The Need to Elevate Research Rigor Involving Regenerative Agents and Orthobiologics as Pain Treatments

Le résumé fourni par la source

We previously addressed the Pain Medicine community regarding the state and future of “Regenerative Medicine” as defined by the National Institutes of Health (NIH) [1]. The NIH characterizes Regenerative Medicine as “the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage or congenital defects.” [2] There are currently multiple regenerative “biologic agents” in consideration including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), adipose tissue-derived stem cells, embryonic stem cells, amniotic fluid and amniotic membrane stem cells, and culture-expanded tissue-derived stem cells, among others that have demonstrated relative promise for clinical application based on tissue and animal model studies [1]. Such agents have been empirically examined for a variety of musculoskeletal pain conditions [1, 3–5]. However, while the results of several randomized controlled trials assessing the efficacy or effectiveness of regenerative and/or biologic agents for specific conditions such as knee and ankle osteoarthritis have been published [6–9], the body of high-quality evidence remains underdeveloped for most musculoskeletal pain conditions. Systematic reviews have generally identified “low” or “very low” quality of evidence due a relative lack of high-quality randomized controlled trials [3, 4]. For instance, the authors of a review on the effectiveness of PRP and BMAC for the treatment of sacroiliac joint complex pain concluded that “the literature is very low quality according to the GRADE system, due to high risk of bias, inconsistency, indirectness, and imprecision” [2]. A systematic review on the effectiveness of intradiscal biologics (including Regenerative Medicine agents) reached similar conclusions; the authors state, “the overall quality of evidence remains low for most applications of regenerative and/or biologic agents in the field of pain medicine due to sample size, methodology, and data reporting flaws” [3] and then emphasize the “need for more randomized sham or placebo-controlled trials and comparative effectiveness studies” [3]. Early adoption of these procedures has preceded traditional rigorous scientific investigation (relative to other medications, procedures, and treatments), and a relatively unregulated and rapidly growing direct-to-consumer marketplace has developed in the United States offering point-of-care biologic therapies for the purported treatment of a variety of diseases, avoiding usual oversight [10]. For instance, between 2009 and 2014, the number of new so-called stem cell businesses in the United States with a commercial presence at least doubled on average every year and from 2014 to 2016, approximately 100 new “stem cell” websites appeared annually [10]. Knoepfler and Turner state, “There is growing concern about the increasing number of clinical centers around the world that are making unwarranted claims or are performing risky biological procedures with agents that may or may not contain biologically active stem cells” [10]. This article intends to provide readers and investigators with a brief overview and introduction of current Food and Drug Administration (FDA) regulations, published resources, and strategies for producing quality research and safe patient care with regenerative agents. We encourage basic scientists and clinical researchers to investigate regenerative agents in an appropriate regulatory and rigorous scientific fashion, as done with other pain-reducing medications and interventions [11]. Before engaging in regenerative medicine research, we recommend investigators determine if the agent requires FDA premarket approval. Premarket approval requires an investigational new drug (IND) and/or device (IDE) application, clinical trials, and direct FDA oversight. All regenerative agents are regulated as a drug, device, and/or biologic product and will require premarket approval—unless the product meets all following conditions: is minimally manipulated [12]; intended for homologous use; does not involve the combination of cells or tissues with another article, except for water, crystalloids, or the sterilizing, preserving, or storage agents; and is used during the same surgical procedure. More regulatory details are described in the FDA's 21 CFR 1271 of the Code of Regulations [12]. The FDA and institutional review board can help investigators determine if the agent meets the FDA exception. Multiple regenerative agents, like PRP and BMAC, fall under the FDA exemption criteria; however, they are overutilized and understudied. More substantial evidence is needed to determine the true efficacy of these agents. Most research involving regenerative medicine lacks essential characteristics needed to identify actual effectiveness. Generally, the causal relationship of an independent variable/exposure/intervention (e.g., regenerative agent) and a dependent variable/outcome (e.g., pain reduction or function improvement) is established when the variables are tested in a specific population free of bias, confounders, or chance. The most effective way to establish a causal relationship or interventional efficacy is with large, blinded, randomized controlled trials or large, well-controlled cohort studies. In 2018, representatives from the American Academy of Orthopedic Surgery (AAOS) and National Institutes of Health (NIH) recognized the current state of research on the topic and published minimum reporting characteristics when investigating FDA-exempt agents like PRP and BMAC [13]. One purpose was to include the necessary variables to determine the regenerative agents’ efficacy. The systematic review by Burnham et al., found that all included studies were missing at least 35% of the recommended AAOS/NIH reporting characteristics. The most commonly overlooked reporting characteristics were product processing details and pre/post-product preparation laboratory analysis. We strongly recommend investigators include and report minimum reporting characteristics into their research. Many of the pre- and post-processed injectate characteristics for agents like PRP can be done at a reasonable cost by limiting the cellular analysis to include red blood cell count, white blood cell count (including differential of neutrophils, monocytes, and lymphocytes), and platelet count. Results will help regulatory boards, clinicians, and patients understand the efficacy of such regenerative agents. It is now time to move forward and determine the true efficacy of regenerative agents for painful conditions. To do so, investigators should adhere to appropriate FDA regulations and incorporate and report minimum reporting characteristics in more extensive well-designed studies. Without better understanding, our patients will continue to be overcharged for treatments with an unknown effectiveness. Conflicts of interest: Zachary L. McCormick serves on the Board of Directors of the Spine Intervention Society.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.