Measuring Survival Benefit in Health Technology Assessment in the Presence of Nonproportional Hazards.

BACKGROUND: Proportional hazards (PH) is an assumption often made by researchers, despite evidence of nonproportionality in a significant proportion of clinical trials. In the presence of non-PH, the interpretation of hazard ratios, medians, and landmark survival as summary measures of treatment effect can become problematic. Several recent studies have recommended restricted mean survival time (RMST) as an alternative metric for survival analysis, particularly where non-PH may apply. OBJECTIVES: To determine the current approaches of health technology assessment (HTA) agencies to value assessment in the presence of non-PH, and the extent to which RMST is accepted as an alternative measure of treatment benefit. METHODS: Methodological guidelines published by 10 HTA agencies were reviewed to establish recommended approaches for presenting survival benefit from clinical trials. Published HTA reports for 23 oncology agents approved by the US Food and Drug Administration and the European Medicines Agency since 2014 were reviewed to determine how guidelines are implemented in practice and identify instances where the PH assumption was tested and RMST analyses reported. RESULTS: Testing for non-PH is not widely incorporated into HTA except by the UK National Institute for Health and Care Excellence. RMST is used infrequently but has been used in a number of countries, particularly by agencies that focus on cost effectiveness. CONCLUSIONS: HTA agencies vary in their approaches to non-PH. Most do not routinely check the PH assumption. RMST has played a role in assessing clinical benefit within HTA, although not consistently within countries (across drugs) or across countries (for the same drug).

Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey.

BACKGROUND: In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries. METHODS: A web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years' experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice. RESULTS: MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries. CONCLUSIONS: This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + .

Impact of elotuzumab treatment on pain and health-related quality of life in patients with relapsed or refractory multiple myeloma: results from the ELOQUENT-2 study.

Treatment of relapsed/refractory multiple myeloma (RRMM) aims to prolong survival while maintaining health-related quality of life (HRQoL) by managing disease-related symptoms and complications-one of the most frequent and debilitating being bone pain. In the ELOQUENT-2 study (NCT01239797), which evaluated the addition of elotuzumab to lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone, pain and HRQoL were assessed in patients with relapsed/refractory disease using the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 module (QLQ-C30) and myeloma-specific module (QLQ-MY20). Mean baseline pain scores were low and remained so throughout treatment with both regimens; mean HRQoL scores did not change substantially from baseline. A significantly higher proportion of patients with objective response than without had clinically meaningful improvements in worst pain over two consecutive treatment cycles (29 versus 12%; p < 0.001). Patients with very good partial response (VGPR) or better reported reduced scores for pain severity and worst pain; those with progressive disease reported increased scores for these domains and pain interference. These findings show that previously reported improvements in progression-free survival and response rate with elotuzumab are achieved without detriment to HRQoL, which is maintained over time.

Identification and Management of Statin-Associated Symptoms in Clinical Practice: Extension of a Clinician Survey to 12 Further Countries.

PURPOSE: Statins are the first-choice pharmacological treatment for patients with hypercholesterolemia and at risk for cardiovascular disease; however, a minority of patients experience statin-associated symptoms (SAS) and are considered to have reduced statin tolerance. The objective of this study was to establish how patients with SAS are identified and managed in clinical practice in Austria, Belgium, Colombia, Croatia, the Czech Republic, Denmark, Portugal, Switzerland, Russia, Saudi Arabia, Turkey, and the United Arab Emirates. METHODS: A cross-sectional survey was conducted (2015-2016) among clinicians (n = 60 per country; Croatia: n = 30) who are specialized/experienced in the treatment of hypercholesterolemia. Participants were asked about their experience of patients presenting with potential SAS and how such patients were identified and treated. RESULTS: Muscle-related symptoms were the most common presentation of potential SAS (average: 51%; range across countries [RAC] 17-74%); other signs/symptoms included persistent elevation in transaminases. To establish whether symptoms are due to statins, clinicians required rechallenge after discontinuation of statin treatment (average: 77%; RAC 40-90%); other requirements included trying at least one alternative statin. Clinicians reported that half of high-risk patients with confirmed SAS receive a lower-dose statin (average: 53%; RAC 43-72%), and that most receive another non-statin lipid-lowering therapy with or without a concomitant statin (average: 65%; RAC 52-83%). CONCLUSIONS: The specialists and GPs surveyed use stringent criteria to establish causality between statin use and signs or symptoms, and persevere with statin treatment where possible.

Clinicians' Perspectives on Cure in Adult Patients with Acute Lymphoblastic Leukemia with Minimal Residual Disease: A Delphi Study.

Hematologic complete remission (CR) is achievable for most adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL). However, minimal residual disease (MRD) in patients with hematologic CR is associated with increased risk of relapse, shorter survival, and poorer transplantation outcomes. This study explored the concept of cure in adults with Philadelphia chromosome-negative (Ph-) BCP-ALL by MRD status at first hematologic CR (CR1) to inform evaluation of the clinical and economic benefits of new agents, where the concept of cure is important but long-term data are not available. The study used modified Delphi methodology involving clinicians experienced in the treatment of adult ALL. Participants completed a questionnaire, which was followed by country-specific panel discussions to discuss results and identify consensus on concepts and definitions. Clinicians from France (n = 4), Germany (n = 4), and the UK (n = 5) took part. Participants described cure in terms of the probability of future relapse. Relapse-free survival (RFS) was the preferred outcome measure to describe cure for the three patient groups considered (patients with MRD at CR1; patients who become negative for MRD after further treatment; patients who continue to have MRD). Consensus was reached on definitions of cure: that cure would begin to be considered at 3 years' RFS and/or would be highly likely at 5 years' RFS. Participants agreed that patients with MRD should usually undergo hematopoietic stem cell transplantation to have the best chance of survival; consensus was reached that alternatives are required when transplantation is not an option. Panels agreed that patients who achieve cure have a higher mortality rate and lower health-related quality of life than the general population. This study provides quantitative and qualitative information on the concept of cure in Ph- BCP-ALL in CR by MRD status applicable to interpreting the value of new therapies.Funding: Amgen.Plain Language Summary: Plain language summary available for this article.

Clinician Concepts of Cure in Adult Relapsed and Refractory Philadelphia-Negative B Cell Precursor Acute Lymphoblastic Leukemia: A Delphi Study.

INTRODUCTION: Despite the poor prognosis for adults with relapsed or refractory (RR) Philadelphia chromosome (Ph)-negative B cell precursor acute lymphoblastic leukemia (ALL), long-term survival is possible and may even be considered as "cure". METHODS: This study used a Delphi panel approach to explore concepts of cure in RR Ph-negative B cell precursor ALL. Ten European experts in this disease area participated in a survey and face-to-face panel meeting. RESULTS: Findings showed that clinicians conceptualize "cure" as a combination of three broad treatment outcomes that vary depending on the treatment stage: complete remission early in treatment (1-3 months) indicates initial success; eradicating cancer cells (minimal residual disease negative status) consolidates the early clinical response; leukemia-free survival is required in the long term. CONCLUSIONS: Although such terminology remains contested, clinicians would begin considering "cure" as early as 2 years provided the patient is off therapy, with most considering the term applicable by the third year. FUNDING: Amgen Inc.

The impact of patient characteristics and disease-specific factors on first-line treatment decisions for BRAF-mutated melanoma: results from a European expert panel study.

Treatment decisions for advanced melanoma are increasingly complex and guidelines provide limited advice on how to choose between immunotherapy and targeted therapy for first-line treatment. A Delphi study was carried out to understand which patient characteristics and disease-related factors inform clinicians' choices of first-line treatment for BRAF-mutated melanoma. Twelve European melanoma specialists experienced in using immunotherapies and targeted agents participated in a double-blind two-phase Delphi study. In phase 1, participants completed a questionnaire developed after reviewing patient characteristics and disease-related factors reported in trials, clinical guidelines, and health technology assessments. Phase 2 was an expert panel meeting to explore outstanding issues from phase 1 and seek consensus, defined as 80% agreement. Twenty patient-related and disease-related characteristics were considered. There was consensus that tumor burden (83% of clinicians) and disease tempo (83%) are very or extremely important factors when selecting first-line treatment. Several components were deemed important when assessing tumor burden: brain metastases (82% of clinicians) and location of metastases (89%). There was consensus that disease tempo can be quantified in clinical practice, but not on a formal classification applicable to all patients. Lactate dehydrogenase level is a component of both tumor burden and disease tempo; all clinicians considered lactate dehydrogenase important when choosing first-line treatment. The majority (92%) did not routinely test programmed death ligand-1 status in patients with melanoma. Clinicians agreed that choosing a first-line treatment for advanced melanoma is a complex, multifactorial process and that clinical judgment remains the most important element of decision-making until research can provide clinicians with better scientific parameters and tools for first-line decision-making.

Estimating healthcare resource use associated with the treatment of metastatic melanoma in eight countries.

Objectives Studies reporting healthcare resourse use (HRU) for melanoma, one of the most costly cancers to treat, are limited. Using consistent, robust methodology, this study estimated HRU associated with the treatment of metastatic melanoma in eight countries. Methods Using published literature and clinician input, treatment phases were identified: active systemic treatment (pre-progression); disease progression; best supportive care (BSC)/palliative care; and terminal care. HRU elements were identified for each phase and estimates of the magnitude and frequency of use in clinical practice were obtained through country-specific Delphi panels, comprising healthcare professionals with experience in oncology (n = 8). Results Medical oncologists are the key care providers for patients with metastatic melanoma, although in Germany dermato-oncologists also lead care. During the active systemic treatment phase, each patient was estimated to require 0.83-2 consultations with a medical oncologist/month across countries; the median number of such assessments in 3 months was highest in Canada (range = 3.5-5) and lowest in France, the Netherlands and Spain (1). Resource use during the disease progression phase was intensive and similar across countries: all patients were estimated to consult with medical oncologists and 10-40% with a radiation oncologist; up to 40% were estimated to require a brain MRI scan. During the BSC/palliative care phase, all patients were estimated to consult with medical oncologists, and most to consult with a primary care physician (40-100%). Limitations Panelists were from centers of excellence, thus results may not reflect care within smaller hospitals; data obtained from experts may be less variable than data from broader clinical practice. Treatments for metastatic melanoma are continually emerging, thus some elements of our work could be superseded. Conclusions HRU estimates were substantial and varied across countries for some resources. These data could be used with country-specific costs to elucidate costs for the management of metastatic melanoma.

Identification and management of patients with statin-associated symptoms in clinical practice: A clinician survey.

BACKGROUND AND AIMS: Discontinuation of statin therapy by patients with hypercholesterolemia because of the onset of side-effects (statin-associated symptoms [SAS]) increases the risk of cardiovascular morbidity and mortality. We aimed to understand how patients with SAS, particularly those with statin-associated muscle symptoms (SAMS), are identified and managed in the outpatient setting. METHODS: A web-based survey involving 60 clinicians in each of 12 countries and 90 clinicians in the US was conducted. Clinicians answered questions about the diagnostic criteria, estimated incidence of SAS, and choice of treatment for patients with SAS. RESULTS: Overall, 810 clinicians (78% cardiologists) completed the survey. An average of 72% of patients with potential SAS were reported to present with muscle-related symptoms (range across countries [RAC] 50-87%) that could be SAMS. Clinicians took a range of steps to confirm SAMS in these patients, including discontinuation of statin (average 59%; RAC 48-67%); re-challenge with ≥ 2 statins (average 74%; RAC 60-85%); modification of statin regimen (average 76%; RAC 65-85%); or a combination of these steps. Overall, 6% of patients with hypercholesterolemia were estimated to eventually have SAS (RAC 2-12%). In patients with SAS, on average 52% continued to receive a low-dose statin, usually with other lipid-lowering therapies (LLT). Of the remaining 49%, 38% received alternative LLT only; 11% did not receive any LLT. CONCLUSION: There is some consistency and stringency in clinical practice for identifying patients with SAS; however, a structured work-up for identification, followed by a defined therapeutic algorithm, may improve their management.

Economic evaluation of gemcitabine in the treatment of pancreatic cancer in the UK.

This study evaluated the cost-effectiveness of gemcitabine as first-line treatment for pancreatic cancer in the UK. Outcomes data and costs based on utilisation data were analysed from a previously reported clinical trial. Outcome measures were average and incremental costs of survival gain, progression-free survival gain and clinical benefit response (a symptom-based measure) for gemcitabine compared with 5-fluorouracil (5-FU) via intravenous injection in the first-line setting. The incremental costs per life-year and per progression-free life-year were pounds sterling 12,206 and pounds sterling 19,888, respectively, for gemcitabine over 5-FU therapy. The incremental cost per clinical benefit responder for gemcitabine over 5-FU was pounds sterling 12,142. If 5-FU was administered by 24-h continuous infusion rather than being given once a week, treatment costs were estimated to be more expensive. The resulting incremental cost per life-year gained with gemcitabine falls to pounds sterling 8,831. Sensitivity analyses (including alterations based on statistical variance) demonstrated that the results were robust and relatively insensitive to variations in key parameters. Gemcitabine is thus a cost-effective therapy for patients with pancreatic cancer and cost per life-year compares favourably with other technologies funded by the National Health Service in the UK.

Measurement of quality of life in schizophrenia: a comparison of two scales.

BACKGROUND: People with schizophrenia have an impaired quality of life (QoL), and various QoL assessment scales are available. However it is not clear which scale should be used in different situations. We aimed to compare a patient-rated subjective QoL scale with an observer-rated QoL scale by measuring their degree of correlation and their respective associative profiles with outcome measures. METHOD: Patients of the UK Schizophrenia Care and Assessment Program completed a patient-rated QoL questionnaire (MANSA). Research staff completed the observer-rated QoL tool (QLS) as part of an assessment of symptomatology and functioning. RESULTS: The two QoL tools were moderately positively correlated (r = 0.39). Both scales were negatively correlated with positive and negative symptoms of schizophrenia and depressive symptoms, and positively correlated with functioning scores. However the two scales were influenced by different factors. The patient-rated QoL was more significantly influenced by depressive symptoms, and the observer-rated QoL was more heavily influenced by negative symptoms. CONCLUSIONS: Patient-rated and observer-rated QoL are moderately related, with a number of joint determinants, but the former is sensitive to depressive influences, whilst the latter is sensitive to the negative symptomatology of schizophrenia.

Exenatide versus insulin glargine in patients with type 2 diabetes in the UK: a model of long-term clinical and cost outcomes.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical and economic outcomes associated with exenatide or insulin glargine, added to oral therapy in individuals with type 2 diabetes inadequately controlled with combination oral agents in the UK setting. METHODS: A published and validated computer simulation model of diabetes was used to project long-term complications, life expectancy, quality-adjusted life expectancy and direct medical costs. Probabilities of diabetes-related complications were derived from published sources. Treatment effects and patient characteristics were extracted from a recent randomised controlled trial comparing exenatide with insulin glargine. Simulations incorporated published quality of life utilities and UK-specific costs from 2004. Pharmacy costs for exenatide were based on 20, 40, 60, 80 and 100% of the US value (as no price for the UK was available at the time of analysis). Future costs and clinical benefits were discounted at 3.5% annually. Sensitivity analyses were performed. RESULTS: In the base-case analysis exenatide was associated with improvements in life expectancy of 0.057 years and in quality-adjusted life expectancy of 0.442 quality-adjusted life years (QALYs) versus insulin glargine. Long-term projections demonstrated that exenatide was associated with a lower cumulative incidence of most cardiovascular disease (CVD) complications and CVD-related death than insulin glargine. Using the range of cost values, evaluation results showed that exenatide is likely to fall in a range between dominant (cost and life saving) at 20% of the US price and cost-effective (with an ICER of 22,420 pounds per QALY gained) at 100% of the US price, versus insulin glargine. CONCLUSIONS: Based on the findings of a recent clinical trial, long-term projections indicated that exenatide is likely to be associated with improvement in life expectancy and quality-adjusted life expectancy compared to insulin glargine. The results from this modelling analysis suggest that that exenatide is likely to represent good value for money by generally accepted standards in the UK setting in individuals with type 2 diabetes inadequately controlled on oral therapy.