Until recently, it was common to initiate a development program directly with a SC dosing regimen only for low-dose/low-volume mAb products with a favorable risk–benefit profile. This was observed in diseases like RA and MS, where the biologicals used are well tolerated, allowing for non-supervised administration after treatment initiation by an experienced healthcare provider. The use of standard prefilled syringe, autoinjector, and pen device platforms, accommodating dosing solutions of approximately 2 mL or less, facilitated self-administration outside of a controlled healthcare setting.

In the past, development programs for higher dose mAbs typically began with an IV regimen, and SC dosing options were later introduced as part of lifecycle management. This approach considered factors such as infusion-related reactions and the absence of suitable drug delivery technologies. However, advancements in high-concentration technologies [35], the availability of dispersion enhancers like hyaluronidase [36], and the development of high-volume on-body delivery systems [37] have made it possible to initiate clinical trials for high-dose mAbs directly with a SC formulation, allowing for a timely launch of the SC product without compromising its development timeline.

This section will discuss considerations specific to high-dose/high-volume mAbs, as many of these mAbs were historically introduced to the market with IV regimens. Given the remaining technical and practical challenges associated with implementing an SC dosing regimen, manufacturers may adopt various approaches, including launching the product with either IV administration only, SC administration only, or both routes of administration.

4.1 Rational Decision Making

Manufacturers have the option to consider different development scenarios for IV versus SC administration (Fig. 1). In scenario 1, only an IV formulation is developed. This is typically the case for molecules where an early and high maximum concentration (Cmax) is necessary for optimal therapeutic effect. While this requirement is not common for mAb-based treatments, other biotherapeutics like alteplase or tenecteplase for acute ischemic stroke or acute myocardial infarction fall into this scenario [5, 8]. Additionally, antibody–drug conjugates that may be cleaved in the interstitial space (data on file, F. Hoffmann-La Roche) cannot be delivered subcutaneously, and drugs that require administration in a controlled healthcare setting do not necessarily require an SC formulation.

Fig. 1

Subcutaneous versus intravenous formulation—Development scenarios. Cmax maximum serum concentration, IV intravenous, SC subcutaneous

Scenario 2 involves the development of a mAb with an SC formulation only. This approach is suitable for molecules used in monotherapy or in combination with other subcutaneously or orally administered drugs. Introducing an IV regimen would add complexity and inconvenience to the overall dosing regimen. Additionally, if the molecule is safe and well tolerated, and at-home self-administration is already established in the indication, there is no need to offer an IV treatment alternative.

In scenario 3, manufacturers pursue the development of a mAb with both IV and SC formulations. This strategy allows for greater flexibility in dosing options, taking into consideration both individual preferences and capabilities and country-specific reimbursement models. The approach enables the harmonization of dosing regimens with combination partners and facilitates the development of fixed-dose combinations tailored to specific indications [3].

Considering the preference for SC administration and its potential for decentralized dosing, the authors recommend prioritizing the development of a SC formulation. This is particularly relevant for high-dose mAbs, where the feasibility of a stable high-concentration dosing solution compatible with standard delivery devices should be evaluated early on. For high-dose mAbs, it is advisable to include an IV formulation in phase I clinical trials, even if the intention is to launch a SC formulation exclusively. This allows for a fallback option if SC dosing is not feasible or well tolerated. Moreover, clinical data on the safety of high maximum serum levels (Cmax) with the IV route can be valuable as supporting evidence for future dose adjustments, alternative formulations, or devices that may impact the molecule's absorption profile.

4.2 Clinical Development Pathway of SC Dosing Alternatives for mAbs—Current Status

The clinical development program for subcutaneously dosed mAbs is contingent upon whether this route is the first to enter the market or if a manufacturer is introducing a novel SC dosing alternative for an already established IV regimen. In the case of developing a new molecule with an SC formulation, the regulatory pathway aligns with the same paradigm as an IV formulation. Manufacturers are required to conduct nonclinical assessments encompassing pharmacology, pharmacokinetics, and toxicology, as well as a comprehensive clinical development program to demonstrate efficacy and safety that supports the submission of a new MAA or BLA.

This section provides a high-level overview of the clinical development pathways for SC dosing alternatives for mAbs with established IV regimens in oncology. It discusses their adaptation to other specialty areas and suggests measures to streamline development for future molecules. For more details, refer to earlier review articles on the topic [1, 37].

4.3 Establishing a Molecule-Agnostic Clinical Bridging Approach from IV to SC Dosing for mAbs in Oncology and Hematology

The established bridging approach for transitioning from an IV to an SC regimen for the same mAb relies on utilizing the same antibody in different formulations. It is anticipated that with comparable exposure (measured as area under the serum concentration–time curve [AUC]), the systemic safety profile of the mAb remains unchanged regardless of the administration route. To gather supportive evidence, manufacturers undertake a dedicated preclinical and toxicology bridging program for the SC formulations.

Following SC administration, it is observed that at comparable AUC, Cmax is lower compared with IV administration due to the slower absorption into the systemic circulation. However, to account for the higher AUC at earlier time points with IV administration, minimum or trough concentrations (Cmin/Ctrough) are higher following SC administration (Fig. 2). Based on this, the clinical evidence package is designed to demonstrate several key aspects: (i) pharmacokinetic non-inferiority (Ctrough and/or AUC) between the IV and SC formulations to ensure comparable efficacy, (ii) consistency in safety, tolerability, and immunogenicity profiles, and (iii) non-inferior efficacy. The ultimate goal is to extrapolate the clinical data generated in one indication to other indications for the same mAb.

Fig. 2

Impact of SC versus IV delivery on the pharmacokinetic profile of a mAb. Cmax maximum serum concentration, Cmin minimum serum concentration, IV intravenous, mAb monoclonal antibody, SC subcutaneous

4.4 Concept Development and Bridging Programs for Approved Products

Table 4 presents the IV and SC dosing regimens along with the clinical trial designs for high-volume mAb presentations with approved formulations for both routes. All manufacturers employed the pharmacokinetic-based bridging approach as described.

Table 4 Clinical trial designs for bridging from IV to SC administration for high-volume mAb presentations—approved products

The concept was initially developed for trastuzumab in HER2-positive breast cancer [38]. The IV form of the mAb was marketed with both weekly (q1w) and every 3 weeks (q3w) dosing regimens adjusted according to body weight. The selection of the two IV dose strengths aimed to achieve comparable mean AUC, surpassing the target concentration based on preclinical xenograft studies. Due to the different individual dose levels, the maximum serum levels with the q1w regimen were significantly lower compared with the q3w regimen. However, a comparison of historical data still demonstrated comparable efficacy [39]. Pharmacokinetic modeling, utilizing data from the established IV formulation and data from a phase I/Ib dose-finding and confirmation study with the SC formulation in a mixed population of healthy volunteers and participants with HER2-positive early breast cancer (eBC) in the adjuvant setting [40], predicted that a q3w SC fixed-dose regimen, at comparable AUC, would result in non-inferior Ctrough compared with the body weight-adjusted IV regimens. Furthermore, the predicted Cmax of the SC regimen would fall within the range of the q1w and q3w IV regimens (Fig. 3). The predicted dose was subsequently validated in a phase III non-inferiority study with a 1:1 randomization of participants with HER2-positive eBC [41].

Fig. 3

Evidence generation with pharmacokinetic-based clinical bridging approach. Hypothesis generation based on available trastuzumab pharmacokinetic data following intravenous administration. The PK profile of the SC formulation is bridged by the q3w and q1w IV regimens. Subcutaneous dose selection concept: Ctrough as least as high as with IV regimen; Cmax bracketed by Cmax of q1w and q3w IV regimens; comparable AUC with IV and SC regimens. *Serum trough concentration (Ctrough) of 20 µg/mL depicts PK target established from preclinical xenograft models. Ctrough serum trough concentration, IV intravenous, mg milligram, kg kilogram, ml milliliter, µg microgram, SC subcutaneous, q1w weekly, q3w every 3 weeks. This figure was published in Bittner B, Schmidt J. Formulation and device lifecycle management: A guidance for researchers and drug developers. 1st ed. William Andrew Publishing (Elsevier); 2022 [37].

Both the population of healthy volunteers and individuals diagnosed with HER2-positive eBC were considered relatively homogeneous and as such ‘sensitive,’ enabling pharmacokinetic comparisons with a reasonably low sample size. This approach of generating comparative pharmacokinetic data in a sensitive population is now recommended in the biosimilar guidelines of both the EMA and the FDA [42, 43]. To underscore the importance of the pharmacokinetic-based clinical bridging approach, the pivotal phase III study selected Ctrough as a co-primary endpoint along with pathological complete response (pCR). Upon initial approval by the EMA in 2013, the data generated in eBC could be extrapolated to metastatic breast cancer (mBC), an indication with the same IV dose and dosing regimen as eBC [44].

The same clinical development concept and adaptive trial design were subsequently implemented for rituximab in B-cell malignancies to bridge from a body surface area-adjusted IV to a fixed SC dosing regimen [45]. In the case of rituximab, conducting clinical trials in healthy volunteers for dose finding was not feasible, necessitating the inclusion of participants diagnosed with follicular lymphoma (FL). Pharmacokinetic-based dose finding and confirmation were performed in participants with FL who responded to IV induction therapy [46], representing a relatively homogeneous and sensitive population with reduced target tissue load. Additional pharmacokinetic and efficacy data were collected in a phase III study in the induction setting, utilizing a 1:1 randomization scheme [47].

Following consultation with European Rapporteurs, supplemental clinical data were required for rituximab indications with different doses and dosing regimens. Consequently, a dedicated pharmacokinetic-based clinical study was conducted in chronic lymphocytic leukemia (CLL) [48], leading to regulatory approval in the EU in 2014. The pivotal studies that supported the filing of the SC formulation in the EU focused solely on Ctrough as the primary endpoint. Similar to trastuzumab, model-based dose selection for rituximab was conducted using available pharmacokinetic data on distribution and elimination from the IV regimen, along with absorption kinetics from the SC studies [46].

Unlike trastuzumab, the initial dose of the rituximab SC regimen is still administered via IV infusion. This deviation is due to the occurrence of sometimes severe infusion-related reactions (IRRs), which can be managed by reducing the infusion rate [49]. This measure was no longer feasible with SC bolus injection.

The SC dosing option for the anti-CD38 monoclonal antibody daratumumab in the treatment of multiple myeloma received authorization from the FDA and EMA in 2020 [5, 8]. In the pivotal phase III non-inferiority study involving individuals with relapsed or refractory multiple myeloma (RRMM), the co-primary endpoints were overall response rate and maximum Ctrough. Participants were randomly assigned in a 1:1 ratio to receive either the SC or IV formulation [50]. Similarly, in 2020, the SC fixed-dose combination of pertuzumab and trastuzumab for HER2-positive breast cancer was approved in both the US and the EU [5, 8]. The clinical development pathway for this combination followed the same approach as described for trastuzumab. Leveraging the established pharmacokinetic-based bridging approach, the Ctrough was the primary endpoint in the pivotal phase III non-inferiority study, while total pathological complete response (tpCR) served as a secondary endpoint [51].

The SC formulation of ravulizumab, an anti-complement component 5 (C5) monoclonal antibody, was approved by the US in 2022 for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA) [5, 8]. The pivotal phase III non-inferiority study for the SC formulation was conducted in individuals with PNH [52], a rare blood disorder with a global prevalence of 16 cases per million people [53]. Participants were enrolled with a 2:1 randomization scheme, receiving either the SC or IV formulation, and had prior treatment with the anti-C5 monoclonal antibody eculizumab. The first dose of ravulizumab was administered intravenously in both groups [52]. The second dose was given 15 days later following the predefined administration route. Subsequently, individuals in the SC arm received weekly doses for the remainder of the trial, while those in the IV arm did not receive additional doses until the primary analysis at day 71, following the approved every 8 weeks (q8w) regimen. After the primary analysis, all participants were offered the option to continue treatment with the SC formulation during an extension period of up to 172 days.

It is worth mentioning that unlike the approved high-volume mAb formulations in oncology, which are available in vial presentations for manual or semi-manual injection using a handheld syringe or infusion pump, SC ravulizumab was developed specifically with an on-body delivery system. This platform had previously received approval for the lipid-lowering anti-proprotein convertase subtilisin kexin type 9 (PCSK9) mAb, evolocumab [5, 8]. The 3.5-mL device was already integrated into the phase III trial described for SC ravulizumab [52].

4.5 Applying the Established Molecule-Agnostic Clinical Development Approach Across Specialty Areas—Ongoing Developments for High-Dose/High-Volume mAbs

Several other high-dose/high-volume mAbs are currently undergoing clinical development across different specialty areas, following the described pharmacokinetic-based bridging approach. For detailed trial designs, refer to Xu et al. [54], who systematically evaluated prior experiences in IV to SC development programs for therapeutic proteins.

In summary, pembrolizumab, nivolumab, atezolizumab in cancer immunotherapy, and ocrelizumab in multiple sclerosis have either completed or are in late-stage clinical development. The manufacturers are utilizing the pharmacokinetic-based clinical bridging approach, incorporating dose-finding studies and non-inferiority assessments with AUC or Ctrough as primary endpoints [20, 55,56,57].

4.6 Accelerating the Molecule-Agnostic Clinical Development Approach—The Target Product Profile

As the focus on healthcare cost and resource optimization grows, along with the demand for at-home dosing options, accelerating the development of SC dosing alternatives for mAbs has become a prominent concern for researchers and drug developers. To progress in a scientifically robust manner, three key questions need to be addressed:

1.

How can the clinical bridging program be streamlined by incorporating predictive nonclinical models, in vitro experiments, and computational tools?

2.

Can evidence from nonclinical and clinical bridging programs be applied to different mAbs and indications?

3.

What optimizations can be made to clinical trial designs and study conduct to achieve earlier key results while maintaining scientific validity?

Manufacturers start with establishing the target product profile for an SC dosing alternative by outlining the desired efficacy, safety, and tolerability profile, dosing regimen, treatment setting, extrapolation to other indications. This approach serves as a basis to define strategies for generating evidence for filing and commercialization (Table 5).

Table 5 The target product profile of an SC dosing alternative for high-dose mAbs

The next section examines the different components of the target product profile and provides an overview of available insights to help expedite the clinical bridging program. It explores the necessity of clinical trial data for bridging from IV to SC dosing, as well as strategies to minimize the size and duration of the development program. Focus is on scenarios where a mAb is currently approved or in advanced stages of clinical development using an IV dosing regimen. The objective for the manufacturer is to develop an SC dosing alternative that demonstrates non-inferior efficacy, safety, and tolerability.

4.6.1 Safety and Tolerability Profile4.6.1.1 Infusion-Related Reactions

When evaluating the advantages and disadvantages of conducting larger clinical trials to bridge between IV and SC formulations of the same mAb, it is crucial to consider the clinical manifestation of potentially severe or fatal infusion-related reactions (IRRs) [58]. These reactions can be associated with cytokine release syndrome, characterized by an increase in inflammatory cytokines occurring approximately 90 min after the first infusion [59]. The incidence and severity of these systemic reactions are carefully assessed as an essential component of all clinical bridging studies [37], and early detection and management of IRRs are mandated [60].

It has been observed that SC dosing of certain mAbs, such as alemtuzumab in multiple sclerosis and daratumumab in multiple myeloma, may reduce the incidence and severity of IRRs. due to slower absorption into the systemic circulation from the interstitial tissue [61, 62]. However, this phenomenon is not consistently observed for all mAbs, and to make marketing claims regarding this potential advantage, manufacturers need to support them with data from clinical trial investigations. Additionally, although there have been advancements in developing predictive nonclinical models for T cell-associated toxicities, this research field is still in its early stages [63]. Therefore, ongoing and future clinical development programs will provide valuable clinical data to further refine and improve these predictive models.

4.6.1.2 Immunogenicity

SC mAb administration is perceived to have a higher immunogenicity risk compared with IV infusion, potentially due to lymphatic absorption [64]. Anti-drug antibodies (ADAs) can neutralize the mAb, affecting efficacy and causing adverse immune reactions [65].

Significant advancements have been made in the development and validation of nonclinical models and computational technologies to predict the immunogenicity risk of mAbs [66, 67]. While these models provide valuable insights and aid in mAb selection, they cannot fully replace clinical immunogenicity assessments. Nonclinical data cannot directly translate to human responses, and ADA formation varies between individuals. Additionally, factors like product ingredients, impurities, aggregation, and subvisible particle concentration can also trigger ADA formation [68]. Therefore, it is essential to evaluate the potential impact of SC dosing on the immunogenicity profile of mAbs in clinical trials. These trials assess the presence of ADAs that may interfere with the biological and clinical activity of the mAb, both at the population and individual level. By obtaining early data, clinicians can develop appropriate strategies to manage immunogenicity risks [69].

For detailed information on the conduct of clinical immunogenicity assessment, it is recommended to refer to the guidelines provided by the FDA and EMA [70, 71].

4.6.1.3 Local Tolerability

Local injection-site reactions are a common side effect with the SC administration of mAbs (refer to USPI and SmPC for trastuzumab, rituximab, daratumumab, pertuzumab-trastuzumab fixed-dose combination [5, 8]). These reactions are typically mild and temporary, characterized by symptoms such as erythema, pruritus, pain, inflammation, rash, induration, itching, and edema [72]. Various factors can contribute to the occurrence of local manifestations, including the mAb formulation (such as pH, volume, excipients), administration technique, and individual characteristics such as body weight, gender, and age [73, 74]. Consequently, local tolerability data for each specific SC mAb presentation need to be collected early in the development process. This data can be obtained through preclinical models and further complemented by clinical data, ideally collected during early dose-finding studies. Ongoing efforts are focused on developing models that simulate large-volume mAb injections using anisotropic porohyperelastic models and data-driven tissue layer geometries, aiming to enhance the understanding of the underlying mechanics and transport processes [75].

4.6.2 Efficacy Profile

The pharmacokinetic-based bridging approach has become the standard method for developing SC dosing alternatives for mAbs with IV infusion regimens. Initially, both pharmacokinetic and efficacy measures were used as co-primary endpoints, but recent development programs have focused on pharmacokinetic parameters as the only primary endpoint. This shift is supported by  the available clinical evidence showing that despite lower Cmax levels, SC versions of a given mAb exhibit non-inferior efficacy to the IV formulation when overall mAb exposure (AUC) and Ctrough are comparable. Nonclinical xenograft models for trastuzumab and rituximab have further validated the acceptability of this approach in regulatory evaluations, demonstrating that the described differences in Cmax do not significantly impact tumor growth inhibition [38,