Author byline as per print journal: Sandeep N Athalye1, MBBS, MD; Dev B Baruah1, MPharm; Shivani Mittra1, MPharm, PhD; Ankit Ranpura1, MD; Kuldeep Kumar1, PhD; Elena Wolff-Holz2, MD

Abstract:
Ethnic sensitivity assessments in the form of bridging pharmacokinetics (PK) studies are often needed for biosimilar monoclonal antibodies (mAbs) to meet regulatory requirements in regions like East Asia. However, mAbs exhibit properties that make them less likely to be affected by ethnic differences, as they do not undergo traditional drug-related metabolism like liver and gut metabolism, unlike small molecule drugs. Current literature indicates that ethnicity generally does not influence the PK, pharmacodynamics (PD), safety, and efficacy of most mAbs. For instance, the recommended doses for most mAbs are similar or have no difference between non-Japanese and Japanese patients. Despite these findings, dedicated Ethnic Sensitivity Studies (ESSs) are still routinely required for approval in countries of East Asia such as Japan, South Korea, China, and Taiwan. This article argues that such requirements should be reconsidered based on the available data on the reference drug rather than being a default obligation in biosimilar development of mAbs. ESSs are not only questionable but also costly and time-consuming for biosimilar mAbs. Eliminating such a requirement could accelerate the development of biosimilar drugs while maintaining safety and efficacy standards, facilitating access to these life-saving therapies across the globe.

Submitted: 21 June 2023; Revised: 26 July 2023; Accepted: 27 July 2023; Published online first: 9 August 2023

Pharmaceutical and biotechnology companies develop new drug products through multi-regional/global clinical trials to register the product in multiple geographies. In these clinical trials, various parameters such as pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy are typically evaluated to establish the drug’s effectiveness and safety profile. As variability in drug exposure and response can be affected by several complex factors, including race and ethnicity, these can sometimes become a rate-limiting step toward product registration [1]. The ICH E5 guidance deals specifically with the role of ethnic factors in the acceptability of foreign clinical data and suggests frameworks to facilitate the review and registration of global trials [2]. Often, to account for potential ethnic variability, bridging studies (e.g. a local phase I PK/PD comparability study or a phase II/III randomized controlled clinical study) or inclusion of subjects with particular ethnic backgrounds in multi-regional clinical trials (MRCTs) are needed to assess a drug’s sensitivity to ethnic factors and to support its registration in specific markets, particularly in countries within East Asia, see Table 1 [3-8].

These requirements for conducting bridging studies also extend to biological products like monoclonal antibodies (mAbs), which, unlike small molecule drugs, do not undergo traditional drug-related metabolism, see Figure 1 [9].MAbs are administered parenterally and reach systemic circulation, either directly (by intravenous (IV) route) or through the lymphatic system (by subcutaneous (SC) or intramuscular (IM) routes). MAbs being large therapeutic proteins are mostly confined to the vascular space, with substantially reduced extravascular concentrations relative to their presence in the vasculature [10]. The elimination of mAbs from the body is primarily facilitated by intracellular catabolism via lysosomal degradation after uptake into cells by either pinocytosis, an unspecific fluid-phase endocytosis, or by a receptor-mediated endocytosis process [11]. Definitive statements regarding the impact of race/ethnicity on drug exposure are often not found on biologicals labels. Body weight and body surface area are the most commonly identified covariates (82%) in population PK models for mAbs [12], and the effect of race/ethnicity or gender on PK is generally insignificant after differences in body weight are considered [13, 14].

The ICH E5 guidelines acknowledge that ethnic factors may not affect all drugs. Therefore, the guidelines recommend characterizing a drug’s potential sensitivity to ethnic factors regarding its PK, PD, and therapeutic effects to determine the type of bridging study needed in a new region [2]. The guidelines specify a list of properties that would make a drug less likely to be sensitive to ethnic factors, such as minimal metabolism, high bioavailability/low susceptibility to dietary absorption effects, and little potential for food and drug interactions. As mentioned earlier, these properties are inherently related to almost all mAbs and make them less likely to be affected by ethnic differences. ICH E5 guidelines also state that in certain situations where a medicine under evaluation is categorized as ethnically insensitive and extrinsic factors in the two regions/countries are generally similar, extrapolation of clinical data might be feasible without a bridging study. Notwithstanding, pharmaceutical companies routinely carry out Ethnic Sensitivity Studies (ESS) for mAbs as a preemptive measure to comply with regulatory demands and facilitate their entrance into new markets, such as East Asia.

Based on the currently available evidence, we believe that the decision to proceed with or without ESS should be evidence-based, considering available information on the reference drug rather than being a mandatory obligation in biosimilar development programmes. This perspective is grounded in the widely accepted principle that experience with the reference product serves as the cornerstone, and the primary objective of biosimilar development is to demonstrate that the purity, potency, safety, and efficacy of the biosimilar are comparable to the reference product, rather than independently establishing the safety and effectiveness of the biosimilar [15]. In this context, we assess the feasibility of excluding ethnic sensitivity assessments such as dedicated phase I bridging trials from the clinical development programmes of biosimilar mAbs.

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This manuscript has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.