The Biologics Price Competition and Innovation (BPCI) Act of 2009 established an abbreviated Biologic License Application (aBLA) pathway for the approval of biosimilars in the US. This act also established the principles of interchangeability (along with switching and alternating) with the reference product. However, the concept of biosimilarity and interchangeability for biosimilars is very different from that of bioequivalence and drug interchangeability for generics .
The BPCI Act gives FDA the authority to designate a biosimilar as interchangeable with its reference product. This means that the biosimilar may be substituted for the originator product by the pharmacist without reference to the prescribing physician .
Definition of interchangeability
As indicated in the subsection (a) (2) amends the Public Health Act subsection 351(k)(3), a biosimilar is considered to be interchangeable with the reference product if:
- the biological product is biosimilar to the reference product, and
- it can be expected to produce the same clinical result in any given patient.
In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biosimilar and the reference product is not greater than the risk of using the reference product without such switching or alternating.
Biosimilarity therefore does not imply interchangeability which is much more stringent.
Some problems have been highlighted with this approach. In order to achieve interchangeability, a biosimilar is expected to produce the same clinical result in any given patient. This can be interpreted to mean that the same clinical result is expected in every single patient. In reality, this is extremely difficult to prove. Producing the same clinical result in any given patient could mean that tests are required in all sub-groups of patients, e.g. elderly, children, and different racial groups . It has also been speculated that this requirement could even lead to lawsuits if adverse effects are recorded in a single patient after switching from one product to another.
FDA has indicated that it believes that biosimilarity must first be established before any studies into interchangeability can be performed. Once biosimilarity has been established drugmakers can then decide whether to further pursue interchangeability or not. This approach, however, has raised questions as to what would happen if a product was deemed not interchangeable .
Switching and alternating biosimilars and originators
From FDA’s perspective, interchangeability includes the concept of switching and alternating between an originator biological product (O) and its biosimilars (B).
The concept of switching is referred to as not only the switch from originator to biosimilar (O to B) or biosimilar to originator (B to O) (narrow sense of switchability), but also originator to originator (O to O) and biosimilar to biosimilar (B to B) (broader sense of switchability). As a result, in order to assess switching, biosimilarity for O to B, B to O, O to O and B to B need to be assessed based on some biosimilarity criteria under a valid study design.
The concept of alternating is referred to as either the switch from the originator to the biosimilar and then switch back to the originator, i.e. O to B to O, or vice versa, i.e. B to O to B. Thus, the difference between ‘the switch from O to B’ or ‘the switch from B to O’ and ‘the switch from B to O’ or the ‘the switch from O to B’ needs to be assessed in order to address the concept of alternating.
Study designs for assessing bioequivalence
For assessment of bioequivalence for generics, a simple crossover design can be used, except for drug products with relatively long half-lives. Since most biosimilars have relatively long half-lives, parallel group designs for studies should be considered.
The problem with parallel group designs, however, is that these types of studies do not provide inter- and intra-subject variabilities and variability due to subject-by-product interaction.
In order to assess biosimilarity for O to B, B to O, B to B and O to O the Balaam’s four sequences, two periods (4×2) crossover design, i.e. BB, OO, BO, OB, may be useful. For addressing the concept of alternating, a two-sequence, three-period dual design, i.e. BOB, OBO, may be useful.
For addressing both concepts of switching and alternating for the interchangeability of biosimilars, a modified Balaam’s crossover design, i.e. BB, OO, BOB, OBO, could be recommended.
Quantitative evaluation of bioequivalence
Development of biosimilars is not an easy matter
FDA and biosimilars: update on key themes
1. Shein-Chung Chow. Quantitative Evaluation of Bioequivalence/Biosimilarity. J Bioequiv Availab 2011; S1
2. GaBI Online - Generics and Biosimilars Initiative. Interchangeability of biosimilars in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 December 09]. Available from: www.gabionline.net/Biosimilars/News/Interchangeability-of-biosimilars-in-the-US
3. GaBI Online - Generics and Biosimilars Initiative. The US biosimilars law may prove a barrier to entry for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 December 09]. Available from: www.gabionline.net/Biosimilars/Research/The-US-biosimilars-law-may-prove-a-barrier-to-entry-for-biosimilars
4. GaBI Online - Generics and Biosimilars Initiative. FDA gives some insight into biosimilar pathway [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 December 09]. Available from: www.gabionline.net/Biosimilars/News/FDA-gives-some-insight-into-biosimilar-pathway