In certain indications, it is well understood that randomized controlled trials lead to slow enrollment and high differential drop-out rate in the standard of care control arm when the standard of ...care is undesirable to patients. This not only impacts the pace of drug development but may also render a randomized trial uninterpretable if drop-out from the control arm is common. Single-arm trials are common in such indications. An external control arm (ECA) built using a propensity score method (Rosenbaum and Rubin, Biometrika 70:41–55, 1983) from subjects outside the current trial but who meet the same eligibility criteria as the subjects of the current trial, is valuable in assessing treatment effect of a new drug that cannot be otherwise assessed with a single-arm trial, or an unintentionally under-powered and arguably biased randomized controlled trial. Propensity score methods have increasingly gained importance in observational medical research, paving the way for the use of these methods in non-randomized clinical trials. In this paper, we describe our experience with building an ECA for drug development related to regulatory activities associated with a new molecular entity (NME). Through analysis of a phase 2 study, we show how best practices from causal statistical methods can be used to build an ECA for a non-randomized drug trial—a novel application of a well-studied method. To prevent selection bias, the selection of subjects for the ECA was carried out by an independent group of statisticians who were blinded to all patient outcome data. We share lessons learnt from our regulatory interactions that provide helpful suggestions on how to advance ECA-based drug development. There has been interest in confirmatory trials that use reduced control arm randomization along with an ECA. We present a design for such a hybrid trial using a propensity score weighting method and describe how a standard propensity score analysis can be used to analyze data resulting from a composite hybrid randomized and external control arm.
Abstract Hizentra® (20% subcutaneous immunoglobulin SCIG) was administered to subjects with primary immunodeficiency disease in two extension studies in the EU and US to assess long-term efficacy and ...tolerability. Subjects (aged 4–69 years) were treated for 148 weeks in the EU (N = 40; 5405 infusions) and 87 weeks in the US (N = 21; 1735 infusions). Weekly doses were 116.0 mg/kg (EU) and 193.2 mg/kg (US); IgG levels were 7.97 g/L (EU) and 11.98 g/L (US). Annualized rates of serious bacterial infections were 0.05 infections/subject/year (EU) and 0.06 infections/subject/year (US). Rates of any infection were 3.33 infections/subject/year (EU) and 2.38 infections/subject/year (US). The rate of bronchopulmonary infections was higher in the EU study. No treatment-related serious AEs occurred; no subject discontinued because of treatment-related AEs. Self-administered Hizentra afforded sustained effective protection from infections and favorable tolerability during an extended treatment period of up to 3 years.
Replacement therapy with immunoglobulin G (IgG) given as intravenous or subcutaneous (SC) infusions is the standard treatment for patients with primary immunodeficiency. Due to the life-long need for ...replacement, increased flexibility in the administration and dosage regimens would improve patients' quality of life. A population pharmacokinetic model that can predict plasma IgG concentrations for various routes, dosage regimens, and patient groups is a valuable tool to improve patient therapy. Such a model was developed based on IgG concentrations from 151 unique adult and pediatric patients who participated in 4 clinical trials of intravenous and SC IgG replacement therapy. Simulations predicted that the same total IgG dose, delivered SC, either in 1 biweekly dose (once every 2 weeks), or in 2 weekly doses, results in IgG peak and trough concentrations that remain within ± 10% of each other throughout the 14-day period. The developed population pharmacokinetic model predicted that biweekly SC Hizentra dosing offers a viable alternative to weekly SC therapy, allowing more flexible and optimized dosage regimens for patients with primary immunodeficiency.
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