Abstract
The article by Ricardo Rodriguez and colleagues recently published in Stem Cells and Development argues for a distinct regulatory categorization and framework for stromal vascular fraction (SVF) [1]. The authors note that the defining feature of adipose-derived stromal cells is that it comprises a subpopulation of adipose-derived cells obtained after several passages in tissue culture, whereas SVF consists of a heterogenous collection of cells isolated from lipoaspirate by mechanical or enzymatic means. They assert that autologous SVF has a different risk and safety profile than that of cultured autologous or allogenic cells and take issue with the FDA's Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use guidance, which explains that adipose is a structural tissue under the FDA's regulations [2].
The authors further argue that the current FDA regulatory framework that considers autologous SVF subject to both sections 351 and 361 of the Public Health Service Act (PHSA) is overly stringent, because it generally categorizes it as a product that is subject to the Agency's premarket authorization requirements that necessitate study under an Investigational New Drug (IND) application to generate evidence of safety and effectiveness and protect patients, and marketing after the submission and approval of a Biologics License Application. They also assert that the development required is a costly and multi-year process that they consider to be an impediment to bringing stem cell therapies into the clinical setting. In place of this paradigm, they propose an alternative regulatory pathway for autologous SVF in which the product would be regulated as a human cellular and tissue-based product (HCT/P) solely under section 361 of the PHSA. Such a pathway would not require premarket authorization and, instead, would simply require following procedures for the prevention of infectious disease transmission along with registration and listing of the establishment. The key features of their proposed path to make these products available to patients include: (1) use of accreditation agencies to develop standards for facilities, (2) the development of a national registry to collect “real world data” from products being used in practice, (3) more active oversight by state and professional medical societies, and (4) linkage of the ability to poststem cell trials on the National Library of Medicine's
Rodriguez and colleagues are to be commended for their desire to accelerate the scientific investigation and development of stem cell therapies and for their thoughtful presentation regarding a potential path forward toward the development of autologous SVF products. However, the arguments that they make and the path that they propose overlook several key aspects that are relevant to promoting scientific advancement of the field of regenerative medicine and ensuring that autologous SVF is safe and effective for the treatment of various specific conditions before it is marketed to patients.
One major oversight is that the development of medical products, such as SVF, for the treatment of specific conditions is distinct from the practice of medicine that is used to administer those products. This is an existing paradigm that has been in place for decades. For example, cord blood products licensed for use in hematologic reconstitution have been produced according to Current Good Manufacturing Practices and have been demonstrated to be safe and effective, or if not, may only be lawfully used under IND application provisions. These cord blood products are then administered in facilities that have been accredited for the appropriate administration of these products.
The authors also overlook a number of interrelated issues, which include: (1) the rationale supporting the current regulatory framework for HCT/Ps, (2) the existing body of clinical evidence regarding stem cell therapies for hematologic and immunologic reconstitution, in contrast to SVF and other stem cell products, and (3) the expectations of patients, providers, and payors for medical products.
The Regulatory Framework for HCT/Ps
Before 1993, the FDA did not have a single regulatory program for HCT/Ps. Instead, it regulated these products on a case-by-case basis, responding as it deemed appropriate to the specific characteristics and concerns raised by each type of product. The agency then announced its plans for a regulatory framework in February of 1997 and published proposed rules shortly after that. Following the process of notice-and-comment rulemaking, these ultimately became final on May 25, 2005 as 21 CFR 1271.
Then, as now, one of the primary purposes of the new regulatory approach proposed was “the improved protection of the public health without the imposition of unnecessary restrictions on research, development, or the availability of new products” [3]. While putting that approach in place, the FDA considered several issues fundamental to the proper regulation of HCT/Ps; among these was how to address safety and efficacy of the products. Ultimately, four criteria that are noted at 21 CFR 1271.10 were developed to distinguish products regulated under both sections 351 and 361 of the PHSA from those regulated under section 361 alone.
To a first approximation, these two different risk-based regulatory tiers for HCT/Ps were developed to distinguish products such as skin, tendons, and bone, used in a similar manner in the recipient as in the donor, from products that undergo more than minimal processing or that are used in a different way in the recipient as in the donor. Looked at another way, these regulatory tiers correspond to categorizing products into two categories: those products for which safety and efficacy can be assumed if appropriate precautions are taken to prevent the transmission or introduction of infectious diseases (361 HCT/Ps), and those entities for which safety and efficacy cannot be taken for granted and, therefore, that must be demonstrated through evaluation in clinical trials (351 HCT/Ps). More simply put, the four criteria distinguish products with well-understood mechanisms of action and a long-standing track record of safety and efficacy for their intended uses from those products for which such information is not available at this time.
Under this framework, the destruction of the structure of adipose tissue through mechanical or enzymatic means is generally more than minimal manipulation, and the use of the resultant cellular product is not homologous when injected into other locations of the body such as the joints, blood, or brain. This is made clear in Agency guidance based on the regulations and, indeed, is fully in keeping with the intent noted when the Agency finalized the tissue regulations in 2005. Autologous SVF represents a heterogenous entity for which safety cannot be assumed, nor can its effectiveness be taken for granted. Quite unlike skin, tendon, bone, and several other structural HCT/Ps, autologous SVF does not have a history of safe and effective use in the clinic for a specific purpose. In fact, autologous SVF meets all the criteria published by the International Society for Cellular Therapy to be an “unproven cellular therapy” [4].
The Existing Body of Clinical Evidence for Stem Cell Therapies
Comparison of the use of autologous SVF for a wide variety of different conditions to the use of hematopoietic stem cells for hematologic or immunologic reconstitution is simply not justified or appropriate at this time. The clinical benefit of hematopoietic stem cells in replacing blood cells for hematologic reconstitution or immunologic reconstitution in specific settings such as the treatment of bone marrow failure syndromes and inherited hematologic disorders, the treatment of hematologic and certain other malignancies, and for the treatment or certain immunologic disorders is documented in hundreds of publications in the literature that have appeared over the past half-century reporting on both safety and efficacy [5]. For example, severe aplastic anemia was previously associated with high mortality. It is now curable in many cases, when necessary, by using hematopoietic stem cell transplantation [6].
In contrast to hematopoietic stem cells administered intravenously for the purpose of hematologic or immunologic reconstitution, the efficacy of the use of autologous SVF injected by any one of several different means (intraarticular, intramuscular, intraocular, intravenous, intrathecal) has not been demonstrated for any indication, including those such as rheumatoid arthritis or osteoarthritis [7], stroke or Parkinson's disease [8], or congestive heart failure [9]. Most studies in the literature report small uncontrolled trials, though some phase 2 trial results are available. However, there are no trials that provide compelling adequate and well-controlled data demonstrating effectiveness to support the use of autologous SVF, and there are no data demonstrating the benefit of autologous SVF over an existing standard of care.
Despite assertions to the contrary, data supporting the safety of autologous SVF for the treatment of human disease are simply inadequate [10]. In terms of the range of potential adverse events that may be observed, Rodriguez and colleagues focus on one report of blindness after autologous SVF administration [11]. However, the extent of the safety issues associated with SVF is almost certainly much broader. Such data for autologous SVF have not been systematically captured in a rigorous manner, and it is well understood that adverse events may be underreported when captured outside of well-monitored clinical trials conducted in accordance with Good Clinical Practices [12].
In summary, clinical trials have yet to demonstrate the safety and efficacy of an autologous SVF product for the treatment of even a single condition, let alone demonstrate that use of an autologous SVF product has clinical benefit over an existing therapy. From a regulatory perspective, because of the lack of data from adequate and well-controlled clinical trials, no autologous SVF products are approved and they are currently investigational products that require an IND application for all potential uses.
Expectations of Patients, Providers, and Payors
Outside of participation in clinical trials conducted under the oversight of an appropriate institutional review board or ethics committee, both patients and providers have come to expect that the products that they receive for the treatment of medical conditions will be of high quality and will be both safe and effective. Payors generally will only cover the costs of products approved by regulatory authorities or those therapies that are demonstrated in multiple peer-reviewed journals to be safe and effective. Based on the current absence of approved products or published clinical trials providing the necessary supportive evidence, payors generally do not cover the cost of autologous SVF treatments.
For this reason, many clinics are actively offering this unapproved treatment for a variety of different serious or life-threatening conditions and charging patients directly [13]. Rodriguez and colleagues basically advocate continuation of this practice with some modification. Under the guise of limited oversight from accreditation agencies and state and professional medical societies, as well by collecting patient outcome data in a registry, they are still essentially advocating patient-funded research in potentially vulnerable patient populations. Charging patients for participation in clinical trials is generally not favored by much of the bioethics community [14]. Some ethicists also consider such charging to undermine research integrity [15]. The reasons that ethicists generally find such patient-funded research objectionable has been well summarized by Emmanuel and colleagues: “Pay to play raises the specter of exploitation of trial participants and their families and threatens principles of social value, fair subject selection, and robust clinical trial design” [15].
Ethical issues aside, from a practical perspective, the lack of compelling clinical benefit reported in early trials of autologous SVF administered for various conditions makes it highly unlikely that data collected in a registry will be able to provide evidence that will convince the combination of patients, providers, and payors that autologous SVF is safe and effective for any specific condition. Patients, and the entire health care ecosystem, are best served by high-quality products that have been evaluated and demonstrated to be safe and effective before marketing.
With that said, the FDA is committed to helping advance the development of cellular therapies to the greatest extent possible. It is doing so through its comprehensive regenerative medicine framework, which includes various guidance documents communicating the Agency's thinking, and through interactions with developers of specific products, enhanced through the Regenerative Medicine Advance Therapy expedited development program for those who qualify [16]. The Agency has also articulated how a collaborative program could be used for product development by investigators located at different sites, and this pathway seems potentially well suited to autologous SVF for certain indications [17]. Autologous cellular therapies do hold tremendous promise, but they will only find their way into routine clinical practice to bring benefit to all patients if they are held to the same standards for the demonstration of safety and efficacy as other unproven medical products.
Footnotes
Author Disclosure Statement
The author has no conflict of interest.
Funding Information
This article is a U.S. government work.