Population Adjustment Methods for Indirect Comparisons: A Review of National Institute for Health and Care Excellence Technology Appraisals

AbstractObjectivesIndirect comparisons via a common comparator (anchored comparisons) are commonly used in health technology assessment. However, common comparators may not be available, or the comparison may be biased due to differences in effect modifiers between the included studies. Recently proposed population adjustment methods aim to adjust for differences between study populations in the situation where individual patient data are available from at least one study, but not all studies. They can also be used when there is no common comparator or for single-arm studies (unanchored comparisons). We aim to characterise the use of population adjustment methods in technology appraisals (TAs) submitted to the United Kingdom National Institute for Health and Care Excellence (NICE).MethodsWe reviewed NICE TAs published between 01/01/2010 and 20/04/2018.ResultsPopulation adjustment methods were used in 7 percent (18/268) of TAs. Most applications used unanchored comparisons (89 percent, 16/18), and were in oncology (83 percent, 15/18). Methods used included matching-adjusted indirect comparisons (89 percent, 16/18) and simulated treatment comparisons (17 percent, 3/18). Covariates were included based on: availability, expert opinion, effective sample size, statistical significance, or cross-validation. Larger treatment networks were commonplace (56 percent, 10/18), but current methods cannot account for this. Appraisal committees received results of population-adjusted analyses with caution and typically looked for greater cost effectiveness to minimise decision risk.ConclusionsPopulation adjustment methods are becoming increasingly common in NICE TAs, although their impact on decisions has been limited to date. Further research is needed to improve upon current methods, and to investigate their properties in simulation studies.</jats:sec

Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries

BACKGROUND: There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used endpoints in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL) varies, leading to the available evidence being valued differently. This research studies the extent to which the value of endpoints for cancer medicines differs among European decision makers. METHODS: We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, Netherlands, Poland and Scotland. Anticancer medicines that received marketing authorisation in Europe between 2011-2013 with at least four available national REAs were evaluated. A total of 79 REAs were included. RESULTS: Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant endpoints such as OS and QoL above surrogate endpoints. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant endpoint. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred endpoint by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies. CONCLUSIONS: European decision making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general

Comparison of overall survival of lisocabtagene maraleucel (liso-cel) versus standard of care (SOC) adjusting for crossover in second-line (2L) R/R large B-cell lymphoma

International audienceIntroduction: TRANSFORM (NCT03575351) is a multinational, phase 3 study that compared efficacy and safety of liso-cel versus SOC, including overall survival (OS) as a key secondary endpoint, as a 2L treatment for patients (pt) with relapsed/refractory (R/R) large B-cell lymphoma who were eligible for transplant. The study design permitted pts treated with 2L SOC to receive liso-cel as third line (3L) treatment if protocol-defined conditions were met and requested by investigators. The intention-to-treat (ITT) analysis of OS for liso-cel versus SOC in TRANSFORM addressed a specific research question that did not account for treatment switching. Additionally, as real-world use of chimeric antigen receptor (CAR) T cell therapies in 3L may be less common compared with TRANSFORM, the ITT analysis may provide a conservative estimate of the treatment effect for liso-cel versus SOC on OS. Here, we conducted a complementary analysis of OS to adjust for crossover and estimate the relative effect of liso-cel versus SOC in the absence of 3L CAR T cell therapy.Methods: An external control arm based on external data from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) phase 3 study (NCT00137995) was created using the inverse probability of treatment weighting (IPTW) method. CORAL provided relatively mature survival data and reflects OS in the absence of CAR T cell therapies, which were not available at the time CORAL was conducted. After aligning inclusion/exclusion criteria of the 2 studies, 258 pts from CORAL were retained. To control for confounding, the 2L SOC cohort from CORAL was weighted to match the baseline distributions of prognostic factors and treatment effect modifiers of the liso-cel population in TRANSFORM. Relative efficacy was estimated by fitting a weighted Cox regression model to survival data for the external SOC arm from CORAL and the liso-cel arm from TRANSFORM.Results: After population adjustment via IPTW, the effective sample size (ESS) for SOC (CORAL) was 43.6% of the unadjusted sample size. The IPTW approach generally reduced imbalances in baseline characteristics between the 2 populations. The adjusted hazard ratio (HR; 95% CI) for liso-cel versus SOC was 0.50 (0.32–0.78), indicating that liso-cel was associated with a survival benefit in comparison with SOC in the absence of treatment switching (Table).Conclusions: These analyses demonstrated that liso-cel is associated with prolonged OS in comparison with SOC under a scenario of no 3L CAR T cell therapy, and the consideration of external data is a suitable alternative to existing statistical methods to adjust for treatment switching

Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries

BACKGROUND: There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used endpoints in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL) varies, leading to the available evidence being valued differently. This research studies the extent to which the value of endpoints for cancer medicines differs among European decision makers. METHODS: We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, Netherlands, Poland and Scotland. Anticancer medicines that received marketing authorisation in Europe between 2011-2013 with at least four available national REAs were evaluated. A total of 79 REAs were included. RESULTS: Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant endpoints such as OS and QoL above surrogate endpoints. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant endpoint. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred endpoint by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies. CONCLUSIONS: European decision making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general

Cuba en sus relaciones con el resto del Caribe : continuidades y rupturas tras el restablecimiento de las relaciones diplomáticas entre Cuba y los Estados Unidos

La doctrina de Obama fomentó y facilitó un nivel de compromiso con Cuba que cambió fundamentalmente las relaciones bilaterales entre Cuba y los Estados Unidos y la alejaron de la confrontación, contrario a sus predecesores. Durante los primeros dos años después del 17 de diciembre, el acercamiento con Cuba fue prometedor para garantizar cooperación y armonía hemisférica, así como para mayores beneficios sociales, económicos y de seguridad para Cuba y sus vecinos del Caribe. Sin embargo, a medida que el mundo se adecúa a la nueva administración en Washington, la cuestión de Cuba se ha vuelto a cargar de consideraciones geopolíticas. De hecho, la región del Caribe está atrapada en una telaraña de incertidumbre, ya que la amenaza de parte de Washington para ahogar el compromiso constructivo con Cuba es real. La presidencia de Trump ha desatado legiones de incertidumbres sobre Cuba, el Caribe y la región latinoamericana. Este libro da cuenta de el complejo entramado de relaciones en las diversas actividades de la política, la economía y las relaciones diplomáticas cubanas