A Framework for the Use and Likelihood of Regulatory Acceptance of Single-Arm Trials

Background Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges. Objective Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses. Methods We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content. Results Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms. Conclusion Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation

The Results of ADVANCE-CIDP IVIG Trial: Intravenous Immunoglobulin 10% Therapy With GAMMAGARD LIQUID Kiovig for Treatment of Relapse in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

BackgroundADVANCE-CIDP IVIG evaluated the efficacy and safety of immune globulin infusion (human) 10% solution (IVIG 10%; GAMMAGARD LIQUID, also known as Kiovig) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as a rescue treatment for patients relapsing during the ADVANCE-CIDP 1 trial.MethodsOpen-label ADVANCE-CIDP IVIG included adult patients with confirmed CIDP relapse (>= 1-point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores from pre-treatment baseline) during ADVANCE-CIDP 1, which assessed the efficacy and safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10%. Patients received an induction IVIG 10% dose (2 g/kg) followed by maintenance infusions at the same monthly equivalent dose of pre-randomization IVIG, 3-weekly for 6 months. The primary outcome was the responder rate (>= 1-point decrease in adjusted INCAT scores at treatment cessation vs. pre-IVIG 10% baseline, in patients receiving placebo in ADVANCE-CIDP 1). Other outcomes included the responder rate across all patients relapsing on fSCIG 10% or placebo in ADVANCE-CIDP 1, time to functional improvement (>= 1-point decrease in adjusted INCAT score), and change in adjusted INCAT scores and Rasch-built Overall Disability Scale (R-ODS) centile scores from pre-IVIG 10% baseline.ResultsOverall, 20 patients received IVIG 10% (n = 4 [fSCIG 10%-relapse group]; n = 16 [placebo-relapse group]). Responder rate (95% confidence interval) was 100.0% (80.6%-100.0%) in the placebo-relapse group and 95.0% (76.4%-99.1%) in the overall-relapse population. Across all patients, median time to functional improvement was 25 days. At treatment cessation, mean changes from pre-IVIG 10% baseline in adjusted INCAT and R-ODS centile scores were -1.9 and 12.9, respectively.ConclusionsIVIG 10% effectively treated CIDP relapse and improved functional abilities

Mycoplasma genitalium: An Emerging Cause of Sexually Transmitted Disease in Women

Mycoplasma genitalium is an emerging sexually transmitted pathogen implicated in urethritis in men and several inflammatory reproductive tract syndromes in women including cervicitis, pelvic inflammatory disease (PID), and infertility. This comprehensive review critically examines epidemiologic studies of M. genitalium infections in women with the goal of assessing the associations with reproductive tract disease and enhancing awareness of this emerging pathogen. Over 27,000 women from 48 published reports have been screened for M. genitalium urogenital infection in high- or low-risk populations worldwide with an overall prevalence of 7.3% and 2.0%, respectively. M. genitalium was present in the general population at rates between those of Chlamydia trachomatis and Neisseria gonorrhoeae. Considering more than 20 studies of lower tract inflammation, M. genitalium has been positively associated with urethritis, vaginal discharge, and microscopic signs of cervicitis and/or mucopurulent cervical discharge in seven of 14 studies. A consistent case definition of cervicitis is lacking and will be required for comprehensive understanding of these associations. Importantly, evidence for M. genitalium PID and infertility are quite convincing and indicate that a significant proportion of upper tract inflammation may be attributed to this elusive pathogen. Collectively, M. genitalium is highly prevalent in high- and low-risk populations, and should be considered an etiologic agent of select reproductive tract disease syndromes in women

Subcutaneous immunoglobulin use in immunoglobulin-naive patients with primary immunodeficiency: a systematic review

Aim: Identify and describe published literature on the use of subcutaneous immunoglobulin (SCIG) as initial immunoglobulin (IG)-replacement therapy for patients with primary immunodeficiency diseases (PID). Methods: We systematically identified and summarized literature in MEDLINE, Embase, BioSciences Information Service and Cochrane Library assessing efficacy/effectiveness, safety/tolerability, health-related quality-of-life (HRQoL) and dosing regimens of SCIG for IG-naive patients with PID. Results: Sixteen studies were included. In IG-naive patients, SCIG managed/reduced infections and demonstrated similar pharmacokinetic parameters to IG-experienced patients; adverse events were mostly minor injection-site pain or discomfort. Three studies reported improvements in HRQoL. Quality of studies was difficult to assess due to limited reporting. Conclusion: Although studies were lacking, available data suggest IG-naive and IG-experienced patients initiating SCIG likely have similar outcomes. </jats:p

Real-World Usage of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% in Patients with Multiple Myeloma Diagnosed with Secondary Immunodeficiency Disease

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Real-World Effectiveness, Safety, and Tolerability of Facilitated Subcutaneous Immunoglobulin 10% in Secondary Immunodeficiency Disease: A Systematic Literature Review

Background: Secondary immunodeficiency disease (SID) is a complex, heterogeneous condition that occurs when extrinsic factors weaken the immune system. Expert consensus guidelines recommend immunoglobulin replacement therapy to manage immunoglobulin G (IgG) levels and mitigate severe, recurrent, and persistent infections. Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% is a dual-vial unit of IgG and recombinant human hyaluronidase; the latter enables absorption of higher volumes of IgG than conventional subcutaneous therapies. Methods: For this systematic literature review, Embase, MEDLINE®, and the Cochrane Library were searched on 9 August 2023, with supplemental congress searches. Results: Eight studies fulfilled the inclusion criteria, reporting real-world evidence of the clinical effectiveness, safety, and tolerability of fSCIG 10% in 183 patients with SID in Europe from September 2014 to August 2021. The potential causes of SID were primarily hematological malignancies, most commonly chronic lymphocytic leukemia. Treatment was typically administered at 4-week or 3-week intervals, with doses of approximately 0.4 g/kg/month. Infections were rare during follow-up, with numerical reductions observed after fSCIG 10% treatment initiation compared with the period before initiation. Adverse reactions, including local infusion site reactions, and tolerability events were uncommon. Conclusions: Given the recency of fSCIG 10% use in patients with SID, there are opportunities for future research to better understand survival and patient-reported outcomes after receiving this treatment. Despite SID heterogeneity, this study demonstrates the feasibility of fSCIG 10% treatment for this condition. © 2025 by the authors