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Summary of the Immunogenicity: Understanding the Regulatory Philosophy workshop, 13-14 October 2014, Munich, Germany


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The 2nd EUCRAF Immunogenicity workshop was successfully held 13-14 October 2014 in Munich. This time the title was “Understanding the Regulatory Philosophy” and the event gathered around 40 participants from pharma and biotech companies from Austria, Germany, Denmark, Finland, France, Korea, Poland, Switzerland, US and the UK. The workshop presented an opportunity for participants to interact with Prof. Pekka Kurki from the Finnish Medicines Agency, a leading regulatory expert who has been closely involved in defining the EU regulatory requirements, and Paul Chamberlain, from Biopharma Excellence and NDA Advisory Board, a biopharmaceutical expert involved in the developing of immunogenicity packages of regulatory dossiers for diverse product types. In addition, Dr. Markku Toivonen from NDA Advisory Board also participated in the panel discussion. Dr. Gabriele Dallmann, from EUCRAF and Biopharma Excellence, moderated the workshop.

The workshop aimed to discuss suitable approaches for satisfying regulatory expectations for presentation of the information required to enable a balanced assessment of risks of undesirable immunogenicity. Besides that, it provided a forum for discussions on recent developments in the field of immunogenicity assessment and its contribution to the overall benefit risk conclusion.

A traditional Bavarian buffet dinner was organized at the Augustiner Keller Brewery on the evening of the first day. It was truly a unique experience as the dining area is located at the basement, at almost ten meters underground of the historic building.

The workshop was divided into five sessions in which participants were actively engaged in the discussion of scenarios and case studies. Major outcomes of the sessions are highlighted in the following:

Session 1: Overview of regulatory philosophy

Session 1 started with a comprehensive introduction to the EMA regulatory guidelines pertaining to immunogenicity (please see the list of the guidelines below). Pekka Kurki mentioned that the Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (EMEA/CHMP/BWMP/14327/2006) is currently under revision. This revision is expected to provide valuable guidance on the marketing authorisation application process for biotechnology-derived proteins. It was discussed that often there is confusion between the term antigenicity and immunogenicity. From the regulatory point of view, immunogenicity is the ability to induce a human humoral and/or cell-mediated immune response, whereas antigenicity is the ability to combine specifically with the final products of the immune response such as secreted antibodies and/or surface receptors on T-cells. Therefore, all therapeutics proteins that are immunogenic have the property of antigenicity, but not all proteins with antigenicity property will be immunogenic in man. The trigger of antigenicity doesn’t necessarily trigger a regulatory concern, as the significance of immunogenicity has to be evaluated at the clinical level. EMA has developed a risk assessment strategy for therapeutic proteins based on risk stratification. The pending revision of the immunogenicity guideline eventually considers the incorporation of the integrated summary of immunogenicity. From a regulator’s perspective, there is no a single risk-based approach to immunogenicity as it is always adapted to the specific product development program. In general, any approach taken should be fully justified, and it is advisable to seek for Scientific Advice from EMA or the National Competent Authorities if there is deviation to the recommendation from the guidelines.

Session 2: What are the pertinent risk factors?

In Session 2, an introduction to the intrinsic and system biology of immunogenicity was presented. The use of in silico, in vitro, and in vivo tools to predict immunogenicity of a protein therapeutic in terms of its T-helper epitope content and was discussed. There are various factors that cause immunogenicity within a particular system and these can be categorized as disease-related or patient-related. Several case studies were presented to show that factors such as genetics, level of tolerance, age, underlying disease, concomitant treatment, dose, route of administration, schedule and duration of the treatment needed to be considered when assessing the risk for immunogenicity.

Session 3: Evaluation of risks and contribution of immunogenicity assessment to the overall benefit-risk assessment

The basis of evaluation of immunogenicity is the valid set of assays. However, there is no technical guidance available in the EU that is specific for assay development. Case examples of recombinant analogue of endogenous protein, yeast-derived therapeutic protein and biosimilar anti-TNF-mAb were presented to illustrate the impact of product type on the nature of the bioanalytical data package. The evolving technology has resulted in the availability of more sensitive assays that are capable of detecting low levels of anti-drug-antibody (ADAs) that could have no clinical impact on drug distribution, clearance, or efficacy. Therefore, the discussion of the antigenicity results requires understanding of the risk for immunogenicity. This risk can be very different for each individual product. The assays should be validated to provide clinical meaningful data. It is also a worthwhile approach to evaluate narratives of subjects for which immunogenicity was determined, in order to find a correlation between the ADA and clinical symptoms and findings. Data are often presented in a dispersed format and the document is assessed by several regulators in isolation. Hence, a good integrated summary of the details on the immunogenicity assays, clinical trial design and sampling, the assay and clinical results together with the discussion of the risks and measures to mitigate them should be seen as an opportunity to assist regulatory reviewers in understanding the overall immunogenicity package.

Cases of high immunogenicity risk are rare but they have to be taken seriously such as in the case of breaking the immune tolerance to endogenous protein, induction of ADA’s that cross-react with endogenous protein or severe systemic adverse drug reaction (ADR) mediated by ADA or cross-reactive antibodies. If a product is developed with such high risks, they can be adequately managed, provided if these risks are identified early in the development through alignment of the immunogenicity with the non-clinical and clinical data, well analysed and discussed and appropriate risk mitigating measures are identified leading to a positive benefit-risk assessment.

Session 4: Managing uncertainty in the post-authorisation setting

Although the guideline describing the regulatory requirements (please see reference list below) regarding immunogenicity is available, there is still ambiguity in the assessment of immunogenicity in areas such as early clinical trial applications and the post-marketing setting. Several approaches where discussed for the post-marketing setting and the Risk Management Plan (RMP) was identified as one key document to be developed from early development stages. The following measures to monitor and assess risks were discussed:

  • passive and active surveillance
  • access to health care registries
  • risk minimization strategies such as provision of product information in SmPC, educational program to doctors and patients

Special topics such as rare potential adverse effects, immunogenicity in paediatric populations, immunological adverse events following a switch between products, intermittent therapy and de-immunisation may need to be addressed in the RMP.

Session 5: Effective presentation of data in the CTD format

In this session, several approaches were presented on how to write a good and integrated immunogenicity summary. As the speakers of the workshop intend to publish the details regarding the topics discussed as well as on the potential format of the integrated immunogenicity summary, EUCRAF will keep you informed on when this will be out for reading!

Guidelines related to immunogenicity

1. EMA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), EMA/CHMP/BWP/247713/2012, 22 May 2014

2. EMA Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples, EMA/INS/GCP/532137/2010, February 2012

3. EMA Guideline onimmunogenicity assessment of biotechnology-derived therapeutic protein, EMEA/CHMP/BMWP/14327/2006, December 2007

4. EMA ICH guideline S6 (R1) - preclinical safety evaluation of biotechnology-derived pharmaceuticals, EMA/CHMP/ICH/731268/1998, June 2011

5. EMA Concept paper on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use, EMA/CHMP/BMWP/86289/2010, 24 May 2012

6. EMA Concept paper/recommendation on the need for a (CHMP) guideline on the validation of bioanalytical methods, EMEA/CHMP/EWP/531305/2008, 18 December 2008

7. EMA Guideline on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98, August 2010

8. EMA Guideline on non-clinical and clinical developement of similar biological medicinal products containing recombinant erythropoietins, EMEA/CHMP/BMWP/301636/2008, 23 July 2009

By William Chin, PhD, Scientific Coordinator, EUCRAF