The power of sample size calculations.

Researchers frequently come across sample size calculations in the scientific literature they read, in projects undertaken by their peers, and likely within their own work. However, despite its ubiquity, calculating a sample size is often perceived as a hurdle and not fully understood. This paper provides a brief overview of sample size estimation to guide readers, researchers, and reviewers through its fundamentals.

Pamidronate for pain in adult chronic nonbacterial osteitis: protocol of a randomized, double-blind, placebo-controlled trial.

Chronic nonbacterial osteitis (CNO) is a rare auto-inflammatory bone disease affecting children and adults. Adult CNO is characterized by painful bone lesions, primarily of the anterior chest wall. There is no approved therapy for adult CNO. Current off-label treatments include intravenous bisphosphonates, which have been shown to alleviate pain through decreasing bone turnover. However, no adequately powered randomized controlled trials (RCTs) have been conducted. This double-blind, placebo-controlled RCT investigates the efficacy of intravenous pamidronate to decrease bone pain in adult CNO patients. Recruiting at the Dutch national referral center for CNO, adult patients with persistent bone pain despite non-steroidal anti-inflammatory drugs, or optionally other standard-of-care treatments are randomized to receive two courses of intravenous pamidronate (at 0 and 3 mo, 30 mg daily, on 3 consecutive d) or placebo. From 6 mo onwards, all patients receive open-label pamidronate for another two courses. The primary outcome is change in score for maximum pain from 0 to 6 mo. Secondary outcomes include change in quantitative intralesional bone turnover as measured on sodium-fluoride positron emission computed tomography ([18F]NaF-PET/CT), inflammation markers, shoulder function, general health, quality of life, fatigue, physical, and work activity. The pamidronate for pain in adult chronic nonbacterial osteitis trial addresses the need for evidence-based treatments in adult CNO. Results will directly impact daily clinical practice, either validating the use of intravenous pamidronate in CNO at the dose used in this trial or prompting the search for alternative regimens or agents. This trial was registered in EudraCT (reference 2020-001068-27) and the Dutch Trial Register (reference NL68020.058.20).

The changing treatment paradigm in prolactinoma - a prospective series of 100 consecutive neurosurgical cases.

PURPOSE: To evaluate patients with prolactinoma treated surgically in a time when elective prolactinoma surgery became routine in our center, using a comprehensive outcome set, focusing on preoperative assessments, surgical outcomes, and health-related quality of life (HR-QoL). METHODS: Cohort of consecutive patients with prolactinoma undergoing surgery between January 2021 and August 2023. Clinical data were collected during multidisciplinary team (MDT) meetings/from medical records at distinct timepoints: (1) pre-surgery, (2) two weeks post-surgery, (3) six months post-surgery, and (4) follow-up (median 15.0 (10.0-24.8 months). HR-QoL was measured using the Leiden Bothers and Needs Pituitary (LBNQ-P) questionnaire. Data were described for all patients, and patients undergoing elective total resection, with additional subgroups of (a) patients undergoing a high-probability-first-total-resection, and (b) reoperations aiming for total resection. RESULTS: One hundred surgically treated patients with prolactinoma were included (72 female). Dopamine agonist intolerance was the most frequent indication (n=68). The surgical goal (debulking/total resection) was achieved in 90% of patients. Long-term complications occurred in 4% of patients. Seventy-eight patients underwent an elective total resection, achieving remission in 91%. The subsets of preoperatively estimated high-probability-first-total-resections (n=52), and reoperations (n=9), achieved remission in 92% and 89%, respectively. LBNQ-P Total Bothers and Total Needs scores improved significantly after surgery (p<0.001, Δ-3.4 (IQR -14.4- -0.9) and p=0.006, Δ-1.8 (IQR -11.9-1.3), respectively. CONCLUSION: High remission rates were achieved, improving HR-QoL, evidencing (repeat) prolactinoma surgery is effective in an experienced pituitary center, as highlighted in the most recent guideline (2023).

Prophylactic Radiologic Interventions for Postpartum Hemorrhage Control in Women With Placenta Accreta Spectrum Disorder: A Systematic Review and Meta-analysis.

OBJECTIVE: To quantify the association between prophylactic radiologic interventions and perioperative blood loss during cesarean delivery in women with placenta accreta spectrum disorder through a systematic review and network meta-analysis. DATA SOURCES: On January 3, 2023, a literature search was conducted in PubMed, EMBASE, Cochrane Library, and Web of Science. We also checked ClinicalTrials.gov retrospectively. Prophylactic radiologic interventions to reduce bleeding during cesarean delivery involved preoperative placement of balloon catheters, distal (internal or common iliac arteries) or proximal (abdominal aorta), or sheaths (uterine arteries). The primary outcome was volume of blood loss; secondary outcomes were the number of red blood cell units transfused and adverse events. Studies including women who received an emergency cesarean delivery were excluded. METHODS OF STUDY SELECTION: Two authors independently screened citations for relevance, extracted data, and assessed the risk of bias of individual studies with the Cochrane Risk of Bias in Non-randomized Studies of Interventions tool. TABULTATION, INTEGRATION, AND RESULTS: From a total of 1,332 screened studies, 50 were included in the final analysis, comprising 5,962 women. These studies consisted of two randomized controlled trials and 48 observational studies. Thirty studies compared distal balloon occlusion with a control group, with a mean difference in blood loss of -406 mL (95% CI, -645 to -167). Fourteen studies compared proximal balloon occlusion with a control group, with a mean difference of -1,041 mL (95% CI, -1,371 to -710). Sensitivity analysis excluding studies with serious or critical risk of bias provided similar results. Five studies compared uterine artery embolization with a control group, all with serious or critical risk of bias; the mean difference was -936 mL (95% CI, -1,522 to -350). Reported information on adverse events was limited. CONCLUSION: Although the predominance of observational studies in the included literature warrants caution in interpreting the findings of this meta-analysis, our findings suggest that prophylactic placement of balloon catheters or sheaths before planned cesarean delivery in women with placenta accreta spectrum disorder may, in some cases, substantially reduce perioperative blood loss. Further study is required to quantify the efficacy according to various severities of placenta accreta spectrum disorder and the associated safety of these radiologic interventions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022320922.

Lipid Levels and Risk of Diabetic Polyneuropathy in 2 Danish Type 2 Diabetes Cohorts.

BACKGROUND AND OBJECTIVES: Reduction of blood lipids may aid in preventing diabetic polyneuropathy (DPN), but evidence remains conflicting. We investigated the association between lipid parameters and DPN risk in individuals with type 2 diabetes mellitus (T2DM). METHODS: We conducted a population-based cohort study of individuals with newly diagnosed T2DM and a cross-sectional study using a clinically recruited T2DM cohort. Triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-HDL cholesterol were measured in routine diabetes care. Each lipid parameter was categorized according to the latest cutoffs in clinical guidelines on dyslipidemia. DPN was assessed with validated hospital diagnosis codes in the population-based cohort and with the Michigan Neuropathy Screening Instrument questionnaire in the clinical cohort. We calculated hazard ratios (HRs) using Cox regression and prevalence ratios (PRs) using Poisson regression. RESULTS: We included 61,853 individuals in the population-based cohort (median age 63 [quartiles 54-72] years) and 4,823 in the clinical cohort (median age 65 [quartiles 57-72] years). The incidence rate of hospital-diagnosed DPN in the population-based cohort was 3.6 per 1000 person-years during a median follow-up of 7.3 years. Achieving guideline targets for HDL, LDL, and non-HDL cholesterol showed no association with DPN risk. By contrast, adjusted HRs (95% CI) for DPN were 1.02 (0.89-1.18) for triglyceride levels between 150 and 204 mg/dL (1.7-2.3 mmol/L) and 1.28 (1.13-1.45) for levels >204 mg/dL (2.3 mmol/L). In the clinical cohort with a DPN prevalence of 18%, DPN associated strongly with triglycerides >204 mg/dL (2.3 mmol/L) with an adjusted PR (95% CI) of 1.40 (1.21-1.62). The prevalence of DPN was modestly elevated for individuals with HDL cholesterol <39 mg/dL (1.0/1.3 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women (PR 1.13 [0.99-1.28]) and for individuals with non-HDL cholesterol >131 mg/dL (3.4 mmol/L) (PR 1.27 [1.05-1.52]). In both cohorts, spline models showed an increasing risk of DPN starting from triglyceride levels >124 mg/dL (1.4 mmol/L). All results were similar among statin users. DISCUSSION: High triglyceride levels are a strong DPN risk factor. Future intervention studies shall determine whether triglyceride reduction is more important for DPN prevention than reduction of other lipids.

Ten things to remember about propensity scores.

Propensity score methods are popular to control for confounding in observational biomedical studies of risk factors or medical treatments. This paper focused on aspects of propensity score methods that often remain undiscussed, including unmeasured confounding, missing data, variable selection, statistical efficiency, estimands, the positivity assumption, and predictive performance of the propensity score model.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Longitudinal HbA1c patterns before the first treatment of diabetes in routine clinical practice: A latent class trajectory analysis.

AIMS: To examine the longitudinal heterogeneity of HbA1c preceding the initiation of diabetes treatment in clinical practice. METHODS: In this population-based study, we used HbA1c from routine laboratory and healthcare databases. Latent class trajectory analysis was used to classify individuals according to their longitudinal HbA1c patterns before first glucose-lowering drug prescription irrespective of type of diabetes. RESULTS: Among 21,556 individuals initiating diabetes treatment during 2017-2018, 20,733 (96 %) had HbA1c measured (median 4 measurements [IQR 2-7]) in the 5 years preceding treatment initiation. Four classes with distinct HbA1c trajectories were identified, with varying steepness of increase in HbA1c. The largest class (74 % of the individuals) had mean HbA1c above the 48 mmol/mol threshold 9 months before treatment initiation. Mean HbA1c was 52 mmol/mol (95 % CI 52-52) at treatment initiation. In the remaining three classes, mean HbA1c exceeded 48 mmol/mol almost 1.5 years before treatment initiation and reached 79 mmol/mol (95 % CI 78-80), 105 mmol/mol (95 % CI 104-106), and 137 mmol/mol (95 % CI 135-140) before treatment initiation. CONCLUSION: We identified four distinct longitudinal HbA1c patterns before initiation of diabetes treatment in clinical practice. All had mean HbA1c levels exceeding the diagnostic threshold many months before treatment initiation, indicating therapeutic inertia.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

The Etiology of Advanced Chronic Kidney Disease in Southeast Asia: A Meta-analysis.

INTRODUCTION: Chronic kidney disease (CKD) etiology varies greatly between developed and developing countries. In addition, differences in underlying pathogenesis and therapeutic options affect the progression towards advanced-CKD. This meta-analysis aims to identify the etiology of advanced-CKD in Southeast Asia. METHODS: A systematic search in four electronic-databases and complementary search on national kidney registries and repository libraries was conducted until July 20, 2023. The risk of bias was assessed using Newcastle-Ottawa Scale for observational studies and Version-2 of Cochrane for intervention studies. A random-effects model was used to estimate pooled prevalence. The protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO; Registration ID:CRD42022300786. RESULTS: We analyzed 81 studies involving 32,834 subjects. The pooled prevalence of advanced-CKD etiologies are diabetic kidney disease (DKD) 29.2% (95%CI 23.88-34.78), glomerulonephritis 20.0% (95%CI 16.84-23.38), hypertension 16.8% (95%CI 14.05-19.70), other 8.6% (95%CI 6.97-10.47), unknown 7.5% (95%CI 4.32-11.50), and polycystic kidney disease 0.7% (95%CI 0.40-1.16). We found a significant increase in DKD prevalence from 21% (9.2%, 95%CI 0.00-33.01) to 30% (95%CI 24.59-35.97) before and after the year 2000. Among upper-middle-income and high-income countries, DKD is the most prevalent (26.8%, 95%CI 21.42-32.60 and 38.9%, 95%CI 29.33-48.79, respectively), while glomerulonephritis is common in lower-middle-income countries (33.8%, 95%CI 15.62-54.81). CONCLUSION: The leading cause of advanced-CKD in Southeast Asia is DKD, with a substantial proportion of glomerulonephritis. An efficient screening program targeting high-risk populations (diabetes mellitus and glomerulonephritis) is needed, with the aim to delay CKD progression.

Patient-Reported Satisfaction with Thyroid Hormone Replacement Therapy for Subclinical Hypothyroidism in Older Adults: A Pooled Analysis of Individual Participant Data from Two Randomized Controlled Trials.

Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] -1.1 [-4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) (p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: -21.1% [-35.6% to -6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH.

Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline.

We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, endocrine hypertension, paediatric endocrinology, and cardiology as well as a methodologist. A systematic literature search was conducted, and because of the rarity of the condition, most recommendations were based on expert opinion and small patient series. The guideline includes a brief description of the genetics and molecular pathophysiology associated with each condition, the patients to be screened, and how to screen. Diagnostic and treatment approaches for patients with genetically determined diagnosis are presented. The recommendations apply to patients with genetically proven familial hyperaldosteronism and not to families with more than one case of primary aldosteronism without demonstration of a responsible pathogenic variant.

[Causes of death: the uncertainty behind the numbers]. / Doodsoorzaken: de onzekerheid achter de cijfers.

When a person dies in the Netherlands it is legally required to report the cause of death. In most cases however, there is uncertainty when classifying causes of death. Additional postmortem diagnostics such as a CT scan or autopsy do not always provide absolute certainty. Data on causes of death can be used to determine what are, on a population level, relevant health problems. One must be cautious to fully rely on these data for making policy or financing healthcare and research. Firstly, incorrectly classifying the cause of death can give a distorted view of the underlying causes. Secondly, relevant health problems, such as obesity, might be overlooked in the statistics when they are not clearly a cause of death.

Neuropathic and Nociplastic Pain Profiles are Common in Adult Chronic Nonbacterial Osteitis (CNO).

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21-41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41-64) of patients displayed central sensitization on CSI, 61% (50-72) screened positive for fibromyalgia on FiRST and 14% (7-23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4-5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach.

Directed acyclic graphs in clinical research.

Directed acyclic graphs (DAGs), or causal diagrams, are graphical representations of causal structures that can be used in medical research to understand and illustrate potential bias, including bias arising from confounding, selection, and misclassification. Further, they provide guidance for researchers about how to address a potential bias.

18F-Sodium fluoride PET-CT visualizes disease activity in chronic nonbacterial osteitis in adults.

Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride-18 positron emission tomography/computed tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluated the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO. A coss-sectional study was performed including 43 adult patients with CNO and 16 controls (patients referred for suspected, but not diagnosed with CNO) who underwent [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax [g/mL]) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients. Structural assessment revealed manubrial and costal sclerosis/hyperostosis and calcification of the costoclavicular ligament as typical features associated with CNO. SUVmax of CNO lesions was higher compared with in-patient reference bone (mean paired difference: 11.4; 95% CI: 9.4-13.5; p < .001) and controls (mean difference: 12.4; 95%CI: 9.1-15.8; p < .001). The highest SUVmax values were found in soft tissue and joint areas such as the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient: 0.546; p < .002). Our data suggest that [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue, and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision making.

Female Sex and Mortality in Patients with Staphylococcus aureus Bacteremia: A Systematic Review and Meta-analysis.

Importance: Staphylococcus aureus is the leading cause of death due to bacterial bloodstream infection. Female sex has been identified as a risk factor for mortality in S aureus bacteremia (SAB) in some studies, but not in others. Objective: To determine whether female sex is associated with increased mortality risk in SAB. Data Sources: MEDLINE, Embase, and Web of Science were searched from inception to April 26, 2023. Study Selection: Included studies met the following criteria: (1) randomized or observational studies evaluating adults with SAB, (2) included 200 or more patients, (3) reported mortality at or before 90 days following SAB, and (4) reported mortality stratified by sex. Studies on specific subpopulations (eg, dialysis, intensive care units, cancer patients) and studies that included patients with bacteremia by various microorganisms that did not report SAB-specific data were excluded. Data Extraction and Synthesis: Data extraction and quality assessment were performed by 1 reviewer and verified by a second reviewer. Risk of bias and quality were assessed with the Newcastle-Ottawa Quality Assessment Scale. Mortality data were combined as odds ratios (ORs). Main Outcome and Measures: Mortality at or before 90-day following SAB, stratified by sex. Results: From 5339 studies retrieved, 89 were included (132 582 patients; 50 258 female [37.9%], 82 324 male [62.1%]). Unadjusted mortality data were available from 81 studies (109 828 patients) and showed increased mortality in female patients compared with male patients (pooled OR, 1.12; 95% CI, 1.06-1.18). Adjusted mortality data accounting for additional patient characteristics and treatment variables were available from 32 studies (95 469 patients) and revealed a similarly increased mortality risk in female relative to male patients (pooled adjusted OR, 1.18; 95% CI, 1.11-1.27). No evidence of publication bias was encountered. Conclusions and Relevance: In this systematic review and meta-analysis, female patients with SAB had higher mortality risk than males in both unadjusted and adjusted analyses. Further research is needed to study the potential underlying mechanisms.

Real-World Evidence to Inform Regulatory Decision Making: A Scoping Review.

Real-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making. A scoping review was conducted using literature databases (PubMed, Embase, Emcare, Web of Science, and Cochrane Library) and websites of regulatory agencies, health technology assessment agencies, research institutes, and professional organizations involved with RWE. Articles were included if: (1) they discussed factors or contexts that impact whether RWE could be necessary or desirable in regulatory decision making; (2) focused on pharmacological or biological interventions in humans; and (3) considered decision making in Europe or North America, or without a focus on a specific region. We included 118 articles in the scoping review. Two major themes and six subthemes were identified. The first theme concerns questions addressable with RWE, with subthemes epidemiology and benefit-risk assessment. The second theme concerns contextual factors, with subthemes feasibility, ethical considerations, limitations of available evidence, and disease and treatment-specific aspects. Collectively, these themes encompassed 43 factors influencing the need for RWE in regulatory decisions. Although single factors may not make RWE fully necessary, their cumulative influence could make RWE essential and pivotal in regulatory decision making. This overview contributes to ongoing discussions emphasizing the nuanced interplay of factors influencing the necessity or desirability of RWE to inform regulatory decision making.