Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review.

PURPOSE: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence. METHODS: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes. RESULTS: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization. CONCLUSIONS: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE.

Overview of global real-world data sources for pediatric pharmacoepidemiologic research.

PURPOSE: Given limited information available on real-world data (RWD) sources with pediatric populations, this study describes features of globally available RWD sources for pediatric pharmacoepidemiologic research. METHODS: An online questionnaire about pediatric RWD sources and their attributes and capabilities was completed by members and affiliates of the International Society for Pharmacoepidemiology and representatives of nominated databases. All responses were verified by database representatives and summarized. RESULTS: Of 93 RWD sources identified, 55 unique pediatric RWD sources were verified, including data from Europe (47%), United States (38%), multiregion (7%), Asia-Pacific (5%), and South America (2%). Most databases had nationwide coverage (82%), contained electronic health/medical records (47%) and/or administrative claims data (42%) and were linkable to other databases (65%). Most (71%) had limited outside access (e.g., by approval or through local collaborators); only 10 (18%) databases were publicly available. Six databases (11%) reported having >20 million pediatric observations. Most (91%) included children of all ages (birth until 18th birthday) and contained outpatient medication data (93%), while half (49%) contained inpatient medication data. Many databases captured vaccine information for children (71%), and one-third had regularly updated data on pediatric height (31%) and weight (33%). Other pediatric data attributes captured include diagnoses and comorbidities (89%), lab results (58%), vital signs (55%), devices (55%), imaging results (42%), narrative patient histories (35%), and genetic/biomarker data (22%). CONCLUSIONS: This study provides an overview with key details about diverse databases that allow researchers to identify fit-for-purpose RWD sources suitable for pediatric pharmacoepidemiologic research.

Long-COVID-19 clinical and health outcomes: an umbrella review.

Background: A growing interest in long-term sequelae of COVID-19 has prompted several systematic literature reviews (SLRs) to evaluate long-COVID-19 effects. However, many of these reviews lack in-depth information on the timing, duration, and severity of these conditions. Objectives: Our aim was to synthesize both qualitative and quantitative evidence on prevalence and outcomes of long-term effect of COVID-19 through an umbrella review. Design: Umbrella review of relevant SLRs on long-COVID-19 in terms of prolonged symptoms and clinical conditions, and comprehensively synthesized the latest existing evidence. Data Sources and Methods: We systematically identified and appraised prior systematic reviews/meta-analyses using MEDLINE, Embase, and Cochrane database of systematic review from 2020 to 2021 following the preferred reporting items for systematic reviews and meta-analyses guidance. We summarized and categorized all relevant clinical symptoms and outcomes in adults with COVID-19 using the Medical Dictionary for Regulatory Activities System Organ Class (MedDRA SOC). Results: We identified 967 systematic reviews/meta-analyses; 36 were retained for final data extraction. The most prevalent SOC were social circumstances (40%), blood and lymphatic system disorders (39%), and metabolism and nutrition disorder (38%). The most frequently reported SOC outcomes within each MedDRA category were poor quality of life (59%), wheezing and dyspnea (19-49%), fatigue (30-64%), chest pain (16%), decreased or loss of appetite (14-17%), abdominal discomfort or digestive disorder (12-18%), arthralgia with or without myalgia (16-24%), paresthesia (27%) and hair loss (14-25%), and hearing loss or tinnitus (15%). Conclusion: This study confirmed a high prevalence of several long COVID-19 outcomes according to the MedDRA categories and indicated that the majority of evidence was rated as moderate to low. Registration: The review was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42022303557).

Epidemiology, Disease Course, and Clinical Outcomes of Perianal Fistulas and Fissures Crohn's Disease: A Nationwide Population-Based Study in Taiwan.

Background: Population-based data on the course of perianal disease in East Asian populations with Crohn's disease (CD) are limited. This study examined the prevalence, clinical course, and compared the outcomes of CD patients with perianal CD (pCD) versus without pCD in Taiwan. Methods: A nationwide population-based study was implemented from 2000 to 2017 by using the Taiwan National Health Insurance Research Database. Results: Of 2424 patients with CD, 358 (14.8%) patients with pCD were identified. Most patients with CD and pCD were men (79.3%). The mean age at CD diagnosis was lower in patients with pCD (33.7 years) than in those without pCD (44.9 years). Approximately half the patients with pCD received the pCD diagnosis at least 6 months before receiving a CD diagnosis. Approximately one-third (121/358) of patients with pCD had recurrent fistula; the median recurrence interval was 239 days. Compared with patients without pCD, patients with pCD had higher mean incidences of hospitalization (7.0 vs 3.8, P < .01), outpatient visits (13 vs 2.9, P < .01), and emergency room visits (10.3 vs 4.4, P < .01) over a 15-year period. Although patients with pCD had higher rates of healthcare utilization, their 15-year mortality rate was lower than that of those without pCD (6.1% vs 17.3%, P < .01). Conclusions: The period prevalence of pCD in Taiwanese patients with CD was 14.8%. Although patients with pCD required more intensive care and had greater healthcare utilization, they did not have inferior survival outcomes compared with those without pCD.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Malignancy rates in Crohn's disease patients with perianal fistula: A German retrospective cohort study.

BACKGROUND: Patients with inflammatory bowel disease are at increased risk of colorectal and extra-intestinal cancer. However, the overall cancer risk in patients with Crohn's disease (CD) with perianal fistulas (PF) (CPF) and those with CD without PF (non-PF CD) is unclear. OBJECTIVE: To describe the prevalence and incidence of cancer in patients with CPF and non-PF CD, and to estimate incidence rate ratio (IRR) of cancer between CPF and non-PF CD groups. METHODS: A retrospective cohort study was conducted using the German InGef (Institute for Applied Health Research Berlin) research database. Patients with a CD record and PF from 1 January 2013 to 31 December 2014 were identified and followed up from 1 January 2015 until the first occurrence of cancer, end of health insurance contributing data, death, or end of study period (31 December 2020). Prevalence of any type of cancer including patients with CD diagnosed with cancer in the selection period and incidence of cancer excluding patients with CD diagnosed with cancer in the selection period were calculated. RESULTS: In total, 10,208 patients with CD were identified. Of 824 patients with CPF (8.1%), 67 had had a malignancy (6-year period crude malignancy prevalence 8.13% [95% confidence interval (CI) 6.36%-10.21%]), which was lower than patients with non-PF CD (19.8% [95% CI 19%-20.6%]). Incidence (per 100,000 person-years) in patients with CPF was 1184 (95% CI 879-1561) and in non-PF CD was 2365 (95% CI 2219-2519). There was no significant difference in the adjusted IRR of cancer for the CPF group compared with the non-PF CD group (0.83 [95% CI 0.62-1.10]; p = 0.219). CONCLUSION: There was no significant difference in the incidence of any cancer in patients with CPF compared with non-PF CD. However, patients with CPF had a higher numerical risk of cancer than the general German population.

Value and Implementation of the Aggregate Safety Assessment Plan.

Aggregate safety assessment involves evaluation of the totality of safety data to characterize the emerging safety profile of a product. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group recently published an approach to developing an Aggregate Safety Assessment Plan (ASAP). Creation of an ASAP facilitates a consistent approach to safety data collection and analysis across studies and minimizes important missing data at the time of regulatory submission. A critical aspect of the ASAP is identification of the Safety Topics of Interest (STOI). The STOI, as defined in the ASAP, comprises adverse events (AEs), which have the potential to impact the benefit: risk profile of a product and typically require specialized data collection or analyses. While there are clear benefits to developing an ASAP for a drug development program, multiple concerns may be encountered with implementation. This article uses the examples of two STOIs to demonstrate the benefits and efficiencies gained with implementation of the ASAP in safety planning as well as in optimally characterizing the emerging safety profile of a product.

A Systematic Review of Epidemiology and Outcomes Associated with Local Surgical and Intersphincteric Ligation Procedures for Complex Cryptoglandular Fistulas.

INTRODUCTION: This systematic literature review (SLR) assessed incidence/prevalence of cryptoglandular fistulas (CCF) and outcomes associated with local surgical and intersphincteric ligation procedures for CCFs. METHODS: Two trained reviewers searched PubMed and Embase for observational studies evaluating the incidence/prevalence of cryptoglandular fistula and clinical outcomes of treatments for CCF after local surgical and intersphincteric ligation procedures for CCF. RESULTS: In total 148 studies met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of those, two assessed incidence/prevalence of cryptoglandular fistulas. Eighteen reported clinical outcomes of surgeries of interest in CCF and were published in the past 5 years. Prevalence was reported as 1.35/10,000 non-Crohn's patients, and 52.6% of non-IBD patients were found to progress from anorectal abscess to fistula over 12 months. Primary healing rates ranged from 57.1% to 100%; recurrence occurred in a range of 4.9-60.7% and failure in 2.8-18.0% of patients. Limited published evidence suggests postoperative fecal incontinence and long-term postoperative pain were rare. Several of the studies were limited by single-center design with small sample sizes and short follow-up durations. DISCUSSION: This SLR summarizes outcomes from specific surgical procedures for the treatment of CCF. Healing rates vary according to procedure and clinical factors. Differences in study design, outcome definition, and length of follow-up prevent direct comparison. Overall, published studies offer a wide range of findings with respect to recurrence. Postsurgical incontinence and long-term postoperative pain were rare in the included studies, but more research is needed to confirm rates of these conditions following CCF treatments. CONCLUSION: Published studies on the epidemiology of CCF are rare and limited. Outcomes of local surgical and intersphincteric ligation procedures show differing success and failure rates, and more research is needed to compare outcomes across various procedures. (PROSPERO; registration number CRD42020177732).

Clinical Presentations of Drug-Induced Hyperprolactinaemia: A Literature Review.

Screening for drug-induced hyperprolactinaemia, a condition characterised by higher-than-normal levels of serum prolactin induced by drug treatments, requires a comprehensive understanding of the clinical presentations and long-term complications of the condition. Using two databases, Embase and MEDLINE, we summarised the available evidence on the clinical presentations and long-term complications of drug-induced hyperprolactinaemia. Clinical and observational studies reporting on drug treatments known or suspected to induce hyperprolactinaemia were included. Database searches were limited to the English language; no date or geographic restrictions were applied. Fifty studies were identified for inclusion, comprising a variety of study designs and patient populations. Most data were reported in patients treated with antipsychotics, but symptoms were also described among patients receiving other drugs, such as prokinetic drugs and antidepressants. Notably, the diagnosis of drug-induced hyperprolactinaemia varied across studies since a standard definition of elevated prolactin levels was not consistently applied. Frequent clinical presentations of hyperprolactinaemia were menstrual cycle bleeding, breast or lactation disorders, and sexual dysfunctions, described in 80% (40/50), 74% (37/50), and 42% (21/50) of the included studies, respectively. In the few studies reporting such symptoms, the prevalence of vaginal dryness impacted up to 53% of females, and infertility in both sexes ranged from 15 to 31%. Clinicians should be aware of these symptoms related to drug-induced hyperprolactinaemia when treating patients with drugs that can alter prolactin levels. Future research should explore the long-term complications of drug-induced hyperprolactinaemia and apply accepted thresholds of elevated prolactin levels (i.e., 20 ng/mL for males and 25 ng/mL for females) to diagnose hyperprolactinaemia as a drug-induced adverse event.Trial Registration PROSPERO International Prospective Register Of Systematic Reviews (CRD42021245259).

Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.

BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).

A systematic review of epidemiology and outcomes of Crohn's disease-related enterocutaneous fistulas.

BACKGROUND: Enterocutaneous fistulas (ECF) are rare sequelae of Crohn's disease (CD) that occur either postoperatively or spontaneously. ECFs are associated with high morbidity and mortality. This systematic literature review assesses the disease burden of CD-related ECF and identifies knowledge gaps around incidence/prevalence, treatment patterns, clinical outcomes, healthcare resource utilization (HCRU), and patient-reported outcomes (PROs). METHODS: English language articles published in PubMed and Embase in the past 10 years that provided data and insight into the disease burden of CD-related ECF (PROSPERO Registration number: CRD42020177732) were identified. Prespecified search and eligibility criteria guided the identification of studies by two reviewers who also assessed risk of bias. RESULTS: In total, 582 records were identified; 316 full-text articles were assessed. Of those, eight studies met a priori eligibility criteria and underwent synthesis for this review. Limited epidemiologic data estimated a prevalence of 3265 persons with ECF in the USA in 2017. Clinical response to interventions varied, with closure of ECF achieved in 10% to 62.5% of patients and recurrence reported in 0% to 50% of patients. Very little information on HCRU is available, and no studies of PROs in this specific population were identified. CONCLUSION: The frequency, natural history, and outcomes of ECF are poorly described in the literature. The limited number of studies included in this review suggest a high treatment burden and risk of substantial complications. More robust, population-based research is needed to better understand the epidemiology, natural history, and overall disease burden of this rare and debilitating complication of CD.

Machine learning for improving high-dimensional proxy confounder adjustment in healthcare database studies: An overview of the current literature.

PURPOSE: Supplementing investigator-specified variables with large numbers of empirically identified features that collectively serve as 'proxies' for unspecified or unmeasured factors can often improve confounding control in studies utilizing administrative healthcare databases. Consequently, there has been a recent focus on the development of data-driven methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic research. In this paper, we survey current approaches and recent advancements for high-dimensional proxy confounder adjustment in healthcare database studies. METHODS: We discuss considerations underpinning three areas for high-dimensional proxy confounder adjustment: (1) feature generation-transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection, and adjustment; and (3) diagnostic assessment. We discuss challenges and avenues of future development within each area. RESULTS: There is a large literature on methods for high-dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges. CONCLUSIONS: There is a growing body of evidence showing that machine-learning algorithms for high-dimensional proxy-confounder adjustment can supplement investigator-specified variables to improve confounding control compared to adjustment based on investigator-specified variables alone. However, more research is needed on best practices for feature generation and diagnostic assessment when applying methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic studies.

Mesenchymal Stem Cell Therapy Awareness, Knowledge, and Use for the Treatment of Fistulizing Crohn's Disease: An International Survey Among Gastroenterologists and Colorectal Surgeons.

INTRODUCTION: Mesenchymal stem (or stromal) cells are a promising therapy for the treatment of various inflammatory and autoimmune diseases. This study aimed to understand awareness, knowledge, and perception of mesenchymal stem cells among gastroenterologists and colorectal surgeons, with particular focus on the perianal fistulizing Crohn's disease indication. METHODS: A web-based questionnaire was distributed to currently practicing and registered gastroenterologists and colorectal surgeons across 15 countries in North America, Europe, and Asia Pacific. RESULTS: Of 146 clinicians, 115 (79%) were aware of mesenchymal stem cells. The majority were moderately to largely interested in this therapy (87%), willing to use it in patients with perianal fistulizing Crohn's disease (82%), and believed it addresses unmet needs for these patients (93%). However, most responders reported having limited or no knowledge of this therapy (64%) or its efficacy (51%), safety (53%), and mechanism of action (65%) in perianal fistulizing Crohn's disease. Many clinicians (46%) also expressed concerns about using this therapy in these patients. Attending discussions and presentations on mesenchymal stem cells and seeing more patients with Crohn's disease were associated with increased awareness (both P < 0.001). CONCLUSIONS: Many clinicians demonstrated an interest in mesenchymal stem cells in general and a willingness to use them to treat perianal fistulizing Crohn's disease, but this survey showed suboptimal knowledge of what mesenchymal stem cells are and how they work in this indication. This may explain clinicians' concerns about use of this therapy and calls out for education activities.

Risk of bias in non-randomized observational studies assessing the relationship between proton-pump inhibitors and adverse kidney outcomes: a systematic review.

BACKGROUND: Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease). METHODS: We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers. RESULTS: Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24-7.34) but associations mostly showed increased risk. CONCLUSION: Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders.

ISPE-Endorsed Guidance in Using Electronic Health Records for Comparative Effectiveness Research in COVID-19: Opportunities and Trade-Offs.

As the scientific research community along with healthcare professionals and decision makers around the world fight tirelessly against the coronavirus disease 2019 (COVID-19) pandemic, the need for comparative effectiveness research (CER) on preventive and therapeutic interventions for COVID-19 is immense. Randomized controlled trials markedly under-represent the frail and complex patients seen in routine care, and they do not typically have data on long-term treatment effects. The increasing availability of electronic health records (EHRs) for clinical research offers the opportunity to generate timely real-world evidence reflective of routine care for optimal management of COVID-19. However, there are many potential threats to the validity of CER based on EHR data that are not originally generated for research purposes. To ensure unbiased and robust results, we need high-quality healthcare databases, rigorous study designs, and proper implementation of appropriate statistical methods. We aimed to describe opportunities and challenges in EHR-based CER for COVID-19-related questions and to introduce best practices in pharmacoepidemiology to minimize potential biases. We structured our discussion into the following topics: (1) study population identification based on exposure status; (2) ascertainment of outcomes; (3) common biases and potential solutions; and (iv) data operational challenges specific to COVID-19 CER using EHRs. We provide structured guidance for the proper conduct and appraisal of drug and vaccine effectiveness and safety research using EHR data for the pandemic. This paper is endorsed by the International Society for Pharmacoepidemiology (ISPE).

A systematic review of the patient burden of Crohn's disease-related rectovaginal and anovaginal fistulas.

BACKGROUND: Crohn's disease (CD)-related rectovaginal fistulas (RVFs) and anovaginal fistulas (AVFs) are rare, debilitating conditions that present a substantial disease and treatment burden for women. This systematic literature review (SLR) assessed the burden of Crohn's-related RVF and AVF, summarizing evidence from observational studies and highlighting knowledge gaps. METHODS: This SLR identified articles in PubMed and Embase that provide data and insight into the patient experience and disease burden of Crohn's-related RVF and AVF. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. RESULTS: Of the 582 records identified, 316 full-text articles were assessed, and 16 studies met a priori eligibility criteria and were included. Few epidemiology studies were identified, with one study estimating the prevalence of RVF to be 2.3% in females with Crohn's disease. Seven of 12 treatment pattern studies reported that patients had or required additional procedures before and/or after the intervention of interest, demonstrating a substantial treatment burden. Seven of 11 studies assessing clinical outcomes reported fistula healing rates between 50 and 75%, with varying estimates based on population and intervention. CONCLUSIONS: This SLR reports the high disease and treatment burden of Crohn's-related RVF and AVF and identifies multiple evidence gaps in this field. The literature lacks robust, generalizable data, and demonstrates a compelling need for substantial, novel research into these rare and debilitating sequelae of CD. Registration The PROSPERO registration number for the protocol for this systematic literature review is CRD42020177732.

Framework for the synthesis of non-randomised studies and randomised controlled trials: a guidance on conducting a systematic review and meta-analysis for healthcare decision making.

INTRODUCTION: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. OBJECTIVES AND METHODS: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. RESULTS: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, 'high-bar evidence' when RCTs are the preferred source of evidence, 'medium,' and 'low' when NRS is the main source of inference). CONCLUSION: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology.

Epidemiology, Etiology, and Treatment of Gastroparesis: Real-World Evidence From a Large US National Claims Database.

BACKGROUND & AIMS: Although gastroparesis carries a considerable health care and patient burden, associated epidemiological data are limited. To provide new real-world evidence for gastroparesis, we estimated disease prevalence, and investigated patient demographics and disease etiology in a large US claims database. METHODS: This retrospective, cross-sectional analysis used de-identified, longitudinal patient-level enrollment and billing data for adults from the Optum Clinformatics Data Mart database, a large US national administrative health insurance claims database. Prevalence was age-, sex-, and geographical region-standardized using the 2018 US census. Descriptive analyses of demographic and clinical variables and underlying disease etiologies were performed. RESULTS: The overall standardized prevalence of gastroparesis was 267.7 (95% confidence interval [CI] 264.8-270.7) per 100,000 US adults, whereas prevalence of "definite" gastroparesis (individuals diagnosed within 3 months of gastric emptying scintigraphy testing with persistent symptoms for more than 3 months) was 21.5 (95% CI 20.6-22.4) per 100,000 persons. Patients with gastroparesis had an overall Charlson Comorbidity Index score of 4.2, indicating substantial comorbidity burden. The most frequently documented comorbidities were chronic pulmonary disease (46.4%), diabetes with chronic complication (37.3%), and peripheral vascular disease (30.4%). Patients most commonly had a diabetic etiology (57.4%; type 1, 5.7% and type 2, 51.7%), followed by postsurgical (15.0%), drug-induced (11.8%), and idiopathic (11.3%) etiologies. CONCLUSIONS: New evidence is provided regarding the prevalence, patient demographics, and etiology of gastroparesis in the US general population. Wider availability of reliable objective gastric emptying measures and further education of medical professionals in recognizing and diagnosing gastroparesis would benefit future studies and improve understanding of disease epidemiology.

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.

The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.

How well can we assess the validity of non-randomised studies of medications? A systematic review of assessment tools.

OBJECTIVE: To determine whether assessment tools for non-randomised studies (NRS) address critical elements that influence the validity of NRS findings for comparative safety and effectiveness of medications. DESIGN: Systematic review and Delphi survey. DATA SOURCES: We searched PubMed, Embase, Google, bibliographies of reviews and websites of influential organisations from inception to November 2019. In parallel, we conducted a Delphi survey among the International Society for Pharmacoepidemiology Comparative Effectiveness Research Special Interest Group to identify key methodological challenges for NRS of medications. We created a framework consisting of the reported methodological challenges to evaluate the selected NRS tools. STUDY SELECTION: Checklists or scales assessing NRS. DATA EXTRACTION: Two reviewers extracted general information and content data related to the prespecified framework. RESULTS: Of 44 tools reviewed, 48% (n=21) assess multiple NRS designs, while other tools specifically addressed case-control (n=12, 27%) or cohort studies (n=11, 25%) only. Response rate to the Delphi survey was 73% (35 out of 48 content experts), and a consensus was reached in only two rounds. Most tools evaluated methods for selecting study participants (n=43, 98%), although only one addressed selection bias due to depletion of susceptibles (2%). Many tools addressed the measurement of exposure and outcome (n=40, 91%), and measurement and control for confounders (n=40, 91%). Most tools have at least one item/question on design-specific sources of bias (n=40, 91%), but only a few investigate reverse causation (n=8, 18%), detection bias (n=4, 9%), time-related bias (n=3, 7%), lack of new-user design (n=2, 5%) or active comparator design (n=0). Few tools address the appropriateness of statistical analyses (n=15, 34%), methods for assessing internal (n=15, 34%) or external validity (n=11, 25%) and statistical uncertainty in the findings (n=21, 48%). None of the reviewed tools investigated all the methodological domains and subdomains. CONCLUSIONS: The acknowledgement of major design-specific sources of bias (eg, lack of new-user design, lack of active comparator design, time-related bias, depletion of susceptibles, reverse causation) and statistical assessment of internal and external validity is currently not sufficiently addressed in most of the existing tools. These critical elements should be integrated to systematically investigate the validity of NRS on comparative safety and effectiveness of medications. SYSTEMATIC REVIEW PROTOCOL AND REGISTRATION: https://osf.io/es65q.