Therapeutic enquiries about biological agents as a tool to identify safety aspects and patterns of use.

BACKGROUND: Biotechnological agents (BA) are increasingly being used in clinical practice. We aimed to determine, whether enquiries about them to a therapeutic consultation service have also become more frequent, and to describe the information requested in these consultations. METHODS: We retrospectively reviewed 14 104 therapeutic consultations collected in a computerised database between 2000 and 2014. Enquiries about BA (monoclonal antibodies, fusion proteins or cytokine antagonists) were chosen. Information on the type of BA, underlying condition, type of enquiry and affiliation of the enquirer was retrieved and compared with data from consultations about other agents. RESULTS: During the study period, 365 enquiries about 30 different BA were received. Only 4% of them were received before 2004, while 48.8% were received after 2010. Rituximab, infliximab, adalimumab and etanercept were most frequently enquired about. Agent selection (n=184) and/or adverse effects (n=174) were the most frequent reasons for making an enquiry. Most enquiries about an agent selection were made about an off-label use (n=164), mainly for systemic autoimmune diseases (n=61). Over half of the enquiries about adverse effects were about their teratogenic potential (n=96). Enquiries about BA more often requested an opinion (87.7% vs 77.7%) were made by physicians (89.9% vs 76.9%), from a hospital (81.6% vs 44.5%) and regarded a specific patient (87.4% vs 74.5%). CONCLUSIONS: Therapeutic consultations about BA are increasing. Most of them are related to uncertainties of health professionals regarding any new medicine: their off-label use, actual adverse effects or the teratogenic potential of the involved agents.

Outcomes of off-label drug uses in hospitals: a multicentric prospective study.

PURPOSE: The study aims to assess the clinical evidence, outcome and cost of off-label use of medicines in the hospital setting. METHODS: A multicentric prospective cohort study of patients treated with off-label medicines was carried out in five tertiary hospitals from May 2011 to May 2012. Information on clinical characteristics of patients, drugs, outcomes and costs was collected. Patients were followed up to 6 months, and information was assessed by reviewing clinical records and interviewing physicians. RESULTS: A total of 226 patients were included. The median (interquartile range (IQR)) age of patients was 46 (33-62) years; 59 % were women. Patients had received a median of three previous treatments, and a lack of response (or suboptimal) was the main reason for off-label use (72.1 %). A total of 232 off-label medicines were administered for 102 different indications. The most frequent medicines were rituximab (49; 21.1 %), botulinum toxin (25; 10.7 %) and omalizumab (14; 6.0 %). In 117 (51.8 %) cases, the level of clinical evidence for their use was low. A partial clinical response was observed in 82 patients (36.3 %), complete response in 71 (31.4 %) and stabilization in 11 (4.9 %). A total of 58 (26.5 %) patients had adverse effects, which in 11 (4.9 %) were severe. The median (IQR) cost per patient was 2,943.07 (541.9-5,872.54). CONCLUSIONS: There was a high variability of off-label medicines and indications. Although the clinical evidence of off-label medicines was often low, clinical response was observed in many patients with previous multiple treatment failure, but at the expense of some adverse effects and a high cost. Registers of patients would be helpful for clinical decisions, although clinical trials are needed.

Available evidence and outcome of off-label use of rituximab in clinical practice.

PURPOSE: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. METHODS: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. RESULTS: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30 months) in 69.2 % of patients showing a short-term response. Median cost per patient was €5,187.5 (IQR €5,187.5-7,781.3). CONCLUSIONS: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Meta-analysis of passive immunoprophylaxis in paediatric patients at risk of severe RSV infection.

AIM: To review respiratory syncytial virus (RSV), passive immunoprophylaxis (PI) trials and meta-analysis (MA). METHODS: A literature review. RESULTS: Two MA of PI were found. Overall 3927 patients were randomized. PI reduces RSV hospitalization in patients with bronchopulmonary dysplasia (RR 0.58; 95% CI 0.41, 0.82) and with acyanotic congenital heart disease (RR 0.29; 95% CI 0.14, 0.62). In patients with cyanotic heart disease or premature infants without bronchopulmonary dysplasia, results are inconclusive. Passive immunoprophylaxis has a null effect in mechanical ventilation and death. CONCLUSION: Passive immunoprophylaxis reduces RSV hospitalization in a subset of patients. However, it has no effect in harder endpoints of RSV disease severity.

Obstacles and solutions for spontaneous reporting of adverse drug reactions in the hospital.

AIM: To describe the opinions of hospital physicians concerning problems regarding the spontaneous reporting of adverse drug reactions (ADRs) and ways to solve them. METHODS: A qualitative study was carried out. Fifteen focus groups were conducted among physicians working in a tertiary teaching hospital. A total of 208 physicians from different medical specialities participated. The focus group discussions were recorded by three different observers and the transcripts of each session were analysed for issues and themes emerging from the text. RESULTS: Four types of obstacles to spontaneous reporting were considered particularly important: (i) problems with the ADR(S) diagnosis; (ii) problems with the usual workload and lack of time; (iii) problems related to the organization and activities of the pharmacovigilance system; (iv) and problems related to potential conflicts. The potential solutions suggested for improving spontaneous reporting were to define the kind of ADR(S) which should be reported, to facilitate an easy contact and quick access to the hospital pharmacovigilance system, to facilitate information and support for reporting and feedback of pharmacovigilance activities. CONCLUSIONS: The perception of the different obstacles by the hospital physicians is an important factor in determining the causes of the underreporting of ADRs and addressing these obstacles could lead to an improvement in spontaneous reporting. A closer relationship between the doctors and the pharmacovigilance centre is suggested as a means of solving these problems. More information is needed to improve the spontaneous reporting of ADR(S) in specialized healthcare.

DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group.

UNLABELLED: Short-term clinical trials with DNase have shown minor to moderate benefits in cystic fibrosis patients. This study was performed to analyse the effectiveness of DNase use in daily practice and to obtain information on its effects in the long term and at different disease stages. Patients being treated in 13 specialised units were included if they started DNase treatment before June 1996. Baseline data before DNase use and data during the DNase treatment period were recorded. Of the 199 patients included in the study 166 continued on DNase treatment while the data were being collected. The mean age (95% CI) was 14.5 (13.7; 15,2) years; 103 (51.8%) patients were female. The mean maximum change in forced expiratory volume in 1 s (FEV(1)) was observed during the first month of treatment [11.1% (6.1; 16.1)]. By the end of the first and the second year of treatment mean changes in FEV(1) were 3.3% (-1.1; 7. 6) and 5.1% (-0.7; 10.9) respectively; at the end of the same periods 34% of patients had improved their baseline FEV(1) by 10% or more but in around 50% of patients the level fell below the baseline. A large inter-individual variability in changes in pulmonary function after the start of DNase treatment was documented. In addition, the medium-term response to treatment was correlated with early response during the first 3 months. No consistent changes in exacerbation pattern were found during the first year of treatment. CONCLUSIONS: The benefits of DNase use in daily practice are limited but apparently can be maintained in the medium term in some patients. A large inter-individual variability in response to DNase treatment has been documented and the benefits are doubtful in around 50% of patients. This observation points to the need to set up a withdrawal trial in these patients, using as an eligibility criterion the early response observed during the first 3 months of treatment.