Are Laboratory Parameter (Biomarker) Values Similar to the Healthy Volunteer Reference Range in Individuals with Diabetes.

BACKGROUND: 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.

Are laboratory parameter (biomarker) values similar to the healthy volunteer reference range in all patient populations?

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 Trans-Celerate 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.

Costs and health care resource utilization among chronic obstructive pulmonary disease patients with newly acquired pneumonia.

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.

Development of a practical screening tool to predict low muscle mass using NHANES 1999-2004.

BACKGROUND: Skeletal muscle mass declines after the age of 50. Loss of skeletal muscle mass is associated with increased morbidity and mortality. OBJECTIVE: This study aims to identify predictors of low skeletal muscle mass in older adults toward development of a practical clinical assessment tool for use by clinicians to identify patients requiring dual-energy X-ray absorptiometry (DXA) screening for muscle mass. METHODS: Data were drawn from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2004. Appendicular skeletal mass (ASM) was calculated based on DXA scans. Skeletal muscle mass index (SMI) was defined as the ratio of ASM divided by height in square centimeters. Elderly participants were classified as having low muscle mass if the SMI was 1 standard deviation (SD) below the mean SMI of young adults (20-40 years old). Logistic regression was conducted separately in males and females age ≥65 years of age to examine the relationship between patients identified as having low muscle mass and health behavior characteristics, adjusting for comorbid conditions. The model was validated on a separate sample of 200 patients. RESULTS: Among the NHANES study population, 551 (39.7 %) males and 374 (27.5 %) females had a SMI below the 1 SD cutoff point. NHANES study subjects with a low SMI were older (mean age, 76.2 vs. 72.7 for male; 76.0 vs. 73.7 for female; and both p < 0.0001) and had a lower body mass index (mean BMI, 24.1 vs. 29.4 for male; 22.9 vs. 29.7 for female; p < 0.0001). In adjusted logistic regression analyses, age (for males) and BMI (for both males and females) remained statistically significant. A parsimonious logistic regression model adjusting for age and BMI only had a C statistic of 0.89 for both males and females. The discriminatory power of the parsimonious model increased to 0.93 for males and 0.95 for females when the cutoff defining low SMI was set to 2 SD below the SMI of young adults. In the validation sample, the sensitivity was 81.6 % for males and 90.6 % for females. The specificity was 66.2 % for males and females. CONCLUSIONS: BMI was strongly associated with a low SMI and may be an informative predictor in the primary care setting. The predictive model worked well in a validation sample.

New therapies for treating Down syndrome require quality of life measurement.

Down syndrome (DS) is the most common genetic cause of cognitive deficits. Using mouse models and therapies for Alzheimer disease, researchers are exploring therapies that may improve cognitive function in people with DS. These developments shift the health economic paradigm of understanding DS from determining the appropriate screening tool to the effect of therapy on quality of life in those with DS. To date, there are no validated quality of life instruments for DS. Research should begin to develop instruments that can evaluate changes in quality of life in therapeutic trials and beyond.

Assessing adherence-based quality measures in epilepsy.

OBJECTIVE: To examine the relationship of three alternative measures of adherence with seven negative outcomes associated with epilepsy for development of a quality measure in epilepsy. DESIGN: Retrospective cohort analysis. SETTING: PharMetrics national claims database. PARTICIPANTS: Patients in the PharMetrics database for the years 2004-08 taking antiepileptic drugs. INTERVENTION: None. MAIN OUTCOME MEASURES: For each definition of adherence, the odds ratios (ORs) comparing non-adherent with adherent groups were assessed for consistency and direction for the number of hospital admissions, emergency room (ER) visits, head injuries including traumatic brain injuries, falls, motor vehicle accidents (MVAs), fractures and a 'seizure' outcome defined as hospital admissions or ER visits with a primary diagnosis of epilepsy or convulsions. RESULTS: The inclusion criteria were met by 31 635 individuals. In the multivariate analysis, the adherent group had lower odds of hospital admissions with ORs for the eight specifications ranging from 0.729 to 0.872 and ER visits where ORs for the eight specifications ranged from 0.750 to 0.893. The eight ORs for head injuries ranged from 0.647 to 0.888. For fractures, the ORs ranged from 0.407 to 0.841. Our proxy for seizure was inconsistently associated with adherence status. CONCLUSIONS: All the adherence measures defined non-adherent groups that were associated with negative outcomes in epilepsy.

Henoch-Schölein purpura and polysaccharide meningococcal vaccine.

BACKGROUND: We describe here a case of Henoch-Schönlein purpura (HSP) that occurred 10 days after administration of the meningococcal polysaccharide vaccine and came to the attention of a Vaccine Safety Datalink (VSD) investigator (but did not occur in the VSD cohort). Periodic case reports have linked vaccines to HSP. OBJECTIVE: To better understand the potential risk for HSP after immunization with the meningococcal polysaccharide vaccine. PATIENTS AND METHODS: We studied the VSD cohort to estimate the 42-day postvaccination incidence rate of HSP in the VSD population 16 to 20 years of age. Electronic data from all 8 VSD sites were gathered. All subjects aged 16 to 20 years who received a meningococcal polysaccharide vaccine were followed for 42 days after that vaccination for evidence of HSP. Background rates were determined by examining all the nonexposed time of the same cohort. RESULTS: No cases of HSP were seen in the 42 days after 49,027 doses of meningococcal polysaccharide vaccine among the entire VSD adolescent and young adult population. The background incidence rate was 4.2 per 100,000 person-years. CONCLUSION: These data provide the strongest evidence so far that HSP is not associated with receipt of meningococcal polysaccharide vaccine in the 16- to 20-year age group.

Economic evaluation of pharmacotherapy of migraine pain: a review of the literature.

This paper reviews the economic evaluation literature on pharmacotherapy for migraine and identifies important trends and gaps in the literature. Given the tremendous economic burden of migraine and the availability of various therapies for migraine treatment, economic evaluation of alternative therapies plays a critical role in identifying the most cost-effective therapy to optimize health care resource allocation and clinical decisions. Particularly, physicians and clinical administrators are expected to take an active role in resource allocation decisions at the clinical level. Thus, it is important for them to be familiar with the economic evaluation in migraine pain management, and most importantly, methodologies of economic analyses and the associated shortcomings of published estimates. In this paper, the methodological characteristics of these studies are examined and their results are compared and interpreted. Alternative treatment and health outcome measures are defined and data sources described while methods for assessing the direct and indirect costs are explored. Directions for future research are identified and discussed.

Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic Rhinitis.

BACKGROUND: Allergic rhinitis causes significant economic losses and substantial reductions in quality of life. Improving a patient's symptoms can therefore enhance the patient's quality of life. OBJECTIVE: To measure the relative cost-effectiveness of prescription second-generation antihistamines (levocetirizine, desloratadine, and fexofenadine) and montelukast based on their impact on quality of life in patients with uncomplicated allergic rhinitis. METHODS: A retrospective, cost-effectiveness model was constructed using 1-year costs to managed care payers and using the Rhinoconjunctivitis Quality of Life Questionnaire to measure the quality of life in patients taking prescription second-generation antihistamines or montelukast for the treatment of allergic rhinitis. Clinical trial results for levocetirizine, desloratadine, fexofenadine (brand and generic), or montelukast were combined as standardized mean differences to create a pooled effectiveness measure. The costs of prescription drugs and physician office visits for allergic rhinitis were used as direct costs measures. Sensitivity was assessed by a Monte Carlo simulation run 1000 times. RESULTS: All the drugs in the study showed significant improvement in quality of life, with levocetirizine showing the greatest improvement. The incremental cost-effectiveness of levocetirizine dominated montelukast (incremental cost-effective ratio, -1317; 95% confidence interval, -7471, -212). The incremental cost-effectiveness favored levocetirizine compared with desloratadine and branded fexofenadine. CONCLUSION: There are significant differences in the cost-effectiveness of various oral prescription agents with regard to improving quality of life of patients with allergic rhinitis.

Bioterrorism surveillance and privacy: intersection of HIPAA, the Common Rule, and public health law.

The threat of bioterrorism in the wake of the September 11, 2001, terrorist attacks cannot be ignored. Syndromic surveillance, the practice of electronically monitoring and reporting real-time medical data to proactively identify unusual disease patterns, highlights the conflict between safeguarding public health while protecting individual privacy. Both the Health Insurance Portability and Accountability Act and the Common Rule (which promulgates protections for individuals in federally sponsored medical research programs) safeguard individuals. Public health law protects the entire populace; uneven state-level implementation lacks adequate privacy protections. We propose 3 models for a nationwide bioterrorism surveillance review process: a nationally coordinated systems approach to using protected health information, creating public health information privacy boards, expanding institutional review boards, or some combination of these.

Cost-effectiveness of second-generation antihistamines and montelukast in relieving allergic rhinitis nasal symptoms.

OBJECTIVE: Allergic rhinitis imposes a significant health and economic burden both on individuals and the healthcare system. Second-generation prescription antihistamines, levocetirizine, fexofenadine, and desloratadine, and the leukotriene receptor antagonist, montelukast, differ in their ability to relieve common rhinitis symptoms. The purpose of this study was to compare the cost-effectiveness of prescription agents based on their effectiveness in relieving nasal symptoms. METHODS: Effectiveness was measured as the composite of nasal symptoms, including congestion, rhinorrhea, and sneezing, from clinical studies that compared each of the 4 comparators to placebo. Direct costs included prescription therapy and rhinitis-related physician office visits. Physician office visit costs were collected from an analysis of the PharMetrics insurance claims database. Sensitivity analyses were conducted using a Monte Carlo simulation to assess the robustness of the average and incremental cost-effectiveness ratios. RESULTS: The cost per clinically significant improvement of nasal symptoms for levocetirizine was less than for the other model comparator agents. The incremental cost-effectiveness ratio for levocetirizine dominated montelukast and desloratadine and was lower than either branded or generic fexofenadine. CONCLUSION: Levocetirizine is a cost-effective therapy for the relief of nasal symptoms of allergic rhinitis.

Cluster randomized trials: opportunities and barriers identified by leaders of eight health plans.

BACKGROUND: Cluster randomized trials (CRTs) offer unique advantages over standard randomized controlled clinical trials (RCTs) and observational methodologies, and may provide a cost-efficient alternative for answering questions about the best treatments for common conditions. OBJECTIVES: To describe health plan leaders' views on CRTs, identify barriers to conducting CRTs, and solicit recommendations for increasing the acceptability of CRTs. RESEARCH DESIGN: Qualitative in-depth telephone interviews with leaders from 8 health plans. SUBJECTS: : Thirty-four health plan leaders (medical directors, pharmacy directors, Institutional Review Board leaders, ethics leaders, compliance leaders, and others). MEASURES: Qualitative analysis of interview transcripts to identify barriers, factors influencing leaders' views, ethical issues, aspects of CRTs that appeal to leaders, and recommendations for increasing acceptability of CRTs. RESULTS: Multiple barriers were identified, including financial costs, concerns about stakeholders' perceptions of CRTs, impact on physicians' prescribing habits, and formulary changes. Most leaders recognized the potential value of studying the comparative effectiveness of therapeutics, and many stressed the need for head-to-head trials. Leaders' views would be influenced by variations in study design and implementation. Recommendations for increasing acceptability of CRTs included ensuring that the fiscal impact of a CRT be budget neutral, and that researchers educate stakeholders and decision-makers about CRTs. CONCLUSIONS: Overall, health plan leaders recognized the need for studies of the comparative effectiveness of therapeutics under real world conditions, and many expressed support for CRTs. However, researchers seeking to conduct CRTs in health plans are likely to face numerous barriers, and preparatory work will be essential.

Priorities among effective clinical preventive services: results of a systematic review and analysis.

BACKGROUND: Decision makers at multiple levels need information about which clinical preventive services matter the most so that they can prioritize their actions. This study was designed to produce comparable estimates of relative health impact and cost effectiveness for services considered effective by the U.S. Preventive Services Task Force and Advisory Committee on Immunization Practices. METHODS: The National Commission on Prevention Priorities (NCPP) guided this update to a 2001 ranking of clinical preventive services. The NCPP used new preventive service recommendations up to December 2004, improved methods, and more complete and recent data and evidence. Each service received 1 to 5 points on each of two measures--clinically preventable burden and cost effectiveness--for a total score ranging from 2 to 10. Priorities for improving delivery rates were established by comparing the ranking with what is known of current delivery rates nationally. RESULTS: The three highest-ranking services each with a total score of 10 are discussing aspirin use with high-risk adults, immunizing children, and tobacco-use screening and brief intervention. High-ranking services (scores of 6 and above) with data indicating low current utilization rates (around 50% or lower) include: tobacco-use screening and brief intervention, screening adults aged 50 and older for colorectal cancer, immunizing adults aged 65 and older against pneumococcal disease, and screening young women for Chlamydia. CONCLUSION: This study identifies the most valuable clinical preventive services that can be offered in medical practice and should help decision-makers select which services to emphasize.

Repeated tobacco-use screening and intervention in clinical practice: health impact and cost effectiveness.

BACKGROUND: This report updates 2001 estimates of disease burden prevented and cost effectiveness of tobacco-use screening and brief intervention relative to that of other clinical preventive services. It also addresses repeated counseling because the literature has focused on single episodes of treatment, while in reality that is neither desirable nor likely. METHODS: Literature searches led to four models for calculating the clinically preventable burden of deaths and morbidity from smoking as well as the cost effectiveness of providing the service annually over time. The same methods were used in similar calculations for other preventive services to facilitate comparison. RESULTS: Using methods consistent with existing literature for this service, an estimated 190,000 undiscounted quality-adjusted life years (QALYs) are saved at a cost of $1100 per QALY saved (discounted). These estimates exclude financial savings from smoking-attributable disease prevented and use the average 12-month quit rate in clinical practice for tobacco screening and brief cessation counseling with cessation medications (5.0%) and without (2.4%). Including the savings of prevented smoking-attributable disease and using the effectiveness of repeated interventions over the lifetime of smokers (23.1%), 2.47 million QALYs are saved at a cost savings of $500 per smoker who receives the service. CONCLUSIONS: This analysis makes repeated clinical tobacco-cessation counseling one of the three most important and cost-effective preventive services that can be provided in medical practice. Greater efforts are needed to achieve more of this potential value by increasing current low levels of performance.

Influenza vaccination health impact and cost effectiveness among adults aged 50 to 64 and 65 and older.

BACKGROUND: Influenza causes approximately 36,000 deaths per year in the United States despite the presence of an effective vaccine. This assessment of the value of influenza vaccination to the U.S. population is part of an update to the 2001 ranking of clinical preventive services recommended by the U.S. Preventive Services Task Force. The forthcoming ranking will include the new recommendation of the Advisory Committee on Immunization Practices to extend influenza vaccination to adults aged 50 to 64 years. METHODS: This service is evaluated on the two most important dimensions: burden of disease prevented and cost effectiveness. Study methods, described in a companion article, are designed to ensure consistency across many services. RESULTS: Over the lifetime of a birth cohort of 4 million, it is estimated that about 275,000 quality-adjusted life years (QALYs) would be saved if influenza vaccination were offered annually to all people after age 50. Eighty percent of the QALYs saved (220,000) would be achieved by offering the vaccine only to persons aged 65 and older. In year 2000 dollars, the cost effectiveness of influenza vaccination is $980 per QALY saved in persons aged 65 and older, and $28,000 per QALY saved in persons aged 50 to 64. When the costs of patient time and travel are excluded, the cost effectiveness ratio of vaccinating 50- to 64-year-olds decreases to $7200 per QALY saved, and vaccinating those aged 65 and older saves $17 per person vaccinated. CONCLUSIONS: Influenza vaccination is a high-impact, cost-effective service for persons aged 65 and older. Vaccinations are also cost effective for persons aged 50 to 64.

Colorectal cancer screening: health impact and cost effectiveness.

BACKGROUND: Colorectal cancer is the second leading cause of cancer-related death in the United States, yet recommended screenings are not delivered to most people. This assessment of colorectal cancer screening's value to the U.S. population is part of the update to a 2001 ranking of recommended clinical preventive services found in the accompanying article. This article describes the burden of disease prevented and cost-effectiveness as a result of offering patients a choice of colorectal cancer screening tools. METHODS: Methods used were designed to ensure consistent estimates across many services and are described in more detail in the companion articles. In a secondary analysis, the authors also estimated the impact of increasing offers for colorectal cancer screening above current levels among the current cross-section of adults aged 50 and older. RESULTS: If a birth cohort of 4 million were offered screening at recommended intervals, 31,500 deaths would be prevented and 338,000 years of life would be gained over the lifetime of the birth cohort. In the current cross-section of people aged 50 and older, 18,800 deaths could be prevented each year by offering all people in this group screening at recommended intervals. Only 58% of these deaths are currently being prevented. In year 2000 dollars, the cost effectiveness of offering patients aged 50 and older a choice of colorectal cancer screening options is $11,900 per year of life gained. CONCLUSIONS: Colorectal cancer screening is a high-impact, cost-effective service used by less than half of persons aged 50 and older.

Priorities among effective clinical preventive services: methods.

Decision makers want to know which healthcare services matter the most, but there are no well-established, practical methods for providing evidence-based answers to such questions. Led by the National Commission on Prevention Priorities, the authors update the methods for determining the relative health impact and economic value of clinical preventive services. Using new studies, new preventive service recommendations, and improved methods, the authors present a new ranking of clinical preventive services in the companion article. The original ranking and methods were published in this journal in 2001. The current methods report focuses on evidence collection for a priority setting exercise, guidance for which is effectively lacking in the literature. The authors describe their own standards for searching, tracking, and abstracting literature for priority setting. The authors also summarize their methods for making valid comparisons across different services. This report should be useful to those who want to understand additional detail about how the ranking was developed or who want to adapt the methods for their own purposes.

The safety of trivalent influenza vaccine among healthy children 6 to 24 months of age.

OBJECTIVE: The objective of this study was to assess the safety of routine trivalent influenza vaccine (TIV) administration among healthy children 6 through 23 months of age, after the Advisory Committee on Immunization Practices recommendation. METHODS: The study was a retrospective case-control study of children receiving TIV in the first 2 seasons after the Advisory Committee on Immunization Practices recommendation. We assessed outcomes in the 42 days after vaccination in a population of 13,383 children. Each case subject was matched, according to age and gender, with 3 control subjects. Hazard ratios were calculated with conditional logistic regression analysis. RESULTS: We found no statistically significantly elevated hazard ratios for the first TIV dose. An elevated risk of pharyngitis was found for children receiving a second TIV dose. No elevated risk of seizure was found. CONCLUSION: These results, for a population of healthy children, showed no medically significant adverse events related to TIV among children 6 to 23 months of age.