Summary of key principles for extrapolation of indications
| In case the reference product has more than one indication, the efficacy and safety of the biosimilar has to be scientifically justified or, if necessary, demonstrated separately for each of the claimed indications. |
| Factors to be considered for such justification: |
| • Clinical experience with the reference product. |
| • Mechanism(s) of action/active site(s) of the active substance in each indication (including its degree of certainty). |
| • Target receptors involved. |
| • Differences in the safety/immunogenicity profile between the therapeutic indications, including considerations on patient-related factors, such as comorbidities, comedication, and immunologic status; and disease-related factors, such as reactions related to the target cells (eg, lysis of tumor cells). |
| • The degree to which the functional moieties of the molecule can be analytically characterized and compared. |
| The extent of data required and the regulatory decision on acceptance of extrapolation will, among other things, involve the following considerations: |
| • Totality of the evidence of biosimilarity derived from the comparability exercise (ie, how close is the resemblance of physicochemical and functional characteristics, of pharmacokinetic profiles and pharmacological effects of the biosimilar to the reference medicinal product). |
| • Potential remaining uncertainties (eg, based on overly insensitive [or overly sensitive] analytical or functional assays. |
| • Acceptable clinical safety profile must have been established for the biosimilar. |
| • Increased immunogenicity of the biosimilar must have been reasonably excluded. |
| • Extrapolation of immunogenicity is only possible from high- to low-risk patient populations and clinical settings (eg, from SC to IV route of administration or from immunocompetent to immunocompromised patients, but normally not vice versa). |
| • Additional tests or studies may be needed to further support extrapolation, which should, if available, preferably include relevant pharmacodynamic parameters and/or specific functional assays reflecting the pharmacologic action(s) of the molecule; clinical studies using outcome endpoints are usually less sensitive to detect potential differences between the biosimilar and the reference product. |
| In case the reference product has more than one indication, the efficacy and safety of the biosimilar has to be scientifically justified or, if necessary, demonstrated separately for each of the claimed indications. |
| Factors to be considered for such justification: |
| • Clinical experience with the reference product. |
| • Mechanism(s) of action/active site(s) of the active substance in each indication (including its degree of certainty). |
| • Target receptors involved. |
| • Differences in the safety/immunogenicity profile between the therapeutic indications, including considerations on patient-related factors, such as comorbidities, comedication, and immunologic status; and disease-related factors, such as reactions related to the target cells (eg, lysis of tumor cells). |
| • The degree to which the functional moieties of the molecule can be analytically characterized and compared. |
| The extent of data required and the regulatory decision on acceptance of extrapolation will, among other things, involve the following considerations: |
| • Totality of the evidence of biosimilarity derived from the comparability exercise (ie, how close is the resemblance of physicochemical and functional characteristics, of pharmacokinetic profiles and pharmacological effects of the biosimilar to the reference medicinal product). |
| • Potential remaining uncertainties (eg, based on overly insensitive [or overly sensitive] analytical or functional assays. |
| • Acceptable clinical safety profile must have been established for the biosimilar. |
| • Increased immunogenicity of the biosimilar must have been reasonably excluded. |
| • Extrapolation of immunogenicity is only possible from high- to low-risk patient populations and clinical settings (eg, from SC to IV route of administration or from immunocompetent to immunocompromised patients, but normally not vice versa). |
| • Additional tests or studies may be needed to further support extrapolation, which should, if available, preferably include relevant pharmacodynamic parameters and/or specific functional assays reflecting the pharmacologic action(s) of the molecule; clinical studies using outcome endpoints are usually less sensitive to detect potential differences between the biosimilar and the reference product. |
Biosimilar: A biosimilar is a biological medicinal product that contains a (copy) version of the active substance of an already authorized original biological medicinal product (reference medicinal product). A biosimilar establishes similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise.
Extrapolation: The regulatory and scientific process of granting a clinical indication to a medicine without own/new clinical efficacy and safety data to support that indication. Extrapolation has been widely exercised, for example, for originator biologicals after changes in their manufacturing process.
Originator/original product: A medicine that has been licensed on the basis of a full registration dossier consisting of quality, nonclinical and clinical data; each approved indication for use was granted on the basis of own efficacy and safety data.
Reference product: A reference product is used as the comparator in head-to-head comparability studies with the biosimilar product to show similarity in terms of quality, safety, and efficacy. Only an originator product that was licensed on the basis of a full registration dossier can serve as a reference product.
Comparability exercise: Head-to-head comparison of 2 versions of a biological medicine with the goal to establish similar quality, safety, and efficacy. It is used to compare, for example, a postchange product with the prechange version when the manufacturing process is changed, or a biosimilar with its reference medicine.
Totality of (the) evidence: A scientific principle that, in the context of biosimilars, establishes biosimilarity by using an extensive set of decisive methods sensitive enough to detect relevant differences, if present. These methods involve a large battery of state-of-the-art physicochemical, analytical, and functional methods and clinical studies.