Using Bayesian Adaptive Trial Designs for Comparative Effectiveness Research: A Virtual Trial Execution.

BACKGROUND: Bayesian and adaptive clinical trial designs offer the potential for more efficient processes that result in lower sample sizes and shorter trial durations than traditional designs. OBJECTIVE: To explore the use and potential benefits of Bayesian adaptive clinical trial designs in comparative effectiveness research. DESIGN: Virtual execution of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) as if it had been done according to a Bayesian adaptive trial design. SETTING: Comparative effectiveness trial of antihypertensive medications. PATIENTS: Patient data sampled from the more than 42 000 patients enrolled in ALLHAT with publicly available data. MEASUREMENTS: Number of patients randomly assigned between groups, trial duration, observed numbers of events, and overall trial results and conclusions. RESULTS: The Bayesian adaptive approach and original design yielded similar overall trial conclusions. The Bayesian adaptive trial randomly assigned more patients to the better-performing group and would probably have ended slightly earlier. LIMITATIONS: This virtual trial execution required limited resampling of ALLHAT patients for inclusion in RE-ADAPT (REsearch in ADAptive methods for Pragmatic Trials). Involvement of a data monitoring committee and other trial logistics were not considered. CONCLUSION: In a comparative effectiveness research trial, Bayesian adaptive trial designs are a feasible approach and potentially generate earlier results and allocate more patients to better-performing groups. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Characteristics and temporal trends in patient registries: focus on the life sciences industry, 1981-2012.

PURPOSE: Patient registries are used to monitor safety, examine real-world effectiveness, and may potentially contribute to comparative effectiveness research. To our knowledge, life sciences industry (LSI)-sponsored registries have not been systematically categorized. This study represents a first step toward understanding such registries over time. METHODS: Studies described as registries were identified in the ClinicalTrials.gov database. Characteristics from these registry records were abstracted and analyzed. RESULTS: Of 1202 registries identified, approximately 47% reported LSI sponsorship. These 562 LSI registries varied in focus: medical devices (n = 193, 34%), specific drugs (n = 173, 31%), procedures (n = 29, 5%), or particular diseases (n = 139, 25%). Thirty-three registries (<6%) evaluated pregnancy outcomes. The most common therapeutic area was cardiovascular (n = 234, 42%); others included endocrinology, immunology, oncology, musculoskeletal disorders, and neurology. The two most often measured outcomes were clinical effectiveness and safety, each of which appeared in 363/562 (65%) of LSI registries. Other outcomes included real-world clinical practice patterns (n = 122, 22%), patient-reported outcomes (n = 106, 19%), disease epidemiology/natural history (n = 69, 12%), and economic outcomes (n = 30, 5%). The number of LSI registries and their geographic diversity has increased over time. CONCLUSIONS: The LSI registries represent a substantial proportion of all patient registries documented in ClinicalTrials.gov. These prospective studies are growing in number and encompass diverse therapeutic areas and geographic regions. Most registries measure multiple outcomes and capture real-world data that may be unavailable through other study designs. This classification of LSI registries documents their use for studying heterogeneity of diseases, examining treatment patterns, measuring patient-reported outcomes, examining economic outcomes, and performing comparative effectiveness research.

Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study.

BACKGROUND: Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making. PURPOSE: Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a 'proof of concept' to stimulate investment in Bayesian adaptive designs for future CER trials. METHODS: We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT. RESULTS: We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization. LIMITATIONS: While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes. CONCLUSION: This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data.

Building a strategic framework for comparative effectiveness research in complementary and integrative medicine.

The increasing burden of chronic diseases presents not only challenges to the knowledge and expertise of the professional medical community, but also highlights the need to improve the quality and relevance of clinical research in this domain. Many patients now turn to complementary and integrative medicine (CIM) to treat their chronic illnesses; however, there is very little evidence to guide their decision-making in usual care. The following research recommendations were derived from a CIM Stakeholder Symposium on Comparative Effectiveness Research (CER): (1) CER studies should be made a priority in this field; (2) stakeholders should be engaged at every stage of the research; (3) CER study designs should highlight effectiveness over efficacy; (4) research questions should be well defined to enable the selection of an appropriate CER study design; (5) the CIM community should cultivate widely shared understandings, discourse, tools, and technologies to support the use and validity of CER methods; (6) Effectiveness Guidance Documents on methodological standards should be developed to shape future CER studies. CER is an emerging field and its development and impact must be reflected in future research strategies within CIM. This stakeholder symposium was a first step in providing systematic guidance for future CER in this field.

Can we reliably benchmark health technology assessment organizations?

OBJECTIVES: In recent years, there has been growth in the use of health technology assessment (HTA) for making decisions about the reimbursement, coverage, or guidance on the use of health technologies. Given this greater emphasis on the use of HTA, it is important to develop standards of good practice and to benchmark the various HTA organizations against these standards. METHODS: This study discusses the conceptual and methodological challenges associated with benchmarking HTA organizations and proposes a series of audit questions based on a previously published set of principles of good practice. RESULTS AND CONCLUSIONS: It is concluded that a benchmarking exercise would be feasible and useful, although the question of who should do the benchmarking requires further discussion. Key issues for further research are the alternative methods for weighting the various principles and for generating an overall score, or summary statement of adherence to the principles. Any weighting system, if developed, would need to be explored in different jurisdictions to assess the extent to which the relative importance of the principles is perceived to vary. Finally, the development and precise wording of the audit questions requires further study, with a view to making the questions as unambiguous as possible, and the reproducibility of the assessments as high as possible.

A practical path forward to more patient-centered value assessment.

To ensure that value assessment accounts for patient needs, we need a better understanding of the outcomes that are most important to patients, write authors from COVIA Health Solutions and the University of Washington School of Pharmacy.

Bayesian meta-analyses for comparative effectiveness and informing coverage decisions.

BACKGROUND: Evidence-based medicine is increasingly expected in health care decision-making. The Centers for Medicare and Medicaid have initiated efforts to understand the applicability of Bayesian techniques for synthesizing evidence. As a case study, a Bayesian analysis of clinical trials of implantable cardioverter defibrillators was undertaken using patient-level data not typically available for analysis. PURPOSE: Conduct Bayesian meta-analyses of the defibrillator trials using published results to demonstrate a Bayesian approach useful to policy makers. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION: We reconsidered trials in a 2007 systematic review by Ezekowitz et al (Ann Intern Med. 2007;147:251-262) and extracted information from the original published articles. Employing a Bayesian hierarchical approach, we developed a base model and 2 variants, and modeled hazard ratios separately within each year of follow-up. We considered sequential meta-analyses over time and found the predictive distribution of the results of the next trial, given its sample size. DATA SYNTHESIS: For the most robust of 3 models, the probability that the mean defibrillator effect (in the population of trials) is beneficial is greater than 0.999. In that model, about 5% of trials in the population of trials would have a detrimental effect. Despite the moderate amount of heterogeneity across the trials, there was stability of conclusions after the first 3 of the 12 total trials had been conducted. This stability enabled reasonable predictions for the results of future trials. LIMITATIONS: Inability to assess treatment effects within subsets of patients. CONCLUSIONS: Bayesian meta-analyses based on literature surveys can effectively inform coverage decisions. Bayesian modeling for endpoints such as mortality can elucidate treatment effects over time. The Bayesian approach used in a sequential manner over time can predict results and help assess the utility of future clinical trials.

EBM, HTA, and CER: clearing the confusion.

CONTEXT: The terms evidence-based medicine (EBM), health technology assessment (HTA), comparative effectiveness research (CER), and other related terms lack clarity and so could lead to miscommunication, confusion, and poor decision making. The objective of this article is to clarify their definitions and the relationships among key terms and concepts. METHODS: This article used the relevant methods and policy literature as well as the websites of organizations engaged in evidence-based activities to develop a framework to explain the relationships among the terms EBM, HTA, and CER. FINDINGS: This article proposes an organizing framework and presents a graphic demonstrating the differences and relationships among these terms and concepts. CONCLUSIONS: More specific terminology and concepts are necessary for an informed and clear public policy debate. They are even more important to inform decision making at all levels and to engender more accountability by the organizations and individuals responsible for these decisions.

Are Key Principles for improved health technology assessment supported and used by health technology assessment organizations?

Previously, our group-the International Working Group for HTA Advancement-proposed a set of fifteen Key Principles that could be applied to health technology assessment (HTA) programs in different jurisdictions and across a range of organizations and perspectives. In this commentary, we investigate the extent to which these principles are supported and used by fourteen selected HTA organizations worldwide. We find that some principles are broadly supported: examples include being explicit about HTA goals and scope; considering a wide range of evidence and outcomes; and being unbiased and transparent. Other principles receive less widespread support: examples are addressing issues of generalizability and transferability; being transparent on the link between HTA findings and decision-making processes; considering a full societal perspective; and monitoring the implementation of HTA findings. The analysis also suggests a lack of consensus in the field about some principles--for example, considering a societal perspective. Our study highlights differences in the uptake of key principles for HTA and indicates considerable room for improvement for HTA organizations to adopt principles identified to reflect good HTA practices. Most HTA organizations espouse certain general concepts of good practice--for example, assessments should be unbiased and transparent. However, principles that require more intensive follow-up--for example, monitoring the implementation of HTA findings--have received little support and execution.

Willingness to pay for cancer prevention.

Cancer inflicts great pain, burden and cost upon American society, and preventing cancer is important but not costless. The aim of this review was to explore the upper limits that American society is paying and appears willing to pay to prevent cancer, by enforced environmental regulations and implemented clinical practice guidelines. Cost-effectiveness studies of clinical and environmental cancer-prevention policies and programmes were identified through a comprehensive literature review and confirmed to be officially sanctioned and implemented, enforced or funded. Data were collected in 2005-6 and analysed in 2007. The incremental cost-effectiveness ratios (ICERs) for clinical prevention policies ranged from under $US2000 to over $US6 000 000 per life-year saved (LYS), exceeding $US100 000 per LYS for only 11 of 101 guidelines. Median ICERs for tobacco-related ($US3978/LYS), colorectal ($US22 694/LYS) and breast ($US25 687/LYS) cancer prevention were within generally accepted ranges and tended not to vary greatly, whereas those for prostate ($US73 603/LYS) and cervical ($US125 157/LYS) cancer-prevention policies were considerably higher and varied substantially more. In contrast, both the median and range of the environmental policies were enormous, with 90% exceeding $US100 000 per LYS, and ICERs ranging from $US61 004 to over $US24 billion per LYS. Notwithstanding a relatively large and accessible literature evaluating the cost effectiveness of clinical and environmental cancer-prevention policies as well as the availability of ICERs for the policies identified in this study, the apparent willingness to pay to prevent cancer in the US still varies greatly and can be extremely high, particularly for many of the environmental cancer-prevention policies.

Health technology assessment in the United States.

OBJECTIVES: To describe and explore the reasons for the current health technology assessment (HTA) landscape in the United States. METHODS: Relying on multiple historical literature and other documents as well as drawing on personal experiences and observations, we describe, evaluate, and explain the evolving and dynamic HTA-related evidence landscape. RESULTS: The present HTA-related landscape is a product of a dynamic, somewhat turbulent path in the United States. Many early aggressive federal efforts beginning in the 1970s were rejected in the 1980s only to be revived by the mid-1990s and continue to strengthen today, likely due to diffusing private sector political opposition from de-linking HTA from policy decisions (e.g., coverage, clinical guidelines) and omitting economic evaluation. Meanwhile, private sector HTA efforts have remained active during the entire period. CONCLUSIONS: The current HTA-related landscape is at least as dynamic as it has been at any point in its turbulent 30-year history and is likely to continue as health reform in the US is debated once again.

How different is research done by the Patient-centered Outcomes Research Institute, and what difference does it make?

Aim: To determine whether research funded by the Patient-centered Outcomes Research Institute (PCORI) is consistent with the original aims of Congress and unique among other major USA funders. Methods: We compared a sample of funded projects from PCORI, NIH (Phase IV) and agency for healthcare research and quality (AHRQ; American Recovery and Reinvestment Act [ARRA]-based comparative effectiveness research funding) from 2014 to 2018 on number of outcomes/study, patient-centeredness of outcomes (those related to survival, function, symptoms and health-related quality of life) and other features that may characterize patient-centered research (e.g., whether conducted in a real-world setting) using PCORI portfolio data and ClinicalTrials.gov. Results: The mean number of outcomes in PCORI studies (≥9) appeared higher than NIH (≥3)/AHRQ (5.5); a higher percentage of outcomes/study were patient-centered: >85% PCORI versus 50% AHRQ and ≤30% NIH. The majority of PCORI studies (≥74%) were conducted in a real-world setting; this characteristic could not be identified for NIH/AHRQ studies. Conclusion: PCORI-funded studies appear to have unique aspects relative to NIH and AHRQ that are consistent with PCORI's aims of patient-centeredness.

Evidence based? Caveat emptor!

Medical practices, clinical practice guidelines, clinical performance measures and measurements, and a variety of health care-related administrative decisions, such as insurance coverage decisions, are claiming to be "evidence based" with increasing frequency. In this paper we examine the "evidence based" label; discuss how evidence ought to have been assembled, evaluated, and synthesized; and when evidence is sufficient for the "evidence-based" moniker to rightfully apply. We also highlight several considerations other than the strength of evidence that are relevant to several common types of health care-related administrative decisions and that influence the extent to which the resulting decisions are truly evidence based.

The effect on social welfare of a switch of second-generation antihistamines from prescription to over-the-counter status: a microeconomic analysis.

BACKGROUND: The US Food and Drug Administration (FDA) recently held a meeting to determine whether the status of second-generation antihistamines (SGAs) should be switched from prescription (Rx) to over-the-counter (OTC) status. OBJECTIVE: This article provides a conceptual microeconomic framework for addressing issues regarding the impact of such a switch on social welfare. METHODS: A review of the economic literature on Rx-to-OTC switches was conducted. Relevant articles published in English between 1990 and 2001 were identified through searches of ABI Info, EconLit, PsychInfo, MEDLINE, CANCERLIT, AIDSLINE, and HealthStar, as well as a general Internet search for statements in the press or on the FDA Web site. The search terms used were Rx, prescription, OTC, over-the-counter, second-generation antihistamines, nonsedating antihistamines, first-generation antihistamines, and sedating antihistamines. Microeconomic models focusing on consumer surplus were employed to determine the potential price response and social-welfare implications of a switch of SGAs to OTC status. RESULTS: Unlike the agents involved in previous Rx-to-OTC switches, SGAs are still under patent protection. Economic theory suggests that a firm that is protected by a patent will price aggressively. The market for OTC SGAs is likely to be more elastic due to a lack of insurance coverage for OTC products; hence, drug manufacturers would be likely to charge a lower price if SGAs were sold OTC. However, a lower price does not necessarily guarantee an improvement in social welfare; the net impact is determined by whether the increase in consumer surplus outweighs the deadweight loss (losses of consumer and producer surplus not transferred to other parties). Additionally, the assumption of a price reduction would be called into question if there were inequalities in marginal costs between the Rx and OTC markets. In this situation, the postswitch price might increase or not be reduced significantly. CONCLUSIONS: It is uncertain whether granting OTC status to SGAs would be cost saving to society, particularly as these drugs are patent protected. The social-welfare implications of such a switch would depend heavily on pricing strategies and consumer behavior. Further analyses are needed to determine how both factors influence social welfare; only then can the costs and benefits of a switch be understood completely.

Effectiveness of budesonide administered via dry-powder inhaler versus triamcinolone acetonide administered via pressurized metered-dose inhaler for adults with persistent asthma in managed care settings.

BACKGROUND: Clinical studies have demonstrated the efficacy and relative safety of inhaled corticosteroids in the treatment of asthma. However, effectiveness and cost-effectiveness comparisons of available inhaled corticosteroids in real-life clinical settings are lacking. OBJECTIVE: This study compared the effectiveness and safety of budesonide administered via dry-powder inhaler versus that of triamcinolone acetonide administered via pressurized metered-dose inhaler in the treatment of adult patients with persistent asthma treated in a managed care setting. METHODS: This was a randomized, open-labe, 52-week study of adult patients (aged >or= 18 years) with persistent asthma enrolled in 25 US health plans. The primary study outcome was mean change from baseline to the end of treatment in symptom-free days. Secondary variables were changes from baseline in number of episode-free days, episode-free days at 52 weeks, forced expiratory volume in 1 second (FEV(1)), forced vital capacity, asthma symptom scores, breakthrough bronchdilator use, patient discontinuations, and health-related quality of life. Patients were issued diaries in which to record use of study medication and concomitant asthma medication use, as well as daytime and nighttime asthma symptom severity. Patients were assessed at weeks 4, 13, 26, 39, and 52. Safety was assessed based on adverse events and changes in laboratory tests, vital signs, and physical examinations. RESULTS: A total of 945 patients (344 men, 601 women; mean [SD] age, 46.8 [14] years) were enrolled; 631 received budesonide and 314 received triacinolane acetonide. Improvements in all effectiveness variables were observed with both treatments. The mean increase from baseline in the number of symptom-free days per month assessed at month 12 was 7.74 (95% CI, 6.81-8.66) for patients receiving budesonide and 3.78 (95% CI, 2.47-5.09) for patients receiving triamcinoline acetonide ( P<0.001). The estimated annual mean (SD) number symptom-free days for patients receiving budesonide was 141.1 (125.0) over the treatment phase, compared with 99.3 (112.1) for those receiving triamcinolone acetonide (P<0.001). Patients receiving budesonide demonstrated significant improvements (compared with those receiving triamcinolone acetonide) in overall quality of life, daytime and nighttime asthma symptom severity, breakthrough bronchodilator use, and FEV(1) (all P<0.001). Safety measures were similar between groups. CONCLUSION: In these managed care settings, budesonide inhalation powder administered via dry-powder inhaler was significantly more effective than triamcinolone acetonide administered via pressurized metered-dose inhaler in the treatment of adults with persistent asthma.

Economic burden of heart failure: a summary of recent literature.

OBJECTIVE: We reviewed literature published from 1995 to 2002 to highlight findings on the economic burden of heart failure (HF). Methods A key-word search of literature indexes for relevant citations identified 54 articles that were then summarized for findings on HF economics. RESULTS: Results were described in terms of burden of illness, cost-effectiveness analysis, and resource utilization and costs. Hospitalization of the elderly is the driving force behind HF costs. Interventions that decrease the frequency of hospital admissions while maintaining clinical and patient reported outcomes are considered a high priority among decision makers and clinicians. Although the cost-effectiveness of therapy with beta-adrenergic blocking agents has been well established in the literature, the cost-effectiveness of hospital- or home-based HF management programs is still under debate. The issues of payer status and physician specialty impact on decreased hospital admission and cost have been inconclusive. CONCLUSIONS: Any intervention capable of decreasing even a small fraction of adverse outcomes, most notably hospital admission and length of stay, could trigger significant cost savings in the management of HF. Public policy makers, together with clinicians identifying cost saving or cost-effective interventions in their practice, are expected to increase their efforts to evaluate the cost-effectiveness and outcomes of medical and pharmacologic interventions in HF.