The first biosimilar was approved in the United States in 2015, but this category of drugs is still fairly misunderstood, according to Jim M. Koeller, MS, Professor, College of Pharmacy, the University of Texas at Austin.
“They’re new to everyone, and we’re all still trying to figure out what these are, how we’ll deal with them, and how institutions will bring them on board,” Mr Koeller said at a recent meeting.
Biosimilars Are Not Generics
Biosimilars are biologics, not generics. Made from living cells, biosimilars are designed to mimic their reference drugs. However, unlike generics, which are exact copies of an original drug, biologics will never be exact replicas of their reference drug.
“Biosimilars are complex molecules to develop, and there’s a huge development process to reverse engineer an original biologic,” said Sue Naeyaert, Senior Director of Biosimilars Policy, EMD Serono.
Batch-to-batch variabilities occur during the manufacturing of biologics, and “a biologic such as rituximab or trastuzumab is not exactly the same as that molecule was 10 to 15 years ago, because manufacturers have developed more sophisticated ways to produce the product to get better yield. By their inherent nature, biologics progressively change over time, so a biosimilar is just trying to match that process and final product,” said Ms Naeyaert.
Earl Dye, PhD, Director of Technical Regulatory Policy, Genentech, Washington, DC, discussed the FDA’s abbreviated approval process for biosimilars under the Biologics Price Competition and Innovation Act to provide a lower-cost alternative to biologics while encouraging continued innovation of new therapies.
“This abbreviated pathway enables a biosimilar developer to rely on certain clinical safety and efficacy data of the reference or innovator biological product, so they’re able to submit a data package that is much more abbreviated and has less preclinical and clinical data in it,” Dr Dye said. The submission requirements for biosimilars include data from analytical studies, preclinical toxicity studies, and clinical studies in ≥1 indications of the innovator biologic drug.
An innovator drug undergoes 3 distinct phases of clinical development for each indication on its label. Conversely, biosimilar developers conduct extensive analytical and functional comparisons of their drug with the innovator drug to demonstrate that the 2 drugs are similar, followed by preclinical, pharmacokinetic, pharmacodynamic, immunogenicity, and clinical studies to show that any differences detected during the initial assessment have no clinical significance.
“One of the important features of the FDA pathway for biosimilars is this concept of extrapolation,” said Dr Dye. Extrapolation refers to a process whereby the developer of the biosimilar can use data from one studied clinical indication to get approval for other indications on the reference biologic drug’s label, without having to do the clinical safety and efficacy studies for those indications, as long as they have a strong scientific rationale.
“By providing that totality of evidence that the FDA uses to make a determination of biosimilarity, they’re able to perform this extrapolation, which goes significantly to reducing the cost of these types of products,” Dr Dye said.
Jim McKay, PhD, Director of Clinical Development and Medical Affairs, Sandoz Biopharmaceuticals, discussed the FDA’s recently issued draft guidance on labeling for biosimilars. “These biosimilar clinical studies are not necessarily designed to look at safety and efficacy independently,” Dr McKay said. For that reason, the FDA has deemed that biosimilar drugs can rely on the safety and efficacy data of their reference drugs, and use these findings in their labeling. The labels for biosimilars and their reference drugs can appear very similar, but slight differences may exist between them, such as specific indications (if extrapolation was not granted for all indications).
Interchangeability, Dr McKay said, requires extra clinical data submission to the FDA on the part of the biosimilar developer. The data must show that switching back and forth between the biosimilar and the reference drug will not reduce the drug’s efficacy or increase the risk to the patient. If the biosimilar is granted that designation and considered an interchangeable biologic, then pharmacists can substitute the biosimilar for the reference drug without obtaining permission from the prescribing physician; however, this is not yet permitted in the United States.
“Pharmacovigilance is drug safety monitoring and surveillance, which is a very important issue for biosimilars and biologics overall,” said Thomas Felix, MD, Medical Director of R&D Policy, Global Regulatory Affairs and Safety, Amgen, Washington, DC.
Biosimilar manufacturers and developers are accountable for measuring the risks and benefits related to their drugs. In the generic experience, accountability for adverse events has been directed toward the originator company, “but that’s not acceptable for the biosimilar concept,” Dr Felix said.
In 2015, the FDA released a draft guidance and a proposed rule on naming biologics, which included adding a hyphenated suffix on all biologics, and subsequent name-changing of biologics that are already in the marketplace. There is also a global discussion involving the World Health Organization to standardize a naming approach across countries.
Overall, physician acceptance of biosimilar drugs “is growing, but there is still a lot of education that needs to happen,” said Ms Naeyaert.