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David A Brott,1 Michael J Goodman,1 Richard P Hermann,1 Isobel Anderson,2 Alexandre Kiazand1 1Patient Safety Center of Excellence, Chief Medical Office Organization, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; 2Patient Safety Center of Excellence, Chief Medical Office Organization, AstraZeneca Pharmaceuticals, Macclesfield, UKCorrespondence: David A BrottTakeda Pharmaceuticals, 300 Massachusetts Avenue, Cambridge, MA, USATel +1 3042408302Email David.Brott@Takeda.comBackground: Identification of laboratory parameter clinical safety signals depends on the terminology and scoring criteria. Grade 1 scoring criteria in the Common Terminology Criteria for Adverse Events (CTCAE) is typically based on the healthy volunteer reference range (HVRR). The objectives of this study were to determine 1) what laboratory parameters in individuals with diabetes are potentially different from the HVRR and 2) what fold change from baseline should be expected in this population.Materials and Methods: Baseline data from the individuals with diabetes clinical trial data (TransCelerate dataset) were compared to the HVRR using a 10% threshold above HVRR to classify laboratory parameters as potentially different from the HVRR. These parameters were then evaluated longitudinally to determine the expected x-baseline values for individuals with diabetes for potential use in identifying drug-induced changes.Results: The baseline data determined that 28% of the laboratory parameters evaluated were potentially different from the HVRR. Longitudinal data analysis determined 1) thresholds for 13 of these laboratory parameters with the subjects above the threshold having greater variability than those below the threshold, and 2) the expected upper limits (x-baseline) were calculated for the laboratory parameters. For example, a 1.8– 2.6 x-baseline value for alanine aminotransferase, depending on how the baseline is calculated, is expected in individuals with diabetes.Conclusion: It is not uncommon for laboratory parameters in individuals with diabetes clinical trials to be potentially different from the HVRR, and the x-baseline criteria for 13 of these laboratory biomarkers was determined for this population. This suggests consideration in modifying the current CTCAE grade 1 criteria of > 1.5– 3.0 x-baseline should be further investigated as to if the current criteria detects too many false-positive signals in this population.Keywords: diabetes, biomarkers, reference range, laboratory parameter, pharmacovigilance

David A Brott,1 Michael J Goodman,1 Richard P Hermann,1 Michael Merz,2 Roser Calvo,1 Nadereh Poorkhalkali,3 Alexandre Kiazand1 1Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; 2Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Webel, Germany; 3Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gothenburg, Sweden Background: Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. Materials and methods: Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer’s, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in TransCelerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. Results: Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer’s and asthma, had at least one biomarker that was higher than the HVRR. Summary: The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials. Keywords: patient populations, reference range, healthy volunteer, biomarkers

Junji Lin,1 Yunfeng Li,2 Haijun Tian,2 Michael J Goodman,1 Susan Gabriel,2 Tara Nazareth,2 Stuart J Turner,2,3 Stephen Arcona,2 Kristijan H Kahler21Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA; 2Health Economics and Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, NJ, USA Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for lung infections and other pathologies (eg, pneumonia); however, few studies have evaluated the impact of pneumonia on health care resource utilization and costs in this population. The purpose of this study was to estimate health care resource utilization and costs among COPD patients with newly acquired pneumonia compared to those without pneumonia. Methods: A retrospective claims analysis using Truven MarketScan® Commercial and Medicare databases was conducted. COPD patients with and without newly acquired pneumonia diagnosed between January 1, 2004 and September 30, 2011 were identified. Propensity score matching was used to create a 1:1 matched cohort. Patient demographics, comorbidities (measured by Charlson Comorbidity Index), and medication use were evaluated before and after matching. Health care resource utilization (ie, hospitalizations, emergency room [ER] and outpatient visits), and associated health care costs were assessed during the 12-month follow-up. Logistic regression was conducted to evaluate the risk of hospitalization and ER visits, and gamma regression models and two-part models compared health care costs between groups after matching. Results: In the baseline cohort (N=467,578), patients with newly acquired pneumonia were older (mean age: 70 versus [vs] 63 years) and had higher Charlson Comorbidity Index scores (3.3 vs 2.6) than patients without pneumonia. After propensity score matching, the pneumonia cohort was nine times more likely to have a hospitalization (odds ratio; 95% confidence intervals [CI] =9.2; 8.9, 9.4) and four times more likely to have an ER visit (odds ratio; 95% CI =4.4; 4.3, 4.5) over the 12-month follow-up period compared to the control cohort. The estimated 12-month mean hospitalization costs ($14,353 [95% CI: $14,037–$14,690]), outpatient costs ($6,891 [95% CI: $6,706–$7,070]), and prescription drug costs ($1,104 [95% CI: $1,054–$1,142]) were higher in the pneumonia cohort than in the control cohort. Conclusion: This study demonstrated elevated health care resource use and costs in patients with COPD after acquiring pneumonia compared to those without pneumonia. Keywords: COPD, health care costs, cost effectiveness/economics, outcomes research