Dr Kaiser shares critical differences in primary outcome readout in clinical studies for biosimilars vs reference products for retinal diseases.
Peter Kaiser, MD: When we look at biosimilars for ophthalmology, the first to be approved are ranibizumab biosimilars. The reason for this is because ranibizumab's patent has expired already. Because of that, other companies are able to enter this space. In the future, we may see aflibercept biosimilars because the aflibercept patent is also expiring in the next few years. For the ranibizumab biosimilars, though, it's not like you can just decide to do a clinical study and the analytical studies right away. It's been many years that companies have been working on these drugs to allow them to receive FDA [United States Food and Drug Administration] approval in the case of ranibizumab-nuna, but several other companies have already completed phase 3 clinical testing and all of the analytical studies and have already submitted them to the FDA for approval. I'm hoping to see several biosimilars for ranibizumab hitting the market shortly.
When we look at the approval pathway for biosimilars, it does differ from the reference product, and specifically, in the analytical studies, the FDA is looking at how similar the reference product is to the biosimilar—[such as] what are the pharmacokinetics and pharmacodynamics of the biosimilar—and they need to be obviously similar to the reference product, but not identical—and I want to underline that—these are not identical medications. From the clinical studies, there are several things that we look for as ophthalmologists. We're used to seeing clinical studies last 1 or 2 years, so it’s very surprising to see the primary outcomes of some of these biosimilar agents at 4 weeks and 8 weeks. For many people, it was very confusing as to why such early time points were the primary outcomes. The answer is very simple: the FDA and EMA [European Medicines Agency] require these early time points. You need to prove from an efficacy standpoint that the biosimilar is noninferior to the reference product. The noise around visual acuity measurements at 4 weeks or 8 weeks is considerably greater than it is at 52 weeks, for example. Even if you were to test the reference product against itself, the hardest time points to meet the biosimilarity noninferiority would be at 4 and 8 weeks. In addition, when you look at the OCT [optical coherence tomography] central retinal thickness at 4 weeks and 8 weeks, there's considerable variability and noise around those time points. Trying to prove noninferiority of OCT outcomes at 4 weeks is considerably harder than showing noninferiority at about 52 weeks. The fact that the biosimilar clinical studies primary outcomes are at 4 and 8 weeks is a regulatory requirement that the companies would've been happy to go at 52 weeks, but the safety is shown because the studies go for 52 weeks to show similar safety between the biosimilar and reference product. When I look at the clinical studies from a safety standpoint, 1 of the areas that I look at in particular is immunogenicity because we want to make sure that we're not seeing, for instance, higher levels of intraocular inflammation and that we're not seeing higher amounts of neutralizing antibodies—all things that we are concerned about as ophthalmologists. The clinical studies look very closely at immunogenicity to make sure that there's no difference between the reference and the biosimilar.
Transcript edited for clarity