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Diana S Meske,1 Ben J Vaughn,2 Ernest A Kopecky,3 Nathaniel Katz4,5 1Collegium Pharmaceutical, Inc, Stoughton, MA, USA; 2Rho, Chapel Hill, NC, USA; 3Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA, USA; 4WCG Analgesic Solutions, Wayland, MA, USA; 5Department of Anesthesia, Tufts University School of Medicine, Boston, MA, USACorrespondence: Diana S MeskeCollegium Pharmaceutical, Inc, Stoughton, MA, USATel +1 517 712 3087Email dsmeske@gmail.comBackground: Many aspects of study conduct impact the observed effect size of treatment. Data were utilized from a recently published meta-analysis of randomized, double-blind, placebo-controlled, clinical trials performed for the United States Food and Drug Administration (FDA) approval of full mu-agonist opioids for the treatment of chronic pain.Methods: The number of study sites in each clinical trial and standardized effect size (SES) were extracted and computed. Standardized effect size was plotted against number of sites, and a two-piece linear model was fit to the plot. Ten studies were included.Results: The SES decreased linearly by 0.13 units for every 10 sites (p=0.037), from 0.75 to 0.36, until an inflection point of 60 sites, after which SES did not decline further. The total number of subjects required for 90% power to discriminate drug from placebo increased from 78 to 336 subjects going from 30 to 60 sites.Conclusion: Results showed that the number of sites was a source of loss of assay sensitivity in clinical trials, which may contribute to the well-known problem of failure to successfully transition from Phase 2 to Phase 3 clinical development. Potential solutions include minimizing the number of sites, more rigorous and validated training, central statistical monitoring with rapid correction of performance issues, and more rigorous subject and site selection.Keywords: randomized controlled trials, opioids, chronic pain, clinical trials, effect size, study site number

Diana S Meske,1 Oluwadolapo D Lawal,1 Harrison Elder,1 Valerie Langberg,2 Florence Paillard,1 Nathaniel Katz1,3 1Analgesic Solutions, Natick, MA, USA, 2The Center for Evidence Synthesis in Health, Brown University, Providence, RI, USA, 3Department of Anesthesiology and Perioperative Medicine, Tufts University School of Medicine, Boston, MA, USA Introduction: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids’ efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for μ-opioid receptor agonists performed for US Food and Drug Administration approval. Methods: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all μ-agonist opioids approved in the USA. Results: Fifteen studies met criteria. Opioid efficacy was statistically significant (p

Clinical trials of analgesics have been plagued with poor assay sensitivity due, in part, to variability in subjects' pain reporting. Herein, we develop and evaluate the focused analgesia selection test (FAST), a method to measure patients' pain reporting skills. Subjects with osteoarthritis of the hip, knee, and/or ankle with pain intensity of ≥3/10 on a 0-10 numerical rating scale were enrolled. Subjects underwent the FAST procedure, which consists of recording subjects' pain reports in response to repeated administration of thermal noxious stimuli of various intensities applied on the arm with the Medoc® Thermal Sensory Analyzer II. Subjects also rated non-noxious stimuli consisting of visual contrast rating. After performing an exercise task, subjects also rated clinical pain and were asked to report whether their pain had increased, decreased, or stayed the same. Overall, 88 subjects were enrolled, and 83 were included in the analyses. FAST's outcomes including the R2, intraclass correlation coefficient (ICC), and coefficient of variation (CoV) indicated that subjects' pain reporting skills were widely distributed. Higher FAST ICC significantly predicted greater changes in clinical pain following exercise (p=0.017), whereas the visual contrast test did not predict postexercise pain. FAST is the first method that measures subjects' pain reporting skills. Using FAST to enrich clinical trials with "good" pain reporters (with high FAST ICC) could increase assay sensitivity. Further evaluation of FAST is ongoing.

Pamela B Landsman-Blumberg,1 Nathaniel Katz,2,3 Kavita Gajria,4 Anna O D’Souza,1 Sham L Chaudhari,1 Paul P Yeung,5 Richard White6 1Real-World Evidence, Xcenda LLC, Palm Harbor, FL, 2Analgesic Solutions, Natick, MA, 3Tufts University School of Medicine, Boston, MA, 4Global Health Economics Outcomes Research, Teva Pharmaceuticals, Inc., Frazer, PA, 5Migraine and Headache Clinical Development, Teva Pharmaceuticals, Inc., Frazer, PA, 6Neuroscience, Angarrack Value Solutions, West Chester, PA, USA Abstract: The study assessed 12-month chronic pain (CP)-related health care utilization and costs among chronic noncancer pain (CNCP) patients who initiated various long-term opioid treatments. Treatments included monotherapy with long-acting opioids (mono-LAOs), monotherapy with short-acting opioids (mono-SAOs), both LAOs and SAOs (combination), and opioid therapy initiated with SAO or LAO and switched to the other class (switch). Using MarketScan® claims databases (2006–2012), we identified CNCP patients with ≥90 days opioid supply after pain diagnosis and continuous enrollment 12 months before pain diagnosis (baseline period) and 12 months after opioid start (post-index period). Outcomes included CP-related health care utilization and costs. Among CNCP patients (n=21,203), the cohort distribution was 74% mono-SAOs, 22% combination, 2% mono-LAOs, and 2% switch. During follow-up, the average daily morphine equivalent dose was highest in mono-LAO patients (96.4 mg) compared with combination patients (89.8 mg), switch patients (64.3 mg), and mono-SAO patients (36.2 mg). After adjusting for baseline differences, the mono-LAO cohort had lower total CP-related costs ($4,933) compared with the mono-SAO ($8,604), switch ($10,470), and combination ($15,190) cohorts (all: P