A multistakeholder Delphi consensus core outcome set for clinical trials in moderate-to-severe asthma (coreASTHMA).

BACKGROUND: Treatments for long-term control of asthma have improved and include a promising but expensive class of biologic therapies. However, the clinical trials evaluating these and other novel treatments have used a variety of different outcomes to evaluate efficacy. The evolution of asthma care calls for a re-examination of outcomes that are most important to patients and other stakeholders. OBJECTIVE: To develop a core set of outcomes to be measured in phase 3 and phase 4 clinical drug trials in patients with moderate-to-severe asthma. METHODS: We used a robust and in-depth multistakeholder consensus process bringing together patients, clinicians, regulators, payers, health technology assessors, researchers, and product developers to reach consensus on outcomes. We used a modified Delphi method to reach consensus, an approach adapted from the Core Outcome Measures in Effectiveness Trials Initiative aligned with contemporary methodological standards for core outcome set development. RESULTS: The following outcomes were included in the final core set: severe asthma exacerbation, change in asthma control, asthma-specific or severe asthma-specific quality of life, asthma-specific hospital stay (ie, >24-hour stays at any level of care) or admission, and asthma-specific emergency department visit. CONCLUSION: These 5 outcomes represent a minimum set of core outcomes for use in phase 3 and phase 4 clinical drug trials in moderate-to-severe asthma. Consistent collection of these outcomes as minimum, independent of whether additional heterogeneous primary or secondary outcomes are included, will allow for meaningful comparisons of the effect of asthma therapies across clinical trials.

Proposed framework for patient-centered outcomes-based measures in alternative payment models.

OBJECTIVES: Alternative payment models (APMs) are part of a growing shift from volume-based, traditional fee-for-service payment models toward payment for value. To date, however, patients have been largely omitted from efforts to design new payment models. We sought to identify key characteristics of outcomes-based quality measures to inform future APMs that are more patient-centered. STUDY DESIGN: Using oncology as a learning case, we explored gaps in current APM quality measures, then engaged multiple stakeholders to identify and prioritize key characteristics of outcomes-based quality measures to guide future APM development. METHODS: We used a mixed-methods approach that consisted of (1) literature review, (2) key informant interviews, (3) stakeholder work group (involving group discussions and completion of an online prioritization survey), and (4) synthesis. RESULTS: Based on the lessons generated at each step of this exploratory project, we suggest a framework to guide deliberations among payers, providers, patients, and other APM stakeholders when selecting outcomes-based measures for future APMs or other value-based payment models. CONCLUSIONS: The proposed framework offers a stepping stone on the path to clinically meaningful, patient-centered, high-value care. Next steps may include a broader review of gaps in APM quality measures across multiple therapeutic areas, additional vetting from a more diverse group of stakeholders, or a formal consensus.

The asthma evidence base: a call for core outcomes in interventional trials.

OBJECTIVES: Biologic therapies are emerging as an option to treat a subset of patients with severe asthma, however no direct comparison between these agents has been conducted. Furthermore, heterogeneity of outcomes in clinical trials makes it difficult to compare these agents and traditional therapies. The extent to which this heterogeneity exists has major implications for evidence-based decisions and is yet to be fully reported. We conducted a literature search to examine outcomes currently being used in clinical trials for asthma. DATA SOURCES: The Cochrane Library and Clinicaltrials.gov were searched for clinical trials of asthma interventions. STUDY SELECTIONS: We limited our search to phase 2 through 4 clinical trials in adults, as early-phase trials tend to have pharmacodynamic and pharmacokinetic endpoints as primary outcomes. Interventions for acute exacerbations were excluded. RESULTS: We identified 117 studies and subsequently identified 111 outcomes. The most prevalent outcomes were asthma control and symptom severity, FEV1, and change in ACQ scale. Twenty patient-reported outcomes instruments were identified and de-facto standard asthma outcomes and PROs were under-reported in examined literature. Existing quality of life tools did not capture the day-to-day experience or the unique treatment burden from oral corticosteroids for patient with severe asthma. Compounding the absence of trials directly comparing therapies, the significant variation we identified in outcome definitions and measurement create hurdles to effectively compare traditional and biologic therapies. CONCLUSION: With the growing number of clinical trials evaluating advanced therapies such as biologics, a wide range of primary and secondary outcomes are evaluated. A core outcome set created by relevant stakeholders is needed to collectively evaluate pooled outcomes in order to allow more meaningful comparisons of asthma therapies and to incorporate the patient experience.

The increasing complexity of the core outcomes landscape.

In this project, we set out to identify ways to increase the uptake of core outcome sets in clinical research. In doing so, we uncovered a growing recognition, across many different health care sectors, of the need for common, relevant outcomes to improve the quality of decision-making. This has led to a plethora of projects, initiatives, and new organizations all intended to develop standardized outcomes and outcome measures for their particular fields. However, the standardized outcome sets developed across siloed initiatives do not carry over to other sectors, such as from research to quality of care. This trend has the potential to lead to confusion and unintended redundancies, as well as wasteful use of both financial and intellectual resources. Better communication and collaboration among different initiatives, and more deliberate alignments of initiative scopes, are needed to ensure a future paradigm in which standards align across contexts where possible and differ for understandable and transparent reasons.

Tobacco Smoking and Tuberculosis among Men Living with HIV in Johannesburg, South Africa: A Case-Control Study.

SETTING: Although there is ample evidence that smoking increases the risk of tuberculosis (TB), the magnitude of impact on TB risk among HIV-infected persons is poorly described. Given that a high proportion of patients with TB are co-infected with HIV in South Africa, the risks arising from the intersection of smoking, TB, and HIV/AIDS have key relevance for tobacco control policies. OBJECTIVE: To evaluate the association of pulmonary tuberculosis (PTB) with current tobacco smoking among men with HIV in South Africa. DESIGN: Case-control study of antiretroviral therapy naïve men with confirmed HIV-infection in Johannesburg. Cases had laboratory-confirmed PTB and controls had no evidence of active TB. Participants were interviewed to collect detailed smoking histories. RESULTS: We enrolled 146 men diagnosed with PTB and 133 controls. Overall, 33% of participants were currently smoking, defined as smoking a cigarette within 2 months (34% cases vs. 32% controls, p = 0.27). Median CD4 count was lower (60 vs. 81 cells/mm3, P = 0.03) and median viral load was higher (173 vs. 67 copies/ul per thousand, P<0.001) among cases versus controls. In adjusted analyses, current smoking tripled the odds of PTB (aOR 3.2; 95%CI: 1.3-7.9, P = 0.01) and former smoking nearly doubled the odds of PTB (aOR 1.8; 95%CI 0.8-4.4, P = 0.18) compared to never smoking. CONCLUSIONS: Males with HIV that smoke are at greater odds for developing PTB than non-smokers. Extensive smoking cessation programs are needed to reduce odds of TB and promote health among adults living with HIV.

Incubation periods of mosquito-borne viral infections: a systematic review.

Mosquito-borne viruses are a major public health threat, but their incubation periods are typically uncited, non-specific, and not based on data. We systematically review the published literature on six mosquito-borne viruses selected for their public health importance: chikungunya, dengue, Japanese encephalitis, Rift Valley fever, West Nile, and yellow fever viruses. For each, we identify the literature's consensus on the incubation period, evaluate the evidence for this consensus, and provide detailed estimates of the incubation period and distribution based on published experimental and observational data. We abstract original data as doubly interval-censored observations. Assuming a log-normal distribution, we estimate the median incubation period, dispersion, 25th and 75th percentiles by maximum likelihood. We include bootstrapped 95% confidence intervals for each estimate. For West Nile and yellow fever viruses, we also estimate the 5th and 95th percentiles of their incubation periods.

Incorporating stakeholder perspectives in developing a translation table framework for comparative effectiveness research.

This project used a stakeholder-driven process to understand the factors that drive the selection of study designs for comparative effectiveness research (CER). The project assembled a diverse stakeholder committee to explore the basis of a translation framework and gathered input through surveys, interviews and an in-person meeting. Stakeholders recommended different study designs for the CER topic areas and identified different outcomes as the most important outcomes to study in each area. During the discussions, stakeholders described a variety of factors that influenced their study design recommendations. The stakeholder activities resulted in the identification of several key themes, including the need to have a highly specific detailed research question before discussing appropriate designs and the need to use multiple studies, potentially of different designs, to address the CER topic areas. The insights and themes from this project may inform efforts to develop a translation table.

U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey.

PURPOSE: The Food and Drug Administration (FDA) regulates prescription drug marketing, not prescribing. However, off-label use is common, often lacks supporting evidence, and may expose patients to unwarranted risk. We sought to determine physicians' knowledge of the FDA-approved indications of commonly prescribed drugs, and to assess whether physicians' belief that an indication is FDA-approved increases with level of evidence supporting such use. METHODS: We conducted a national random sample mail survey of 599 primary care physicians and 600 psychiatrists from November 2007 to August 2008. Physicians were presented with 14 drug-indication pairs (e.g., gabapentin [Neurontin] for diabetic neuropathy) that varied in their FDA-approval status and levels of supporting evidence. RESULTS: The adjusted response rate was 47%, respondents were similar to non-respondents, and physicians commonly prescribed the drugs examined. The average respondent accurately identified the FDA-approval status of just over half of the drug-indication pairs queried (mean 55%; median 57%). Accuracy increased modestly (mean 60%, median 63%) when limited to drugs the respondent reported having prescribed during the previous 12 months. There was a strong association between physicians' belief that an indication was FDA-approved and greater evidence supporting efficacy for that use (Spearman's rho 0.74, p < 0.001). However, 41% of physicians believed at least one drug-indication pair with uncertain or no supporting evidence (e.g., quetiapine [Seroquel] for dementia with agitation) was FDA approved. CONCLUSIONS: These findings highlight a pressing need for more effective methods to inform physicians about the evidence base, or lack thereof, for drugs they prescribe off label.

Physicians' experience with surrogate decision making for hospitalized adults.

BACKGROUND: Hospitalized patients frequently lack decision-making ability, yet little is known about physicians' approaches to surrogate decision making. OBJECTIVE: To describe physicians' experiences with surrogate communication and decision making for hospitalized adults. DESIGN: Cross-sectional written survey. PARTICIPANTS: Two hundred eighty-one physicians who recently cared for adult inpatients in one academic and two community hospitals. MEASUREMENTS: Key features of physicians' most recent surrogate decision-making experience, including the nature of the decision, the physician's reaction, physician-surrogate communication and physician-surrogate agreement about the best course of action. RESULTS: Nearly three fourths of physicians (73%, n = 206) had made a major decision with a surrogate during the past month. Although nearly all patients (90%) had a surrogate, physicians reported trouble contacting the surrogate in 21% of cases. Conflict was rare (5%), and a majority of physicians agreed with surrogates about the medical facts (77%), prognosis (72%) and best course of action (65%). After adjustment for patient, physician and decision characteristics, agreement about the best course of action was more common among surrogates for older patients [prevalence ratio (PR) = 1.17 for each decade; 95% confidence interval (CI) 1.02-1.31], ICU patients (PR = 1.40; CI 1.14-1.51) and patients who had previously discussed their wishes (PR = 1.60; CI 1.30-1.76), and less common when surrogates were difficult to contact (PR = 0.59; CI 0.29-0.92) or when the physician self-identified as Asian (PR = 0.60; CI 0.30-0.94). CONCLUSION: Surrogate decision making is common among hospitalized adults. Physician-surrogate decision making may be enhanced if patients discuss their preferences in advance and if physician contact with surrogate decision makers is facilitated.

National trends in treatment of type 2 diabetes mellitus, 1994-2007.

BACKGROUND: Diabetes mellitus is common, costly, and increasingly prevalent. Despite innovations in therapy, little is known about patterns and costs of drug treatment. METHODS: We used the National Disease and Therapeutic Index to analyze medications prescribed between 1994 and 2007 for all US office visits among patients 35 years and older with type 2 diabetes. We used the National Prescription Audit to assess medication costs between 2001 and 2007. RESULTS: The estimated number of patient visits for treated diabetes increased from 25 million (95% confidence interval [CI], 23 million to 27 million) in 1994 to 36 million (95% CI, 34 million to 38 million) by 2007. The mean number of diabetes medications per treated patient increased from 1.14 (95% CI, 1.06-1.22) in 1994 to 1.63 (1.54-1.72) in 2007. Monotherapy declined from 82% (95% CI, 75%-89%) of visits during which a treatment was used in 1994 to 47% (43%-51%) in 2007. Insulin use decreased from 38% of treatment visits in 1994 to a nadir of 25% in 2000 and then increased to 28% in 2007. Sulfonylurea use decreased from 67% of treatment visits in 1994 to 34% in 2007. By 2007, biguanides (54% of treatment visits) and glitazones (thiazolidinediones) (28%) were leading therapeutic classes. Increasing use of glitazones, newer insulins, sitagliptin phosphate, and exenatide largely accounted for recent increases in the mean cost per prescription ($56 in 2001 to $76 in 2007) and aggregate drug expenditures ($6.7 billion in 2001 to $12.5 billion in 2007). CONCLUSIONS: Increasingly complex and costly diabetes treatments are being applied to an increasing population. The magnitude of these rapid changes raises concerns about whether these more costly therapies will result in proportionately improved outcomes.