Real-world Observational Studies Research Articles

Collaborative Real-World Evidence Among Regulators: Lessons and Perspectives.

The International Coalition of Medicines Regulatory Authorities (ICMRA), comprising 38 global medicines regulatory authorities, collaborates on shared challenges, notably during the COVID-19 pandemic. This article focuses on the ICMRA COVID-19 Real-World Evidence (RWE) and Observational Studies Working Group. The Working Group aimed to address challenges related to RWE and observational studies during the pandemic, resulting in impactful studies and ICMRA statements on international collaboration for RWE and COVID-19 vaccine safety. Reflecting on 3 years of collaboration, the Working Group surveyed members for insights, and recommendations were formulated to enhance research preparedness, collaboration, and response to future public health emergencies. The lessons learned highlight the importance of global collaborations, governance structures for rapid decision-making, and effective utilization of existing networks. Recommendations include the establishment of an international governance structure, a "coalition of the willing" for swift research collaboration, dedicated sub-groups, periodic workshops, common protocols, joint timelines, and data model templates, leveraging existing infrastructure, and strengthening outreach for transparency and engagement. The Working Group envisions repurposing into an RWE strategic and operational entity, contributing to global public health emergency response mechanisms. In conclusion, the Working Group's success lies in effective communication, collaborative research, and leveraging existing infrastructure, with ongoing contributions to global emergency response mechanisms.

Treatment Recommendation for Dyspnea in Patients with Advanced Disease: Revised Clinical Guidelines from the Japanese Society for Palliative Medicine.

Dyspnea is one of the most common and distressing symptoms in patients with cancer and noncancer advanced diseases. The Japanese Society for Palliative Medicine revised previous guidelines for the management of respiratory symptoms in patients with cancer and newly developed clinical guidelines for managing dyspnea in patients with advanced disease, based on the result of systematic reviews for each clinical question and consensus among experts. We describe the recommendations of the guidelines as well as provide insights into the reasoning behind the recommendations and their development process. There has been a paucity of evidence regarding the interventions for dyspnea in patients with advanced disease. Thus, more clinical research that includes not only randomized controlled trials but also real-world observational studies is warranted.

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts.

Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products. In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies. Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.

Adenoma detection rate by colonoscopy in real-world population-based studies: a systematic review and meta-analysis.

Adenoma detection rate (ADR) is a quality indicator set at a minimum of 25% in unselected populations by the European Society of Gastrointestinal Endoscopy (ESGE). Nevertheless, a lack of pooled observational data resembling real-world practice limits support for this threshold. We aimed to perform a systematic review with meta-analysis to evaluate the pooled rates for conventional adenoma detection, polyp detection (PDR), cecal intubation, bowel preparation, and complications in population-based studies. The PubMed, Scopus, and Web of Science databases were searched until May 2023 for populational-based studies reporting overall ADR in unselected individuals. A random-effects model was used for meta-analysis. 31 studies were included, comprising 3 644 561 subjects. A high quality of procedures was noticeable, with a high cecal intubation rate and low complication rate. The overall pooled ADR, PDR, and rate of cancer detection were 26.5% (95%CI 23.3% to 29.7%), 38.3% (95%CI 32.5% to 44.1%), and 2.7% (95%CI 1.5% to 3.9%), respectively. ADR varied according to indication: screening 33.3% (95%CI 24.5% to 42.2%), surveillance 42.9% (95%CI 36.9% to 49.0%), and diagnostic 24.7% (95%CI 19.5% to 29.9%), with subgroup analysis revealing rates of 34.4% (95%CI 22.0% to 40.5%) for post-fecal occult blood test and 26.6% (95%CI 22.6% to 30.5%) for primary colonoscopy screening. Diminutive conventional adenomas yielded a pooled rate of 59.9% (95%CI 43.4% to 76.3%). The pooled rate for overall serrated lesion detection was 12.4% (95%CI 8.8% to 16.0%). Male sex and higher age were significantly associated with an ADR above the benchmark. This first meta-analysis relying on real-world observational studies supports the ESGE benchmark for ADR, while suggesting that different benchmarks might be used according to indication, sex, and age.

Two assumptions of the prior event rate ratio approach for controlling confounding can be evaluated by self-controlled case series and dynamic random intercept modeling

ObjectivesThe prior event rate ratio (PERR) is a recently developed approach for controlling confounding by measured and unmeasured covariates in real-world evidence research and observational studies. Despite its rising popularity in studies of safety and effectiveness of biopharmaceutical products, there is no guidance on how to empirically evaluate its model assumptions. We propose two methods to evaluate two of the assumptions required by the PERR, specifically, the assumptions that occurrence of outcome events does not alter the likelihood of receiving treatment, and that earlier event rate does not affect later event rate. Study Design and SettingWe propose using self-controlled case series (SCCS) and dynamic random intercept modeling (DRIM), respectively, to evaluate the two aforementioned assumptions. A nonmathematical introduction of the methods and their application to evaluate the assumptions are provided. We illustrate the evaluation with secondary analysis of deidentified data on pneumococcal vaccination and clinical pneumonia in The Gambia, West Africa. ResultsSCCS analysis of data on 12,901 vaccinated Gambian infants did not reject the assumption of clinical pneumonia episodes had no influence on the likelihood of pneumococcal vaccination. DRIM analysis of 14,325 infants with a total of 1719 episodes of clinical pneumonia did not reject the assumption of earlier episodes of clinical pneumonia had no influence on later incidence of the disease. ConclusionThe SCCS and DRIM methods can facilitate appropriate use of the PERR approach to control confounding. Plain Language SummaryThe prior event rate ratio is a promising approach for analysis of real-world data and observational studies. We propose two statistical methods to evaluate the validity of two assumptions it is based on. They can facilitate appropriate use of the prior even rate ratio.

Adverse Events with Hypoglossal Nerve Stimulation in the Treatment of Obstructive Sleep Apnea-A Systematic Review of Clinical Trials and Real-World Data.

Background/Objectives: Hypoglossal nerve stimulation (HNS) emerged as an alternative treatment for patients with obstructive sleep apnea (OSA) a decade ago. Long-term clinical trials and real-world data show that HNS treatment provides significant and sustained improvements in both OSA disease control and quality-of-life measures over time. Given the nature of HNS treatment, with the requirement of using an implantable neurostimulation system, patient safety is a critical domain in the assessment of this technology. The objective of this review was to evaluate adverse events (AEs) and complications with HNS therapy in a systematic review of published evidence. Methods: Medline, Cochrane, and Web of Science were systematically searched to identify randomized controlled and real-world observational studies reporting relevant outcomes with HNS therapy for treatment of OSA that included procedure-, device-, and treatment-related AEs. Results: Out of 418 articles screened, 27 were reviewed for eligibility, and 17 studies, the majority found to have low-to-moderate risk of bias, with data on 1962 patients were included for further analysis. Across included studies, reporting of AEs was heterogeneous with regard to the classifications used and the extent of reporting. Over an average follow-up duration of 17.5 ± 16.9 months, the pooled mortality rate was 0.01% (95% CI = 0.0 to 0.2%), with all reported deaths being unrelated to HNS treatment. The HNS system survival probability over the follow-up time of 60 months was 0.9834 (95% CI = 0.9768 to 0.9882), with infections and request for removal by patients being the most common indications. The pooled surgical revision rate was 0.08% (95% CI 0.0 to 0.2%). Most reported treatment-related side effects were transient stimulation-related discomfort (0.08%, 95% CI = 0.0 to 0.2%) and tongue abrasions (0.07%, 95% CI = 0.0 to 0.2%). Based on the systematic review, a standardized set of endpoints was defined, aiming to harmonize safety data relevant to HNS therapy. Conclusions: In this systematic review, HNS therapy for treatment of OSA is associated with a positive patient safety profile. AEs occur mainly at device implantation and during the treatment acclimatization period. Due to a lack of available evidence, partially implantable HNS systems are underrepresented in this review, which limits the generalizability of the results. Significant heterogeneity was found for adverse event reporting. A framework for reporting HNS outcomes that includes AEs and side effects is proposed to facilitate comparability of the reported data.

Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis.

Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297). MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH. Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66-.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74-.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality. Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

A randomized, double-blind, placebo-controlled trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis

BackgroundSpasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. MethodsThis was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. ResultsOf 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were −0.23 for nabiximols and −0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. ConclusionDespite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. Clinical trial registration number (ClinicalTrials.gov): NCT04657666

The cenobamate KORK study-A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add-on lacosamide, perampanel, and brivaracetam.

In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal-onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real-world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult-to-treat epilepsies. Our aim was to investigate the efficacy of add-on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add-on lacosamide, perampanel, and brivaracetam therapy. Patients were enrolled from the CENKORK study, which is a prospective, non-interventional, open-label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure-free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow-up, leaving 150 cases for the 1-year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6-month and 1-year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6-month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). Add-on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. This observational study was carried out in 172 adult patients with difficult-to-treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Immune Checkpoint Inhibitors and Cardiotoxicity: A Comparative Meta-Analysis of Observational Studies and Randomized Controlled Trials.

Immune checkpoint inhibitors (ICIs) have uncommon associations with cardiotoxicity, yet these cardiotoxic effects are associated with high mortality. An accurate assessment of risk for cardiotoxicity is essential for clinical decision-making, but data from randomized controlled trials often differ from real-world observational studies. A systematic search of PubMed, Embase, Cochrane Library, and Scopus was performed, including phase II and III randomized controlled trials (RCTs) and observational studies (OSs) reporting myocarditis or pericardial disease, myocardial infarction, or stroke with an immunotherapy. Odds ratios (ORs) were used to pool results between ICIs and other cancer therapy in RCTs and OSs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. In total, 54 RCTs (N=38 264) and 24 OSs (N=12 561 455) were included. In RCTs, ICI use resulted in higher risk of myocarditis (OR, 3.55 [95% CI, 2.10-5.98]), pericardial disease (OR, 2.73 [95% CI, 1.57-4.77]), and myocardial infarction (OR, 1.83 [95% CI, 1.03-3.25]), compared with non-ICI (placebo or chemotherapy). In OSs, ICI use was not associated with myocarditis, pericardial disease, or myocardial infarction compared with controls; however, combination ICIs demonstrated higher risk of myocarditis compared with single ICI use (OR, 3.07 [95% CI, 1.28-7.39]). Stroke risk was not increased with use of ICIs in RCTs. We demonstrated increased risk of ICI myocarditis, pericardial disease, and myocardial infarction in RCTs but not OSs. Results of this study suggest there are differences between ICI cardiotoxicity risk, possibly suggesting differences in diagnoses and management, in clinical trials versus the OSs.

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability?

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg-400 mg) and the plasma levels (3.8 mg/L-54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined.

SYNERGIA-MOROCCO: EFFECTIVENESS OF HYPERTENSION MANAGEMENT WITH AN AMLODIPINE AND PERINDOPRIL ARGININE-BASED STRATEGY IN MOROCCO: STUDY DESIGN AND PRELIMINARY DATA

Objective: In Morocco, 1 in 3 adults currently live with hypertension; over 70%1 are not aware or not effectively treated. Among treated hypertensive patients, many receive monotherapy and remain uncontrolled. WHO recommends the addition of an angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker or a diuretic in patients who are uncontrolled on a calcium-channel blocker and a monthly follow-up after initiation until patients reach targets. However, there is limited evidence from real-world observational studies in Morocco on the effectiveness of this approach on blood pressure control. This study aims to evaluate the effectiveness of an amlodipine and perindopril arginine-based strategy for 90 days in hypertensive patients previously uncontrolled on monotherapy of amlodipine. Design and method: This is a multicenter prospective observational study. Eighty (80) primary care physicians across Morocco will recruit about 1 600 uncontrolled hypertensive adult patients who start perindopril-arginine on top of previous amlodipine monotherapy. During the study, physicians will be free to adapt treatment per their judgement, including dose adaptations, the addition of a third drug or the use of a single pill combination (SPC) as a substitute for the free combination of amlodipine/perindopril at the same dose when patients become controlled. The primary outcome will be the change in sitting office blood pressure between baseline and day 90. Secondary outcomes will include; the change in the blood pressure between baseline and the initiation of the SPC and between the initiation of the SPC and the end of the study, and the difference in the proportion of participants with side effects between the free combination and SPC. Results: The first patient was enrolled in the study on October 30, 2023. On January 10, 2024, 1 400 patients were recruited, and 760 had the 30-day follow-up visit. Conclusions: In Morocco, hypertension is a significant public health issue but current treatment optimisation strategies lack evidence from real-world data. The recruitments started as planned, and this will be the first real-world study from Morocco on the short-term effectiveness of treating hypertension with an amlodipine and perindopril arginine-based combination strategy on blood pressure control.

Abstract 926: Adaptive universal platform for real-world observational studies (AUPROS): An emerging model for clinical, epidemiologic, and precision oncology research

Abstract Background: Adaptive Universal Platform for Real-world Observational Studies (AUPROS) is an emerging study design and platform for the generation of real-world evidence (RWE) particularly in malignancies with rare molecular aberrations. Here, we evaluate the efficiency of AUPROS as an innovative model for real-world observational studies in oncology. Methods: We conducted a mixed-methods study to evaluate three AUPROS studies at Princess Margaret Cancer Centre either locally or as a part of national and international collaborations: 1) METAL (Molecular Epidemiology of ThorAcic Lesions; n=11,378), 2) THANKS (Translational Head And NecK Study; n=3,506), and 3) CARMA (Canadian Cancers with Rare Molecular Alterations; NCT04151342; n=3,879). Specifically, we reviewed data collected, study elements, protocol language, coordination, institutional review boards (IRBs), and contracts. We also performed stakeholder-directed survey and discussions, analysis of funding, research output, and collaborations, as well as a Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis. Results: AUPROS is an innovative study design that borrows design elements from master protocol trials, adaptive trials, and master observational trials as well as retrospective and ambispective designs, enabling comprehensive data collection. The universality of AUPROS allowed for multi-purpose analyses of various real-world data (RWD) including epidemiological, clinical, patient-reported outcomes, biospecimens, and imaging data. The adaptive nature created opportunities for multi-source funding (e.g., academic, pharmaceutical, philanthropic, among others), as well as national/international collaborations and involvement in consortia (e.g., ILCCO, TCGA, BEACON, and INHANCE). Additionally, AUPROS has allowed the development of an expanding national RWE platform that involves collaborations among medical and radiation oncologists and surgeons across different tumor sites. As assessed by research output analyses, AUPROS provided a platform for enhanced research productivity in different areas and utilizing various data sources (METAL=130; THANKS=31; CARMA=5 publications). Our survey and SWOT analysis identified several cost and operational benefits of AUPROS over conventional observational studies, as well as several challenges pertinent to ethics approvals, sustainability, complex coordination, and data quality. Conclusions: AUPROS is an innovative model for real-world observational studies with significant logistical and methodological benefits over conventional RWD study designs. Our findings may help broaden the use of AUPROS to address emerging needs in the scope of precision oncology and clinico-epidemiological research. Citation Format: Samir H. Barghout, Stavroula Raptis, Luna Jia Zhan, Faisal Al-Agha, M Catherine Brown, Devalben Patel, Geoffrey Liu. Adaptive universal platform for real-world observational studies (AUPROS): An emerging model for clinical, epidemiologic, and precision oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 926.

Methodological biases in observational hospital studies of COVID-19 treatment effectiveness: pitfalls and potential.

This study aims to discuss and assess the impact of three prevalent methodological biases: competing risks, immortal-time bias, and confounding bias in real-world observational studies evaluating treatment effectiveness. We use a demonstrative observational data example of COVID-19 patients to assess the impact of these biases and propose potential solutions. We describe competing risks, immortal-time bias, and time-fixed confounding bias by evaluating treatment effectiveness in hospitalized patients with COVID-19. For our demonstrative analysis, we use observational data from the registry of patients with COVID-19 who were admitted to the Bellvitge University Hospital in Spain from March 2020 to February 2021 and met our predefined inclusion criteria. We compare estimates of a single-dose, time-dependent treatment with the standard of care. We analyze the treatment effectiveness using common statistical approaches, either by ignoring or only partially accounting for the methodological biases. To address these challenges, we emulate a target trial through the clone-censor-weight approach. Overlooking competing risk bias and employing the naïve Kaplan-Meier estimator led to increased in-hospital death probabilities in patients with COVID-19. Specifically, in the treatment effectiveness analysis, the Kaplan-Meier estimator resulted in an in-hospital mortality of 45.6% for treated patients and 59.0% for untreated patients. In contrast, employing an emulated trial framework with the weighted Aalen-Johansen estimator, we observed that in-hospital death probabilities were reduced to 27.9% in the "X"-treated arm and 40.1% in the non-"X"-treated arm. Immortal-time bias led to an underestimated hazard ratio of treatment. Overlooking competing risks, immortal-time bias, and confounding bias leads to shifted estimates of treatment effects. Applying the naïve Kaplan-Meier method resulted in the most biased results and overestimated probabilities for the primary outcome in analyses of hospital data from COVID-19 patients. This overestimation could mislead clinical decision-making. Both immortal-time bias and confounding bias must be addressed in assessments of treatment effectiveness. The trial emulation framework offers a potential solution to address all three methodological biases.

Comparative Efficacy of Talquetamab vs. Current Treatments in the LocoMMotion and MoMMent Studies in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phaseI/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons. An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4mg/kg weekly [QW] and 0.8mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model. After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001. Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM. MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584.

Does Comorbid Food Allergy Affect Response to Omalizumab in Patients with Asthma?

The intrinsic link between food allergy and asthma is well-established, and comorbidity can exacerbate both conditions. Omalizumab, an anti-immunoglobulin E (IgE) antibody, has the biological plausibility to manage both conditions, but only a few small studies have assessed omalizumab in patients with comorbid asthma and food allergy. We conducted a post hoc analysis of placebo-controlled, randomized clinical trials (IA05 in children and 008/009 in adolescents/adults) and real-world observational studies (EXCELS and PROSPERO). For each study, patients with asthma were stratified by whether they had physician-reported food allergy, as per baseline characteristics data. For patients with comorbid food allergy, there was evidence for increased atopy at baseline (numerically higher total IgE levels and atopic comorbidities). The collective body of evidence found that omalizumab consistently improved general and asthma-specific patient-centered outcomes (food allergy-specific outcomes were not available). For patients with asthma, omalizumab improved healthcare resource use (emergency room visits, hospitalizations, unscheduled doctor visits), quality of life (asthma-specific Asthma Quality of Life Questionnaire), productivity (missed work/school days and the Work Productivity and Activity Impairment: Asthma), and asthma outcomes (asthma exacerbations and Asthma Control Test score) regardless of comorbid food allergy. There was no loss of omalizumab efficacy even though patients with both asthma and food allergy appeared to be generally more atopic. Omalizumab may be a viable management option for patients with these comorbidities. NCT00079937; NCT01922037; NCT00252135.

The Society for Cardiovascular Magnetic Resonance Registry at 150,000

ObjectivesTo summarize the status of the SCMR Registry at 150,000 exams. BackgroundCardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The SCMR Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine (DICOM) images. MethodsThe processes for data security, data submission, and research access are outlined. We interrogated the Registry and present a summary of its contents. ResultsData were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (~100 terabytes of storage). The human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% female, 72% Caucasian, and had a mortality rate of 8%. The most common indication was cardiomyopathy (27%), and most frequently used current procedural terminology (CPT) code was 75561 (35%). Macrocyclic gadolinium-based contrast agents represented 89% of contrast utilization after 2015. Short-axis cines were performed in 99% of scans, short-axis LGE in 66%, and stress perfusion sequences in 30%. Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction (LVEF) < 35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct late gadolinium enhancement (LGE), compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. ConclusionsThe vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility. Condensed AbstractThe SCMR Registry is a central regulatory-compliant cloud-based repository for real-world clinical data and DICOM images for multicenter cardiovascular research, including outcomes-based data. The Registry contains 299,622,066 DICOM images and 456,678 patient-years follow-up. Data compiled from 154,458 CMR scans across 20 US sites demonstrated cardiomyopathy as the most common indication and 89% macrocyclic gadolinium contrast utilization after 2015. There was an overall mortality rate of 8%, with higher rates in those with LVEF<35%, abnormal wall motion, ischemia presence, or infarct LGE. The Registry aims to promote evidence-based CMR utilization through a collaborative effort to positively impact cardiovascular outcomes.

Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs.

Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

RWD84 Building Federated Data Networks With Common Data Models to Generate Insights Through Real-World Evidence Observational Studies in Oncology

RWD84 Building Federated Data Networks With Common Data Models to Generate Insights Through Real-World Evidence Observational Studies in Oncology

Resolution of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Defibrotide Following HCT in Adult and Pediatric Patients: Pooled Analysis of Defifrance and EBMT PASS Registries

Introduction Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Defibrotide is approved for the treatment of severe VOD/SOS post-HCT in patients aged &amp;gt;1 month in the European Union and for VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. Outcomes from two real-world observational studies were pooled for analysis of treatment duration and time to resolution of VOD/SOS in patients given defibrotide for the treatment of severe or nonsevere VOD/SOS post-HCT. Methods DEFIFrance was an observational study that collected retrospective and prospective data on patients receiving defibrotide at 53 French transplant centers from July 2014 to March 2020. VOD/SOS severity was categorized retrospectively/prospectively using adult European Group for Blood and Marrow Transplantation (EBMT) criteria in patients aged ≥18 years, and in patients aged &amp;lt;18 years using pediatric EBMT criteria. EBMT PASS was a multinational, prospective, observational study that enrolled defibrotide-treated patients from April 2015 to July 2018. VOD/SOS severity was graded based on investigators' clinical expertise. For this pooled analysis, mild/moderate and severe/very severe cases in DEFIFrance were combined with nonsevere and severe cases in EBMT PASS, respectively. Investigators in both registries diagnosed VOD/SOS using classical/standard criteria. Results Overall, 414 defibrotide-treated patients with VOD/SOS post-HCT were included (336 from DEFIFrance and 78 from EBMT PASS). The median (interquartile range [IQR]) time from HCT to VOD/SOS diagnosis was 13 (IQR: 8, 21) and 14 (IQR: 8, 22) days in patients with severe and nonsevere VOD/SOS, respectively. Overall, 299/410 patients (73%) had resolution of VOD/SOS. Disease severity data was missing from 4 patients. Among 275 adult patients, VOD/SOS resolution was achieved in 44/60 (73.3%) with nonsevere and 128/215 (59.5%) with severe VOD/SOS. Median treatment duration was 15.5 days (IQR: 13, 22) for nonsevere and 18.5 days (IQR: 13.5, 22) for severe VOD/SOS. Of 135 pediatric patients, VOD/SOS resolution occurred in 47/48 (98%) with nonsevere and 80/87 (92%) with severe VOD/SOS. Median treatment duration was 16 days (IQR: 13, 21) in nonsevere and 21 days (IQR: 12.5, 29) in severe VOD/SOS. Among adult patients with resolution of VOD/SOS, symptoms resolved after day 21 in 32% of patients with nonsevere and 31% of patients with severe VOD/SOS. A higher proportion of pediatric patients with severe (44%) compared with nonsevere VOD/SOS (15%) required &amp;gt;21 days of treatment for resolution of symptoms; correspondingly, 85% of pediatric patients with nonsevere and 56% with severe VOD/SOS had resolution with ≤21 days of defibrotide treatment. Kaplan-Meier (KM)-estimated survival at day 100 post-HCT among patients with severe VOD/SOS was 84% (95% confidence interval [CI]: 78%, 88%) in those who achieved VOD/SOS resolution and 14% (95% CI: 8%, 22%) in those who did not; among patients with nonsevere VOD/SOS, this was 94% (95% CI: 87%, 98%) and 35% (95% CI: 15%, 57%), respectively. Serious treatment-emergent adverse events (TEAEs) of interest occurred in 25% of patients with VOD/SOS resolution. In patients treated for ≤21 days and &amp;gt;21 days, respectively, the most common serious TEAEs of interest by category were infection (14% and 15%) and hemorrhage (12% and 13%). Among patients with VOD/SOS resolution, the most common causes of death were infection (severe: 11%; nonsevere: 2%) and graft-versus-host disease (severe: 6%; nonsevere: 2%). Conclusion Time to resolution of VOD/SOS tended to be longer in patients with severe versus nonsevere VOD/SOS, with many patients requiring &amp;gt;21 days of therapy to achieve resolution. A higher proportion of adult vs pediatric patients attained a CR &amp;gt;21 days after initiation of defibrotide treatment. Day 100 survival was higher in patients with VOD/SOS resolution versus without, regardless of severity, highlighting the importance of VOD/SOS resolution. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies, supporting the utility of defibrotide treatment per the prescribing information.