Hurdles of environmental risk assessment procedures for advanced therapy medicinal products: comparison between the European Union and the United States.

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.

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.

Chronic obstructive pulmonary disease (COPD) in Spain and the different aspects of its social impact: a multidisciplinary opinion document.

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent diseases in the World, and one of the most important causes of mortality and morbidity. In adults 40 years and older, it affects more than 10% of the population and has enormous personal, family and social burden. Tobacco smoking is its main cause, but not the only one, and there is probably a genetic predisposition that increases the risk in some patients. The paradigm of this disease is changing in Spain, with an increase of women that has occurred in recent years. Many of the physio pathological mechanisms of this condition are well known, but the psychological alterations to which it leads, the impact of COPD on relatives and caregivers, the limitation of daily life observed in these patients, and the economic and societal burden that they represent for the health system, are not so well-known. A major problem is the high under-diagnosis, mainly due to difficulties for obtaining, in a systematic way, spirometries in hospitals and health-care centers. For this reason, the Fundación de Ciencias de la Salud and the Spanish National Network Center for Research in Respiratory Diseases (CIBERES) have brought together experts in COPD, patients and their organizations, clinical psychologists, experts in health economics, nurses and journalists to obtain their opinion about COPD in Spain. They also discussed the scientific bibliometrics on COPD that is being carried out from the CIBERES and speculated on the future of this condition. The format of the meeting consisted in the discussion of a series of questions that were addressed by different speakers and discussed until a consensus conclusion was reached.

[Multicenter study of pain assessment in hospitals]. / Estudio multicéntrico de la evaluación del dolor en el medio hospitalario.

OBJECTIVE: To evaluate the recording of pain intensity in hospital charts. METHODS: A cross-sectional study was carried out in 15 hospitals in a sample of admitted patients with pain. Clinical data, including pain intensity, were gathered from the hospital records. Multiple analysis of variance was used to identify factors related to the intensity of pain recorded in the patients' charts. RESULTS: A total of 1038 patients with a mean (SD) age of 56.1 (18.9) years were included. Pain intensity was noted in the charts of 47.9% (95% confidence interval [CI], 44.9%-50.9%) of the patients. Pain intensity had been noted for 68.9% (95% CI, 61.4%-76.4%) of the patients with cancer, 43% (95% CI, 38.2%-47.8%) of postoperative patients, 38.2% (95% CI, 35%-41.4%) of trauma patients, and 26.6% (95% CI, 16.9%-36.3%) of postpartum women. There was great interhospital variability. Factors associated with the recording of pain intensity in medical charts were hospital characteristics (large hospitals, teaching hospitals, hospitals and internal medicine and surgical specialities) and type of patient (cancer and trauma cases and patients reporting pain to the staff). CONCLUSION: There is inadequate written recording of intensity of pain in hospitals, even though there is considerable interhospital variation. Pain intensity assessment and recording is an indicator of quality of health care and should become a routine practice in hospital health care.

Prevalence of pain in adults admitted to Catalonian hospitals: a cross-sectional study.

OBJECTIVE: To survey the prevalence of pain in patients admitted to different hospitals of Catalonia and to describe which factors are related to pain. METHODS: A cross-sectional study was performed in 1675 patients from fifteen hospitals in Catalonia (Spain). Clinical and demographic data, as well as the existence of pain intensity evaluations and analgesic therapy, were obtained from medical charts. Characteristics of pain were given by patients after being interviewed by trained interviewers. The main-outcome measure was the existence of pain (at the interview, in the previous 24h, at the admission and at any time after admission) that was assessed by a visual analogue scale (VAS). The relationship of prevalence of pain to patients' characteristics was carried out by means of a multiple-logistic-regression model with pain presence as the dependent variable of interest. RESULTS: A great variability in the prevalence and intensity of pain among different hospitals was observed. At the time of the interview, 48.5% (95% CI: 46.1-50.9%) of the patients had pain and the median VAS was 40mm (range: 10-100mm), and the prevalence of pain during the previous 24h was similar (47.6%; 95% CI: 45.2-50%). At admission, 26.7% (95% CI: 24.6-28.8%) of patients were in pain, whereas 62% (95% CI: 59.7-64.3%) reported having pain at some time during their stay. Pain intensity annotations were absent in 51.3% (95% CI: 47.9-54.7%) of the medical records of the patients with pain. The factors associated with pain were younger age, female gender, presence of surgery, orthopaedic surgery wards, large hospital and prescribed analgesics. CONCLUSION: A high prevalence of clinically relevant pain in in-patients was found as well as a great variability according to type of patients, clinical wards and hospitals. This study gives clear evidence of the lack of adequate management of pain in the majority of the hospitals and calls for the implementation of organisational and educational measurements that may settle this epidemic problem.

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.

Appropriateness of antibiotic prescriptions in community-acquired acute pediatric respiratory infections in Spanish emergency rooms.

OBJECTIVE: To describe the variability and appropriateness of antibiotic prescriptions in community-acquired acute respiratory infections (ARI) during childhood in Spain. METHODS: A descriptive, multicenter study of variability in clinical practice was conducted by evaluating a prospective series of pediatric patients attending the emergency rooms of 11 Spanish hospitals and diagnosed with community-acquired ARI. The appropriateness of the antibiotic prescriptions was assessed by comparing our clinical practice with consensus guidelines developed for this study. RESULTS: We collected data from 6,249 ARI emergencies studied on 30 separate days. Antibiotics were prescribed in 58.7% of the ARI (bronchiolitis, 11.5%; bronchitis, 40.2%; pharyngotonsillitis, 80.9%; nonspecified ARI, 34.8%; pneumonia, 92.4%; otitis, 93.4%; sinusitis, 92.6%). The most commonly used antibiotics were amoxicillin/clavulanate (33.2%), amoxicillin (30.2%), cefuroxime axetil (8.5%) and azithromycin (6%). According to the consensus guidelines developed for this study, therapy was considered to be appropriate in 63.1% of the ARI (first choice, 52.1%; alternative choice, 11.0%) and inappropriate in 36.9%. The percentages of inappropriate prescription according to ARI groups were: bronchiolitis, 11.5%; bronchitis, 31.5%; pharyngotonsillitis, 54.8%; nonspecified ARI, 34.7%; pneumonia, 13.9%; otitis, 25.6%; and sinusitis, 22.2%. CONCLUSIONS: There is excessive use of antibiotics in acute respiratory infections that are presumably viral in origin. An important number of ARI of potentially bacterial origin are treated with antibiotics that are not sufficiently efficacious or that have a broader spectrum than necessary.

Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa.

The aim of this study was to investigate the long-term effectiveness and safety of inhaled antibiotic treatment in non-cystic fibrosis patients with bronchiectasis and chronic infection by Pseudomonas aeruginosa, after standard endovenous and oral therapy for long-term control of the infection had failed. After completing a 2-week endovenous antibiotic treatment to stabilize respiratory status, 17 patients were randomly allocated to a 12-month treatment either with inhaled ceftazidime and tobramycin (group A) or a symptomatic treatment (group B). One patient from group A abandoned inhaled treatment because of bronchospasm and another from group B died before the end of the study. The remaining 15 patients, seven from group A and eight from group B, completed the study. Both groups had similar previous characteristics. The number of admissions and days of admission (mean +/- SEM) of group A [0.6 (1.5) and 13.1 (34.8)] were lower than those of group B [2.5 (2.1) and 57.9 (41.8)] (P < 0.05). Forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), PAO2 and PACO2 were similar in the two groups at the end of follow-up, showing a comparable decline in these parameters. There were no significant differences either in the use of oral antibiotics or in the frequency of emergence of antibiotic-resistant bacteria between groups. Microbiological studies suggested that several patients had different Pseudomonas aeruginosa strains. None of the patients presented impaired renal or auditory function at the end of the study. This study suggests that long-term inhaled antibiotic therapy may be safe and lessen disease severity in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa which do not respond satisfactorily to antibiotics administered via other routes.

Assessment of antibiotic prescription in acute respiratory infections in adults. The Spanish Study Group on Antibiotic Treatments.

OBJECTIVE: This study aims to ascertain the variability in the use of antibiotics for the treatment of acute respiratoryinfections in several hospital emergency services in Spain, as well as the appropriateness of antibiotics prescription through evaluation by a panel of experts using available scientific evidence. METHOD: A cross-sectional study was carried out in the emergency services of 10 hospitals in different Spanish regions. We chose patients diagnosed as having acute respiratory infection, aged over 14 years. Among the collected variables were: type of respiratory infection, antibiotic prescription, comorbidity, qualification of the prescribing doctor and hospital admission. The consensus conference held by a panel of experts established first choice treatment and the alternative and inappropriate use for each respiratory infection, based on the available scientific evidence. All the observed prescriptions in our study were classified according to this pattern. RESULTS: A sample of 2899 acute respiratory infections was studied (5.5% of all emergencies). Antibacterial agent treatment was prescribed in 82.6% of these, varying according to the infection between 98.5% of pneumonias and 49% of croup-influenza-common cold. The most commonly used antibiotics were amoxicillin-clavulanate and cefuroxime. The global percentage of inappropriate prescription was 40.5% (95% CI; 35.4-45.5). The prescriptions were inappropriate in 16.9% of cases of pharyngotonsillitis, 17.8% of chronic bronchitis, 26.9% of acute bronchitis, 29.3% of pneumonias, 30.8% of otitis and sinusitis and in 70.8% of croup, flu, common cold and non-specified infections. Significant variability among participating centres was observed, both in choice of antibiotics and in their degree of appropriateness. CONCLUSIONS: There is excessive use of antimicrobial drugs in acute respiratory infections, and the majority are used for viral infections. There is indiscriminate use of broad spectrum antibiotics, which are valid in some infections but clearly inappropriate in others. Similarly, there are important differences in the choice of antibiotics and their degree of appropriateness among hospitals.

Impact of analgesic drug-use guidelines for the management of postoperative pain: a drug utilization study.

OBJECTIVE: Postoperative pain is inadequately treated in many surgical settings. The present study evaluates the impact of analgesic drug-use guidelines in the management of postoperative pain. PATIENTS AND METHODS: A prospective drug utilization study was carried out in 3 stages in a traumatology, orthopedic and rehabilitation tertiary hospital. The first stage, aimed at describing the patterns of use of analgesic strategies in the management of postoperative pain, identified habits, practices and misconceptions regarding this therapeutic area. After this, an ad hoc representative institutional working group agreed on analgesic drug-use guidelines for the management of postoperative pain. These were then published, presented and discussed with surgeons and nurses. After the guidelines had been implemented, their impact was evaluated in terms of the analgesics used, their dosage and their administration schedule. RESULTS: 101 patients were studied before the implementation of the guidelines and 108 patients after. Patients receiving opiate analgesics during the immediate postoperative period increased from 70-94% (p < 0.05). First-choice analgesics used according to the guidelines increased from 40-89% of choices after the implementation of the guidelines (p < 0.05). Administration of analgesics at regular predetermined intervals increased from 45-58% of medical orders, but this increase was not statistically significant (p = 0.07). Prescription of analgesics at adequate doses increased from 67-87% (p < 0.05). CONCLUSION: Education on the treatment of postoperative pain is made up of several messages including the drug of choice and dose regimen. Prescribers seemed more receptive to a change in drug rather than issues related to the correct dose regimen. More research is needed to assess how educational activities can improve the management of postoperative pain.

[Use of levofloxacin in the hospital]. / Utilización hospitalaria de levofloxacino.

Levofloxacin is a new, recently commercialized fluoroquinolone. We aimed to assess the use of levofloxacin after its inclusion in the hospital drug guide. In a prospective observational study, patients treated with levofloxacin in a university hospital were selected from July 2000 to June 2001. Using a structured questionnaire, data were recorded on patients' demographic characteristics and comorbidities, indications for levofloxacin use and previous use of other antibiotics. In addition, the adherence to the instructions for use as recommended by the antibiotic subcommittee of the hospital, and the use of other alternative antibiotics were analyzed. Ninety-seven patients were treated [mean age 67 years; range 17-93; 64 men], of whom 83 (85.6%) had comorbidity and 51 (52.6%) a possible allergy to the betalactam antibiotics. The treatment began after the use of other antibiotics in 47 (48.5%) patients. The main clinical indications were pneumonia (54; 55.7%) and acute exacerbation of chronic bronchitis (25; 25.8%). The use of other antibiotics was possible in 56 (57.7%) patients, and levofloxacin was only used according to the recommended indications in 41 (42.3%). Levofloxacin is mainly used in the treatment of patients with respiratory infections, those who are allergic to the betalactam antibiotics and those previously treated with other antibiotics; however, in many cases, the use of other antibiotics may still be possible. As part of the antibiotic policy, it is necessary to define the indications of use for new antibiotics introduced in the hospital and surveillance studies need to be developed.

[Multicenter study of the variability and adequacy of antimicrobial therapy for community-acquired pneumonia in adults]. / Estudio multicéntrico de variabilidad e idoneidad de la prescripción antibiótica en la neumonía adquirida en la comunidad del adulto.

We performed a study to evaluate the variability and adequacy of prescribing antibiotics in community-acquired pneumonia (CAP) in 10 Spanish hospitals. We studied 452 patients with CAP. Initial empirical administration of antibiotics was prescribed in 90.7% of the cases, 82.5% as monotherapy. Macrolides and third and second generation cephalosporins were the most widely used groups of antibiotics. Penicillin and amoxicillin were only prescribed in 1. 7% of the patients. A significant variability between hospitals was observed. Reference patterns for the use of antibiotics in CAP were devised by a panel of experts. According to the recommendations of this panel, 29% of the total prescriptions were not adequate, with this percentage reaching 65% in outpatients older than 65 years or with comorbidity. This was mainly due to the fact that monotherapy with erythromycin, which was considered inadequate, was the most widely prescribed treatment.

[Analgesics in the postoperative period of abdominal interventions. The Study Group on Postoperative Analgesia of the Spanish Society of Clinical Pharmacology]. / Analgésicos en el postoperatorio de intervenciones abdominales, y Grupo de Estudio sobre la Analgesia Postoperatoria de la Sociedad Española de Farmacología Clínica.

BACKGROUND: Analgesics can avoid postoperative pain. The aim of this study was to evaluate their prescription after abdominal surgery. PATIENTS AND METHODS: Prospective study including patients who had undergone abdominal surgery in two hospitals in Barcelona, in 1993. Prescription and administration of analgesic drugs, and pain severity during the first 48 hours of the postoperative period were evaluated. RESULTS: One hundred and sixty-four patients (83 men) were included. The most frequently prescribed drugs were metamizol (111; 68%), pethidine (83, 51%), and diclofenac (44; 27%). A high percentage of analgesic prescriptions on an "as needed" basis was recorded. Administered doses were lower than those recommended, and lower than those prescribed. Fifty-three percent of patients suffered significant pain during the first day. CONCLUSION: A too low proportion of analgesic drugs is prescribed in a predetermined schedule, in contrast to "as needed" prescription. Opiate derivatives are underused. All analgesic drugs are prescribed at inadequate dosage. This prescription pattern is associated with a high prevalence of postoperative pain.

[The use of the determination of plasma theophylline concentrations in the hospital]. / Uso de la determinación de las concentraciones plasmáticas de teofilina en el hospital.

BACKGROUND: The evaluation of the determination of plasmatic concentrations of theophylline (PCT) in clinical practice is scarce. An observational study was carried out with the aim of discerning the reasons why PCT determinations are requested, the theophyllinemias obtained and the attitude of the medical staff in a hospital. METHODS: PCT determinations obtained in 113 patients over a period of 3 months were analyzed. Information concerning treatment and daily doses of theophylline, reasons for theophylline determination, apart from those included in the request for theophyllinemia determination, clinical history and treatment sheets were collected. RESULTS: Treatment with theophylline had been indicated in 78 patients (69%) with chronic bronchitis, and 30 (26%) with asthma. All the patients received medication in addition to theophylline. Daily dosage (SD) was 734 (260) mg and the daily doses as to body weight (SD) was 11 (4) mg/kg/day. 188 DNPT were performed, however 22 (12%) were inadequate; of the remaining 166 PCT determinations 117 (69%) had been requested with no indication of insufficient clinical response, suspicion of undesirable effects or modifying factors of the pharmacokinetics of theophylline. The mean plasmatic concentration (SD) was 11.3 (7) micrograms/ml. PCT was infratherapeutic in 74 PCT determinations (44%), therapeutic in 73 (44%) and toxic in 19 (11%). Therapeutic concentrations were obtained in only 16 (35%) of the 45 patients in whom a second PCT determination had been carried out. CONCLUSIONS: In this study scarce individualization in the indication of treatment and the doses of theophylline administered are observed. The reason for soliciting determination of theophyllinemia and dosage adjustment in terms of plasmatic concentrations are also commented upon.

Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced dyskinesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.