Towards more tolerable subcutaneous administration: Review of contributing factors for improving combination product design

Biologics, such as antibodies, proteins, and peptides, are a rapidly growing class of innovative treatments for many serious diseases. Historically, most biologics by default have been administered to patients via the intravenous (IV) route. Subcutaneous (SC) injection is a safe, effective, and increasingly accepted alternative route of administration for biotherapeutics. SC-administered biologics have seen steady growth in approvals by the US Food and Drug Administration (FDA) in recent years, with just over half of all approved injectables between 2017 and 2021 being SC products. In this timeframe, metabolism and endocrinology diseases were the dominant therapeutic areas to receive FDA approvals for SC-administered biologics, accounting for 18% of approvals, followed by inflammation/immunology and dermatology products. Similarly, an analysis of all biologic injectables in clinical development between 2015 and 2022 also revealed a trend toward increasing SC product development, with oncology products accounting for 19% of SC-administered biologics in development in 2022.

The SC route of administration offers notable advantages over IV infusions. For patients, particularly for those with chronic diseases that require regular treatment dosing and long-term regimens, SC administration could help reduce treatment burden, increase convenience, and improve quality of life as it allows for self-administered or caregiver-supported dosing at home or in settings other than an infusion center. It also has quantifiable economic benefits in terms of lower hospital and clinical costs, reduced healthcare resource utilization and healthcare provider (HCP) time, and increased patient throughput. Additionally, SC injection permits the treatment of patients with poor venous access and preserves venous access in patients at risk of vascular exhaustion.

As with any injection, SC treatment administration can be associated with a subjective level of local pain and discomfort, which may influence the utilization of SC administered products and negatively affect treatment adherence and overall patient experience. With innovations in the SC drug delivery space increasingly focusing on finding ways to deliver higher doses/volumes, it is essential to better understand the multiple intertwined elements of device attributes, delivery process, drug formulation, and patient/emotional factors that influence SC injection pain to guide the future of SC product design and improve the overall patient experience.

As part of the work of the SC Drug Development & Delivery Consortium, this manuscript builds upon the previous Consortium publication focused on technologies that enable SC delivery of high-dose and/or large-volume biologics. With the aim to extract trends in combination product variables (device, delivery, and formulation attributes) that may influence SC injection pain, the SC Consortium conducted a survey of all public information that attempted to quantify injection pain experience for the SC products tested. In this article, we briefly describe the physiology of injection pain and methods of measurement, and provide a comprehensive review of known attributes from published literature that contribute to SC injection pain/discomfort from three perspectives: device and delivery factors that cause physical pain, formulation factors that trigger biophysical/biochemical pain responses, and human factors impacting pain perception, including HCP experience and injection training, as well as patient emotional/psychological experience. We also provide an assessment of the comparative and interdependent factors likely to lead to more or less favorable pain outcomes in human trials to help guide the design of high-dose/high-volume (HD/HV) SC products. While interpretation across studies is difficult without broad assumptions, it is helpful in diagnosing apparent trends for the pharmaceutical industry.

This manuscript focuses primarily on injection pain and tolerability during and immediately after injection, as opposed to potential subsequent and longer duration pharmacologically or immunologically driven adverse events (e.g., injection site reactions) which may also be painful and impact the overall injection experience. Additionally, whereas IV administration allows for delivery of large doses without volume limitations, SC injections have traditionally been limited to low volumes, mostly ≤ 1 mL up to 2 mL for bolus injection (i.e., autoinjector, prefilled pen, or prefilled syringe). Only recently have new technologies pushed the boundaries for SC injections above 2 mL using larger volume autoinjectors, syringe infusion pumps, on-body delivery systems, or permeation enhancers. Therefore, much of the work cited herein is derived from earlier lower injection volume precedents and may also draw on SC injection pain experiences from non-protein biologic therapies.