Panelists Question Efficacy, Immunogenicity Studies for Biosimilars

Over 15 years of regulatory experience with biosimilar approvals, evidence has accumulated that phase 3 comparative efficacy studies may not yield useful data, panelists said at the Terrapinn Festival of Biologics Basel 2020. However, these studies play an important role in convincing providers to use biosimilars, they added.

Further, biosimilar immunogenicity studies also serve a doubtful role, and product drift, or variation in reference product quality over a period of time raises the question whether originator biologics should be subject to repeat testing over time to verify that they still meet the standards by which they were approved, panelists said.

The discussion was moderated by Lawrence Hill, chief development officer of Gan & Lee Pharmaceuticals in New Providence, New Jersey; and panelists included Sridevi Khambhampaty, vice president of Intas Pharmaceuticals in India; Bert Thomas, senior vice president of business development of Bio-Thera Solutions in China; and Sundar Ramanan, a global regulatory affairs executive with Biocon Biologics in India.

“The phase 3 studies may not really be essential for biosimilars,” Khambhampaty said. “A good amount of analytical similarity, coupled with a pharmacokinetic study, which proves the bioequivalence of the product, would be adequate for the licensure of some of the biosimilars, because the phase 3 studies are not really adding value in terms of demonstrating similarity.”

Looking Beyond the Amino Acid Level

Analytical studies look at differences at the amino acid level. “There’s a whole battery of biological assays that speak to the efficacy of the molecule. With these high-resolution studies, it’s really questionable whether clinical efficacy studies would be able to find out more of importance,” Khambhampaty said.

However, she added that postmarketing studies can elucidate important characteristics of a biosimilar and how it’s really used in the real-world setting.

For these reasons, she voiced approval for a move toward less emphasis on clinical efficacy studies for biosimilar approval, as is being made by the UK Medicines and Healthcare Products Regulatory Agency. “We have to see how the other agencies across the world are going to embrace this. We have seen some movements in the insulin guidance from the FDA. They do not want to do phase 3 studies anymore.”

Hill responded that for generics these confirmatory efficacy studies traditionally have not been done, and doubts have been raised that generics are as effective as the originator products. If phase 3 efficacy trials were abolished for biosimilars, these drugs could be vulnerable to the same kinds of arguments by originator companies, he said.

“Arguments have to be backed by data,” Khambhampaty said. “There is adequate data for the safe use of biosimilars, and the wealth of data there is now for the biosimilars that have been in the market for 10 years would be adequate to argue against that.”

Thomas agreed that pharmacokinetic studies are going to be adequate to demonstrate biosimilarity. But he noted that “by setting the bar high” and requiring comparative clinical efficacy studies, “it does give regulators some credence that biosimilars are what they say they are,” which is equivalent in safety and efficacy to originator products.

Public vs Regulatory Perceptions

“Some doctors and patients don’t really understand the difference between small molecules and biologics and don’t really appreciate the nuances there,” he said. Efficacy studies help with the balancing act of getting biosimilars into circulation even if they don’t contribute much on the scientific level toward understanding the relative differences between originators and biosimilars, he said.

Hill agreed with the point, adding that the move toward a more purely scientific evaluation of biosimilars makes sense, but there’s always going to be “a small cohort” of doubters who want the efficacy studies.

Immunogenicity studies help to evaluate the immune response to a monoclonal antibody. The panel discussed whether these studies also contribute to the weight of useful scientific evidence. Although complex molecules, biosimilars are much more easily characterized than previously as science has advanced, and tweaks can be made during the manufacturing product to produce very precise changes, as needed, said Ramanan.

“We need to ask the question at this point in time what need is there for an immunogenicity study?” he said. “Data and knowledge should drive the amount of data required for a biosimilar to be approved.”

The decision whether to require these studies should be “judicious,” he added, because patients taking monoclonal antibodies are often in advanced stages of disease and their safety and well-being are critical. “The bar should be set high.” However, it does appear that scientific knowledge and process reliability have advanced to the point that “we can begin to move away from the immunogenicity study.”

Panelists noted that regulatory bodies may require biosimilar developers to conduct studies using biosimilar reference product source from the markets in which they will be marketed. For example, a developer may have to demonstrate equivalence to Herceptin (trastuzumab) from both Europe and the United States. In theory the reference drug should be the same no matter where it is sold. “It’s nonsensical,” Thomas said, noting the added time and expense needed to gather data that may be completely redundant.

However, from this argument comes the issue of product drift, or batch variation, Thomas noted that the assumption generally made is that the originator product is going to be the same. It has been demonstrated that reference product quality varies over time, which makes it more difficult for biosimilar manufacturers to hit the target on equivalence.

“For us biosimilar manufacturers, it’s a huge issue.” Maybe originator products should be checked on a regular basis for consistency, he said.