Funding the new biologics – CCOHTA report on the cost effectiveness of infliximab for Crohn ’ s disease : Pearls and pitfalls

Presented at a workshop held at the University of Calgary, September 24, 2002. The workshop was supported by an unrestricted grant from Schering Pharmaceuticals, Pointe-Claire, Quebec Division of Gastroenterology, McMaster University, Hamilton, Ontario Correspondence: Dr John K Marshall, Division of Gastroenterology (4W8), McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5. Telephone 905-521-2100 extension 76782, fax 905-521-4958, e-mail marshllj@mcmaster.ca JK Marshall. Funding the new biologics – CCOHTA report on the cost effectiveness of infliximab for Crohn’s disease: Pearls and pitfalls. Can J Gastroenterol 2002;16(12):877-879.

I nfliximab, a monoclonal antibody to tumour necrosis fac- tor (TNF)-alpha, is approved in Canada for the treatment of Crohn's disease that is either refractory to other medical treatments or complicated by enterocutaneous fistulas.Efficacy for each of these indications has been documented in well-designed clinical trials, and its use has been endorsed by consensus guidelines (1).Indeed, for patients with difficult intestinal symptoms and few treatment options, infliximab is a welcome option.However, physicians, patients, insurers and policy advisors have been forced to weigh the obvious appeal of infliximab against its cost, estimated to exceed $5000 per dose for a 70 kg patient (2).With recent clinical trials advocating an intensive three-dose induction regimen and repeat infusions every eight weeks to maintain remission (3), the costs of treatment are substantial.Therefore, the use of infliximab would make good economic sense only if gains in health and quality of life are sufficient to justify its cost, or if that cost could be offset by the avoidance of hospitalizations or surgery, reductions in the requirement for other medications or the return of patients to productive employment.
To understand better the tradeoffs in costs and benefits associated with infliximab therapy in a Canadian practice setting, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) commissioned an economic evaluation of its use in Crohn's disease that is resistant to conventional medical therapy (2).The full report of this analysis can be obtained through the CCOHTA Web site (www.ccohta.ca).The investigators (including this author) constructed a Markov model to compare the expected costs and health outcomes of four alternative treatment regimens over one year, from the perspective of a Canadian provincial ministry of health.The strategies were: usual care (modeled as a weighted mixture of outpatient and inpatient medical care and admission for surgery); a single infusion of infliximab; a single infusion of infliximab with repeated treatments for subsequent relapses; and an initial infusion of infliximab followed by maintenance infusions every eight weeks for patients who respond.Direct medical costs (in 2001 Canadian dollars) were assessed from the perspective of a Canadian provincial Ministry of Health, and outcomes were measured in quality-adjusted life years (QALY).Given the short time horizon, neither costs nor effects were discounted.
The model's base-case analysis found usual care to be the least costly but least effective strategy.A single infusion of infliximab improved outcomes, but at an incremental cost of $181,201 for each additional QALY gained.The re-treatment and maintenance strategies yielded progressively more QALY, but with substantially higher incremental cost-utility ratios (ICUR) of $480,111/QALY and $696,078/QALY, respectively.While the use of cost-per-QALY benchmarks to direct health care funding decisions is highly controversial (4-6), thresholds from $20,000/QALY to $100,000/QALY have been proposed (4).By any of these criteria, the use of infliximab to improve health outcomes in patients with Crohn's disease is costly.
These results might not be surprising, given the high acquisition cost of infliximab itself.However, readers are cautioned to consider more than these bottom line numeric results when applying the economic model to clinical practice.Complete information never exists for determining the optimum treatment for individual patients or when formulating health care policy.Decision analysis utilizes the best available information to estimate the costs and outcomes of alternative strategies.In doing so, the decisionmaking process is made more explicit and key areas of uncertainty are illuminated.However, no decision model is perfect or immune from criticism.It is, therefore, essential that readers scrutinize the assumptions on which the model is designed, consider the certainty with which model parameters are defined, and judge the strength of its conclusions.
To its credit, the CCOHTA analysis is methodologically sound, uses state of the art techniques in its analysis and presentation, and remains the only fully published economic analysis of infliximab treatment relevant to a Canadian practice setting.In particular, both conventional stochastic sensitivity analysis and newer techniques of probabilistic sensitivity analysis were used to explore the effects of parameter uncertainty on the model's conclusions.The latter analysis yields an 'acceptability cure' that plots the probability that each strategy is the most cost effective across a range of cost-per-QALY thresholds.This innovative approach presents the key model results to decision makers without endorsing a particular cost-per-QALY ratio.
As with any cost utility Markov model, the CCOHTA analysis required three key data components to characterize each health state: estimated probabilities of 'transitioning' to other health states; profiles of resource utilization and costs accrued while in the state; and an estimate of the health state's relative value or 'utility'.For each data com-ponent, a number of key assumptions were made and are detailed in the CCOHTA report (2).For example, some parameters (eg, health state resource profiles) relied on expert opinion to compensate for a lack sufficiently detailed empirical data.For others, such as health state transitions in usual care, adequate data were available only from another jurisdiction (Olmsted County, Minnesota) (7).Similarly detailed data from a contemporary Canadian population would have been preferred, but were not available.Empirical Canadian data were available for other parameters, such as health state utilities (8).Assumptions were still required, however, to transpose those weights to the particular health states used in the CCOHTA model.
Several key aspects of the CCOHTA model's core structure should also be considered when interpreting its results.For example, a relatively short time horizon (one year) was chosen to mirror the follow-up period available from published clinical trials.Thus, more remote downstream benefits of infliximab therapy (such as the cumulative benefits of avoiding surgery) might have been under-represented.On the other hand, the long term efficacy of infliximab is not known.Despite its advantages in comparing cost effectiveness across programs, even the QALY can be criticized as a measure of health outcome for failing to capture and balance all dimensions of the health of Crohn's disease patients.Finally, the model was analyzed from the perspective of a provincial ministry of health and, as a result, considered only direct medical costs.It is well recognized that patients with active Crohn's disease incur considerable indirect costs (9,10).If the model were restructured to consider a societal perspective, the capacity of infliximab ther-apy to return some patients to productive employment could make its use more economically attractive.
It is especially important to emphasize that the CCOHTA infliximab model, like any economic analysis, must be continually updated from the moment of publication.Readers must reinterpret results as new data on efficacy and toxicity emerge, and in light of other therapeutic advances.Gains in efficacy offered by more intensive dosing schedules (like those used in the recent ACCENT I trial [3]), must be balanced against substantial increases in medication cost.Moreover, relatively small changes in drug costs could dramatically influence the net incremental costs of infliximab treatment.In the CCOHTA model, for example, a 25% reduction in the cost of infliximab reduced the incremental cost utility ratio of a single infusion below $100,000/QALY, compared with usual care.

CONCLUSIONS
In summary, the CCOHTA cost-utility analysis is methodologically rigorous, and remains the only fully published economic model of the use of infliximab for refractory Crohn's disease.When interpreting its results, decision makers are encouraged to consider the many assumptions required for its design, and the strengths and limitations of its analysis.Like other economic models, the CCOHTA report does not single-handedly resolve policy dilemmas.At best, it helps to frame the problem and provides explicit data with which informed decisions can be made.When allocating precious health care resources, policy-makers must consider several dimensions, including compassion for patients with refractory disease and few treatment alternatives.