How Aggregate Safety Assessment Planning Supports Investigational New Drug Safety Reporting Decisions.

In June 2021, FDA released a Draft Guidance on Sponsor Responsibilities for IND Safety Reporting and cited components of a recommended Safety Surveillance Plan (SSP). To meet the expectations of the 2021 FDA guidance, sponsors should document their plan for aggregate safety assessment. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group has proposed an Aggregate Safety Assessment Plan (ASAP) that addresses this recommendation. The 2021 FDA guidance also discusses potential strategies for unblinded review of safety data from ongoing studies by an independent Assessment Entity, which could occur via planned periodic evaluations or "triggered" reviews based on blinded data assessments. The Assessment Entity reviewing unblinded data makes recommendations as to whether the threshold has been met for submission of an aggregate IND safety report. In this paper, we discuss how the ASAP supports IND aggregate safety reporting decisions, including elements to be included in a proposed SSP appendix to the ASAP. In addition, the authors advocate for the benefits of developing a charter (or specific section of the Data Monitoring Committee charter, if applicable) that describes the responsibilities and conduct of the Assessment Entity. With these components in place, study sponsors will meet the objective of having clearly defined processes for the monitoring of clinical trial safety data in aggregate and making IND safety reporting decisions.

Fibrosing Mediastinitis Caused by Histoplasmosis in an Adolescent.

Fibrosing mediastinitis (FM) is a rare, potentially progressive disease resulting from an idiosyncratic immune response to a variety of stimuli that lead to fibrous infiltration of the mediastinum and possible narrowing of the bronchovascular structures. We report an unusual case of FM in a pediatric patient presenting as myopericarditis and progressing to pericardial thickening and encasement of the mediastinal vascular structures needing surgical intervention. Imaging, including transthoracic echocardiography, cardiac computed tomography, and cardiac magnetic resonance played a crucial role in the diagnosis, assessment, and follow-up. Contrast-enhanced computed tomography can be especially helpful to demonstrate potential findings associated with FM.

Aggregate IND Safety Reporting for Smaller Companies and Programs.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements.

Value and Implementation of the Aggregate Safety Assessment Plan.

Aggregate safety assessment involves evaluation of the totality of safety data to characterize the emerging safety profile of a product. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group recently published an approach to developing an Aggregate Safety Assessment Plan (ASAP). Creation of an ASAP facilitates a consistent approach to safety data collection and analysis across studies and minimizes important missing data at the time of regulatory submission. A critical aspect of the ASAP is identification of the Safety Topics of Interest (STOI). The STOI, as defined in the ASAP, comprises adverse events (AEs), which have the potential to impact the benefit: risk profile of a product and typically require specialized data collection or analyses. While there are clear benefits to developing an ASAP for a drug development program, multiple concerns may be encountered with implementation. This article uses the examples of two STOIs to demonstrate the benefits and efficiencies gained with implementation of the ASAP in safety planning as well as in optimally characterizing the emerging safety profile of a product.

Assessing adverse events in clinical trials during the era of the COVID-19 pandemic.

Interpretation of safety data for clinical trials that were ongoing at the onset of the COVID-19 pandemic or were started subsequent to the beginning of the pandemic may be affected in a variety of ways. Pandemic-related issues can influence the extent of study participation and introduce data collection gaps. A SARS-CoV-2 infection among study subjects as a post-randomization event may introduce a number of confounding factors that can alter the frequency of adverse events, in some cases appearing as an increase in the frequency of an adverse event associated with a study drug relative to a comparator. The authors discuss clinical challenges and statistical concerns, specifically the estimand framework, including examples for consideration, to address these challenges in safety evaluation wrought by the COVID-19 pandemic. Our aim is to shed light on the importance of starting an early dialogue among the drug development team on the evaluation of safety, critical for benefit-risk evaluation throughout the drug development process.

Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies.

BACKGROUND: Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). OBJECTIVE: We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. METHODS: Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). RESULTS: Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib (respectively, 311.9 and 5.7 events per 100 PY) versus 15 mg (respectively, 274.6 and 4.4 events per 100 PY). Serious adverse event rates (15/30 mg, 7.1/7.7 events per 100 PY) were similar in both groups. Acne was the most frequently reported adverse event (15/30 mg, 13.3/20.2 events per 100 PY). Serious infection rates were similar across treatment groups. Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY. Rates of malignant neoplasms were within the expected range for the general population. CONCLUSIONS: Upadacitinib was well tolerated, and no new important safety risks were observed among adults and adolescents with moderate-to-severe AD treated for approximately 1 year compared to the known safety profile of upadacitinib.

Evaluation of response to 13-valent conjugated pneumococcal vaccination in patients with rheumatoid arthritis receiving upadacitinib: results from a phase 2 open-label extension study.

OBJECTIVE: To assess the immunogenicity of pneumococcal 13-valent conjugate vaccination (PCV-13) in patients with rheumatoid arthritis receiving upadacitinib and background methotrexate (MTX). METHODS: Eligible patients from the phase 2 open-label extension trial BALANCE-EXTEND (NCT02049138) receiving stable dosing of upadacitinib 15 mg or 30 mg once daily plus background MTX were given PCV-13. Antibody titres were collected prevaccination and 4 and 12 weeks postvaccination. The primary endpoint was the proportion of patients with satisfactory humoral response to PCV-13, defined as a ≥2-fold increase in ≥6 of 12 pneumococcal antigens at 4 weeks postvaccination. RESULTS: Of 111 patients (upadacitinib 15 mg, N=87; 30 mg, N=24), 85.6% were women, 97.3% used concomitant MTX and 44.1% used oral corticosteroids. At 4 weeks, 67.5% (95% CI 57.4 to 77.5) of patients receiving upadacitinib 15 mg and 56.5% (36.3 to 76.8) receiving 30 mg had a satisfactory PCV-13 response. Responses were similar in patients who used or did not use concomitant corticosteroids. No deaths or serious adverse events were reported. CONCLUSIONS: Approximately two-thirds of patients receiving upadacitinib 15 mg once daily achieved a satisfactory humoral response to PCV-13 despite receiving concomitant MTX. Concomitant corticosteroid use did not negatively affect PCV-13 response.

Using the Bayesian detection of potential risk using inference on blinded safety data (BDRIBS) method to support the decision to refer an event for unblinded evaluation.

In the Sponsor Responsibilities-Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies: Draft Guidance for Industry (June 2021) the Food and Drug Administration recommends that sponsors develop a Safety Surveillance Plan as a key element of a systematic approach to safety surveillance and describes two possible approaches to assess the aggregate safety data. One approach regularly analyzes unblinded serious adverse events (SAEs) by treatment group. The alternative approach prespecifies estimated background rates for anticipated SAEs in the study population (e.g., myocardial infarctions in an older adult population). If the event rate in the blinded data from the study population exceeds a "trigger rate," then an unblinded analysis by treatment group is conducted. The Bayesian detection of potential risk using inference on blinded safety data (BDRIBS) method has been previously described and offers a quantitative approach for assessing blinded events. In this article we provide a procedural workflow for blinded review of safety data that is consistent with the unblinding "trigger approach" for aggregate safety review. In addition, this publication contextualizes the use of BDRIBS within the broader safety surveillance framework, extends the method to allow for multiple studies, and offers examples of its use in various settings via an R-Shiny application that allows for dynamic visualization and assessment.

Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Interdisciplinary Safety Evaluation for Learning and Decision-Making.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.

The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.

Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme.

OBJECTIVES: This integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA). METHODS: Treatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks). RESULTS: 3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups. CONCLUSION: In the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab. TRIAL REGISTRATION NUMBERS: SELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.

A Framework for Safety Evaluation Throughout the Product Development Life-Cycle.

Evaluation of the safety profile of medicines is moving from a more reactive approach, where safety experts and statisticians have been primarily focusing on the review of clinical trial data and spontaneous reports, to a more proactive endeavor with cross-functional teams strategically evolving their understanding of the safety profile. They do this by anticipating the ultimate benefit-risk profile and its related risk management implications from the start of development. The proposed approach is based on assessments of integrated program-level safety data. These data stem from multiple sources such as preclinical information; clinical and spontaneous adverse event reports; epidemiological, real-world, and registry data; as well as, potentially, data from social media. Blended qualitative and quantitative evaluations allow integration of data from diverse sources. Adding to this, a collaborative multidisciplinary view, which is focused on continuous learning and decision-making via diverse safety management teams, ensures that companies look at their growing safety database and associated risk management implications from every relevant perspective. This multifaceted and iterative approach starts early in the development of a new medicine, continues into the post-marketing setting, and wanes as the product matures and the safety profile becomes more well understood. Not only does this satisfy regulatory requirements but, crucially, it provides the healthcare system and treated patients with a better understanding of the drug's safety profile.

Global Regulatory Landscape for Aggregate Safety Assessments: Recent Developments and Future Directions.

Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments. We will show how these trends lead to opportunities for closer interdisciplinary collaboration, for bridging the gap between preand postmarketing surveillance, and for a more proactive determination of patient populations with a positive benefit-risk profile for product use. We will conclude by pointing to ongoing and future work that seeks to provide specific solutions for ongoing aggregate safety evaluation.

Incidence of inpatient venous thromboembolism in treated patients with rheumatoid arthritis and the association with switching biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in the real-world setting.

Objectives: To assess incidence rates (IRs) of VTE in patients with rheumatoid arthritis (RA) on different DMARDs and DMARD switchers. Methods: Adults with RA on a DMARD between 2007 and 2017 were studied in a US claims database. Conventional synthetic DMARD (csDMARD) users, first biologic/targeted synthetic DMARD (b/tsDMARD) users and b/tsDMARD switchers (from a b/tsDMARD to another b/tsDMARD) were followed for inpatient VTE (pulmonary embolism (PE)/deep vein thrombosis (DVT)). Crude and adjusted IR and 95% CIs of VTE were estimated. HRs for VTE were estimated via Cox regression. VTE risk was also evaluated by number of switches between b/tsDMARDs and in patients without a VTE history. Results: The age and sex standardised IR (95% CI) of VTE (per 100 person-years) was 0.86 (0.70 to 1.03), 0.60 (0.52 to 0.68) and 0.58 (0.51 to 0.65) for b/tsDMARD switchers, first b/tsDMARD users and csDMARD users, respectively. After adjustment, b/tsDMARD switchers had an increased risk of VTE, compared with csDMARD users, HRadj (95% CI) being 1.36 (1.16 to 1.58), 1.36 (1.13 to 1.63) and 1.47 (1.18 to 1.83) for VTE, DVT and PE, respectively. Compared with first b/tsDMARD users, the HRadj (95% CI) for VTE was 1.35 (1.15 to 1.60) for first b/tsDMARD switchers and 1.48 (1.19 to 1.85) for second b/tsDMARD switchers. Conclusions: In RA, b/tsDMARD switchers have a higher VTE risk compared with csDMARD users and first b/tsDMARD users. Switching b/tsDMARDs may be a proxy for higher disease severity or poorly controlled RA and an important confounder to consider in obtaining unbiased estimates of VTE risk in observational RA safety studies.

Monitoring Drug Safety in Rheumatoid Arthritis Prevention Trials.

This commentary discusses issues particular to drug safety monitoring in prevention trials. Although the general approach to safety assessment applies across all clinical trials, prevention trials pose special challenges given that the patient population is currently asymptomatic or experiencing only mild symptoms of the targeted disease. This sways the risk-benefit analysis balance toward minimal acceptable risk. Definition of the predisease state with validated biomarkers or other assessment tools is essential. The timing and required length of exposure to the disease intervention to produce an effect requires special methodologic considerations. In addition, prevention trials generally have a longer duration with higher dropout rates. As a result, there is an enhanced focus on lessening patient burden in regard to data collection and finding ways to minimize the safety signal to noise ratio to enable product causality assessment. To meet these challenges, clinical safety monitoring in prevention trials involves 3 essential steps: safety planning, systematic data collection and evaluation, and transparent communication of safety information. We discuss some of these issues using historical experience with primary prevention cardiovascular trials and then focus on unique issues surrounding patient populations at risk for rheumatoid arthritis.

Safety of Adalimumab Dosed Every Week and Every Other Week: Focus on Patients with Hidradenitis Suppurativa or Psoriasis.

BACKGROUND: Adalimumab is approved for the treatment of hidradenitis suppurativa (HS), plaque psoriasis, and other inflammatory conditions. OBJECTIVE: Our objective was to examine the safety of adalimumab administered every other week (EOW) and every week (EW) in patients with HS and psoriasis and to investigate informative data from non-dermatologic indications. METHODS: The safety of adalimumab 40-mg EOW versus EW dosing was examined during placebo-controlled and open-label study periods in patients with HS (three studies), psoriasis (two studies), Crohn's disease (six studies), ulcerative colitis (three studies), and rheumatoid arthritis (one study). RESULTS: No new safety risks or increased rates of particular adverse events (AEs) were identified with EW dosing. In patients with HS or psoriasis, the overall safety of adalimumab 40-mg EOW and EW was generally comparable. In studies of adalimumab for non-dermatologic indications, including Crohn's disease, ulcerative colitis, and rheumatoid arthritis, the overall AE rates were similar for EW and EOW dosing. CONCLUSION: In patients with HS or psoriasis, the safety of adalimumab EW and EOW was comparable and consistent with the expected adalimumab AE profile. The safety of adalimumab EW dosing in patients with dermatologic conditions is supported by data comparing adalimumab EW and EOW dosing for Crohn's disease, ulcerative colitis, and rheumatoid arthritis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00918255, NCT01468207, NCT01468233, NCT00645814, NCT00077779, NCT00055497, NCT01070303, NCT00195715, NCT00348283, NCT00385736, NCT00408629, and NCT00573794.

RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study.

INTRODUCTION: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study. METHODS: Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma. RESULTS: In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo. CONCLUSION: RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis). FUNDING: AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.

Local vaccine site reactions and contact allergy to aluminum.

Childhood vaccines are a routine part of pediatric care in the United States; clinicians must be able to recognize and interpret associated localized adverse reactions. Redness and induration at the site of injection are commonly reported and are considered to be the result of local inflammation or hematoma formation, although other atypical reactions can occur. We report the case of a 6-month-old infant who developed subcutaneous nodules at the sites of his 4- and 6-month Pentacel (DTaP/Hib/IPV, diphtheria, tetanus, acellular pertussis, Haemophilus b conjugate, and inactivated poliovirus vaccine) and 6-month Prevnar (heptavalent pneumococcal vaccine) injections. Infectious disease and immunodeficiency examinations were unremarkable. Aluminum contact allergy was considered, and contact allergy testing confirmed sensitivity to aluminum. Although rare, aluminum contact allergy after routine immunization can occur and should be considered in the differential diagnosis of persistent subcutaneous nodules after vaccination.