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OBJECTIVE: To describe and evaluate vigiGroup - a consensus clustering algorithm which can identify groups of individual case reports referring to similar suspected adverse drug reactions and describe associated adverse event profiles, accounting for co-reported adverse event terms.
METHODS: Consensus clustering is achieved by grouping pairs of reports that are repeatedly placed together in the same clusters across a set of mixture model-based cluster analyses. The latter use empirical Bayes statistical shrinkage for improved performance. As baseline comparison, we considered a regular mixture model-based cluster analysis. Three randomly selected drugs in VigiBase, the World Health Organization\'s global database of Individual Case Safety Reports were analyzed: sumatriptan, ambroxol and tacrolimus. Clustering stability was assessed using the adjusted Rand index, ranging between -1 and +1, and clinical coherence was assessed through an intruder detection analysis.
RESULTS: For the three drugs considered, vigiGroup achieved stable and coherent results with adjusted Rand indices between +0.80 and +0.92, and intruder detection rates between 86% and 94%. Consensus clustering improved both stability and clinical coherence compared to mixture model-based clustering alone. Statistical shrinkage improved the stability of clusters compared to the baseline mixture model, as well as the cross-validated log-likelihood.
CONCLUSIONS: The proposed algorithm can achieve adequate stability and clinical coherence in clustering individual case reports, thereby enabling better identification of case series and associated adverse event profiles in pharmacovigilance. The use of empirical Bayes shrinkage and consensus clustering each led to meaningful improvements in performance.

This is a Brighton Collaboration case definition of the term \"Sensorineural Hearing Loss\" to be utilized in the evaluation of adverse events following immunization. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for Lassa Fever and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and define levels of diagnostic certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network.

There is strong evidence of under-reporting of harms in manuscripts on randomized controlled trials (RCTs) compared with the volume of raw data retrieved from these trials. Many guidelines have been developed to tackle this, but they have failed to address some important issues that would allow for standardization and transparency. As a consequence, harms reporting in manuscripts remains suboptimal.
The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) aimed to deliver accurate recommendations for better reporting of harms in clinical trials manuscripts on anti-osteoarthritis (OA) drugs. These could help to better inform clinicians on harms recorded in RCTs and further help researchers conducting meta-analyses.
Using the outcomes of several systematic reviews on the safety of anti-OA drugs, we summarized the ways in which harms have been reported in OA RCT manuscripts to date. Next, we drafted some recommendations and initiated a modified Delphi process that involved a panel of clinicians and clinical researchers to build an expert consensus on recommendations from the ESCEO for the reporting of harms in future manuscripts on RCTs assessing anti-OA drugs.
These recommendations emphasize that all treatment-emergent adverse events (AEs) should always be taken into account for harms reporting, with no frequency threshold, and describe how specific AEs should be reported; they also provide a list of the most relevant organ systems to be considered according to each class of drug for reporting of harms within the results section of a manuscript. Irrespective of the drug, the ESCEO recommends that total, severe and serious AEs and withdrawals due to AEs should always be reported; guidance on the reporting of specific events pertaining to each category is provided. The ESCEO also recommends the reporting of information on drug effect on biological parameters, with specific guidance.
These recommendations may contribute to improve transparency in the field of safety of anti-OA medications. Pharmaceutical companies developing drugs for OA, and researchers conducting clinical trials, are encouraged to comply with them when reporting harms-related results in manuscripts on RCTs. The ESCEO also encourages journals to refer to the ESCEO recommendations in their instructions to authors for the publication of manuscripts on trials of anti-OA medications.

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Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely.
To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA).
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years.
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016.
The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy.
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance\'s (CARRA\'s) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.

To promote establishment of effective ototoxicity monitoring programs (OMPs), this report reviews the U.S. national audiology guidelines in relation to \"real world\" OMP application. Background is provided on the mechanisms, risks and clinical presentation of hearing loss associated with major classes of ototoxic medications.
This is a non-systematic review using PubMed, national and international agency websites, personal communications between ototoxicity experts, and results of unpublished research. Examples are provided of OMPs in various healthcare settings within the U.S. civilian sector, Department of Defense (DoD), and Department of Veterans Affairs (VA).
The five OMPs compared in this report represent a convenience sample of the programs with which the authors are affiliated. Their opinions were elicited via two semi-structured teleconferences on barriers and facilitators of OMP, followed by a self-administered questionnaire on OMP characteristics and practices, with responses synthesized herein. Preliminary results are provided from an ongoing VA clinical trial at one of these OMP sites. Participants were 40 VA patients who received cisplatin chemotherapy in 2014-2017. The study arms contrast access to care for OMP delivered on the treatment unit versus usual care as provided in the audiology clinic.
Protocols of the OMPs examined varied, reflecting their diverse settings. Service delivery concerns included baseline tests missed or completed after the initial treatment, and monitoring tests done infrequently or only after cessation of treatment. Perceived barriers involved logistics related to accessing and testing patients, such as a lack of processes to help patients enter programs, patients\' time and scheduling constraints, and inconvenient audiology clinic locations. Use of abbreviated or screening methods facilitated monitoring.
The most effective OMPs integrated audiological management into care pathways of the clinical specialties that prescribe ototoxic medications. More OMP guidance is needed to inform evaluation schedules, outcome reporting, and determination of actionable ototoxic changes. Guidance is also lacking on the use of hearing conservation approaches suitable for the mass testing needed to support large-scale OMP efforts. Guideline adherence might improve with formal endorsement from organizations governing the medical specialty stakeholders in OMP such as oncologists, pulmonologists, infectious disease specialists, ototolaryngologists and pharmacists.

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