I have been wrong a few times in the sixty-plus years I’ve been on Earth. Was I wrong about the risk of technical failure in biosimilar development in my June26th post on virtual biosimilar development? To be clear, what I mean by technical failure is that the molecule produced and taken through testing turns out to be non-comparable to the original biologic, either because it has less effectiveness or greater risks of adverse events, including immunogenicity. Therecent news about the 40% “first-cycle” approval rate for the first ten biosimilar applications reviewed by the FDA caused me to take another look at the risk of technical failure. I do not believe that the startling low first cycle approval rate indicates that the technical difficulty of creating a reasonably good biosimilar is very high, and that the better explanation for the low initial approval rate may be expressed in one of my very favorite films of all time, “Cool Hand Luke.” “Captain,” the brutal Warden of the chain gang prison to which Cool Hand Luke is sentenced, explains the need to punish Luke by saying “What we’ve got here is a failure to communicate.” While I would never ever suggest any real similarity or parallel between the FDA and that prison, it does seem to me that the best explanation for the low first-pass approval rate for biosimilar applications is indeed a failure to communicate. A closer look at the six biosimilar applications which received Complete Response Letters (CRLs) instead of approval helps to clarify the issue. Here is a list of the biosimilars that received a CRL and the basis for the CRL:
1. Hospira’s Epoetin zeta approval was delayed by manufacturing concerns. There were no concerns about the actual molecules safety or efficacy (the drug has been on the market in Europe for some time).
2. Pfizer’s Epoetin alph was also delayed because of manufacturing concerns; previous requests for more clinical data were satisfied. So this molecule also is approvable by the FDA.
There were three different applications for biosimilars for Pegfilgrastim and all have been delayed.
3. Coherus’ Pegfilgrastim was delayed by the FDA’s request for a reanalysis of a subset of samples with a revised immunogenicity assay and to provide additional manufacturing-related process information. Clinical data on efficacy and adverse reactions apparently were apparently satisfactory to the FDA. So although is possible that the revised immunogenicity assay will disclose some issue with the molecule, it is more likely that the delays in the Pegfilgrastim biosimilar applications indicate that the FDA is simply unsure of exactly how to assess immunogenicity for pegylated biosimilar proteins.
4. Apotex’s Pegfilgrastim––Apotex has not disclosed the concerns raised by the FDA in its CRL.
5. Sandoz’s Pegfilgrastim––There also was no disclosure by Sandoz of the concerns expressed by the FDA in its CRL. However, the data from 3 clinical trials, including two trials for safety and efficacy in breast cancer patients would seem to demonstrate that the molecule is safe and effective in treating chemotherapy-induced neutropenia. Here too it appears that the FDA has additional concerns to be addressed for pegylated proteins and is still considering how to best resolve those concerns.
6. Celtrion’s infliximab was approved in the second cycle after the provision of additional data. This proves that the molecule was a reasonable and functional biosimilar but that Celtrion and the FDA had not reached an earlier understanding as to exactly what needed to be included in the biosimilar application.
There are two conclusions that can be drawn from this limited data set of the first ten applications. First, manufacturing issues are always a concern for biologics. Biosimilar manufacturers need to make a good biosimilar, but they also need to make it in an impeccable facility. Second, the FDA has concerns about pegylated proteins (such as Pegfilgrastim) that are still evolving. Manufacturing issues aside, the developers of cytokines and antibody biosimilars have produced approvable molecules. The 29 biosimilars on the market in the EU with very few (if any) involuntary withdrawals for safety are clear evidence of the relative rate technical success. The European experience with biosimilars points to the conclusion that the risk of technical failure in biosimilar development is low. The early going at the FDA represents a learning curve in the data collection, submission, and review process for the biosimilar developers and the FDA. I do not believe I was wrong about the technical difficulty of creating a biosimilar. What we’ve got here is a failure to communicate precisely what needs to be done to obtain the FDA’s approval.