Treatment of knee OA with PRP and minimally manipulated autologous cells are already widely used in the United States. The existing studies do not show that these therapies are associated with substantial risk of harm.12,39 Where a proposed therapy does not present significant safety concerns, the focus can be directed toward phase II, III, and IV trials. For optimal evaluation of efficiency, prospective multicenter trials with randomization and placebo control are need. Given the prevalence of OA and the number of proposed biological treatments, randomization schemes with a 3:1 or 4:1 ratio of treatment groups to placebo will accelerate progress.
Although radiographs are helpful in assessing the knee mechanical axis and are reproducible for assessing joint space with appropriate technique, they are relatively insensitive to focal chondral defects and are inadequate for staging early disease. Because of its direct multiplanar acquisition, tomographic nature, and superior soft-tissue contrast, MRI is necessary to evaluate cartilage morphology and has shown superior reproducibility compared with arthroscopy.44,45 Recent advances in quantitative MR allow for assessment of cartilage relaxometry, targeting specific changes in proteoglycan content and collagen orientation, respectively, that improves the sensitivity of MRI for changes of early knee OA.
Characterization of the treated population with respect to clinical, structural, and biological attributes and disease state (eg, subtype, grade) is important. In addition to cell and protein composition, establishing specimen biorepositories will facilitate genomic and molecular analyses that can synergize with existing NIH areas of emphasis such as Helping to End Addiction Long-term, Molecular Transducers of Physical Activity Consortium, and precision medicine initiatives.
For evaluation of knee OA treatments, the primary clinical research goals are to determine efficacy in relation to pain, function, and structure, with additional goals of evaluating cost-effectiveness if proven to be efficacious. Key elements from a federally funded pre-post observational trial in Veterans that influenced the consensus trial design include establishment of a biorepository, targeted biospecimen analysis, linkage of the resulting compositional data with clinical data, and PRO metrics along with the use of MRI to establish and stage OA disease and to assess structural outcomes.41,44-48 The MIBO checklists for PRP (Table 2) and cell therapy (Table 3) should be used as a guide for clinical study design and standardized reporting.29 Elements recommended for a knee OA clinical trial are summarized in Table 4.
A patient panel highlighted the tremendous need and demand for effective treatments to restore function and alleviate musculoskeletal pain. This is particularly true for degenerative conditions such as OA and tendinopathy. The clinical history with minimally manipulated autogenous cell products and culture-expanded cells without genetic modifications for musculoskeletal indications suggest that these treatments can be considered “lower risk.”
Two international models for the use of culture-expanded MSC to treat orthopaedic complications were examined. In Japan, provisional approval is granted for a biologic that has been shown to be safe in a small sample of patients and with data showing a potential therapeutic effect.49 The manufacturer then has 7 years through postmarket studies to prove efficacy. If efficacy is not shown during postmarket surveillance, the product is withdrawn. In Chile, the government partnered with a private medical clinic to provide therapies based on culture-expanded bone MSC for a variety of musculoskeletal conditions. Data from this public-private partnership have demonstrated a low incidence of adverse effects and suggest therapeutic efficacy, most notably for OA.50
Patient demand and clinical need along with the international experience support exploration of new pathways developed through the 21st Century Cures Act to accelerate clinical evaluation of the use of autogenous cell sources and culture-expanded cell-based therapies to treat musculoskeletal conditions.32
The authors thank Fei Wang, PhD, the National Institute of Arthritis and Musculoskeletal and Skin Diseases collaborator who inspired and assisted with the conference and consensus statement development, and Erin Ransford, Manager, Research Advocacy, who assisted with all aspects of conference development and coordination. This symposium was funded by the American Academy of Orthopaedic Surgeons, the Stanford University Department of Orthopaedic Surgery, and NIH U-13 AR073668 (Chu).
Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, references 11, 15, 17, 21, 22, 28, 38, 39 are level I studies. References 23, 24, 25, 26, 34, 35, 36, 41, 44, 47, 51, 52 are level II studies. References 43, 48, 45 are level III studies. References 2, 4, 5, 12, 13, 16, 31, 40, 42, 50 are level IV studies. References 1, 3, 6, 7, 8, 9, 10, 14, 18, 19, 20, 27, 29, 30, 32, 33, 37, 46, 49 are level V expert opinion.
References printed in bold type are those published within the past 5 years.
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