of the Right to Try act. She explains that her companies were only allowed to charge patients what it cost the company to make and send the treatments to a patient’s doctors, and that her companies never charged patients for anything.
I also emailed the FDA spokesperson, who responded, “FDA does not review or approve requests for use under the Right to Try Act. FDA’s role is limited to receipt and posting of certain information submitted under the Right to Try Act. Section 561B (C)(b) of the Right to Try Act (Public Law 115-176), “Investigational Drugs For Use By Eligible Patients,’ describes the requirement to be in compliance with the applicable regulations set forth in section 312.8(d)(1) of the CFR [Code of Federal Regulations].”
At this point, it seems clear to me that a company can’t profit from selling its unapproved treatments to patients outside of clinical trials, but that it’s unlikely the rule would be enforced because as Turner put it, “The FDA is not actively involved in scrutinizing any of this.” The Right to Try law stops the agency from overseeing requests.
When I present this information to Feshbach, however, he explains that I am missing a key detail. The price of the treatment itself cannot exceed the company’s cost of providing access to it, but the law does not address additional costs like having a doctor administer the treatment on-site.
While the cost of knee injections average $5,000, some stem cell treatments cost tens of thousands of dollars. In 2018, one company said it may even charge several hundreds of thousands to patients who requested their Right to Try a treatment that had demonstrated little efficacy even in the company’s own trials. The company later announced it would offer the treatment to only a limited number of patients through expanded access, and that it would do so for free. One for-profit cancer treatment company currently offers Right to Try treatments alongside other options.
Outside the Clinical Trial Box
Some types of minimally manipulated regenerative medicine are still exempt from much FDA oversight, requiring only that their facilities keep up manufacturing standards that limit contamination. Even in these instances, there is a movement among some researchers to collect better data on patient outcomes, in hopes of better understanding who benefits from the treatments and when.
At the Center for Regenerative Orthopedic Medicine at the Feinstein Institutes for Medical Research, where Daniel Grande, PhD is the scientific director, he and others provide, for a fee, platelet-rich plasma and stem cell injections derived from a patient’s own bone marrow or fat, with techniques that fall under the FDA’s lowest-risk tier and are thus not subject to the clinical trial process.
But he laments the lack of consistent data reporting in the field. He says you can do a literature search and find thousands of papers on a particular procedure only to realize they’re mostly individual case studies or lack a control group. “We want to bring a standardization to the clinic,” he says. For example, when Grande gives a patient a platelet-rich plasma treatment, he takes a sample of the blood and conducts a complete blood count, which analyzes the concentration of different cells and biomarkers in your blood to evaluate overall health and diagnose certain diseases. Next, he takes a sample of just the plasma. Both are stored in freezers for continued analysis. “Then [I] follow these patients from zero to one year to see how they actually do,” he adds.
Grande is not alone. His group has teamed up with several other institutions, including the Cedars-Sinai Medical Center, Northwell Health, Hospital for Special Surgery, Cleveland Clinic, Mayo Institute, Stanford University and the University of Colorado Denver, to form the Biological Alliance of Regenerative Medicine and Biorepository. He says its members have committed to measuring the same variables through treatment and sharing data in hopes of answering questions about who the treatments are most likely to help and how many stem cells are actually needed for best results. In the first year, their goal is to enroll 1,400 patients. Grande also hopes the effort may lead to insurance companies eventually reimbursing for the procedures.
“There’s a movement underway nationally to better characterize these regenerative therapies in a way that everybody can either figure out what’s going on [with them],” Grande adds. “There’s a call to action for trying to better characterize these things and to provide information to not only clinicians, but also [to] the public about what works and what doesn’t, so that people can be informed.”