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Payer decision-making with limited comparative and cost effectiveness data: the case of new pharmacological treatments for gout
  1. Michele Meltzer1,
  2. Laura T Pizzi2,
  3. Eric Jutkowitz3
  1. 1Department of Rheumatology, Jefferson Medical College, Philadelphia, Pennsylvania, USA
  2. 2Department of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia, Pennsylvania, USA
  3. 3Department of Health Policy & Management, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA
  1. Correspondence to Laura T Pizzi
    , Jefferson School of Pharmacy, 130 South 9th Street, Philadelphia, PN 19107, USA; laura.pizzi{at}

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Healthcare is an imperfect market characterised by minimal comparative data on drugs and other health technologies.1 Healthcare payers and providers must often decide whether to accept or reject a drug treatment before comparative effectiveness data are available, since approval processes require controlled efficacy trials in defined populations and settings.2 Though there has long been USA opposition to including cost in examinations of effectiveness, other developed nations have not only supported it but formalised cost as a component of comparative effectiveness evaluations.3,,5

In recent years, new treatments for gout – one of the oldest and best understood causes of arthritis – have emerged which exemplify the challenges of defining the comparative and cost effectiveness of innovation. Despite available drugs that effectively lower serum uric acid level, gout is often poorly controlled due to patient factors (eg, non-adherence to medications) and provider factors (eg, lack of knowledge or experience in titrating medication treatments and/or managing side effects) 6 ,7 High levels of serum uric acid are correlated with gout (>6 mg/dl). Allopurinol was released over 40 years ago8 and remains the mainstay of treatment, though there is fear of potential hypersensitivity and drug interactions.9 ,10 In addition, incorrect or inadequate dosing and/or lack of patient compliance can result in refractory gout.11

Recognising these issues, researchers have been developing new treatments for gout. Febuxostat, a novel oral non-purine analogue inhibitor of xanthine oxidase, was approved by the US Food and Drug Administration in 2009, with other therapies recently approved (pegloticase) or in development (RDEA594).12,,14

As pointed out by Mushlin and Ghomrawi, in a technology-driven medical system, preference for simpler and cheaper therapies (such as allopurinol) is unlikely unless there are supporting comparative effectiveness data.15 This case study will focus exclusively on examining the comparative and cost effectiveness a new drug – febuxostat – to an older therapy, allopurinol. We chose this comparison because febuxostat was the first of the new therapies to be approved and it is orally administered (as opposed to drugs such as pegloticase which are injectable).

Comparative effectiveness of febuxostat versus allopurinol

There have been three main trials that have compared febuxostat with allopurinol,16,18,19 and a fourth study that compared febuxostat with placebo.17 Table 1 provides a summary of these studies. Adverse events presented are limited to skin rash and liver abnormalities, the two major adverse events of concern in the clinical practice setting.

Table 1

Summary of randomised controlled trials of febuxostat (all dosages shown are mg/day)

Exclusion criteria included secondary hyperuricaemia, xanthinuria; severe renal impairment (eClcr <30 ml/min; ALT and AST both 1.5 times the upper limit of normal; consumption of more than 14 alcoholic drinks per week or a history of alcoholism or drug abuse within 5 years; or a medical condition that, in the investigator's opinion, would interefere with treatment, safety or adherence to the protocol.

In summary, these studies found that febuxostat is more effective than allopurinol in lowering serum uric acid level. In addition, these studies found that febuxostat patients did not experience an increased rate of skin rashes or overall adverse events compared with allopurinol.16,,18 While it would seem that, based on these findings, the head to head trials comparing febuxostat with allopurinol suggest favourable comparative effectiveness of febuxostat, limitations in the trial designs and study populations make the real world comparative effectiveness between these two drugs unclear. For one, allopurinol dosage titration was not performed according to European league against rheumatism (EULAR) guidelines, which call for a low starting dose (100 mg daily) then increased by 100 mg every 2–4 weeks.20 In addition, most subjects in the clinical trials were predominantly Caucasian males, yet gout occurs in women and other ethnic groups. Finally, though gout is common in individuals with impaired renal function (creatinine clearance less than 30 ml/min), these patients were excluded from the clinical trials.

Cost effectiveness of febuxostat versus allopurinol

To examine the economic and clinical value of febuxostat relative to allopurinol, we constructed a decision analytic model (figure 1). Though cost effectiveness analyses are most informative when they include robust comparative effectiveness data, the price of febuxostat warranted examination of the cost effectiveness of febuxostat (80 mg) relative to allopurinol. We conducted this analysis using a payer perspective and a 1-year time frame. Model inputs were obtained from published head to head clinical trials (table 2).16 ,17 ,19 Treatment success was defined as lowering serum urate level below 6 mg/dl. If the medication was unsuccessful in lowering serum urate, we assumed that there would be a switch in medication (ie, febuxostat to allopurinol; allopurinol to febuxostat) to the alternative therapy. In addition to the cost of medication, we assumed that there were costs associated with adverse events (gout flares, adverse events) as well as a cost associated with treatment failure.

Figure 1

Decision analytic framework.

Table 2

Model assumptions

Although in clinical practice, flares may be expected as part of successful treatment, there are costs associated with them and thus we included these costs in our model. Results from the clinical trials indicated that intensity of gout flares varied over time. Flares were much more common within the first 8 weeks of treatment compared with the rest of the year. We accounted for this by including the two distinct opportunities to experience a flare (one during the first 8 weeks then another beyond 8 weeks but within 1 year).

The model results suggested that febuxostat was more effective then allopurinol, but the total cost of treating patients with febuxostat as a first line therapy was $2077 compared with $1698, a difference of $379/year per patient. It is possible that the assumptions of the clinical trials and subsequently this cost effectiveness analysis actually over estimate the total cost of allopurinol treatment. If allopurinol was slowly titrated to optimal dose consistent with EULAR guidelines, it is likely that there would have been fewer gout flares and therefore the total cost of allopurinol treatment would have been even lower.

To account for the limitations of the clinical trial data, we conducted a series of one-way sensitivity analyses. In the sensitivity analyses we modified each variable input by 10% around the mean to evaluate if such changes altered our primary results. Based on the assumptions of our model and sensitivity analyses, the price of febuxostat is the primary driver of total costs. Under the assumptions of the current model and holding all other inputs constant, febuxostat would have to cost less than $9 a month to be as cost-effective as allopurinol. No other variable when changed caused a change in the overall conclusion of the base case.

Thus, from a payer perspective it is cheaper to have a patient first on allopurinol (with correct titration of the dose), then switch to febuxostat if allopurinol is unsuccessful in lowering serum urate level. This approach is consistent with the recommendations from the National Institute for Clinical Effectiveness (NICE) in the UK.21 ,22


We used the case of gout to illustrate an approach to evaluate the cost effectiveness of a new treatment given limited clinical trial data. Limited clinical trial data present not only a challenge in determining comparative effectiveness, but also cost effectiveness. However, it is especially important to conduct cost effectiveness studies when the price of a innovative new therapy is higher than the standard of care. To account for biases in the data and to test for potential ‘real world’ variability sensitivity analyses should be conducted. However, given the limitations of the trials (eg, exclusion of individuals with renal impairment, use of an allopurinol titration scheme which may not reflect actual practices), additional postmarketing research conducted in dynamic real world healthcare settings is necessary to enable payers and providers to decide how a new product, in this case febuxostat, fits within the standard of care.



  • Competing interests None.

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