Postmarketing Surveillance Data Research Articles

Myocarditis following the use of different immune checkpoint inhibitor regimens: A real-world analysis of post-marketing surveillance data

BackgroundsAlthough myocarditis has been reported in patients treated with immune checkpoint inhibitors (ICIs), there are few real-world studies to compare the occurrences and characteristics of myocarditis after different ICI regimens. MethodsDisproportionality analysis and Bayesian analysis were utilized for data mining of the suspected adverse events of myocarditis after ICIs use based on the Food and Drug Administration's Adverse Event Reporting System (FAERS) from January 2004 to June 2018. The times to onset and fatality rates of myocarditis following different ICI regimens were also compared. ResultsA total of 315 reports of myocarditis adverse events were identified with ICIs. Among 6 ICI monotherapies, avelumab had the highest association with myocarditis based on the highest reporting odds ratio (ROR = 42.65, 95% two-sided CI = 15.86–114.72), proportional reporting ratio (PRR = 42.61, χ2 = 159.63) and empirical Bayes geometric mean (EBGM = 41.87, 95% one-sided CI = 15.57). The combination therapies of ipilimumab plus pembrolizumab or nivolumab had higher RORs, PRRs and EBGMs than did pembrolizumab or nivolumab monotherapy. Myocarditis associated with the ipilimumab plus nivolumab treatment appeared to have earlier onset (16.5 [IQR 14–29.75] days vs 32 [IQR 16–77] days, p<0.01) and higher fatality rate (65.75% vs 50.40%, p<0.05) than that associated with nivolumab monotherapy. ConclusionsAnalysis of FAERS data provides more precise profile on the occurrences and characteristics of myocarditis after different ICI regimens. The findings support continued surveillance, risk factor identification, and comparative studies.

Drug-Associated Delirium Identified in The Food and Drug Administration Adverse Events Reporting System

Introduction: Drug toxicity and polypharmacy are major risk factors for delirium, especially in older adult patients with underlying comorbidities. However, numerous case reports have described drugs with a lower suspicion of being deliriogenic. The objective of this study was to identify deliriogenic drugs in the Food and Drug Administration Adverse Events Reporting System (FAERS) to broaden the public knowledge and understanding. Study Design: Retrospective pharmacovigilance evaluation. Methods: FAERS reports from 2004 through 2015 were reviewed for delirium-associated terms, which were utilized to identify drugs most frequently reported to cause delirium. Drugs were categorized as: 1) known to be deliriogenic; 2) potentially deliriogenic; or 3) new potential to be deliriogenic. The 100 most frequently reported drugs were analyzed in reporting odds ratios (ROR). Results: Of the known deliriogenic drugs (n=32), paroxetine (ROR 4.1, CI 4.0-4.3), olanzapine (ROR 3.3, CI 3.2-3.4), and clozapine (ROR 2.9, CI 2.8-3.0) were most reported. Of the potentially deliriogenic drugs (n=54), duloxetine (ROR 3.2, CI 3.1-3.3), varenicline (ROR 3.1, CI 3.0-3.2), and gabapentin (ROR 2.9, CI 2.7-3.0) were most reported. Three drugs were considered to have new potential to be deliriogenic: heparin (ROR 1.5, CI 1.4-1.6), metformin (ROR 1.3, CI 1.3-1.4), and dalfampridine (ROR 1.1, CI 1.1-1.2). Conclusion: The majority of drugs were considered potentially deliriogenic. FAERS can provide post-marketing surveillance data to guide future studies on potentially deliriogenic drugs to guide management of causal agents.

Impact of hip arthroplasty registers on orthopaedic practice and perspectives for the future.

Total hip arthroplasty (THA) registers are established in several countries to collect data aiming to improve the results after THA. Monitoring of adverse outcomes after THA has focused mainly on revision surgery, but patient-reported outcomes have also been investigated.Several surgery-related factors influencing the survival of the THA have been thoroughly investigated and have changed clinical practice. These factors include surgical approach, specific implants, the size of the components, type of fixation and different bone cements.Register data have been used to examine the risk of venous thromboembolism and bleeding after THA. These investigations have resulted in shorter duration of thromboprophylaxis and a reduced frequency of blood transfusion.Registers may provide specific information to surgeons on the outcome of all THAs that they have performed with a detailed analysis of revisions rates and reasons for the revisions.A number of other stakeholders can use register data to provide benchmarks. The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man supplies data to the Orthopaedic Device Evaluation Panel (ODEP), which provides benchmarks at 3, 5, 7, 10, and 13 years graded from A*, A, B and C.Future perspectives: National registers have to play a major role in documenting the quality of THA in order to describe best practice and report implant outliers. The registers have to be used for research and post-market surveillance and register data may be a source for intelligent decision tools.Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180091

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data

BackgroundSecukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS).MethodsThe integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab.ResultsA total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs.ConclusionsSecukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Adverse events and modes of failure related to the Impella percutaneous left ventricular assist devices: a retrospective analysis of the MAUDE database.

Robust data on the commonly reported complications and failure modes associated with Impella (Abiomed Inc, Danvers, MA) is limited. We analyzed the post-marketing surveillance data from the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database to assess these

Adverse events and modes of failure related to the FilterWire EZ Embolic Protection System: Lessons learned from an analytic review of the FDA MAUDE database.

To assess the commonly reported complications and failure modes for FilterWire EZ Embolic Protection Devices (EPD) by analyzing the postmarketing surveillance data from the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. EPDs prevent distal embolization of atheroembolic materials during percutaneous interventions resulting in reduced microvascular obstruction and improved microcirculation while maintaining tissue perfusion. The FilterWire EZ EPD (Boston Scientific, Natick, MA) is approved for use in interventions of de novo saphenous vein grafts (SVG) and carotid artery stenosis. Robust data on the commonly reported complications and failure modes associated with the FilterWire EZ device are limited. The MAUDE database was queried from September 1, 2008, through September 30, 2018, for FilterWire EZ system, yielding 474 reports. After exclusion of duplicate and incomplete reports, 464 device reports were included in the final analysis. Device-related adverse events were most commonly reported for carotid (n = 281) and SVG (n = 101) interventions. The most commonly reported major complications were: ischemic stroke (n = 57), vessel perforation or dissection (n = 12), death (n = 8), and myocardial infarction (n = 5). Minor complications included: hypotension (n = 68), bradycardia (n = 41), and vasospasm (n = 27). The most commonly reported failure modes were: detachment and/or damage of the device components (n = 118), device entrapment (n = 90), and stent-related issues (n = 46). Analysis of the MAUDE dataset is helpful in identifying the commonly reported adverse events and failure modes of FilterWire EZ devices. This platform serves as an important tool for both physicians and manufacturers to optimize device performance and clinical outcomes.

Adverse Events and Modes of Failure Related to Impella RP: Insights from the Manufacturer and User Facility Device Experience (MAUDE) Database.

Right ventricular (RV) mechanical circulatory support remains an important adjunctive therapy for RV failure refractory to medical therapy. Impella RP (Abiomed, Danvers, MA) is approved for providing temporary RV support for patients with acute right heart failure or decompensation following left ventricular assist device implantation, myocardial infarction, heart transplant, or open-heart surgery. Robust data on the most commonly reported complications and failure modes for the Impella RP are lacking. We analyzed the post-marketing surveillance data from the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database to assess these endpoints. The MAUDE database was queried for the time period January 1, 2009, through December 31, 2018, for Impella devices by Searching for the following event types: "injury", "malfunction", "death", and "other". The search yielded 436 device reports. Impella RP medical device reports were screened, and 35 reports were included for the final analysis. In cases of reported complications, Impella RP was placed most commonly for right ventricular failure (RVF) developing in postcardiotomy patients (20%). The most commonly reported complications included bleeding (42.9%) and vascular complications (22.8%). The modes of failure included damage or fracture of the device elements (34.2%); thrombus, or clot in the system (17.1%); and device detachment (8.6%). Findings from the MAUDE database highlight the failure modes of the Impella RP device that should be addressed in order to improve the device performance and obtain improved clinical outcomes when utilized for RVF.

Techniques to Optimize the Use of Optical Coherence Tomography: Insights from the Manufacturer and User Facility Device Experience (MAUDE) Database.

Optical coherence tomography (OCT) is a high-resolution intravascular imaging modality used to assess coronary arteries and as an adjunctive tool for optimization of percutaneous coronary interventions. Overall, the rate of complications and adverse events related to intravascular imaging is low. Limited data exist on the most commonly reported complications and modes of failure related to the use of OCT. Therefore, we analyzed the post-marketing surveillance data from the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database to assess the reported complications and failure modes for OCT and reviewed techniques to optimize device use. The MAUDE database was queried for all event reports involving coronary OCT devices. Two independent reviewers identified 49 device reports included in the final analysis. Modes of failure and device-related patient complications were assessed. Of the 49 cases with reported device-related issues, 6.1% involved malfunction prior to insertion of the OCT catheter, and 30.6% of reported events did not result in an associated patient-related adverse event. The most commonly reported adverse events included coronary dissection and difficulty removing the catheter within a previously stented segment. No events of contrast-induced nephropathy were reported. Findings from the MAUDE database highlight the modes of device-related events associated with OCT. Device issues are uncommon, and as a result, users should be aware of optimal techniques to prevent and minimize adverse events related to device use.

ADVERSE EVENTS AND MODES OF FAILURE RELATED TO THE IMPELLA PERCUTANEOUS LEFT VENTRICULAR ASSIST DEVICES: A RETROSPECTIVE ANALYSIS OF THE MAUDE DATABASE

Robust data on the commonly reported complications and failure modes associated with Impella (Abiomed Inc, Danvers, MA) is limited. We analyzed the post-marketing surveillance data from the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database to assess these

Medication Risk Management: A Subjective Review of Present Scenario

Historically, the FDA has interpreted the requirement that a drug must be “safe” to mean that the benefits of a drug outweigh its risks. The determination was made on a “categorical” basis, where the totality of risks was weighted against the totality of benefits when considered for the purposes outlined in the drug product’s labeling. If a drug did not meet this criterion, it was not approved or its label was rewritten to narrow the conditions for use. This logic was endemic in the FDA for most of the 20th century. On average, two to four drugs over each 5-year period were withdrawn from the marketplace after post-marketing surveillance data uncovered new risks. Similarly, on occasion, the FDA would require some special “tool” or intervention to improve a product’s safety profile. Harm associated with medication remains the second most common type of incident in hospitals, as reported by the Clinical Excellence Commission. Health services actively review medication safety. The vast majority of medication errors result in no injury. A minor injury may result, for example, in a patient needing an increased level of monitoring. Even if incidents result in minor injury, managers and staff still take any errors very seriously, reviewing the actions around the incident and making improvements as a result. FDA’s new concepts for risk management amount to a “cultural shift” in the logic of drug approval and the FDA’s role. The key events that led to this change can be traced to a series of reports that highlighted the need for improved medical safety. In 1999, the IOM released a report entitled, “To Err is Human.” This report reviewed the nature and cause of medication errors, estimating that up to 98,000 people died each year due to these errors. In their assessment the IOM included both adverse drug reactions and human errors in drug administration. The report captured the attention of news reporters and the government. Headlines proclaimed alarm at the larger number of fatalities caused by medical errors. Consequently, there was a government-wide initiative started to develop methods and institute procedures to reduce medical errors. Statements made by FDA officials regarding some of these withdrawals suggested that the FDA no longer believed that passive oversight and re-labeling drugs with new warnings was sufficient. Furthermore, the FDA no longer believed that it was sufficient to identify safe conditions of use in the label and that healthcare professionals and patients had to comply with advocated directions of use for the drug to remain on the market.

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management

Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis

Proton pump inhibitors, PPIs, are widely prescribed and sold globally. Although initially intended for time-limited treatment of acute disorders, such as gastric ulcers and esophagitis, PPIs are now commonly used for prolonged durations and are considered safe for over the counter access. Recent studies have raised concern over associations between PPI use and acute kidney injury, chronic kidney disease, end-stage renal disease, and electrolyte abnormalities. The growing concern over potentially serious adverse drug reactions warrants an evaluation of post marketing surveillance data. In this study of over ten million FDA Adverse Event Reporting System records, we provided evidence of kidney injury and electrolyte imbalances in an alarming number of patients taking PPIs. Additionally, we assessed differences between specific PPIs and observed significant electrolyte and renal abnormalities for each individual drug with varying magnitudes.

Risky Technologies: Systemic Uncertainty in Contraceptive Risk Assessment and Management

Focusing on the controversial birth control pills Yaz and Yasmin, this article explores how debates about the safety of these drugs have materialized in risk evaluations and the management of technological risk. Drawing on in-depth interviews with stakeholders and content analysis of legal, medical, and regulatory documents, I highlight how professional contraceptive risk assessment is characterized by systemic uncertainty and doubt, resulting in increased responsibility for users themselves to manage the drugs’ potentially increased risks of venous thromboembolism. The analysis centers on three key areas in the assessment process that denote disagreement: risk measurement in postmarket surveillance data, the distinctiveness of the drugs’ benefits when compared to other contraceptive technologies, and the weighing of the risks and benefits against each other. While professionals negotiate uncertainty both in epidemiological research and in clinical practice, users are constructed as agents who should manage risk individually. Such processes are underlined by a diffusion of responsibility in the systemic management of contraceptive risk. This article suggests, more broadly, that medical technologies can be conceptualized as artifacts that are instrumental in the dispersion of risks.

Medication Risk Management.

Historically, the FDA has interpreted the requirement that a drug must be "safe" to mean that the benefits of a drug outweigh its risks. The determination was made on a "categorical" basis, where the totality of risks was weighted against the totality of benefits when considered for the purposes outlined in the drug product's labeling. If a drug did not meet this criterion, it was not approved or its label was rewritten to narrow the conditions for use. This logic was endemic in the FDA for most of the 20th century. On average, two to four drugs over each 5-year period were withdrawn from the marketplace after post-marketing surveillance data uncovered new risks. Similarly, on occasion, the FDA would require some special "tool" or intervention to improve a product's safety profile. Harm associated with medication remains the second most common type of incident in hospitals, as reported by the Clinical Excellence Commission. Health services actively review medication safety. The vast majority of medication errors result in no injury. A minor injury may result, for example, in a patient needing an increased level of monitoring. Even if incidents result in minor injury, managers and staff still take any errors very seriously, reviewing the actions around the incident and making improvements as a result. FDA's new concepts for risk management amount to a "cultural shift" in the logic of drug approval and the FDA's role. The key events that led to this change can be traced to a series of reports that highlighted the need for improved medical safety. In 1999, the IOM released a report entitled, "To Err is Human." This report reviewed the nature and cause of medication errors, estimating that up to 98,000 people died each year due to these errors. In their assessment, the IOM included both adverse drug reactions and human errors in drug administration. The report captured the attention of news reporters and the government. Headlines proclaimed alarm at the larger number of fatalities caused by medical errors. Consequently, there was a government-wide initiative started to develop methods and institute procedures to reduce medical errors. Statements made by FDA officials regarding some of these withdrawals suggested that the FDA no longer believed that passive oversight and re-labeling drugs with new warnings was sufficient. Furthermore, the FDA no longer believed that it was sufficient to identify safe conditions of use in the label and that healthcare professionals and patients had to comply with advocated directions of use for the drug to remain on the market.

An integrated safety analysis of combined acetaminophen and ibuprofen (Maxigesic ® /Combogesic®) in adults.

IntroductionAcetaminophen (APAP) and ibuprofen (IBP) are two analgesic compounds with a long history of use. Both are considered safe at recommended over-the-counter daily doses. Chronic use, high doses, or concomitant medication can produce safety risks for both drugs. APAP is associated with increased risk of hepatic injury, while IBP can produce gastric bleeding and thromboembolic events. Using a combination of APAP and IBP provides superior analgesia without transgressing daily dose limits of each individual drug.MethodsThe present study aimed to determine if treatment with a fixed-dose combination (FDC) containing APAP and IBP results in any unexpected adverse events (AEs) and/or changes in the safety profiles of its two ingredients compared to monotherapy. The analysis will examine clinical safety data obtained from either single dose trials, multiple dose trials, a long-term exposure trial, and post-marketing surveillance data of APAP/IBP FDC tablets (Maxigesic®/Combogesic®, AFT Pharmaceuticals Ltd). The largest dataset was obtained by pooling the four randomized-controlled, multiple-dose clinical studies with either APAP 325 mg + IBP 97.5 mg (FDC 325/97.5, three tablets per dose) or APAP 500 mg + IBP 150 mg (FDC 500/150, two tablets per dose). At maximum doses, the two FDCs are bioequivalent, permitting the pooling of data for the analysis of safety.ResultsA safety population of 922 patients who received full doses of either FDC, APAP alone, IBP alone, or placebo was compiled from the four studies. A total of 521 AEs were experienced with the incidence of FDC AEs similar to or below either monotherapy group or placebo. The FDC did not alter the incidence and percentage of the most common AEs, including gastrointestinal events and postoperative bleeding.ConclusionOverall, the FDC is well tolerated and has a strong safety profile at single and multiple doses with improved efficacy over monotherapy.

300.08 Safety of Optical Coherence Tomography: Insights from the Manufacturer and User Facility Device Experience (MAUDE) Database

Overall, the rate of complications and adverse events related to intravascular imaging are rare. Limited data exist on the most commonly reported complications and modes of failure related to the use of optical coherence tomography (OCT). We analyzed the post-marketing surveillance data from the

21st Century Cures Act: The Problem with Preemption in Light of Deregulation

The 21st Century Cures Act introduced innovative changes to the Food and Drug Administration’s regulatory processes. In an effort to address the slow, costly, and burdensome approval process for high-risk devices, the Cures Act modernized clinical trial data by allowing reviewers to determine whether devices merit expedited review and to consider post-market surveillance data in the premarket approval process. These changes will get life-saving devices to the people who need them faster than ever before. But the tradeoff is a greater risk of injury to the patient. The 2008 Supreme Court decision Riegel v. Medtronic, Inc., held that any device receiving premarket approval is federally preempted from state tort claims. This means injured patients of medical device malfunctions are barred from seeking remedy against the manufacturers. Thus, the Cures Act potentially puts patients at greater risk but does nothing to provide those patients remedies for injury. This Note argues that federal preemption for medical devices receiving premarket approval should be reconsidered. Because the regulatory framework for which Riegel was decided has now shifted, the Court should reevaluate its prior ruling. Additionally, Congress should amend the preemption clause in the Food, Drug, and Cosmetic Act to allow for state tort action. Finally, Congress should create a victim compensation fund, run by HHS, to allow victims to make no-fault injury claims and receive payments for their suffering.

The Alzheimer's comorbidity phenome: mining from a large patient database and phenome-driven genetics prediction.

ObjectiveAlzheimer’s disease (AD) is a severe neurodegenerative disorder and has become a global public health problem. Intensive research has been conducted for AD. But the pathophysiology of AD is still not elucidated. Disease comorbidity often associates diseases with overlapping patterns of genetic markers. This may inform a common etiology and suggest essential protein targets. US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collects large-scale postmarketing surveillance data that provide a unique opportunity to investigate disease co-occurrence pattern. We aim to construct a heterogeneous network that integrates disease comorbidity network (DCN) from FAERS with protein–protein interaction (PPI) to prioritize the AD risk genes using network-based ranking algorithm.Materials and MethodsWe built a DCN based on indication data from FAERS using association rule mining. DCN was further integrated with PPI network. We used random walk with restart ranking algorithm to prioritize AD risk genes.ResultsWe evaluated the performance of our approach using AD risk genes curated from genetic association studies. Our approach achieved an area under a receiver operating characteristic curve of 0.770. Top 500 ranked genes achieved 5.53-fold enrichment for known AD risk genes as compared to random expectation. Pathway enrichment analysis using top-ranked genes revealed that two novel pathways, ERBB and coagulation pathways, might be involved in AD pathogenesis.ConclusionWe innovatively leveraged FAERS, a comprehensive data resource for FDA postmarket drug safety surveillance, for large-scale AD comorbidity mining. This exploratory study demonstrated the potential of disease-comorbidities mining from FAERS in AD genetics discovery.

Large-scale mining disease comorbidity relationships from post-market drug adverse events surveillance data

BackgroundSystems approaches in studying disease relationship have wide applications in biomedical discovery, such as disease mechanism understanding and drug discovery. The FDA Adverse Event Reporting System (FAERS) contains rich information about patient diseases, medications, drug adverse events and demographics of 17 million case reports. Here, we explored this data resource to mine disease comorbidity relationships using association rule mining algorithm and constructed a disease comorbidity network.ResultsWe constructed a disease comorbidity network with 1059 disease nodes and 12,608 edges using association rule mining of FAERS (14,157 rules). We evaluated the performance of comorbidity mining from FAERS using known disease comorbidities of multiple sclerosis (MS), psoriasis and obesity that represent rare, moderate and common disease respectively. Comorbidities of MS, obesity and psoriasis obtained from our network achieved precisions of 58.6%, 73.7%, 56.2% and recalls 87.5%, 69.2% and 72.7% separately. We performed comparative analysis of the disease comorbidity network with disease semantic network, disease genetic network and disease treatment network. We showed that (1) disease comorbidity clusters exhibit significantly higher semantic similarity than random network (0.18 vs 0.10); (2) disease comorbidity clusters share significantly more genes (0.46 vs 0.06); and (3) disease comorbidity clusters share significantly more drugs (0.64 vs 0.17). Finally, we demonstrated that the disease comorbidity network has potential in uncovering novel disease relationships using asthma as a case study.ConclusionsOur study presented the first comprehensive attempt to build a disease comorbidity network from FDA Adverse Event Reporting System. This network shows well correlated with disease semantic similarity, disease genetics and disease treatment, which has great potential in disease genetics prediction and drug discovery.

388. Characteristics and outcomes of prospectively reported pregnancies exposed to certolizumab pegol from a safety database

Introduction Anti-tumour necrosis factor (anti-TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNFs are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc-free anti-TNF approved for treatment of rheumatic diseases and/or Crohn’s disease, has no active placental transfer. Objective/Hypothesis To provide information on pregnancy outcomes in women receiving CZP, especially those with early pregnancy exposure. Methods Prospective and retrospective data on maternal CZP exposure, including timing and duration, outcomes, comorbidities, and major malformations were extracted from the UCB Pharma safety database through 6 March 2017. This analysis was limited to prospective reports to avoid bias associated with retrospective submissions. Numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. Results From a total of 1541 maternal CZP-exposed pregnancies, 1137 were reported prospectively, of which 528 pregnancies (including 10 twins) had 538 known outcomes: 459 live births (85%), 47 miscarriages (9%), 27 elective abortions (5%), and 5 stillbirths (1%). Of the 459 live births, 8 (2%) cases of major congenital malformations were reported. Of the 528 prospective pregnancies with known outcomes, 436 (83%) were exposed to CZP during the 1st trimester, when most organogenesis occurs; 201 (45%) pregnancies were exposed during all 3 trimesters. Discussion This analysis represents the largest published cohort of pregnant women exposed to an anti-TNF for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a malformative effect of CZP compared to the EU general population (2–3%), nor an increased risk of foetal death. These data are reassuring for women of childbearing age considering treatment with CZP, however, the ongoing collection of post-marketing surveillance data, including the ongoing MotherToBaby study from the Organization of Teratology Information Specialists, will provide further important information.