The manufacturer's submission presented a de novo economic analysis that compared cetuximab plus radiotherapy with radiotherapy alone. The model used individual patient data from the randomised controlled trial (RCT) to estimate costs and health effects during the trial period for each patient. When trial observations were censored, the model extrapolated costs and health effects.
The base-case analysis compared cetuximab plus radiotherapy with radiotherapy alone and resulted in an incremental cost-effectiveness ratio (ICER) of 6400 pounds sterling per quality-adjusted life year (QALY) gained. The manufacturer undertook a univariate sensitivity analysis, which demonstrated that the model was not sensitive to change when assessing the effect of uncertainty in a variety of inputs. Relatively large variability was observed when the timeframe of the analysis changed from a lifetime to the period of the trial follow-up, resulting in an ICER of 20,000 pounds sterling per QALY gained.
The Evidence Review Group (ERG) reviewed the economic model and identified a number of concerns. The most important of these was that the only RCT informing the economic analysis (the Bonner trial [Bonner et al, Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med, 2006. 354(6): p. 567-78.]) did not match the patient population specified in the manufacturer's decision problem.
In addition, the ERG identified a series of issues and uncertainties about the methods for extrapolation of the trial data, assessment of health-related quality of life (HRQoL), and estimation of resource use and costs. The ERG concluded that the methods used were probably appropriate but was unable to determine, in the majority of cases, the likely influence of using alternative methods on the results of the economic model. However, the ERG concluded that altering the method of extrapolation would be unlikely to cause the ICER to increase to above 20,000 pounds sterling.
The ERG felt that although the economic analyses undertaken by the manufacturer demonstrated that cetuximab in combination with radiotherapy was cost effective compared with radiotherapy alone under a broad range of different assumptions (assuming a threshold of 20,000 pounds sterling per QALY), the cost-effectiveness estimates might not be directly applicable to the population specified in the manufacturer's decision problem.
Following an appeal hearing, the Appeal Panel requested that the manufacturer provide subgroup survival data (derived from the Bonner trial) for each of the separate Karnofsky performance-status score subgroups (Karnofsky performance-status scores of 100%, 90%, 80%, 70% and less than 70%). The manufacturer stated that the number of patients in some of the subgroups was small (numbers ranged from 12 to 91), and this should be taken into consideration when interpreting these data. For patients with Karnofsky performance-status scores of 100% and 90%, the survival hazard ratios (HRs) were in favour of cetuximab plus radiotherapy over radiotherapy alone. For patients with Karnofsky performance-status scores of 80%, 70% and less than 70%, the survival HRs were in favour of radiotherapy alone over cetuximab plus radiotherapy.
The manufacturer was further asked by the Appeal Panel to provide cost-effectiveness estimates for the subgroup analyses described above. The analyses were conducted using the manufacturer's original cost-effectiveness model. The manufacturer's analysis gave ICERs for cetuximab in combination with radiotherapy versus radiotherapy alone of 13,151 pounds sterling and 4,467 pounds sterling per additional QALY gained for patients with Karnofsky performance-status scores of 100% and 90%, respectively. For patients with Karnofsky performance-status scores of 70%, radiotherapy alone dominated cetuximab in combination with radiotherapy (that is, radiotherapy alone was more effective in terms of QALYs gained and was less expensive). For patients with Karnofsky performance-status scores of 80% and less than 70%, the manufacturer reported ICERs for cetuximab in combination with radiotherapy versus radiotherapy alone of 58,200 pounds sterling and 37,000 pounds sterling per additional QALY gained, respectively.
The Committee considered the ICER presented by the manufacturer in its original submission and the ERG's original comments. The Committee noted that the ICER of 6400 pounds sterling for cetuximab in combination with radiotherapy versus radiotherapy alone was robust to the main sensitivity analyses. The Committee considered the ICERs presented by the manufacturer for each Karnofsky performance-status score subgroup separately. It noted that the ICERs for patients with a score of 90% or greater were favourable and similar to the overall estimate in the base case. The Committee was persuaded that although there was uncertainty about the number of patients within the subgroups who would have met the criteria to receive chemoradiotherapy, cetuximab in combination with radiotherapy is cost effective for patients with a Karnofsky performance-status score of 90% or greater and for whom chemoradiotherapy is not an option. However, for those with a Karnofsky performance-status score of 80% or less, the HR for survival did not favour cetuximab and therefore the ICERs were unfavourable. The Committee therefore was unable to recommend cetuximab for people with low performance status.
Refer to Sections 3 and 4 of the original guideline document for details of the economic analyses provided by the manufacturer, the ERG comments, and the Appraisal Committee considerations.
