The Suitability of End Point Designs for Health Technology Assessment in Chronic Pain Studies.

OBJECTIVES: To identify the pain instruments and study end points most commonly used in clinical trial settings and to provide insight into the extent to which outcome measures in clinical studies are meeting payer needs. METHODS: A literature review was conducted to identify published clinical studies and ongoing/recently completed registered trials in chronic pain. Inclusion criteria were interventional study, chronic pain in adults, and pain measured within the primary end point. RESULTS: Of 1256 PubMed citations and 3006 clinical trial registry entries, 356 reported large clinical studies in pain populations (e.g., malignant, neuropathic, functional, and musculoskeletal). Studies were designed for superiority in 28% of PubMed citations and 8% of registry entries. The primary end points of most studies were single-dimension pain instruments, such as the numerical rating scale (n = 131) and the visual analogue scale (n = 69). In cases in which multidimensional pain end points were used, this was most commonly the Brief Pain Inventory (n = 37). Payer-relevant end points were typically limited to secondary end points, and were limited and/or reported inconsistently in published studies and ongoing/recently completed studies: preference-weighted quality of life (36% and 42%), resource use (2% and 8%), physical function (28% and 39%), and psychological function (25% and 24%). CONCLUSIONS: Most pain trials were not designed to show superiority to an active comparator, and they used single-dimension pain scales as their primary end point in combination with a broader selection of secondary end points. The inclusion of payer-relevant end points among clinical trials was inconsistent.

A KNIME Workflow for Automated Structure Verification.

Adequate characterization of chemical entities made for biological screening in the drug discovery context is critical. Incorrectly characterized structures lead to mistakes in the interpretation of structure-activity relationships and confuse an already multidimensional optimization problem. Mistakes in the later use of these compounds waste money and valuable resources in a discovery process already under cost pressure. Left unidentified, these errors lead to problems in project data packages during quality review. At worst, they put intellectual property and patent integrity at risk. We describe a KNIME workflow for the early and automated identification of these errors during registration of a new chemical entity into the corporate screening catalog. This Automated Structure Verification workflow provides early identification (within 24 hours) of missing or inconsistent analytical data and therefore reduces any mistakes that inevitably get made. Automated identification removes the burden of work from the chemist submitting the compound into the registration system. No additional work is required unless a problem is identified and the submitter alerted. Before implementation, 14% of samples within the existing sample catalog were missing data on initial pass. A year after implementation, only 0.2% were missing data.

RWE Framework: An Interactive Visual Tool to Support a Real-World Evidence Study Design.

OBJECTIVES: Real-world evidence (RWE) is essential for the development of pharmaceutical and medical technologies and informs treatment-related decisions by regulatory agencies, payers, healthcare providers, and patients. Given that planning RWE studies present diverse challenges, we developed the RWE Framework, a concise, visual, interactive tool designed to align multidisciplinary stakeholders toward common goals and encourage a methodical approach to RWE study planning. METHODS: A search of published literature and internet-based resources was performed to identify guidance on RWE study planning with decision and/or visual aids. A conceptual framework for a study design tool was developed based on best practices for RWE studies, enhanced with an infographic design, and refined by multidisciplinary input from RWE researchers. RESULTS: The searches confirmed an unmet need for a concise tool to support a broad range of RWE study designs: only two sources with decision/visual aids were identified. The novel RWE Framework comprises sequential decision steps with instructions to guide users through consideration of research objectives, product approval status, study setting, outcomes of interest, data availability in routine practice, need for primary data collection and/or randomization, study type and methodology, and applicable regulatory standards. Pilot testing using case studies of pharmaceutical assets demonstrated the utility of RWE Framework and applicability for use in team environments. CONCLUSIONS: The RWE Framework is a novel, concise, visual, and interactive tool to inform RWE study planning. It addresses a broad range of real-world study types and research objectives and was found to enhance RWE decision-making by multidisciplinary teams. Further validation is warranted.

Cost-effectiveness modeling for neuropathic pain treatments: investigating the relative importance of parameters using an open-source model.

AIMS: The study objective was to develop an open-source replicate of a cost-effectiveness model developed by National Institute for Health and Care (NICE), in order to explore uncertainties in health economic modeling of novel pharmacological neuropathic pain treatments. MATERIALS AND METHODS: The NICE model, consisting of a decision tree with branches for discrete levels of pain relief and adverse event (AE) severities, was replicated using R, and used to compare a hypothetical neuropathic pain drug to pregabalin. Model parameters were sourced from NICE's clinical guidelines and associated with probability distributions to account for underlying uncertainty. A simulation-based scenario analysis was conducted to assess how uncertainty in efficacy and AEs affected the net monetary benefit (NMB) for the hypothetical treatment at a cost-effectiveness threshold of £20,000 per QALY. RESULTS: Relative to pregabalin, an increase in efficacy was associated with greater NMB than an improvement in tolerability. A greater NMB was observed when efficacy was marginally higher than that of pregabalin, while maintaining the same level of AEs than when efficacy was equivalent to pregabalin, but with a more substantial reduction in AEs. In the latter scenario, the NMB was only positive at a low cost-effectiveness threshold. LIMITATIONS: The replicate model shares the limitations described in the NICE guidelines. There is a lack of support in scientific literature for the assumption that increased efficacy is associated with a greater reduction in tolerability. The replicate model also included a single comparator, unlike the NICE model. CONCLUSIONS: Pain relief is a stronger driver of NMB than tolerability, at a cost-effectiveness threshold of £20,000 per QALY. Health technology assessment decisions which are influenced by NICE's model may reward efficacy gains, even if they are associated with more severe AEs. This contrasts with recommendations from clinical guidelines for neuropathic pain, which place more equal weighting on improvements in efficacy and tolerability as value drivers.

A systematic review of cost-effectiveness modeling of pharmaceutical therapies in neuropathic pain: variation in practice, key challenges, and recommendations for the future.

OBJECTIVES: Complexities in the neuropathic-pain care pathway make the condition difficult to manage and difficult to capture in cost-effectiveness models. The aim of this study is to understand, through a systematic review of previous cost-effectiveness studies, some of the key strengths and limitations in data and modeling practices in neuropathic pain. Thus, the aim is to guide future research and practice to improve resource allocation decisions and encourage continued investment to find novel and effective treatments for patients with neuropathic pain. METHODS: The search strategy was designed to identify peer-reviewed cost-effectiveness evaluations of non-surgical, pharmaceutical therapies for neuropathic pain published since January 2000, accessing five key databases. All identified publications were reviewed and screened according to pre-defined eligibility criteria. Data extraction was designed to reflect key data challenges and approaches to modeling in neuropathic pain and based on published guidelines. RESULTS: The search strategy identified 20 cost-effectiveness analyses meeting the inclusion criteria, of which 14 had original model structures. Cost-effectiveness modeling in neuropathic pain is established and increasing across multiple jurisdictions; however, amongst these studies, there is substantial variation in modeling approach, and there are common limitations. Capturing the effect of treatments upon health outcomes, particularly health-related quality-of-life, is challenging, and the health effects of multiple lines of ineffective treatment, common for patients with neuropathic pain, have not been consistently or robustly modeled. CONCLUSIONS: To improve future economic modeling in neuropathic pain, further research is suggested into the effect of multiple lines of treatment and treatment failure upon patient outcomes and subsequent treatment effectiveness; the impact of treatment-emergent adverse events upon patient outcomes; and consistent and appropriate pain measures to inform models. The authors further encourage transparent reporting of inputs used to inform cost-effectiveness models, with robust, comprehensive and clear uncertainty analysis and, where feasible, open-source modeling is encouraged.

Estimating the health care burden of prescription opioid abuse in five European countries.

BACKGROUND: Opioid abuse, including abuse of prescription opioids ("RxOs") and illicit substances like heroin, is a serious public health issue in Europe. Currently, there is limited data on the magnitude of RxO abuse in Europe, despite increasing public and scientific interest in the issue. The purpose of this study was to use the best-available data to derive comparable estimates of the health care burden of RxO abuse in France, Germany, Italy, Spain, and the United Kingdom (EU5). METHODS: Published data on the prevalence of problem opioid use and the share of opioid abuse patients reporting misuse of non-heroin opioids were used to estimate the prevalence of RxO abuse in the EU5 countries. The costs of RxO abuse were calculated by applying published estimates of the incremental health care costs of opioid abuse to country-specific estimates of the costs of chronic pain conditions. These estimates were input into an economic model that quantified the health care burden of RxO abuse in each of the EU5 countries. Sensitivity analyses examined key assumptions. RESULTS: Based on best-available current data, prevalence estimates of RxO abuse ranged from 0.7 to 13.7 per 10,000 individuals across the EU5 countries. Estimates of the incremental health care costs of RxO abuse ranged from €900 to €2,551 per patient per year. The annual health care cost burden of RxO abuse ranged from €6,264 to €279,927 per 100,000 individuals across the EU5 countries. CONCLUSION: This study suggests that RxO abuse imposes a cost burden on health systems in the five largest European countries. The extent of RxO abuse in Europe should be monitored given the potential for change over time. Continued efforts should be made to collect reliable data on the prevalence and costs of RxO abuse in Europe to facilitate an accurate characterization of the extent of this potentially growing problem.

Reliability and validity of two tests of soccer skill.

Twenty-four players from the 1st/2nd (elite) and 24 players from the 3rd/4th (non-elite) university football teams were recruited to evaluate the Loughborough Soccer Passing Test (LSPT) and Loughborough Soccer Shooting Test (LSST) as tools to assess soccer skill. The LSPT requires players to complete 16 passes as quickly as possible. The LSST requires players to pass, control, and shoot the ball to targets on a full-sized goal. Participants completed two main trials each separated by at least one day. During both trials, the participants were given practice efforts before recording the mean of the next two (LSPT) or 10 (LSST) attempts as the performance score. For the LSPT, the mean time taken, added penalty time, and overall performance time were less in the elite players (elite: 43.6 s, s = 3.8; non-elite: 52.5 s, s= 7.4; P= 0.0001). For the LSST, there was no difference in the mean points scored per shot between groups (elite: 1.34, s = 0.46; non-elite: 1.28, s = 0.53). However, the elite players had higher mean shot speed (elite: 80 km h(-1), s = 4.5; non-elite: 74 km h(-1), s = 4.2; P < 0.0001) and performed each shot sequence faster (elite: 7.87 s, s= 0.29; non-elite: 8.07 s, s= 0.35; P= 0.037) than the non-elite players. Performance on both tests was more repeatable in elite players. In conclusion, the LSPT and LSST are valid and reliable protocols to assess differences in soccer skill performance.