Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry.

Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification.

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA.

Treatment Decision Drivers in Stage III Non-Small-Cell Lung Cancer: Outcomes of a Web-Based Survey of Oncologists in the United States.

PURPOSE: We conducted a cross-sectional survey of practicing medical oncologists in the United States to obtain insight into physician and patient treatment decision making in stage III non-small-cell lung cancer (NSCLC). METHODS: A convenience sample of 150 oncologists completed a 38-question Web-based survey in January 2019. RESULTS: Surveyed oncologists (82% community based) had an average of 15 years of clinical experience and had treated an average of 20 patients newly diagnosed with stage III NSCLC in the previous 6 months. Oncologists reported presenting 55% of their patients with stage III NSCLC to tumor boards. For patients with new unresectable stage III NSCLC seen in the previous 6 months, concurrent chemoradiation therapy (cCRT) was reported as the initial treatment in an average of 48% of patients. The most frequent reason for delays in starting the initial chosen treatment was insurance preauthorization processes (reported by 65% of oncologists). A total of 55% of all patients with unresectable stage III NSCLC who received cCRT went on to receive consolidation immunotherapy; for patients who received consolidation chemotherapy after cCRT, the rate of immunotherapy was lower (42%). Biomarker test results were given as the reason for oncologists not recommending immunotherapy after cCRT in approximately a quarter of cases. The 112 oncologists with eligible patients who declined immunotherapy reported previous treatment fatigue as the reason in 34% of patients and insurance challenges in 19% of patients. CONCLUSION: Oncologists reported notable deviations from treatment guidelines for stage III NSCLC. Our findings highlight important opportunities to improve decision making and the coordination of care in stage III NSCLC.

Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group.

Precision medicine is a dynamic area embracing a diverse and increasing type of approaches that allow the targeting of new medicines, screening programs or preventive healthcare strategies, which include the use of biologic markers or complex tests driven by algorithms also potentially taking account of patient preferences. The International Society for Pharmacoeconomics and Outcome Research expanded its current work around precision medicine to (1) describe the evolving paradigm of precision medicine with examples of current and evolving applications, (2) describe key stakeholders perspectives on the value of precision medicine in their respective domains, and (3) define the core factors that should be considered in a value assessment framework for precision medicine. With the ultimate goal of improving health of well-defined patient groups, precision medicine will affect all stakeholders in the healthcare system at multiple levels spanning the individual perspective to the societal perspective. For an efficient, timely and practical precision medicine value assessment framework, it will be important to address these multiple perspectives through building consensus among the stakeholders for robust procedures and measures of value aspects, including performance of precision mechanism; aligned reimbursement processes of precision mechanism and subsequent treatment; transparent expectations for evidence requirements and study designs adequately matched to the intended use of the precision mechanism and to the smaller target patient populations; recognizing the potential range of value-generation such as ruling-in and ruling-out decisions.

Are Global Health Systems Ready for Transformative Therapies?

BACKGROUND: We have seen significant advancement in a range of health technologies, some with transformative or curative potential. Nevertheless, it is often unclear how global health systems recognize or reward innovation. OBJECTIVES: To consider what is transformative, challenges for transformative therapies, and downstream health ecosystem effects. METHODS: A systematic review of publications in English between 2012 and 2018 was conducted with a focus on value assessment processes and health system effects of a range of breakthrough health technology categories. After screening 9012 records, 222 unique studies were identified. The study also included an analysis of 100 health technology assessments (HTAs) from 5 markets to consider how and in what ways global HTA bodies evaluate transformative therapies. Global sales and technology/procedure utilization data were also evaluated to gain insights into patient access and commercial impact. RESULTS: This article evaluated uncertainties around evidence of efficacy, safety, and duration of effect, as well as underlying study quality and methodological considerations in the target categories. Although many HTA evaluations had similar approaches to assessing parameters such as safety, there were significant differences across technology categories. Technology-driven trends also surfaced where global HTA and payer systems may not yet be prepared to recognize and reward emerging technology impacts, including use of next-generation diagnostic results to guide care, considering novel impacts on therapy sequencing and clinical pathway management, and changes in payment and health delivery models. CONCLUSIONS: Some trends stemming from rapid evolution of breakthrough therapies will prompt reconsideration of our conventional value assessment and reward models, because health system measurement and management processes have not fully anticipated their effects.

PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics.

BACKGROUND: The programmed death receptor 1 (PD-1) protein is a cell-surface receptor on certain lymphocytes that, with its ligand programmed death ligand 1 (PD-L1), helps to down-regulate immune responses. Many cancer types express PD-L1 and evade immune recognition via the PD-1/PD-L1 interaction. Precision therapies targeting the PD-1/PD-L1 pathway have the potential to improve response and thereby offer a novel treatment avenue to some patients with cancer. However, this new therapeutic approach requires reliable methods for identifying patients whose cancers are particularly likely to respond. Therefore, we conducted a systematic literature review assessing evidence on test validation and scoring algorithms for PD-L1 immunohistochemistry (IHC) tests that might be used to select potentially responsive patients with bladder/urothelial cell, lung, gastric, or ovarian cancers for immunotherapy treatment. METHODS AND RESULTS: To identify evidence on commercially available PD-L1 IHC assays, we systematically searched MEDLINE and Embase for relevant studies published between January 2010 and September 2016 and appraised abstracts from recent oncology conferences (January 2013 to November 2016). Publications that met the predefined inclusion criteria were extracted and key trends summarized. In total, 26 eligible primary studies were identified, all of which reported on the test validation metrics associated with PD-L1 IHC tests in lung cancer, most using immunohistochemistry testing. There was significant heterogeneity among the available tests for PD-L1. Specifically, no definitive cutoff for PD-L1 positivity was identifiable, with more than one threshold being reported for most antibodies. Studies also differed as to whether they evaluated tumor cells only or tumor cells and tumor-infiltrating immune cells. However, all of the tests developed and validated to support a therapeutic drug in the context of phase 2-3 clinical trials reported more than 90% inter-reader concordance. In contrast, other PD-L1 antibodies identified in the literature reported poorer concordance. CONCLUSIONS: Published validation metric data for PD-L1 tests are mainly focused on immunohistochemistry tests from studies in lung cancer. The variability in test cutoffs and standards for PD-L1 testing suggests that there is presently no standardized approach. This current variability may have implications for the uptake of precision treatments.

Health Technology Assessment for Molecular Diagnostics: Practices, Challenges, and Recommendations from the Medical Devices and Diagnostics Special Interest Group.

BACKGROUND: Health technology assessments (HTAs) are increasingly used to inform coverage, access, and utilization of medical technologies including molecular diagnostics (MDx). Although MDx are used to screen patients and inform disease management and treatment decisions, there is no uniform approach to their evaluation by HTA organizations. OBJECTIVES: The International Society for Pharmacoeconomics and Outcomes Research Devices and Diagnostics Special Interest Group reviewed diagnostic-specific HTA programs and identified elements representing common and best practices. METHODS: MDx-specific HTA programs in Europe, Australia, and North America were characterized by methodology, evaluation framework, and impact. Published MDx HTAs were reviewed, and five representative case studies of test evaluations were developed: United Kingdom (National Institute for Health and Care Excellence's Diagnostics Assessment Programme, epidermal growth factor receptor tyrosine kinase mutation), United States (Palmetto's Molecular Diagnostic Services Program, OncotypeDx prostate cancer test), Germany (Institute for Quality and Efficiency in Healthcare, human papillomavirus testing), Australia (Medical Services Advisory Committee, anaplastic lymphoma kinase testing for non-small cell lung cancer), and Canada (Canadian Agency for Drugs and Technologies in Health, Rapid Response: Non-invasive Prenatal Testing). RESULTS: Overall, the few HTA programs that have MDx-specific methods do not provide clear parameters of acceptability related to clinical and analytic performance, clinical utility, and economic impact. The case studies highlight similarities and differences in evaluation approaches across HTAs in the performance metrics used (analytic and clinical validity, clinical utility), evidence requirements, and how value is measured. Not all HTAs are directly linked to reimbursement outcomes. CONCLUSIONS: To improve MDx HTAs, organizations should provide greater transparency, better communication and collaboration between industry and HTA stakeholders, clearer links between HTA and funding decisions, explicit recognition of and rationale for differential approaches to laboratory-developed versus regulatory-approved test, and clear evidence requirements.

The application of economics concepts to stratified medicine--use of health economics data to support market access for stratified medicine interventions.

Stratified medicine (SM), as opposed to empirical medicine, is the practice of using biomarkers or diagnostic tests to guide the choice of therapeutic treatments. The link between the diagnostic test and the therapy provides new opportunities for value creation and may strengthen the value proposition to pricing and reimbursement authorities. However, SM provides new challenges for the value assessment process, in particular health technology assessment (HTA) and pricing and reimbursement (P&R) decisions. Although health economics (HE) should be relevant for all stakeholders, not all stakeholders are comfortable with analysis/interpretation of economic data relevant to SM interventions as this approach is still in an early/emergent stage in most markets. This article addresses how different stakeholders are using health economic data in the overall value of information analysis to inform prioritization and reimbursement of SM interventions. Findings of an expert discussion outlines key challenges affecting various stakeholders when applying health economic data in the healthcare decision-making process for SM interventions.

Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group.

BACKGROUND: Personalized medicine technologies can improve individual health by delivering the right dose of the right drug to the right patient at the right time but create challenges in deciding which technologies offer sufficient value to justify widespread diffusion. Personalized medicine technologies, however, do not neatly fit into existing health technology assessment and reimbursement processes. OBJECTIVES: In this article, the Personalized Medicine Special Interest Group of the International Society for Pharmacoeconomics and Outcomes Research evaluated key development and reimbursement considerations from the payer and manufacturer perspectives. METHODS: Five key areas in which health economics and outcomes research best practices could be developed to improve value assessment, reimbursement, and patient access decisions for personalized medicine have been identified. RESULTS: These areas are as follows: 1 research prioritization and early value assessment, 2 best practices for clinical evidence development, 3 best practices for health economic assessment, 4 addressing health technology assessment challenges, and 5 new incentive and reimbursement approaches for personalized medicine. CONCLUSIONS: Key gaps in health economics and outcomes research best practices, decision standards, and value assessment processes are also discussed, along with next steps for evolving health economics and outcomes research practices in personalized medicine.

The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology.

Skin disease is one of the top 15 groups of medical conditions for which prevalence and health care spending increased the most between 1987 and 2000, with approximately 1 of 3 people in the United States with a skin disease at any given time. Even so, a national data profile on skin disease has not been conducted since the late 1970s. This study closes the gap by estimating the prevalence, economic burden, and impact on quality of life for 22 leading categories of skin disease. The estimated annual cost of skin disease in 2004 was 39.3 billion dollars, including 29.1 billion dollars in direct medical costs (costs of health services and products) and 10.2 billion dollars in lost productivity costs (defined as costs related to consumption of medical care, costs associated with impaired ability to work, and lost future earning potential because of premature death). Based on a methodology of willingness to pay for symptom relief, the additional economic burden of skin disease on quality of life amounted to an estimated 56.2 billion dollars. Including the economic burden on quality of life, the total economic burden of skin disease to the US public in 2004 was approximately 96 billion dollars.

Насколько эффективными в уменьшении воздействия следующей пандемии гриппа будут стратегии противовирусной вакцинации и профилактики и лечения антивирусными препаратами?

Данный сводный доклад Сети фактических данных по вопросам здоровья (СФДЗ) посвящен вопросу о потенциальной эффективности антивирусной вакцинации и лечебно-профилактического применения антивирусных препаратов для снижения тяжести пандемии гриппа. Пандемия гриппа представляется неизбежной, однако неизвестно будет ли она вызвана вирусом H5N1 или другим вирусом и насколько она будет тяжелой. До момента реального появления вирусного штамма, который вызовет пандемию гриппа, нет возможности получить прямые доказательства эффективности вакцины и стратегий лечебно-профилактического применения антивирусных препаратов для снижения смертности и заболеваемости или для сдерживания или замедления распространения пандемии гриппа. В настоящем сводном докладе СФДЗ обобщены существующие сведения (включая, но не ограниченные документами ВОЗ) и фактические данные, относящиеся к пандемиям гриппа, которые могут быть полезны для руководителей и организаторов здравоохранения. В списке источников приведены ссылки на ряд стратегических документов, содержащих более детальную информацию. Сеть фактических данных по вопросам здоровья (СФДЗ) – это инициированная и координируемая Европейским региональным бюро ВОЗ информационная служба для лиц, ответственных за принятие решений в системах общественного здравоохранения стран Европейского региона ВОЗ. Информация, предоставляемая СФДЗ, может быть полезна и для других заинтересованных сторон.

How effective would antiviral vaccination and antiviral drug prevention and treatment strategies be for reducing the impact of the next influenza pandemic?

This is a Health Evidence Network (HEN) synthesis report on the potential effectiveness of antiviral vaccination and antiviral drug prevention and treatment for reducing the impact of an influenza pandemic. An influenza pandemic seems inevitable, but it is not known whether this will be caused by H5N1 or another virus or how severe it will be. Until the actual emergence of the influenza virus strain responsible for an influenza pandemic, there is no direct evidence of the effectiveness of vaccine and antiviral drug prevention and treatment strategies for lowering mortality and morbidity, or for containing or delaying the spread, of an influenza pandemic. This HEN synthesis report is a summary of existing information (including but not limited to WHO policy documents) and evidence related to influenza pandemics that might be useful to policy-makers. The list of references includes links to several policy documents for further details. HEN, initiated and coordinated by the WHO Regional Office for Europe, is an information service for public health and health care decision-makers in the WHO European Region. Other interested parties might also benefit from HEN.

Solution behavior of IFN-beta-1a: an empirical phase diagram based approach.

An empirical phase diagram approach has been developed as a practical tool to aid macromolecular preformulation/formulation studies. This method employs an eigenvector based procedure to visualize and interpret complex data sets. Human Inteferon-beta-1a, an important therapeutic protein, was used to further develop the method and test its utility. The protein was characterized in solution as a function of pH (2-8), temperature (10 degrees C-85 degrees C) and ionic strength (I = 0.1 and 1.0) using intrinsic and ANS fluorescence, Far-UV circular dichroism (Far-UV CD), Fourier Transform Infrared spectroscopy (FTIR) and derivative UV absorbance spectroscopies, as well as differential scanning calorimetry (DSC) to supplement spectroscopic thermal stability studies. Derivative UV absorbance data were initially used to construct a pH-temperature phase diagram at each ionic strength. Three distinctive phases at I = 0.1 and two major phases at I = 1.0 were identified corresponding to different conformation/aggregation states of the protein. For the first time, heterogeneous data sets (i.e., data from different techniques) including Far-UV CD, fluorescence and UV absorbance results were used to generate empirical phase diagrams. Results from different data sets are compared; precautions in applying the method and its overall utility are discussed.

Expression-based discovery of variation in the human glutathione S-transferase M3 promoter and functional analysis in a glioma cell line using allele-specific chromatin immunoprecipitation.

Discovery and functional evaluation of biologically significant regulatory single nucleotide polymorphisms (SNP) in carcinogen metabolism genes is a difficult challenge because the phenotypic consequences may be both transient and subtle. We have used a gene expression screening approach to identify a functional regulatory SNP in glutathione S-transferase M3 (GSTM3). Anttila et al. proposed that variation in GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression variation, we measured GSTM3 expression in lymphoblast cells from a human Centre d'Etude du Polymorphisme Humain family and observed a low expression phenotype. Promoter sequencing revealed two novel GSTM3 promoter SNPs: A/C and A/G SNPs, 63 and 783 bp upstream of the codon 1 start site, respectively. In this pedigree, the two children homozygous for the -63C/C genotype had 8-fold lower GSTM3 expression relative to the two children with the -63A/A genotype, with no association between A-783G SNP and GSTM3 expression. Further evaluation using genotyped glioma cell lines and with luciferase reporter constructs showed that the -63C allele was associated with lower GSTM3 expression (P < 0.0001 and P < 0.003). RNA pol II chromatin immunoprecipitation was combined with quantitative probed-based allelic discrimination genotyping to provide direct evidence of a 9-fold reduced RNA pol II binding capacity for the -63C allele. These results show that the GSTM3 -63C allele strongly affects gene expression in human cell lines and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions.