Tumor Necrosis Factor Inhibitor Treatment and Persistence Patterns in the Peripregnancy Period in Patients With Inflammatory Autoimmune Diseases

ACR Open Rheumatology · 2026-04-29

OBJECTIVE: Systemic inflammatory conditions affect many women during their reproductive years and tumor necrosis factor inhibitors (TNFi) are one of the most common biologic classes used to help manage disease in this population. Although treatment guidelines now recommend continuing TNFi in pregnancy, studies examining recent real-world treatment trends in this population are limited. The objective of this study was to describe TNFi treatment patterns in the peripregnancy period among patients treated with TNFi before pregnancy, and to describe differences by autoimmune condition, over time. METHODS: A retrospective cohort study was conducted using two US administrative health insurance claims databases: Merative MarketScan Commercial Database (CCAE) and Merative MarketScan Multi-State Medicaid Database (MDCD) between 2010 and 2022. Participants were pregnant women aged 18 to 49 years with ≥1 dispensing for TNFi in the six months before pregnancy start and a diagnosis of psoriasis (PSO), psoriatic arthritis (PsA), ulcerative colitis (UC) or Crohn's disease (CD), and/or rheumatoid arthritis (RA). RESULTS: There were 6,031 pregnancies (5,025 women) in CCAE and 825 pregnancies (714 women) in MDCD included. Continuation in pregnancy was highest in UC or CD (89.3% in CCAE and 84.0% in MDCD), followed by RA (71.9% in CCAE and 71.9% in MDCD), and PSO/PsA (66.6% in CCAE and 65.7% in MDCD). Across all conditions, the proportion continuing TNFi significantly increased over time (P < 0.01). CONCLUSION: This study extends our understanding of peripregnancy TNFi treatment patterns in women with autoimmune diseases, illustrating an increasing trend of TNFi continuation in pregnancy across two administrative data sources in the United States.

The Ethics of Clinical Research on Diseases of the Fetus and Newborn: Balancing Benefit-Risk, Autonomy, and Maternal-Fetal Interests.

PubMed · 2025-12-30

Pregnant persons historically have been excluded from clinical trials. Recently, there has been a shift from exclusion toward inclusion of pregnant persons in research while acknowledging the complexity of reproductive ethics and the intertwined interests of the pregnant person and fetus. Our objective was to use a principle-based approach to review the ethics of clinical research concerning pregnancy-related disorders that predominantly affect fetal well-being.Ethical principles are applied to the design of interventional trials in two rare conditions of pregnancy, hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT).Severe HDFN and FNAIT are fetal and neonatal diseases caused by maternal alloantibodies with potential outcomes including maternal and neonatal morbidity, preterm delivery, and fetal or neonatal death. Early-onset severe HDFN was the initial indication for a phase 2 open-label study of nipocalimab in pregnancy, given poor outcomes after prior severe HDFN pregnancy(s). After establishing proof of concept, a phase 3 randomized placebo-controlled study was initiated based on the ethical principles of equipoise and generating socially valuable data to support the efficacy and safety of nipocalimab in severe HDFN. However, off-label use of antenatal intravenous immunoglobulin (IVIg) in standard-risk FNAIT pregnancies made a randomized placebo-controlled study challenging. Thus, the FNAIT clinical program for nipocalimab in pregnant persons with standard-risk FNAIT includes a randomized, placebo-controlled study limited to sites that do not use antenatal IVIg, and a global randomized open-label study of nipocalimab or IVIg.Knowledge of the clinical course and management of severe HDFN and FNAIT, the non-clinical and non-pregnant human clinical evidence, and input from physicians, patients, and health authorities permitted the design of clinical protocols that satisfy the principles of beneficence and non-maleficence in these rare and complex diseases. · Ethical principles apply to pregnancy-related disorders affecting fetal well-being.. · Placebo-controlled randomized trials in HDFN are based on equipoise.. · FNAIT programs must account for the off-label use of IVIg..

Improving the Pediatric Research Federal Review Process

PEDIATRICS · 2025-07-16

In an era of increasing skepticism of publicly funded research, it remains imperative for researchers to understand the regulatory frameworks and processes that govern pediatric research. Research involving children involves complex regulations that can present challenges to researchers, clinicians, and institutional review board (IRB) members. Designing and conducting pediatric research poses unique ethical challenges, the most notable being defining and categorizing risk appropriately, inherent subjectivity in risk assessment, and navigating complicated federal regulations. A better understanding of these challenges will enhance the efficiency of pediatric research while maintaining essential safeguards.This perspective aims to inform pediatric researchers and clinicians on the federal research review process and outline relevant challenges and recommendations for its improvement.In the United States, pediatric research is governed by the Department of Health and Human Services (DHHS) through its Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA). The Code of Federal Regulations (CFR) is a compendium of rules for these government agencies.1,2 The DHHS regulations are under Title 45, Part 46 with specific pediatric research subsections (Subpart D; 45 CFR 46.404-407).1 The FDA rules are found in Title 21, with pediatric research regulations in 21 CFR 50.51-54.2 When a research protocol is federally funded, DHHS regulations apply. Research protocols, including an FDA-regulated product, follow FDA regulations regardless of federal funding.2This “alphabet soup” of letters and numbers used to categorize pediatric research may be confusing for clinical researchers unfamiliar with this language. Pediatric research is classified into 4 categories, each dependent on assessment of risk and potential for benefit.3 Pediatric research may be classified as (1) minimal risk (with or without direct benefit), (2) greater than minimal risk with the potential for direct benefit, (3) research with a “minor increase in minimal risk,” without direct benefit or (4) research with “more than a minor increase” in risk without potential for direct benefit (Figure 1A). Research in this fourth category must undergo federal review under (45 CFR 46.407; 21 CFR 50.54), often referred to as “407 reviews or panels.” These reviews require extensive collaboration between the institution and federal agencies to coordinate the review, a public hearing, and publication of recommendations (Figure 1B). This process is cumbersome and often avoided by researchers and IRBs. Given that there have been very few protocols reviewed (approximately 15) since the regulations were established in 1991, this review and approval pathway is likely underutilized. Additionally, research teams may choose to modify interventions or eliminate specific procedures that would trigger a 407 review, often due to the lengthy timeline and substantial coordination such reviews entail.Further complicating this risk assessment, all proposed research protocols must be evaluated using component analysis. Each research intervention is analyzed independently to evaluate the risk of that specific intervention and the potential for benefit.4 For example, in a therapeutic trial with an investigational agent with a potential for direct benefit, a research-only biopsy (without the potential for benefit) must be assessed independently to analyze if it represents only a minor increase in risk. The presence of potential for benefit of one research component does not automatically allow an IRB to approve the entire protocol.The risk language (“minor increase” and “more than a minor increase”) in the regulations is inherently subjective and thus variable, presenting a challenge to standardize risk assessments among protocols.5 Variability in risk assessments can exist across IRBs, a challenge for multicenter studies not using a single, central IRB.5 The categorical differences in risk classification among “minimal,” “minor,” and “greater than minor” can be difficult to distinguish (Figure 1C for risk-level examples). To address this problem, the OHRP and FDA should work to align and delineate a single guidance with more comprehensive definitions and risks for common research interventions, comparable to those outlined by the European Union.6The federal 407 review process has been criticized for being inefficient, lacking transparency, and slowing research in rare and devastating diseases.7 One review estimated the median time from submission to study enrollment to be 19 months, with public access to protocols, meeting transcripts, and final review decisions limited by inaccessible historical records and incomplete maintenance of online federal archives.7 This lack of transparency impacts researchers and IRB members who are searching for information on deliberations that occurred during previous reviews, ultimately creating further delay.A comprehensive, publicly accessible governmental database containing information from all 407 previous panels should be established. Meeting transcripts, supporting documents, and expert reports should be posted and maintained, allowing researchers and IRBs to access valuable information that may expedite and increase the quality and efficiency of future reviews. This central database would promote greater transparency, accountability, and trust in the 407 review process.The development and implementation of standardized 407 review submission forms with clear next steps and timelines, similar to investigational new drug applications, can create greater accessibility and clarity for researchers. Some delays surrounding these reviews are due to the time required of institutions to prepare these referrals, and standardized forms could streamline the process. A more efficient review system would minimize delays, reduce the fear and stigma around federal panel reviews, enhance communication among researchers, local IRBs, and federal agencies, and improve the efficiency and oversight of pediatric clinical trials.Pediatric researchers, clinicians, and IRB members examining previous 407 panels may wonder if previous discussions about specific interventions, such as the use of a central venous access device in a placebo intervention arm, may apply to a research protocol they are designing or reviewing. Current federal guidelines do not discuss the applicability of prior federal reviews, which creates confusion and may permit undue risk to participants. As outlined by the FDA and OHRP, each agency maintains the authority to determine the generalizability of a particular research intervention to prevent redundant federal reviews. If the research is sufficiently similar to previously reviewed research, the FDA and OHRP can waive the need for full panel or subcommittee reviews.8 Draft guidance seeking to clarify this process was published in the Federal Register in March 2023, but remains to be finalized (April 2025).8 To date, the federal agencies have not acted on this ability to create general guidance. To improve this process, a formal submission system managed by the FDA and OHRP would allow IRBs to submit such candidate 407 protocols and delineate similarities. The decision to apply this expedited process would remain at the discretion of the FDA and OHRP, but would allow increased efficiency for the federal review and increased agency for researchers and IRBs.There are several other opportunities to improve the review process for pediatric research, which may contain components that are more than a minor increase in risk without the potential for direct benefit. When federal agencies review pediatric research protocols, those agencies should maintain the authority to initiate a federal review and assign the appropriate risk category. This would improve transparency and possibly result in draft guidance surrounding pediatric research interventions, which ultimately may allow safer pediatric research. For future reviews, in addition to background materials and details on specific deliberations, the creation of a brief, standardized, and publicly available summary report may provide a more useful and objective reference for all stakeholders.To maintain the trust of pediatric clinicians, researchers, IRBs, and research participants, the 407 federal review process must be updated to improve transparency and foster efficiency such that researchers and IRBs are motivated to work with the oversight agencies instead of around them. Education of local IRB members, pediatric researchers, and pediatric clinicians through well-developed and transparent federal guidance would safeguard children from undue risk, provide generalizable knowledge that may improve the understanding of pediatric conditions, and the translation of safer and more efficacious research-based interventions to the bedside.

Feedback from a workshop by the European Bioanalysis Forum on assay validation requirements for <i>in vitro</i> assays following the publication of ICH M12 guideline – a plea for context-of-use over ICH M10 standards

Bioanalysis · 2025-02-21 · 2 citations

assays such as plasma protein-binding studies. Even though the ICH M12 does not directly reference the ICH M10 Guideline on Bioanalytical Method Validation and Sample Analysis, its release prompted further discussions on assay validation requirements for these studies during the 17th European Bioanalysis Forum Open Symposium held in Barcelona, Spain, from 19 to 21 November 2024, where we advocated for a Context-of-Use driven approach over rigid adherence to ICH M10 standards. Context-of-Use driven validation ensures assays are tailored to the specific scientific and regulatory needs, optimizing resource allocation and innovation in drug development. This short opinion paper explores the potential and undesired implications of ICH M12 on bioanalytical validation practices, highlights the distinction between exploratory assays and assays having a clinical impact, and underscores the necessity for tailored validation strategies.

Proceedings of the 15 ^th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals

mAbs · 2025-04-03 · 3 citations

The European Immunogenicity Platform (EIP) celebrated the 15th edition of its Open Symposium on Immunogenicity of Biopharmaceuticals and its associated one-day workshop on 22-24 February 2024 in Lisbon. The meeting attracted experts and newcomers across industry, regulatory agencies, and academia, who actively participated in 3 days of discussion on risk assessment, monitoring, and mitigation of unwanted immunogenicity of biologics. Besides oral presentations, poster sessions were held to maximize scientific exchange and networking opportunities. Therapeutic proteins and emerging gene and cell-based therapies present promising therapeutic options for addressing unmet medical needs or when conventional treatment approaches have failed. Nonetheless, the development of an immune response against these therapeutic agents is a significant concern, as it occurs in a considerable number of cases across various products and indications. The specific anti-drug antibodies that develop can lead to adverse safety events, inhibition of drug activity, or accelerated clearance, all of which result in a loss of treatment efficacy. The EIP serves as a forum for experts and newcomers in the immunogenicity field, fostering discussion among scientists from industry and academia, encouraging interactions with regulatory agencies, and disseminating knowledge and advancements in immunogenicity sciences to the broader scientific community. This report covers the main topics discussed during the EIP 15th Open Symposium on Immunogenicity of Biopharmaceuticals, and the one-day workshop on practical aspects of immunogenicity held prior to the conference. Key topics included immunogenicity testing, clinical relevance of immunogenicity, immunogenicity risk assessment and mitigation, and current regulatory considerations.

European Bioanalysis Forum recommendation on embracing a context-of-use-driven scientific validation for chromatographic assays in the light of ICH M10

Bioanalysis · 2025-09-02 · 2 citations

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M10 guideline provides a global framework for bioanalytical method validation in studies intended for regulatory submission. While its structure ensures consistency and data reliability, the guideline also acknowledges that not all studies require the same level of validation. This paper examines where full compliance is essential and where scientific judgment allows for leaner, context-driven validation, such as in early-stage development, for additional matrices, metabolites, nonstandard biological matrices or studies intended for internal decision-making. Drawing on recent recommendations from the European Bioanalysis Forum, we introduce a decision-making flowchart and parameter table to support consistent application of a Context-of-Use approach to validation. These tools help guide when flexibility is appropriate while ensuring transparency and robustness in the data. The paper advocates continued dialogue both with end users of the data and the regulatory authorities to support a modernized, risk-based validation framework that remains aligned with patient needs and scientific integrity. We believe the recommendations in this paper are fully in alignment with the intent and core principles of ICH M10, while encouraging their application in a way that remains scientifically driven and proportionate to the purpose of the assay.

A Benefit–Risk Conceptual Framework for Biologic Use During Pregnancy: A Mini‐Review

Clinical Pharmacology & Therapeutics · 2024-03-20

Recent reports related to in utero exposure of marketed immunosuppressive biologics led to clinical recommendations to delay live vaccinations for infants due to the concern of reduced vaccine effectiveness and/or increased risk of vaccine-related disease. These delays can increase the risk of children contracting vaccine preventable diseases, yet the alternative cessation of biologics during pregnancy may result in increased autoimmune disease activity for the pregnant person, raising complex benefit-risk (B-R) considerations and trade-offs. Our goal is to develop a conceptual framework for B-R assessment based on the key benefits and risks pregnant people would consider for themselves and their children when continuing (vs. discontinuing) a biologic during pregnancy. The proposed framework defines the decision contexts, key domains and attributes for potential benefits, and risks of biologic use during pregnancy, informed by a literature review of indications for biologics and refined with key clinical stakeholders. The framework includes both the pregnant person taking the biologic and the infant potentially exposed to the biologic in utero, with potential benefit and risk domains and attributes for each participant. To advance this conceptual framework, there are considerations of potential biases and uncertainty of available data that will be imperative to address when quantifying the B-R framework. For these reasons, we recommend the formation of a consortium to ensure development of a robust, validated framework that can be adopted in the healthcare setting.

Rethinking the Andragogical Effectiveness of Discussion Boards in an MBA Program

American Journal of Distance Education · 2024-11-18

Design of a Phase 3, Global, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn

American Journal of Perinatology · 2024-08-28 · 21 citations

Abstract Nipocalimab is a neonatal fragment crystallizable (Fc) receptor (FcRn)—blocking monoclonal antibody that inhibits placental immunoglobulin G (IgG) transfer and lowers circulating maternal IgG levels. In an open-label, single-arm, phase 2 study, nipocalimab demonstrated evidence of safety and efficacy that support further investigation in a pivotal phase 3 trial of recurrent hemolytic disease of the fetus and newborn (HDFN). The phase 3 AZALEA study aims to evaluate the efficacy and safety of nipocalimab in a larger population at risk for severe HDFN, defined as HDFN associated with poor fetal outcomes or neonatal death. AZALEA is a multicenter, randomized, placebo-controlled, double-blind, phase 3 study enrolling alloimmunized pregnant individuals (N ≈ 120) at risk for severe HDFN based on obstetric history. Participants are randomized 2:1 to receive intravenous 45 mg/kg nipocalimab or placebo weekly from 13–16 to 35 weeks gestational age (GA). During the double-blind treatment period, participants receive standard-of-care weekly monitoring for fetal anemia until planned delivery at 37 to 38 weeks of GA. Postnatal follow-up periods are 24 weeks for maternal participants and 104 weeks for neonates/infants. The primary endpoint is the proportion of pregnancies that do not result in intrauterine transfusion (IUT), hydrops fetalis, or fetal loss/neonatal death from all causes. Key secondary endpoints include the severity of HDFN as measured by a composite HDFN severity index, the earliest time to occurrence of IUT or hydrops fetalis, the modified neonatal mortality and morbidity index in liveborn neonates, and the number of IUTs received. Other endpoints are safety, patient- and caregiver-reported outcomes, pharmacokinetics, pharmacodynamics (e.g., IgG, FcRn receptor occupancy), and immunogenicity of nipocalimab. AZALEA, the first placebo-controlled, randomized, multicenter, prospective trial in severe HDFN, is designed to evaluate the safety and efficacy of nipocalimab, a potential preventive and noninvasive intervention, in at-risk HDFN pregnancies.

Project GIVE: using a virtual genetics service platform to reduce health inequities and improve access to genomic care in an underserved region of Texas

Journal of Neurodevelopmental Disorders · 2024-09-09 · 5 citations

BACKGROUND: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of improving pediatric health outcomes. We describe our experience of establishing a virtual pediatric genomic service in this region to expeditiously identify, recruit, and evaluate pediatric patients with undiagnosed diseases. METHODS: We have utilized an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform called Consultagene to receive referrals from healthcare providers in the RGV. Using this portal, genetic services, including virtual evaluation and genome sequencing (GS), are being delivered to children with rare diseases. The study has also integrated effective methods to involve and educate community providers through in-person meetings and Continuing Professional Education (CPE) events. RESULTS: The recruitment efforts have proven highly successful with the utilization of Consultagene in this medically underserved region. The project's ongoing engagement efforts with local healthcare providers have resulted in progressively more referrals to the study over time, thus improving inclusion and access to genomic care in the RGV. Additionally, the curated CPE content has been well received by healthcare providers in the region. CONCLUSIONS: Project GIVE study has allowed advanced genetic evaluation and delivery of GS through the virtual Consultagene portal, effectively circumventing the recognized socioeconomic and logistical barriers to accessing genetic services within this border community.