An Overview of Current Methods for Real-world Applications to Generalize or Transport Clinical Trial Findings to Target Populations of Interest.

It has been well established that randomized clinical trials have poor external validity, resulting in findings that may not apply to relevant-or target-populations. When the trial is sampled from the target population, generalizability methods have been proposed to address the applicability of trial findings to target populations. When the trial sample and target populations are distinct, transportability methods may be applied for this purpose. However, generalizability and transportability studies present challenges, particularly around the strength of their conclusions. We review and summarize state-of-the-art methods for translating trial findings to target populations. We additionally provide a novel step-by-step guide to address these challenges, illustrating principles through a published case study. When conducted with rigor, generalizability and transportability studies can play an integral role in regulatory decisions by providing key real-world evidence.

An observational analysis of disease burden in patients with cold agglutinin disease: Results from a large US electronic health record database.

BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA). Information regarding the impact of CAD from the patient and health care system perspective is limited. OBJECTIVE: To understand longitudinal trends in outcomes in patients with CAD, including anemia severity, hemolytic status, administration of CAD-related therapies, and health care resource utilization (HCRU). METHODS: This retrospective, observational cohort study used data from the US Optum Electronic Health Record database. Included patients were aged 18 years and older at the index date (first CAD mention in physician"s notes), had 1 or more medical encounters with an AIHA-related diagnosis code during the study period, and had 3 or more CAD mentions during the patient identification period (January 2008 to March 2019). The baseline period was the 12 months preceding the index date. Anemia severity (severe, hemoglobin < 8.0 g/dL; moderate, 8.0-10.0 g/dL; mild, 10.1-11.9 g/dL; no anemia, ≥ 12.0 g/dL) and hemolytic status (elevated lactate dehydrogenase [LDH; > 250 µ/L] and/or elevated bilirubin [> 1.2 mg/dL]) were assessed at baseline and 6-monthly followup intervals. Use of CAD-related therapies, blood transfusions, and all-cause HCRU were analyzed every 6 months; results were stratified by anemia severity. RESULTS: The analysis included 610 adults with CAD (median [interquartile range; IQR] age 72.0 [61.0-78.0] years; 65.4% female). Median (IQR) duration of follow-up was 42.8 (22.8-68.4) months. The proportion of patients with moderate/severe anemia was 51.0% at baseline, 57.7% over 12 months' follow-up, and 66.6% over full follow-up. During the full follow-up period, approximately 50% of patients had elevated bilirubin and LDH levels. Corticosteroids were the most frequently used medication (65.6% of patients) over full follow-up. Mean (SD) number of blood transfusions per patient was 3.26 (9.21) over 12 months and 5.47 (17.11) over the full follow-up. At full follow-up, 68.7% of patients with severe anemia received a transfusion vs 12.6% and 0.0% with moderate or mild anemia, respectively. At 12 months, 34.1%, 97.7%, and 29.3% of patients had 1 or more hospitalizations, outpatient services, or emergency department visits (full follow-up: 52.5%, 99.0%, and 53.9%), respectively. Across all time periods, HCRU was greater in patients with severe anemia vs mild or moderate anemia. CONCLUSIONS: CAD imposed a substantial long-term burden on patients and health care systems, and despite the use of several therapies, hemolysis and anemia still occurred. The use of CAD-related therapies and HCRU was generally greater with greater anemia severity. These results suggest a lack of effective treatment options available for patients with CAD at the time of this analysis. DISCLOSURES: This study was sponsored by Sanofi. Dr Wilson, Dr Joly, Mr Carita, and Ms Miles are employees and stockholders of Sanofi. Dr Adeyemi was an employee and may have held stocks at Sanofi at the time of the study. Ms Miles and Ms Kuang were employees of Aetion Inc at the time of this study; Aetion Inc is a software company that received funding from Sanofi for the current study. Dr Pham is a consultant for Sanofi and Argenx.

Data Mining of Free-Text Responses: An Innovative Approach to Analyzing Patient Perspectives on Treatment for Chronic Rhinosinusitis with Nasal Polyps in a Phase IIa Proof-of-Concept Study for Dupilumab.

PURPOSE: Patient perspective is an important and increasingly sought-after complement to clinical assessment. The aim of this study was to transcribe individual patients' experience of treatment in a dupilumab clinical trial through free-text responses with analysis using natural language processing (NLP) to obtain the unique perspective of patients on disease impact and unmet needs with existing treatment to inform future trial design. PATIENTS AND METHODS: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) who were enrolled in a Phase IIa randomized controlled trial comparing dupilumab with placebo (NCT01920893) were invited to complete a self-assessment of treatment (SAT) tool at the end of treatment, asking, "What is your opinion on the treatment you had during the trial? What did you like or dislike about the treatment?" Free-text responses were analyzed for the overall cohort and according to treatment assignment using natural language processing including sentiment scoring. In a mixed-methods approach, quantitative patient-reported outcome (PRO) results were utilized to complement the qualitative analysis of free-text responses. RESULTS: Of 60 patients enrolled in the study, 43 (71.6%) completed the SAT and responses from 37 patients were analyzed (placebo, n = 16; dupilumab, n = 21). Word analyses showed that the most common words were "smell," "improve," "staff," "great," "time," and "good." Across the whole cohort, "smell" was the most common symptom-related word. The words "smell" and "experience" were more likely to occur in patients treated with dupilumab. Patients treated with dupilumab also had more positive sentiment in their SAT responses than those who received placebo. The results from this qualitative analysis were reflected in quantitative PRO results. CONCLUSION: "Smell" was important to patients with CRSwNP, highlighting its importance as a patient-centric efficacy outcome measure in the context of clinical trials in CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01920893. Registered 12 August 2013, https://www.clinicaltrials.gov/ct2/show/NCT01920893.

Indirect Treatment Comparison of the Efficacy and Safety of Sarilumab Monotherapy in Rheumatoid Arthritis Patients with Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs.

INTRODUCTION: To evaluate the comparative efficacy and safety of subcutaneous sarilumab 200 mg monotherapy administered every 2 weeks (q2w) versus other monotherapies of biologic, targeted and conventional synthetic disease-modifying antirheumatic drugs (bDMARDs, tsDMARDs, csDMARDs) at recommended doses for treatment of rheumatoid arthritis in patients who are intolerant of or inadequate responders to csDMARDs (csDMARD-IR). METHODS: A systematic literature review and network meta-analysis (NMA) were conducted on 24-week efficacy outcomes: Health Assessment Questionnaire Disability Index (HAQ-DI) score, American College of Rheumatology (ACR) 20/50/70 criteria, and European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28) < 2.6. In addition, serious infections and serious adverse events (SI/SAE) were examined at 24 weeks. RESULTS: Nine trials were selected for the NMA. Sarilumab 200 mg showed superiority versus adalimumab monotherapy on all efficacy outcomes and versus tofacitinib monotherapy on ACR20. Compared with csDMARDs, sarilumab 200 mg showed superiority on ACR 20/50/70 criteria and DAS28 < 2.6 but had similar efficacy on HAQ-DI. Efficacy of sarilumab 200 mg was similar versus certolizumab, etanercept, tofacitinib and tocilizumab 8 mg/kg monotherapy across all efficacy outcomes. SI/SAE appeared similar for sarilumab 200 mg versus all comparators. CONCLUSION: In csDMARD-IR patients, sarilumab 200 mg monotherapy has superior efficacy and similar safety versus csDMARDs, superior efficacy and similar safety versus adalimumab, and similar efficacy and safety versus bDMARDs and tsDMARDs. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.

Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor α inhibitors: systematic literature review and network meta-analyses.

Objective: To compare efficacy and safety of subcutaneous sarilumab 200 mg and 150 mg every 2 weeks plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARDs) versus other targeted DMARDs+csDMARDs and placebo+csDMARDs, in inadequate responders to csDMARDs (csDMARD-IR) or tumour necrosis factor α inhibitors (TNFi-IR). Methods: Systematic literature review and network meta-analyses (NMA) conducted on 24 week efficacy and safety outcomes: Health Assessment Questionnaire Disability Index, modified total sharp score (mTSS, including 52 weeks), American College of Rheumatology (ACR) 20/50/70, European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28)<2.6; serious infections/serious adverse events (including 52 weeks). Results: 53 trials were selected for NMA. csDMARD-IR: Sarilumab 200 mg+csDMARDs and 150 mg+csDMARDs were superior versus placebo+csDMARDs on all outcomes. Against most targeted DMARDs, sarilumab 200 mg showed no statistically significant differences, except superiority to baricitinib 2 mg, tofacitinib and certolizumab on 24 week mTSS. Sarilumab 150 mg was similar to all targeted DMARDs. TNFi-IR: Sarilumab 200 mg was similar to abatacept, golimumab, tocilizumab 4 mg and 8 mg/kg intravenously and rituximab on ACR20/50/70, superior to baricitinib 2 mg on ACR50 and DAS28<2.6 and to abatacept, golimumab, tocilizumab 4 mg/kg intravenously and rituximab on DAS28<2.6. Sarilumab 150 mg was similar to targeted DMARDs but superior to baricitinib 2 mg and rituximab on DAS28<2.6 and inferior to tocilizumab 8 mg on ACR20 and DAS28<2.6. Serious adverse events, including serious infections, appeared similar for sarilumab versus comparators. Conclusions: Results suggest that in csDMARD-IR and TNFi-IR (a smaller network), sarilumab+csDMARD had superior efficacy and similar safety versus placebo+csDMARDs and at least similar efficacy and safety versus other targeted DMARDs+csDMARDs.

Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA.

AIMS: To evaluate short- and long-term glycaemic control and hypoglycaemia incidence in insulin-naïve patients ≥30 years of age with type 2 diabetes (T2DM) initiating basal insulin (BI) with or without oral anti-hyperglycaemic drugs (OADs). METHODS: This was an observational, retrospective longitudinal analysis of electronic medical records from 5 European countries and the USA. A multivariable logistic regression model assessed baseline and short-term (0-3 months post BI initiation) factors associated with long-term (3-24 months) glycaemic control and hypoglycaemia. RESULTS: Overall, 40 627 patients were included; 20.9% and 27.8% achieved the general HbA1c target of ≤7% at 3 and 24 months post BI initiation, respectively. Failure to achieve HbA1c ≤7% at 3 months was associated with increased risk of failing to achieve target at 24 months (odds ratio [OR], 3.70 [95% CI, 3.41-4.00]). Over 24 months, 8.9% of patients experienced a recorded hypoglycaemic event. Hypoglycaemia during the initial 3-month period was associated with longer-term risk of these events over the ensuing 3 to 24 months (OR, 5.71 [95% CI, 4.67-6.99]). CONCLUSIONS: Initiating BI with or without OADs is associated with short- and long-term suboptimal glycaemic control; the majority of patients fail to achieve HbA1c target ≤7% in the first 3 months, or after 2 years of BI treatment. Treatment response and hypoglycaemia incidence by 3 months post BI initiation are associated with longer-term glycaemic control and hypoglycaemic risk, respectively. These results support the need for early anti-hyperglycaemic interventions that more effectively control blood glucose levels without increasing the risk of hypoglycaemia.

Alzheimer's Disease Severity is Not Significantly Associated with Short Sleep: Survey by Actigraphy on 208 Mild and Moderate Alzheimer's Disease Patients.

BACKGROUND: In epidemiological surveys, cognitive decline has been found to be associated with both short and long sleep duration. OBJECTIVE: Our goal was to objectively determine how total sleep time (TST) at night was associated or not with apathy or severity scores in patients with Alzheimer 's disease (AD). METHODS: During an observational first step of a clinical trial, sleep was assessed in institutionalized patients with mild or moderate AD using actigraphy (MW8, Camtech, Cambridge, UK) for 14 consecutive 24-hour periods. Sleep parameters analyzed were: TST, time in bed (TIB), wake after sleep onset (WASO), sleep efficiency (SE) defined by the ratio TST/TIB, in percentage), the number and length of awakenings, the night fragmentation index, the interdaily stability, and intradaily variability indexes. Statistical association analyses were tested between these values and AD apathy and severity scores. RESULTS: 208 individuals coming from 82 centers worldwide (France, Germany, Spain, Italy, Portugal, Poland, United States, Canada, and Australia) and≥50 years old participated. Their average TST was 7 hours and 35 minutes and the average WASO 58 minutes. TST and SE were significantly higher in patients with apathy and the number of awakenings was significantly lower. TST was also positively associated with functional disability (ADCS-ADL scores), but it was not found significantly greater in patients with a moderate AD severity compared to the mild. CONCLUSION: Despite several and long awakenings, TST was not shorter in patients with AD. TST was even significantly increased with disability and apathy.

Multinational development of a questionnaire assessing patient satisfaction with anticoagulant treatment: the 'Perception of Anticoagulant Treatment Questionnaire' (PACT-Q).

BACKGROUND: The side effects and burden of anticoagulant treatments may contribute to poor compliance and consequently to treatment failure. A specific questionnaire is necessary to assess patients' needs and their perceptions of anticoagulant treatment. METHODS: A conceptual model of expectation and satisfaction with anticoagulant treatment was designed by an advisory board and used to guide patient (n = 31) and clinician (n = 17) interviews in French, US English and Dutch. Patients had either atrial fibrillation (AF), deep venous thrombosis (DVT), or pulmonary embolism (PE). Following interviews, three PACT-Q language versions were developed simultaneously and further pilot-tested by 19 patients. Linguistic validations were performed for additional language versions. RESULTS: Initial concepts were developed to cover three areas of interest: 'Treatment', 'Disease and Complications' and 'Information about disease and anticoagulant treatment'. After clinician and patient interviews, concepts were further refined into four domains and 17 concepts; test versions of the PACT-Q were then created simultaneously in three languages, each containing 27 items grouped into four domains: "Treatment Expectations" (7 items), "Convenience" (11 items), "Burden of Disease and Treatment" (2 items) and "Anticoagulant Treatment Satisfaction" (7 items). No item was deleted or added after pilot testing as patients found the PACT-Q easy to understand and appropriate in length in all languages. The PACT-Q was divided into two parts: the first part to measure the expectations and the second to measure the convenience, burden and treatment satisfaction, for evaluation prior to and after anticoagulant treatment, respectively. Eleven additional language versions were linguistically validated. CONCLUSION: The PACT-Q has been rigorously developed and linguistically validated. It is available in 14 languages for use with thromboembolic patients, including AF, PE and DVT patients. Its validation and psychometric properties have been tested and are presented in a separate manuscript.

A French cost-consequence analysis of the renoprotective benefits of irbesartan in patients with type 2 diabetes and hypertension.

OBJECTIVES: We performed a cost-consequence analysis in a French setting of the renoprotective benefit of irbesartan in hypertensive type 2 diabetes patients over a 25-year period. RESEARCH DESIGN AND METHODS: A previously published Markov model simulated progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease and death. Three treatment strategies with analogous blood pressure control were compared: (A) control--conventionally medicated antihypertensive therapy (excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonists and dihydropyridine calcium channel blockers) initiated at microalbuminuria; (B) early irbesartan--(300 mg daily added to control, initiated with microalbuminuria) and (C) late irbesartan--(300 mg daily, initiated with overt nephropathy). Probabilities came from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial and other sources. Clinical and economic outcomes were projected over 25 years. Annual discount rates were 3%. RESULTS: Compared to control, early use of irbesartan added (mean +/- standard deviation) 1.51 +/- 0.08 undiscounted life years (discounted: 0.94 +/- 0.05 years), while late irbesartan added 0.07 +/- 0.01 (0.04 +/- 0.01) years/patient. Early irbesartan added 1.03 +/- 0.06 discounted quality-adjusted life years (QALYs), while late irbesartan added 0.06 +/- 0.01 QALYs. Early and late irbesartan treatments were projected to save 22,314 +/- 1273 euro and 6619 +/- 820 euro/patient, respectively versus control. Sensitivity analysis showed that even over short time horizons both irbesartan treatments were superior to the control group. CONCLUSIONS: In France, early irbesartan treatment improved quality and length of life and reduced costs in hypertensive patients with type 2 diabetes and microalbuminuria. Late irbesartan therapy is beneficial, but earlier irbesartan leads to better outcomes.

Irbesartan is projected to be cost and life saving in a Spanish setting for treatment of patients with type 2 diabetes, hypertension, and microalbuminuria.

OBJECTIVES: The purpose of this study was to project the cumulative incidence of end-stage renal disease (ESRD), life expectancy, and costs in a Spanish setting of treating patients with diabetes, hypertension, and microalbuminuria with either standard hypertension treatment alone or standard hypertension treatment plus irbesartan 300 mg daily. METHODS: A peer-reviewed, published Markov model that simulated progression from microalbuminuria to nephropathy, doubling of serum creatinine, ESRD, and all-cause mortality in patients with hypertension, type 2 diabetes, and microalbuminuria was adapted to a Spanish setting. Two strategies were compared: (1) irbesartan versus (2) standard hypertension care with comparable blood pressure control; both began in diabetic hypertensive subjects with microalbuminuria. Cumulative incidence of ESRD, costs, and life expectancy were projected for a hypothetical cohort of 1000 subjects. Future costs and life expectancy were discounted at 3% yearly. A 25-year time horizon and third party payer perspective were used. RESULTS: When compared to standard blood pressure control, irbesartan was projected to reduce the cumulative incidence of ESRD from (mean +/- standard deviation) 24 +/- 1% to 9 +/- 2%, save 11,082 +/- 2,996 euro, and add 1.40 +/- 0.27 life years per treated patient. The superiority of irbesartan over standard care was robust under a wide range of plausible assumptions. CONCLUSION: Treating patients with hypertension, microalbuminuria, and type 2 diabetes with irbesartan was projected to reduce the incidence of ESRD, extend life, and reduce costs.

Cost-effectiveness of early irbesartan treatment versus control (standard antihypertensive medications excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease.

OBJECTIVE: The aim of this study was to determine the most cost-effective time point for initiation of irbesartan treatment in hypertensive patients with type 2 diabetes and renal disease. RESEARCH DESIGN AND METHODS: This study was a Markov model-simulated progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease, and death in hypertensive patients with type 2 diabetes. Two irbesartan strategies were created: early irbesartan 300 mg daily (initiated with microalbuminuria) and late irbesartan (initiated with overt nephropathy). These strategies were compared with control, which consisted of antihypertensive therapy with standard medications (excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) with comparable blood pressure control, initiated at microalbuminuria. Transition probabilities were taken from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial, and other published sources. Costs and life expectancy, discounted at 3% yearly, were projected over 25 years for 1,000 simulated patients using a third-party payer perspective in a U.S. setting. RESULTS: Compared with control, early and late irbesartan treatment in 1,000 patients were projected to save (mean +/- SD) 11.9 +/- 3.3 million dollars and 3.3 +/- 2.7 million dollars, respectively. Early use of irbesartan added 1,550 +/- 270 undiscounted life-years (discounted 960 +/- 180), whereas late irbesartan added 71 +/- 40 life-years (discounted 48 +/- 27) in 1,000 patients. Early irbesartan treatment was superior under a wide-range of plausible assumptions. CONCLUSIONS: Early irbesartan treatment was projected to improve life expectancy and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria. Later use of irbesartan in overt nephropathy is also superior to standard care, but irbesartan should be started earlier and continued long term.

European psychometric validation of the CONTILIFE: a Quality of Life questionnaire for urinary incontinence.

OBJECTIVE: To validate 5 language versions (French, Dutch, German, English and Danish) of CONTILIFE, a urinary incontinence-specific measure of Quality of Life (QoL). METHODS: CONTILIFE was administered to Belgian, Danish, English, French, German, and Dutch women with genuine stress incontinence. The internal consistency, the construct and clinical validity, and the responsiveness to change over time were assessed using standardised procedures. RESULTS: 505 women filled in the CONTILIFE at baseline. Quality of completion was good. The mean number of missing data varied between 0.33 (1.17%) and 0.94 (3.36%) according to the country. Internal consistency was good for all dimensions except for the Effort Activities dimension. Construct validity was good for the Danish, French and pooled sample, and acceptable for English, German and Dutch samples. The distribution of QoL scores differed according to the number of urinary leaks (p<0.007). 477 women completed the questionnaire twice with a 28-day interval. Responsiveness to clinical improvement was good (/ES/> or =0.50) except for the Sexuality and Well-Being dimensions. CONCLUSION: In this international European study, CONTILIFE matched the psychometric requirements to be used as a valid, reliable, and sensitive measure of the QoL of the patients. The Daily Activities, Effort Activities, Self-Image and Emotional Consequences dimensions are the most relevant and valid dimensions for purposes of comparison.