Using Real-World Data in the Health Technology Assessment of Pharmaceuticals: Strengths, Difficulties, and a Pragmatic Way Forward.

In the past decade, there have been increasing calls for greater use of real-world evidence (RWE) and data (RWD), with the explicit goal of enabling faster provision of effective medicines to patients in need. The push for decision makers to accept RWE is especially noticeable in the pursuit of regulatory approval, but RWE, particularly when used to estimate the relative effectiveness of interventions, is not always readily accepted by agencies responsible for reimbursement and pricing of new pharmaceuticals and, to a varying degree, is not accepted across jurisdictions. This lack of trust hampers the use of RWE despite a very large and growing literature base on the principles of how RWE should be used. In this article, we suggest an important part of the explanation of why this situation has arisen and make suggestions for its alleviation. Given that problems commonly arise that are particular to the question being asked and the data sources being used, general guidance on the principles of how to use RWD cannot cover all eventualities. Therefore, we are suggesting the creation of an archive, or repository, to record uses of RWD in support of decisions by funding bodies or their advisors. This article introduces a proposed, structured classification of decision types using RWE, around which evidence can be assembled in a curated source (RWD/RWE taxonomy) and thus facilitate judgments on when evidence is "good enough." This article is part of a series in a special issue of this journal that looks at the barriers to optimal use of RWE in health technology assessment and how to overcome them. We begin significantly to populate our "taxonomy" with examples in an accompanying article. We also propose recommendations for international standards of evaluating the acceptability of RWD governance practices.

The Real-World Evidence Workstream in EUreccA 2025: How the Task Was Addressed.

This is one of a series of articles that consider the barriers to optimal use of real-world evidence (RWE) in health technology assessment (HTA) as well as ways to overcome them. The work was carried out as part of EUreccA 2025 (European Initiative for New Reimbursement and Access Approaches 2025), in particular with the RWE workstream embodied within that collaboration. The starting premises of this workstream were as follows: (1) the acceptance of RWE by HTA agencies and payers in the assessment of drugs is suboptimal and variable between jurisdictions, and (2) if that were not the case, the path of new pharmaceuticals to patients could be quicker and less expensive. Elsewhere in this issue we set out the conclusions we had reached in the EUreccA RWE workstream. In this article, we set out the methodology used to conduct the totality of the EureccA 2025 RWE workstream effort, which led us to those conclusions. The main results, strengths, and limitations of the individual parts are discussed further in separate articles in this supplement. Through scoping work, we generated 4 key topics within which to identify and address the barriers to optimal RWE use in HTA. Through pragmatic literature searches, stakeholder engagement, and case studies, we suggest ways in which the problems identified may be addressed as a contribution to progress in this area.

Structure and Content of a Taxonomy to Support the Use of Real-World Evidence by Health Technology Assessment Practitioners and Healthcare Decision Makers.

This is one of a series of articles that consider the barriers to optimal use of real-world evidence (RWE) in health technology assessment and how to overcome them. The work was performed as part of EUreccA 2025, in particular with the RWE workstream embodied within that collaboration. Elsewhere in this issue we described the reasoning and process that led us to develop practical tools to support RWE use, including this taxonomy and explained the methods used to do so. The taxonomy classifies questions that are typically addressed using real-world data in health technology assessment and the data sources typically used to address these questions. In this article, we describe the taxonomy itself. For as many of the pairings as possible, we have provided links to advice and methods on how to address the associated question using those data. We have also provided links to examples of RWE use in practical decision making to answer the questions posed. Our work is not complete, but we believe it is sufficient to demonstrate the value of such a taxonomy and information source if it is completed and curated as a "wiki" by the community that would use it.

Across-Country Variations of Real-World Data and Evidence for Drugs: A 5-European-Country Study.

OBJECTIVES: This study aimed to describe the role of real-world data (RWD) and real-world evidence (RWE) in health technology assessment (HTA) in 5 European countries and to identify the hurdles to the acceptance of RWE and suggest directions toward its more effective use. METHODS: Authors from France, Germany, Italy, and Sweden used a common template to extract evidence. For England, the Cancer Drugs Fund was described and analyzed as a particular model for the use of RWD to provide evidence for coverage decisions and managed entry agreements. RESULTS: In all countries except Germany, HTA bodies acknowledged the relevance of RWD/RWE to address postlaunch uncertainties. In Germany, evidence from randomized controlled trials remains the gold standard, and evidence based on RWD is generally rejected. Multiple sources of RWD exist, but the quality, the immediate relevance of existing sources, and their interoperability limit their adaptation to the specifics of a given drug. This leads to skepticism about the validity of the evidence. Timing is also a key issue: the production of evidence may not be synchronized with the HTA and pricing bodies' agendas. The Cancer Drugs Fund case emphasizes that a strong partnership among all stakeholders and a pragmatic use of existing data, alongside clinical evidence provided by companies, are key success factors. CONCLUSIONS: A continuous investment in national health information systems is a key issue for providing valid RWE. Processes and aids to guide the acceptability and usage of RWE derived from pairing between sources and questions are essential.

Data Governance for Real-World Data Management: A Proposal for a Checklist to Support Decision Making.

OBJECTIVES: Real-world data (RWD) and real-world evidence (RWE) can provide extensive information on healthcare for use in health technology assessment and decision making. Nevertheless, there is a lack of consensus surrounding the appropriate data governance (DG) practices for RWD/RWE. Data sharing is also a large concern, especially considering evolving data protection regulations. Our objective is to propose recommendations for international standards of evaluating the acceptability of RWD governance practices. METHODS: After reviewing the literature, we created a checklist targeting DG practices for RWD/RWE. We then carried out a 3-round Delphi panel, including European policy makers, health technology assessment experts, and hospital managers. The consensus for each statement was measured and the checklist adjusted accordingly. RESULTS: The literature review identified the main topics regarding RWD/RWE DG practices: data privacy and security, data management and linkage, data access management, and the generation and use of RWE. Members of the Delphi panel (21 experts/25 invited) were presented a total of 24 statements related to each of the topics. Experts demonstrated a progressive level of consensus and importance ratings in all topics and to most statements. We suggest a refined checklist in which the statements rated less important or with less consensus have been removed. CONCLUSIONS: This study suggests how the DG of RWD/RWE could be qualitatively evaluated. We propose checklists that could be used by all RWD/RWE users to help ensure the quality and integrity of RWD/RWE governance and complement data protection law.

Varying Willingness to Pay Based on Severity of Illness: Impact on Health Technology Assessment Outcomes of Inpatient and Outpatient Drug Therapies in The Netherlands.

OBJECTIVES: Since 2015, Zorginstituut Nederland (ZIN) has linked disease severity ranges of 0.10 to 0.40, 0.41 to 0.70, and 0.71 to 1.00 with willingness-to-pay (WTP) reference values of €20 000, €50 000, and €80 000 per quality-adjusted life year gained, respectively. We sought to review whether these changes have affected ZIN health technology assessment (HTA) outcomes for specialist and outpatient drugs. METHODS: ZIN recommendations for specialist and outpatient drugs published between January 1, 2012, and December 31, 2020, that included a pharmacoeconomic report were reviewed. Data were extracted on disease severity, proportional shortfall calculation, reported WTP reference value, outcomes related to the cost-effectiveness of the product, budget impact, and ZIN's recommendation including rationale for their advice. RESULTS: A total of 51 HTAs were included. Of the 20 HTAs published before June 2015, a total of 9 received positive recommendations, 7 were conditionally reimbursed, and 4 received negative recommendations. None reported WTP reference values. Of the 31 evaluations published after June 2015, a total of 4 products received positive recommendations, 1 was conditionally approved, and 26 received negative recommendations initially. Most products (65%) reported disease severity to be >0.70. CONCLUSIONS: Since 2015, most products have fallen within the highest category of disease severity. Although pre-2015 outcomes were varied, post-2015 products overwhelmingly received negative recommendations, and the proportion of products for which price negotiations were recommended has increased. These differences in outcomes may result from the introduction of an explicit WTP reference value, whether or not in combination with the severity-adjusted ranges, but may also reflect other national policy changes in 2015.

Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM-003 trial for pomalidomide plus low-dose dexamethasone.

In the phase III MM-003 trial, pomalidomide plus low-dose dexamethasone (POM+LoDEX) improved overall survival (OS) versus high-dose dexamethasone (HiDEX) in 455 patients with relapsed and refractory multiple myeloma (RRMM) after treatment with bortezomib and lenalidomide. Here, a two-stage Weibull method was used to adjust for the crossover of patients in the HiDEX arm to pomalidomide-based therapy. The adjusted difference in median OS between patients in the POM+LoDEX and HiDEX arms was 7·0 months (12·7 vs. 5·7 months, respectively). These findings provide important evidence for understanding the clinical efficacy of pomalidomide on OS benefits seen in RRMM patients.

The Suitability of End Point Designs for Health Technology Assessment in Chronic Pain Studies.

OBJECTIVES: To identify the pain instruments and study end points most commonly used in clinical trial settings and to provide insight into the extent to which outcome measures in clinical studies are meeting payer needs. METHODS: A literature review was conducted to identify published clinical studies and ongoing/recently completed registered trials in chronic pain. Inclusion criteria were interventional study, chronic pain in adults, and pain measured within the primary end point. RESULTS: Of 1256 PubMed citations and 3006 clinical trial registry entries, 356 reported large clinical studies in pain populations (e.g., malignant, neuropathic, functional, and musculoskeletal). Studies were designed for superiority in 28% of PubMed citations and 8% of registry entries. The primary end points of most studies were single-dimension pain instruments, such as the numerical rating scale (n = 131) and the visual analogue scale (n = 69). In cases in which multidimensional pain end points were used, this was most commonly the Brief Pain Inventory (n = 37). Payer-relevant end points were typically limited to secondary end points, and were limited and/or reported inconsistently in published studies and ongoing/recently completed studies: preference-weighted quality of life (36% and 42%), resource use (2% and 8%), physical function (28% and 39%), and psychological function (25% and 24%). CONCLUSIONS: Most pain trials were not designed to show superiority to an active comparator, and they used single-dimension pain scales as their primary end point in combination with a broader selection of secondary end points. The inclusion of payer-relevant end points among clinical trials was inconsistent.

Choosing vs. allocating: discrete choice experiments and constant-sum paired comparisons for the elicitation of societal preferences.

BACKGROUND: There is growing evidence of a reluctance to allocate health care solely on the basis of maximizing quality-adjusted life years (QALYs). Stated preference methods can be used to elicit preferences for efficiency vs. equity in the allocation of health-care resources. OBJECTIVE: To compare discrete choice experiment (DCE) and constant-sum paired comparison (CSPC) methods for eliciting societal preferences. METHODS: Over a series of choice pairs, DCE respondents allocated a fixed budget to one preferred group and CSPC respondents allocated budget percentages between the groups. Questionnaires were compared in terms of completion rates, preference consistency, dominant preferences and derived attribute importance. RESULTS: There was no significant difference in the proportions that rated the questionnaires somewhat or extremely difficult, but a significantly greater proportion completed the DCE compared to the CSPC. Preference consistency was also higher in the DCE. The incidence of dominant preferences, including for aggregate QALYs, was low and not significantly different between questionnaires. Similarly, no CSCP respondents equalized budgets or outcomes in every task. Final health state was the most important attribute in both questionnaires, but the rankings diverged for the other attributes. Notably, the total patients' treated attribute was important in the CSPC but insignificant in the DCE, perhaps reflecting a 'prominence effect'. CONCLUSIONS: Despite lower completion rates and preference consistency, CSPC may offer advantages over DCE in eliciting preferences over the distribution of resources and/or outcomes as well as attribute levels, avoiding extreme 'all-or-nothing' distributions and possibly aligning respondent attention more closely with a societal perspective.

Taking stock: A multistakeholder perspective on improving the delivery of care and the development of treatments for Alzheimer's disease.

Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines.

Health economic modelling of treatment sequences for rheumatoid arthritis: a systematic review.

The objective of the work reported in this paper was to critically assess how sequential disease-modifying anti-rheumatic drugs (DMARDs) have been modelled in the context of economic evaluation of the use of DMARDs for treatment of rheumatoid arthritis (RA). A secondary purpose was to identify the methodological challenges of modelling sequential therapies. Systematic searches of 10 databases were undertaken in February 2013. Studies were included if they were in the English language and a full comparative economic evaluation was reported. They were appraised by use of the Drummond checklist (Appendix to this paper). Data extracted included economic evaluation data, data relating to sequential treatment, and data on the modelling methods used. Fifty-seven studies were identified, with 25 (44 %) modelling a sequence of treatments. Forty-three (75 %) were cost-utility analyses. Eleven (19 %) were UK studies and 11 (19 %) were US. The remainder were mainly European (26 (46 %)). A distinction was made between studies of recent-onset RA (14 (25 %)) and those of established RA (42 (74 %)). One study (1 %) was unclear. Individual-level models were more likely to meet the Drummond criteria and evaluate sequences. No study identified an optimum sequence of multiple treatments given a set of treatment options. The level of reporting of the methods and evidence used to assess the effect of downstream treatments in the sequence was generally poor. When lifelong models and downstream treatment sequences were considered, evidence gaps were identified. The review discovered that methods have not been consistently applied, leading to varied estimates of cost-effectiveness. Treatment sequences have not been fully considered and modelled, potentially resulting in inaccurate estimates of cost-effectiveness.

Cost Effectiveness of Endovascular Ultrasound Renal Denervation in Patients with Resistant Hypertension.

BACKGROUND: Resistant hypertension (rHTN) is defined as blood pressure (BP) of ≥ 140/90 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. Endovascular ultrasound renal denervation (uRDN) aims to control BP alongside conventional BP treatment with antihypertensive medication. This analysis assesses the cost effectiveness of the addition of the Paradise uRDN System compared with standard of care alone in patients with rHTN from the perspective of the United Kingdom (UK) health care system. METHODS: Using RADIANCE-HTN TRIO trial data, we developed a state-transition model. Baseline risk was calculated using Framingham and Prospective Cardiovascular Münster (PROCAM) risk equations to estimate the long-term cardiovascular risks in patients treated with the Paradise uRDN System, based on the observed systolic BP (SBP) reduction following uRDN. Relative risks sourced from a meta-analysis of randomised controlled trials were then used to project cardiovascular events in patients with baseline SBP ('control' patients); utility and mortality inputs and costs were derived from UK data. Costs and outcomes were discounted at 3.5% per annum. Modelled outcomes were validated against trial meta-analyses and the QRISK3 algorithm and real-world evidence of RDN effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty surrounding the model inputs and sensitivity of the model results to changes in parameter inputs. Results were reported as incremental cost-effectiveness ratios (ICERs). RESULTS: A mean reduction in office SBP of 8.5 mmHg with uRDN resulted in an average improvement in both absolute life-years (LYs) and quality-adjusted life-years (QALYs) gained compared with standard of care alone (0.73 LYs and 0.67 QALYs). The overall base-case ICER with uRDN was estimated at £5600 (€6500) per QALY gained (95% confidence interval £5463-£5739 [€6341-€6661]); modelling demonstrated > 99% probability that the ICER is below the £20,000-£30,000 (€23,214-€34,821) per QALYs gained willingness-to-pay threshold in the UK. Results were consistent across sensitivity analyses and validation checks. CONCLUSIONS: Endovascular ultrasound RDN with the Paradise system offers patients with rHTN, clinicians, and healthcare systems a cost-effective treatment option alongside antihypertensive medication.

Cost-effectiveness of a novel AI technology to quantify coronary inflammation and cardiovascular risk in patients undergoing routine Coronary Computed Tomography Angiography.

AIMS: Coronary Computed Tomography Angiography (CCTA) is a first line investigation for chest pain in patients with suspected obstructive coronary artery disease (CAD). However, many acute cardiac events occur in the absence of obstructive CAD. We assessed the lifetime cost-effectiveness of integrating a novel artificial intelligence-enhanced image analysis algorithm (AI-Risk) that stratifies the risk of cardiac events by quantifying coronary inflammation, combined with the extent of coronary artery plaque and clinical risk factors, by analysing images from routine CCTA. METHODS AND RESULTS: A hybrid decision-tree with population cohort Markov model was developed from 3,393 consecutive patients who underwent routine CCTA for suspected obstructive CAD and followed up for major adverse cardiac events over a median(IQR) of 7.7(6.4-9.1) years. In a prospective real-world evaluation survey of 744 consecutive patients undergoing CCTA for chest pain investigation, the availability of AI-Risk assessment led to treatment initiation or intensification in 45% of patients. In a further prospective study of 1,214 consecutive patients with extensive guideline recommended cardiovascular risk profiling, AI-Risk stratification led to treatment initiation or intensification in 39% of patients beyond the current clinical guideline recommendations. Treatment guided by AI-Risk modelled over a lifetime horizon could lead to fewer cardiac events (relative reductions of 4%, 4%, 11%, and 12% for myocardial infarction, ischaemic stroke, heart failure and cardiac death, respectively). Implementing AI-Risk classification in routine interpretation of CCTA is highly likely to be cost-effective (Incremental cost-effectiveness ratio £1,371-3,244), both in scenarios of current guideline compliance or when applied only to patients without obstructive CAD. CONCLUSIONS: Compared with standard care, the addition of AI-Risk assessment in routine CCTA interpretation is cost effective, by refining risk guided medical management.

Romiplostim and eltrombopag for immune thrombocytopenia: methods for indirect comparison.

OBJECTIVES: Immune thrombocytopenia (ITP) causes increased platelet destruction and suboptimal platelet production, increasing risk of bleeding. This analysis uses a Bayesian metaregression model to indirectly compare effectiveness of the thrombopoietin mimetics romiplostim and eltrombopag for increasing platelet counts, and contrasts the results with those of non-Bayesian approaches. METHODS: Ten databases were searched during 2010. Placebo-controlled trials of 24 weeks' duration were included. An indirect comparison was undertaken using Bayesian metaregression, which includes all trials in a single model. This was compared with previous analyses in which data for each intervention were combined using simple pooling, logistic regression or meta-analysis, followed by indirect comparison of pooled values using the Bucher method. RESULTS: Two trials of romiplostim and one of eltrombopag were included. The indirect evidence suggests romiplostim significantly improves overall platelet response compared with eltrombopag. Bayesian metaregression gave an odds ratio (OR) for eltrombopag versus romiplostim of 0.11 (95 percent credible interval 0.02-0.66); p values and Bayesian posterior probabilities ranged from 0.01 to 0.05 for all analyses. There was no significant difference in durable platelet response in any of the analyses, although the direction of effect favored romiplostim (OR = 0.15; 95 percent credible interval, 0.01-1.88); p values and Bayesian posterior probabilities ranged from 0.08 to 0.40 across analyses. Results were relatively consistent between analyses. CONCLUSIONS: Bayesian metaregression generated similar results to other indirect comparison methods, and may be considered the most robust as it incorporates all data in a single model and accounts appropriately for parameter uncertainty.

Cost-effectiveness of a paclitaxel-eluting stent (Eluvia) compared to Zilver PTX for endovascular femoropopliteal intervention.

OBJECTIVES: Antiproliferative therapies based on paclitaxel have been developed to extend the durability of endovascular interventions for lower-extremity atherosclerotic peripheral artery disease, resulting in improved primary vessel patency and fewer target lesion revascularizations. This study evaluated the cost-effectiveness of the sustained-release, paclitaxel-eluting Eluvia stent (Boston Scientific, Marlborough, MA) versus the paclitaxel-coated Zilver PTX stent (Cook Medical, Bloomington, IN) for endovascular intervention in the superficial femoral or proximal popliteal artery. DESIGN: A microsimulation model was constructed from a United States Medicare perspective with a 24-month time horizon. Patients entering the model were assigned to initial endovascular intervention with either Eluvia or Zilver PTX. Each month patients were exposed to the risks of primary vessel patency loss, target lesion revascularization, amputation, and death. Clinical input parameters were taken from a randomized trial (IMPERIAL) comparing the two interventions at 24-months follow-up. Cost parameters were obtained from analyses of Medicare administrative and claims data. Cost-effectiveness analysis entailed sampling a complete set of clinical and cost parameters from their respective distributions, and then running cohorts of 10,000 patients through each intervention arm of the model. One-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case microsimulation, at 24 months, the modeled target lesion revascularization was 11.6% for Eluvia and 19.0% for Zilver PTX, and the mean total direct costs were $20,010 and $21,356, respectively (Eluvia average savings=$1,346). In probabilistic sensitivity analyses, Eluvia was cost-effective in 87.8% of all simulations at a willingness-to-pay threshold of $10,000 per target lesion revascularization prevented. Eluvia was more effective and less costly (dominant) than Zilver PTX in 73.6% of simulations. CONCLUSIONS: In this comparison of a paclitaxel-eluting to a paclitaxel-coated stent for endovascular femoropopliteal intervention, Eluvia was more effective and less costly (dominant) than Zilver PTX from a US Medicare perspective. These findings should be considered when formulating reimbursement policy and clinical practice guidelines.

Paclitaxel is a drug used in the treatment of peripheral artery disease (PAD) to help maintain primary vessel patency and reduce the need for revascularization procedures. This study evaluated the cost-effectiveness of the paclitaxel-eluting Eluvia stent (Boston Scientific, Marlborough, MA) versus the paclitaxel-coated Zilver PTX stent (Cook Medical, Bloomington, IN) in Medicare patients with PAD. Cost-effectiveness is defined as the degree to which a particular treatment option is effective relative to its costs. Therefore, this study compared both the effectiveness, in terms of target lesion revascularization rates, and the costs of Eluvia versus Zilver PTX over 24 months.A microsimulation model was developed from a United States Medicare perspective with a 24-month time horizon. Simulated patients entered the model and were assigned to receive either Eluvia or Zilver PTX. Monthly, patients were exposed to the risks of primary vessel patency loss, target lesion revascularization (TLR), amputation, and death. These risks were taken from a randomized controlled trial that compared Eluvia and Zilver PTX over 24 months. Patients also accrued costs over time. The costs used in the model were obtained from Medicare administrative and claims data analyses.In health economics, a treatment is considered to be the dominant treatment option if it is both more effective and less costly than the alternative treatment. In this case, Eluvia was found to be dominant over Zilver PTX because it was associated with lower TLR rates and lower costs. These findings should be considered when formulating reimbursement policy and clinical practice guidelines.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis.

BACKGROUND: Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. METHODS: A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. RESULTS: Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98). CONCLUSIONS: Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Consistency between direct and indirect trial evidence: is direct evidence always more reliable?

OBJECTIVES: To present a case study involving the reduction in incidence of febrile neutropenia (FN) after chemotherapy with granulocyte colony-stimulating factors (G-CSFs), illustrating difficulties that may arise when following the common preference for direct evidence over indirect evidence. METHODS: Evidence of the efficacy of treatments was identified from two previous systematic reviews. We used Bayesian evidence synthesis to estimate relative treatment effects based on direct evidence, indirect evidence, and both pooled together. We checked for inconsistency between direct and indirect evidence and explored the role of one specific trial using cross-validation. A subsequent review identified further studies not available at the time of the original analysis. We repeated the analyses on the enlarged evidence base. RESULTS: We found substantial inconsistency in the original evidence base. The median odds ratio of FN for primary pegfilgrastim versus no primary G-CSF was 0.06 (95% credible interval: 0.02-0.19) based on direct evidence, but 0.27 (95% credible interval: 0.13-0.53) based on indirect evidence (P value for consistency hypothesis 0.027). The additional trials were consistent with the earlier indirect, rather than the direct, evidence, and there was no inconsistency between direct and indirect estimates in the updated evidence. The earlier inconsistency was due to one trial comparing primary pegfilgrastim with no primary G-CSF. Predictive cross-validation showed that this study was inconsistent with the evidence as a whole and with other trials making this comparison. CONCLUSIONS: Both the Cochrane Handbook and the NICE Methods Guide express a preference for direct evidence. A more robust strategy, which is in line with the accepted principles of evidence synthesis, would be to combine all relevant and appropriate information, whether direct or indirect.

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in breast cancer in the United Kingdom.

OBJECTIVE: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) after chemotherapy in the United Kingdom (UK). METHODS: A mathematical model was constructed simulating the experience of women with breast cancer undergoing chemotherapy. Three strategies were modeled: primary prophylaxis (G-CSFs administered in all cycles), secondary prophylaxis (G-CSFs administered in all cycles after an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim, lenograstim, and pegfilgrastim. Costs were taken from UK databases and utility values from published sources. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. RESULTS: In the UK, base-case analysis with a willingness-to-pay (WTP) threshold of £20K per quality-adjusted life year gained and also using list prices, the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 38%, secondary prophylaxis with pegfilgrastim for baseline FN risk 11% to 37%, and no G-CSFs for baseline FN risk less than 11%. Using a WTP threshold of £30K and list prices, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 29%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, earlier stage at diagnosis, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. CONCLUSION: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on the FN risk level for an individual patient, patient age and stage at diagnosis, and G-CSF price.

Cost-effectiveness of lanthanum carbonate versus sevelamer hydrochloride for the treatment of hyperphosphatemia in patients with end-stage renal disease: a US payer perspective.

OBJECTIVE: To assess the cost-effectiveness of lanthanum carbonate (LC) versus sevelamer hydrochloride (SH) as a treatment for hyperphosphatemia in end-stage renal disease (ESRD) patients. METHODS: A Markov model was developed to estimate health outcomes; quality-adjusted life years (QALYs) and life-years saved (LYS), as well as associated costs. The model incorporated patient-level data from a randomized head-to-head crossover study that compared the reduction of serum phosphorus using LC and SH for 4 weeks each. The model included patients previously treated with calcium-based binders. Both the intent-to-treat (ITT) population and the cohort of patients who completed treatment in both periods of the study (i.e., completer population) were assessed. The baseline risks of cardiovascular disease (CVD), all-cause mortalities for CVD, and non-CVD patients were derived from a large US renal database. Patient outcomes were modeled for 10 years, and incremental cost-effectiveness ratios (ICERs) were calculated for LC relative to SH. Deterministic and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the base-case model. RESULTS: For the ITT population, the ICERs of LC versus SH were $24,724/QALY and $15,053/LYS, respectively (in US dollars). When the completer population was considered, the ICERs of LC versus SH were $15,285/QALY and $9,337/LYS (Table 2), respectively. The PSA indicated 61.9% and 85.8% probabilities for ITT and completer populations of LC being cost-effective at the $50,000/QALY willingness-to-pay threshold, respectively. CONCLUSION: LC is a cost-effective strategy compared with SH in the treatment of ESRD patients with hyperphosphatemia who were previously treated with calcium-based binders. Sensitivity analyses demonstrated the robustness of the pharmacoeconomic model.

Assessing the cost-effectiveness of the rivastigmine transdermal patch for Alzheimer's disease in the UK using MMSE- and ADL-based models.

OBJECTIVE: Assess long-term cost-effectiveness of rivastigmine patch in Alzheimer's disease (AD) management in the UK, using cognitive and functional models based on clinical trial efficacy data. METHODS: Incremental costs and Quality Adjusted Life Years (QALYs) associated with rivastigmine patch and capsule treatment versus best supportive care (BSC) were calculated using two economic models, one based solely on Mini-Mental State Examination (MMSE) scores, and one also incorporating activities of daily living (ADL) scores. The clinical pathway was populated with data from a clinical trial of rivastigmine patch (9.5 mg/24 h) and capsules (12 mg/day) versus placebo. Costs were based on the UK health and social care costs and basic UK National Health Service (NHS) prices. Disease progression was modelled beyond the trial period over 5 years using published equations to predict natural decline in AD patients. Base case costing variables included drugs, clinical monitoring, and institutionalization. RESULTS: The MMSE model estimated incremental costs per QALY of £10 579 for rivastigmine patch and £15 154 for capsule versus BSC. The MMSE-ADL model estimated incremental costs per QALY of £9114 for rivastigmine patch and £13 758 for capsules. The main difference between the models was a greater number of institutionalized days avoided for rivastigmine versus BSC estimated by the MMSE-ADL model. CONCLUSIONS: Both the MMSE and MMSE-ADL models suggest that rivastigmine patch and capsules are cost-effective treatments versus BSC. Incorporating ADL evidence makes a marginal but important difference to estimates in this case. Future economic evaluations of AD treatment should include measures of both cognition and functioning.