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Health economics: implications for novel antirheumatic therapies
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1. A Kavanaugh
1. Correspondence to:
Dr A Kavanaugh
Center for Innovative Therapy and Division of Rheumatology, Allergy, and Immunology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA USA 92093-0943; akavanaughucsd.edu

Abstract

This paper discusses the pharmacoeconomics issues relating to the use of the newer therapies for rheumatoid arthritis (RA), namely the tumour necrosis factor (TNF) inhibitors. Results of recent studies have provided some evidence regarding the cost effectiveness of these agents. However, as the use of TNF inhibitors evolves—including their use in other systemic inflammatory diseases—this will be influenced by several factors including treatment of patients with early RA, longer term treatment, problems related to toxicity, quality of life, productivity, and market forces. Thus, pharmacoeconomic considerations are likely to remain a central factor in the use of novel therapies in rheumatology, and awareness about these will aid clinicians to select the most favourable therapies for their patients with arthritis.

• health economics
• antirheumatic therapy
• novel biological agents
• pharmacoeconomic considerations
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Rheumatoid arthritis (RA) is a chronic autoimmune condition that exacts a considerable toll from affected patients.1 The joint destruction and progressive functional disability characteristic of uncontrolled RA are associated with substantial economic costs not only to the patients and their families, but also to society. In recent years, significant progress in understanding the immunopathogenesis of RA combined with advances in biotechnology has led to the development of agents that therapeutically target specific components of the dysregulated immune system. Such “biological agents”, particularly the inhibitors of the key proinflammatory cytokine tumour necrosis factor α (TNFα), have proved highly effective not only in improving the signs and symptoms of disease, but also in attenuating the progression of joint damage, improving quality of life, and preserving functional status.2,3,4,5,6,7,8,9,10 The introduction of TNF inhibitors has engendered a dramatic change in the therapeutic approach for RA.11 Thus, the ability to improve clinical outcomes in such a meaningful way has resulted in the goals of treatment being raised. Remission is now considered not only highly desirable, but also an appropriate goal for treating RA patients. In addition, biological agents have been shown to have impressive utility in systemic inflammatory diseases other than RA, including psoriatic arthritis, ankylosing spondylitis, psoriasis, and inflammatory bowel disease.

2: Health economic argument regarding new therapies for rheumatoid arthritis (RA)

• RA is a serious condition, associated with substantial morbidity and accelerated mortality

• The natural course of RA is one of progressive joint damage and disability

• RA is expensive, as affected persons have significant functional disability

• The costs of RA vary directly with the severity and activity of disease

• Newer therapies may be cost effective, depending upon their clinical benefit

Despite some variation in absolute costs of RA noted among the studies, there are several consistent key themes across them. Indirect costs typically exceed direct costs, not infrequently by a factor of two. It should be noted that this was not true in all studies; also, with higher acquisition costs for medication, it would be expected that direct costs would increase. Importantly, in most of the studies, the costs of disease were not uniformly distributed among the RA population. This skewing, evidenced by the common finding that mean costs far exceed median costs, reflects the substantially higher costs incurred by a subset of the RA patients assessed. A key observation was that patients with the most severe RA incurred the highest costs. Relevant to pharmacoeconomic assessments of TNF inhibitors, patients with the most severe disease have been the type of RA patient for whom these agents have been most commonly used. The strongest predictor of cost was functional disability, typically measured with the Health Assessment Questionnaire (HAQ). Very consistently, elevated HAQ scores resulted in greater costs of RA.36,37,39,41,43–45 In a recent rigorous analysis from Spain, there was an increment of more than US$11 000 (US 2003 dollars) per unit of HAQ score among RA patients. Germane to pharmacoeconomic analysis, worsening in HAQ score over time resulted in higher costs whereas improvements resulted in lower costs of disease. The implication of this is that therapeutic agents capable of achieving significant improvements in functional status would be expected to lower the costs of disease. Improvement in functional status correlate with, and can also be used to quantify, improvements in quality of life, a key metric for cost assessments.12,46 COST EFFICACY OF NEWER THERAPIES FOR RHEUMATOID ARTHRITIS In RA, there is a growing body of data addressing the potential cost effectiveness of TNF inhibitors.47–56 Even prior to the introduction of these agents to the clinic, cost assessments suggested that their relatively higher acquisition costs would substantially affect their overall value.56 Nevertheless, because of their remarkable clinical efficacy in RA, it appears that TNF inhibitors may have an incremental cost within the range of generally accepted medical interventions. Much of these data comes from follow up of patients participating in clinical trials of infliximab, etanercept, and adalimumab in RA. In general, changes in health states, such as the HAQ score, are modelled over time using data from the studies. Simulations are performed using sensitivity analysis to account for reasonable variations in relevant outcomes. Either directly or indirectly—for example by transforming functional status—utilities can be created for the various transition states that then define the level of response to treatment in terms of QALYs gained. Cost effectiveness estimated can then be generated. Remarkably, studies using distinct populations and agents have come to similar estimates (table 1).12,47,48,50,53 Thus, treatment with a TNF inhibitor costs roughly US$30 000 per discounted QALY gained. The costs are even lower if the base estimates are expanded to include savings in indirect costs.12 Several caveats are relevant to these types of study.19,20 It has been argued that improvements in HAQ in research studies tend to be exaggerated and do not reflect efficacy achieved in clinical practice. The use of modelling, necessary to obtain data over a sufficiently long time frame, also has the potential to introduce inaccuracy. On the other hand, some factors make the estimates derived from clinical trials potentially conservative. For example, there are inherent differences in clinical trials as opposed to clinical practice, such as forced regular visits and the inability to capture “failure costs”. Perhaps most importantly, these assessments used data from all of the treated patients. If the analysis was restricted to those patients achieving good or superior clinical outcomes, as would more closely approximate clinical practice, greater cost efficacy would be expected.

Table 1

Cost effectiveness of tumour necrosis factor inhibitors12

Despite potential imperfections in the analyses, the consistent demonstration that the cost per QALY for TNF inhibitors is approximately US$30 000 is critically important. In general, largely for historical political reasons, interventions that achieve a cost per QALY gained of less than US$50 000 are considered to be “cost effective”. This benchmark is widely referenced and quoted for interventions in other disciplines. Thus, the issues surrounding the use of TNF inhibitors segue into political considerations, related to access and availability of agents for different disease states.

CONCLUSION

The relatively higher acquisition costs of novel biological agents has brought pharmacoeconomic considerations to the forefront in rheumatology. Fortunately, as regards RA, there are myriad data confirming the substantial cost implications of this pernicious disease. For the TNF inhibitors, the notable clinical efficacy observed needs to be factored into a comprehensive assessment of their value. Results from a number of studies have begun to make a compelling case that these agents may indeed be cost effective.

As the use of TNF inhibitors evolves, additional health economic issues may also come into play. For example, when considering treatment of patients with early RA, a topic gaining wider discussion each year, distinct pharmacoeconomic issues might arise.57,58 If patients with early RA achieved incremental or sustained efficacy with new agents, that could make them more cost effective. However, the need for longer term treatment or longer term implications of toxicity could make them less cost effective. As the use of TNF inhibitors extends to other systemic inflammatory diseases, such as psoriatic arthritis and ankylosing spondylitis, additional specific pharmacoeconomic assessments will need to be performed.59,60 Of note, these conditions typically affect a younger population, many of whom are in their prime working years. In the case of psoriatic arthritis, the impact of skin involvement on productivity and quality of life also needs to be factored into any pharmacoeconomic assessment.

Additional factors may impact on the health economic implications for TNF inhibitors. For example, as more agents are brought to the clinic, will market forces cause their price to decline? This has certainly been the case with other classes of medication, such as proton pump inhibitors, where competition has resulted in drastically lowered prices. Similarly, will there ever be cheaper generic versions of biological agents?61 The situation regarding generic versions is more complex for biologicals than it is for small easily synthesised chemicals. Factors such as variable glycosylation have been shown to affect both the efficacy and toxicity of biological agents; these considerations will certainly impact regulatory approval and, ultimately, cost.

Given the current healthcare environment, pharmacoeconomic considerations are likely to remain a central factor affecting the use of novel therapies in rheumatology and in other disciplines. Understanding these issues will help clinicians choose the optimal therapies for their patients with arthritis.

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Footnotes

• Competing interests: none declared

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