Search Results (11)

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by complement-mediated hemolytic anemia and thrombosis. The first treatments approved were complement 5 inhibitors (C5is), eculizumab and ravulizumab. Recently approved treatments include pegcetacoplan, iptacopan, danicopan (as an add-on to a C5i), and crovalimab. Methods: A systematic literature review (SLR) was conducted to identify clinical evidence on all available treatments. Outcomes evaluated were hemoglobin and lactate dehydrogenase (LDH) levels, transfusion avoidance, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and safety. Results: In total, 133 records met the inclusion criteria. Of these, 54 records reporting on 11 Phase 3 trials and 2 extension studies are summarized. Eight trials and one extension study evaluated complement inhibitor (CI)-naïve patients, three trials evaluated CI-experienced patients with residual anemia, and one extension study evaluated both groups. In both patient groups, all treatments led to improved outcomes. Conclusions: This SLR is the first to provide an overview of clinical trials assessing the efficacy and safety of all currently approved PNH treatments, which could help inform clinical decisions. Although some head-to-head trials are available, direct comparative evidence remains limited for several comparators, necessitating an indirect treatment comparison (ITC) to assess the efficacy and safety across the treatment landscape. Full article

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group’s (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies. Full article

The application of the Health Technology Assessment Regulation (HTAR) gives way to joint European work, such as the Joint Clinical Assessment (JCA). This requires the definition of a PICO (Population–Intervention–Comparator–Outcome) question representative of all the member states of the European Union. The key to answering the PICO will be the synthesis of evidence through direct comparisons when there are randomized clinical trials (RCTs) including the same comparators, and via indirect treatment comparisons (ITCs) when comparators differ across RCTs. The aim of this report is to provide a synthesized and clear methodological framework to guide those stakeholders involved in JCAs when interpreting the results of ITCs, including descriptions on: (1) assumptions associated with ITCs; (2) how to select the method for ITC; (3) strengths and limitations associated with the methods; and (4) basics for understanding the method for ITC. This methodological framework could help those health care institutions, patient associations, consumer organizations, health-related nongovernmental organizations, health technology developers, and healthcare professionals involved in JCAs to better understand ITCs and incorporate this evidence into decision-making. Full article

Gene therapies that induce the body to produce therapeutic anti-vascular endothelial growth factor (anti-VEGF) proteins are an emerging topic related to neovascular age-related macular degeneration (nAMD). Continuous delivery of anti-VEGF protein directly to the target tissue offers the possibility of lifelong efficacy without the need for repeated and frequent eye injections. This novel approach could revolutionize patient management through optimizing clinical outcomes while simplifying service delivery. However, such gene therapies are anticipated to face unique challenges related to patients’ access and health technology assessment (HTA), and their integration into real-world eyecare practices. This article presents key elements raised at the European Access Academy (EAA) Fall convention (held in Rome in October 2024) regarding anticipated HTA challenges for gene therapies in nAMD. The important role of HTA and policymakers in ensuring that emerging gene therapies are accessible to all eligible patients is also highlighted. This article mainly focuses on the need for a fit-for-purpose EU HTA framework to address the widely varying utilization of standard of care in nAMD clinical practice, and to incorporate considerations about the long-term durability of gene therapies in nAMD. The importance of integrating real-world evidence (RWE) into the EU HTA framework is also discussed. Full article

The dynamic nature of infectious diseases introduces inherent challenges to the design of vaccine clinical trials, which consequently makes vaccine indirect treatment comparisons (ITCs) and meta-analyses (MAs) more challenging compared with regular pharmaceuticals. However, comparisons of efficacy and safety between vaccines are being frequently required in vaccine decision making due to a low number of head-to-head clinical trials in the vaccine landscape. The introduction of the European Union Health Technology Assessment (HTA) Regulation (EU HTAR) aims to harmonize HTA efforts across Europe. However, the EU HTAR could also escalate existing challenges for conducting vaccine MAs and ITCs. Such challenges include generating efficacy evidence in time for Joint Clinical Assessment (JCA), incorporating high levels of heterogeneity due to infectious disease-specific characteristics, and tackling a high number of PICOs per submission—likely driven by heterogeneity in the available data and differences in national vaccine calendars. Opportunities to tackle these challenges include introducing a stepwise approach to vaccine assessment in JCA, best-practice recommendations for conducting/interpreting vaccine MAs and ITCs, and condensing the number of PICOs to create larger ‘catch-all’ ITC networks. This perspective article explores these challenges and opportunities further. Full article

Background: Chimeric antigen receptor T-cell (CAR-T) therapies have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of diffuse large B-cell lymphoma (DLBCL), primarily based on single-arm trials or indirect comparisons with stem cell transplantation. However, no direct head-to-head comparisons of CAR-T therapies have been conducted, largely due to their high cost. To assess their true value, indirect treatment comparisons (ITCs) are essential. These comparisons, however, are prone to confounding biases, which necessitate careful adjustments through the identification and measurement of relevant variables. Materials and Methods: This study aims to identify the variables used for adjustment in ITCs of CAR-T therapies for DLBCL and examine the methodologies employed to select them. A rapid literature review was conducted in PubMed in September 2023, focusing on ITCs involving CAR-T therapies for DLBCL. The search was based on keywords categorized into three groups: techniques (ITCs and related terms), drugs (CAR-T therapies), and indication (DLBCL). Results: The rapid literature review identified 21 articles, of which 11 were selected for analysis. Exclusions were made for articles that did not identify confounders, were letters to editors, or addressed conditions other than DLBCL. Among the 11 selected publications, 10 did not clearly specify the methodology used to identify adjustment variables. A total of 25 potential confounders were identified across the studies, with substantial variability in the set of variables used, reflecting a lack of standardization in confounder selection. Commonly identified confounders included the number of prior treatment lines and Eastern Cooperative Oncology Group Performance Status (ECOG PS), although their inclusion as adjustment variables in ITCs was inconsistent, often due to missing data. Conclusions: While the identified confounders are clinically relevant, the methodologies for selecting them remain unclear, resulting in significant variability across studies. Additionally, key variables commonly considered in health technology assessments (HTAs), such as age, sex, and disease severity, were inconsistently incorporated into ITCs. To improve the reliability and consistency of ITC outcomes, there is a pressing need for standardized methodologies for identifying and adjusting for confounders. Full article

Introduction: Health technology assessment (HTA) agencies express a clear preference for randomized controlled trials when assessing the comparative efficacy of two or more treatments. However, an indirect treatment comparison (ITC) is often necessary where a direct comparison is unavailable or, in some cases, not possible. Numerous ITC techniques are described in the literature. A systematic literature review (SLR) was conducted to identify all the relevant literature on existing ITC techniques, provide a comprehensive description of each technique and evaluate their strengths and limitations from an HTA perspective in order to develop guidance on the most appropriate method to use in different scenarios. Methods: Electronic database searches of Embase and PubMed, as well as grey literature searches, were conducted on 15 November 2021. Eligible articles were peer-reviewed papers that specifically described the methods used for different ITC techniques and were written in English. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 73 articles were included in the SLR, reporting on seven different ITC techniques. All reported techniques were forms of adjusted ITC. Network meta-analysis (NMA) was the most frequently described technique (in 79.5% of the included articles), followed by matching-adjusted indirect comparison (MAIC) (30.1%), network meta-regression (24.7%), the Bucher method (23.3%), simulated treatment comparison (STC) (21.9%), propensity score matching (4.1%) and inverse probability of treatment weighting (4.1%). The appropriate choice of ITC technique is critical and should be based on the feasibility of a connected network, the evidence of heterogeneity between and within studies, the overall number of relevant studies and the availability of individual patient-level data (IPD). MAIC and STC were found to be common techniques in the case of single-arm studies, which are increasingly being conducted in oncology and rare diseases, whilst the Bucher method and NMA provide suitable options where no IPD is available. Conclusion: ITCs can provide alternative evidence where direct comparative evidence may be missing. ITCs are currently considered by HTA agencies on a case-by-case basis; however, their acceptability remains low. Clearer international consensus and guidance on the methods to use for different ITC techniques is needed to improve the quality of ITCs submitted to HTA agencies. ITC techniques continue to evolve quickly, and more efficient techniques may become available in the future. Full article

The aim of this study was to evaluate the comparative clinical effectiveness and cost-utility of the active transcutaneous Osia^® System versus the passive transcutaneous Baha^® Attract System for patients with conductive or mixed hearing loss or single-sided deafness in an Australian healthcare setting. In the absence of direct comparative evidence, an indirect treatment comparison (ITC) of the clinical effectiveness and utility gains was needed. The ITC was informed by three studies identified through a systematic literature review. A Markov model was developed to evaluate the cost-utility of the Osia System. The literature review identified three studies suitable to inform an ITC: Mylanus et al. 2020 and Briggs et al. 2022 (Osia System) and den Besten et al. 2019 (Baha Attract System). The Osia System was found to be clinically superior to the Baha Attract System, across objective audiological outcomes resulting in a clinically meaningful utility benefit of 0.03 measured by the Health Utility Index with at least equivalent safety. In conclusion, the Osia System is more effective than the Baha Attract System, providing better hearing and health-related quality of life outcomes. In an Australian healthcare setting, the Osia System is cost-effective as demonstrated in a cost-utility analysis versus the Baha Attract System. Full article

(1) Background: The relative efficacy and safety of brigatinib compared with other next-generation anaplastic lymphoma kinase (ALK) inhibitors remains unclear, as first-line head-to-head trials have not been conducted. (2) Methods: Electronic databases were systematically searched for eligible randomized controlled trials (RCT) from January 2010 to October 2021. Outcomes evaluated by indirect treatment comparison (ITC) included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. (3) Results: Nine RCTs with 2484 patients assessing crizotinib, ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib were included. In intent-to-treat (ITT) patients, brigatinib significantly prolonged blinded independent review committee-assessed PFS compared with crizotinib (HR: 0.48, 95% CI: 0.35 to 0.66) and ceritinib (HR: 0.38, 95% CI: 0.23, 0.60) and had a comparable PFS with other 2nd-generation ALK inhibitors. Subgroup analyses of patients with baseline brain metastases and Asian patients yielded results similar to the base case. Brigatinib significantly reduced the risk of death compared with crizotinib (HR: 0.50, 95% CI: 0.28, 0.87) after adjusting for treatment crossover in the crizotinib arm. No significant differences were observed in OS between brigatinib and other next-generation ALK inhibitors. Brigatinib had significantly superior effects in ORR and intracranial ORR compared to crizotinib. The incidence of grade ≥3 AEs was similar between brigatinib and other next-generation ALK inhibitors (except for alectinib), while brigatinib could significantly delay the time to worsening in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status (GHS)/quality of life (QoL) vs. crizotinib (HR: 0.69, 95% CI: 0.49, 0.98). (4) Conclusions: Brigatinib had longer PFS compared to crizotinib and ceritinib and had comparable efficacy and safety profile with other 2nd-generation ALK inhibitors in first-line treatments for patients with ALK-positive non-small-cell lung cancer. Full article

Selecting a first-line (1L) maintenance option for ovarian cancer is challenging given the variety of therapies, differing trials, and the lack of head-to-head data for angiogenesis and poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, indirect treatment comparisons (ITCs) can aid treatment decision making. This study assessed the feasibility of two ITCs, a network meta-analysis (NMA) and a population-adjusted ITC (PAIC), comparing the efficacy of the PARP inhibitor niraparib in the PRIMA trial (NCT02655016) with other 1L maintenance treatments. A systematic literature review was conducted to identify trials using the Cochrane Handbook for Systematic Reviews of Interventions to assess differences in trial design, population characteristics, treatment arms, and outcome measures. All 12 trials identified were excluded from the NMA due to the absence of a common comparator and differences in survival measures and/or inclusion criteria. The PAIC comparing PRIMA and PAOLA-1 trials was also not feasible due to differences in inclusion criteria, survival measures, and the previous receipt of chemotherapy/bevacizumab. Neither ITC met recommended guidelines for analysis; the results of such comparisons would not be considered appropriate evidence when selecting 1L maintenance options in ovarian cancer. ITCs in this setting should be performed cautiously, as many factors can preclude objective trial comparisons. Full article

To date, no head-to-head trials have compared the efficacy of brigatinib and alectinib against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve, advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib as a common comparator, using a Bayesian model with non-informative prior distribution and assessed the between-study heterogeneity of the studies. The primary efficacy endpoint was progression-free survival (PFS), and efficacy was ranked using the surface under the cumulative ranking (SUCRA) curve values. ITC analysis showed that there were no significant differences in PFS between the brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest by efficacy in the overall patient population, whereas brigatinib ranked the highest by efficacy in the CNS metastasis sub-group. Although there were no significant differences in the incidence of G3–5 adverse events between the brigatinib and alectinib arms in the overall patient population, the data were deemed insufficient for the CNS metastasis sub-group analysis. This study provides critical information to clinicians regarding the efficacy of brigatinib for ALK-p, ALK-inhibitor-naïve, advanced NSCLC patients, with and without CNS metastasis. Larger randomized, controlled trials are warranted to confirm our results. Full article