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Single-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment. The implication is that comparison with other data is necessary. However this comparison has limitations due to (1) the post hoc choice of the reference used for comparison, (2) the confusion bias for which an adjustment approach is imperative and, (3) the other biases, measure and attrition among others. When these limitations are taken into account this should, first and foremost, lead to the conduct of externally controlled trials instead of single-arm trials as is proposed by the latest version of ICH E10. Moreover, the external control must be formalised in the study protocol with a priori selection of both the reference control and the formal method of comparison: test in relation to a standard, adjustment on individual data, a synthetic control group or matching-adjusted indirect comparisons (MAIC). Lastly, externally controlled studies must be restricted to situations where randomisation is infeasible. To be acceptable, these studies must be able to guarantee freedom from residual confusion bias, which is only truly acceptable if the observed effect is dramatic and the usual course of the disease is highly predicable.

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BACKGROUND: Rituximab maintenance therapy was shown to significantly extend overall survival (OS) and progression-free survival (PFS) in relapsed/refractory follicular lymphoma (FL) in the pivotal EORTC 20981 trial. OBJECTIVE: To assess the long-term costs and cost effectiveness of rituximab maintenance therapy after induction therapy versus current standard practice (observation) from the French National Health Service perspective. METHODS: A lifetime transition model was developed comparing rituximab maintenance with observation. PFS and OS were obtained from the EORTC 20981 trial with a median follow-up of 28 months and extrapolated from 2-year Kaplan-Meier curves using a Weibull distribution. PFS and OS benefits of rituximab were conservatively assumed to last only 5 years. Utility data were obtained from a multicentre observational study using the EQ-5D questionnaire. Direct medical costs were obtained from French official sources. All costs are reported in euro, year 2006 values. RESULTS: The EORTC 20981 study demonstrated that rituximab maintenance was effective in the management of relapsed/refractory FL. The model results showed that life expectancy and QALYs were increased by 22% and 28%, respectively, in patients treated with rituximab. The incremental cost-effectiveness ratios (ICERs) were euro 7612 per life-year gained and euro 8729 per QALY gained. In a one-way sensitivity analysis, most of the ICERs fell within the range of euro 7000-12,000. The results tend to show that rituximab maintenance therapy may be a cost-effective strategy in the management of relapsed/refractory FL in France, with ICERs below those observed for other therapies in the oncology field. The cost of rituximab was partly offset by the lower cost of relapse due to a longer time in the disease-free health state for patients in the rituximab arm.

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This study aimed at estimating the paediatric RotaVirus GastroEnteritis (RVGE) burden in children aged up to 5 years, and at evaluating health and economic benefits of a universal infant vaccination with a pentavalent rotavirus vaccine, in France. A decision analytic model was constructed considering a cohort of French children from birth to 5 years old. In the absence of a universal rotavirus immunisation programme, the model predicts that of every new French birth cohort, 336,738 children would present a RVGE case, which would result in 33,386 hospitalisations, 14 deaths and more than 279,000 work days lost for the parents. The management of these RVGE cases would cost 63 million euro to the National Healthcare Payer and would reach up to 117 million euro when all indirect costs were included. The introduction of a universal rotavirus vaccination would avoid 249,400 RVGE cases and consequently about 25,700 hospitalisations, 6000 nosocomial infections, 81,200 emergency visits, 39,900 general practitioner or paediatrician consultations, 11 deaths and 206,700 parental work days lost. RVGE total costs would be reduced by 47 million euro for the National Healthcare Payer and by 88 million euro from the Societal perspective. Therefore, a routine universal rotavirus vaccination programme represents an opportunity to significantly reduce the high paediatric RVGE burden in France.

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Patients with schizophrenia suffer numerous relapses and rehospitalizations that are associated with high direct and indirect medical expense. Suboptimal therapeutic efficacy and, in particular, problems with compliance are major factors leading to relapse. Atypical antipsychotic agents offer improved efficacy and a lower rate of extrapyramidal adverse effects compared with conventional antipsychotic drugs. Long-acting intramuscular risperidone combines these benefits with improvements in compliance associated with depot injections. To assist decision making regarding the place of long-acting risperidone in therapy, a cost-effectiveness analysis of strategies involving first-line treatment with long-acting risperidone, oral olanzapine or depot haloperidol was performed from the perspective of the Belgian healthcare system. A decision tree model was created to compare the cost effectiveness of three first-line treatment strategies in a sample of young schizophrenic patients who had been treated for 1 year and whose disease had not been diagnosed for longer than 5 years. The model used a time horizon of 2 years, with health state transition probabilities, resource use and cost estimates derived from clinical trials, expert opinion and published prices. The four health states in the model were derived from an analysis of the literature. The principal efficacy measure was the proportion of patients successfully treated, defined as those who responded to initial treatment and who had none to two episodes of clinical deterioration without needing a change of treatment over the 2-year period. Comprehensive sensitivity analysis was carried out to test the robustness of the model. A greater proportion of patients were successfully treated with long-acting risperidone (82.7%) for 2 years, compared with those treated with olanzapine (74.8%) or haloperidol (57.3%). Total mean costs per patient over 2 years were 16,406 Euro with long-acting risperidone, 17,074 Euro with olanzapine and 21,779 Euro with haloperidol (year of costing 2003). The mean cost-effectiveness ratios were 19,839 Euro, 22,826 Euro and 38,008 Euro per successfully treated patient for long-acting risperidone, olanzapine and haloperidol, respectively. Results of the sensitivity analysis confirmed that the results were robust to a wide variation of different input variables (effectiveness, dosing distribution, patient status according to healthcare system). Long-acting risperidone was the dominant strategy, being both more effective and less costly than either oral olanzapine or depot haloperidol. Long-acting risperidone appears to represent a favourable first-line strategy for patients with schizophrenia requiring long-term maintenance treatment.

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