This report evaluates the level of evidence currently available to support the effectiveness and safety of using recombinant activated coagulation factor VII (rFVIIa) for clinical indications not approved by the U. S. Food and Drug Administration (FDA). rFVIIa is approved for a variety of uses in hemophilia patients who have developed antibody inhibitors that compromise the use of standard factor replacement. Use of this costly biologic product has expanded beyond these hemophilia-related indications to encompass a range of off-label uses, most of which are in-hospital uses. These uses differ substantially from the drug’s FDA approved label. The purpose of this report is two-fold: (1) To document the full range of clinical indications for which rFVIIa is being used and the types of studies available to evaluate these uses and (2) To provide a comparative effectiveness review of rFVIIa vs. usual care for several in-hospital clinical indications: intracranial hemorrhage, massive bleeding secondary to trauma, and the selected surgical procedures of cardiac surgery, liver transplantation, and prostatectomy.

Off-label drug use refers to any use of a medication that deviates from the product labeling approved and required by the FDA. The FDA drug approval process mandates randomized clinical trials that demonstrate efficacy and safety for specific indications prior to marketing. Once approval is given, however, the FDA does not regulate whether drugs are prescribed for off-label indications. In most instances, the data supporting off-label drug use falls short of the rigor that accompanies FDA review. This uncertainty may be acceptable, as when a drug’s use is infrequent. Nevertheless, concerns increase when off-label use is clinically distinct from approved indications, when off-label use becomes frequent, when a drug is costly, or when a drug is used in different clinical settings (e.g., shifts from outpatient to in-hospital use).

rFVIIa is a form of human factor VII produced by recombinant technology. This intravenously delivered product works as a potent procoagulant by effectively bypassing parts of the clotting process normally required for clotting. It can facilitate control of bleeding in situations where standard human blood product transfusions have failed. Novoseven® is the only form of rFVIIa available commercially. Developed in the late 1980s, rFVIIa was approved by the FDA in 1999 for use in patients with Hemophilia A and Hemophilia B with antibody inhibitors that lead to unresponsiveness to factor VIII or factor IX, respectively. Both of these X-linked genetic conditions are rare, and most hemophilia patients never require rFVIIa for treatment of bleeding episodes. While the hemophilia population has remained stable over the past decade, in-hospital, off-label use of rFVIIa has increased. 

BACKGROUND: The CDC recommends routine voluntary HIV testing of all patients 13-64 years of age. Despite this recommendation, HIV testing rates are low even among those at identifiable risk, and many patients do not return to receive their results. OBJECTIVE: To examine the costs and benefits of strategies to improve HIV testing and receipt of results. DESIGN: Cost-effectiveness analysis based on a Markov model. Acceptance of testing, return rates, and related costs were derived from a randomized trial of 251 patients; long-term costs and health outcomes were derived from the literature. SETTING/TARGET POPULATION: Primary-care patients with unknown HIV status. INTERVENTIONS: Comparison of three intervention models for HIV counseling and testing: Model A = traditional HIV counseling and testing; Model B = nurse-initiated routine screening with traditional HIV testing and counseling; Model C = nurse-initiated routine screening with rapid HIV testing and streamlined counseling. MAIN MEASURES: Life-years, quality-adjusted life-years (QALYs), costs and incremental cost-effectiveness. KEY RESULTS: Without consideration of the benefit from reduced HIV transmission, Model A resulted in per-patient lifetime discounted costs of $48,650 and benefits of 16.271 QALYs. Model B increased lifetime costs by $53 and benefits by 0.0013 QALYs (corresponding to 0.48 quality-adjusted life days). Model C cost $66 more than Model A with an increase of 0.0018 QALYs (0.66 quality-adjusted life days) and an incremental cost-effectiveness of $36,390/QALY. When we included the benefit from reduced HIV transmission, Model C cost $10,660/QALY relative to Model A. The cost-effectiveness of Model C was robust in sensitivity analyses. CONCLUSIONS: In a primary-care population, nurse-initiated routine screening with rapid HIV testing and streamlined counseling increased rates of testing and receipt of test results and was cost-effective compared with traditional HIV testing strategies.

Background: Sodium consumption raises blood pressure, increasing the risk for heart attack and stroke. Several countries, including the United States, are considering strategies to decrease population sodium intake.

Objective: To assess the cost-effectiveness of 2 population strategies to reduce sodium intake: government collaboration with food manufacturers to voluntarily cut sodium in processed foods, modeled on the United Kingdom experience, and a sodium tax.

Design: A Markov model was constructed with 4 health states: well, acute myocardial infarction (MI), acute stroke, and history of MI or stroke.

Data Sources: Medical Panel Expenditure Survey (2006), Framingham Heart Study (1980 to 2003), Dietary Approaches to Stop Hypertension trial, and other published data.

Target Population: U.S. adults aged 40 to 85 years.

Time Horizon: Lifetime.

Perspective: Societal.

Outcome Measures: Incremental costs (2008 U.S. dollars), quality-adjusted life-years (QALYs), and MIs and strokes averted.

Results of Base-case Analysis: Collaboration with industry that decreases mean population sodium intake by 9.5% averts 513 885 strokes and 480 358 MIs over the lifetime of adults aged 40 to 85 years who are alive today compared with the status quo, increasing QALYs by 2.1 million and saving $32.1 billion in medical costs. A tax on sodium that decreases population sodium intake by 6% increases QALYs by 1.3 million and saves $22.4 billion over the same period.

Results of Sensitivity Analysis: Results are sensitive to the assumption that consumers have no disutility with modest reductions in sodium intake.

Limitation: Efforts to reduce population sodium intake could result in other dietary changes that are difficult to predict.

Conclusion: Strategies to reduce sodium intake on a population level in the United States are likely to substantially reduce stroke and MI incidence, which would save billions of dollars in medical expenses.

Primary Funding Source: Department of Veterans Affairs, Stanford University, and the National Science Foundation.

Abstract Objective. To develop and evaluate a clinical decision support system (CDSS) named Assessment and Treatment in Healthcare: Evidenced-Based Automation (ATHENA)-Opioid Therapy, which encourages safe and effective use of opioid therapy for chronic, noncancer pain. Design. CDSS development and iterative evaluation using the analysis, design, development, implementation, and evaluation process including simulation-based and in-clinic assessments of usability for providers followed by targeted system revisions. Results. Volunteers provided detailed feedback to guide improvements in the graphical user interface, and content and design changes to increase clinical usefulness, understandability, clinical workflow fit, and ease of completing guideline recommended practices. Revisions based on feedback increased CDSS usability ratings over time. Practice concerns outside the scope of the CDSS were also identified. Conclusions. Usability testing optimized the CDSS to better address barriers such as lack of provider education, confusion in dosing calculations and titration schedules, access to relevant patient information, provider discontinuity, documentation, and access to validated assessment tools. It also highlighted barriers to good clinical practice that are difficult to address with CDSS technology in its current conceptualization. For example, clinicians indicated that constraints on time and competing priorities in primary care, discomfort in patient-provider communications, and lack of evidence to guide opioid prescribing decisions impeded their ability to provide effective, guideline-adherent pain management. Iterative testing was essential for designing a highly usable and acceptable CDSS; however, identified barriers may limit the impact of the ATHENA-Opioid Therapy system and other CDSS on clinical practices and outcomes unless CDSS are paired with parallel initiatives to address these issues.

Objectives: Model-based cost-effectiveness analyses support decision-making. To augment model credibility, evaluation via comparison to independent, empirical studies is recommended. Methods: We developed a structured reporting format for model evaluation and conducted a structured literature review to characterize current model evaluation recommendations and practices. As an illustration, we applied the reporting format to evaluate a microsimulation of human papillomavirus and cervical cancer. The model's outputs and uncertainty ranges were compared with multiple outcomes from a study of long-term progression from high-grade precancer (cervical intraepithelial neoplasia [CIN]) to cancer. Outcomes included 5 to 30-year cumulative cancer risk among women with and without appropriate CIN treatment. Consistency was measured by model ranges overlapping study confidence intervals. Results: The structured reporting format included: matching baseline characteristics and follow-up, reporting model and study uncertainty, and stating metrics of consistency for model and study results. Structured searches yielded 2963 articles with 67 meeting inclusion criteria and found variation in how current model evaluations are reported. Evaluation of the cervical cancer microsimulation, reported using the proposed format, showed a modeled cumulative risk of invasive cancer for inadequately treated women of 39.6% (30.9-49.7) at 30 years, compared with the study: 37.5% (28.4-48.3). For appropriately treated women, modeled risks were 1.0% (0.7-1.3) at 30 years, study: 1.5% (0.4-3.3). Conclusions: To support external and projective validity, cost-effectiveness models should be iteratively evaluated as new studies become available, with reporting standardized to facilitate assessment. Such evaluations are particularly relevant for models used to conduct comparative effectiveness analyses.

Background: Sodium consumption raises blood pressure, increasing the risk for heart attack and stroke. Several countries, including the United States, are considering strategies to decrease population sodium intake.

Objective: To assess the cost-effectiveness of 2 population strategies to reduce sodium intake: government collaboration with food manufacturers to voluntarily cut sodium in processed foods, modeled on the United Kingdom experience, and a sodium tax.

Design: A Markov model was constructed with 4 health states: well, acute myocardial infarction (MI), acute stroke, and history of MI or stroke.

Data Sources: Medical Panel Expenditure Survey (2006), Framingham Heart Study (1980 to 2003), Dietary Approaches to Stop Hypertension trial, and other published data.

Target Population: U.S. adults aged 40 to 85 years.

Time Horizon: Lifetime.

Perspective: Societal.

Outcome Measures: Incremental costs (2008 U.S. dollars), quality-adjusted life-years (QALYs), and MIs and strokes averted.

Results of Base-case Analysis: Collaboration with industry that decreases mean population sodium intake by 9.5% averts 513 885 strokes and 480 358 MIs over the lifetime of adults aged 40 to 85 years who are alive today compared with the status quo, increasing QALYs by 2.1 million and saving $32.1 billion in medical costs. A tax on sodium that decreases population sodium intake by 6% increases QALYs by 1.3 million and saves $22.4 billion over the same period.

Results of Sensitivity Analysis: Results are sensitive to the assumption that consumers have no disutility with modest reductions in sodium intake.

Limitation: Efforts to reduce population sodium intake could result in other dietary changes that are difficult to predict.

Conclusion: Strategies to reduce sodium intake on a population level in the United States are likely to substantially reduce stroke and MI incidence, which would save billions of dollars in medical expenses.

Primary Funding Source: Department of Veterans Affairs, Stanford University, and the National Science Foundation.

Background: Decisions on the timing and extent of vaccination against pandemic (H1N1) 2009 virus are complex.

Objective: To estimate the effectiveness and cost-effectiveness of pandemic influenza (H1N1) vaccination under different scenarios in October or November 2009.

Design: Compartmental epidemic model in conjunction with a Markov model of disease progression.

Data Sources: Literature and expert opinion.

Target Population: Residents of a major U.S. metropolitan city with a population of 8.3 million.

Time Horizon: Lifetime.

Perspective: Societal.

Interventions: Vaccination in mid-October or mid-November 2009.

Outcome Measures: Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness.

Results of Base-Case Analysis: Assuming each primary infection causes 1.5 secondary infections, vaccinating 40% of the population in October or November would be cost-saving. Vaccination in October would avert 2051 deaths, gain 69 679 QALYs, and save $469 million compared with no vaccination; vaccination in November would avert 1468 deaths, gain 49 422 QALYs, and save $302 million.

Results of Sensitivity Analysis: Vaccination is even more cost-saving if longer incubation periods, lower rates of infectiousness, or increased implementation of nonpharmaceutical interventions delay time to the peak of the pandemic. Vaccination saves fewer lives and is less cost-effective if the epidemic peaks earlier than mid-October.

Limitations: The model assumed homogenous mixing of case-patients and contacts; heterogeneous mixing would result in faster initial spread, followed by slower spread. Additional costs and savings not included in the model would make vaccination more cost-saving.

Conclusion: Earlier vaccination against pandemic (H1N1) 2009 prevents more deaths and is more cost-saving. Complete population coverage is not necessary to reduce the viral reproductive rate sufficiently to help shorten the pandemic.

Primary Funding Source: Agency for Healthcare Research and Quality and National Institute on Drug Abuse.

Background: The pandemic potential of influenza A (H5N1) virus is a prominent public health concern of the 21st century.

Objective: To estimate the effectiveness and cost-effectiveness of alternative pandemic (H5N1) mitigation and response strategies.

Design: Compartmental epidemic model in conjunction with a Markov model of disease progression.

Data Sources: Literature and expert opinion.

Target Population: Residents of a U.S. metropolitan city with a population of 8.3 million.

Time Horizon: Lifetime.

Perspective: Societal.

Interventions: 3 scenarios: 1) vaccination and antiviral pharmacotherapy in quantities similar to those currently available in the U.S. stockpile (stockpiled strategy), 2) stockpiled strategy but with expanded distribution of antiviral agents (expanded prophylaxis strategy), and 3) stockpiled strategy but with adjuvanted vaccine (expanded vaccination strategy). All scenarios assumed standard nonpharmaceutical interventions.

Outcome Measures: Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness.

Results of Base-Case Analysis: Expanded vaccination was the most effective and cost-effective of the 3 strategies, averting 68% of infections and deaths and gaining 404 030 QALYs at $10 844 per QALY gained relative to the stockpiled strategy.

Results of Sensitivity Analysis: Expanded vaccination remained incrementally cost-effective over a wide range of assumptions.

Limitations: The model assumed homogenous mixing of cases and contacts; heterogeneous mixing would result in faster initial spread, followed by slower spread. We did not model interventions for children or older adults; the model is not designed to target interventions to specific groups.

Conclusion: Expanded adjuvanted vaccination is an effective and cost-effective mitigation strategy for an influenza A (H5N1) pandemic. Expanded antiviral prophylaxis can help delay the pandemic while additional strategies are implemented.

Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality.