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.

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.

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.

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.

'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 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.

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.

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).

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.

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.

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.

Safely Returning America to Work: Part I: General Guidance for Employers.

: Businesses are struggling to re-open as the world continues to deal with the coronavirus 2019 (COVID-19) pandemic. The reopening of businesses will require employers to implement safe return-to-work strategies through evaluation, testing, work modifications, and development of appropriate workplace policies. There will be unique challenges along the way as no one approach will be ideal for all workplaces and industries. This document is intended to provide return-to-work guidance for both employers and the occupational and environmental medicine physicians who will be supporting businesses in implementing safe return-to-work strategies.

When Context Is Hard to Come By: External Comparators and How to Use Them.

External comparators, also referred to as historical or synthetic controls, present transformational opportunities for broad context and insights alongside clinical research results. The recent confluence of access to quality real-world data (RWD), advanced epidemiologic methods, and legislative directives to regulators for expanded use of RWD is increasing interest in real-world external comparators, opening the door to achieve broader generalizability and learn more, faster. In this less standardized area of research, tailored scientific methodology must be applied for external comparators to accomplish clinical development objectives. Here, we describe methodological considerations for design and illustrate how RWD comparators have been used for regulatory and reimbursement decisions.

Masking in Pragmatic Trials: Who, What, and When to Blind.

Masking (or blinding) of treatment assignment is routinely implemented in classical randomized clinical trials (RCTs) to isolate the effect of the intervention itself and to minimize the potential for bias that could occur with traditional trials. Such biases could be introduced with the conduct, assessment of endpoints, management of conditions, analysis, and reporting when the treatment assignments are known. However, masking of treatments is not only complex but it hinders how generalizable the findings are to the "real world" clinical setting. Pragmatic RCTs (pRCTs) are intended to evaluate the effects of interventions within routine medical care, and as such, do not typically mask treatment groups; moreover, pRCTs assess comparators that are available in routine medical practice, not masked placebos. Whether pRCTs should be masked if intended for regulatory or other purposes has recently been questioned. The literature on pRCTs, while extensive, does not address how much actual benefit is gained from masking outcomes and how masking may affect the "real world" nature of a study. Here, we propose an approach to evaluate sources of bias, describe stakeholders in the conduct of pRCTs who are most likely affected, and offer a framework for considering how masking may be implemented effectively while maintaining generalizability.

When Context Is Hard to Come By: External Comparators and How to Use Them.

External comparators, also referred to as historical or synthetic controls, present transformational opportunities for broad context and insights alongside clinical research results. The recent confluence of access to quality real-world data (RWD), advanced epidemiologic methods, and legislative directives to regulators for expanded use of RWD is increasing interest in real-world external comparators, opening the door to achieve broader generalizability and learn more, faster. In this less standardized area of research, tailored scientific methodology must be applied for external comparators to accomplish clinical development objectives. Here, we describe methodological considerations for design and illustrate how RWD comparators have been used for regulatory and reimbursement decisions.

An Exploratory Analysis of Real-World End Points for Assessing Outcomes Among Immunotherapy-Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non-small-cell lung cancer. PATIENTS AND METHODS: Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non-small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS: Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post-programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION: These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.