Leveraging Real-World Evidence: A Paradigm Shift in Regulation.

SUMMARY: The study methodology and regulatory frameworks for real-world data collection is quickly evolving, opening new avenues to use valid and robust real-world evidence (RWE) to support regulatory decision making. Although the Food and Drug Administration has historically accepted specific applications of RWE to support regulatory determinations, significant progress has been made in recent years to examine conditions in which this information can be used to support specific types of premarket decisions. Of note, hybrid study designs that incorporate aspects of randomized clinical trials, including randomization and pragmatic outcomes, are expected to be a driving factor to accelerate the adoption of RWE in regulatory contexts. Generation of RWE to better understand effectiveness and safety of orthopaedic- and trauma-related devices requires careful planning, but it is achievable as demonstrated by the Bioventus Observational Non-Interventional EXOGEN Studies (BONES) clinical development program. This article examines the role of RWE in regulatory decision making and reviews key concepts in RWE study design methodology to facilitate creation of valid scientific evidence in support of marketing authorizations.

The repair of horizontal cleavage tears yields higher complication rates compared to meniscectomy: a systematic review.

PURPOSE: Horizontal cleavage tears of the meniscus (HCTs) are primarily degenerative in nature, and, however, can be the result of trauma. Such tears account for 12-35% of all tear patterns and can be treated by partial meniscectomy or arthroscopic repair. The purpose of this review was to systematically assess the outcomes and complications for patients undergoing the surgical treatment of HCTs. METHODS: This review has been conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses. The electronic databases PubMed, MEDLINE, and EMBASE were searched from data inception to December 30, 2018 for articles addressing the surgical treatment of HCTs. The Methodological Index for Non-randomized Studies was used to assess study quality. Data are presented descriptively. RESULTS: Overall, 23 studies were identified, comprising of 702 patients (708 knees) with a mean age of 36.6 ± 9.9 years and a mean follow-up of 33.6 ± 19.6 months. The majority of patients were treated with a partial meniscectomy (59.0%), followed by repair (32.8%) and total meniscectomy (8.2%). Both meniscectomy and repair patients had improvements which surpassed minimal clinically important differences with regard to clinical (e.g. pain, function, daily living) and radiographic outcomes. The overall complication rate was 5.1%, primarily involving patients undergoing meniscal repair (12.9% of all knees undergoing a repair). CONCLUSION: Although meniscal repair theoretically may provide improvement in biomechanical loading, patients undergoing repair had higher complication rates than those undergoing partial meniscectomy. Clinicians should consider the available implants in determining which tear patterns to repair and future studies with long-term follow-up are needed to investigate complications (e.g. secondary meniscal procedures) as well as the potential for delay in the development of osteoarthritis. LEVEL OF EVIDENCE: Level IV.

AO Patient Outcomes Center: Design, Implementation, and Evaluation of a Software Application for the Collection of Patient-Reported Outcome Measures in Orthopedic Outpatient Clinics.

BACKGROUND: Patient-reported outcomes are increasingly utilized in routine orthopedic clinical care. Computer adaptive tests (CATs) from the Patient-Reported Outcomes Measurement Information System (PROMIS) offer a brief and precise assessment that is well suited for collection within busy clinical environments. However, software apps that support the administration and scoring of CATs, provide immediate access to patient-reported outcome (PRO) scores, and minimize clinician burden are not widely available. OBJECTIVE: Our objective was to design, implement, and test the feasibility and usability of a Web-based system for collecting CATs in orthopedic clinics. METHODS: AO Patient Outcomes Center (AOPOC) was subjected to 2 rounds of testing. Alpha testing was conducted in 3 orthopedic clinics to evaluate ease of use and feasibility of integration in clinics. Patients completed an assessment of PROMIS CATs and a usability survey. Clinicians participated in a brief semistructured interview. Beta-phase testing evaluated system performance through load testing and usability of the updated version of AOPOC. In both rounds of testing, user satisfaction, bugs, change requests, and performance of PROMIS CATs were captured. RESULTS: Patient feedback supported the ease of use in completing an assessment in AOPOC. Across both phases of testing, clinicians rated AOPOC as easy to use but noted difficulties in integrating a Web-based software application within their clinics. PROMIS CATs performed well; the default assessment of 2 CATs was completed quickly (mean 9.5 items) with a satisfactory range of measurement. CONCLUSION: AOPOC was demonstrated to be an easy-to-learn and easy-to-use software application for patients and clinicians that can be integrated into orthopedic clinical care. The workflow disruption in integrating any type of PRO collection must be addressed if patients' voices are to be better integrated in clinical care.

Outcomes after orthopedic trauma.

BACKGROUND: Clinical orthopedic research needs better ability to assess patient expectations with regard to orthopedic trauma surgery outcomes. The aim of this study was to investigate to which extent patient expectations prior to surgery could be met after surgery. METHODS: Patients (≥18 years) with surgical ankle fractures were prospectively recruited at 5 orthopedic trauma clinics in the United States (USA), Canada, and Brazil and followed up for 12 months. Patients were asked to complete a previously validated trauma expectation factor (TEF) questionnaire prior to surgery and a trauma outcome measure (TOM) 1 year after surgery. RESULTS: At 1 year, 155 patients had provided complete records. Almost half (49%; 76/155) had a 1-year TOM score equaling or exceeding their preoperative TEF score (95% CI: 41-57%). The remaining scores failed to meet patient expectations. TOM scores matched or exceeded patient expectations for 33% of patients in the USA and 47% in Canada, but for 69% in Brazil ( p = 0.001 (USA); p = 0.024 (Canada)). This geographical effect was attributable to higher patient expectations in North America as compared to Brazil (average TEF scores: 36 (North America) versus 31 (Brazil); p < 0.001). Patients with lower household income or smokers were more likely to be satisfied with their treatment ( p = 0.02 and p = 0.05, respectively). Furthermore, patients with severe type C fractures had better rates of satisfaction (62%) than patients with simpler B (50%) or type A fractures (33%) ( p = 0.01 [C type versus A type]). CONCLUSIONS: Orthopedic surgeons have difficulty in meeting or exceeding presurgical patient expectations of long-term outcomes for ankle fracture surgery. This study provides evidence that culture, geography, and surgeon-patient communication have considerable influence on patient expectations.

The Influence of Local Bone Density on the Outcome of One Hundred and Fifty Proximal Humeral Fractures Treated with a Locking Plate.

BACKGROUND: There is biomechanical evidence that bone density predicts the mechanical failure of implants. The aim of this prospective study was to evaluate the influence of local bone mineral density on the rate of mechanical failure after locking plate fixation of proximal humeral fractures. METHODS: We enrolled 150 patients who were from fifty to ninety years old with a closed, displaced proximal humeral fracture fixed with use of a locking plate from July 2007 to April 2010. There were 118 women and thirty-two men who had a mean age of sixty-nine years. Preoperative computed tomography (CT) scans were done to assess bone mineral density of the contralateral humerus, and dual x-ray absorptiometry of the distal end of the radius of the unaffected arm was conducted within the first six weeks postoperatively. At follow-up evaluations at six weeks, three months, and one year postoperatively, pain, shoulder mobility, strength, and multiple functional and quality-of-life outcome measures (Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire; Shoulder Pain and Disability Index [SPADI]; Constant score; and EuroQuol-5D [EQ-5D]) were done and standard radiographs were made. We defined mechanical failure as all complications related to bone quality experienced within one year. RESULTS: After locking plate fixation, fifty-three (35%) of 150 patients had mechanical failure; loss of reduction and secondary screw loosening with perforation were common. CT assessments of local bone mineral density showed no difference between patients with and without mechanical failure (89.82 versus 91.51 mg/cm3, respectively; p = 0.670). One-year DASH, SPADI, and Constant scores were significantly better for patients without mechanical failure (p ≤ 0.05). CONCLUSIONS: We did not find evidence of an association between bone mineral density and the rate of mechanical failures, which may suggest that patients with normal bone mineral density are less prone to sustain a proximal humeral fracture. Future studies should target other discriminating factors between patients with and without mechanical failure. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Factors predicting surgeons' preferred and actual roles in interactions with their patients.

BACKGROUND: Although shared decision making offers clinical benefits, there is a lack of research investigating physicians' roles in interactions with their patients. Research examining what characterizes physicians who involve patients in decision making is also limited. The authors investigated surgeons' preferred and usual roles in interactions with patients, and whether these roles are influenced by their gender, experience, area of expertise, numeracy, and cultural background. METHODS AND RESULTS: Participants were a diverse sample of 292 surgeons from 60 countries. Surgeons completed a survey about their usual and preferred roles in medical decision making. They also completed the Berlin Numeracy Test-a brief instrument designed to measure numeracy in culturally diverse educated individuals. Most surgeons preferred to share decision making with patients, but very few reported having a collaborative role in typical interactions. Female surgeons showed a stronger preference for collaborative decision making than their male counterparts (OR = 2.08). However, female surgeons more often played an active role in medical decision making, involving patients less often (OR = 5.39). Surgeons with low numeracy (OR = 3.83), less experienced surgeons (OR = 3.15), and surgeons from individualistic countries (OR = 1.82) rarely involved patients in decision making. CONCLUSIONS: Most surgeons reported that shared decision making was their preferred method for medical decision making. Unfortunately, many of them were insufficiently equipped to take a more collaborative role in interactions with patients. Gender, numeracy, length of experience, and cultural background limited their willingness to collaborate. Future research should identify effective interventions that help overcome barriers to shared decision making.

How to document and report orthopedic complications in clinical studies? A proposal for standardization.

INTRODUCTION: The documentation of complications is critical for the evaluation of therapeutic interventions in orthopedics. However, there is a lack of accepted methodological standardization and definitions. We propose a concept to support the consensus development of a standardized management and classification of complications in clinical research. METHODS: Complication events are examined regarding their clinical presentation, their timing of occurrence as well as their potential causal interrelationship for any given patient. Their clinical presentation is distinguished by their likely triggers, their therapeutic management, and their outcome. Complications are events (including relevant deviations from their expected healing process) that are harmful to patients and can be described as local to the treated injury/disease or systemic (when they affect the rest of the body). The treatment of a complication, e.g. by way of an unplanned surgical intervention, and its outcome should be carefully documented. Complication review boards with independent clinicians should be established to validate complication records. APPLICATION AND RELEVANCE: In this proposal, a number of complication examples are presented to illustrate the concept and demonstrate its practical use. This management and classification system has already proven valuable in the documentation and analysis of complication data from a number of published clinical studies. Because of this new standardized assessment process, it facilitates the communication of complications between clinicians and researchers, and helps to develop clear definitions for specific orthopedic complications.

TEFTOM: A Promising General Trauma Expectation/Outcome Measure-Results of a Validation Study on Pan-American Ankle and Distal Tibia Trauma Patients.

Background. In orthopedics, there is no instrument specifically designed to assess patients' expectations of their final surgery outcome in general trauma populations. We developed the Trauma Expectation Factor Trauma Outcome Measure (TEFTOM) to investigate the fulfilment of patients' expectations one year after surgery as a measure of general trauma surgical outcomes. The aim of this paper was to assess the psychometric characteristics of this new general trauma outcome measure. Methods. The questionnaire was tested in 201 ankle and distal tibia fracture patients scheduled for surgery. Patients were followed up for twelve months. The TEFTOM questionnaire was evaluated for its criterion validity, internal consistency, reproducibility, and responsiveness. Results. TOM showed good criterion validity against the American Academy of Orthopaedic Surgeons Foot and Ankle Scale (Pearson's correlation coefficient = 0.69-0.77). Internal consistency was acceptable for TEF (Cronbach's alpha = 0.65-0.76) and excellent for TOM (Cronbach's alpha = 0.76-0.85). Reproducibility was moderate to very good (intraclass coefficient correlation (ICC) ≥0.67) for TEF and very good (ICC ≥0.92) for TOM. TOM also proved to be responsive to changes in patients' condition over time (Wald test; P < 0.001). Conclusions. TEFTOM is a promising tool for measuring general trauma outcomes in terms of patients' expectation fulfilment that proved to be valid, internally consistent, reproducible, and responsive to change.

The natural history of knee osteoarthritis: India-based knee osteoarthritis evaluation (iKare): a study protocol.

METHODOLOGY: Multi-center, cross-sectional, observational study. STUDY CENTER(S): Multiple centers in India. NUMBER OF PARTICIPANTS: 1,000. PRIMARY RESEARCH OBJECTIVE: To characterize patients and treatment utilized for orthopedic patients presenting to both private and public hospital centers in India with knee pain and symptoms suggestive of knee arthritis. INCLUSION CRITERIA: All patients 18 years of age or older who present to a recruiting hospital for treatment of knee pain will be eligible for participation. The subjects must be able to understand and complete the questionnaire. EXCLUSION CRITERIA: Patients with total knee replacement, open wound or evidence of recent surgery, or with a current or a history of tumor and/or fracture in the tibial plateau, femoral condyle or patella, in the affected knee are not eligible. STUDY OUTCOMES: This study aims to characterize the following: general demographics of patients presenting with knee pain, severity of knee symptoms at time of presentation, severity of knee pathology at time of presentation, factors associated with the decision to seek medical care, previous treatments and health care contacts, planned treatment, and gaps in treatment perceived by the patient and treating surgeons.

Viscosupplementation for knee osteoarthritis: current evidence and recommendations.

Osteoarthritis (OA) is the most common joint disorder worldwide and is a leading cause of pain and disability. Appropriate management of younger patients with milder disease remains a challenging area of intense research. Viscosupplementation attempts to restore the biomechanical and biochemical functions of normal synovial fluid hyaluronic acid. Several preparations with varying characteristics are currently available. The literature suggests a small benefit and relative safety, but several recent large meta-analyses have reported conflicting results. Major clinical guidelines provide inconclusive recommendations. Viscosupplementation may be a viable option in younger patients with milder OA where other non-operative modalities are also only modestly successful, but further investigation is clearly warranted. Limitations due to study heterogeneity, outcome reporting, and bias can each be addressed with improved research methodology.

Challenges in conducting multicenter, multicultural, and multilingual trials: a view from the literature and real-life experience reports.

A trend toward international multicenter clinical trials in the medical device industry is helping to increase recruitment figures and to improve the generalizability of results, among other factors. However, working globally creates its own unique set of problems, which are rarely discussed in the literature. This article considers these issues from multicenter, multicultural, and multilingual perspectives. A multicenter study implies a replication of work to coordinate research sites that are working under different regulations. Standardizing elements of the clinical trial is essential for proper comparison of results. Multicultural differences manifest themselves in different forms in international clinical research. However, the impact of culture on a study's success is a real issue, particularly when patient-reported outcomes form part of the trial. A trial that is conducted globally obviously requires the use of local language material, but this element is fraught with the possibility of mistranslation and misunderstanding. In this article, we also examine the composition of a research team and how to keep everyone involved in a global clinical trial both informed and enthused about a trial that may last several years. Examples from our own clinical investigations are reported throughout this article.

Evaluating implants in orthopaedic trials: tips for conducting research.

The availability of quality research on orthopaedic implants is important for orthopaedic clinical practice, though in many cases such research is deficient in the literature. Randomized trials are dwarfed in number by observational studies which, though also valuable, do not provide the same validity of evidence. This is partly due to the unique challenges faced by orthopaedic clinicians when attempting to conduct randomized trials in areas such as randomization, blinding, and follow-up. These challenges can be addressed with the use of techniques such as expertise-based randomization, assessment that is objective and independent, and implementation of a protocol for consistent follow-up before the study is underway. Although they do not eliminate all of the hurdles faced in implant evaluation trials, the tips outlined in this article have the potential to significantly ease the burdens of conducting high-quality research.

Clinical outcome of implant removal after fracture healing. Design of a prospective multicentre clinical cohort study.

BACKGROUND: The clinical results of removal of metal implants after fracture healing are unknown and the question whether to remove or to leave them in is part of discussion worldwide. We present the design of a prospective clinical multicentre cohort study to determine the main indications for and expectations of implant removal, the influence on complaints, the incidence of surgery related complications and the socio-economic consequences of implant removal. METHODS/DESIGN: In a prospective multicentre clinical cohort study at least 200 patients with a healed fracture after osteosynthesis with a metal implant are included for analyzing the outcome after removal. Six hospitals in the Netherlands are participating. Special questionnaires are designed. The follow up after surgery will be at least six months. The primary endpoint is the incidence of surgery related complications. Secondary endpoints are the influence of removal on preoperative symptoms and complaints and the socio-economic consequences. DISCUSSION: By performing this study we hope to find profound arguments to remove or not to remove metal implants after fracture healing that can help to develop clear guidelines for daily practice. TRIAL REGISTRATION: NTR1297, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1297.

Implant removal of osteosynthesis: the Dutch practice. Results of a survey.

BACKGROUND: The aim of this survey study was to evaluate the current opinion and practice of trauma and orthopaedic surgeons in the Netherlands in the removal of implants after fracture healing. METHODS: A web-based questionnaire consisting of 44 items was sent to all active members of the Dutch Trauma Society and Dutch Orthopaedic Trauma Society to determine their habits and opinions about implant removal. RESULTS: Though implant removal is not routinely done in the Netherlands, 89% of the Dutch surgeons agreed that implant removal is a good option in case of pain or functional deficits. Also infection of the implant or bone is one of the main reasons for removing the implant (> 90%), while making money was a motivation for only 1% of the respondents. In case of younger patients (< 40 years of age) only 34% of the surgeons agreed that metal implants should always be removed in this category. Orthopaedic surgeons are more conservative and differ in their opinion about this subject compared to general trauma surgeons (p = 0.002). Though the far majority removes elastic nails in children (95%).Most of the participants (56%) did not agree that leaving implants in is associated with an increased risk of fractures, infections, allergy or malignancy. Yet in case of the risk of fractures, residents all agreed to this statement (100%) whereas staff specialists disagreed for 71% (p < 0.001). According to 62% of the surgeons titanium plates are more difficult to remove than stainless steel, but 47% did not consider them safer to leave in situ compared to stainless steel. The most mentioned postoperative complications were wound infection (37%), unpleasant scarring (24%) and postoperative hemorraghe (19%). CONCLUSION: This survey indicates that there is no general opinion about implant removal after fracture healing with a lack of policy guidelines in the Netherlands. In case of symptomatic patients a majority of the surgeons removes the implant, but this is not standard practice for every surgeon.

What should an ideal spinal injury classification system consist of? A methodological review and conceptual proposal for future classifications.

Since Böhler published the first categorization of spinal injuries based on plain radiographic examinations in 1929, numerous classifications have been proposed. Despite all these efforts, however, only a few have been tested for reliability and validity. This methodological, conceptual review summarizes that a spinal injury classification system should be clinically relevant, reliable and accurate. The clinical relevance of a classification is directly related to its content validity. The ideal content of a spinal injury classification should only include injury characteristics of the vertebral column, is primarily based on the increasingly routinely performed CT imaging, and is clearly distinctive from severity scales and treatment algorithms. Clearly defined observation and conversion criteria are crucial determinants of classification systems' reliability and accuracy. Ideally, two principle spinal injury characteristics should be easy to discern on diagnostic images: the specific location and morphology of the injured spinal structure. Given the current evidence and diagnostic imaging technology, descriptions of the mechanisms of injury and ligamentous injury should not be included in a spinal injury classification. The presence of concomitant neurologic deficits can be integrated in a spinal injury severity scale, which in turn can be considered in a spinal injury treatment algorithm. Ideally, a validation pathway of a spinal injury classification system should be completed prior to its clinical and scientific implementation. This review provides a methodological concept which might be considered prior to the synthesis of new or modified spinal injury classifications.