A new approach to clinical research: Integrating clinical care,quality reporting,and research using a wound care network‐based learning healthcare system

The disparity between ideal evidence from randomized controlled trials and real‐world evidence in medical research has prompted the United States Food and Drug Administration to consider the use of real‐world data to better understand safety and effectiveness of new devices for a broader patient population and to prioritize real‐world data in regulatory decision making. As the healthcare system transitions from volume‐ to value‐based care, there is a growing need to harness the power of real‐world data to change the paradigm for wound care clinical research and enable more generalizable clinical trials. This paper describes the implementation of a network‐based learning healthcare system by a for‐profit consortium of wound care clinics that integrates wound care management, quality improvement, and comparative effectiveness research, by harnessing structured real‐world data within a purpose‐built electronic health record at the point of care. Centers participating in the consortium submit their clinical data and quality measures to a qualified clinical data registry for wound care, enabling benchmarking of their data across this national network. The common definitional framework of the purpose‐built electronic health record and the 21 wound‐specific quality measures help to standardize the potential sources of bias in real‐world data, making the consortium data useful for comparative effectiveness research. This consortium can transform wound care clinical research and raise the standards of care, while helping physicians achieve success with the Merit‐Based Incentive Payment System.     

Randomised controlled trials as part of clinical care: A seven‐step routinisation framework proposal

Evidence translation in wound care relies on the need for evidence generation. Clinical practice may generate evidence only if evidence‐generating research projects, such as randomised controlled trials (RCTs), became routinised in clinical settings. The aim of this study was to identify optimal trial‐related practices to routinise trial‐related activities in Melbourne‐located wound clinics as reported by clinicians and researchers. We conducted a secondary analysis of the available data on how to routinise RCTs in clinical care, with a focus on enablers and suggestions provided by the participants during face‐to‐face and telephone interviews. Data were obtained from a qualitative observational study nested within a randomised, double‐blinded, placebo‐controlled trial on clinical effectiveness of aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers (ASPiVLU). We developed a seven‐step Routinisation of Trials in Clinical Care Framework. These steps include: (1) pre‐trial clinical site assessment, (2) optimising pre‐recruitment arrangements, (3) developing and updating trial‐related skills, (4) embedding RCT recruitment as part of routine clinical care, (5) promoting teamwork and trial‐related collaboration, (6) addressing trial‐related financial issues, and (7) communicating trial results to clinicians.     

Harnessing electronic healthcare data for wound care research: Standards for reporting observational registry data obtained directly from electronic health records

The United States Food and Drug Administration will consider the expansion of coverage indications for some drugs and devices based on real‐world data. Real‐world data accrual in patient registries has historically been via manual data entry from the medical chart at a time distant from patient care, which is fraught with systematic error. The efficient automated transmission of data directly from electronic health records is replacing this labor‐intensive paradigm. However, real‐world data collection is unfamiliar. The potential sources of bias arising from the source of data and data accrual, documentation, and aggregation have not been well defined. Furthermore, the technological aspects of data acquisition and transmission are less transparent. We explore opportunities for harnessing direct‐from‐electronic health record registry reporting and propose the ABCs of Registries (Analysis of Bias Criteria of Registries), which are an evaluation framework for publications to minimize potential bias of real‐world data obtained directly from an electronic health record method. These standards are based on a point‐of‐care data documentation process using a common definitional framework and data dictionaries. By way of example, we describe a wound registry obtained directly from electronic health records. This qualified clinical data registry minimizes bias by ensuring complete and accurate point‐of‐care data capture, standardizes usual care linked to quality reporting, and prevents post‐hoc vetting of outcomes. The resulting data are of high quality and integrity and can be used for comparative effectiveness research in wound care. In this way, the effort needed to succeed with the Quality Payment Program is leveraged to obtain the real‐world data needed for comparative effectiveness research.     

Ozone therapy for the treatment of chronic wounds: A systematic review

Chronic wounds present a significant burden to the health care system and the patient. Ozone therapy has been proposed as a treatment for chronic wounds, potentially acting by eliciting mild oxidative stress or disinfection. The purpose of this systematic review is to evaluate the potential benefits and harms of ozone therapy as an advanced care intervention for chronic wounds. Studies were extracted from Google Scholar, PubMed, the Cochrane Library, and reference lists. General inclusion criteria included English‐language randomised human trials reporting the use of ozone therapy in the topical treatment of chronic wounds. Primary outcome data included the extent of chronic wound healing, and secondary outcomes included adverse effects. Studies were assessed for level of bias and data quality. Nine studies (n = 453 patients) matched the inclusion criteria and underwent meta‐analysis. Overall, there was a significant improvement in wound closure with ozone therapy. Results consistently favour the application of ozone as a treatment for chronic wounds; however, there is no conclusive evidence of ozone therapy as superior compared with standard treatments. Compared with standard care, ozone therapy as an advanced wound care treatment may improve the proportion of chronic wounds healed in a shorter amount of time, but further research is required.     

Examining the effects of HIV self‐testing compared to standard HIV testing services: a systematic review and meta‐analysis

Introduction : HIV self‐testing (HIVST) is a discreet and convenient way to reach people with HIV who do not know their status, including many who may not otherwise test. To inform World Health Organization (WHO) guidance, we assessed the effect of HIVST on uptake and frequency of testing, as well as identification of HIV‐positive persons, linkage to care, social harm, and risk behaviour. Methods : We systematically searched for studies comparing HIVST to standard HIV testing until 1 June 2016. Meta‐analyses of studies reporting comparable outcomes were conducted using a random‐effects model for relative risks (RR) and 95% confidence intervals. The quality of evidence was evaluated using GRADE. Results : After screening 638 citations, we identified five randomized controlled trials (RCTs) comparing HIVST to standard HIV testing services among 4,145 total participants from four countries. All offered free oral‐fluid rapid tests for HIVST and were among men. Meta‐analysis of three RCTs showed HIVST doubled uptake of testing among men (RR = 2.12; 95% CI: 1.51, 2.98). Meta‐analysis of two RCTs among men who have sex with men showed frequency of testing nearly doubled (Rate ratio = 1.88; 95% CI: 1.17; 3.01), resulting in two more tests in a 12–15‐month period (Mean difference = 2.13; 95% CI: 1.59, 2.66). Meta‐analysis of two RCTs showed HIVST also doubled the likelihood of an HIV‐positive diagnosis (RR = 2.02; 95% CI: 0.37, 10.76, 5.32). Across all RCTs, there was no indication of harm attributable to HIVST and potential increases in risk‐taking behaviour appeared to be minimal. Conclusions : HIVST is associated with increased uptake and frequency of testing in RCTs. Such increases, particularly among those at risk who may not otherwise test, will likely identify more HIV‐positive individuals as compared to standard testing services alone. However, further research on how to support linkage to confirmatory testing, prevention, treatment and care services is needed. WHO now recommends HIVST as an additional HIV testing approach.     

Ethical issues in surgical research

Higher standards of evidence for surgical procedures are likely to be demanded in the future by health insurance providers. Consequently, more formal and rigorous surgical research, including RCTs, will become more prevalent. Facing the ethical challenges of surgical research requires understanding of the ethically significant differences between surgical practice and research and the ways in which the ethical standards appropriate for the design and conduct of clinical research differ from the ethics of clinical care.     

Improving venous ulcer healing: designing and reporting randomised controlled trials

The randomised controlled trial (RCT) is often considered the gold standard for judging the benefits of treatments. The application of randomised controlled clinical trials to treatments of venous ulcer healing has lagged behind that of other areas of medicine. To interpret the results of an RCT, readers must understand a variety of aspects of their design, analysis and interpretation. Venous ulcer disease has a high prevalence and has a significant socioeconomic impact in most parts of the world. The management of venous ulcers causes a considerable strain on the health system and is likely to worsen in future. The multi‐layer high compression system is described as the current gold standard for treating venous ulcers. A recent meta‐analysis of bandaging systems found that multi‐layer compression bandages appeared to be superior to single‐layer bandages in promoting venous ulcer healing. However, it was noted that many of the studies had small sample sizes and the quality of research in the area was poor. The consolidating standards of reporting trials (CONSORT) statement can help clinicians to discern high‐quality studies from ones of poorer quality. This paper discusses how CONSORT can help clinicians and researchers to design and report quality studies to contribute to evidence‐based venous ulcer healing.     

Systematic review of randomized controlled trial quality in pediatric kidney transplantation

Limited pediatric-specific research can lead to sub-standard evidence for clinical decision making in children. We sought to systematically evaluate the methodological quality and the reporting standards of randomized controlled trials (RCTs) of transplantation trials in children. We included RCTs of kidney transplant recipients that had enrolled at least one child (aged 17 years or less) and that were reported in English language, peer reviewed journals from 2000 onward in the Cochrane Renal Group’s specialized register. Trial reports were assessed against the 22 item checklist of the CONsolidated Standards Of Reporting Trials (CONSORT) statement. Twenty-seven RCTs were included. The reporting of the essential components of the methods, results and discussion domains was unsatisfactory. Mean CONSORT criteria score for the pediatric trials was 67% and 66% for trials including both adults and children (p value for the difference = 1.00). Trial reporting quality in pediatric transplantation trials is not different from trials involving adults. It is evident that the reporting standards of RCTs in both adult and pediatric transplantation require major improvements. This work bench-marks current standards for future quality improvement.     

External validity of randomized controlled trials of interventions in venous leg ulceration: A systematic review

We set out to evaluate quality of reporting of data related to external validity from randomized controlled trials (RCTs) assessing treatment interventions for active venous leg ulcers. Using a systematic review study design, we identified 144 full‐text RCTs of treatment interventions, where the wound was assessed and published in English from 1998 to 2018. We found that the median study sample size was 75.5. Weighted mean wound size was 13.22 cm² and weighted mean wound duration was 22.20 months. Forty‐six (32%) reported numbers screened for eligibility and 27 (19%) reported the number who declined to participate; 19 (13%) reported on patient ethnicity; 60 (42%) reported comorbidities; and 5 (4%) reported current medication use. When reported, 60/102 (59%) excluded patients with an ankle‐brachial pressure index <0.8; 68/135 (50%) were conducted in Europe, 6/135 (4%) in Asia, and 74/104 (71%) were conducted in outpatient facilities; 3 (2%) reported socioeconomic factors and 88 (61%) reported on adverse events. We concluded that there is inadequate reporting of data related to external validity in reports of RCTs assessing venous leg ulcers treatment interventions. Significant variability exists in the ankle‐brachial pressure index cutoff point for inclusion or exclusion, making generalizability difficult to assess.     

Deficiencies in reporting inclusion/exclusion criteria and characteristics of patients in randomized controlled trials of therapeutic interventions in pressure injuries: a systematic methodological review

Wound care is a complex procedure and the related research may include many variables. Deficiencies in the sample inclusion and exclusion criteria may limit the generalizability of randomized controlled trials (RCTs) for wound patients in the real world. This study aimed to evaluate deficiencies in reporting the inclusion and exclusion criteria and the characteristics of patients in RCTs of pressure injuries (PI) therapeutic interventions. We conducted a systematic methodological review in which 40 full text RCTs of PI treatment interventions published in English, from 2008 to 2020, were identified. Data on the general characteristics of the included RCTs and data about inclusion/exclusion criteria and characteristics of patients were collected. The inclusion/exclusion criteria were categorized into five domains (definition of disease, precision, safety, ethical/legal and administrative). Study duration (in weeks) was 8.0 (quartile 1: 2.0; quartile 3: 48.0); only 5.0% of the trials mentioned race, skin colour or ethnicity, and 37.5% reported the duration of the wound. Only 9 (22.5%) studies reported the drugs that the included patients were using and 10 (25.0%) RCTs reported adverse events. The presence of the five domains was observed only in 12.5% of RCTs and only 12 (30.0%) had the precision domain. Much more research is required in systematic assessments of the external validity of trials because there is substantial disparity between the information that is provided by RCTs and the information that is required by clinicians. We concluded that there are deficiencies in reporting of data related to inclusion/exclusion criteria and characteristics of patients of RCTs assessing PI therapeutic interventions.     

Chronic venous leg ulcer treatment: Future research needs

The prevalence and costs of chronic venous ulcer care in the US are increasing. The Johns Hopkins University Evidence‐Based Practice Center recently completed a systematic review of the comparative effectiveness of advanced wound dressings, antibiotics, and surgical management of chronic venous ulcers. Of 10,066 citations identified in the literature search, only 66 (0.06%) met our liberal inclusion criteria for providing evidence on the effectiveness of interventions for chronic venous ulcers. Based on review of those studies, members of our team and a panel of informed stakeholders identified important research gaps and methodological deficiencies and prioritized specific future research needs. Based on that review, we provide the results of our assessment of future research needs for chronic venous ulcer care. Advanced wound dressings were considered to have the highest priority for future research, followed by venous surgery and antibiotics. An imperative from our assessment is that future research evaluating interventions for chronic venous ulcers meet quality standards. In a time of increasing cost pressure, the wound care community needs to develop high‐quality evidence to justify the use of present and future therapeutic modalities.     

Wound care evidence,knowledge and education amongst nurses: a semi‐systematic literature review

The aims of this study were to determine the knowledge and skills of nurses involved in wound care, to provide a critical overview of the current evidence base underpinning wound care and to determine the extent of utilisation of existing evidence by nurses involved in the management of wounds in practice. A semi‐systematic review of the literature was undertaken on Cinahl, Medline Science Direct and Cochrane using the search terms: wound, tissue viability, education, nurse, with limitations set for dates between 2009 and 2017 and English language. Shortfalls were found in the evidence base underpinning wound care and in links between evidence and practice, prevalence of ritualistic practice and in structured education at pre‐ and post‐registration levels. The evidence underpinning wound care practice should be further developed, including the conduction of independent studies and research of qualitative design to obtain rich data on both patient and clinician experiences of all aspects of wound management. More structured wound care education programmes, both at pre‐registration/undergraduate and professional development levels, should be established.     

Quality of life and symptom assessment in randomized clinical trials of bladder cancer: A systematic review

ObjectivesPatient-reported outcomes (PRO) help patients, caretakers, clinicians, and policy makers make informed decisions regarding treatment effectiveness. Our objective was to assess the quality of PRO reporting and methodological strengths and weaknesses in randomized controlled trials (RCT) in bladder cancer.MethodsA systematic literature search of bladder cancer RCT published between January 2004 and March 2014 was performed. Relevant studies were evaluated using a predetermined extraction form that included trial demographics, clinical and PRO characteristics, and standards of PRO reporting based on recommendations of the International Society for Quality of Life Research.ResultsIn total, 9 RCTs enrolling 1,237 patients were evaluated. All studies were in patients with nonmetastatic disease. In 5 RCTs, a PRO was the primary end point. Most RCTs did not report the mode of administration of the PRO instrument or the methods of collecting data. No RCT addressed the statistical approaches for missing data.ConclusionsWe found that few RCTs in bladder cancer report PRO as an outcome. Efforts to expand PRO reporting to more RCTs and improve the quality of PRO reporting according to recognized standards are necessary for facilitating clinical decision making.     

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient‐centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient‐centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature‐based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty‐two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.     

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40 , 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51 , 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.     

Orthopaedic trial networks

Randomized controlled trials (RCTs) are considered the most robust design for evaluating health care interventions. However, it is difficult to acquire funding for RCTs, and they are complex to set up. Threats to their successful conduct and impact on clinical practice, particularly in surgical trials, include problems with recruitment, notably in terms of clinical equipoise and patient acceptability. Historically, RCTs are less common in surgical specialties, and their contribution to the orthopaedic literature remains small. Orthopaedic networks, such as orthopaedic associations, specialist societies, travel fellowships, and clinical research networks, provide an opportunity to meet the challenges of promoting RCTs in orthopaedic clinical practice. This can include identifying important research questions to help prioritize funding; educating and training surgeons in the design and practice of RCTs; helping to promote and coordinate RCTs; and disseminating the findings of RCTs. Orthopaedic trial networks should be encouraged to promote a research culture in which RCTs are feasible and to ensure that scarce resources utilized to support their funding are used most efficiently and to best effect. In particular, the use of networks is encouraged to support the conduct of RCTs in achieving patient recruitment, which is crucial in providing the evidence base to inform orthopaedic practice. Furthermore, to improve generalizability, acceptance of study findings and communication between orthopaedic surgeons, as well as international collaboration in trials, should be part of the strategy for the future.     

Remote assessment of diabetic foot ulcers using a novel wound imaging system

Telemedicine allows experts to assess patients in remote locations, enabling quality convenient, cost‐effective care. To help assess foot wounds remotely, we investigated the reliability of a novel optical imaging system employing a three‐dimensional camera and disposable optical marker. We first examined inter‐ and intraoperator measurement variability (correlation coefficient) of five clinicians examining three different wounds. Then, to assess of the system's ability to identify key clinically relevant features, we had two clinicians evaluate 20 different wounds at two centers, recording observations on a standardized form. Three other clinicians recorded their observations using only the corresponding three‐dimensional images. Using the in‐person assessment as the criterion standard, we assessed concordance of the remote with in‐person assessments. Measurement variation of area was 3.3% for intraoperator and 11.9% for interoperator; difference in clinician opinion about wound boundary location was significant. Overall agreement for remote vs. in‐person assessments was good, but was lowest on the subjective clinical assessments, e.g., value of debridement to improve healing. Limitations of imaging included inability to show certain characteristics, e.g., moistness or exudation. Clinicians gave positive feedback on visual fidelity. This pilot study showed that a clinician viewing only the three‐dimensional images could accurately measure and assess a diabetic foot wound remotely.     

The framing of research questions using the PICOT format in randomized controlled trials of venous ulcer disease is suboptimal: A systematic survey

Despite several publications on venous ulcers, there is still a lack of evidence from randomized controlled trials (RCTs) to support certain treatments for patients with this disorder. Well‐designed research questions using the PICOT (Population; Intervention; Comparator; Outcome; Time‐frame) format in RCTs can improve the quality of research. The objectives of this study were to assess how the PICOT format is used to frame research questions in RCTs published on venous ulcer disease and to determine the factors associated with better adherence to the PICOT format. We conducted a systematic survey of RCTs on venous ulcers published in the PubMed database between January 2009 and May 2016. All RCTs published in English addressing therapeutic interventions for venous ulcer disease in human subjects were included. We examined whether the five elements of the PICOT format were used in formulating the research question and scored them between 0 and 5. The primary outcome of this systematic survey was the percentage of studies that adequately reported all five PICOT elements. Eighty‐five (85) RCTs were included with median PICOT score of 3 (IQR = 1.5). Four elements of PICOT were present in 28 reports (32.9%) and only 2 RCTS (2.3%) reported all the PICOT elements. Population and intervention were often appropriately described, in (70/85) 82.4% and (83/85) 97.6% of the studies, respectively; however, comparison intervention and outcome were presented in only (53/85) 62.3% and (48/85) 56.5% of studies, respectively. Very few RCTs (7.1%; 6/85) reported the study time frame. No journal or RCT characteristics were found to be significantly associated with better reporting. Use of the PICOT format to frame research questions in RCTs published on venous ulcers is suboptimal, and our study reinforces the importance of framing a good research question to improve the design of trials and quality of evidence in venous ulcer disease.     

Effectiveness of an acellular synthetic matrix in the treatment of hard‐to‐heal leg ulcers

Hard‐to‐heal leg ulcers are a major cause of morbidity in the elderly population. Despite improvements in wound care, some wounds will not heal and they present a significant challenge for patients and health care providers. A multi‐centre cohort study was conducted to evaluate the effectiveness and safety of a synthetic, extracellular matrix protein as an adjunct to standard care in the treatment of hard‐to‐heal venous or mixed leg ulcers. Primary effectiveness criteria were (i) reduction in wound size evaluated by percentage change in wound area and (ii) healing assessed by number of patients healed by end of the 12 week study. Pain reduction was assessed as a secondary effectiveness criteria using VAS. A total of 45 patients completed the study and no difference was observed between cohorts for treatment frequency. Healing was achieved in 35·6% and wound size decreased in 93·3% of patients. Median wound area percentage reduction was 70·8%. Over 50% of patients reported pain on first visit and 87·0% of these reported no pain at the end of the study. Median time to first reporting of no pain was 14 days after treatment initiation. The authors consider the extracellular synthetic matrix protein an effective and safe adjunct to standard care in the treatment of hard‐to‐heal leg ulcers.     

Harnessing electronic healthcare data for wound care research: Wound registry analytic guidelines for less‐biased analyses

Publications based on large healthcare databases that contain data pertaining to wound‐related outcomes are starting to appear more frequently. However, concern exists in regard to study design adequacy, the methodology used to minimize misclassifications, bias, and confounding, and lack of full reporting. The STROBE guidelines were published to encourage fuller reporting of observational studies and have now been extended using the RECORD statement to better document routinely collected healthcare data. In this paper, elements of the RECORD statement have been used to create guidelines for study design, cohort matching, reporting criteria, and analysis frameworks in regard to analyses of populations involving comparative effectiveness research. It is recommended that researchers present full data analysis with minimal inclusion and exclusion criteria and preplanned subgroups analyses rather than attempt to emulate randomized controlled trials, as patterns of product administration are likely to be vastly different to those using controlled trials; moreover, missing data are very common. Suggestions for creating better matched cohorts, classification of wound‐ and patient‐related variables, and a rationale for reporting at a minimum a particular set of benchmarks to better characterize wound care populations is also presented. Adherence to these guidelines would improve the credibility of studies and make comparisons between studies much easier. Finally, an adaptation of the Cochrane risk of bias tool is presented in connection with the proposed guidelines for systematic reviewers to assess these kinds of retrospective studies.