Knee osteoarthritis (OA) is a degenerative disease with primary and secondary types and is one of the five leading causes of disability among noninstitutionalized adults. OA is believed to affect the cartilage, and pathophysiologic changes also occur in the synovial fluid, the joint capsule, and underlying bone over time. Treatments focus on relieving symptoms and improving mobility. When conservative treatments (e.g., nonsteroidal anti-inflammatory drugs, physical and/or occupational therapy, weight loss for overweight or obese patients) fail to provide sufficient relief, any of several minimally invasive treatments are typically offered (autologous [i.e., self-derived] mesenchymal stem cell [MSC] injections, arthroscopic debridement, microfracture, osteochondral autograft, chondrocyte or platelet-rich plasma injections, or polymer spacers/synthetic scaffolds). This report focuses on autologous MSC injections.
Methods of obtaining and preparing autologous MSCs vary widely. The amount of manipulation and whether other agents are added to the mix determine how the FDA classifies them and whether they are subject to regulatory approval processes. Clinicians collect MSCs from the patient’s anterior superior iliac crest or stromal vascular fraction (i.e., adipose tissue) and process the cells in one of three manners: 1) isolating and expanding MSCs in a laboratory before reimplantation to the patient’s knee a few weeks later; 2) adding growth factors, antibiotics, or proprietary supplements to MSCs before reimplantation; 3) collecting and isolating MSCs by gradient centrifugation, and then reinjecting the concentrated MSCs into the patient during the same visit (i.e., no expansion or culturing and not subject to FDA regulation).
Several problems can arise when MSCs are cultured outside the body, including having a suitable culture medium for MSC growth and differentiation. Reported processes have involved use of fetal bovine serum, human serum, and/or other growth factors; however, animal-derived products can trigger severe immunologic responses (i.e., anaphylaxis) when the cultured MSCs are reimplanted into the patient. Among other risks is the potential for viral or bacterial transmission through contaminated cell media supplements. Some MSC culturing processes may add antibiotics to prevent infection, which could also trigger anaphylaxis. Other risks include unanticipated transformation of MSCs, potentially leading to cancer or differentiation into an undesired type of cell, such as osteocytes (bone) or cartilage upon reinjection into the patient. The mechanism by which MSCs lead to bone or cartilage formation is unclear at this time.
FDA categorizes therapeutic stem-cell-based products as human cells, tissues, and cellular and tissue-based products, including those intended for implantation, transplantation, infusion, or transfer into humans. Whether autologous MSCs are subject to FDA regulatory approval processes depends on the amount of cell manipulation. Some centers offering the procedure collect, concentrate, and reinject MSCs into the patient the same day without adding other agents. FDA considers processes that include culturing, expanding, and adding growth factors or antibiotics to be significant manipulations that require regulation. Some companies and clinicians have countered that the activity reflects the “practice of medicine” and not development of a new drug or biologic because processing of a patient’s MSCs is individualized for that patient. However, in July 2012, the U.S. District Court for the District of Columbia ruled in a case brought by FDA against Regenerative Sciences, Inc., (Colorado, USA) that ex vivo expansion and manipulation of autologous MSCs exceeded minimal processing and was subject to FDA regulation. The court granted FDA a permanent injunction preventing the company from making its product unless it completes the required regulatory approval processes. According to a later report in the Wall Street Journal, the company moved some of its clinical operations to the Cayman Islands to enable continued patient access to the therapy. Another company, CellTex Therapeutics Corp., received an FDA warning about its autologous MSC product and has indicated it will conduct clinical trials to seek regulatory approval. No U.S. companies have yet received FDA approval for any autologous MSC therapy.
The International Society for Stem Cell Research (ISSCR) published Guidelines for the Clinical Translation of Stem Cells (which includes MSCs) in 2008 and emphasizes that “processing and manufacture of any cell product should be conducted under expert, independent review and oversight, to ensure as much as possible the quality and safety of the cells.” ISSCR recommends that diffusion of these products not occur outside the context of well-designed and -conducted clinical trials. Seven ongoing studies — one of which is a U.S. study — continue to assess the feasibility and safety of autologous MSCs for OA.
1. How does autologous MSC implantation compare with other OA treatments (i.e., for reducing time to next intervention or to partial- or full-knee replacement, reducing pain, improving range of motion, improving function, increasing articular cartilage volume, and quality of life [QOL])?
Five low-quality nonrandomized retrospective and prospective controlled studies reported on 266 patients (Koh et al. 2012; Lee et al. 2012; Nejadnik et al. 2010; Varma et al. 2010; Wakitani et al. 2002). Each study compared MSCs with a different minimally invasive treatment. Study design weaknesses (e.g., lack of control for important patient variables in the study groups, lack of statistical analyses, incomplete reporting) and the absence of data for many outcomes prevent effective comparison of the efficacy of MSC with that of other minimally invasive treatments for relief of pain, and improving range of motion, knee function, QOL, and other outcomes.
2. What adverse events (AEs) are reported in studies of autologous MSCs, and how do AEs reported with autologous MSC implantation compare with AEs reported for other surgical treatments for OA?
Three of the five studies (Koh et al. 2012; Nejadnik et al. 2010; Wakitani et al. 2002) provided AE data on 146 patients; no comparative data were provided. Reported AEs were minor pain, swelling, and a second intervention in one case.
Excerpted with permission from ECRI Institute’s database of Emerging Technology Evidence Reports. To download the full report, visit www.ecri.org/managedcare.
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