Predictive factors of tumour necrosis inhibitor treatment persistence for rheumatoid arthritis: An observational study in 8052 patients.

OBJECTIVES: To determine whether changes in ultrasonography (US) features of monosodium urate crystal deposition is associated with the number of gouty flares after stopping gout flare prophylaxis. METHODS: We performed a 1-year multicentre prospective study including patients with proven gout and US features of gout. The first phase of the study was a 6-month US follow-up after starting urate-lowering therapy (ULT) with gout flare prophylaxis. After 6 months of ULT, gout flare prophylaxis was stopped, followed by a clinical follow-up (M6 to 12) and ULT was maintained. Outcomes were the proportion of relapsing patients between M6 and M12 according to changes of US features of gout and determining a threshold decrease in tophus size according to the probability of relapse. RESULTS: We included 79 gouty patients (mean [±SD] age 61.8±14 years, 91% males, median disease duration 4 [IQR 1.5; 10] years). Among the 49 completers at M12, 23 (47%) experienced relapse. Decrease in tophus size≥50% at M6 was more frequent without than with relapse (54% vs. 26%, P=0.049). On ROC curve analysis, a threshold decrease of 50.8% in tophus size had the best sensitivity/specificity ratio to predict relapse. Probability of relapse was increased for patients with a decrease in tophus size <50% between M0 and M6 (OR 3.35 [95% confidence interval 0.98; 11.44]). CONCLUSION: A high reduction in US tophus size is associated with low probability of relapse after stopping gout prophylaxis. US follow-up may be useful for managing ULT and gout flare prophylaxis.

Incidence of solitary pulmonary nodules in Northeastern France: a population-based study in five regions.

BACKGROUND: The discovery of a solitary pulmonary nodule (SPN) on a chest imaging exam is of major clinical concern. However, the incidence rates of SPNs in a general population have not been estimated. The objective of this study was to provide incidence estimates of SPNs in a general population in 5 northeastern regions of France. METHODS: This population-based study was undertaken in 5 regions of northeastern France in May 2002-March 2003 and May 2004-June 2005. SPNs were identified by chest CT reports collected from all radiology centres in the study area by trained readers using a standardised procedure. All reports for patients at least 18 years old, without a previous history of cancer and showing an SPN between 1 and 3 cm, were included. RESULTS: A total of 11,705 and 20,075 chest CT reports were collected for the 2002-2003 and 2004-2005 periods, respectively. Among them, 154 and 297 reports showing a SPN were included, respectively for each period. The age-standardised incidence rate (IR) was 10.2 per 100,000 person-years (95% confidence interval 8.5-11.9) for 2002-2003 and 12.6 (11.0-14.2) for 2004-2005. From 2002 to 2005, the age-standardised IR evolved for men from 16.4 (13.2-19.6) to 17.7 (15.0-20.4) and for women from 4.9 (3.2-6.6) to 8.2 (6.4-10.0). In multivariate Poisson regression analysis, gender, age, region and period were significantly associated with incidence variation. CONCLUSIONS: This study provides reference incidence rates of SPN in France. Incidence was higher for men than women, increased with age for both gender and with time for women. Trends in smoking prevalence and improvement in radiological equipment may be related to incidence variations.

Quality assessment of economic evaluation studies in pediatric surgery: a systematic review.

PURPOSE: To assess economic evaluation studies (EES) in pediatric surgery and to identify potential factors associated with high-quality studies. METHODS: A systematic review of the literature using PubMed and Cochrane databases was conducted to identify EES in pediatric surgery published between 1 June 1993 and 30 June 2013. Assessment criteria are derived from the Drummond checklist. A high quality study was defined as a Drummond score ≥7. Logistic regression analysis was used to determine factors associated with high quality studies. RESULTS: 119 studies were included. 43.7% (n=52) of studies were full EES. Cost-effectiveness analysis was the most frequent (61.5%) type of full EES. Only 31.6% of studies had a Drummond score ≥7 and 73% of these were full EES. The factors associated with high quality were identification of costs (OR: 14.08; 95% CI: 3.38-100; p<0.001), estimation of utility value (OR: 8.13; 95% CI: 2.02-43.47; p=0.005) and study funding (OR: 3.50; 95% CI: 1.27-10.10; p=0.02). CONCLUSION: This review shows that the number and the quality of EES are low despite the increasing number of studies published in recent years. In the current context of budget constraints, our results should encourage pediatric surgeons to focus more on EES.

EQOFIX: a combined economic and quality-of-life study of hemophilia B treatments in France.

BACKGROUND: EQOFIX is a medicoeconomic study that analyzed the health-related quality of life (HRQoL) and costs of care of the moderate and severe forms of hemophilia B, treated on demand or by prophylaxis with either plasma-derived Factor IX (pdFIX) or recombinant FIX (rFIX). STUDY DESIGN AND METHODS: The primary objectives were evaluations of the impact of hemophilia B on HRQoL and of the costs associated with its management. The secondary objectives were evaluations of the clinical efficacy and costs of care of pdFIX and rFIX. In this observational study we included and followed for 1 year severe and moderate hemophilia B patients without inhibitor. HRQoL was evaluated through generic and disease-specific questionnaires. Information on the health resources consumed was collected every 3 months. RESULTS: The EQOFIX cohort was composed of 155 patients, including 51 children and 104 adults, with 114 having severe disease and 41 having moderate disease. The regimens were prophylactic for 61 and on demand for 94. Altogether, 78 were treated with rFIX and 77 with pdFIX. There was no difference in the QoL between the pdFIX and rFIX treatments. The extra cost of prophylaxis was €22,605 per bleeding event prevented. The consumption of FIX was 1.4-fold higher for the patients treated with rFIX than for the patients treated with pdFIX. CONCLUSION: Our findings in a cohort composed of 25% of the French population of moderate and severe hemophilia B patients show, with similar clinical and HRQoL results, that treatment with rFIX is more expensive than treatment with pdFIX.

Quality of life after the initial treatments of non-small cell lung cancer: a persistent predictor for patients' survival.

BACKGROUND: Health-related quality of life (HRQoL) before treatment may predict survival of patients with non-small-cell lung cancer (NSCLC). We investigated the predictive role of HRQoL after the initial treatments, on the survival of these patients. METHODS: A prospective multi-center study conducted in northeastern France. The SF-36 and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core-30 (QLQ C-30) were mailed to patients 3 months after the end of the diagnostic process. High scores for functioning dimensions on both questionnaires indicated better QoL, and low scores for symptom dimensions on the QLQ C-30 indicated few symptoms. Cox regression modeling was used to identify predictive factors of survival. RESULTS: In total, 230 (63.5%) patients responded to the SF-36 and QLQ C-30. Before completing the questionnaires, almost 60% of patients had undergone some chemotherapy, about 10% underwent radio/chemotherapy or both and more than 30% underwent surgery or surgery plus chemo/radiotherapy. On SF-36, the highest mean score was for social functioning dimension (55.5 ± 28), and the lowest was for the physical role dimension (17.9 ± 32.2). On QLQ C-30, for the functioning dimensions, the highest mean score was for cognitive functioning (74.6 ± 25.9) and the lowest was for role functioning (47.2 ± 34.1). For symptom dimensions, the lowest score was for diarrhoea (11.5 ± 24.2) and the highest was for fatigue (59.7 ± 27.7). On multivariate analysis, high bodily pain, social functioning and general health scores (SF-36) were associated with a lower risk of death (hazard ratio 0.580; 95% confidence interval [0.400-0.840], p = 0.004; HR 0.652 [0.455-0.935], p < 0.02; HR 0.625 [0.437-0.895] respectively). Better general QoL on QLQ C-30 was related to lower risk of death (HR 0.689 [0.501-0.946], p = 0.02). CONCLUSION: Adding to previous knowledge about factors that may influence patients QoL, this study shows a persisting relationship between better perceived health in HRQoL after the initial treatment of NSCLC and better survival.

Cytomegalovirus exposure, immune exhaustion and cancer occurrence in renal transplant recipients.

The role of Cytomegalovirus (CMV) in carcinogenesis is controversial. We studied whether CMV may contribute to cancer occurrence in renal transplant recipients. We studied a prospective cohort of 455 consecutive patients who received a kidney transplant between January 1995 and December 2006. All cancers and types of cancers were assessed. Lymphocyte phenotype and cytokines production were analysed according to CMV status in a subset population of this cohort. Mean follow-up was 84 ± 29 months. One hundred and nineteen cancers (26.2%) occurred during the study follow-up. There was a higher cumulated incidence of cancers in CMV-exposed patients (30.4% vs. 20%; P=0.018). Mean time to cancer occurrence was shorter in CMV-exposed patients than in CMV-naïve patients (4.7 ± 2.6 vs. 6.7 ± 2.8; P = 0.001). Cox regression analysis revealed that both pretransplant CMV exposure (HR, 1.83; 95% CI, 1.17-2.88; P = 0.009) and post-transplant CMV replication (HR, 2.17; 95% CI, 1.02-4.59; P = 0.044) were risk factors for cancer. Among CD8+ T cells, exhausted T cells assessed as CD57+CD28- were expanded in CMV-exposed patients (26 ± 20 vs. 9 ± 8%; P < 0.0001), whereas CD8+CD57+IL2- cells were more frequent in CMV-exposed patients. Our results highly suggest that CMV increases the risk of cancer after transplantation.

Induction-related cost of patients with acute myeloid leukaemia in France.

OBJECTIVE: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost. SETTING: "Induction" patient's hospital stay from admission for "induction" to discharge after induction. METHOD: The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors. MAIN OUTCOME MEASURE: Only direct medical costs were included: treatment and hospitalisation. RESULTS: Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻4). This result is robust and was confirmed by sensitivity analysis. CONCLUSION: Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML.

Cost of pretherapeutic staging of patients with colorectal cancer metastases in a French population.

BACKGROUND: Little is known about the economic burden of pretherapeutic staging of patients presenting colorectal cancer metastases. OBJECTIVE: The aim of this study was to estimate the cost of pretherapeutic staging and identify cost determinants for 132 patients presenting colorectal metastases and living in the north-east of France. METHOD: Staging cost was estimated using direct medical costs from the point of view of the French Health Insurance System. Independent factors were identified using a linear regression model, and bootstrap resampling was used to estimate unbiased standard errors and 95% confidence intervals. RESULTS: The overall mean cost for pretherapeutic staging was estimated to be 1534€ [95% CI: 1250€-1818€]. Staging costs increased significantly with the number of medical procedures performed during the staging, and according to health care patterns (in-patient hospital stay versus out-patient episodes, public versus private care). CONCLUSION: These results could now be used to estimate the impact of new imaging techniques on clinical practices and pretherapeutic staging costs.

Solitary pulmonary nodules: consequences for patient quality of life.

PURPOSE: The aim was to describe levels of health-related quality of life (HRQoL) and its determinants in patients with solitary pulmonary nodule (SPN) and to compare them with the French general population. METHODS: A prospective multicentre study of patients diagnosed with SPN, in northeastern regions of France, was carried out between 2002 and 2005. Six months after the end of diagnostic procedure, patients completed the SF-36 self-reported questionnaire (where 100 indicates high HRQoL). For a comparison, HRQoL data from a sample of the French general population collected by INSEE in 2002-2003 (n = 17,750). RESULTS: Among 171 participating patients, 39 had malignant nodules and had lesser mean scores on physical and emotional role, vitality and social functioning (-6 to -18 points) than those with nonmalignant nodule. Compared to the French general population, patients with SPN had lower scores, by 11-30 points, in all dimensions (P < 0.001). Older age and smoking history were associated with low HRQoL. CONCLUSIONS: Six months after receiving a diagnosis of SPNs, whether malignant, patients have worse HRQoL compared to the French general population. It indicates areas where physicians can help patients coping with their disease.

Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need.

Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these issues, the roundtable recommends the possibility of early scientific opinions by the office of the Transparency Commission in order to discuss comparators and the relevance of responder subgroups. It also recommends the possibility of granting a temporary ASMR, on condition of subsequent confirmation by production of data, when reimbursement appears justified in a subpopulation of the MA for which only subgroup analysis is available.

Does the availability of positron emission tomography modify diagnostic strategies for solitary pulmonary nodules? An observational study in France.

BACKGROUND: Previous studies showed that at the individual level, positron emission tomography (PET) has some benefits for patients and physicians in terms of cancer management and staging. We aimed to describe the benefits of (PET) in the management of solitary pulmonary nodules (SPNs) in a population level, in terms of the number of diagnostic and invasive tests performed, time to diagnosis and factors determining PET utilization. METHODS: In an observational study, we examined reports of computed tomography (CT) performed and mentioning "spherical lesion", "nodule" or synonymous terms. We found 11,515 reports in a before-PET period, 2002-2003, and 20,075 in an after-PET period, 2004-2005. Patients were followed through their physician, who was responsible for diagnostic management. RESULTS: We had complete data for 112 patients (73.7%) with new cases of SPN in the before-PET period and 250 (81.4%) in the after-PET period. Patients did not differ in mean age (64.9 vs. 64.8 years). The before-PET patients underwent a mean of 4 tests as compared with 3 tests for the after-PET patients (p = 0.08). Patients in the before-PET period had to wait 41.4 days, on average, before receiving a diagnosis as compared with 24.0 days, on average, for patients in the after-PET period who did not undergo PET (p < 0.001). In the after-PET period, 11% of patients underwent PET during the diagnostic process. A spiculated nodule was more likely to determine prescription for PET (p < 0.001). Multivariate analysis revealed that patients in both periods underwent fewer tests when PET was prescribed by general practitioners (p < 0.001) and if the nodule was not spiculated (p < 0.001). The proportion of unnecessary invasive approaches prescribed (47% vs. 49%) did not differ between the groups. CONCLUSION: In our study, 1 year after the availability of PET, the technology was not the first choice for diagnostic management of SPN. Even though we observed a tendency for reduced number of tests and mean time to diagnosis with PET, these phenomena did not fully relate to PET availability in health communities. In addition, the availability of PET in the management of SPN diagnosis did not reduce the overall rate of unnecessary invasive approaches.

Cost effectiveness of high-dose chemotherapy with autologous stem cell support as initial treatment of aggressive non-Hodgkin's lymphoma.

The GOELAMS 072 study showed that first-line high-dose chemotherapy (HDT) with peripheral blood stem cell transplant (PBSCT) support was superior to the standard chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine and prednisone; CHOP) in adults with aggressive non-Hodgkin's lymphoma (NHL). The aim of the study was to evaluate the pharmacoeconomic profile of HDT with PBSCT support relative to standard CHOP therapy as first-line treatment in adults with aggressive NHL. We performed a cost-effectiveness analysis from the French Public Health Insurance perspective, restricted to hospital costs (euro, year 2008 values). The clinical effectiveness criterion was censured overall survival (OS) difference after a median follow-up of 4 years for the entire cohort. A total of 197 patients were included (CHOP, n = 99; HDT, n = 98). Uncertainty was assessed using non-parametric bootstrap simulations and various scenario analyses. Five-year OS did not differ significantly between groups for the entire cohort. Nevertheless, subgroup analyses appeared to be more relevant for decision making: among patients with a high-intermediate risk according to the age-adjusted International Prognostic Index (IPI), HDT yielded a significantly higher 5-year OS than CHOP (74% vs 44%; p = 0.001). Among these patients, the mean censured OS survival, adjusted for time discounting and quality of life (QOL), increased with HDT by 1.20 years (95% CI 1.19, 1.21). The cost per life-year saved with HDT was estimated as euro34 315 (95% CI 32 683, 35 947) in this subgroup. Results suggested that HDT with PBSCT support might be considered a cost-effective strategy among patients with high-intermediate-risk NHL according to the age-adjusted IPI. Its place and its cost effectiveness potential versus, or in combination with, rituximab still need further research.

Relative added value: what are the tools to evaluate it?

The relative added value of a drug is currently evaluated in France by the Transparency Commission (TC) of the National Health Authority (HAS), by assigning a level of Improvement in Actual Benefit (IAB). IAB is based on two parameters, efficacy and safety of the product, in a defined target population, either as compared to one or more other drugs with similar indications, or within therapeutic strategy. The items used for evaluation, including the level of clinical effect, the relevance of the comparator, the choice of comparison criteria and the methodology used (indirect comparison, non-inferiority studies, etc.), have been reviewed by the working group in Giens with regard to an analysis of the opinion on TC issued between 2004 and 2007 in several therapeutic areas First of all, this attempt at rationalisation based on the criteria used to assess the relative added value demonstrated the rareness of direct comparative data, and was followed by a discussion on the possible broadening of the evaluation criteria. The group discussed taking into account the Public Health Impact (PHI), which has now been incorporated into the assessment of Actual Benefit (AB). The group believes that PHI seems to be more related to the notion of IAB than to that of AB. Indeed, it is frequently the relative added value of a new drug that produces an impact in public health. Conversely, considering the comparative evaluation criteria of PHI, which are not systematically taken into account in IMSR (such as improvement in the health of the population, meeting a public health need or impact on the healthcare system), PHI could legitimately be included in the assessment of the relative added value of a drug. Other parameters such as compliance or impact on professional practice have been considered. Thus, the notion of relative added value, evaluated at initial registration, could be based on an expected improvement in medical service. The notion of expected medical service leads to the requirement of producing additional data in real life (post-registration studies), which would support the definitive notion of improvement in actual benefit at the time of renewed registration, while taking into account the place occupied by the drug in the therapeutic strategy.

Management of SPN in France. Pathways for definitive diagnosis of solitary pulmonary nodule: a multicentre study in 18 French districts.

BACKGROUND: The process of diagnosis and management of solitary pulmonary nodules (SPNs) between 1 and 3 cm is not standardized. This multicentre study investigated how diagnosis of newly discovered SPNs is managed in routine practice. METHODS: We examined 11,515 radiology reports of patients undergoing chest computed tomography (CT) at all 76 radiology centres in 18 French administrative districts covering 8,220,000 people. Information on diagnostic procedures and treatment administered from discovery to definitive diagnosis of SPN was collected prospectively. RESULTS: We identified 152 cases of newly diagnosed SPNs. Follow-up was complete for 112 patients. The median number of diagnostic tests was 4 and the mean time to diagnosis was 41.4 days. Marked variability was observed in the sequence of diagnostic tests, and 8 diagnostic pathways were identified. Patients' characteristics and radiological features of SPNs influenced the number of tests performed. Referral by specialist, history of smoking and spiculated SPN predicted the performance of at least one invasive procedure (P < 0.01). Definitive diagnosis was a malignant disease in 30 patients (26%). CONCLUSION: The diagnosis of SPN is a complex process that physicians approach in markedly different ways. Implementing practice guidelines for managing the diagnosis of SPN requires clarification.

Cost-of-illness study of severe haemophilia A and B in five French haemophilia treatment centres.

OBJECTIVE: The aim of this study was to assess the consumption of anti-haemophilic drugs by adults and children with severe haemophilia A or B (residual activity of FVIII or FIX < or =2%) and to quantify the average direct medical costs. METHOD: A retrospective multicentre cost-of-illness study from the perspective of French national health insurance system. The costs include only the use of clotting factors. MAIN OUTCOME MEASURE: Consumption was expressed in UI/kg/year and costs in euros/kg/year. RESULTS: From January 1, 2001 to December 31, 2002, data from 81 adults and 30 children with severe haemophilia A (n = 92) or B (n = 19) and included in the "SNH" were collected and analysed. A coagulation factor inhibitor was present in 10 patients (9%). Four of them were high responders. Mean age and body weight were respectively 28 +/- 17 years and 58 +/- 24 kg. Except for one adult patient, all (99%) had outpatient treatment, 44 patients (40%) were hospitalized and treated by recombinant or/and plasma-derived FVIII or FIX or/and rFVIIa. Overall median annual consumption of anti-haemophilic drugs per patient was estimated at 1,333 UI/kg, with a median cost-of-illness of 1,156 euros/kg. Patients with severe haemophilia B consumed more than patients with severe haemophilia A, though not significantly (P = 0.096), with a median of 2,167 vs. 1,100 UI/kg/year and a median cost of 1,760 vs. 917 euros/kg/year (P = 0.13). Children consumed respectively more than adults (P = 0.008), with a median of 3,204 vs. 1,106 UI/kg/year and a median cost of 2,614 vs. 913 euros/kg/year (P = 0.012). The median cost for patients with an inhibitor was 3,291 euros/kg/year, approximately threefold higher than that of patients without an inhibitor (926 euros/kg/year) (P = 0.022). CONCLUSION: It suggests a higher consumption and cost of anti-haemophilic drugs among children when compared to adults. Haemophilia B patients did not consume significantly more than haemophilia A patients, whereas the consumption and cost for patients with or without inhibitors differed significantly.

Relative Added Value: What are the Tools to Evalue it?

The relative added value of a drug is currently evaluated in France by the Transparency Commission (TC) of the National Health Authority (HAS), by assigning a level of Improvement in Actual Benefit (IAB). IAB is based on two parameters, efficacy and safety of the product, in a defined target population, either as compared to one or more other drugs with similar indications, or within therapeutic strategy. The items used for evaluation, including the level of clinical effect, the relevance of the comparator, the choice of comparison criteria and the methodology used (indirect comparison, non-inferiority studies, etc.), have been reviewed by the working group in Giens with regard to an analysis of the opinion on TC issued between 2004 and 2007 in several therapeutic areas. First of all, this attempt at rationalisation based on the criteria used to assess the relative added value demonstrated the rareness of direct comparative data, and was followed by a discussion on the possible broadening of the evaluation criteria. The group discussed taking into account the Public Health Impact (PHI), which has now been incorporated into the assessment of Actual Benefit (AB). The group believes that PHI seems to be more related to the notion of IAB than to that of AB. Indeed, it is frequently the relative added value of a new drug that produces an impact in public health. Conversely, considering the comparative evaluation criteria of PHI, which are not systematically taken into account in IMSR (such as improvement in the health of the population, meeting a public health need or impact on the healthcare system), PHI could legitimately be included in the assessment of the relative added value of a drug. Other parameters such as compliance or impact on professional practice have been considered. Thus, the notion of relative added value, evaluated at initial registration, could be based on an expected improvement in medical service. The notion of expected medical service leads to the requirement of producing additional data in real life (post-registration studies), which would support the definitive notion of improvement in actual benefit at the time of renewed registration, while taking into account the place occupied by the drug in the therapeutic strategy.