Introduction
Protein therapeutics are rapidly improving the current treatment landscape due to their high treatment specificity by avoiding off target effects. However, most of the therapeutic proteins have the potential to elicit immune reactions. Immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy (FDA Guidance.) These ADAs have been shown to affect the drug exposure and may also lead to the loss of efficacy (PMID: 25342759, 22759910, 21486979). ADAs generated due to therapy can also predispose patients to immunological adverse events such as anaphylaxis, cytokine release syndrome, and cross-reactive neutralization of endogenous proteins mediating critical functions leading to negative effect on patient safety and efficacy of the drug (PMID: 20305665, FDA Guidance for Industry: Immunogenicity assessment for Therapeutic Proteins). Thus, it is critical to understand the immunogenicity assessment, formation and detection of ADAs and develop possible strategies to prevent ADA formation, during the drug development process, specifically in the development of biologics and therapeutic proteins. In addition, any information on immune responses observed during the clinical trial is also critical in understanding the effects of ADA responses on the pharmacokinetics, pharmacodynamics, efficacy and safety of these therapeutic proteins.
Integrated Summary of Immunogenicity
The key approach for summarizing the immunogenicity assessment and data for biologic product is Integrated Summary of Immunogenicity (ISI), a critical component of the regulatory submission process. The ISI is a document that details the immunogenicity-related risks for the therapeutic protein, how these risks are evaluated during the clinical development and the strategies required for managing these risks. As both patient-related and product-related factors may affect immunogenicity of therapeutic protein products, both of these factors are critical elements which form an immunogenicity risk assessment (FDA Guidance). The “integrated” summary document describes association between the bioanalytical signals of immune response (ADA) observed with the clinical endpoints, like safety, efficacy, PK and PD and aligns with the potential risk factors for individual clinical studies. (PMID: 30767660).
An ISI is required to be submitted to the regulatory authorities as a part of marketing authorization requirement, thus providing with all the necessary information to understand the nature and extent of the immunogenicity risks for the therapeutic protein at both the population and individual subject levels. This helps the regulatory authorities to make informed decision for clinical trial approval or marketing authorization. The detailed summary of immunogenicity can be submitted in Module 5.3.5.3 (Report of Analysis of Data from More than One Study) of the eCTD, while a brief outline can be presented in Modules 2.7.2.4 (Special Studies: Immunogenicity) and 2.5.3 (Overview of Clinical Pharmacology) of the eCTD (ICH M4E R2). In addition, when applicable this information is also required to be included in the prescribing information summarized in the subsection of ADVERSE REACTIONS.
What are the contents of Integrated Summary of Immunogenicity (ISI)?
An ISI is a comprehensive document that consolidates the data on immunogenicity collected throughout the clinical development of biologics, i.e., during clinical trial and preclinical testing. The key components of ISI typically include:
1. Immunogenicity Risk Assessment
The key part of ISI is determining and evaluating the potential risks that may occur due to immunogenicity assessment and how that might impact the efficacy and safety of therapeutic proteins. For example, the presence of neutralizing antibodies could reduce the effectiveness of a biologic product, while an immune-mediated adverse event (like anaphylaxis) could present safety concerns. The ISI should address the severity and clinical relevance of these impacts. This would also involve identifying the factors influencing immunogenicity, such as product- or patient-related factors that may influence the magnitude and likelihood for immunogenicity and the risks associated.
2. Assay Strategy and Clinical Approach
The ISI would also summarize the bioanalytical assay design strategies for immunogenicity assessment used across different clinical studies, including assay validation (FDA Guidance for Industry: Immunogenicity Testing of Therapeutic Protein Products-Developing and Validating Assays for ADA Detection). ISI should also include the overview of the clinical study designs, and the detailed immunogenicity testing and sampling plans for these studies, including the planned sampling timepoints. It should also detail any justification of risk evaluation relative to product-specific risk assessment.
3. Immunogenicity Testing Data
The ISI should detail the immunogenicity data generated for therapeutic protein summarizing all the findings of immunogenicity analysis from the nonclinical studies, clinical studies and post-marketing studies. The early-stage immunogenicity data derived from both animal studies and in vitro studies includes information regarding the type and magnitude of immune responses in animals. Immunogenicity testing data generated during the different phases of clinical studies typically involves monitoring the occurrence of ADAs, neutralizing anti-bodies (NAbs), and monitoring their effects on pharmacokinetics and efficacy of the biologic product. This section should include a summary of ADA incidence including ADA positive, treatment-induced, an assessment of transient or persistence in ADAs; finally an effect on PK PD, efficacy, and safety
4. The findings from different phases of the studies will help in understating of the effect of different doses and regimens on the immune system over a period.
5. Risk Evaluation and Mitigation Strategies
This section in the ISI summarizes the overall immunogenicity results for therapeutic protein, along with evaluation on the impact of immunogenicity on safety and efficacy in the intended patient population. Any planned risk mitigation strategies regarding how immunogenicity will be monitored in the post marketing stage should also be described in the ISI.
Conclusion
ISI represents an indispensable document in clinical development of therapeutic proteins by effectively presenting all the critical data on immunogenicity assessment and immunogenicity testing of protein therapeutics essential for patient safety and regulatory decision making. ISI ensures there is adequate understanding, assessment and management of immunogenicity at every stage.
Allucent’s team of experienced clinical pharmacologist and scientific writers can help plan and draft ISI in accordance with the current regulatory recommendations for submission to regulatory agencies. To learn more about how Allucent can support and advance your clinical pharmacology efforts, click here.
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