Subtle Differences among Biological Products

Custom Synthesis, Despite the requirement to be highly similar, biosimilars and reference products are allowed to have minor differences in clinically inactive ingredients. Furthermore, because biological products are produced in living cells, there may be slight variations between batches of biological products, including biosimilars, even among batches produced at the same facility.

“You can synthesize small-molecule drugs and expect to get the same product each time,” Simon Hotchin, executive director of Regulatory Affairs at Amgen, Inc., said at the AACR meeting. “But the manufacturing of biological products is a proprietary, highly complex, and multistep process.”

Biological products have “inherent variability,” agreed Dr. Hurvitz. But FDA’s manufacturing and quality-control standards ensure that naturally occurring variations in biological products do not affect a product’s safety or effectiveness, she noted. In addition, as with all biological products, FDA requires manufacturers to monitor the safety and side effects of new biosimilars in patients.

The Concept of Extrapolation

Although biosimilars do not need to be independently tested for efficacy and safety, conducting a trial can help establish biosimilarity. One of the largest such trials to date compared a proposed trastuzumab biosimilar with trastuzumab in more than 450 patients with HER2-positive metastatic breast cancer.

At 24 weeks of treatment, the overall response rates were similar for patients receiving the biosimilar and for those receiving trastuzumab (69.6% versus 64.0%, respectively), the study found.

There were no notable differences in side effects between the two treatment groups in the trial, but the study authors cautioned that additional follow-up is needed to ensure that the therapies have equal safety and effectiveness over the long term.

Although the proposed trastuzumab biosimilar was not tested in patients with stomach cancer, it was approved for both breast and stomach cancers—the same diseases for which the reference drug is approved. This is an example of a concept FDA calls “extrapolation.”

“Understanding extrapolation is really important, and there are misconceptions about this concept,” said Dr. Lim. If a company can show that its product is indeed biosimilar to its reference product for the agency to approve it for one indication, then, based on extrapolation, there is the potential for the biosimilar product to be approved for one or more conditions of use for which the reference product is also licensed, she explained.

Extrapolation is a familiar concept among regulators, Dr. Hurvitz noted.“Clinicians are going to have to be trained in the concept of extrapolation if they are to embrace the approval of biosimilars for applications beyond the initial approved setting.”