Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight.

AIMS: To describe and characterize the first cohort of Post-Authorization Safety Study (PASS) protocols reviewed under the recent European pharmacovigilance legislation. METHODS: A systematic approach was used to compile all publicly available information on PASS protocols and assessments submitted from July 2012 to July 2015 from Pharmacovigilance Risk Assessment Committee (PRAC) minutes, European Medicines Agency (EMA) and European Network of Pharmacovigilance and Pharmacoepidemiology (ENCePP) webpages. RESULTS: During the study period, 189 different PASS protocols were submitted to the PRAC, half of which were entered in the ENCePP electronic register of post-authorization studies (EU-PAS) by July 2015. Those protocols were assessed during 353 PRAC reviews. The EMA published only 31% of the PRAC feedback, of which the main concerns were study design (37%) and feasibility (30%). Among the 189 PASS, slightly more involved primary data capture (58%). PASS assessing drug utilization mainly leveraged secondary data sources (58%). The majority of the PASS did not include a comparator (65%) and 35% of PASS also evaluated clinical effectiveness endpoints. CONCLUSIONS: To the best of our knowledge this is the first comprehensive review of three years of PASS protocols submitted under the new pharmacovigilance legislation. Our results show that both EMA and PASS sponsors could respectively increase the availability of protocol assessments and documents in the EU-PAS. Protocol content review and the high number of PRAC comments related to methodological issues and feasibility concerns should raise awareness among PASS stakeholders to design more thoughtful studies according to pharmacoepidemiological principles and existing guidelines.

A prospective observational study of oseltamivir safety and tolerability in infants and young children ≤24 months.

PURPOSE: Infants and young children are at elevated risk of influenza-associated complications, but information on the safety of antiviral therapies is limited in this age group. METHODS: In this prospective open-label observational safety study, children aged ≤24 months with a clinical diagnosis of influenza in routine practice received either no antiviral treatment ('unexposed' group) or oseltamivir treatment or prophylaxis ('exposed' group), according to the physician's judgment. Patients were followed up for 30 days after the baseline visit. RESULTS: Adverse events (AEs) were analysed in 1065 patients; they were reported in 390/711 (54.9%) in the unexposed group, 167/340 (49.1%) patients in the exposed group, and 6/14 prophylaxis patients. Cough and rhinitis were the most common events, reported more often in unexposed children (22.9 and 20.3% respectively) than in exposed children (13.2 and 10.0%; p < 0.001); pyrexia, diarrhoea and vomiting were less common, occurring at similar rates in exposed and unexposed patients. Nasal congestion (3.5%), bronchitis (5.6%) and upper respiratory tract infection (1.5%) were reported more frequently in exposed patients than in unexposed patients (0.7, 2.7 and 0.1% respectively; p < 0.05). In the exposed group, 11.2% of patients (n = 38) experienced 41 AEs considered at least possibly related to oseltamivir, none being assessed as serious. Overall, there were 79 serious AEs in 59 patients. Eleven discontinued treatment because of an AE. CONCLUSIONS: Oseltamivir has a good tolerability profile in infants and children aged ≤24 months. These findings contributed to the recent FDA approval of oseltamivir for treating infants aged 2-51 weeks.

Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry.

BACKGROUND: Influenza A(H5N1) continues to cause infections and possesses pandemic potential. METHODS: Data sources were primarily clinical records, published case series, and governmental agency reports. Cox proportional hazards regression was used to estimate the effect of treatment on survival, with adjustment using propensity scores (a composite measure of baseline variables predicting use of treatment). RESULTS: In total, 308 cases were identified from 12 countries: 41 from Azerbaijan, Hong Kong SAR, Nigeria, Pakistan, and Turkey (from clinical records); 175 from Egypt and Indonesia (from various sources); and 92 from Bangladesh, Cambodia, China, Thailand, and Vietnam (from various publications). Overall crude survival was 43.5%; 60% of patients who received ≥1 dose of oseltamivir alone (OS(+)) survived versus 24% of patients who had no evidence of anti-influenza antiviral treatment (OS(-)) (P <.001). Survival rates of OS(+) groups were significantly higher than those of OS(-) groups; benefit persisted with oseltamivir treatment initiation

Adjunctive use of anticoagulants at the time of percutaneous coronary intervention in patients with an acute coronary syndrome treated with fondaparinux: a multinational retrospective review.

Aim: This retrospective chart review was designed to evaluate physician adherence to the prescribing information for fondaparinux regarding adjunctive anticoagulant use during percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome (ACS). Methods and results: Medical record abstractors at each site obtained information regarding the use of fondaparinux and adjunctive anticoagulants during PCI. Physician adherence to fondaparinux prescribing information regarding the administration of an adjunctive anticoagulant during PCI was estimated using generalized estimating equations. This retrospective study, conducted in 2008-2010, included a total of 1056 patient records from 27 sites across 6 countries (Canada, France, Germany, Greece, Poland, and Sweden). Over 98% of patients had been treated with fondaparinux at the recommended 2.5 mg dose. Use of adjunctive anticoagulant during PCI was 97.5%, giving an adjusted adherence rate of 98.8% (95% confidence interval: 0.97-0.99), with 86.3% of patients receiving unfractionated heparin. Although the sub-group of patients with ST-elevation myocardial infarction who underwent primary PCI was too small to make a definitive conclusion, 70.4% of the 159 patients did not receive fondaparinux immediately prior to (<24 h) or during primary PCI, suggesting that their treating physicians may have been adherent to the prescribing information. Conclusion: Physician adherence to the prescribing information for adjunctive anticoagulation during PCI in patients with an ACS receiving fondaparinux was high. The results were consistent in each of the six countries and across patient sub-groups.

The long-term international safety experience of imiglucerase therapy for Gaucher disease.

BACKGROUND: Gaucher disease is a lysosomal storage disorder resulting from a deficiency of the lysosomal enzyme glucocerebrosidase. Since approval by the FDA in 1994 and EMEA in 1997, enzyme replacement therapy with Cerezyme (imiglucerase for injection) has been the standard of care for the treatment of Gaucher disease. OBJECTIVE: To review the long-term international safety experience of imiglucerase from 1994 through 2004. MATERIALS AND METHODS: All spontaneous adverse event reports captured in the pharmacovigilance database for imiglucerase from 1994 through 2004 were analyzed. All adverse events were classified using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Patients without prior exposure to imiglucerase from 1994 through 2005 were assessed for the development of antibodies to imiglucerase as detected by enzyme-linked immunosorbant and radioimmunoprecipitation assays. RESULTS: Analysis of the long-term safety experience with imiglucerase therapy demonstrates a stable and low rate of adverse events and seroconversion from 1994 through 2005. The majority of frequently reported adverse events related to imiglucerase were infusion-associated reactions which were predominantly self-limiting in nature and did not require discontinuation of treatment. Between 1994 and 2005, IgG antibodies to imiglucerase were detected in approximately 15% of treatment-naïve patients. CONCLUSIONS: The long-term stability of reported events and seroconversion is a reflection of a well-characterized cell expression system and a mature quality-controlled manufacturing process. Imiglucerase is a safe therapy for the treatment of Gaucher disease with a stable and low rate of reported adverse events and seroconversion.