Jean-David Zeitoun

Functional digestive symptoms and quality of life in patients with Ehlers-Danlos syndromes: results of a national cohort study on 134 patients.

Background and Objectives Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders. Gastrointestinal manifestations in EDS have been described but their frequency, nature and impact are poorly known. We aimed to assess digestive features in a national cohort of EDS patients. Methods A questionnaire has been sent to 212 EDS patients through the French patient support group, all of which had been formally diagnosed according to the Villefranche criteria. The questionnaire included questions about digestive functional symptoms, the GIQLI (Gastrointestinal Quality of Life Index), KESS scoring system and the Rome III criteria. Results Overall, 135 patients (64% response rate) completed the questionnaire and 134 were analyzable (123 women; 91%). Mean age and Body Mass Index were respectively 35±14.7 years and 24.3±6.1 kg/m2. The most common EDS subtype was hypermobility form (n=108; 80.6%). GIQLI and KESS median values were respectively 63.5 (27-117) and 19 [13.5-22]. Eighty four percent of patients had functional bowel disorders (FBD) according to the Rome III criteria. An irritable bowel syndrome according to the same criteria was observed in 64 patients (48%) and 48 patients (36%) reported functional constipation. A gastro-esophageal reflux disease (GERD) was reported in 90 patients (68.7%), significantly associated with a poorer GIQLI (60.5±16.8 versus 75.9±20.3; p<0.0001). GIQLI was also negatively impacted by the presence of an irritable bowel syndrome or functional constipation (p=0.007). There was a significant correlation between FBD and GERD. Conclusions Natural frequency of gastrointestinal manifestations in EDS seems higher than previously assessed. FBD and GERD are very common in our study population, the largest ever published until now. Their impact is herein shown to be important. A systematic clinical assessment of digestive features should be recommended in EDS.

Inconsistencies among European Union pharmaceutical regulator safety communications: a cross-country comparison

Background The European Medicines Agency (EMA) and national regulators share the responsibility to communicate to healthcare providers postmarketing safety events but little is known about the consistency of this process. We aimed to compare public availability of safety-related communications and drug withdrawals from the EMA and European Union member countries for novel medicines. Methods and Findings We performed a cross-sectional analysis using public Dear Healthcare Professional Communications (DHPCs) for all novel medicines authorized between 2001 and 2010 by the EMA and available for use in France, Netherlands, Spain, and the United Kingdom. Between 2001 and 2010, the EMA approved 185 novel medicines. DHPCs could not be ascertained for the EMA. Among the 4 national regulators, as of April 30, 2013, at least one safety DHPC or withdrawal occurred for 53 (28.6%) medicines, totaling 90 DHPCs and 5 withdrawals. Among these 53 medicines, all 4 national agencies issued at least one communication for 17 (32.1%), three of the four for 25 (47.2%), two of the four for 6 (11.3%), and one of the four for 5 (9.4%). Five drugs were reported to be withdrawn, three by all four countries, one by three and one by two. Among the 95 DHPCs and withdrawals, 20 (21.1%) were issued by all 4 national regulators, 37 (38.9%) by 3 of the 4, 22 (23.2%) by 2 of the 4, and 16 (16.8%) by one. Consistency of making publicly available all identified safety DHPC or withdrawal across regulator pairs varied from 33% to 73% agreement. Conclusions Safety communications were not made publicly available by the EMA. Among the 4 European member countries with national regulators that make DHPCs publicly available since at least 2001, there were substantial inconsistencies in safety communications for novel medicines. The impact of those inconsistencies in terms of public health remains to be determined.

Infliximab infusion time in patients with inflammatory bowel diseases: Is longer really safer?

BACKGROUND AND OBJECTIVEnInfliximab, a monoclonal antibody directed against tumor necrosis factor α (TNFα), is commonly used during flares and on a regular basis to maintain the remission of inflammatory bowel diseases (IBD). It is usually administered in 2-hours infusion and 2 hours of monitoring after as recommended. However, recent reports suggest that infliximab infusions over a shorter period (30 minutes to 1 hour) are well tolerated. We aimed to compare the tolerability of 1-hour and 2-hours infliximab infusions in patients with IBD in our institution.nnnMETHODSnWe analyzed data from all patients treated with infliximab between 1999 and September 2010. Infliximab was administered in 1-hour infusion and 1 hour monitoring since 2009. Only the early adverse events were analyzed.nnnRESULTSnAdverse events during infusion were compared between one group of patients who had 1-hour infusion (989 infusions) and the other who had 2-hours infusion (2102 infusions). The incidence of adverse events was 10.6% in the 2-hours infusion group versus 6.3% in the 1-hour infusion group (P=0.36).nnnCONCLUSIONSnThese results suggest that the occurrence of infliximab infusion-related adverse events is similar across the two groups, regardless of the infusion cycle. One-hour infusion could then be proposed safely for all patients.

Regulatory anticipation of postmarket safety problems for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study.

The aim of the study is to describe preapproval safety concerns expressed by the European Medicines Agency (EMA) following regulatory review and to compare those concerns with subsequent issuance of postmarket safety communications.

Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study

AIMSnRegulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA).nnnMETHODSnWe performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30u2009days before the EMAs 210u2009day regulatory deadline.nnnRESULTSnAmong 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337u2009days (IQR 276-406) and was not associated with PMSEs (Pu2009=u20090.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; Pu2009=u20090.01). Finally, 26 medicines were approved near the 210u2009day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; Pu2009=u20090.32).nnnCONCLUSIONSnNeither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines.

Readmissions After Surgery: A French Nationwide Cross-Sectional Study of 1,686,602 Procedures Performed in 2010

BackgroundSurgical readmissions have been extensively studied in North America, but very few data from other countries are available. We aimed to describe surgical readmissions in France and to assess their association with hospital status, surgical volume, and day surgery activity.MethodsWe performed a cross-sectional study encompassing all 1270 French hospitals, except for military hospitals and hospitals with very small volume. Data were retrieved from the national database regarding all patients undergoing surgery between January 1, 2010 and November 30, 2010. The main outcome measure was 30-day readmission rate. Association with hospital status, surgical volume, and the level of day surgery were assessed. Risk adjustment was performed based upon administrative categories.ResultsAfter exclusion of deaths and hospital transfers, there were 1,686,602 patients in the study cohort. Thirty-day readmission rate was 5.9xa0%. Distribution was skewed, with 21.5xa0% of procedures accounting for 33.5xa0% of all 30-day readmissions. Early readmissions (≤3xa0days) were associated with higher mortality as compared to those occurring later (>7xa0days) (3.2 vs. 2.6xa0%; pxa0<xa00.0001). After multivariate analysis, University hospitals were shown to be affected by a significantly greater risk of 30-day readmission as compared to private hospitals (odds ratio 1.46 [95xa0% CI 1.42–1.5]). Other independent factors were as follows: male gender, longer initial hospital stay, and comorbidities.ConclusionsSurgical 30-day readmission rate was low, with early readmissions being associated with higher mortality. Conversely to prior research, University hospitals were shown to be associated with significantly higher risk of 30-day readmissions, even after risk adjustment.

Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study.

Post‐marketing research in oncology has rarely been described. We aimed to characterize post‐marketing trials for a consistent set of anticancer agents over a long period. We performed a cross‐sectional analysis of post‐marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post‐marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2,345 post‐marketing trials; 1,362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post‐marketing trials (range 8–530) and overall population to be enrolled per trial (1–8,381). Post‐marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post‐marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3 to 26.1% depending on the analysis method. In conclusion, we found that post‐marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low.

Pharmacogenomic biomarkers as inclusion criteria in clinical trials of oncology-targeted drugs: a mapping of ClinicalTrials.gov

Purpose:The aim of this study was to describe pharmacogenomics-based inclusion criteria (enrichment) and the main characteristics of clinical trials involving oncology-targeted therapies.Methods:Clinical trials of oncology-targeted therapies approved after 2005 with pharmacogenomic testing required or recommended in their label were retrieved from a mapping of the ClinicalTrials.gov database.Results:We examined information for 12 drugs and 858 trials. Overall, 434 trials (51%) were enriched on the biomarker first mentioned in the label and 145 (17%) were enriched on another biomarker, whereas 270 trials (31%) included all patients. The median proportion of trials corresponding to both the drug’s indication and drug’s target was 35%. Of the 361 trials that tested drugs in another disease than the first one in the label, 219 (61%) were without enrichment and 87 (24%) were actually enriched but on another biomarker than the first one in the label.Conclusion:Several drugs have been tested in trials enriched on many different biomarkers. Nonetheless, most targeted therapies have been developed only using biomarker-positive patients; therefore, exclusion of biomarker-negative patients from treatment relies on only preclinical data and on biological understanding of the disease and target.Genet Med 18 8, 796–805.

Synchronous perianal metastasis of lung adenocarcinoma: report of a case.

A 53-year-old woman was referred to our proctology unit for non-healing perianal ulceration. Her medical history was significant for active smoking since she was 18. She had been treated for three months by her primary care physician with antibiotics and local ointments. Physical examination showed a perianal ulceration which was highly suspicious of malignancy (Fig. 1). Exploration under anaesthesia did not find any suspicious lesion in the anal canal or the lower rectum and a biopsy was made. Histopathological analysis was in favour of a moderately differentiated adenocarcinoma, with clear cells. The immunohistochemistry profile revealed a primary lung cancer: high expression of TTF1 and cytokeratin K7, without cytokeratin K20 (Fig. 2). Computed tomography scan was performed, showing a pulmonary mass of the left lung, which was assumed to be the primary cancer. She also had multiple susand sub-diaphragmatic lymphadenopathies, as well as liver and subcutaneous metastasis. She is currently treated with cisplatin and pemetrexed.

Postmarketing studies for novel drugs approved by both the FDA and EMA between 2005 and 2010: a cross-sectional study

Objectives To characterise postmarketing studies for drugs that were newly approved by the US Food and Drug Administration and the European Medicines Agency. Design and setting Cross-sectional analysis of postmarketing studies registered in ClinicalTrials.gov until September 2014 for all novel drugs approved by both regulators between 2005 and 2010. Regulatory documents from both agencies were used. Primary and secondary outcome measures All identified postmarketing studies were classified according to planned enrolment, funding, status and geographical location, and we determined whether studies studied the originally approved indication. Results Overall, 69 novel drugs approved between 2005 and 2010 were eligible for inclusion. A total of 6679 relevant postmarketing studies were identified; 5972 were interventional (89.4%). The median number of studies per drug was 55 (IQR 33–119) and median number of patients to be enrolled per study was 60 (IQR 28–183). Industry was the primary sponsor of 2713 studies (40.6%) and was a primary or secondary sponsor in 4176 studies (62.5%). In all, 2901 studies (43.4%) were completed, 487 (7.3%) terminated, 1013 (15.2%) active yet not recruiting, 1895 (28.4%) recruiting and 319 (4.8%) not yet recruiting. A total of 80% of studies were conducted in only one country and 84.4% took place in Europe and/or North America; 2441 (36.5%) studied another indication than the originally approved indication. Studies designed in the originally approved indication were found to be more industry-sponsored than others 68.7%vs53.7%; P<0.0001. Conclusions Postmarketing pharmaceutical research was highly variable and predominantly located in North America and Europe. Postmarketing studies were frequently designed to study indications other than the originally approved one. Although some findings were reassuring, others question the lack of coordination of postmarketing research.