European Health Economics SAS, Mulhouse, France. E-mail: gisela.kobelt{at}he-europe.com
Cost-effectiveness analyses of new treatments of chronic diseases at their launch are difficult, as they have to be based on short-term clinical trials. However, payers in a number of countries request that such analyses be presented for reimbursement decisions. As a consequence, a number of assumptions regarding effectiveness in clinical practice, including the effect beyond the clinical trial, need to be made until post-launch follow-up studies become available several years later. In such models, it is common and accepted practice to combine clinical, epidemiological, economic and quality of life data.
For our analysis, we have used the actual primary clinical data from one trial (ATTRACT) and applied them to the economic model. All four cost-effectiveness analyses mentioned were based on ATTRACT and were performed when infliximab was introduced. Also, all four analyses have merged the active treatment groups, as there was no statistically significant difference between them. While there may be differences for individual patients that might be relevant to the treating physician, such interpretations cannot be included in an economic model that has to be based on available data from the trial. The purpose of merging the groups is to increase the sample size for modelling. Distributing each of the four treatment arms separately into the six disease states of the model carries the risk of estimating transition probabilities based on very few patients or even individual patients in some of these states, making any estimates questionable. It is correct that costs and effects should be based on the same population. However, we believe that using the cost for infliximab of 3 mg/kg for the entire cohort is the correct approach, as it represents the currently recommended dose. Using a different dose will obviously change the cost, and the sensitivity analysis on the price of infliximab (table 6) is indicative on how sensitive the analysis is to the drug cost.
One issue when using epidemiological cohort studies is generally that patients have been followed from onset of disease, and will therefore, at baseline, seldom correspond to patients in clinical trials. This is particularly true in this case where the ATTRACT trial enrolled patients with advanced disease. However, we have used a novel approach where the demographics and disease parameters of the clinical trial patients are matched to a subsample drawn from the epidemiological cohorts. Thus the extrapolation is not based on the full cohort, but on a group of patients with the same disease severity and duration as the trial patients. The majority of patients in this subsample will represent the later years of the follow-up studies and their treatment will thus closely resemble current practice, prior to introduction of tumour necrosis factor inhibitors. However, the choice of this sample also limits the length of follow-up available. Our model is therefore limited to the maximum 10 yr for which actual data are available from the 516-yr follow-up.
Economic analysis must be based on data and assumptions should be limited. We have therefore limited the treatment effect to the period for which actual data are available. Similarly, we have used the placebo+methotrexate group as the comparator in the base case, as it is the only directly comparable dataset with a high internal validity. It is indeed likely that this group does not fully represent a comparator, particularly in view of the enrolment criteria for the trial. However, rather than speculate about how treatment (and treatment effect) for this group might differ, treatment with infliximab is also compared to a cohort of similar patients drawn from the epidemiological cohorts in an alternative model to answer concerns about the placebo group not representing clinical practice. In this standard practice comparison, the placebo effect in the trial is eliminated and it is thus by no means counter-intuitive that cost-effectiveness improves.
At the time of our analysis, no data on consequences of treatment cessation were available, but it seems reasonable to assume that due to the very nature of a disease modifying treatment, the effect would carry over at least for some time. We have therefore incorporated assumptions regarding the loss of the effect when treatment is discontinued, based on very limited data from patients who discontinued in the clinical trial. As the purpose of this approach was to estimate what might happen in clinical practice, we have applied them to the model that compares infliximab to standard treatment, and it is therefore not relevant to compare the two models.
Economic evaluation should indeed incorporate toxicity of treatments. However, in the absence of real-life data, we have used treatment discontinuation as a proxy for adverse events or lack of effect (10%, applied to costs, as Health Assessment Questionnaire measurements for these patients were available after discontinuation). Comparatively, Maksymowich et al. show a discontinuation rate for adverse events of 7.4% after a mean of 5.3 infusions. While this approach admittedly ignores the cost of treating adverse events, it limits the number of assumptions that have to be made. Incorporating toxicity results from different small studies will flaw the analysis, as patient populations are not necessarily comparable. Also, neither Shergy et al. nor Yazici et al. establish whether cancer was treatment related or not. Lastly, Malone bases his assessment on the registration trials for etanercept and infliximab, not on clinical practice, and does not include toxicity. This thus seems in contradiction to the authors demand that real-life data be used.
Finally, it has to be borne in mind that cost-effectiveness analyses are by definition entirely country specific. Absolute and relative prices, treatment patterns and health-care systems differ, and a cost per QALY in Sweden or in the UK is only applicable to Sweden or the UK. We have used the actual drug usage from the clinical trial and country-specific drug costs to calculate the intervention cost. Any comparisons to the USA or to specific reimbursement practices in another country are therefore irrelevant. It is however reassuring to see that applying the same clinical trial to a US-specific model gives similar results.
The authors have declared no conflicts of interest.
Accepted 17 April 2003