Handbook for health care professionals on biosimilar biologic drugs: Immunogenicity

Addressing a key safety issue: immunogenicity

Biologic drugs are large molecules, usually given by injection. They can stimulate/activate the body's immune system, potentially producing anti-drug antibodies (ADA). This is called immunogenicity.

Often, immunogenicity can only be detected using sophisticated laboratory tests and has no impact on the patient. In other cases, immunogenicity can affect patient safety by causing an adverse reaction or by reducing the drug's efficacy. A number of different factors (Table 2) can influence the immunogenicity of a biologic drug.

For these reasons, biosimilar authorization needs an assessment of immunogenicity. This usually requires studies showing that there are no expected clinically meaningful differences in immunogenicity between the reference biologic drug and the biosimilar. The investigation of immunogenicity is usually part of the pivotal comparative safety and efficacy clinical trials.

Source: Schellekens, H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457-62.

Figure 2 - Text description

The following may affect the immunogenicity of a biologic drug:

• small variations in the amino acid sequence
• post-translational modifications such as glycosylation
• impurities and contaminants introduced through the production process
• formulation of the drug (for example, non-medicinal ingredients)
• length of treatment
• route of administration
• patient characteristics
• dosage
• other factors

It's important to remember that the type of assay used to detect immunogenicity may itself have an impact on the detection of immunogenicity.

The comparative study or studies should characterize:

• the time-course of ADA development
• how long the ADA persist in the body
• the impact of ADA on the biosimilar's:
  • safety
  • efficacy
  • pharmacokinetics
• the incidence and magnitude of any ADA response

The manufacturer must also file a risk management plan (RMP) explaining how they will monitor immunogenicity after the biosimilar has been authorized. The RMP monitors and detects known inherent safety concerns and potentially unknown safety signals that may result from the biosimilar's impurity profile and other characteristics. The biosimilar sponsor should continue to assess unwanted immunogenicity and its clinical significance following market authorization.

For more information on RMPs, refer to the Monitoring safety and effectiveness section.

For details on the requirements for immunogenicity testing, consult:

• Guidance document: Information and submission requirements for biosimilar biologic drugs