EMA and FDA response to concerns regarding extrapolation of clinical data
| Concern | EMA | FDA | Points to consider |
|---|---|---|---|
| MOA may be distinct in each therapeutic indication | Extrapolation will be considered on a case-by-case basis. Where the MOA differs between indications or are not fully understood, separate clinical trials are likely to be necessary | For instance, separate trials are likely to be necessary for rheumatology versus oncology. | |
| For a given MOA, several mechanisms may exist | Almost superimposable biological data must be provided, covering all functional aspects of the agent, even if not considered clinically relevant. Where MOA are not fully understood, separate clinical trials are likely to be necessary | ||
| Risk of undertreating patients/varied safety profiles in different patient groups | Data should be produced using a patient population and clinical endpoint most sensitive to detect clinically meaningful differences in efficacy and safety | Disease activity at baseline represents an important variable related to outcome measures in RA—likely to have limited impact on a direct comparison between biosimilar and reference products when sensitive measures are used, but needs consideration when efficacy is compared with reference product trials. | |
| Individual patient characteristics may influence the response | Homogeneous population should be used—differences in response can then be attributed to the biosimilar. | Careful consideration must be given to comorbidities/concomitant medications and intersubject variability. | EMA approach—it will be difficult to identify a homogeneous population for a heterogeneous condition such as RA |
EMA, European Medicines Agency; FDA, Food and Drug Administration; MOA, mechanism of action; RA, rheumatoid arthritis.