Comments from the AAPS Ligand Binding Assay Bioanalytical Focus Group and the Therapeutic Product Immunogenicity Focus Group
By Shannon Dogmanits and Joseph C. Marini
Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins
On 24 September 2015, the European Medicines Agency (EMA) released a draft Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins EMEA/CHMP/BMWP/14327/2006 Rev. 1. This draft revises the previous guideline, effective April 2008, which provided general recommendations for conducting a systematic evaluation of immunogenicity from a marketing authorization perspective.
Therapeutic biological/biotechnology-derived antibodies and proteins have the capacity to induce an immune response in patients, leading to the development of anti-drug antibodies (ADA). Although the potential for immunogenicity has been substantially reduced using enhanced protein engineering technologies, the consequences of unwanted ADA can range from no clinical significance to the loss of efficacy of the therapeutic, to severe life-threatening conditions such as anaphylaxis or cross-reactivity with the endogenous target.
The revised draft guideline aims to increase the quality of the immunogenicity risk assessment and management programs both pre- and post-authorization. This draft was revised based on EMA experience from marketing authorization applications and extensive knowledge gathered by the agency over time. It details more specific requirements for the development and validation of assays used to detect and measure ADAs in humans, and it describes how the assessment of risk and investigation of immunogenicity should be based on an integrated analysis of the immunological, pharmacokinetic, and clinical efficacy and safety data to better understand the clinical consequences.
In January 2016, the Ligand Binding Assay Bioanalytical focus group (LBABFG) and the Therapeutic Product Immunogenicity focus group (TPIFG) worked together to conduct an in-depth review of the draft. A “comment document” was assembled to compare the new draft guideline to the current guideline to point out changes. The comment document was then sent to members of both the LBABFG and TPIFG Steering Committees for their review and comments. AAPS members were also given the opportunity to review and email their feedback. Comments were consolidated from pharmaceutical and biotechnology companies, contract research organizations, consultants, and other interested individuals. The LBABFG and TPIFG reviewed, refined, and clarified the comments before sending them to their leadership teams for review and approval. The approved comments were then sent to the AAPS Executive Council for review and approval before being submitted to EMA on 31 January 2016. To date, the EMA has not published an overview of these comments. However, once published, they can be found on the EMA website.
Following submission of the comments, the EMA Working Parties Secretariats invited five members of the LBABFG and TPIFG to participate in an EMA-sponsored invitation-only workshop to discuss issues raised during public consultation. In addition, EMA invited other members of the LBABFG and TPIFG to participate in the workshop as speakers. The Workshop on immunogenicity assessment of biotechnology-derived therapeutic proteins took place on 09 March 2016 in London. Other participants included experts from the Committee for Medicinal Products for Human Use, Biosimilars Medicinal Products Working Party, Biologics Working Party, other regulatory authorities, and stakeholders who provided comments on the draft guideline.
The workshop complemented the external consultation with a discussion among the experts on the key issues relevant to the assays and methods used to explore and assess the immunogenicity of therapeutic proteins. It focused on:
- the development of adequate assays for detecting and measuring immune response in humans, including challenges in assessing relative immunogenicity;
- innovative nonclinical models that could better predict immunogenicity of biotechnology-derived therapeutic proteins in humans; and
- immunogenicity and risks associated with the use of products containing therapeutic proteins including pharmacovigilance aspects.
The various AAPS participants were excited to represent the submitted comments in person and to have their voices heard. The general consensus is that this revised guidance, once implemented, will meet the needs of the immunogenicity bioanalytical community.