Immune responses toward therapeutic proteins may cause significant adverse effects, such as loss of efficacy, hypersensitivity and autoimmunity. For that reason, it is imperative to assess the potential of therapeutic proteins along and beyond the pre-clinical and clinical development phases. In consequence, an increasing body of evidence is created along the product’s lifecycle, encompassing multiple and diverse aspects of its immunogenicity potential.
These accumulating data typically become more complex as time goes by, since they stem from different sources and studies. Therefore, in order to be clinically meaningful, they must be assessed in a comprehensive and integrated manner.
In this setting, one of the points that is key to allow that assessment by regulators during applications for marketing authorization in a timely and efficient way is the effective presentation of the relevant information in regulatory dossiers.
Up to some years ago, these data were usually scattered along different modules of the Common Technical Document (CTD), making it difficult to find them embedded in sections of the document that were not exclusive for immunogenicity.
Moreover, dossiers traditionally provide summary presentations of results of risk evaluations, instead of explaining the immunogenicity factors related to product and patients that can influence efficacy and safety. The resulting uncertainty generated on whether some risks were properly addressed frequently triggered regulatory questions and delays.
A recently proposed integrated summary of immunogenicity (ISI) has been considered helpful by regulators and is becoming the standard for that purpose. It allows the integration of the risk analysis with the risk evaluation and mitigation aspects. Its preparation should start as soon as the lead candidate is selected, and it should be updated along clinical development.
Some points are key in the successful preparation of the ISI. Neglecting them may lead to information gaps and uncertainties.
Risk factors to immunogenicity reactions must be adequately understood, by observing aspects related to the product itself, the target population, the indication, as well as usual concurrent diseases and concomitant medications.
The strategy adopted to assess immunogenicity potential (including anti-drug assays and pharmacokinetic [PK] studies) must be properly described and justified. A meaningful link between risk assessment, related clinical observations and risk mitigation must be made explicit. This is done by correlating the observations of the biochemical and immunological assays with PK data, pharmacodynamic data and clinical information.
The overall impact of immunogenicity on the benefit-risk balance of the product must be assessed. Measures to assess the risks and vulnerable subpopulations in the clinical setting must be proposed. If applicable, mitigation strategies must be described and justified.
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