Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

'Teenagers are into perfect-looking things': Dating, sexual attitudes and experiences of adolescents with severe obesity.

BACKGROUND: This qualitative study explored the dating and sexual health attitudes and behaviours among adolescents with severe obesity (body mass index [BMI] > 99th%) attending a multidisciplinary weight-management programme. METHODS: Semi-structured interviews were conducted with 19 participants (12 females, 7 males; Mage = 16.8) and analysed through reflective thematic analysis. RESULTS: Participants described polarized dating behaviours in which dating and sexual relationships were either avoided due to this not being a priority, lack of time, feared rejection, and/or body size as perceived barrier or in contrast, when approached, involved greater sexual risk. CONCLUSIONS: These findings have numerous implications including the need for increased education on the romantic developmental challenges faced by adolescents with severe obesity, the importance of ongoing screening of high-risk sexual behaviours and body dissatisfaction from frontline care providers, and the ability to support referrals to psychosocial services when appropriate.

The multiplicity of caregiving burden: a qualitative analysis of families with prolonged disorders of consciousness.

Objective: To understand the multiple and sometimes conflicting roles substitute decision makers (SDMs) of individuals in a vegetative state (VS), minimally conscious state (MCS), or with locked-in syndrome (LIS) perform while caring for a loved one and the competing priorities derived from these roles.Methods: We conducted semi-structured qualitative interviews using a constructive-grounded theory design. Twelve SDMs, who were also family members for 11 patients, were interviewed at two time points (except one) for a total of 21 in-depth interviews.Results: Participants described that caregiving is often the central role which they identify as their top priority and around which they coordinate and to some extent subordinate their other roles. In addition to caregiving, they participated in a wide variety of roles, which were sometimes in conflict, as they became caregivers for a loved one with chronic and complex needs. SDMs described the caregiver role as complex and intense that lead to physical, emotional, social, and economic burdens.Conclusion: SDMs report high levels of burdens in caring for a person with a prolonged disorder of consciousness. Lack of health system support that recognized the broader context of SDMs lives, including their multiple competing priorities, was a major contributing factor.

Experiences of family of individuals in a locked in, minimally conscious state, or vegetative state with the health care system.

Primary Objective: To understand the experiences of family members of individuals in a locked-in state (LIS), minimally conscious state (MCS), or vegetative state (VS) with the health-care system when caring for their family member.Research Design: The study adopted a qualitative descriptive approach drawing on central tenets of constructivist grounded theory described by Charmaz. Our analysis drew on emphasizing connections between theory, concepts, and empirical data using a constant comparative method.Methods and Procedures: Semi-structured interviews were conducted with family members of individuals in a LIS, MCS, or VS. Participants were recruited between June 2014 and December 2016.Main Outcomes and Results: 22 interviews were conducted, which comprised interviews with 12 family members. The following themes were identified: care coordination challenges, lack of flexibility in health-care policies, and inappropriate care settings.Conclusions: Family members of individuals in a LIS, MCS, or VS described playing a significant role in the lives of their family member. Based on the results of this study, flexibility in health-care policies and/or programming should be adopted in the face of the challenges identified. Implementation of interventions to support caregivers and transitions is increasingly important.

A qualitative study of patient education needs for hip and knee replacement.

BACKGROUND: Quality health information is key to patient engagement, self-management and an enhanced healthcare experience. There is strong evidence to support involving patients and their families in the development and evaluation of health-related educational material. These factors were the impetus for our high volume joint replacement centre to undertake a qualitative study to elicit patient experiences to inform the development of effective strategies and education along the care continuum for hip and knee replacement. METHODS: Purposively selected patients from postoperative follow-up clinics were recruited to participate in a focus group or telephone interview. We developed a semi-structured interview guide that addressed four specific aspects of the patient's experience with educational material: pre-surgery, hospital stay, recovery period and future recommendations. The focus groups and interviews continued to the point of saturation and were audio-recorded and transcribed verbatim. Interview transcripts were coded and then inductively organized into larger categories using thematic analysis. RESULTS: Six focus groups and seven telephone interviews were conducted, totalling 32 participants. One of the key themes that emerged was a need for more education concerning pain management post-operatively; specifically, patients wanted more information on expected levels of pain, pain medication usage, management of side effects and guidelines for weaning off the medication. There was surprising variability in patients' descriptions of their pre-surgery, surgery and recovery experiences. These corresponded to an equally diverse range of preferences for educational content, delivery and timing. Many patients reported using the web while others preferred traditional formats for information delivery. There was some interest in receiving education using mobile technology. CONCLUSIONS: Our findings validate the importance of multi-modal patient education tailored to individual preferences and experiences, which may differ according to such characteristics as gender and age. The gap in pain management information is a critical finding for healthcare providers working with patients undergoing joint replacement. Developing pain management education in different formats that addresses frequently asked questions will enhance patient engagement and, their overall experience and recovery.

Building Bridges to Integrate Care (BRIDGES): Incubating Health Service Innovation across the Continuum of Care for Patients with Multiple Chronic Conditions.

Integrating care for people with complex needs is challenging. Indeed, evidence of solutions is mixed, and therefore, well-designed, shared evaluation approaches are needed to create cumulative learning. The Toronto-based Building Bridges to Integrate Care (BRIDGES) collaborative provided resources to refine and test nine new models linking primary, hospital and community care. It used mixed methods, a cross-project meta-evaluation and shared outcome measures. Given the range of skills required to develop effective interventions, a novel incubator was used to test and spread opportunities for system integration that included operational expertise and support for evaluation and process improvement.

Cholesterol screening in US adults and awareness of high cholesterol among individuals with severe hypertriglyceridemia: National Health and Nutrition Examination Surveys 2001-2008.

BACKGROUND: Cholesterol screening is an effective method for identifying individuals with elevated triglyceride levels. Individuals with severe hypertriglyceridemia (SHTG; ≥500 mg/dL) have a substantially higher risk for developing coronary heart disease and acute pancreatitis than individuals with lower triglyceride levels. OBJECTIVE: The aims of this study were to estimate the proportion of US adults who reported having their cholesterol checked, to evaluate the characteristics associated with having cholesterol checked, and to assess factors that are associated with awareness of having high cholesterol among adults with SHTG. METHODS: The sample included 7988 adults who participated in the National Health and Nutrition Examination Surveys 2001-2008. Polytomous logistic regression models were used to identify factors that were associated with time since the last cholesterol screening, categorized as never screened, screened less than 2 years ago, and screened 2 or more years ago. RESULTS: Approximately 71% of the US adults reported ever having their cholesterol checked. Only 56% of the individuals with SHTG were aware of having high cholesterol. Factors associated with awareness of high cholesterol among those with SHTG included obesity, education, having insurance, having diabetes, and having a history of cardiovascular events. CONCLUSIONS: Most adults in the United States have had their cholesterol checked; however, only half of those with SHTG were aware of having high cholesterol. Awareness is the first step in implementing strategies to attenuate the health risks associated with dyslipidemia.

Longitudinal changes in high-density lipoprotein cholesterol and cardiovascular events in older adults.

OBJECTIVE: While low high-density lipoprotein cholesterol (HDL-C) is associated with increased risk of cardiovascular (CV) events, there are limited data evaluating the association of longitudinal change in HDL-C with CV event risk in older populations. The aim of this study was to examine the association between within-subject changes in HDL-C levels and CV events in an older population. DESIGN: Observational cohort study. PATIENTS: 1293 men and 1422 women age ≥50 years, with ≥2 consecutive HDL measurements, and no prior CVD as part of Framingham Offspring Study. MEASUREMENTS: A clinical CV event was defined as the first occurrence of any of the following: coronary heart disease (coronary death, myocardial infarction, coronary insufficiency and angina), cerebrovascular event, peripheral artery disease or heart failure. RESULTS: Median total follow-up time across subjects was 9·6 years. Change in HDL-C was evaluated as between-exam (approximately 3·5 years) percentage change in HDL-C, categorized as ≥10% decrease, <10% change (stable) and ≥10% increase. Crude and adjusted sex-specific Cox hazards regression models with change in HDL-C as a time-dependent covariate quantified the association with CV events. Mean baseline age of the analysis sample was 53 years. There were 233 and 111 CV events among men and women, respectively. Change in HDL-C was not significantly associated with CVD incidence in men or women, without or with adjustment for confounders including baseline HDL-C or use of relevant medications. CONCLUSION: In conclusion, relatively short-term (3·5 years) changes in HDL-C levels do not affect CV events in men and women.

Front-line ownership: generating a cure mindset for patient safety.

Great advances have been made in standardization and human factors engineering that have reduced variability and increased reliability in healthcare. As important as these advances are, the authors believe there is another important but largely ignored layer to the safety story in healthcare that has prevented us from progressing. In the field of infection prevention and control (IPAC), despite great attempts over several decades to improve compliance with hand hygiene, surveillance, environmental cleaning, isolation protocols and other control measures, very significant challenges remain. We believe this failure is in part due to the power gradients, often dysfunctional relationships and lack of safety mindfulness that exist in hospitals and healthcare more generally. Furthermore, safety culture requires different approaches and considerable ongoing attentiveness. If this is the case, and the authors contend in this paper that it is, then the role of the front line is much more important than many of our healthcare safety and IPAC approaches suggest.

Noninterventional studies in the COVID-19 era: methodological considerations for study design and analysis.

The global COVID-19 pandemic has generated enormous morbidity and mortality, as well as large health system disruptions including changes in use of prescription medications, outpatient encounters, emergency department admissions, and hospitalizations. These pandemic-related disruptions are reflected in real-world data derived from electronic medical records, administrative claims, disease or medication registries, and mobile devices. We discuss how pandemic-related disruptions in healthcare utilization may impact the conduct of noninterventional studies designed to characterize the utilization and estimate the effects of medical interventions on health-related outcomes. Using hypothetical studies, we highlight consequences that the pandemic may have on study design elements including participant selection and ascertainment of exposures, outcomes, and covariates. We discuss the implications of these pandemic-related disruptions on possible threats to external validity (participant selection) and internal validity (for example, confounding, selection bias, missing data bias). These concerns may be amplified in populations disproportionately impacted by COVID-19, such as racial/ethnic minorities, rural residents, or people experiencing poverty. We propose a general framework for researchers to carefully consider during the design and analysis of noninterventional studies that use real-world data from the COVID-19 era.

Real-world evidence for regulatory decision-making: updated guidance from around the world.

Leveraging the value of real-world evidence (RWE) to make informed regulatory decisions in the field of health care continues to gain momentum. Improving clinical evidence generation by evaluating the outcomes and patient experiences at the point-of-care would help achieve the ultimate aim of ensuring that effective and safe treatments are rapidly approved for patient use. In our previous publication, we assessed the global regulatory landscape with respect to RWE and provided a review of the regional availability of frameworks and guidance through May 2021 on the basis of 3 key regulatory elements: regulatory RWE frameworks, data quality guidance, and study methods guidance. In the current review, we have updated and elaborated upon recent developments in the regulatory RWE environment from a regional perspective under the same 3 regulatory elements stated above. In addition, we have also included a new category on procedural guidance. The review also discusses the perceived gaps and potential opportunities for future development and harmonization in this field to support framework establishment in regions without pre-existing RWE policies. Additionally, the article reviews current developments of health technology assessment (HTA) bodies pertaining to RWE and discusses the status of evidentiary alignment among regulators and HTA agencies.

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction.

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.

A Framework for Extension Studies Using Real-World Data to Examine Long-Term Safety and Effectiveness.

Understanding the long-term benefits and risks of treatments, devices, and vaccines is critically important for individual- and population-level healthcare decision-making. Extension studies, or 'roll-over studies,' are studies that allow for patients participating in a parent clinical trial to 'roll-over' into a subsequent related study to continue to observe and measure long-term safety, tolerability, and/or effectiveness. These designs are not new and are often used as an approach to satisfy regulatory post-approval safety requirements. However, designs using traditional clinical trial infrastructure can be expensive and burdensome to conduct, particularly, when following patients for many years post trial completion. Given the increasing availability and access of real-world data (RWD) sources, direct-to-patient technologies, and novel real-world study designs, there are more cost-efficient approaches to conducting extension studies while assessing important long-term outcomes. Here, we describe various fit-for-purpose design options for extension studies, discuss related methodological considerations, and provide scientific and operational guidance on practices when planning to conduct an extension study using RWD. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Real-World Evidence for Regulatory Decision-Making: Guidance From Around the World.

PURPOSE: Interest in leveraging real-world evidence (RWE) to support regulatory decision making for product effectiveness has been increasing globally as evident by the increasing number of regulatory frameworks and guidance documents. However, acceptance of RWE, especially before marketing for regulatory approval, differs across countries. In addition, guidance on the design and conduct of innovative clinical trials, such as randomized controlled registry studies, pragmatic trials, and other hybrid studies, is lacking. METHODS: We assessed the global regulatory environment with regard to RWE based on regional availability of the following 3 key regulatory elements: (1) RWE regulatory framework, (2) data quality and standards guidance. and (3) study methods guidance. FINDINGS: This article reviews the available frameworks and existing guidance from across the globe and discusses the observed gaps and opportunities for further development and harmonization. IMPLICATIONS: Cross-country collaborations are encouraged to further shape and align RWE policies and help establish frameworks in countries without current policies with the goal of creating efficiencies when considering RWE to support regulatory decision-making globally.

Real-world Overall Survival Using Oncology Electronic Health Record Data: Friends of Cancer Research Pilot.

In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real-world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real-world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE-189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD-1) in combination with platinum doublet chemotherapy (PD-1 combination) in first-line nonsquamous metastatic non-small cell lung cancer guided retrospective cohort selection. The Kaplan-Meier product limit estimator was used to calculate 12-month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD-1 combination cohort. Twelve-month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD-1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real-world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set-specific factors that drive results.

The Friends of Cancer Research Real-World Data Collaboration Pilot 2.0: Methodological Recommendations from Oncology Case Studies.

The purpose of this study was to evaluate the potential collective opportunities and challenges of transforming real-world data (RWD) to real-world evidence for clinical effectiveness by focusing on aligning analytic definitions of oncology end points. Patients treated with a qualifying therapy for advanced non-small cell lung cancer in the frontline setting meeting broad eligibility criteria were included to reflect the real-world population. Although a trend toward improved outcomes in patients receiving PD-(L)1 therapy over standard chemotherapy was observed in RWD analyses, the magnitude and consistency of treatment effect was more heterogeneous than previously observed in controlled clinical trials. The study design and analysis process highlighted the identification of pertinent methodological issues and potential innovative approaches that could inform the development of high-quality RWD studies.

Managing work disability to help patients return to the job.

Improving the timeliness and quality of your guidance on work disability lessens the impact of health problems on patients' lives and livelihoods.

"I don't want them to think that what they said matters": How treatment - seeking adolescents with severe obesity cope with weight-based victimization.

Adolescents with severe obesity are subject to a high prevalence of weight-based victimization that may lead to pervasive mental health symptoms. However, different coping strategies could potentially modulate these psychological consequences. This study aims to explore how treatment-seeking adolescents with severe obesity cope with weight-based victimization. This was a qualitative research study using an interpretive phenomenological analytic approach. One-on-one semi structured interviews were completed with 19 adolescents (63% female) enrolled in a weight management program. The interviews were transcribed and sequentially analysed until data saturation was attained. The majority of participants (89.5%) described being a victim of weight-based victimization and highlighted a significant emotional toll. Two key themes were identified that captured the various coping strategies used by participants. Over half (52.9%) described approach coping strategies where they acted on the source to invoke change by standing up for themselves, helping others in similar situations or becoming a bully themselves. Whilst the majority (94.1%) used avoidant coping strategies such as feigning a strong exterior façade, denial, isolation and self-harm. Nearly half (47.1%) used both strategies. Treatment-seeking adolescents with severe obesity commonly use avoidant coping strategies to deal with weight-based victimization. These strategies are associated with negative mental health outcomes and should be evaluated when counselling adolescents with obesity who have experienced weight-based victimization.

Comparing Findings From a Friends of Cancer Research Exploratory Analysis of Real-World End Points With the Cancer Analysis System in England.

PURPOSE: This study compared real-world end points extracted from the Cancer Analysis System (CAS), a national cancer registry with linkage to national mortality and other health care databases in England, with those from diverse US oncology data sources, including electronic health care records, insurance claims, unstructured medical charts, or a combination, that participated in the Friends of Cancer Research Real-World Evidence Pilot Project 1.0. Consistency between data sets and between real-world overall survival (rwOS) was assessed in patients with immunotherapy-treated advanced non-small-cell lung cancer (aNSCLC). PATIENTS AND METHODS: Patients with aNSCLC, diagnosed between January 2013 and December 2017, who initiated treatment with approved programmed death ligand-1 (PD-[L]1) inhibitors until March 2018 were included. Real-world end points, including rwOS and real-world time to treatment discontinuation (rwTTD), were assessed using Kaplan-Meier analysis. A synthetic data set, Simulacrum, on the basis of conditional random sampling of the CAS data was used to develop and refine analysis scripts while protecting patient privacy. RESULTS: Characteristics (age, sex, and histology) of the 2,035 patients with immunotherapy-treated aNSCLC included in the CAS study were broadly comparable with US data sets. In CAS, a higher proportion (46.7%) of patients received a PD-(L)1 inhibitor in the first line than in US data sets (18%-30%). Median rwOS (11.4 months; 95% CI, 10.4 to 12.7) and rwTTD (4.9 months; 95% CI, 4.7 to 5.1) were within the range of US-based data sets (rwOS, 8.6-13.5 months; rwTTD, 3.2-7.0 months). CONCLUSION: The CAS findings were consistent with those from US-based oncology data sets. Such consistency is important for regulatory decision making. Differences observed between data sets may be explained by variation in health care settings, such as the timing of PD-(L)1 approval and reimbursement, and data capture.

Composite playground safety measure to correlate the rate of supracondylar humerus fractures with safety: an ecologic study.

BACKGROUND: More than 200,000 children are injured at playgrounds in the United States each year. Our goal was to introduce a composite measure of playground safety and use this instrument to correlate the incidence of supracondylar humerus fractures with playground safety in an ecologic study design. METHODS: We used a novel "overall-safety rating," defined as a composite of 3 previously validated instruments (National Program for Playground Safety School score, surface depth compliance, and the use zone compliance) to measure the overall safety of all playgrounds within a region. The regions were rated from most to least safe based on average playground safety as measured by this new method. The incidence of supracondylar fractures was calculated using Hasbro Children's Hospital Emergency Department data and state of Rhode Island Census data from 1998 to 2006. The incidence was then correlated with playground safety as defined by our composite measure. RESULTS: Compared with the neighborhood deemed the safest, the least safe district had 4.7 times greater odds of supracondylar humerus fracture. Overall composite safety score of the district was linearly correlated with the injury rate observed in the population at risk (R=0.98; P=0.04). CONCLUSIONS: Using our novel composite playground safety score, we found that the incidence of supracondylar humerus fractures was increased in districts with playgrounds with lower scores, suggesting that improvements in playground infrastructure may potentially reduce the incidence of supracondylar humerus fractures, and other injuries, in children. LEVEL OF EVIDENCE: Level IV.