Biotechnology Healthcare - November/December 2008 - (Page T1) Tumor Necrosis Factor Inhibitors A review of dosing patterns and related economic considerations umor necrosis factor (TNF) inhibitors represent a major advancement in the treatment of rheumatoid arthritis (RA) (Furst 2007). All TNF inhibitors have been shown to be effective disease-modifying anti rheumatic drugs; however, response to therapy and the dose needed to sustain response are difficult to predict in individual patients (van Vollenhoven 2007, Furst 2007). In fact, in RA, the recommended maintenance regimens for some of these agents accommodate dose adjustments for incomplete response. Although the use of etanercept (Enbrel) at a dose greater than the starting dose of 50 mg per week is not recommended, an infliximab (Remicade) dose can be increased up to 10 mg/kg or administered as often as every 4 weeks, and adalimumab (Humira) 40 mg can be increased to weekly versus every other week in patients who are not receiving methotrexate (Enbrel 2008, Remicade 2007, Humira 2008). Furthermore, numerous observational studies suggest that, at least in some instances, all TNF inhibitors may be used at doses that exceed the standard recommendations (Durez 2005, Edrees 2005, van Vollenhoven 2004). Given the economic implications of dose elevation, it is critical to understand the nature of dosing patterns. Principal considerations presented in this Clinical Brief are specific to the evaluation of dosing patterns in RA, but they can be also broadly applied to other indications. T Key concepts in assessing dosing patterns and dose elevation In general, dosing is affected by a number of factors that interact in a complex, dynamic pattern over time. It would be an oversimplification to assume that dose elevation is a dichotomous variable, or that there is a straightforward linear relationship between dosing changes and treatment costs. Hypothetical treatment scenarios, depicted in the accompanying Figure (page 2), demonstrate that in each patient exposed to therapy, dosing patterns can evolve uniquely along three key dimensions: the actual amount of drug administered; when in the course of therapy dosing changes occur; and the duration of dosing changes. First, however, it is important to understand the initial dose; in particular, not to overlook whether treatment is initiated at a high dose. For instance, the Figure (page 2) shows that although dosing remained stable throughout a 10-week period for both Patient A and B, the initial dose administered to Patient B was elevated at twice the recommended starting dose, and subsequently the total dose was double that of Patient A. The magnitude of dose escalation, which is determined by the amount of drug and the frequency of administration, can vary considerably among patients. For example, other things being equal, higher costs will result from a 100 percent dose increase observed with Patient D than from the 50 percent dose increase seen with Patient C. Further, the timing of dose increases has substantial cost implications. Patients who increase their dose early will incur significantly greater drug costs than patients with the same magnitude of increase later in treatment. Lastly, the duration of dose escalation also has substantial economic implications. The cost of a one-time dose increase (Patient E) would be insignificant compared with the cost of a dose increase of the same magnitude and timing that persisted throughout the course of therapy (Patient F). Different methods have been used for measuring dose elevation with the TNF inhibitors (Sidiropoulos 2004, Stern 2004, Harley 2003). However, most of these methods focus on the percent of patients who experience some form of dose escalation, which, in the absence of information on the above dimensions, can obscure the true extent of the incremental costs. The following is a brief overview of the limitations associated with the methods frequently described in the literature. Prevalence estimates. Many observational studies report the percentage of patients who have met the studydefined criteria for dose escalation (Durez 2005, Edrees 2005, van Vollenhoven 2004). The limitation of this approach is that it does not specify the magnitude, timing, and duration of dose increases, making it difficult to understand the cost impact. These shortcomings are illustrated by the following definitions of dose escalation found in the literature. • Ending dose exceeds the initial dose – This definition ignores the vast period that lies between treatment initiation and the end of the study. It excludes patients whose dose increased during treatment and then returned to the same dose at treatment initiation, or those whose treatment was initiated at high doses. It also gives equal weight to all patients who meet the criterion, despite individual differences in magnitude, timing, and duration of dose increases, all of which collectively impact costs. • Any dose that exceeds the initial dose – This definition can exclude patients with a high initial dose. It does not distinguish the magnitude, timing of inception, or the duration of dose increase. 1
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