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Editorial Commentary: Adoption of New Medical Technology Requires Replication of Consistent Results Across Multiple Studies: Biologic Injections for Knee Osteoarthritis

      Abstract

      Determining when to adopt new treatment methods in a clinical practice is a challenging undertaking. Uncertain outcomes of emerging technology can undermine the impartial assessment of risk and benefit. “Optimism bias” can lead to premature adoption of technology. An additional risk is that influential colleagues often persuade clinicians to innovate. “Replicability” or obtaining consistent results across studies aimed at answering the same scientific question must be a goal prior to adoption of innovative devices and treatments. The ability to replicate the results by a separate research group in a similar population with different input data is critical to gaining acceptance from providers without a personal stake in the development of technology.
      Amniotic suspension allograft (ASA), as presented by Gomoll, Mandelbaum, Farr, Archambault, Sherman, Tabet, Kimmerling, and Mowry in “An Initial Injection and a Crossover Injection of Amniotic Suspension Allograft Following Failed Treatment With Hyaluronic Acid or Saline Are Equally Effective in the Treatment of Moderate Symptomatic Knee Osteoarthritis Over 12 Months”, represents a welcome innovative entrant into the effort to solve biologically symptomatic knee osteoarthritis.
      • Gomoll A.H.
      • Mandelbaum B.R.
      • Farr J.
      • et al.
      An initial injection and a crossover injection of amniotic suspension allograft following failed treatment with hyaluronic acid or saline are equally effective in the treatment of moderate symptomatic knee osteoarthritis over 12 months.
      This technology joins platelet-rich plasma, bone marrow aspirate concentrate, stem cells, exosomes, immunomodulating drugs, among others, attempting to find either a temporary treatment or ideally a permanent cure to osteoarthritis. Such effort seems distinctly worthwhile to these reviewers, clinicians without any personal stake or intellectual property in the field. Indeed, it is not hard to imagine a future in which joint replacement becomes a historic surgery, largely replaced by various osteo-biologics that enable our body’s innate cellular machinery to either suppress the proinflammatory synovial microenvironment created by chronic degeneration of articular cartilage or repair the damage of age and injury. However, our imaginations similarly have seen a future in which fusion reactors provide limitless, clean, and cheap power for our civilization for some time without meaningful progress toward this goal.
      Gomoll et al. in this publication describe a third chapter in their single blinded 200 patient 1:1:1 randomized study between amniotic suspension allograft, hyaluronic acid (HA), and saline control.
      • Gomoll A.H.
      • Mandelbaum B.R.
      • Farr J.
      • et al.
      An initial injection and a crossover injection of amniotic suspension allograft following failed treatment with hyaluronic acid or saline are equally effective in the treatment of moderate symptomatic knee osteoarthritis over 12 months.
      In the first publication, the clinical results of this study were described.
      • Farr J.
      • Gomoll A.H.
      • Yanke A.B.
      • Strauss E.J.
      • Mowry K.C.
      ASA Study Group
      A randomized controlled single-blind study demonstrating superiority of amniotic suspension allograft injection over hyaluronic acid and saline control for modification of knee osteoarthritis symptoms.
      In the second publication, the authors describe the safety profile of ASA, including immunologic reaction to the injection with anti-HLA levels.
      • Gomoll A.H.
      • Farr J.
      • Cole B.J.
      • et al.
      Safety and efficacy of an amniotic suspension allograft injection over 12 months in a single-blinded, randomized controlled trial for symptomatic osteoarthritis of the knee.
      In this publication, the authors describe the results of the 95 patients who reported unacceptable pain from the HA and saline groups and define their outcome with subsequent crossover to ASA injections. Figure 6 visually encapsulates the results of the present study, demonstrating the 1-year outcomes from ASA injection
      • Gomoll A.H.
      • Farr J.
      • Cole B.J.
      • et al.
      Safety and efficacy of an amniotic suspension allograft injection over 12 months in a single-blinded, randomized controlled trial for symptomatic osteoarthritis of the knee.
      and that previous HA and saline injection did not appear to deteriorate the results. As in any emerging technology, these reviewers are left wanting more. Comparing ASA to HA and not cortico-steroid and the use of single-blinding in the original study instead of double-blinding create doubts about the utility of ASA in our minds that will ultimately need to be settled with additional study. It is clear from the author’s statements that this double blind RCT Phase III trial is ongoing, and we commend the authors for this rigorous step-wise approach to determine the efficacy of ASA in moderate knee osteoarthritis.
      Indeed, this article makes the reviewers reflect upon the process of adopting new technologies, in general. The question of when to adopt technological advancement in medicine has, surprisingly, little written on it.
      • Leopold S.S.
      When should we adopt new technology into our practices?.
      ,
      • Wyatt R.W.B.
      • Jayakumar P.
      • Barber T.C.
      • Fleeter T.B.
      • Graves S.E.
      • Bozic K.
      A strategic approach to introducing new technology into orthopaedic practices.
      Perhaps the foundational works of this question begin with the 1947 Nuremberg Code, defining 10 points of “Permissible Medical Experimentation

      Nuremberg Code. The Doctor’s Trial: The medical case of the subsequent Nuremberg Proceedings. United States Holocaust Memorial Museum Online Exhibitions. Accessed February 13, 2019.

      and the Belmont Report in 1978, establishing the three core principles of respect for persons, beneficence, and justice after the Tuskegee syphilis experiment.
      • Geiger J.D.
      • Hirschl R.B.
      Innovation in surgical technology and techniques: Challenges and ethical issues.
      However, these works speak more to the ethics of the development of technology and experimental design. Institutional Review Boards (IRBs) and Food and Drug Administration (FDA) provides a safety net for practicing clinicians by only approving innovations and technology that have demonstrated safety and efficacy in a controlled study. The thornier and more immediate question for the clinician is when to adopt these technologies and why?
      By its nature, innovation involves uncertainty that makes assessment of risk and benefit more difficult than other currently established technology, as a result of its newness and unfamiliarity. This uncertainty of outcome will look artificially good when compared to an existing accepted treatment that has well known limitations.
      • Miller M.E.
      • Siegler M.
      • Angelos P.
      Ethical issues in surgical innovation.
      This asymmetry between the known limited treatment and the unknown treatment with possibility has been labeled an “optimism bias” that can lead to adoption of a technology when it may not otherwise be due. It does not take a long memory to recall when thermal capsulorraphy appeared to solve multidirectional instability and metal on metal hip arthroplasty promised to solve hip osteoarthritis in young laborers. Both of these problems remain significant limitations in orthopedic practice. Alternatively, trans-examic acid (TXA) underwent a period of investigation, in which many providers worried the medication would increase thromboembolism and lead to increased high morbidity complications. Now TXA is widely administered perioperatively in the prophylactic management of blood loss in trauma, spine, and arthroplasty surgery.
      Cost presents another thorny issue that the responsible clinician should consider when deciding when to adopt technology. Highly cross-linked polyethylene’s adaptation was slowed, secondary to concerns that it was not cost effective compared to conventional polyethylene. However, one must consider the entire episode of care involving the anticipated life cycle of new products to understand their cost, risks and benefits. This leads to the need for high-quality in vivo studies that stretch the expected life of an implant. The absence of such studies contributes to their uncertainties and makes it hard to assess the cost effectiveness of new products.
      “Replicability” is obtaining consistent results across studies aimed at answering the same scientific question, each of which has obtained its own data and subjects.

      National Academies of Sciences, Engineering, and Medicine; Policy and Global Affairs; Committee on Science, Engineering, Medicine, and Public Policy; Board on Research Data and Information; Division on Engineering and Physical Sciences; Committee on Applied and Theoretical Statistics; Board on Mathematical Sciences and Analytics; Division on Earth and Life Studies; Nuclear and Radiation Studies Board; Division of Behavioral and Social Sciences and Education; Committee on National Statistics; Board on Behavioral, Cognitive, and Sensory Sciences; Committee on Reproducibility and Replicability in Science. Reproducibility and Replicability in Science. Washington, DC: National Academies Press (US); 2019

      For these authors, “replicability” is a critical aspect of innovation, which must be met prior to the adoption of innovative devices and treatments. The ability to replicate the results by a separate research group in a similar population with different input data is critical to gaining acceptance from providers without a personal stake in the development of technology.
      These factors create a challenging environment not just for the clinician to make decisions, but also for the clinicians to inform patients in an unbiased and impartial way, to say nothing of the varying landscape in which patients have different appetites for risk, information, and willingness to engage with the new and innovative. It should not be surprising that in such a challenging environment, clinicians are often persuaded to try a new therapy when an influential colleague adopts the innovation first.
      • Paul M.
      Persuading doctors to quickly adopt new treatments. Influential colleagues push doctors beyond comfort zone to try new therapies.
      The contagion model describes how one doctor will be “infected” by another using new technology, particularly when the influential colleague is respected and opinionated, but not too bossy. This scenario depicts one way we adopt technology, and likely ring true in all of our experiences.
      Adopting technology is challenging with high-quality studies and impossible without it. Our organizations and societies must support the highest-quality research with multicentered randomized controlled trials. For their efforts in pursuing these goals, the Gomoll et al. group should be congratulated for their efforts. While their study is not definitive in solving this problem for the clinician reader, it is a useful data point, one that we can certainly use more of as we strive to practice in a difficult and constantly changing world.

      Supplementary Data

      References

        • Gomoll A.H.
        • Mandelbaum B.R.
        • Farr J.
        • et al.
        An initial injection and a crossover injection of amniotic suspension allograft following failed treatment with hyaluronic acid or saline are equally effective in the treatment of moderate symptomatic knee osteoarthritis over 12 months.
        Arthroscopy. 2023; 38: 66-78
        • Farr J.
        • Gomoll A.H.
        • Yanke A.B.
        • Strauss E.J.
        • Mowry K.C.
        • ASA Study Group
        A randomized controlled single-blind study demonstrating superiority of amniotic suspension allograft injection over hyaluronic acid and saline control for modification of knee osteoarthritis symptoms.
        J Knee Surg. 2019; 32 (Erratum in: J Knee Surg 2019;32:e2): 1143-1154
        • Gomoll A.H.
        • Farr J.
        • Cole B.J.
        • et al.
        Safety and efficacy of an amniotic suspension allograft injection over 12 months in a single-blinded, randomized controlled trial for symptomatic osteoarthritis of the knee.
        Arthroscopy. 2021; 37: 2246-2257
        • Leopold S.S.
        When should we adopt new technology into our practices?.
        Arch Orthop Trauma Surg. 2021; 141: 2337-2340
        • Wyatt R.W.B.
        • Jayakumar P.
        • Barber T.C.
        • Fleeter T.B.
        • Graves S.E.
        • Bozic K.
        A strategic approach to introducing new technology into orthopaedic practices.
        Instr Course Lect. 2020; 69: 393-404
      1. Nuremberg Code. The Doctor’s Trial: The medical case of the subsequent Nuremberg Proceedings. United States Holocaust Memorial Museum Online Exhibitions. Accessed February 13, 2019.

        • Geiger J.D.
        • Hirschl R.B.
        Innovation in surgical technology and techniques: Challenges and ethical issues.
        Semin Pediatr Surg. 2015; 24: 115-121
        • Miller M.E.
        • Siegler M.
        • Angelos P.
        Ethical issues in surgical innovation.
        World J Surg. 2014; 38: 1638-1643
      2. National Academies of Sciences, Engineering, and Medicine; Policy and Global Affairs; Committee on Science, Engineering, Medicine, and Public Policy; Board on Research Data and Information; Division on Engineering and Physical Sciences; Committee on Applied and Theoretical Statistics; Board on Mathematical Sciences and Analytics; Division on Earth and Life Studies; Nuclear and Radiation Studies Board; Division of Behavioral and Social Sciences and Education; Committee on National Statistics; Board on Behavioral, Cognitive, and Sensory Sciences; Committee on Reproducibility and Replicability in Science. Reproducibility and Replicability in Science. Washington, DC: National Academies Press (US); 2019

        • Paul M.
        Persuading doctors to quickly adopt new treatments. Influential colleagues push doctors beyond comfort zone to try new therapies.