Marketing of Unproven and Unapproved Regenerative Medicine Therapies

You may have received the same blast email that I have received a number of times from a company in Scottsdale, Arizona, that opens with “End of Year Blowout Sale: 3 for 1 on Exosomes or Whartons Jelly.” The email further states that these products are “manufactured in an FDA-registered, cGMP compliant, ISO Certified lab,” despite the fact that such birth products can be used only in a registered FDA clinical trial, since a directive from the United States (US) Food and Drug Administration (FDA) on May 31, 2021. This is a good example of the aggressive, direct-to-consumer marketing of unapproved and unproven cell therapies.

As I am writing this editorial, I see this headline from MedPage Today, January 22, 2024: “FDA Warns Exosome Maker for Marketing Outside Its IND”. According to this article, the manufacturer received an Investigational New Drug (IND) for a phase I/IIa clinical trial evaluating a single intravenous dose of a drug to treat COVID-19. However, the company apparently advertised their product for numerous other conditions outside of this specific IND. Furthermore, the FDA cited the company for “significant deviations” from current good manufacturing practice requirements as well as issues with sterility testing of their product.

The 2 instances documented above point out some of the challenges in the rapidly growing regenerative medicine arena. The allure of regenerative medicine has led to a global industry of direct-to-consumer offerings of biologic products that, despite their promising potential, often have very little clinical data to support their use. This has been a pervasive problem in the area of regenerative medicine and is only growing. Regenerative medicine and orthobiologics can be lucrative, leading to aggressive marketing of products that have not been tested adequately for safety and/or efficacy. In this editorial I will explain some of the tactics used in these persuasive and aggressive marketing schemes. I will then briefly describe the criteria that should be considered before a product might be considered “proven”, and finally I will list some mechanisms that can be used to report deceptive advertising claims and inappropriate marketing of unproven therapies.

Features of Unproven Therapies

There are a number of features that should be considered by clinicians when evaluating the legitimacy or potential clinical efficacy of an advertised orthobiologic. Perhaps the most common red flag is claims of efficacy for an implausibly wide range of differing conditions. Such broad claims of efficacy do not make biological or clinical sense - one size would not fit all. In the musculoskeletal realm it is unreasonable to expect that a given orthobiologic could have the same (positive) effect on tendon, cartilage, bone, muscle, etc. The absence of data on the underlying mechanism of action and resultant unclear scientific rationale for a therapy also raise concerns. Such products often lack adequate preclinical (animal) and clinical studies, with absence of information about the safety profile. Another common problem is the lack of a standardized approach to characterize potency, purity, and critical quality attributes of a product. This is often associated with a lack of information to ensure consistency in manufacturing of a regenerative medicine product. Another hallmark of unproven interventions that are marketed prematurely directly to patients is the requirement for the patient to pay for entry into a “clinical trial” for an experimental treatment, in contrast to a standard approved clinical trial where the treatment cost is covered by the trial sponsor.

Common Marketing Tactics for Unproven Interventions

A number of different tactics are used in the direct-to-consumer marketplace to promote regenerative medicine therapies. Such strategies have been called “tokens of scientific legitimacy” and are used to persuade consumers that an advertised treatment has undergone rigorous development and testing. ² One common tactic is registering on ClinicalTrials.gov, which is the US government database for clinical trials. Simple registration of a study does not prove legitimacy or that the protocol has undergone comprehensive review. The FDA is aware that patients and consumers are being referred to ClinicalTrials.gov, or are told that a product is registered with the FDA, as a way to suggest that the products being offered are in compliance with FDA regulations. This is often inaccurate. The inclusion of a product in the ClinicalTrials.gov database or the fact that a firm has registered with the FDA does not mean the product is marketed legally.

There may also be claims of approval by local Institutional Review Boards and ethics committees. Similarly, the manufacturer may list “scientific advisory boards” with purported experts and key opinion leaders. The manufacturer may also cite research that appears related but does not directly pertain to the product in question. A clinic may state that they have had inspection of their devices by a regulatory agency, and use this to support their claims of legitimacy, despite the fact that simple inspection and clearance does not imply approval for use of unproven therapies. Lastly, patient testimonials and endorsements by celebrities may be used in advertising.

Criteria to Consider a Product “Proven”

The most important factor to consider when evaluating a product is the level and rigor of peer-reviewed clinical data. The gold standard is a randomized, double-blind, placebo-controlled clinical trials. Such trials are admittedly difficult to carry out, as they often require extensive financial, human, and scientific resources. I found that it can be challenging to enroll patients in these trials, as patients are often not willing to be randomized to the placebo/control treatment, due to the bias that the proposed treatment is superior. This is where musculoskeletal practitioners, as the responsible clinician, need to dispel misinformation and provide a rigorous and balanced view of these new and emerging therapies for our patients. In addition to rigorous clinical data, the clinician should consider whether there is a standardized and validated process for manufacturing and assessment of product quality attributes.

There are circumstances where randomized clinical trials can be difficult to carry out or are not practical, such as for uncommon conditions with small numbers of affected persons. In some cases, persons with serious medical needs or with conditions that may not meet clinical trial inclusion criteria may be granted access to unapproved products on a limited basis. There is regulatory flexibility to provide access to investigational products in such circumstances based on expanded access programs. Such regulatory exemptions are reasonable, but need to be monitored carefully so that they are not abused. If a medical product receives accelerated approval without evidence of effectiveness, then it may be very difficult to carry out later clinical trials, as a product developer will not be motivated to carry out studies if they are already on the market.

Reporting Mechanisms for Unproven Products and Questionable Practices

It is well documented that patients may experience complications and adverse side effects from regenerative medicine treatments. On rare occasions, significant complications requiring surgeon intervention have been reported. ¹ In addition to pain and suffering, the patient may have experienced financial losses in addition to adverse effects from not receiving appropriate medical care for their condition. Patients rarely seek recourse in these circumstances, due to costs and uncertain outcomes of litigation. However, the responsible clinician should consider reporting unscrupulous practitioners in the uncommon circumstance where we see a patient harmed by inappropriate use of unproven therapies. It is incumbent upon us as musculoskeletal practitioners to advocate for a rigorous approach to our evaluation and use of regenerative medicine therapies.

Different countries have reporting mechanisms that patients and clinicians can use to report safety concerns regarding medical products and treatments. In the US, the FDA runs a program called MedWatch. ⁴ This program provides a mechanism for reporting serious adverse events or complications in patients treated with regenerative medicine products. While reporting adverse events is generally voluntary, such reporting is mandatory when a product is being evaluated under an IND application. A physician’s license to practice medicine is governed at the level of their state medical licensing board, and the Federation of State Medical Boards (FSMB) is another potential mechanism for adverse event reporting. The US Federal Trade Commission (FTC) oversees marketing and advertising and is another mechanism that can be used to register complaints against providers who engage in deceptive advertising. Globally, many low- and middle-income countries have very limited or no regulatory bodies that oversee medicinal products, further adding to the challenges in corralling the widespread promulgation of unproven regenerative medicine products. A recent proposal for an “Expert Advisory Committee on Regenerative Medicine” through the World Health Organization would begin to promote regulatory approaches and provide educational material and guidance in this area. ³ Lastly, clinicians may contact relevant professional societies or associations that work to promote responsible use of orthobiologics, such as the International Society for Cell and Gene Therapy and the International Society for Stem Cell Research.

Future Outlook and Summary

There is no doubt that regenerative medicine approaches to augment the biological events governing tissue healing and repair hold great potential. While current data supports that these approaches may be “symptom-modifying,” with further research and development we may learn how these modalities may actually be truly “structure-modifying” (i.e., tissue regeneration). In particular, cell and gene therapies hold tremendous promise, and current advances in cell manufacturing and gene editing suggest further exciting possibilities. However, the appeal of regenerative medicine has also led to a rapidly growing industry of direct-to-consumer marketing of often unproven and unapproved products. This is a very lucrative field with a constantly evolving regulatory environment, which has led to a proliferation of unscrupulous persons and commercial entities. The combination of the following factors often represents a “perfect storm” that feeds into the allure of regenerative medicine therapies: (1) the patient has a challenging orthopaedic problem, such as the young patient with early osteoarthritis; (2) we as physicians have imperfect solution for said problem; (3) “regenerative medicine” and “stem cells” has the allure of being “cutting edge”; and (4) the patient has disposable income. Savvy and aggressive marketing schemes take advantage of “tokens of scientific legitimacy” to imply safety and efficacy and to promote their products. It is incumbent upon musculoskeletal physicians and scientists to advocate for the responsible use of these promising, but sometimes still unproven, therapies.

—Scott A. Rodeo, MD
Hospital for Special Surgery