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Preciosa M ColomaDepartment of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The NetherlandsAbstract: 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.Keywords: pre-Phase I studies, exploratory IND, microdosing, oncology, cancer drug development

Objective: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED)., Methods: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17). Key safety outcomes included treatment-emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue)., Results: Sixty-eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: -2.93) and nivasorexant (LSM: -2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): -.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo., Discussion: In this proof-of-concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED., Public Significance: The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin-1 receptor in BED., (© 2023 Wiley Periodicals LLC.)

Despite progress in understanding the pathological mechanisms underlying psychiatric disorders, translation from animal models into clinical use remains a significant bottleneck. Preclinical studies have implicated the orexin neuropeptide system as a potential target for psychiatric disorders through its role in regulating emotional, cognitive, and behavioral processes. Clinical studies are investigating orexin modulation in addiction and mood disorders. Here we review performance-outcome measures (POMs) arising from experimental medicine research methods which may show promise as markers of efficacy of orexin receptor modulators in humans. POMs provide objective measures of brain function, complementing patient-reported or clinician-observed symptom evaluation, and aid the translation from preclinical to clinical research. Significant challenges include the development, validation, and operationalization of these measures. We suggest that collaborative networks comprising clinical practitioners, academics, individuals working in the pharmaceutical industry, drug regulators, patients, patient advocacy groups, and other relevant stakeholders may provide infrastructure to facilitate validation of experimental medicine approaches in translational research and in the implementation of these approaches in real-world clinical practice., Competing Interests: Declaration of interest Amy C. Beckenstrom: Part-time employee of P1vital Ltd. Preciosa M. Coloma: Full-time employee of, and owns shares at, Idorsia Pharmaceuticals Ltd. Gerard R. Dawson: Full-time employee of P1vital Ltd. Ailidh K. Finlayson: Part-time employee of P1vital Ltd. Asad Malik: Full-time employee of P1vital Ltd. Anke Post: None. Michel Alexander Steiner: Full-time employee of, and owns shares at, Idorsia Pharmaceuticals Ltd. Marc N. Potenza: Dr. Potenza has consulted for Opiant Therapeutics, Game Day Data, Baria-Tek, the Addiction Policy Forum, AXA and Idorsia Pharmaceuticals; has been involved in a patent application with Yale University and Novartis; has received research support from Mohegan Sun Casino and the Connecticut Council on Problem Gambling; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse-control disorders or other health topics; has consulted for and/or advised gambling and legal entities on issues related to impulsive, compulsive and addictive disorders; has edited journals and journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts. Conflict of interest statement Dr. Potenza discloses the following. Dr. Potenza has consulted for Opiant Therapeutics, Game Day Data, Baria-Tek, the Addiction Policy Forum, AXA and Idorsia Pharmaceuticals; has been involved in a patent application with Yale University and Novartis; has received research support from Mohegan Sun Casino and the Connecticut Council on Problem Gambling; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse-control disorders or other health topics; has consulted for and/or advised gambling and legal entities on issues related to impulsive, compulsive and addictive disorders; has edited journals and journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts. Dr Coloma and Dr Steiner are full-time employees of, and own shares at, Idorsia Pharmaceuticals Ltd. Dr Malik and Dr Dawson are full-time employees of P1vital Ltd. Dr Beckenstrom and Dr Finlayson are part-time employees of P1vital Ltd. The other authors do not report disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.

Background: Huntington's disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging., Objective: To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel., Methods: Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population., Results: The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4-15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits., Conclusion: This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research.

Background: Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age)., Methods: The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status., Results: Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-)., Conclusions: Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The National Institute on Aging and Alzheimer's Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer's disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer's disease., Objectives: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N))., Design: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers., Setting: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study., Participants: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable., Measurements: Three CSF biomarkers, namely amyloid β1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test - Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores., Results: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework's definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures., Conclusions: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials., Competing Interests: Samantha C. Burnham: reports speaker honoraria from Novartis outside the scope of the submitted work and research funding paid to her employers from F. Hoffmann-La Roche Ltd. Preciosa M. Coloma: is a full-time employee of, and own shares in, F. Hoffmann-La Roche Ltd. Simon Laws: received personal fees from Alzhyme outside the scope of the submitted work. James Doecke: reports research funding paid to his employers from F. Hoffmann-La Roche Ltd. David Ames: reports receipt of financial assistance to his employer to assist with an international drug trial of an anti-Alzheimer’s agent, owned by Eli Lilly. Christopher C. Rowe: reports speaker honoraria from GE Healthcare and Avid Radiopharmaceuticals, consulting fees from Avid Radiopharmaceuticals, AstraZeneca, and Piramal Imaging, and research grants from Avid Radiopharmaceuticals, GE Healthcare, and Piramal Imaging all outside the scope of the submitted work. Colin L. Masters: reports personal fees from Prana Biotechnology, Eli Lilly, and Actinogen outside the scope of the submitted work. Victor L. Villemagne: reports speaker honoraria from GE Healthcare, Piramal Imaging, and Avid Radiopharmaceuticals, and consulting fees from Lundbeck, AbbVie, Shanghai Green Valley Pharmaceutical Co. outside the scope of the submitted work and consulting fees from F. Hoffmann-La Roche Ltd. All other authors declare no conflicts of interest

Objectives: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI))., Design: Cross-sectional., Setting: Olmsted County, Minnesota., Participants: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C-Pittsburgh compound B ( 11 C-PiB) positron emission tomography (PET) (N=1,782)., Measurements: We defined an abnormal (high) 11 C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ)., Results: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z-score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants., Conclusion: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274-2281, 2018., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Background: Several initiatives have assessed if mining electronic health records (EHRs) may accelerate the process of drug safety signal detection. In Europe, Exploring and Understanding Adverse Drug Reactions (EU-ADR) Project Focused on utilizing clinical data from EHRs of over 30 million patients from several European countries. Rofecoxib is a prescription COX-2 selective Non-Steroidal Anti-Inflammatory Drugs (NSAID) approved in 1999. In September 2004, the manufacturer withdrew rofecoxib from the market because of safety concerns. In this study, we investigated if the signal concerning rofecoxib and acute myocardial infarction (AMI) could have been identified in EHR database (EU-ADR project) earlier than spontaneous reporting system (SRS), and in advance of rofecoxib withdrawal. Methods: Data from the EU-ADR project and WHO-VigiBase (for SRS) were used for the analysis. Signals were identified when respective statistics exceeded defined thresholds. The SRS analyses was conducted two ways- based on the date the AMI events with rofecoxib as a suspect medication were entered into the database and also the date that the AMI event occurred with exposure to rofecoxib. Results: Within the databases participating in EU-ADR it was possible to identify a strong signal concerning rofecoxib and AMI since Q3 2000 [RR LGPS = 4.5 (95% CI: 2.84-6.72)] and peaked to 4.8 in Q4 2000. In WHO-VigiBase, for AMI term grouping, the EB05 threshold of 2 was crossed in the Q4 2004 (EB05 = 2.94). Since then, the EB05 value increased consistently and peaked in Q3 2006 (EB05 = 48.3) and then again in Q2 2008 (EB05 = 48.5). About 93% (2260 out of 2422) of AMIs reported in WHO-VigiBase database actually occurred prior to the product withdrawal, however, they were reported after the risk minimization/risk communication efforts. Conclusion: In this study, EU-EHR databases were able to detect the AMI signal 4 years prior to the SRS database. We believe that for events that are consistently documented in EHR databases, such as serious events or events requiring in-patient medical intervention or hospitalization, the signal detection exercise in EHR would be beneficial for newly introduced medicinal products on the market, in addition to the SRS data.

We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Recent reports have suggested declining age-specific incidence rates of dementia in high-income countries over time. Improved education and cardiovascular health in early age have been suggested to be bringing about this effect. The aim of this study was to estimate the age-specific dementia incidence trend in primary care records from a large population in the Netherlands., Methods and Findings: A dynamic cohort representative of the Dutch population was composed using primary care records from general practice registration networks (GPRNs) across the country. Data regarding dementia incidence were obtained using general-practitioner-recorded diagnosis of dementia within the electronic health records. Age-specific dementia incidence rates were calculated for all persons aged 60 y and over; negative binomial regression analysis was used to estimate the time trend. Nine out of eleven GPRNs provided data on more than 800,000 older people for the years 1992 to 2014, corresponding to over 4 million person-years and 23,186 incident dementia cases. The annual growth in dementia incidence rate was estimated to be 2.1% (95% CI 0.5% to 3.8%), and incidence rates were 1.08 (95% CI 1.04 to 1.13) times higher for women compared to men. Despite their relatively low numbers of person-years, the highest age groups contributed most to the increasing trend. There was no significant overall change in incidence rates since the start of a national dementia program in 2003 (-0.025; 95% CI -0.062 to 0.011). Increased awareness of dementia by patients and doctors in more recent years may have influenced dementia diagnosis by general practitioners in electronic health records, and needs to be taken into account when interpreting the data., Conclusions: Within the clinical records of a large, representative sample of the Dutch population, we found no evidence for a declining incidence trend of dementia in the Netherlands. This could indicate true stability in incidence rates, or a balance between increased detection and a true reduction. Irrespective of the exact rates and mechanisms underlying these findings, they illustrate that the burden of work for physicians and nurses in general practice associated with newly diagnosed dementia has not been subject to substantial change in the past two decades. Hence, with the ageing of Western societies, we still need to anticipate a dramatic absolute increase in dementia occurrence over the years to come.

Purpose: In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks., Methods: A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories., Results: From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1-16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products., Conclusions: There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

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., Competing Interests: Compliance with Ethical Standards Funding No sources of funding were used to assist in the preparation of this study. Conflict of interest Josep Pane and Irene Rebollo are employees of Alcon, Novartis which manufactures NAIMDs. Preciosa Coloma, Katia Verhamme and Miriam Sturkenboom have no conflicts of interest that are directly relevant to the content of this study.

Most approaches used in postmarketing drug safety monitoring, including spontaneous reporting and statistical risk identification using electronic health care records, are primarily suited to pick up only acute adverse drug effects. With the availability of increasingly larger electronic health record and administrative claims databases comes the opportunity to monitor for potential adverse effects that occur only after prolonged exposure to a drug, but analysis methods are lacking. We propose an adaptation of the self-controlled case series design that uses the notion of accumulated exposure to capture long-term effects of drugs and evaluate extensions to correct for age and recurrent events. Several variations of the approach are tested on simulated data and two large insurance claims databases. To evaluate performance a set of positive and negative control drug-event pairs was created by medical experts based on drug product labels and review of the literature. Performance on the real data was measured using the area under the receiver operator characteristics curve. The best performing method achieved an area under the receiver operator characteristics curve of 0.86 in the largest database using a spline model, adjustment for age, and ignoring recurrent events, but it appears this performance can only be achieved with very large data sets., (© The Author(s) 2014.)

Unlabelled: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy., Introduction: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data., Methods: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates., Results: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses., Conclusions: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

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 sources is essential to enable better detection, strengthening and validation of signals. In this study, we investigated the potential of electronic healthcare records (EHRs) to be used alongside an SRS as an independent system, with the aim of improving signal detection., Methods: A signal detection strategy, focused on a limited set of adverse events deemed important in pharmacovigilance, was performed retrospectively in two data sources-(1) the Exploring and Understanding Adverse Drug Reactions (EU-ADR) database network and (2) the EudraVigilance database-using data between 2000 and 2010. Five events were considered for analysis: (1) acute myocardial infarction (AMI); (2) bullous eruption; (3) hip fracture; (4) acute pancreatitis; and (5) upper gastrointestinal bleeding (UGIB). Potential signals identified in each system were verified using the current published literature. The complementarity of the two systems to detect signals was expressed as the percentage of the unilaterally identified signals out of the total number of confirmed signals. As a proxy for the associated costs, the number of signals that needed to be reviewed to detect one true signal (number needed to detect [NND]) was calculated. The relationship between the background frequency of the events and the capability of each system to detect signals was also investigated., Results: The contribution of each system to signal detection appeared to be correlated with the background incidence of the events, being directly proportional to the incidence in EU-ADR and inversely proportional in EudraVigilance. EudraVigilance was particularly valuable in identifying bullous eruption and acute pancreatitis (71 and 42 % of signals were correctly identified from the total pool of known associations, respectively), while EU-ADR was most useful in identifying hip fractures (60 %). Both systems contributed reasonably well to identification of signals related to UGIB (45 % in EudraVigilance, 40 % in EU-ADR) but only fairly for signals related to AMI (25 % in EU-ADR, 20 % in EudraVigilance). The costs associated with detection of signals were variable across events; however, it was often more costly to detect safety signals in EU-ADR than in EudraVigilance (median NNDs: 7 versus 5)., Conclusion: An EHR-based system may have additional value for signal detection, alongside already established systems, especially in the presence of adverse events with a high background incidence. While the SRS appeared to be more cost effective overall, for some events the costs associated with signal detection in the EHR might be justifiable.

Introduction: 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.