Integrated Summary of Immunogenicity (ISI) – an effective approach for reducing regulatory risk
Paul Chamberlain and Gabriele Dallmann summarise in the following the main aspects of the Integrated Summary of Immunogenicity as presented during a one-day workshop.
All therapeutic proteins, even those that share a common structure sequence with endogenous human proteins, have an intrinsic potential to induce undesirable immunogenicity in human subjects. An exogenous medicinal product can cause an immune response, i.e. immunogenicity, involving:
- Antigen-binding to pre-existing antibodies
- Induction of anti-drug antibodies (ADA)
- Stimulation of B/T-lymphocytes
- and/or innate immune effector cells
- Or a combination of these mechanisms
This would be regarded as an unfavourable effect if there were a potentially negative impact on the overall clinical benefit-to-risk conclusion. Thus, the determination of the immunogenicity potential and its clinical impact is an essential element of the development package of a novel or biosimilar protein.
Depending on various factors, proteins may have different risks levels for immunogenicity:
Furthermore, in order to discuss this for every product, there is also a methodological bias to be considered:
1. ADA assays do not directly measure immunogenicity:
- They only measure antigenicity in vitro
- Immunogenicity is inferred by pre- versus post-treatment difference’
2. Different assay methods give different results
- Percentage of ADA incidence and titer is highly assay-dependent
- Common standards do not exist (for assay controls or methodology)
- Relevant historical data do not exist
- ADA assays for therapeutic monoclonal antibodies are highly susceptible to interference by residual drug
Thus, bioanalytical signals must be interpreted by correlation with relevant clinical endpoints. Furthermore, comparison of immunogenicity data of different products is fully inadequate.
One of the recently published draft guidelines introduces this concept together with an extremely well structured proposal on how to present the immunogenicity data for a therapeutic protein subject to regulatory review:
Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. Draft. EMEA/CHMP/BMWP/14327/2006/Rev. 1
This document, published in September 2015 and currently under finalisation at the EMA, updates an earlier guidance. Now it particularly emphases the concept of the “Integrated data analysis and presentation”, which is fully suitable and necessary as there are not many areas which require an interdisciplinary approach as the immunogenicity area does.
This inter-disciplinary work has also operational consequences, i.e. where to place the Integrated Summary of Immunogenicity (ISI) in the CTD? The ICH and CHMP recommendations are to include this as Section 184.108.40.206 of the CTD format; although, in our experience of submitting the ISI since 2008, both EU and US regulatory authorities have accepted this as Section 220.127.116.11 – which allows additional flexibility to incorporate the data analyses that are essential to interpret impact on overall clinical benefit and risk.
The four main headings of the ISI and the main expected content are listed in the following:
1. Analysis of risk factors
- Previous experience of product / product class
- Physicochemical & structural aspects
- Conditions of use
- Patient- & disease-related factors
- Intrinsic immunogenic potential
- Expression system / Post-translational modification
- Stability / impurities
- Formulation & packaging
Remember: Understanding the nature of the risk is fundamental to controlling risk!
2. Risk-based immunogenicity program
- Bioanalytical (ADA assay) strategy
- Clinical evaluation plan
- Justification of risk evaluation relative to product-specific risk assessment
- Note: PK assay also critical
The important feature here is to include assay to measure free (active) drug!
3. Immunogenicity results
- Incidence of ADA, including nAbs
- ADA titers vs. time
- ADA vs. PK
- ADA vs. PD, efficacy and safety
- Impact of pre-existing ADA’s
The important feature here is to correlate the data!
4. Conclusions on the risk(s) of immunogenicity
- Impact on overall clinical benefit/risk
- Tools to manage risk
- How to link adverse events observed during post-authorisation phase to immunogenicity risk
- Identification of risk groups
- Threshold level for negative clinical impact
- Risk detection & mitigation tools
Section 1 of the ISI, “Analysis of risk factors”, could be included as part of the IMPD and IND documentation used to support clinical trial applications from Phase 1 onwards. This risk analysis can be iteratively updated to reflect the results of clinical studies. Accordingly, beginning this process at the earliest stage of biopharmaceutical product development can help to reduce regulatory risk during clinical development.
Please do not hesitate to ask us if you need support in
- defining the immunogenicity risk mitigation strategy for a novel product or a biosimilar candidate,
- advice on design of the evaluation programme,
- assistance with preparation of the appropriate regulatory documentation,
- writing the ISI (Integrated Immunogenicity Summary).