[Editor’s Note]

Drug development is often described as “a journey where failure is more familiar than success.” In particular, designing clinical trials aligned with global standards and engaging effectively with overseas regulatory authorities remain among the greatest challenges faced by Korean pharmaceutical and biotech companies. In response to this unmet need, The Bio is launching a new expert column by Hanlim Moon, CEO of MediRama.

Dr. Moon is a seasoned veteran who has spent decades at global big pharma companies, experiencing the entire process of oncology drug development and personally navigating the thresholds of major regulatory agencies worldwide. As both a medical doctor and a clinical development strategist, his deep insights are expected to serve as a practical guide for companies attempting to cross the “valley of death” between nonclinical and clinical development. Published monthly, this column aims to become a practical playbook—covering key tactical approaches at each stage of drug development as well as in-depth analyses of regulatory review trends at global agencies. This column is highly recommended for professionals in the pharmaceutical and biotech industry targeting the global market.

Antibody–drug conjugates (ADCs) are a therapeutic platform that combines the target specificity of monoclonal antibodies with the potent anticancer activity of small-molecule cytotoxic payloads. Over the past two decades, ADCs have demonstrated sustained growth within the field of oncology drug development. In particular, since 2019, ADCs targeting HER2, TROP2, Nectin-4, tissue factor, and other antigens have been approved in succession, establishing ADCs as an important treatment option across both solid tumors and hematologic malignancies¹.

Despite this quantitative and qualitative expansion, systematic analyses of how clinical pharmacology data have actually been utilized in FDA regulatory decision-making during ADC development have been limited. Prior to the FDA’s publication of Clinical Pharmacology Considerations for Antibody–Drug Conjugates in 2024, many ADCs were approved in the absence of clear regulatory guidance. As a result, recurring regulatory issues and postmarketing requirements (PMRs) were often perceived only as isolated, case-specific events. Motivated by this gap, the author published a comprehensive review analyzing FDA-approved ADCs from 2000 to 2025, focusing on clinical pharmacology assessments and regulatory decision-making¹.

To share the key findings of this review with a broader audience of developers and clinical development professionals, the author also delivered lectures on this topic as part of the MediRama EDGE program. Building on that lecture content, this article reorganizes and expands the repeatedly observed FDA clinical pharmacology review points into an academic review format, with the goal of more clearly conveying the regulatory significance of clinical pharmacology data from an ADC developer’s perspective.

Structural Characteristics of ADCs and Clinical Pharmacology Evaluation Centered on Bioanalytical Approaches

ADCs are complex constructs composed of an antibody, a linker, and a payload. In vivo, multiple analytes coexist, including intact conjugated ADC, total antibody, unconjugated antibody, free payload, and active metabolites²,³. Due to these structural characteristics, ADC clinical pharmacology assessment cannot rely on a single analytical metric. The FDA requires each component to be defined as a distinct analyte and quantitatively evaluated accordingly. This principle forms the foundation of pharmacokinetic (PK) and exposure–response (E–R) analyses and underpins ADC clinical pharmacology evaluation as a whole².

A review of historical FDA approval cases reveals that early ADC development programs often failed to fully address these requirements. In particular, payload exposure assessments frequently relied on ELISA-based methods, which were limited in their ability to clearly distinguish free versus bound payload or to accurately capture low systemic exposure levels. Consequently, clinically interpretable exposure data were often insufficient, and the adoption and validation of LC-MS/MS-based analytical methods were repeatedly identified as critical deficiencies during regulatory review¹.

Within this context, the FDA now views bioanalytical strategy in ADC development not merely as a technical support function, but as essential infrastructure enabling clinical pharmacology interpretation and regulatory decision-making. Inadequate assay sensitivity, specificity, or long-term stability have repeatedly resulted in PMRs, underscoring that without an appropriate bioanalytical approach, exposure–response analyses, dose justification, and overall safety assessments may be fundamentally limited¹. Ultimately, the adequacy of the bioanalytical approach in ADC development has become a regulatory determinant directly affecting approvability, rather than an isolated experimental consideration.

Central Role of Exposure–Safety Relationships in FDA Regulatory Decisions

A comprehensive review of ADC approval cases shows that while exposure–efficacy relationships were often inconsistent across drugs and indications, exposure–safety relationships were repeatedly used as key evidence in regulatory decision-making¹. Serious adverse events such as hepatotoxicity, veno-occlusive disease, and interstitial lung disease demonstrated relatively consistent correlations with ADC or payload exposure¹.

A representative example is gemtuzumab ozogamicin (Mylotarg). Despite dose reductions, no clear loss of efficacy was observed; however, a correlation between increased early exposure (Cmax) and the risk of veno-occlusive disease was identified. As a result, safety-based dose optimization became a central regulatory rationale¹. This case illustrates that efficacy signals alone are insufficient in ADC development, and that safety-driven clinical pharmacology interpretation plays a decisive role in shaping regulatory strategy.

Expanding Regulatory Expectations for Intrinsic Factors and Drug–Drug Interactions

In recent ADC approvals, regulatory expectations regarding patient-specific factors have continued to expand. Body weight, racial and ethnic distribution, and pharmacokinetic changes in patients with hepatic or renal impairment have been repeatedly reviewed, with PMRs or postmarketing commitments (PMCs) imposed when data were insufficient¹.

Drug–drug interactions (DDIs) have also emerged as a critical consideration. When payloads are substrates of CYP enzymes or transporters, ADCs may carry DDI risks similar to those of small-molecule anticancer agents. Accordingly, the FDA has called for systematic evaluation through relevant guidance documents². More recently, the potential for combination use with antibody therapies such as FcRn (neonatal Fc receptor) inhibitors has also come under consideration, further broadening the scope of ADC clinical pharmacology assessment¹.

Regulatory Considerations for Immunogenicity Assessment

Immunogenicity was previously regarded as a supplementary assessment in ADC development, but recent FDA approval cases have highlighted its growing regulatory importance¹. ADCs may generate novel structural epitopes not only from the antibody itself, but also from the linker–payload conjugation, thereby posing a risk for anti-drug antibody (ADA) development².

While ADA assessments were conducted in most approved ADCs, there was variability in whether neutralizing antibody (nAb) evaluations were performed and in the depth of their analyses¹. In cases where nAb assessments were omitted or assay drug tolerance was inadequate, these limitations frequently resulted in PMRs or PMCs. This trend suggests that the FDA places greater emphasis on the completeness of functional immunogenicity assessment rather than on ADA incidence alone.

Clinical Pharmacology Implications for ADC Development Strategy

In summary, clinical pharmacology in ADC development is no longer viewed as a supportive analytical discipline, but rather as a core strategic component that directly influences regulatory decision-making. From early development stages, it is critical to establish clear analytical strategies for the ADC and each of its components, and to build dose justification frameworks centered on safety-based exposure–response relationships.

Furthermore, comprehensive clinical pharmacology evaluations encompassing patient factors, drug–drug interactions, and immunogenicity are essential to minimizing the likelihood of post-approval regulatory obligations. A systematic understanding of the recurring clinical pharmacology issues observed in prior approvals—and proactive integration of these insights into early development strategies—represents the most practical approach to reducing uncertainty in future ADC development programs.

1. Koo S, Kim C, Lim JH, Lee E, Kim Y, Sung S, Moon H.
A review of clinical pharmacology considerations in antibody–drug conjugates approved by the US Food and Drug Administration between 2000 and 2025.Transl Clin Pharmacol. 2025;33(4):197–211.

2. U.S. Food and Drug Administration.
Clinical Pharmacology Considerations for Antibody–Drug Conjugates: Guidance for Industry.
Silver Spring, MD: FDA; March 2024.

3. U.S. Food and Drug Administration.
Safety Testing for Metabolites: Guidance for Industry.
Silver Spring, MD: FDA; March 2020.

 

Source: The Bio (https://www.thebionews.net)