Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls.

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.

Real-world data (RWD)-derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real-world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G-BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real-world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.

Trends and Outcomes of Catheter Ablation for Ventricular Tachycardia in a Community Cohort.

OBJECTIVES: This study examined the trend in growth of catheter ablation for ventricular tachycardia (VT) performed in the United States with analysis of rates and predictors of major adverse events. BACKGROUND: Sustained VT is a significant cause of sudden death, heart failure (HF), and recurrent shocks in implantable cardioverter-defibrillator (ICD) recipients. Catheter ablation for VT reduces arrhythmia recurrence. Limited data are available regarding the use, safety, and long-term outcomes after VT ablation. METHODS: Using the U.S. Medicare database linked to the Social Security Death Index, we examined the annual use of VT ablation in 21,073 patients over 12 years, with 30-day risk of mortality, nonfatal major adverse events (MAEs), 1-year risk of mortality, re-hospitalization, repeat ablation, and factors associated with adverse outcomes. RESULTS: Among 21,073 patients (age 70 ± 9 years; 77% men; 90% white), there were 1,581 (7.5%) non-fatal MAEs within 30 days. There were 963 (4.6%) vascular complications, 485 (2.3%) pericardial complications, and 201 (1%) strokes and/or transient ischemic attacks. Mechanical circulatory support use was infrequent (2.3%). The 30-day and 1-year mortality rates were 4.2% and 15.0%, respectively. The 1-year incidence of repeat ablation was 10.2 per 100 person-years and re-hospitalization for HF or VT was 15.4 per 100 person-years and 18 per 100 person-years, respectively. Patients with an ICD had increased 30-day (4.9% vs. 0.86%) and 1-year mortality (17.5% vs. 2.54% [22.9 per 100 person-years vs. 3.1 per 100 person-years]; hazard ratio [HR]: 2.93; 95% confidence interval [CI]: 2.21 to 3.88). Rates of hospitalization for HF (18 per 100 person-years vs. 1.8 per 100 person-years; HR: 4.00; 95% CI: 2.78 to 5.78) or VT recurrence (22.7 per 100 person-years vs. 2.1 per 100 person-years; HR: 5.70; 95% CI: 4.09 to 7.96) were also higher at 1 year. Between 2000 and 2012, annual VT ablation volumes increased >4-fold. CONCLUSIONS: Catheter ablation for VT is frequently performed. Short-term MAEs and 1-year mortality is significant and is highest in patients with an ICD. These findings may provide greater insight of outcomes in an unselected real-world population undergoing VT ablation.

Safety and Effectiveness of Medical Device Therapy.

When enough females and males are enrolled in clinical trials, much more relevant information is available on potential sex differences in device safety and effectiveness. Unfortunately, females have largely been underrepresented in clinical studies of cardiac medical device therapies for heart failure. In this chapter, sex differences in heart failure characteristics and cardiac electrophysiology and their influence on the safety, effectiveness, and application of implantable cardioverter defibrillators (ICDs), subcutaneous ICDs (S-ICDs), and cardiac resynchronization therapy (CRT) will be discussed. In this way, the research community will hopefully become more appreciative of the potential differences in device effects between females and males.

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

Toward Sex-Specific Guidelines for Cardiac Resynchronization Therapy?

An important treatment for patients with heart failure is cardiac resynchronization therapy (CRT). Even though only 20% of women were included in clinical trials for CRT, a benefit has been shown in recent studies for subgroups of women compared to their male counterparts. Given this low inclusion rate of women in clinical studies, professional society guideline-based CRT recommendations, such as those by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), may not truly represent the best treatment for women, especially since most of the reports that showed this greater benefit in women were published after the latest guidelines. Despite having research and multiple publications regarding sex-specific heart failure outcomes and response to CRT, the ACCF/AHA/HRS guidelines have not yet been updated to account for the recent information regarding the differences in benefit for women and men with similar patient characteristics. This review discusses the physiology behind CRT, sex-specific characteristics of heart failure, and cardiac electrophysiology and summarizes the current sex-specific literature to encourage consideration of CRT guidelines for women and men separately.

Comparative Effectiveness of Cardiac Resynchronization Therapy Defibrillators Versus Standard Implantable Defibrillators in Medicare Patients.

Previous analyses have shown that there is lower mortality with cardiac resynchronization therapy defibrillators (CRT-D) in patients with left bundle branch block (LBBB) but demonstrated mixed results in patients without LBBB. We evaluated the comparative effectiveness of CRT-D versus standard implantable defibrillators (ICDs) separately in patients with LBBB and right bundle branch block (RBBB) using Medicare claims data. Medicare records from CRT-D and ICD recipients from 2002 to 2009 that were followed up for up to 48 months were analyzed. We used propensity scores to match patients with ICD to those with CRT-D. In LBBB, 1:1 matching with replacement resulted in 54,218 patients with CRT-D and 20,763 with ICD, and in RBBB, 1:1 matching resulted in 7,298 patients with CRT-D and 7,298 with ICD. In LBBB, CRT-D had a 12% lower risk of heart failure hospitalization or death (hazard ratio [HR] 0.88, 95% confidence interval 0.86 to 0.90) and 5% lower death risk (HR 0.95, 0.92 to 0.97) compared with ICD. In RBBB, CRT-D had a 15% higher risk of heart failure hospitalization or death (HR 1.15, 1.10 to 1.20) and 13% higher death risk (HR 1.13, 1.07 to 1.18). Sensitivity analysis revealed that accounting for covariates not captured in the Medicare database may lead to increased benefit with CRT-D in LBBB and no difference in RBBB. In conclusion, in a large Medicare population, CRT-D was associated with lower mortality in LBBB but higher mortality in RBBB. The absence of certain covariates, in particular those that determine treatment selection, may affect the results of comparative effectiveness studies using claims data.

Cardiac resynchronization therapy in women versus men: observational comparative effectiveness study from the National Cardiovascular Data Registry.

BACKGROUND: Women have been under-represented in trials of cardiac resynchronization therapy-defibrillators (CRT-D). Previous studies suggest that women benefit from CRT-D at shorter QRS duration than men and that there may be no benefit of CRT-D in patients without left bundle branch block (LBBB) regardless of patient sex. METHODS AND RESULTS: We compared sex-specific death risk in 75 079 patients with New York Heart Association class III or IV heart failure, reduced left ventricular ejection fraction, and prolonged QRS duration (≥120 ms) receiving either CRT-D or implantable cardioverter defibrillator in subgroups according to QRS morphology and 10-ms increments in QRS duration. We applied propensity score weighting to control for differences between treatments. Among patients with LBBB, women receiving CRT-D had a lower relative death risk than those receiving an implantable cardioverter-defibrillator (absolute difference, 11%; hazard ratio=0.74 [95% confidence interval, 0.68-0.81]). In men, the lower mortality with CRT-D versus implantable cardioverter defibrillator was less pronounced (absolute difference, 9%; hazard ratio=0.84 [0.79-0.89]; sex×device interaction P=0.025). In those without LBBB, the mortality difference was modest and did not differ between women and men (absolute difference, 3%; hazard ratio=0.88 [0.79-0.97] in women and absolute difference, 2%; hazard ratio=0.95 [0.91-0.998] in men; interaction P=0.17). In subgroups according to QRS duration, CRT-D was associated with better survival in both sexes with LBBB and QRS ≥130 ms, whereas there was no clear relation between QRS duration and survival in patients without LBBB regardless of patient sex. CONCLUSIONS: In a large real-world population CRT-D was associated with a lower mortality risk in both sexes with LBBB, although more pronounced among women. Only among those with LBBB, both sexes had better survival with longer QRS duration. The mortality differences in patients without LBBB were attenuated in both sexes.