➢ The introduction of new devices, biologics, and combination products to the orthopaedic marketplace is increasing rapidly.
➢ The majority of these new technologies obtain clearance to market by demonstrating substantial equivalence to a predicate (previously approved device) according to the U.S. Food and Drug Administration (FDA) 510(k) process.
➢ Surgeons play a critical role in the introduction of new technologies to patients and must take a leadership role in promoting safe, efficacious, appropriate, and cost-effective care, especially for operative procedures.
➢ Surgeons should monitor and document their patients’ clinical outcomes and adverse events when using new technology, to ensure that the new technology is performing as desired.
Orthopaedic surgery is an ever-changing specialty. Over the last fifty years, innovative orthopaedic technologies have had a profound effect on millions of patients worldwide. For example, total joint replacement is one of the safest, most efficacious, and most cost-effective surgical procedures ever developed. Fracture-fixation devices, spinal instrumentation, arthroscopic and minimally invasive procedures, and bone-graft substitutes are several other examples of advancements that have revolutionized our specialty. Many of these surgical procedures and technologies were initially pursued by surgeon-innovators, who recognized a specific need to improve patient outcomes. Other innovations have been improvements on existing devices that have primarily entered the market through the U.S. Food and Drug Administration (FDA) 510(k) route of substantial equivalence. The development of new technologies results in a continuous evolution of orthopaedic care and a requirement for orthopaedic surgeons to gain knowledge of their appropriate use and implementation in clinical practice. The purpose of the present report is to address the principal issues that surgeons should contemplate when considering the use of new technologies in clinical practice.
One Example: New Technologies and Joint Replacement
Despite the positive advances derived from orthopaedic innovation, some discoveries have been associated with unintended adverse events that have caused unexpected morbidity and mortality1. Occasionally, these modifications have not been vetted as rigorously as the new technologies themselves. Charnley’s original total hip replacement featured a one-piece femoral component with a 22.5-mm head, which later was changed by others to a larger-diameter head, resulting in increased volumetric wear of conventional polyethylene2. Implants with sharp corners and other undesirable design features led to cement fractures, so-called cement disease (periprosthetic osteolysis)3, loss of bone stock, component loosening, and difficult revision surgery. The modularity of implants was, in some cases, associated with component disassociation or fracture and biomechanically assisted crevice corrosion4,5. Metal-on-metal (MOM) articulations have been associated with metallic particles and ion-induced bone and soft-tissue destruction, whereas ceramic-on-ceramic (COC) articulations may lead to implant breakage, striped wear, and squeaking6-8.
More recently, the utility of specific innovations for hip and knee arthroplasty has been challenged, including the use of sex-specific and high-flexion knee replacements, hip components with a modular femoral neck, monoblock acetabular sockets, and COC bearings9. These kinds of design changes that were thought to be innovative are not specific to joint replacement or even orthopaedic surgery. New devices, biologics, and other technologies have influenced virtually every specialty in medicine. Issues related to the introduction of novel technologies impact patients, medical caregivers, hospitals, manufacturers, payers, governmental agencies, and numerous other stakeholders10. However, in 1993, Professor Rik Huiskes, a biomechanical engineer from Nijmegen, the Netherlands, emphasized that it is the surgeon’s responsibility to ask critical questions, to demand appropriate documentation of validation of new implant designs, and to demand proof of preclinical and clinical certification of efficacy and safety when introducing a new device (in this case, a hip replacement) for use in clinical practice11. In many cases, companies obtain this proof for new devices from standards published by ASTM International or the International Organization for Standardization (ISO) or from FDA guidance documents. The issue, in some cases, is that innovation may outpace the creation of the standards or guidance documents that are needed to ensure the safety and efficacy of the new device.
The case of novel bearings for joint replacement highlights the dilemma that surgeons face when considering new technologies. During the late 1980s and 1990s, it became obvious that the long-term durability of total hip replacement implants was limited by periprosthetic osteolysis due to the biological effects of conventional polyethylene wear debris and sterilization techniques that caused oxidation of the ultra-high molecular weight polyethylene. At the same time, total hip replacement was being performed for younger patients who were interested in engaging in a more physically active lifestyle. These facts spawned additional research and the eventual use of alternative bearings, including use of so-called hard-on-hard bearings such as MOM, COC, and others. MOM devices had been previously used in the early days of hip replacement (e.g., in the McKee-Farrar, Sivash, and Ring prostheses). However, suboptimal materials and imprecise implant specifications led to excessive wear and metallic wear particles. MOM articulations were generally abandoned until the end of the twentieth century12. Thereafter, there was a rejuvenation of MOM articulations due to the use of MOM resurfacing arthroplasty, the use of total hip replacement for a younger patient population, and dissatisfaction with conventional polyethylene. A consensus workshop concerning MOM bearing surfaces was held to discuss many of these issues13. By 2009, metal-on-polyethylene (MOP) articulations constituted only 51% of hip implants used in the United States; MOM (35%) and COC (14%) constituted the remainder14. However, with the introduction of cross-linked polyethylene and increasing problems noted with these hard-on-hard bearings (cytotoxicity, hypersensitivity, pseudotumors, etc.)7,15, the use of MOM articulations has dramatically decreased. Indeed, MOM total hip replacement and hip resurfacing arthroplasty are now rarely performed16-21. Although COC is still used in Europe and Asia, its use in the U.S. has also markedly decreased because of concerns such as difficulties in properly seating ceramic inserts, chipping and breakage, edge-loading and striped wear, squeaking, and other problems6,9,22,23. The success of cross-linked polyethylene has been no less than dramatic, and therefore the quest for improved articulations over the current ones has a very high bar to surmount24-26. In addition to joint replacement registries, governmental agencies are now more closely monitoring the introduction and performance of all implants, including joint replacements27. Increased modularity as a new source for the generation of metal byproducts from various types of corrosion has recently become a major issue28,29.
The use of novel biologics and combination products in orthopaedic surgery has also come under increased scrutiny. Several recent evidence-based systematic reviews and meta-analyses as well as a review article resulting from an American Academy of Orthopaedic Surgeons (AAOS) expert panel meeting have indicated that there is insufficient clinical evidence to support the use of platelet-rich plasma (PRP) for most orthopaedic applications, including the treatment of soft-tissue injuries (Achilles tendinopathy and acute rupture, tears of the anterior cruciate ligament, patellar tendinopathy, rotator cuff tears, and lateral epicondylitis of the elbow), the treatment of cartilage defects and osteoarthritis, and bone-healing (e.g., following arthrodesis of the spine, ankle, and foot)30-32. There was a plea for standardization of PRP preparation and delivery method as these factors may affect clinical efficacy. Patients receiving PRP as opposed to other treatments for osteoarthritis of the knee had a higher incidence of nonspecific adverse events32. PRP treatments are more costly than conventional treatments30. Despite this fact, the market for PRP has been projected to grow to approximately $126 million in 201630. This predicted increase may be due to public advertising and market pressures30. Future randomized clinical studies and economic analyses to substantiate or refute the efficacy and safety of PRP are greatly needed. Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been approved by the FDA for specific indications in the spine (one-level lumbar fusion in skeletally mature patients with degenerative disc disease from L2 to S1), for the treatment of acute open tibial shaft fractures stabilized with an intramedullary nail, and for certain oral and maxillofacial uses (FDA Public Health Notification, July 1, 2008). Spine fusion procedures accounted for approximately 92.8% of rhBMP-2 use; however, 85% of the usage was for other than labeled indications (e.g., posterolateral fusion) and therefore was considered “off-label” by the FDA33. However, a critical review of the clinical trials on the use of rhBMP-2 revealed that there have been emerging concerns regarding insufficient numbers to assess safety, under-reporting of serious complications, conflicts of interest, and potential bias, including selection of control groups, invalid assumptions, and methodological errors34. The safety and effectiveness data from the individual participants in the rhBMP-2 studies were subsequently reviewed by an independent group (the Yale University Open Data Access Project, YODA), who concluded that the individual studies were at risk of bias and that while the use of BMP-2 increased spine fusion rates, it also increased perioperative pain and did not reduce pain at twenty-four months in comparison with conventional iliac crest bone-grafting35. In addition, another report by the same authors indicated that clinical journals had under-reported complications and adverse effects from the individual sites36. Further evidence of the problem of conflict of interest in peer-reviewed publications was the withdrawal (because of academic misconduct) of a study published in The Journal of Bone & Joint Surgery (British volume) on the outcomes of rhBMP-2 on tibial fractures with bone defects37.
Cell-based therapies for the treatment of traumatic and degenerative musculoskeletal conditions are another area of innovation, although this issue is controversial38. Articular cartilage, tendon, intervertebral disc, bone, and related mesenchymal tissues have limited regenerative potential after injuries or degenerative disorders. The use of autologous and even allogeneic mesenchymal cells or other pluripotential cells that can be biologically induced to develop into more mature differentiated cells and tissues of choice is enticing38. In this regard, fetal cells may have even more pluripotential ability for musculoskeletal regeneration39. These potential treatments bring with them numerous regulatory, financial, and ethical issues as well as concerns related to manufacturing, appropriate preclinical and clinical testing, and determination of safety and efficacy40. Few cell-based orthopaedic technologies have demonstrated evidence of clinical efficacy and safety; nonetheless, such technologies are currently being marketed and sold as the requirements for regulatory approval of allogeneic materials are much lower than those for medical devices41.
How Should New Technologies Be Introduced into Orthopaedics?
Protocols and methodologies for the introduction of new technologies, devices, drugs, biologics, and surgical procedures in medicine have been fervently debated worldwide. For example, the FDA has a well-defined system in which new devices are first classified according to the risk to the patient (i.e., low risk [Class I], moderate/controlled risk [Class II], and high risk [Class III])42. The pathway for approval of a new device is dependent on the particular class designation. General controls apply to all three classes of medical devices to help to ensure their safety and efficacy. General controls include provisions for device registration, good manufacturing practices (GMPs), labeling, misbranding, adulteration, notification for repair, replacement and refund, and record-keeping41,43. Most low-risk (Class-I) devices are subject only to general controls and may be exempt from the requirement of extensive new studies demonstrating safety and efficacy (Premarket Notification 510[k]); however, some Class-I devices may still need to demonstrate substantial equivalence to a predicate (previously approved device) according to the 510(k) process prior to obtaining clearance to market. Most Class-II devices require Premarket Notification 510(k); i.e., they must be substantially equivalent to another previously approved device and are subject to general and special controls. Special controls are “regulatory requirements for which general controls alone are insufficient to provide reasonable assurance of the safety and effectiveness of the device and for which there is sufficient information to establish special controls to provide such assurance.”43 Special controls include performance standards, special labeling requirements, premarket data requirements, postmarket surveillance, and patient registries. All Class-III devices are subject to general and special controls but also must demonstrate reasonable safety and efficacy in one or more approved clinical trials. This latter requirement is accomplished under an Investigational Device Exemption (IDE) that allows the device to be used in controlled clinical trials in order to gather appropriate data that are required to substantiate a Premarket Approval Application (PMA) that subsequently will be reviewed by the FDA. Some Class-II and III devices that are used in small numbers of patients (fewer than 4000 cases in the U.S. per year) may gain approval through a Human Device Exemption (HDE). Devices that gain approval to market under an HDE are still subject to general and specific controls and must be evaluated in clinical studies demonstrating that their probable benefits outweigh their risks. The Custom Device Exemption (CDE) pathway has been available since 1976, when amendments were passed establishing medical device regulation. In 2012, the FDA Safety and Innovation Act (FDASIA) directed changes to the CDE pathway and increased the number of devices per patient scenario using the CDE pathway to five units per year from the previous allotment of one per year44. Regardless of which pathway is pursued, the FDA also has to approve the labeling of the device and information given to the provider and public concerning the device. Post-approval device surveillance is an integral part of the process.
The IDEAL (Idea, Development, Exploration, Assessment, Long-term Follow-up) framework for the evaluation and introduction of new technologies for surgery emanated from a series of meetings that took place at Balliol College, University of Oxford, U.K., between 2007 and 2009, which involved a multinational group of clinicians and methodologists45. A series of manuscripts outlining a strategy for assessing and implementing the introduction of innovative technologies on the basis of scientific principles and evidence-based medicine was published45-47. The IDEAL paradigm outlines a series of progressive stages that end users and manufacturers should consider when contemplating new technology: Stage 1 represents the conceptualization of the innovation (during which proof of concept and the safety of the idea are stressed), Stage 2a represents the development of the innovation (during which technical aspects and safety are stressed), Stage 2b represents early dispersion and exploration (during which the innovation is perfected), Stage 3 represents assessment (during which the innovation is widely used), and Stage 4 represents long-term implementation and monitoring46. Rigorous clinical trials and thorough documentation of complications according to a recognized classification system are important to gauge the ongoing safety and efficacy of the new technology47. Prospective randomized clinical trials (the “gold standard”) with statistical oversight and public disclosure are important aspects of this program45. The IDEAL process should be facilitated by governmental regulatory agencies, funding agencies, publishers and journal editorial boards, professional societies, and manufacturers. These IDEAL concepts and standards should be applicable not only to devices and drugs but also to new surgical procedures. One example in which this process was utilized was the introduction of laparoscopic cholecystectomy46.
How Should a Surgeon Learn to Use New Technology?
Acquiring the surgical skill to properly use a medical device in clinical practice is critical to success. This point is particularly important for experienced surgeons who have not had recent skill-building or training. Sachdeva described three phases of skill development48. The first skill is gaining cognitive information related to indications, the decision to perform surgery, alternatives, and how the new technology would improve patient outcomes as well as preoperative, intraoperative, and postoperative care. In addition, the surgeon should be able to observe and assess the procedure and its many nuances. The second skill is task-learning of the new technology under the direction of an experienced surgeon. This skill can be developed by visiting a surgeon or through hands-on laboratory programs. Feedback from experienced surgeons is important for building confidence and a high level of skill. The goal is to be competent in all essential steps of the procedure. The final phase is independence; during this phase, which is ongoing, skills are refined and perfected. The acquisition of skills will vary depending on complexity of surgery, a surgeon’s innate learning aptitude, technical ability, and training.
Hospital credentialing before use may be required in some areas of new technology. For example, before performing laparoscopic surgery, surgeons must show competency in simulated courses administered by the American College of Surgeons49. There are no similar processes in orthopaedic surgery. Another common method of surgical training for FDA-approved devices that use the IDE pathway is an educational activity sponsored by industry. These activities are often short courses with both didactic and hands-on training. More recently, training may occur with an online module. Both the short course and online modules have limitations as bias is present; the material is learned over a short period of time, often many months before initial use; and the models may lack fidelity. This type of training is less effective than actual supervised observation during the management of patients50.
Ethical Considerations in the Use of New Technology
New technology must be used responsibly. The adoption of new technology should occur when there is sufficient evidence that patients will benefit without risk of new harms or, if risk is equivalent to or greater than benefit, when no treatment or diagnostic alternatives are available. This situation requires that the risks, as well as the patient’s tolerance for the known risks, are well understood. The surgeon must carefully consider the clinical indications for the use of new technology and must be adequately trained and credentialed, where required. Patients must be informed that they are being managed with new technology and that the surgeon may not have extensive experience with its use, and this communication should be documented. The surgeon has a duty to track his or her own results to measure effectiveness. Finally, the costs of new technology must be balanced against alternatives.
Sussman emphasized that innovation is prone to surgeon bias and therefore requires careful scrutiny of study design, appropriate control groups, and clinically meaningful outcome parameters51. Informed consent is mandatory to ensure full disclosure51. Hofbauer et al. stressed that innovative products in orthopaedic surgery should be based on high-quality evidence and that the effects of marketing and potential conflicts of interest among all involved parties should be transparent52. Indeed, value-driven innovation has many stakeholders, including patients, surgeons, manufacturers/vendors, professional societies, hospitals, payers, and regulatory agencies10. Hospitals have a major responsibility in this regard. These institutions partake in credentialing and privileging surgeons and others to perform procedures and to administer treatments and medications. There is potential corporate liability in these actions, for which the hospital bears some of the burden. Hospitals must ensure that the health-care-delivery team is competent and proficient and has the necessary qualifications to administer treatment53. Advantages of new technologies should not be overstated or embellished to capture more patients and economic gain. When a new device, treatment, or other technology is introduced, the patient being managed with the new technology should be fully informed of all perceived benefits and risks, and, postoperatively, the outcome and complications must be carefully documented. Physicians play a critical role in the introduction of new technologies to patients but must also take a leadership role in promoting safe, efficacious, appropriate, and cost-effective care, especially for surgical procedures54-57.
Different ideological approaches have evolved to help to optimize the introduction of new devices and other technologies to the orthopaedic community. One strategy for product development and assessment emphasizes a pyramid founded on progressive levels of evidence, beginning with expert opinion (the lowest level) and advancing to laboratory (basic-science) investigations, clinical studies (ranging from case series to case-control studies and cohort studies), and finally, the pivotal gold standard: the randomized clinical trial58. Malchau et al. suggested that once the clinical arena has been entered, stepwise introduction of new devices should progress from prospective randomized trials to multicenter studies and finally to national or internationally based registry studies59,60. Mont and colleagues proposed that newly approved implants should first be made available on a limited basis to specialized centers with advanced clinical, analytical, and infrastructure capabilities, with these centers contributing the data to a national registry61. The innovation cycle is another framework for the introduction of new surgical technologies and helps to ensure that patients have access to the most effectual and valued discoveries while encountering the least harm62. A simple algorithm for the assessment of new spinal devices emphasizes answers to six basic questions involving the proposed and actual function of the device, the clinical benefit, alternatives, performance, and cost-effectiveness63.
Another issue when adopting new technology is off-label use. Off-label use is entirely appropriate and within the practice of medicine, but when new medical devices are used off-label, there may be associated unintended consequences. The lack of investigations, the lack of clinical experiences, and the general lack of clarity of adverse events when using new medical devices off-label can lead to unexpected poor outcomes that harm patients. Off-label use is further complicated by poorly understood regulations prohibiting manufacturers from promoting the use of technologies not included in the labeled indications. The interpretation of this rule has seriously limited the availability of peer-reviewed literature discussing off-label use and has restricted product representatives from sharing information with surgeons.
New Devices and Drugs, Medical Practice, and the FDA
The FDA does not regulate medical practice in the U. S.; this latter responsibility resides with the state medical boards. However, the FDA has the authority to “clear” or approve all medical devices, drugs, and biologics for use by medical practitioners in the U.S. This mission includes approval of the labeling that accompanies the new technology. It is the physician’s responsibility to ensure that devices (as well as drugs and biologics) are used in a safe manner according to scientific rationale and the practitioner’s best knowledge and judgment64. It is important for surgeons to monitor their patients’ clinical outcomes and adverse events when using new technology to ensure that the new technology is performing as desired. Furthermore, physicians should maintain satisfactory medical records of the outcomes and complications associated with devices, drugs and biologics, especially new technologies that do not have an extensive track record of long-term use. This is particularly important in the case of physician-directed use of older technologies for different applications than initially approved by the FDA (so-called off-label use). One example is the use of rhBMP-2 in anatomical locations other than those for which it was initially approved.
The Future of Innovation
Some have commented that there are too many perceived barriers to device innovation in all medical subspecialties65. In the 1990s, a conference held in Chantilly, Virginia, focusing on the obstacles that surgeons and industry were facing concerning the approval of new technologies into the marketplace resulted in the formation of the Orthopaedic Device Forum, sponsored by the AAOS. This forum, now in its twentieth year, comprises members of the AAOS, FDA, National Institutes of Health (NIH), Centers for Medicare & Medicaid Services (CMS), Orthopedic Surgical Manufacturers Association (OSMA), ASTM International, Orthopaedic Research Society (ORS), and the Board of Specialty Societies (BOS) of the AAOS and meets bi-yearly to address concerns related to getting new technology into the marketplace in a safe and timely manner.
Recently, the structure and methodology by which the approval of new medical technologies occurs in the U.S. have come under increased scrutiny66. Should the current FDA system of approval be revised, revamped, or completely abandoned? Is “substantial equivalence” too low of a bar given the plethora of devices, drugs, and biologics currently in the marketplace? Should superiority rather than equivalence be the new standard? How should the government choose review panels to adjudicate on new technologies in a scientific and transparent manner that minimizes bias and opportunism? What post-approval surveillance mechanisms need to be maintained for new technologies, and who should fund these endeavors? These questions are ones in which all interested parties, including medical practitioners, must become engaged.
Source of Funding: No funding was received by the authors in support of this manuscript.
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. In addition, one or more of the authors has a patent or patents, planned, pending, or issued, that is broadly relevant to the work. Also, one or more of the authors has had another relationship, or has engaged in another activity, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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