One size does not fit all: Insights for engaging front-line clinicians in pragmatic clinical trials.

INTRODUCTION: Despite the proliferation of pragmatic clinical trials (PCTs) conducted in health care delivery settings, we know relatively little about how practicing clinicians perceive their potential roles in such research. Empirical evidence and practical guidance concerning clinician engagement in research is needed to inform the design and successful implementation of PCTs. METHODS: We conducted a two-phase qualitative study to better understand how and to what extent practicing clinicians should be involved in PCTs and to develop guidance for researchers on engaging front-line clinicians in PCTs. In phase one, clinicians who spend the majority of their time providing direct patient care participated in 90-min focus groups. In phase two, we conducted key informant interviews with PCT research teams and clinicians participating in the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness) trial. RESULTS: Thirty-four physicians, nurses, and other care providers from four health care delivery organizations participated in focus groups. Focus group participants stressed the importance of engaging clinicians early in the PCT planning process to identify clinically relevant study questions, provide input on study design, and customize study protocols to fit unique clinic workflows. We conducted 18 interviews with principal investigators, project managers, and clinicians involved in the ADAPTABLE trial across six clinical data research networks. Study team members described trying multiple approaches to optimize in-clinic recruitment and enrollment of eligible patients. Successful strategies involved several key factors related to research team interactions with eligible patients, clinicians, and clinic staff. CONCLUSIONS: More active involvement by a range of clinical stakeholders in PCT planning may help researchers avoid common barriers to trial implementation. We propose a "medium-touch" approach to involving clinicians in PCT recruitment and enrollment that focuses clinician effort where it is most critical-to reassure eligible patients that trial participation is a safe alternative for them.

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.

Stakeholder perspectives regarding alternate approaches to informed consent for comparative effectiveness research.

INTRODUCTION: Traditional informed consent approaches, involving separate discussions and lengthy consent forms, may be an imperfect fit for comparative effectiveness research (CER) that is integrated into usual care and compares non-investigational treatments. However, systematic efforts to collect broad stakeholder perspectives about alternative streamlined approaches to disclosure and consent in this context have been limited. METHODS: We used a deliberative engagement method to solicit the views of a multi-stakeholder group regarding 3 alternative models of disclosure, consent, and authorization in CER studies: Opt-In, Opt-Out, and "General Approval". Participants considered the acceptability of these 3 models for observational and randomized CER studies of hypertension medications and for alternative treatments for spinal stenosis, all conducted in the context of a learning health care system. RESULTS: Fifty-eight stakeholders participated in the all-day deliberative engagement session. Following deliberation, a majority of stakeholders (67%) liked the General Approval model for the observational hypertension study, more than the number who reported liking Opt-Out or Opt-In (45% and 36%, respectively). Support was lower for General Approval model in the context of a randomized hypertension study, with 80% liking a traditional Opt-In approach, compared with 54% liking Opt-Out, and 11% liking General Approval. Similarly, for the spinal stenosis CER studies, while most stakeholders preferred a streamlined Opt-Out approach for the observational design, most preferred a traditional Opt-In approach for the randomized version. CONCLUSIONS: This multi-stakeholder group was more favorable towards streamlined models for disclosure and authorization for observational CER than randomized designs. These findings are consistent with arguments that informed consent requirements should be tailored to the context of the research design, rather than a standard "one size fits all" approach.

Framing the conversation: use of PRECIS-2 ratings to advance understanding of pragmatic trial design domains.

BACKGROUND: There continues to be debate about what constitutes a pragmatic trial and how it is distinguished from more traditional explanatory trials. The NIH Pragmatic Trials Collaborative Project, which includes five trials and a coordinating unit, has adopted the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) instrument. The purpose of the study was to collect PRECIS-2 ratings at two points in time to assess whether the tool was sensitive to change in trial design, and to explore with investigators the rationale for rating shifts. METHODS: A mixed-methods design included sequential collection and analysis of quantitative data (PRECIS-2 ratings) and qualitative data. Ratings were collected at two annual, in-person project meetings, and subsequent interviews conducted with investigators were recorded, transcribed, and coded using NVivo 11 Pro for Windows. Rating shifts were coded as either (1) actual change (reflects a change in procedure or protocol), (2) primarily a rating shift reflecting rater variability, or (3) themes that reflect important concepts about the tool and/or pragmatic trial design. RESULTS: Based on PRECIS-2 ratings, each trial was highly pragmatic at the planning phase and remained so 1 year later in the early phases of trial implementation. Over half of the 45 paired ratings for the nine PRECIS-2 domains indicated a rating change from Time 1 to Time 2 (N = 24, 53%). Of the 24 rating changes, only three represented a true change in the design of the trial. Analysis of rationales for rating shifts identified critical themes associated with the tool or pragmatic trial design more generally. Each trial contributed one or more relevant comments, with Eligibility, Flexibility of Adherence, and Follow-up each accounting for more than one. CONCLUSIONS: PRECIS-2 has proved useful for "framing the conversation" about trial design among members of the Pragmatic Trials Collaborative Project. Our findings suggest that design elements assessed by the PRECIS-2 tool may represent mostly stable decisions. Overall, there has been a positive response to using PRECIS-2 to guide conversations around trial design, and the project's focus on the use of the tool by this group of early adopters has provided valuable feedback to inform future trainings on the tool.

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.

Understanding practice-based research participation: The differing motivations of engaged vs. non-engaged clinicians in pragmatic clinical trials.

BACKGROUND/AIMS: Pragmatic clinical trials (PCTs) represent an increasingly used strategy for "real-world" trials. Successful PCTs typically require participation of community-based practices. However, community clinicians often have limited interest or experience in clinical research. Many barriers to practice-based research have been described, but possible motivations to participate among community practices not active in research have not been well explored. The tendency is for researchers to assume similar motivations and priorities across all candidate practices. This is not necessarily the case. A better understanding of the range of reasons clinicians might see for participating in pragmatic trials could be key to promoting this type of practice-based research. METHODS: Semi-structured interviews were conducted with 30 clinicians and staff members. Half of the interviewees had experience doing practice-based clinical trials and half did not. Individuals in these two groups were also diversified in terms of their practice size and location. Participants were asked about motivations and barriers to doing practice-based research in the context of a planned osteoporosis pragmatic clinical trial. Interviews were transcribed, coded, and analyzed. RESULTS: Barriers identified for both experienced and not-experienced clinicians and staff members included: a lack of time, increased paperwork, disruption to work flows, and concern over practice finances. Similar findings have been reported in the US, UK, Europe, and Australia. However, regarding positive motivations of practices to participate, we found systematic differences in attitude between research-engaged and research-naïve practices that have not been previously reported. The research-experienced group offered a greater number and variety of reasons to take part than the not-experienced group. While both groups expressed motivations related to patient care, clinicians and staff members experienced in practice-based clinical trials were much more likely to cite intellectual, professional, and societal benefits not envisioned by the other group. CONCLUSIONS: We conclude that clinicians not already participating in practice-based trials may have a narrower range of motivations than those already participating. The lack of a broader view of possible benefits to participation may also translate into more obdurate recruiting challenges. These results point to the need for recruitment, engagement, and messaging approaches differentially tailored to the needs and interests of non-participating practices.

PAYER PERSPECTIVES ON FUTURE ACCEPTABILITY OF COMPARATIVE EFFECTIVENESS AND RELATIVE EFFECTIVENESS RESEARCH.

OBJECTIVES: Our objective was to gather perspectives from payers on how comparative effectiveness research (CER) in the United States and relative effectiveness (RE) research in Europe will impact evidentiary standards for access decisions of new drugs by 2020. METHODS: We conducted semi-structured interviews with fourteen senior officials representing public and private payers, health technology assessment groups, and pricing and reimbursement bodies in the United States and Europe. An online survey assessed current use of CER/RE evidence and potential trends that might influence its use for decision making by 2020. A semi-structured interview elicited payers' definitions of CER/RE and was structured around four hypothetical cases resembling drugs expected to be more common or poised to create policy challenges by 2020. Topics included acceptance of study designs and analytic methods associated with CER/RE. A systematic content review was done to extract relevant information. RESULTS: According to key informants, randomization will remain an essential component for assessing comparative or relative effectiveness. They anticipate greater use of policy levers such as conditional reimbursement or prior authorization to manage diffusion of new drugs. Case studies provided important insights into situations when certain types of CER evidence may be acceptable (e.g., observational data when differences between drugs are largely convenience). CONCLUSIONS: Industry perceptions that CER/RE will change payers' evidentiary requirements in the future are consistent with our findings. Growing investment in payers' own data and increased reliance on policy tools to control diffusion of new drugs may also influence the type of evidence industry will be required to produce by 2020.

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.

Improving the efficiency and effectiveness of pragmatic clinical trials in older adults in the United States.

Pragmatic clinical trials (PCTs) seek to improve the generalizability and increase the statistical power of traditional explanatory trials. They are a major tenet of comparative effectiveness research. While a powerful study design, PCTs have been limited by high cost, modest efficiency, and limited ability to fill relevant evidence gaps. Based on an American Reinvestment and Recovery Act (ARRA) supported meeting of national stakeholders, we propose several innovations and future research that could improve the efficiency and effectiveness of such studies focused in the U.S. Innovations discussed include optimizing the use of community based practices through partnership with Practice Based Research Networks (PBRNs), using information technology to simplify PCT subject recruitment, consent and randomization processes, and utilizing linkages to large administrative databases, such as Medicare, as a mechanism to capture outcomes and other important PCT variables with lower subject and research team burden. Testing and adaptation of such innovations to PCT are anticipated to improve the public health value of these increasingly important studies.

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.

Academic medical centers and underserved communities: modern complexities of an enduring relationship.

BACKGROUND: Most private academic medical centers are located in underserved areas, yet fiscal pressures have led many to struggle with balancing their commitment to surrounding communities with other missions. OBJECTIVE: To explore stakeholders' views regarding the ethical, legal, and financial obligations of private academic medical centers to their surrounding neighborhoods. DESIGN, PARTICIPANTS, AND MEASURES: QualitatiVe analysis of key informant interviews during 2008 with medical students, faculty and community physicians, administrators, and community health leaders at a large urban academic medical center. Grounded theory was used to iteratively review, code, and revise a taxonomy of themes, with abstraction of illustrative quotes. RESULTS: Nineteen in-depth interviews were conducted. All respondents believed academic medical centers have an obligation to their surrounding communities but characterized the extent of this obigation in a variety of ways. Respondents disagreed about how the core mission of an academic center should be defined, although many recognized the tripartite mission, conflict centered on the balance that should be sought between research and clinical care. A majority of interviewees expressed frustration with the nation's current health care system. Many provided unprompted recommendations regarding how academic medical centers might engage their underserved communities, including conducting formal needs analyses, promoting ongoing dialogue, and using information technology to bridge the provision of clinical care in community and academic settings. CONCLUSIONS: These data provide enriching perspectives from stakeholders regarding this enduring yet evolving relationship. The diversity of views illustrates one of the challenges that will accompany health care reform impacting academic medical centers and their surrounding, often underserved, communities.

Physicians' views on the importance of patient preferences in surrogate decision-making.

OBJECTIVES: To explore the degree to which physicians report reliance on patient preferences when making medical decisions for hospitalized patients lacking decisional capacity. DESIGN: Cross-sectional survey. SETTING: One academic and two community hospitals in a single metropolitan area. PARTICIPANTS: Two hundred eighty-one physicians who recently cared for hospitalized adults. MEASUREMENTS: A self-administered survey addressing physicians' beliefs about ethical principles guiding surrogate decision-making and physicians' recent decision-making experiences. RESULTS: Overall, 72.6% of physicians identified a standard related to patient preferences as the most important ethical standard for surrogate decision-making (61.2% identified advanced directives and 11.4% substituted judgment). Of the 73.3% of physicians who reported recently making a surrogate decision, 81.8% reported that patient preferences were highly important in decision-making, although only 29.4% reported that patient preference was the most important factor in the decision. Physicians were significantly more likely to base decisions on patient preferences when the patient was in the intensive care unit (odds ratio (OR)=2.92, 95% confidence interval (CI)=1.15-7.45) and less likely when the patient was older (OR=0.76 for each decade of age, 95% CI=0.58-0.99). The presence of a living will, prior discussions with the patient, and the physicians' beliefs about ethical guidelines did not significantly predict the physicians' reliance on patient preferences. CONCLUSION: Although a majority of physicians identified patient preferences as the most important general ethical guideline for surrogate decision-making, they relied on a variety of factors when making treatment decisions for a patient lacking decisional capacity.

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.