Core Clinical Data Elements for Cancer Genomic Repositories: A Multi-stakeholder Consensus.

The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology.

Evaluating Oncologists' Practice Patterns and Decision-Making in Locally Advanced or Metastatic Urothelial Carcinoma: The US Physician PARADIGM Study.

BACKGROUND: The treatment landscape for locally advanced/metastatic urothelial carcinoma (la/mUC) has evolved. This study examined US prescribing patterns and clinical decision-making for first-line (1L) and first-line maintenance (1LM) treatment. MATERIALS AND METHODS: US-based oncologists (N = 150) completed an online survey on patient demographics, practice patterns, and important factors considered in 1L/1LM selection. Multivariable logistic regression was used to assess factors associated with more vs less frequent 1L/1LM prescribing. RESULTS: Physician reports estimated that 23% of patients with la/mUC had not received any systemic therapy in the previous 6 months; however, 46% received 1L, 32% received second-line, and 22% received subsequent-line systemic treatments. Of patients who were receiving 1L treatment, 72% were estimated to be receiving 1L platinum-based chemotherapy. Around 69% of patients eligible for 1LM received the treatment. Physicians categorized as frequent prescribers reported overall survival (OS), disease control rate (DCR), and rate of grade 3/4 adverse events (AEs) as factors associated with 1L treatment selection (all P < .05). OS, rate of grade 3/4 immune-mediated AEs, and inclusion in institutional guidelines were reported as attributes used in 1LM treatment selection (all P < .05). Multivariable analysis revealed OS, DCR, and rate of grade 3/4 AEs as important factors in oncologists' 1L treatment selection; academic practice setting and use of Response Evaluation Criteria in Solid Tumors version 1.1 were associated with 1LM use (all P < .05). CONCLUSION: OS and AEs were found to be relevant factors associated with offering 1L and 1LM treatment. Variability exists in physicians' decision-making in the real-world setting for la/mUC.

The science and practice of current environmental risk assessment for gene therapy: a review.

Gene therapy is a fast-growing field showing great potential to treat genetic diseases and cancer. With accelerating gene therapy development and approval, their environment risk assessment (ERA) becomes increasingly important. An ERA is an assessment of the risks to human health and the environment upon exposure to a medicinal product as the result of its release during clinical development or after entering the market. Because ERA is an important component of regulatory submission, drug developers must perform a robust assessment to ensure the safety of unintended persons, animal, plants, microorganisms and environment at large. Global regulations on gene therapy ERA continue to evolve. Gene therapy ERAs are carried out according to general principles as provided in regulatory guidelines for application of clinical trials and marketing authorizations. The current review intends to summarize regulations and content requirements on gene therapy ERA in European Union, the USA and Japan. The approved gene therapy products by EMA and US Food and Drug Administration are analyzed for the critical aspects of their ERAs to provide the current status and practice of gene therapy ERAs by drug developers. For this purpose, the main contents of these gene therapy ERAs are summarized. Critical safety factors of gene therapy ERAs are described. With more experience and knowledge to be accumulated, gene therapy ERAs are expected to be less challenging with commonly used viral vectors.

Inhibition of Polyinosinic-Polycytidylic Acid-Induced Acute Pulmonary Inflammation and NF-κB Activation in Mice by a Banana Plant Extract.

NF-κB activation is pivotal for the excess inflammation causing the critical condition and mortality of respiratory viral infection patients. This study was aimed to evaluate the effect of a banana plant extract (BPE) on suppressing NF-κB activity and acute lung inflammatory responses in mice induced by a synthetic double-stranded RNA viral mimetic, polyinosinic-polycytidylic acid (poly (I:C)). The inflammatory responses were analyzed by immunohistochemistry and HE stains and ELISA. The NF-κB activities were detected by immunohistochemistry in vivo and immunofluorescence and Western blot in vitro. Results showed that BPE significantly decreased influx of immune cells (neutrophils, lymphocytes, and total WBC), markedly suppressed the elevation of pro-inflammatory cytokines and chemokines (IL-6, RANTES, IFN-γ, MCP-1, keratinocyte-derived chemokine, and IL-17), and restored the diminished anti-inflammatory IL-10 in the bronchoalveolar lavage fluid (BALF) of poly (I:C)-stimulated mice. Accordingly, HE staining revealed that BPE treatment alleviated poly (I:C)-induced inflammatory cell infiltration and histopathologic changes in mice lungs. Moreover, immunohistochemical analysis showed that BPE reduced the pulmonary IL-6, CD11b (macrophage marker), and nuclear NF-κB p65 staining intensities, whilst restored that of IL-10 in poly (I:C)-stimulated mice. In vitro, BPE antagonized poly(I:C)-induced elevation of IL-6, nitric oxide, reactive oxygen species, NF-κB p65 signaling, and transient activation of p38 MAPK in human lung epithelial-like A549 cells. Taken together, BPE ameliorated viral mimic poly(I:C)-induced acute pulmonary inflammation in mice, evidenced by reduced inflammatory cell infiltration and regulation of both pro- and anti-inflammatory cytokines. The mechanism of action might closely associate with NF-κB signaling inhibition.

Optimal Care for Kidney Health: Development of a Merit-based Incentive Payment System (MIPS) Value Pathway.

The Merit-based Incentive Payment System (MIPS) is a mandatory pay-for-performance program through the Centers for Medicare & Medicaid Services (CMS) that aims to incentivize high-quality care, promote continuous improvement, facilitate electronic exchange of information, and lower health care costs. Previous research has highlighted several limitations of the MIPS program in assessing nephrology care delivery, including administrative complexity, limited relevance to nephrology care, and inability to compare performance across nephrology practices, emphasizing the need for a more valid and meaningful quality assessment program. This article details the iterative consensus-building process used by the American Society of Nephrology Quality Committee from May 2020 to July 2022 to develop the Optimal Care for Kidney Health MIPS Value Pathway (MVP). Two rounds of ranked-choice voting among Quality Committee members were used to select among nine quality metrics, 43 improvement activities, and three cost measures considered for inclusion in the MVP. Measure selection was iteratively refined in collaboration with the CMS MVP Development Team, and new MIPS measures were submitted through CMS's Measures Under Consideration process. The Optimal Care for Kidney Health MVP was published in the 2023 Medicare Physician Fee Schedule Final Rule and includes measures related to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use, hypertension control, readmissions, acute kidney injury requiring dialysis, and advance care planning. The nephrology MVP aims to streamline measure selection in MIPS and serves as a case study of collaborative policymaking between a subspecialty professional organization and national regulatory agencies.

Clinical and Economic Outcomes in Patients With Metastatic Urothelial Carcinoma Receiving First-Line Systemic Treatment (the IMPACT UC I Study).

BACKGROUND: The IMPACT UC I study assessed real-world treatment patterns, outcomes, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic treatment after the FDA approval of 1L immune checkpoint inhibitor (ICI) monotherapy. PATIENTS AND METHODS: This retrospective study used 100% Medicare fee-for-service claims from 1/1/2015 to 6/30/2019 to identify patients aged ≥18 years diagnosed with UC with evidence of metastatic disease, continuously enrolled for 6 months before and after initial diagnosis. Patients were grouped by 1L treatment: cisplatin-containing chemotherapy, carboplatin-containing chemotherapy, ICI monotherapy, or nonplatinum-containing therapy. Unadjusted time on 1L treatment (TOT), overall survival (OS), HCRU, and total healthcare costs were analyzed. RESULTS: Of 18 888 patients with mUC, 8630 (45.7%) had received identified 1L systemic treatment; platinum-containing chemotherapy was the most common (cisplatin-containing chemotherapy, 37.6%; carboplatin-containing chemotherapy, 30.2%). Cisplatin- and carboplatin-containing chemotherapy had the shortest time-to-treatment initiation (median, 1.7-3.0 months) and longest TOT (median, 4.0-4.3 months). Median OS was longest with cisplatin-containing chemotherapy (20.0 months) and shortest with ICI monotherapy (7.6 months). Cisplatin- and carboplatin-containing chemotherapy were associated with highest HCRU; total healthcare costs were approximately 2-fold higher with ICI monotherapy vs other 1L treatments ($10 359 vs $5042-$5709 per patient per month). CONCLUSION: 1L platinum-containing chemotherapy resulted in the longest median OS and highest HCRU, whereas 1L ICI treatment had the shortest median OS and the highest costs. Over 50% of patients diagnosed with advanced UC (aUC) received no systemic therapy, highlighting the importance of optimal 1L treatment decisions in aUC.

Semiquantitative sensitization safety assessment of extractable and leachables associated with parenteral pharmaceutical products.

Extractable and leachables (E&Ls) associated with parenteral pharmaceutical products should be assessed for patient safety. One essential safety endpoint is local or systemic sensitization. However, there are no regulatory guidelines for quantitative sensitization safety assessment of E&Ls. A semiquantitative sensitization safety assessment workflow is developed to refine the sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products. The workflow is composed of two sequential steps: local skin sensitization and systemic sensitization safety assessment. The local skin sensitization step has four tiers. The output from this step is the acceptable exposure level for local sensitization (AELls) and this safety threshold can be used for local sensitization safety assessment. From the derived AELls, the systemic sensitization safety assessment at step 2 proceeds in 2 tiers. The output from this workflow is the derivation of acceptable exposure level for systemic sensitization (AELss). When the estimated human daily exposure (HDE) is compared with the AELss, the margin of exposure is calculated to determine the sensitization safety of E&Ls following parenteral administration. The current work represents an initial effort to develop a scientifically robust process for sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products.

Isothermal Background-Free Nucleic Acid Quantification by a One-Pot Cas13a Assay Using Droplet Microfluidics.

High sensitivity and specificity nucleic acid detection has been achieved by the Cas13a collateral effect in combination with a separate recombinase polymerase amplification (RPA). However, these emerging methods cannot provide accurate quantification of nucleic acids because the two-step assay performance may be compromised if the RPA and Cas13a reactions are simply unified in a single step. In this work, we first addressed the challenges associated with enzymatic incompatibility and the macromolecular crowding effect in the one-pot assay development, making the consolidated RPA-Cas13a assay a facile and robust diagnostic tool. Next, we found that the one-pot reaction cannot precisely quantify the targets at low concentrations. Thus, by leveraging droplet microfluidics, we converted the one-pot assay to a digital quantification format, termed Microfluidics-Enabled Digital Isothermal Cas13a Assay (MEDICA). Due to the droplet compartmentation, MEDICA greatly accelerates the reaction and enables relative detection in 10 min and the end-point quantification in 25 min. Moreover, MEDICA facilitates the droplet binarization for counting because of background-free signals generated by trans-cleavage reporting of Cas13a. Our clinical validation highlights that CRISPR-based isothermal assays are promising for the next generation of nucleic acid quantification methods.

Diagnostic and economic value of biomarker testing for targetable mutations in non-small-cell lung cancer: a literature review.

We aimed to assess the diagnostic and economic value of next-generation sequencing (NGS) versus single-gene testing, and of liquid biopsy (LBx) versus tissue biopsy (TBx) in non-small-cell lung cancer biomarker testing through literature review. Embase and MEDLINE were searched to identify relevant studies (n = 43) from 2015 to 2020 in adults with advanced non-small-cell lung cancer. For NGS versus single-gene testing, concordance was 70-99% and sensitivity was 86-100%. For LBx versus TBx, specificity was 43-100% and sensitivity was ≥60%. Turnaround times were longer for NGS versus single-gene testing (but not vs sequential testing) and faster for LBx versus TBx. NGS was cost-effective, and LBx reduced US per-patient costs. NGS versus single-gene testing and LBx versus TBx were concordant. NGS and LBx may be cost-effective for initial screening.

Plain language summary Patients with lung cancer with specific genetic mutations can benefit from medications that are specific to those mutations, known as targetable mutations. There are many methods to test for specific genetic mutations in patients with lung cancer. To detect genetic mutations, doctors can test the blood or urine, or they can test biopsy tissue; a small piece of the tumor removed from the lung. These tests can either look for mutations in one specific gene at a time, or they can use technology that reads the entire DNA sequence to observe multiple genes at once. In this review, we examined scientific reports to answer important questions about using genetic testing to find targetable mutations in patients with lung cancer. How accurate are different genetic tests? How fast can doctors get results from different genetic tests? How much do different genetic tests cost? We found that reading the entire DNA sequence was as accurate as testing one specific gene. Reading the entire DNA sequence takes more time than testing one specific gene, but it might reduce overall costs. Testing blood or urine was not as accurate as testing tissue, but it took less time for doctors to receive genetic test results and reduced costs.

Discovery of Missing Proteins from an Aneuploidy Cell Line Using a Proteogenomic Approach.

With the steadfast development of proteomic technology, the number of missing proteins (MPs) has been continuously shrinking, with approximately 1470 MPs that have not been explored yet. Due to this phenomenon, the discovery of MPs has been increasingly more difficult and elusive. In order to face this challenge, we have hypothesized that a stable aneuploid cell line with increased chromosomes serves as a useful material for assisting MP exploration. Ker-CT cell line with trisomy at chromosome 5 and 20 was selected for this purpose. With a combination strategy of RNA-Seq and LC-MS/MS, a total of 22 178 transcripts and 8846 proteins were identified in Ker-CT. Although the transcripts corresponding to 15 and 15 MP genes located at chromosome 5 and 20 were detected, none of the MPs were found in Ker-CT. Surprisingly, 3 MPs containing at least two unique non-nest peptides of length ≥9 amino acids were identified in Ker-CT, whose genes are located on chromosome 3 and 10, respectively. Furthermore, the 3 MPs were verified using the method of parallel reaction monitoring (PRM). These results suggest that the abnormal status of chromosomes may not only impact the expression of the corresponding genes in trisomy chromosomes, but also influence that of other chromosomes, which benefits MP discovery. The data obtained in this study are available via ProteomeXchange (PXD028647) and PeptideAtlas (PASS01700), respectively.

Real-World Clinical Outcomes in Patients with Locally Advanced or Metastatic Merkel Cell Carcinoma Treated in U.S. Oncology Clinical Practices: Results from SPEAR-Merkel.

BACKGROUND: Immunotherapy (IO) has been associated with improved outcomes in patients with locally advanced Merkel cell carcinoma (laMCC) and metastatic Merkel cell carcinoma (mMCC). The primary objective of SPEAR-Merkel was to explore treatment patterns, clinical outcomes, and health care resource utilization (HCRU) in patients with laMCC or mMCC initiating first-line (1L) treatment with avelumab, non-avelumab IO, or chemotherapy in a U.S. community oncology setting. METHODS: Adult patients with laMCC or mMCC initiating 1L avelumab, non-avelumab IO, or chemotherapy from January 1, 2015, to March 31, 2019, were identified from the U.S. Oncology Network electronic health care record database and followed up through September 30, 2019. Baseline characteristics and HCRU were analyzed descriptively, including physician-stated overall response rate in the real-world clinical setting. Kaplan-Meier methods were used to measure duration of response, real-world progression-free survival (rwPFS), and overall survival (OS). RESULTS: Among the overall population (n = 94), 28 received 1L avelumab (9 laMCC, 19 mMCC), 26 received 1L non-avelumab IO (8 laMCC, 18 mMCC), and 40 received 1L chemotherapy (10 laMCC, 30 mMCC). The real-world overall response rate was 64.3%, 61.5%, and 42.5%, respectively. From 1L treatment initiation, median rwPFS was 11.4, 8.1, and 6.1 months, and median OS was 20.2 months, not reached, and 14.7 months for the respective cohorts. CONCLUSION: SPEAR-Merkel showed that patients with laMCC or mMCC treated with IO had improved outcomes compared with chemotherapy in clinical practice. The study provides insight on utilization and clinical outcomes associated with newer, more innovative therapies in clinical practice, which may help clinicians understand the variety of newer treatment options for both laMCC and mMCC. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, SPEAR-Merkel is the first study to evaluate real-world clinical outcomes in patients with locally advanced Merkel cell carcinoma (laMCC) and metastatic Merkel cell carcinoma (mMCC) receiving first-line (1L) avelumab, non-avelumab immuno-oncology therapies, or chemotherapy in a real-world setting. SPEAR-Merkel showed clinical benefit for immuno-oncology therapies compared with chemotherapy. The study provides insight on uses and clinical outcomes associated with innovative therapies in clinical practice, which may help clinicians understand the variety of newer treatment options for both laMCC and mMCC. The study is of particular importance as it shows that chemotherapy is still being used as 1L treatment despite its inferior clinical and safety profile.

The Impact of Adverse Events on Health Care Resource Utilization, Costs, and Mortality Among Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: We investigated the association between adverse events (AEs) suspected to be immune-related and health care resource utilization, costs, and mortality among patients receiving programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitor (ICI) monotherapy for urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, or Merkel cell carcinoma. PATIENTS AND METHODS: We conducted a retrospective cohort study using medical and pharmacy claims and enrollment information from U.S. commercial and Medicare Advantage with Part D enrollees in the Optum Research Database from March 1, 2014, through April 30, 2019. Claims were linked with mortality data from the Social Security Death Index and the National Death Index. Eligible patients had at least one ICI claim between September 1, 2014, and April 30, 2019. RESULTS: After adjusting for potential confounding variables, we found patients with AEs had more than double the risk of an inpatient stay (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.9-2.5) and an 80% higher risk of an emergency visit (HR, 1.8; 95% CI, 1.6-2.1) than patients without AEs. Adjusted 6-month total costs were $24,301 higher among patients with an AE versus those without ($99,037 vs. $74,736; 95% CI, $18,828-29,774; p < .001). Mean ± SD AE-related medical costs averaged $2,359 ± $7,496 per patient per month, driven by inpatient visits, which accounted for 89.9% of AE-related costs. Adjusted risk of mortality was similar in patients with and without AEs. CONCLUSION: Patients with AEs had higher risks of hospitalizations, emergency room visits, and higher health care costs, driven by inpatient stays, than patients without AEs. The adjusted risk of mortality was similar between the two cohorts. IMPLICATIONS FOR PRACTICE: Patients taking immune checkpoint inhibitors (ICIs) who had adverse events (AEs) had significantly higher health care costs and utilization, driven by inpatient stays, compared with patients who did not. Given this high cost associated with AEs and the differences in the side effect profile of ICIs versus traditional chemotherapy, it is important for physicians to be cognizant of these differences when treating patients with ICIs. Ongoing evaluation, earlier recognition, and more effective, multidisciplinary management of AEs may improve patient outcomes and reduce the need for costly inpatient stays.

Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel.

Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carcinoma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & methods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials.

Lay abstract Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Because MCC progresses quickly, many patients have a poor prognosis. Avelumab is a type of drug that helps the patient's immune system to fight cancer. Avelumab was the first such drug approved by the US FDA for treating metastatic MCC based on the results of the JAVELIN Merkel 200 clinical trial. In SPEAR-Merkel, we studied how MCC patients with locally advanced as well as metastatic disease responded when they were treated with first-line avelumab in a real-world setting. These patients were from oncology practices in communities throughout the USA. Overall response rates in SPEAR-Merkel were comparable between patients with locally advanced and metastatic MCC. Importantly, we found that these patients experienced survival benefit similar to patients in the JAVELIN Merkel 200 (part B) study and other real-world studies.

Real-world symptoms, disease burden, resource use and quality of life in US patients with advanced renal cell cancer.

Aim: To assess symptoms, healthcare resource utilization and health-related quality of life in advanced renal cell carcinoma (aRCC) clinical practice. Materials & methods: The USA point-in-time survey of physicians and patients was conducted between February and September 2019. Results: Data were available for 227 patients. Mean (standard deviation) number of symptoms was 3.4 (3.2); differences were observed across International Metastatic RCC Database Consortium risk categories (p < 0.001), with fewer symptoms in favorable-risk patients. Disease burden, measured by greater healthcare resource utilization and worse health-related quality of life, was high, particularly in International Metastatic RCC Database Consortium intermediate- or poor- versus favorable-risk patients. In total, 45 patients (21.6%) were hospitalized due to aRCC within a 6-month period, 35 (16.8%) had one hospitalization and ten (4.8%) experienced ≥2 hospitalizations due to aRCC. Mean (standard deviation) 19-Item Functional Assessment of Cancer Therapy Kidney Symptom Index score was 53.6 (13.2) for this population, significantly lower than the reference value (59.8; p < 0.001). Conclusion: A clear need exists for improved disease management in patients with aRCC.

Lay abstract Late-stage/advanced renal cell carcinoma (aRCC) is kidney cancer that has spread to other body parts. aRCC is expensive to treat and affects patients in many ways. New treatments have become available, including tyrosine kinase inhibitors and immuno-oncology therapies. The type of treatment recommended depends on the patient's International Metastatic RCC Database Consortium risk score. This is a way of classifying patients as having a good, intermediate or poor survival risk. We asked physicians questions about their patients such as their age, how long they had aRCC, their treatment and symptoms, and asked patients how aRCC affected their lives, including how often they visited doctors and hospitals. aRCC had the greatest effect on patients with poor-risk scores. Those patients had more symptoms and worse quality of life than patients with intermediate or good risk scores. Treatment also affected patients' lives, although not as much as risk score. Patients with aRCC need better treatment options to help improve their quality of life.

Measuring Quality in Kidney Care: An Evaluation of Existing Quality Metrics and Approach to Facilitating Improvements in Care Delivery.

BACKGROUND: Leveraging quality metrics can be a powerful approach to identify substantial performance gaps in kidney disease care that affect patient outcomes. However, metrics must be meaningful, evidence-based, attributable, and feasible to improve care delivery. As members of the American Society of Nephrology Quality Committee, we evaluated existing kidney quality metrics and provide a framework for quality measurement to guide clinicians and policy makers. METHODS: We compiled a comprehensive list of national kidney quality metrics from multiple established kidney and quality organizations. To assess the measures' validity, we conducted two rounds of structured metric evaluation, on the basis of the American College of Physicians criteria: importance, appropriate care, clinical evidence base, clarity of measure specifications, and feasibility and applicability. RESULTS: We included 60 quality metrics, including seven for CKD prevention, two for slowing CKD progression, two for CKD management, one for advanced CKD and kidney replacement planning, 28 for dialysis management, 18 for broad measures, and two patient-reported outcome measures. We determined that on the basis of defined criteria, 29 (49%) of the metrics have high validity, 23 (38%) have medium validity, and eight (13%) have low validity. CONCLUSIONS: We rated less than half of kidney disease quality metrics as highly valid; the others fell short because of unclear attribution, inadequate definitions and risk adjustment, or discordance with recent evidence. Nearly half of the metrics were related to dialysis management, compared with only one metric related to kidney replacement planning and two related to patient-reported outcomes. We advocate refining existing measures and developing new metrics that better reflect the spectrum of kidney care delivery.

Health Preference Research in Europe: A Review of Its Use in Marketing Authorization, Reimbursement, and Pricing Decisions-Report of the ISPOR Stated Preference Research Special Interest Group.

OBJECTIVE: This study examines European decision makers' consideration and use of quantitative preference data. METHODS: The study reviewed quantitative preference data usage in 31 European countries to support marketing authorization, reimbursement, or pricing decisions. Use was defined as: agency guidance on preference data use, sponsor submission of preference data, or decision-maker collection of preference data. The data could be collected from any stakeholder using any method that generated quantitative estimates of preferences. Data were collected through: (1) documentary evidence identified through a literature and regulatory websites review, and via key opinion leader outreach; and (2) a survey of staff working for agencies that support or make healthcare technology decisions. RESULTS: Preference data utilization was identified in 22 countries and at a European level. The most prevalent use (19 countries) was citizen preferences, collected using time-trade off or standard gamble methods to inform health state utility estimation. Preference data was also used to: (1) value other impact on patients, (2) incorporate non-health factors into reimbursement decisions, and (3) estimate opportunity cost. Pilot projects were identified (6 countries and at a European level), with a focus on multi-criteria decision analysis methods and choice-based methods to elicit patient preferences. CONCLUSION: While quantitative preference data support reimbursement and pricing decisions in most European countries, there was no utilization evidence in European-level marketing authorization decisions. While there are commonalities, a diversity of usage was identified between jurisdictions. Pilots suggest the potential for greater use of preference data, and for alignment between decision makers.

Treatment patterns, outcomes and clinical characteristics in advanced renal cell carcinoma: a real-world US study.

Aim: Assessing treatment patterns, outcomes and clinical characteristics in advanced renal cell carcinoma clinical practice. Materials & methods: A US cross-sectional physician survey conducted February-September 2019. Results: Surveyed physicians reported first-line treatment of 445 patients involving tyrosine kinase inhibitor monotherapy (51.0%), immuno-oncology (IO/IO combination) therapy (25.8%) or other regimens (23.1%). A total of 60.9% had physician-assessed IMDC risk. Of these 61.9, 50.9 and 27.6% of patients with favorable, intermediate and poor risk, respectively, received tyrosine kinase inhibitor monotherapy. A total of 16.7, 26.9 and 34.5% of patients with favorable, intermediate or poor risk received IO/IO combination therapy. Complete/partial responses (∼35% patients) remained comparable across first-line treatments. Conclusion: Guideline-recommended therapies are not widely prescribed. Many patients experienced poor clinical outcomes highlighting a need for more effective treatments.

Health-related quality of life (QoL) in patients with advanced melanoma receiving immunotherapies in real-world clinical practice settings.

BACKGROUND: Pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are approved advanced melanoma (AM) immunotherapies. To address limited health-related quality of life (QoL) real-world evidence with immunotherapies in AM, we compared QoL in AM patients receiving either treatment in clinical practice. METHODS: A prospective US observational study enrolled adult AM patients initiating first-line PEMBRO or IPI + NIVO between June 2017 and March 2018. Endpoints included the QLQ-C30 global health score (GHS) and EuroQol visual analog scale (EQ-VAS) scores. Mean changes were compared using repeated measures mixed-effects models and are presented covariate adjusted. RESULTS: 225 PEMBRO and 187 IPI + NIVO patients were enrolled. From baseline through week 24, PEMBRO was associated with 3.2 mean GHS score increase (95% CI 0.5, 5.9; p = .02), while no change was observed with IPI + NIVO; 0.2 (95% CI - 2.6, 3.0; p = 0.87). Among objective treatment-responders, GHS scores associated with PEMBRO increased 6.0 (95% CI 3.1, 8.8; p < .0001); IPI + NIVO patients increased 3.8 (95% CI 0.8, 6.9; p = .01). In treatment non-responders, IPI + NIVO was associated with GHS/QoL deterioration of - 3.7 (95% CI - 6.8, - 0.6; p = .02), PEMBRO non-responders demonstrated no change; 0.7 (95% CI - 2.3, 3.7; p = 0.6). Between treatments, PEMBRO patients increased 2.6 greater in EQ-VAS (95% CI 0.6, 4.5; p = .01) vs IPI + NIVO at 24 weeks. CONCLUSIONS: PEMBRO was associated with better 24-week QoL compared to IPI + NIVO in actual clinical practice settings. Real-world data has known limitations, but with further confirmation these results may have implications for treatment selection.

Revisit of test-then-pool methods and some practical considerations.

Test-then-pool is a simple statistical method that borrows historical information to improve efficiency of the drug development process. The original test-then-pool method examines the difference between the historical and current information and then pools the information if there is no significant difference. One drawback of this method is that a nonsignificant difference may not always imply consistency between the historical and current information. As a result, the original test-then-pool method is more likely to incorrectly borrow information from the historical control when the current trial has a small sample size. Statistically, it is more natural to use an equivalence test for examining the consistency. This manuscript develops an equivalence-based test-then-pool method for a continuous endpoint, explains the relationship between the two test-then-pool methods, explores the choice of an equivalence margin through the overlap probability, and proposes an adjustment to the nominal testing level for controlling type I error under the true consistency scenario. Furthermore, the analytical forms of the type I error and power for the two test-then-pool methods are derived, and practical considerations for using them are presented.

Treatment patterns and outcomes for patients with advanced melanoma in US oncology clinical practices.

AIM: To describe recent evolution in treatment patterns and outcomes for advanced melanoma (AMel). METHODS: This retrospective observational study analyzed de-identified electronic health record data from the Flatiron Health database for 1140 adult patients who initiated first-line therapy for AMel from 1 January 2014 to 30 June 2016 with follow-up through 28 February 2017. RESULTS: The most common first-line regimens were ipilimumab-based therapies (34%), anti-PD-1 monotherapy (26%) and BRAF/MEK inhibitor(s) (20%). First-line ipilimumab-based and BRAF inhibitor regimens decreased after the third quarter of 2014 (3Q2014), and by 2Q2016, 55 and 91% of BRAF-mutant and BRAF wild-type cohorts, respectively, received a first-line anti-PD-1 regimen. Median overall survival from first-line initiation for all patients was 18.8 months (95% CI: 16.3-23.3). CONCLUSION: Results illustrate changing paradigms of therapy and real-world patient outcomes for AMel.