When faced with the prospect of proving pharmacokinetic “equivalence” of a biosimilar to an innovator biologic, it may be natural to assume that standard bioequivalence study designs and analysis methods would be sufficient to meet the objectives of the study; after all, such study designs have been successfully employed for many years to bring generic drugs to market. However, there are a number of characteristics of biologics which set them apart from traditional generic drugs, as summarised in Table 1, below.
Table 1: Typical characteristics of traditional generic drugs compared to biologics
|
Traditional Generics |
Biologics |
|
|
Molecular Structure |
Simple, relatively small (up to 300 Da) |
Large complex proteins (up to 270,000 Da) |
|
Synthesis |
Chemically sythesised structure identical to reference drug |
Compounds produced by cell lines are similar, but not identical, to reference drug |
|
Typical Dosing Route |
Oral preffered |
Intravenous or subcutaneous necessary |
|
Typical Half-Life |
0.5-8 hours |
1-6 weeks |
|
Anti-Drug Antibody Formation |
Not applicable |
Possible formation which can affect pharmacokinetic properties |
Since innovator biologics were first introduced in the 1980s, sales have grown considerably year-on-year, and by 2011 global sales had reached approximately 142 billion USD (equivalent to 19% of the global biopharmaceutical market) with more than a third of this attributed to the top ten biologics. However, the period of exclusivity for these top 10 biologics is fast approaching, with a patent cliff anticipated between now and 2019. This patent cliff creates an enormous opportunity to develop generic versions of biologics (commonly referred to as biosimilars).
Although the route to market for traditional generics is well defined and has been successfully negotiated for many drugs over the years - typically a small number of studies in healthy volunteers are sufficient to prove physiochemical and pharmacokinetic equivalence - the corresponding route to market for biosimilars is relatively new and considerably more complex. Some of the key differences between traditional bioequivalence studies and those conducted to prove biosimilarity (in terms of pharmacokinetic comparability) are summarised in Table 2, below.
Table 2: Key differences between proving pharmacokinetic comparability in bioequivalence studies versus biosimilarity studies
|
Bioequivalence |
Biosimilarity |
|
|
Compound Type |
Traditional generic |
Biologic |
|
Typical Study Design |
Cross-over |
Parallel |
|
Typical Sample Size |
16-32 |
100-200 |
|
Pharmacokinetic Parameters |
Cmax and AUC sufficient |
Cmax and AUC required, along with t1/2 and/or CL |
|
Acceptance Limits for 90%CI of Ratio |
Inflexible (0.80, 1.25) |
Flexible (with justification) |
|
Immune Response |
Not applicable |
Must be measured |
|
Drug Purity |
Regulations dictate that test and reference formulations should differ by no more than 5% |
Correction factor may be required for PK parameters if test and reference formulations differ considerably in protein content |
|
Region-Specific Reference Drugs |
Not applicable |
Complex manufacturing process may cause geographical differences |
CI, Confidence interval.
Due to their long half-lives and the potential to illicit an immune response, biologics are not compatible with simple cross-over designs; therefore, parallel designs must be utilised (significantly increasing the sample size). Unlike standard equivalence studies, the assessment of comparability must extend beyond absorption (Cmax) and overall exposure (AUC), with half-lives (t1/2) and clearance (CL) also investigated. Acceptance limits for the 90% confidence interval of the ratio of pharmacokinetic parameters must be predefined and approved by regulators; although in our experience the traditional equivalence limits of (0.80, 1.25) tend to remain favourable (perhaps due to familiarity). Anti-drug antibodies have the potential to affect pharmacokinetic characteristics and should therefore be measured and their impact considered. The relative protein content of the test and reference drugs also need to be considered, with a suitable correction factor applied to the pharmacokinetic parameters, if necessary. Furthermore, region-specific versions of reference drugs may exist in some instances (e.g. Humira®); therefore, if the ultimate aim is to license the new biosimilar across multiple regions, it may be necessary to incorporate more than one reference drug in the study.
Careful consideration to all of the above, along with guidance from regulators on a study-by-study basis, should help ensure that biosimilar trials are a complete success.