Expert Panel Examines Biosimilar Pathway
The FDA does not usually require animalstudies for biosimilars; therefore, the process can move directly to pharmacokinetic and pharmacodynamic studies.
In a Pharmacy Times®Peer Exchange series, experts Antony Mato, MD, MSCE; Tim Peterson, PharmD, BCOP; Marc Earl, PharmD, BCOP; and Bhavesh Shah, RPh, BCOP, provided an overview of biosimilars and storage conditions, the steps for the FDA’s biosimilar approval process, insights on challenges with regulation, and the extrapolation of indications for biosimilars compared with their original product.
The experts began by diving into a comparison of biosimilars. Given the rising regional marketing and clinical testing of biosimilar agents, it is important for patients and providers to have up-to-date information in the biosimilar landscape.
“Clinical pharmacists are in a unique position to provide appropriate patient and provider education. There’s also an increased impact by pharmacists in managing the formularies with multiple biosimilars available,” Mato said.
Peterson noted that to adequately define what biosimilars really are, there needs to be an understanding of the distinctions between different biologics, which represent the largest-growing therapeutic class in the United States, according to the panel. Biologics are different from the small-molecule drugs that clinical pharmacists are familiar with.
“For small-molecule drugs, the brand originator versus the generic, it’s very easy to recreate these identical copies with a chemical synthesis. We have these raw materials that we know the chemical formula for, so we can make these copies,” Peterson said.
Because biologics are developed from recombinant DNA using a vector inserted into a host cell, they can be very large molecules with high molecular weights. This means that there are differences in amino acid sequences, protein aggregation and folding, and variability between manufacturers in processing.
The FDA has defined a biosimilar as an agent that does not have a clinically significant difference in safety, purity, or potency compared with its reference product. Additionally, when comparing biosimilars with their reference products, biosimilars will maintain the same dosing route of administration and general concentration, but there will be storage differences. For example, Shah explained that when infliximab-dyyb (Inflectra) was adopted, there were data that were not available for storage. Additionally, researchers found that infliximab (Remicade) actually has 6 months of room temperature storage, which infliximab-dyyb did not have. These differences are ultimately attrib-uted to how long the drug has been in the market and whether there have been studies to validify these settings.
“In newly approved biosimilars, we may not see those changes, but I think eventually we’ll see the similarities in the storage between the molecules,” Shah explained. “There are differences with various other biosimilars and reference products in terms of storage requirements, so we should definitely be aware of that as we are adopting these new agents.”
Furthermore, there are differences in the FDA approval process for biosimilars and biologics. Shah said that biosimilars bypass the phase 3 randomized controlled trials, via a shortened pathway with an increased availability for the molecule. Additionally, there are biosimilar drugs that have been approved based on healthy subjects, without even being done for the indications for which the FDA has for the reference product, according to the panel.
A shorter approval pathway is encompassed by comparing the primary structure, the secondary structure, and the tertiary structure, which includes glycosylation, fucosylation, and the complement dependent cytotoxicity. Once those analytic studies are done, Shah said, it then moves to animal studies. However, the FDA does not usually require animal studies for biosimilars; therefore, the process can move directly to pharmacokinetic and pharmacodynamic studies.
The experts then extrapolated on the meaning of “highly similar” in biosimilars.
“From an analytic perspective, I’m looking at structural similarities, [which] are the key to driving the mechanism of action of the drug. Having [structural similarities] being appropriately designed would be important, and then the pharmacokinetics and dynamics also need to be similar between the reference product and the biosimilars,” Shah said.
Additionally, the FDA will be looking into the immunogenicity of biologic agents, which are known to have different levels of immunogenicity depending on glycosylation and minor structural variations. The FDA requires this testing to have a comparator between the reference and the biosimilar because if there are increased rates of immunogenicity being elicited in patients with biosimilars, it could lead to neutralizing antibodies. This would then lead to reduced efficacy or allergic and anaphylactic reactions, serum sickness, autoimmune disorders, and other effects.
Overall, the FDA’s quality assurance process is rigorous and highly regulated with critical quality attributes that every manufacturer must meet based on the standards set by the reference product. The experts also defined interchangeability and how biosimilars may meet this requirement. Shah noted that this is a regulatory term and that there are no approved products that have an interchangeability designation.
“Basically, interchangeability occurs at the distribution level, at the pharmacist level, where the pharmacist could actually substitute 1 drug for another without the provider’s authority. Of course, all states have regulation around this,” Shah said. “It’s more at the distribution level, at the pharmacy level, than at an institutional level, where providers and pharmacists actually make determination on switching their patient based on the clinical profile of the patient.”
He also noted that interchangeability status does not indicate a higher standard or whether the FDA has required more data to be classified as such. The biosimilar goes through the safe pathway, such as a similarity pathway.
Rather, interchangeability relies more on the pharmacist’s intervention, in which a biosimilar may be switched to any preferred biosimilar without a provider’s knowledge. It is not a process that phar-macists such as Shah have adopted, who instead favors transparency with physicians. Furthermore, there is state-by-state variability and legislation regarding pharmacy-level substitution and room in the future for the process to address interchangeability between biosimilars.
Finally, the experts looked at whether there are differences in efficacy compared with the biologic and the process of extrapolation of indication. Earl explained that he views extrapolating indications apart from efficacy and more with the analytical studies that are done on these products.
“It’s very rigorous, and I would encourage folks to look at that science to understand if these products are very similar or not. That first step shows they’re very similar to one another, and most of the indication limitation is related to some patent issues with the branded product and maybe not so much clinical issues,” Earl said. “I try to understand if I believe in the science or not, and I do. Therefore, it would be acceptable to extrapolate to any of the indications the FDA has. That’s caused a lot of conversation in our institution with a lot of our physicians and our pharmacy team.”
Additionally, the biosimilar can never have more indications than the originator product, and it can never be studied in a unique way beyond the originator product.
Peterson said it is important to note that upon applying for an extrapola-tion for additional indications for the originator product, the manufacturer must prove that the mechanism of action is similar among different indications. They must also prove that the bioactivity is similar regardless of the indication, and that they have acknowledged the different patient populations who are being treated with the different indications, comorbidities, medications, and even differences potentially in pharmacokinetics and pharmacodynamics in various patient populations.