3 FDA Regulation of Adult Stem Cell Therapies as Used in Sports Medicine

10.1055/b-0035-123574

3 FDA Regulation of Adult Stem Cell Therapies as Used in Sports Medicine

Mary Ann Chirba, Berkley Sweetapple, Charles P. Hannon, and John A. Anderson

3.1 Introduction

Over the past decade, interest in regenerative medicine and adult stem cell therapies in sports medicine has expanded rapidly around the world. With the ability to self-renew and differentiate into multiple types of cells and tissues, adult stem cells hold significant promise. In sports medicine, basic science and clinical research is investigating the use of stem cells in several areas including, but not limited to: osteoarthritis, ¹ ^, ² articular cartilage repair, ³ ^, ⁴ anterior cruciate ligament (ACL) reconstruction, ⁵ ^, ⁶ ^, ⁷ ^, ⁸ tendon healing, ⁹ ^, ¹⁰ ^, ¹¹ ^, ¹² and meniscus regeneration. ¹³ ^, ¹⁴ ^, ¹⁵

To the authors’ knowledge, the first randomized control trial on the intra-articular injection of human mesenchymal stem cells into the knee was recently published, and demonstrated their safe use and potential ability to regenerate meniscal tissue. ¹⁵ A review of clinicaltrials.gov indicates that in May 2014, over 45 clinical trials were being conducted worldwide on the use of stem cells in orthopedic pathologies of the knee. Interest in the field of regenerative medicine has even prompted elite athletes to travel worldwide to receive intra-articular therapies such as Regenokine^® and Regenexx^®, which are advertised as containing adult stem cells. With great promise, however, comes potentially great risk. Safety concerns remain because the process of differentiating into so many cell and tissue types is not well understood, and the means of regulating these pathways are often unknown.

Pluripotent stem cells may hold the greatest therapeutic potential because they can differentiate into virtually any cell type. Pluripotent stem cells are isolated in three ways: (1) directly from human embryos (embryonic stem cells, ESCs), (2) from cloned embryos through somatic cell nuclear transfer (SCNT), or (3) from adult cells reprogrammed to a pluripotent state (induced pluripotent stem cells; IPSCs). ¹⁶ As pluripotent stem cell work can involve the creation and destruction of embryos and the possibility for reproductive cloning of entire organisms, and raises concerns about uncontrolled growth (such as teratomas), their use has been complicated by serious ethical concerns and significant technical challenges. This has led to varying regulatory approaches by different countries. Some regulatory bodies will allow the use of ESCs derived from discarded embryos or in vitro fertilization. ¹⁶ A smaller number will permit the creation of new ESC lines for research purposes. ¹⁶ Others ban SCNT research, limit research to existing cell lines, or ban pluripotent work altogether. In the United States, research on ESCs was previously limited because federal funds could not be used to create new ESC lines. However, this has changed under the Obama administration.

Although more limited in their ability to differentiate, multipotent adult stem cells create less ethical and political controversy, tend to carry less risk, and pose fewer technical challenges than their pluripotent counterparts. In recent years, many specialties, including sports medicine and orthopedics, plastic and reconstructive surgery, cardiology, and ophthalmology, have been increasingly active in researching and developing adult stem cell therapies. Much of this work has focused on mesenchymal stem cells (most commonly bone marrow-derived and adipose-derived stem cells [ASCs]). Bone marrow-derived mesenchymal stem cells can differentiate into several types of connective tissue including cartilage, bone, tendon, ligament, and muscle. ¹⁷ ^, ¹⁸ Other sources of adult stem cells that have common characteristics, but are distinctive and reflective of their tissue of origin include synovium, umbilical cord, muscle, and adipose tissue. ¹⁸ ^, ¹⁹ Each of these distinctive cell types has shown varying ability to differentiate into cartilage, bone, muscle, tendon, ligament, as well as fat. ¹⁸ Interest in using ASCs in sports medicine continues to grow as they are readily accessible, abundant, and a reliable source for isolation of adult stem cells. ²⁰ ^, ²¹ To date, however, research on their use in the field of sports medicine has been limited to proof of concept/basic science studies, case reports, and phase I safety trials. ²⁰ ^, ²²

In the United States, the growing enthusiasm for using adult stem cell therapies in sports medicine and other areas of medical practice is often coupled with significant legal and regulatory obstacles to doing so. It is therefore important for the physician to understand how adult stem cells are regulated in the United States, and how these complex rules are likely to affect what can and cannot be done in clinical practice. The aim of this discussion is to explain the Food and Drug Administration’s (FDA) current regulatory framework in the adult stem cell context and evaluate its impact on the use of stem cells in sports medicine today.

3.2 Regulation of Adult Stem Cell Therapies in the United States

The U. S. Food and Drug Administration (FDA) regulates cell and tissue products as part of its implementation of two federal laws: the Public Health Service Act (PHSA) and the Food, Drug and Cosmetics Act (FDCA). An adult stem cell is a “biological product” under the PHSA because like a “therapeutic serum, … blood, blood component or derivative, … protein … or analogous product,” it is “applicable to prevention, treatment or cure of a disease or condition in human beings.” ²³ An adult stem cell also falls within the FDCA’s definition of a “drug” because it is an “article intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease” and “intended to affect the structure or function of the body ….” ²⁴ Finally, stem cells can constitute a “medical device,” which the FDCA defines as “any product or equipment used to diagnose a disease or other conditions, to cure, to treat or to prevent disease.” ²⁵ Products that satisfy more than one definition can also function as combination products.

The FDA oversees cell therapies through its Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH). Since 2001, the FDA has used a three-tiered, risk-based regulatory framework to promote the safety and efficacy of human cells, tissues, and cellular and tissue-based products (HCT/Ps). ²⁶ Current good tissue practices (cGTPs) apply throughout. Otherwise, the extent of regulation varies directly with the product’s potential risk, especially with regard to the risk of introduction, transmission, and spread of communicable disease. Thus, depending on how a particular cell or tissue product is categorized, a physician may face relatively simple registration requirements or be held to the demanding premarketing approval requirements that bind the likes of Pfizer, Merck, and other global pharmaceutical companies when commercializing a product for mass consumption.

Before examining the regulations more closely, it is helpful to define four key terms: manufacturer, establishment, combination with another article, and minimal manipulation. ²⁷ A physician becomes a “manufacturer” of HCT/Ps by engaging in any or all steps in HCT/P recovery, processing, storage, labeling, packaging, or distribution. An “establishment” is a physician’s office, clinic, or any place of business under one management that manufactures HCT/Ps. As explained later, combining HCT/Ps with other “articles” can increase safety concerns and thereby increase the degree of regulatory oversight. For this reason, the regulations exempt combining the HCT/P with “water, crystalloids, or a sterilizing, preserving, or storage agent, provided that their addition poses no additional concerns regarding clinical safety.”

The most important term, and the most difficult to determine in practice is “minimal manipulation.” The regulation defines it separately for structural tissue and cells/nonstructural tissues, ²⁷ and both are relevant to sports medicine although manipulation of cells and nonstructural tissues is the focus of this discussion. For structural tissue, minimal manipulation involves “processing of the HCT/P [that] does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.” For cells or nonstructural tissues, minimal manipulation is “processing of the HCT/P [that] does not alter the relevant biological characteristics of cells or tissues.” The degree of cell manipulation is critical in determining where an HCT/P will fall in the following three-tiered framework.

3.2.1 Category 1: No HCT/P Oversight

Products in this category are not regulated as HCT/Ps because they are deemed to be of low risk. Category 1 includes vascularized human organs for transplantation, whole blood and blood-derived products, and extracted human products such as collagen and bone marrow that are minimally manipulated, for homologous use and not combined with another article (except for the purpose of sterilizing, preserving, or storing). ²⁷ By default, Category 1 also includes cells that are expressly exempted from Categories 2 and 3, described later. For this discussion, the most significant exemption covers “an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure” ²⁸ —but again, this applies only if HCT/Ps are minimally manipulated, for homologous use and not combined with other articles. Physicians or clinicians who use Category 1 products must follow cGTPs, but otherwise need not register as an establishment with the FDA’s CBER or submit a list of the HCT/Ps used.

3.2.2 Category 2: Section 361 Products with Minimal Oversight

The FDA views Section 361 products as posing a greater risk with regard to safety and regulates them more extensively to prevent contamination, infection, and disease transmission. Section 361 products that are commonly used in sports medicine include bone, cartilage, ligament, tendon, and skin. ²⁹ However, to fall within Section 361, these products must be:

No more than minimally manipulated which, again, for structural tissue, means preserving the “original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement” ²⁷ and for cells or nonstructural tissues, prevents a change in the “relevant biological characteristics of cells or tissues” ²⁷ during processing, storage, etc.
Used for a homologous purpose.
Combined with no other cells, tissues, or articles except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that their addition poses no additional concerns regarding clinical safety.
These products must also have either
1. No systemic effect or otherwise depend on the metabolic activity of living cells for their primary function or
2. A systemic effect or depend on the metabolic activity of living cells for their primary function, and for
  - Autologous use
  - Allogeneic use in a first- or second-degree blood relative, or
  - Reproductive use.

For cells and nonstructural tissues, certain methods have been expressly characterized as minimal manipulation; that is, as involving no change in cell function or characteristics during processing, storage, and the like. They include the following:

Centrifugation
Cutting, grinding, or shaping
Soaking in antibiotic solution
Sterilization by ethylene oxide treatment or irradiation
Cell separation
Lyophilization
Cryopreservation or freezing

Physicians who use or “manufacture” Section 361 HCT/Ps must employ cGTPs, register their office or clinic as an “establishment,” and submit an annually updated list of each HCT/P manufactured to CBER. ³⁰ ^, ³¹ They need not obtain premarketing approval before using the product or follow current Good Manufacturing Practices (cGMPs) in preparing them.

3.2.3 Category 3: Section 351’s Extensive Regulation of HCT/Ps as Biologics and Drugs

Products are most likely to shift from the comparatively relaxed oversight of Section 361 to the more stringent requirements of Section 351 if—at least in the FDA’s view— they present greater risks. While Section 361 focuses on safety and preventing infection and disease transmission, Section 351 concentrates on both safety and effectiveness. For the clinician, this imposes more onerous requirements (such as cGMPs and premarketing approval) with little distinction between individuals and small physician practices versus larger pharmaceutical industries. Thus, cells or processing methods that fail to satisfy any of Section 361’s requirements will cast a product into the heavily regulated Section 351 track.

A product will fall within Section 351 if it is one or more of the following:

More than minimally manipulated, which for cells and nonstructural tissue means to present a risk of change in cell morphology, function, expression, or other relevant biological characteristics during processing, storage, etc.
Used for a nonhomologous purpose.
Combined with other articles that may pose additional concerns regarding clinical safety.
Have a systemic effect or otherwise rely on the metabolic activity of living cells for its primary function, and be used in a context other than autologous use, allogeneic use in a first or second degree relative, or reproductive use.

Like Section 361, Section 351 requires an establishment to register and file a list of its HCT/Ps with CBER each year. The main reason why Section 351 is more problematic in the clinical setting, however, is that, it also requires the physician or clinic to complete the burdensome and expensive process of obtaining formal premarket approval from the FDA. This can involve submitting a New Drug Application, an Investigational New Drug Application, Biologics License Application, or, when dealing with a Section 501k medical device, a premarket approval application or premarket notification. Costly and time-consuming controlled clinical trials may be needed to establish product safety, purity, potency, efficacy, and stability. In addition, physicians using Section 351 HCT/Ps must follow the FDA-prescribed cGMPs and prescription drug labeling requirements that govern commercial pharmaceutical manufacturers. Without premarket approval, cGMPs, and/or proper labeling, a Section 351 HCT/P is an “adulterated” and/or “misbranded” drug and biologic under the FDCA and the PHSA, respectively. This remains true even if the patient is being treated with her own cells. Using such adulterated and misbranded products exposes the physician and the clinic to FDA sanctions including orders of retention, recall, destruction of the HCT/P, cessation of manufacturing, and/or shutdown of the entire facility. ³²

It must be emphasized that Section 351 applies equally to autologous and allogeneic use in contrast to Section 361, which treats autologous and allogeneic use differently. Consequently, treating a patient with a Section 351 HCT/P means that the physician as “manufacturer” and the office, clinic, or hospital as “establishment” are “marketing” the cell product. Treatment of this kind requires premarket approval even if those cells are to be injected into the same patient from which they were harvested.

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