Mining Electronic Healthcare Record Databases to Augment Drug Safety Surveillance

It is perhaps a fundamental truth in medicine that there is no intervention – be it a drug, a medical device or a procedure – that is without risks. Even with the most rigorous eff orts in drug approval and regulation, there is not a drug out there that is 100% safe under all conditions. Randomized controlled trials (RCTs) are considered to be the most stringent approach to determining cause-and-eff ect relationship between an intervention and an outcome, but such trials are rarely designed or powered to detect uncommon or unexpected adverse events.1-4 Once drugs are marketed, they are used in a more diverse group of people, oft en for much longer periods, and sometimes with a wider range of therapeutic indications. While monitoring the risks associated with drug use has come a long way since the thalidomide disaster in the 1960s and the institution of spontaneous reporting systems (SRS), it has become evident that adverse eff ects of drugs may be detected - and acted upon – too late, when millions of persons have already been exposed.5-6 Th ere has been a growing clamor for improving the current passive-reactive paradigm of drug safety surveillance. Prominent issues in the last few years have emphasized the importance of a life-cycle approach to drug safety monitoring and the need to explore new methods to improve surveillance of drugs post-marketing.7-8 It has been posited that electronic healthcare record (EHR) databases represent an important resource for proactive surveillance and can augment existing pharmacovigilance systems. Various public-private initiatives worldwide have been launched, and great investments have been made, to explore the secondary use of EHR for this purpose.9-10 In this thesis, we draw on the experience of the EU-ADR network (Exploring and Understanding Adverse Drug Reactions by Integrative Mining of Clinical Records and Biomedical Knowledge, http://www.euadr-project.org/), a federation of eight EHR databases in four countries in Europe, to demonstrate the feasibility of combining diverse and diff erently structured data and pave the way for large-scale drug safety monitoring. We describe the opportunities and challenges that come with heterogeneity in database structure, with diff erences in language and coding of both drugs and diseases, and with the diversity in the organization of European healthcare systems

Phase 0 clinical trials: Theoretical and practical implications in oncologic drug development

Drug discovery and development has become a risky, expensive, and protracted process, with the cost of introducing a new drug to the market going as high as US$2 billion and the entire process taking at least 10-15 years. Great advances in biomedical research in recent years have not resulted in translation into medical product development, and there has been substantial decline in both new drug applications and biological license applications. To address this so-called "pipeline problem," both the US Food and Drug Administration and its European counterpart, the European Agency for the Evaluation of Medicinal Products (now European Medicines Agency) endorsed the concept of Phase 0 studies (also known as exploratory investigational new drug studies), aimed towards identifying, early in the process of drug development, viable candidates and eliminating those lacking promise. Primary study endpoints of trials conducted under an exploratory investigational new drug can include evaluation of analogs for lead selection, modulation of a molecular target in vivo, whole-body imaging for tissue distribution/target binding affinity, and agent pharmacokinetics. Phase 0 trials bridge the gap between traditional preclinical testing and clinical studies and are intended to provide a better understanding of a new compound's pharmacokinetics, pharmacodynamics, and target localization before initiation of Phase I trials. When such information can be obtained earlier, decisions regarding drug development can also be made at an earlier point in time, potentially reducing costs of initial preclinical studies and time-to-first-in-human testing. This review provides an overview of the various conditions that have to be met in order for a Phase 0 trial to be successful, citing examples of two candidate drugs that have been further developed after Phase 0 trials in oncology. Challenges and opportunities with Phase 0 trials are discussed, including ethical issues associated with trials that have no therapeutic or diagnostic intent

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textabstractIntroduction: There is growing interest in whether social media can capture patient-generated information relevant for medicines safety surveillance that cannot be found in traditional sources. Objective: The aim of this study was to evaluate the potential contribution of mining social media networks for medicines safety surveillance using the following associations as case studies: (1) rosiglitazone and cardiovascular events (i.e. stroke and myocardial infarction); and (2) human papilloma virus (HPV) vaccine and infertility. Methods: We collected publicly accessible, English-language posts on Facebook, Google+, and Twitter until September 2014. Data were queried for co-occurrence of keywords related to the drug/vaccine and event of interest within a post. Messages were analysed with respect to geographical distribution, context, linking to other web content, and author’s assertion regarding the supposed association. Results: A total of 2537 posts related to rosiglitazone/cardiovascular events and 2236 posts related to HPV vaccine/infertility were retrieved, with the majority of posts representing data from Twitter (98 and 85 %, respectively) and originating from users in the US. Approximately 21 % of rosiglitazone-related posts and 84 % of HPV vaccine-related posts referenced other web pages, mostly news items, law firms’ websites, or blogs. Assertion analysis predominantly showed affirmation of the association of rosiglitazone/cardiovascular events (72 %; n = 1821) and of HPV vaccine/infertility (79 %; n = 1758). Only ten posts described personal accounts of rosiglitazone/cardiovascular adverse event experiences, and nine posts described HPV vaccine problems related to infertility. Conclusions: Publicly available data from the considered social media networks were sparse and largely untrackable for the purpose of providing early clues of safety concerns regarding the prespecified case studies. Further research investigating other case studies and exploring other social media platforms are necessary to further characterise the usefulness of social media for safety surveillance

Evaluating the Safety Profile of Non-Active Implantable Medical Devices Compared with Medicines

Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit–risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features of the drug safety evaluation process could, if adopted and adapted for NAIMDs, lead to better and more systematic evaluations of the latter

NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: A populationbased case-control study

Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), low-dose aspirin and statins may decrease the risk of oesophageal adenocarcinoma (OAC) among patients with Barrett's oesophagus (BO). However, previous studies did not adequately address bias and confounding. Our objective was to estimate the risk of OAC among patients with BO exposed to NSAIDs, statins and PPIs. Design: Case-control study nested within a BO cohort. Setting: Two primary care databases (the UK and the Netherlands (NL)). Participants: Cases were adults ≥18 years of age with OAC or high-grade dysplasia (HGD) diagnosis ≥1 year after BO diagnosis. Controls were matched on age, sex, year of BO diagnosis and database. Exposure: Drug use was assessed from BO diagnosis until matching date. Outcome measure: Adjusted ORs with 95% CI were calculated by conditional logistic regression. Results: Within the BO cohort (n=15 134), 45 OAC (UK: 40, NL: 5) and 12 HGD cases (NL: 12) were identified. ORa for OAC during NSAID use was 1.2 (95% CI 0.6 to 2.5) and during statin use for <3 years 0.5 (95% CI 0.1 to 1.7). When including HGD cases (n=57), ORa for NSAID use was 0.9 (95% CI 0.5 to 1.8) and for statin use <3 years 0.5 (95% CI 0.1 to 1.7). Higher doses of statins showed lower estimates for OAC and HGD, though not statistically significant. Low-dose aspirin and PPIs did not significantly decrease the risk of OAC and HGD. Conclusions: In this population-based nested case- control study, use of NSAIDs, PPIs, low-dose aspirin or statins did not reduce the risk of HGD and OAC among patients with BO. These findings indicate that for an unselected group of patients with BO chemoprevention by use of drugs to reduce progression to HGD and OAC should not be directly considered as routine care

Using Electronic Health Care Records for Drug Safety Signal Detection A Comparative Evaluation of Statistical Methods

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Useful Interplay Between Spontaneous ADR Reports and Electronic Healthcare Records in Signal Detection

Background and Objective: Spontaneous reporting systems (SRSs) remain the cornerstone of post-marketing drug safety surveillance despite their well-known limitations. Judicious use of other available data source