M. L. De Bruin

Use of the conditional marketing authorization pathway for oncology medicines in Europe

Conditional marketing authorization (CMA) in the European Union (EU) is an early access pathway for medicines that show promising therapeutic effects, but for which comprehensive data are not available. Using a mixed quantitative‐qualitative research design, we evaluated how CMA has been used in marketing authorization of oncology medicines in the period 2006 to 2013. We show that compared to full marketing authorization, CMA is granted based on less comprehensive data. However, this is accompanied by significantly longer assessment times and less consensus among regulators about marketing authorization. Moreover, development time from first‐in‐human testing to marketing authorization did not differ between full marketing authorization and CMA, but was significantly longer for CMA compared to accelerated approved products in the United States (US). Results indicate that CMA is not used by companies as a prospectively planned pathway to obtain early access, but as a “rescue option” when submitted data are not strong enough to justify full marketing authorization.

The risk of venous thromboembolism in patients with multiple sclerosis: the Clinical Practice Research Datalink

In patients with multiple sclerosis (MS), disability and autoinflammatory processes may result in an increased risk of venous thromboembolism (VTE)

Risk Management Plans as a Tool for Proactive Pharmacovigilance: A Cohort Study of Newly Approved Drugs in Europe

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk‐proportionate pharmacovigilance planning.

Drug-Induced Progressive Multifocal Leukoencephalopathy : Lessons Learned From Contrasting Natalizumab and Rituximab

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety.

Reduced in-hospital survival rates of out-of-hospital cardiac arrest victims with obstructive pulmonary disease ☆

AIM Out-of-hospital cardiac arrest (OHCA) due to sustained ventricular tachycardia/fibrillation (VT/VF) is common and often lethal. Patients co-morbidities may determine survival after OHCA, and be instrumental in post-resuscitation care, but are poorly studied. We aimed to study whether patients with obstructive pulmonary disease (OPD) have a lower survival rate after OHCA than non-OPD patients. METHODS We performed a community-based cohort study of 1172 patients with non-traumatic OHCA with ECG-documented VT/VF between 2005 and 2008. We compared survival to emergency room (ER), to hospital admission, to hospital discharge, and at 30 days after OHCA, of OPD-patients and non-OPD patients, using logistic regression analysis. We also compared 30-day survival of patients who were admitted to hospital, using multivariate logistic regression analysis. RESULTS OPD patients (n=178) and non-OPD patients (n=994) had comparable survival to ER (75% vs. 78%, OR 0.9 [95% CI: 0.6-1.3]) and to hospital admission (56% vs. 57%, OR 1.0 [0.7-1.4]). However, survival to hospital discharge was significantly lower among OPD patients (21% vs. 33%, OR 0.6 [0.4-0.9]). Multivariate regression analysis among patients who were admitted to hospital (OPD: n=100, no OPD: n=561) revealed that OPD was an independent determinant of reduced 30-day survival rate (39% vs. 59%, adjusted OR 0.6 [0.4-1.0, p=0.035]). CONCLUSION OPD-patients had lower survival rates after OHCA than non-OPD patients. Survival to ER and to hospital admission was not different between both groups. However, among OHCA victims who survived to hospital admission, OPD was an independent determinant of reduced 30-day survival rate.

Use of incretin agents and risk of pancreatic cancer: a population‐based cohort study

To investigate the association between the use of incretin agents and the risk of pancreatic cancer.

Genetic, clinical and pharmacological determinants of out-of-hospital cardiac arrest: rationale and outline of the AmsteRdam Resuscitation Studies (ARREST) registry

Introduction Out-of-hospital cardiac arrest (OHCA) is a major public health problem. Recognising the complexity of the underlying causes of OHCA in the community, we aimed to establish the clinical, pharmacological, environmental and genetic factors and their interactions that may cause OHCA. Methods and analysis We set up a large-scale prospective community-based registry (AmsteRdam Resuscitation Studies, ARREST) in which we prospectively include all resuscitation attempts from OHCA in a large study region in the Netherlands in collaboration with Emergency Medical Services. Of all OHCA victims since June 2005, we prospectively collect medical history (through hospital and general practitioner), and current and previous medication use (through community pharmacy). In addition, we include DNA samples from OHCA victims with documented ventricular tachycardia/fibrillation during the resuscitation attempt since July 2007. Various study designs are employed to analyse the data of the ARREST registry, including case–control, cohort, case only and case-cross over designs. Ethics and dissemination We describe the rationale, outline and potential results of the ARREST registry. The design allows for a stable and reliable collection of multiple determinants of OHCA, while assuring that the patient, lay-caregiver or medical professional is not hindered in any way. Such comprehensive data collection is required to unravel the complex basis of OHCA. Results will be published in peer-reviewed journals and presented at relevant scientific symposia.

Safety learning from drugs of the same class: room for improvement.

This study was aimed at assessing the extent of safety learning from data pertaining to other drugs of the same class. We studied drug classes for which the first and second drugs were centrally registered in the European Union from 1995 to 2008. We assessed whether adverse drug reactions (ADRs) associated with one of the drugs also appeared in the Summary of Product Characteristics (SPC) of the other drug, either initially or during the postmarketing phase. We identified 977 ADRs from 19 drug pairs, of which 393 ADRs (40.2%) were listed in the SPCs of both drugs of a pair. Of these 393 that were present in both SPCs of a drug pair, 241 (61.3%) were present when the drug entered the market and 152 (30.7%) appeared in the postmarketing phase. The mention of ADRs in the SPCs of both same‐class drugs in the postmarketing phase was associated with type A ADRs, marketing in the same regulator country, a longer time interval between entry into the market by the two drugs, and an earlier date of ADR. Although there appears to be some degree of safety learning from same‐class drugs, there is still room for improvement, possibly by increasing proactive risk management.

Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization.

THU0090 Cardiovascular Morbidity in Patients with Ankylosing Spondylitis: A Population-Based Cohort Study

Background It is well recognized that rheumatoid arthritis is an independent risk factor for cardiovascular (CV) disease. For ankylosing spondylitis (AS), the literature on this risk is relatively scarce, and shows conflicting results. Furthermore, these studies did not explore the role of non-steroidal anti-inflammatory drugs (NSAIDs) use. Objectives To examine the incidence and risk of ischemic heart disease (IHD) and acute myocardial infarction (AMI) in patients with AS compared with population-based controls, and explore the role of recent NSAID use. Methods All incident patients with AS from the UK Clinical Practice Research Datalink (1987-2012) were matched with up to 7 persons without AS by year of birth, sex and practice. Incidence rates, cumulative incidence rates and hazard ratios (HR) for the development of IHD and AMI were calculated, with time-varying adjustments for age, sex, comorbidity and drug use. When further exploring the role of NSAIDs on the risk of IHD, patients with AS were stratified according to the use of coxibs, naproxen or other traditional NSAIDs in the previous 3 months. Results In total, 3,809 patients with AS (mean age at index date 43.7 years, 70.5% male, median duration of follow-up 6.6 years) were matched with 26,197 control subjects. At baseline, 4.3% of the patients had IHD compared with 3.4% of the controls (p-value<0.01), and 1.8% of the patients had AMI compared with 1.4% of the controls (p-value=0.02). After excluding patients with IHD and/or AMI at baseline, the incidence rates were 1.2/1000 person years (pys) and 0.9/1000 pys for IHD and AMI, respectively. The age-gender adjusted (adj.) HR of developing IHD was 1.2 (95% Confidence interval [CI] 1.0-1.5), and for AMI 0.9 (95% CI 0.7-1.3). After statistical adjustment for recent use of NSAIDs, the increased risk of IHD disappeared (adj. HR 1.1 95% CI 0.9-1.3). In the fully adjusted model, the risk remained almost unchanged (adj. HR 1.0, 95% CI 0.8-1.3). In patients with AS, stratification according to the use of coxibs, naproxen or other NSAIDs, showed that exposure to NSAIDs other than naproxen or coxibs increased the risk of IHD to 1.5 (95% CI 1.1-2.1) compared with controls irrespective of their NSAID use. However, within patients with AS this risk was not different from AS patients who did not use NSAIDs other than naproxen or coxibs (p=0.17). Conclusions Patients with AS seemed at increased risk of developing IHD, but this effect could be attributed to their recent NSAID use. Although it cannot be excluded that NSAID use is (partly) a reflection of disease activity, rheumatologists should carefully balance the beneficial effects of NSAIDs and the increased risk of IHD. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1853