Although they lack a globally harmonized classification system, cell therapies fall under the broad umbrella of regenerative medicine. There are several types of cells that can be used for cell therapy and the type of cells administered depends on the treatment. Collectively, these therapies are heralded for their ability to promote the repair of diseased, dysfunctional or injured tissue. What this ultimately means is that cellular therapies offer the potential to treat conditions for which few, if any, treatments exist.
Around the world, there are clinics making dramatic claims about cure-all cell-based treatments that have not gone through regulated clinical trials — which means their safety and efficacy has not been proven to regulatory bodies. If this confusion surrounding cell therapies isn’t addressed, it could become a problem that ultimately discredits a whole industry on the brink of booming.
It is estimated that the unproven cell therapy market is currently worth $2.4 billion and treats approximately 60,000 patients annually. While it’s difficult to identify exactly how many clinics exist, a 2016 analysis of online direct-to-consumer marketing activity in the U.S. found 351 distinct businesses offering interventions at 570 physical locations — and this number has undoubtedly grown.
But when it comes to cell therapy, “potential” is still the key word in the discussion. Currently, the only stem cell-based products approved by the U.S. Food & Drug Administration consist of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood — and there are fewer than 10 of these products on the market. Kite Pharma, Novartis and Dendreon hold the only immune cell therapy approvals in the U.S. This is likely to change in the future, however. According to the FDA, there are nearly 800 active cell therapy Investigational New Drugs (INDs) on file with the agency.
• Unclear scientific rationale to suggest potential efficacy
• Lack of understanding of the mechanism of action and/or the biological function to support clinical use
• Insufficient data from in vitro assays, animal models and clinical studies regarding the safety profile to support the use in patients
• Lack of a standardized approach to confirm product quality and ensure consistency in cell manufacturing
• Inadequate information disclosed to patients to enable proper informed consent
• Use within non-standardized or non-validated administration methods
• Uncontrolled experimental procedures in humans
Positioning a Scientific Community on Unproven Cellular Therapies: The 2015 International Society for Cellular Therapy Perspective
The potential for miracle cures also brings with it the potential for large financial gain, which has sparked the growing private interest in the cell therapy space. While the pharmaceutical industry might be quick to dismiss these bogus cell therapy clinics, the unfortunate reality is that the general public is still confused. And in that confusion arises a genuine concern that the popularity of unproven cell-based therapies will have a negative impact on the future of legitimate, science-based cellular therapies — which is an issue the industry should not dismiss.
FDA IS DOING ITS PART
The FDA is not ignoring the rise of unproven cell therapy clinics and has acknowledged the role that regulatory gaps have played in the proliferation of direct-to-consumer cell therapy treatments.
In August 2017, the agency stepped up its efforts to enforce regulations and oversight of stem cell clinics. When this was announced, FDA Commissioner Scott Gottlieb acknowledged that new, complex therapies are challenging the traditional approach to regulations.
“The field of regenerative medicine, because of the very nature of the science and the rapidly evolving clinical developments, not infrequently lends itself to often close calls between what constitutes an individualized treatment being performed by a doctor within the scope of his medical practice on the one hand, and what constitutes a medical product that is currently subject to the authorities Congress has already charged the FDA with exercising,” said Gottlieb.
Part of the allure of unproven cell therapy clinics is that they promise to solve unmet medical needs. When a potential cure to an ailment is tied up in the FDA approval process, patients are more likely to seek help elsewhere. In order to find a balance between safety concerns and innovation, the FDA made a major move in November 2017 to modernize product licensing pathways by introducing an additional expedited program in which a product could be designated as a regenerative medicine advanced therapy (RMAT). The expedited RMAT program — like the fast-track designation, priority review, accelerated approval, and breakthrough therapy designation that were introduced a year prior with the 21st Century Cures Act — is now helping to speed the development of new regenerative therapies, particularly those aimed at life-threatening conditions.
Last May, the FDA stayed true to its promise to increase oversight and enforcement to “protect people from dishonest and unscrupulous stem cell clinics” and sought permanent injunctions against clinics in Florida and California after they failed to address violations outlined in FDA warning letters, including serious cGMP violations.
GOOD GUYS DON'T ALWAYS WEAR WHITE HATS
Unfortunately, the pharmaceutical industry continues to struggle with its image problem. Many patients still perceive the pharma industry as impersonal and rapacious. Unproven cell therapy clinics are capitalizing on this stigma, and creating environments that appear to be warm, welcoming and highly personalized.
“Providers of unproven cell are seen as entities which are really taking care of patients versus pharma, which is perceived as unconcerned with personal needs. Pharma is seen from the patient perspective as more concerned about business, while unproven cell therapy clinics seem to be the good guys — which, in reality, is the opposite of the truth,” says Massimo Dominici, M.D., associate professor of medical oncology and head of the Laboratory of Cellular Therapies at University/Hospital of Modena, Italy.
Formerly serving as the president of the International Society for Cellular Therapy (ISCT), Dominici is now chairing the ISCT Presidential Task Force on the Use of Unproven and/or Unethical Cell and Gene Therapies. Established in 1992, ISCT is a growing global organization of clinicians, regulators, researchers, technologists and industry partners dedicated to translating cell and gene therapies for the benefit of patients worldwide. Its unproven cell therapy task force is a major player in the fight to characterize unproven and unethical cell and gene interventions, and promote safe and effective practices worldwide.
What it comes down to is that unproven clinics are doing a much better job of branding themselves. One Connecticut-based clinic’s website, for example, features personalized testimonials as well as the Buddhist quote, “When love meets pain it becomes compassion.”
“The marketing around unproven clinics is quite similar to that of five-star hotels. Essentially this is what people are looking for and how they want to be treated,” says Dominici. “But at the end of the day…it’s fake.”
THE DANGERS ARE REAL
The most obvious danger linked to unproven cell therapy treatments and clinics is patient safety. Without a detailed evaluation of the manufacturing facility and process, there’s no way to assess the general safety and risk factors of a specific cell therapy product. And without going through the proper channels outlined by registered clinical trials, there’s no standard for logging, reporting or following up adverse events — and plenty have occurred already.
So far, there has been several cases of poor outcomes linked to unproven cell therapy treatments performed in clinics including documented deaths, a patient who became blind due to an injection of stem cells into the eye and another patient who grew a spinal tumor after receiving a spinal cord injection.
There is also a certain degree of psychological harm that can come from unproven treatments related to side effects, possible financial loss (treatments can cost up to $40,000), and unrealistic expectations that do not yield tangible results.
Not only do safety and ethical issues negatively impact patients — they also affect the future of the entire cell therapy community. Negative experiences with unproven cellular therapy can erode financial confidence, which could restrict investment decisions.
“Unproven cellular therapies, which are marketed as safe and effective, can have a destabilizing influence on financial sector confidence that emerging cell therapies are well-founded and ready for development,” stated ISCT in its latest reference guide.
WHAT CAN PHARMA DO?
When it comes to the fight against unproven cell therapy treatments, pharma’s voice is somewhat missing from the battlefield — and this might actually be a wise approach.
For pharma, part of the solution involves a cultural shift. The industry has already begun to realize that in this new era of personalized medicines, it is necessary to interface with patients much earlier in the drug development process and continue that relationship all the way through commercialization. This approach will invariably generate higher levels of patient trust, which in turn will help improve pharma’s “bad guy” image.
But cultural shifts don’t happen overnight, and the issue of unproven cell therapies is immediate. So why are the drugmakers who are investing millions of dollars in the development of legitimate cell therapies not fighting back?
Because the issue is a delicate one, and has to be dealt with carefully, explains Dominici. In a situation where patients don’t entirely trust the pharma industry, fueling the fire may just make things worse.
“Yes, I would call for bigger commitment from pharma, but not alone. If they stand up by themselves, they risk fire-back. This is why the involvement of organizations like ISCT is so important,” says Dominici.
Third parties, such as ISCT, are already hard at work raising awareness of the dangers of unproven therapies. Pharma’s collaboration with such organizations is crucial, and will allow drugmakers to add their voices to a trusted, unified front against unproven therapies. Partnerships that include academia, industry, regulatory bodies and patient advocates will enhance credibility and minimize potential concerns about an industry-biased conflict of interest.
The ISCT Presidential Task Force on Unproven Cell and Gene Therapy is working towards a series of initiatives, including establishing a global, publicly-accessible, cell therapy patient safety registry and providing additional tools to patients that can be used as guidance in evaluating a potential treatment.
“Teaching and communication — not policing — are key,” says Dominici.
Around the world, drugmakers are expanding cellular therapy portfolios, putting their faith in the future potential of this emerging class of therapies. A collaborative, concerted effort from all parties is needed to ensure that the true potential of cellular therapies is not lost in the shadows of unproven treatments.