New FDA Guidances Tighten Regulation of Stem Cells

Legitimate stem cell research may eventually revolutionize regenerative medicine, and some innovative therapies have already been appropriately studied and commercialized. By comparison, cell and tissue therapies promoted for orthopaedic conditions have often been poorly studied and lightly regulated.

Nonetheless, they have proliferated commercially in the medical device market and in so-called stem cell clinics offering autologous, point-of-care interventional procedures. Only rigorous research can substantiate the claims of these offerings.

The U.S. Food and Drug Administration (FDA) recently issued two important new guidances on cell and tissue therapies. The guidances substantially sharpen and narrow the language around therapies promoted for orthopaedic conditions, including adipose-derived products.

When fully implemented, the guidances will have far-reaching implications for the use of so-called stem cells in orthopaedics. However, the FDA makes it clear that it will exercise enforcement discretion for 36 months and employ a risk-based approach that focuses first on serious diseases and risky routes of administration.

Refining the definition of 361 HCT/P
The new guidances clarify which human cell and tissue-based products (HCT/Ps) meet the so-called tissue rules for regulation under 361 status (Fig. 1). The term 361 refers to legislation allowing certain HCT/Ps to be relatively lightly regulated (e.g., to avoid infection). This is in distinction to 351 status that requires more stringent criteria to demonstrate safety and efficacy as a biological product. The guidances also clarify which HCT/Ps are exempt from the lighter 361 criteria altogether due to their use within the same surgical procedure.


Fig. 1 Criteria for regulation of an HCT/P solely under 361 requirements.
Source: U.S. Food and Drug Administration

Although the definitions of 361, 351, and exempt status are not new, the guidances give fresh examples for specific orthopaedic product classes. The guidances further focus on the two most controversial aspects of the less restrictive 361 requirements—the definition of minimal manipulation and the definition of homologous use. Although the guidances define the terms and phrases used within each of the above definitions, specific examples of the “big seven” tissues used in orthopaedic products—bone, adipose, amnion, skin, fascia, cartilage, and bone marrow—are illuminating. Commonly used bone grafts are least likely to change status. Blood products and platelet-rich plasma are regulated by a different mechanism and are outside the scope of the new guidances.

Winners and losers among the big seven
Orthopaedic surgeons may feel reassured that most traditional HCT/P off-the-shelf bone grafts, including chips, particles, dowels, and screws, meet the definition of minimal manipulation. Also, homologous uses of bone include allogeneic mineralized or demineralized cortical bone for filling gaps in the extremities and spine, or for posterolateral spinal fusions. The traditional use of bone autograft within the same surgical procedure is also protected, as long as processing is limited to rinsing, cleansing, sizing, and shaping.

However, some applications of bone products, such as acid and temperature treatments that demineralize bone and dissolve collagen into a gel, are deemed more than minimally manipulated. Also, demineralized bone matrix (DBM) products are subject to additional guidance. For DBMs, the addition of glycerol, calcium phosphate, or sodium hyaluronate merits they be regulated as a device and not a 361 HCT/P, thus requiring more stringent standards to demonstrate their safety and efficacy. This may have future implications for the use of this very common product in terms of informed consent.

However, applications of the so-called stromal vascular fraction of adipose tissue receive very close scrutiny in the guidances. Because the FDA affirms that adipose is a structural tissue, harvesting by liposuction, enzymatic digestion, mechanical disruption, and isolation of cellular/noncellular components is considered more than minimal manipulation. FDA further states that adipose used to treat arthritis or tendonitis by promoting regeneration is not a homologous use, as fat has been determined to be structural and provides cushion and support only, disregarding any metabolic function of the adipocytes. Processing adipose such as rinsing and cleansing by centrifugation or filtration may be employed in the same surgical procedure. But attempts to isolate cells by enzymatic digestion or mechanical disruption are not within the scope of the same surgical procedure exemption. Again, these regulations have potential consequences regarding informed consent.

Other tissue types receive a mixed treatment. Amniotic membrane with chorion and cells removed, preserved, and packaged in sheets is considered minimally manipulated (although membrane ground and packaged as particles is not). However, the use of amniotic membrane to support bone regeneration, for wound healing, or to reduce scarring, is not homologous use. Skin meshed, cryopreserved, and packaged as sheets with or without the epidermis removed is minimally manipulated, but skin with the epidermis removed and ground to particles is not. Similarly, cartilage homogenized into a slurry or fascia lata ground into particles are not considered minimally manipulated. Pericardium used for dural defects is a homologous use. In general, a tissue product promoted for myriad uses is likely not homologous for all applications.

One complex aspect of the guidances is their treatment of bone marrow. Bone marrow that is minimally manipulated, intended for homologous use, and not combined with another article is regulated more like a solid organ and is not subject to the definition of HCT/P or its 361 versus 351 distinction.

However, bone marrow that does not meet these criteria is subject to HCT/P regulation. Bone marrow is a source of hematopoetic progenitor cells (HPCs) and is defined as a nonstructural tissue. Therefore, HPCs cultured and expanded into terminally differentiated cells are not minimally manipulated. HPCs used to treat a disorder of the hematopoetic system is a homologous use, but use of HPCs to treat a cardiac or neurologic disorder is not.

The guidance does not list specific examples of orthopaedic product classes. But given the complex and unique regulatory status of marrow, a very clear regulatory rationale will need to exist for bone marrow products.

Conclusion
Cell and tissue therapies promoted for orthopaedic conditions are often lightly regulated. Although the FDA has clarified the regulatory status of the big seven orthopaedic tissue classes, it will exercise enforcement discretion and employ a risk-based approach that will forestall action. Continued vigilance by the AAOS fellowship will ensure patient safety. Vendors committed to innovation can win commercially by gaining full regulatory compliance ahead of competitors.

S. Raymond Golish, MD, PhD, MBA, is chair of the AAOS Biomedical Engineering Committee. He can be reached at ray@golish.com.

J. Tracy Watson, MD, is chair of the AAOS Biological Implants Committee. He can be reached at jtwatson1@email.arizona.edu.

William M. Mihalko, MD, PhD, is chair of the AAOS Orthopaedic Device Forum. He can be reached at wmihalko@campbellclinic.com.

More on Stem Cells
In the April issue of AAOS Now, the article, “AAOS Tackles Controversies Surrounding the Use of Biologics in Orthopaedic Surgery,” illustrated that the clinical use of biologics to treat orthopaedic problems has greatly outpaced the evidence. The rise, according to author Constance R. Chu, MD, is primarily due to widespread use of “minimally manipulated” autologous therapies that are either blood products or have been interpreted as falling within the Public Health Service Act Section 361 pathway, which does not require premarket approval from the FDA.

References:

  1. U.S. Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. Guidance for industry and Food and Drug Administration Staff. Accessed February 2018: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585403.pdf
  2. U.S. Food and Drug Administration. Same surgical procedure exception under 21 CFR 1271.15(b): questions and answers regarding the scope of the exception. Guidance for industry. Accessed February 2018: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM419926.pdf
  3. U.S. Food and Drug Administration. Jurisdictional update: human demineralized bone matrix. Accessed February 2018: www.fda.gov/CombinationProducts/JurisdictionalInformation/JurisdictionalUpdates/ucm106586.htm

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