Understanding Biosimilar Development and Approvals

Patti Seymour

In 2019, there were 10 new biosimilar approved by the FDA, which followed seven in 2018, five in 2017, three in 2016, and the inaugural approved biosimilar in 2015.

Those approved last year include help for rheumatoid arthritis, plaque psoriasis, breast cancer, metastatic stomach cancer, metastatic colorectal cancer, nonsquamous nonsmall cell lung cancer, glioblastoma, metastatic renal cell carcinoma, cervical cancer, B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The biosimilar approvals “will further help to create competition, increase patient access, and potentially reduce the cost of important biological drug therapies,” the FDA said.

While the numbers have gone up each year, many in the healthcare industry believe it’s still slow.

Patti Seymour, MBA, CSCP, managing director in BDO’s BioProcess Technology Group, explains clear regulatory and intellectual property (IP) guidance are both key to providing a well-defined path to approval of biosimilar products in the U.S. and elsewhere

“This allows product developers to more accurately estimate their costs and reduce the uncertainty associated with development of these products,” she says. “Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have done a good job providing clear regulatory guidance for biosimilars, and both have traditionally been willing to meet with developers to provide feedback on plans.”

Conversely, the IP landscape and process for issue resolution for biosimilars is far less clear than it is for generic small molecule therapeutics. Seymour notes this increases uncertainty and perceived risk and ultimately reduces the number of groups willing to invest in biosimilar development in the U.S.

“Finally, obtaining innovator product samples to use as a comparator while developing biosimilars can be challenging and is another obstacle to biosimilar development,” she says.

Challenges for ApprovalHoward Levine, Ph.D., national leader of BDO’s BioProcess Technology Group, says developing a biosimilar product, particularly a glycosylated product such as a monoclonal antibody, is highly challenging technically, requiring strong process development as well as analytical method development to ensure that the biosimilar is highly comparable to the innovator product.

“Development of a biosimilar product is in many ways more challenging-from a chemistry, manufacturing and controls perspective-than developing an innovator product,” he says. “The reason is the need to match the attributes of a highly complex biomolecule. This includes, for example, making sure the biosimilar has similar levels of specific glycoforms or other post-translational modifications as the innovator product.”

Furthermore, for virtually all biosimilar products, some clinical testing is required. Unlike the clinical evaluation for small molecule generics, which is limited and well understood, the clinical testing requirements for a biosimilar are negotiated with regulatory agencies.

“Requirements depend on the indication, patient population and the regulator’s assessment of the analytical similarity of the biosimilar molecule,” Levine says. “For example, biosimilar candidates that are deemed highly similar analytically may have reduced clinical evaluation requirements.”

As a result of these challenges, the cost and timelines for developing biosimilar products are significantly higher than for generic small molecule therapeutics. By some estimates, these costs can even exceed $100 million per biosimilar development program.

One interesting example - which underlines the obstacles standing in the way of increased competition in the biosimilar space - is Humira (adalimumab) biosimilars. Levine notes that over the past three years, the FDA has approved five Humira biosimilars: adalimumab-bwwd from Samsung Bioepis; adalimumab-atto from Amgen; adalimumab-adaz from Sandoz; and adalimumab-adbm from Boehringer Ingelheim; and adalimumab-afzb from Pfizer. However, none are yet on the market.

“All but BI (Boehringer Ingleheim), as well as three other companies with Humira biosimilars in development, have reached agreements with AbbVie to delay launch until 2023, when the company’s patents expire, preserving AbbVie’s effective monopoly for several more years,” he says.

In order to help in the development of biosimilars in the future, Levine notes that economic modeling can be key.

“It allows developers to forecast commercial manufacturing costs, which can better inform program decisions during development-especially in biosimilars,” he says.