Charting a Pathway to Follow-On Biologics

Debates about science, manufacturing, and European regulations will shape the approval process for follow-on biologics in the United States.
Jun 02, 2009
Volume 33, Issue 6

Eukaryotic cells are typical expression systems for therapeutic proteins, including follow-on biologics.
Biopharmaceuticals represent a growing proportion of medicines in development and of prescription-drug sales. As economic conditions force patients and benefits providers to reduce their expenses, calls for generic versions of biological therapies are getting louder. But before the US Food and Drug Administration can establish an approval pathway, it must confer with innovator companies and follow-on manufacturers to define how similar follow-on drugs must be to innovator products, improve control of the manufacturing process, manage end-product variability, determine the extent of clinical trials necessary for the approval of a follow-on biologic, and establish patent protection for innovators.

What's in a name?

Industry professionals use various words to refer to generic versions of biologicals, and each word means different things to different people. For a discussion about follow-on biologics to be coherent, the parties must agree on the terms that they will use. FDA defines a generic drug as "a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use" (1). Follow-on biologics that receive European regulatory approval meet all of these criteria and thus, by this definition, could be considered true generics, says Islah Ahmed, medical director in global medical affairs at Hospira (Lake Forest, IL).

HeLa cells, which are used for research purposes, are heterogeneous and difficult to characterize.
Most manufacturers disagree with this interpretation, however. Follow-on biologics cannot be expected to be identical to innovators' molecules because of the products' complex structure and because biopharmaceuticals are sensitive to the manufacturing process, which influences product heterogeneity, says Gillian Cannon, commercial lead at Merck BioVentures (Whitehouse Station, NJ).

Some regulators agree that follow-on biologics cannot be considered generic drugs. "With current methodologies for physicochemical and biological characterization, it is not possible to exclude minute differences that would be undetectable but nevertheless relevant," says Christian Schneider, chairman of the European Medicines Agency's (EMEA) working party on similar biological medicinal products.

Because of living cells' sensitivity and the limitations of manufacturing and characterization technology, the best a follow-on manufacturer can achieve might be a product that is similar to, not identical to, an innovator drug. Hence, the term "biosimilar" was created to distinguish follow-on biologics from generic drugs. The World Health Organization defines a biosimilar as "a biological product used in medicine that would be similar to and would enter the market subsequent to an approved innovator biological through a specific regulatory pathway" (2).


Even before the biopharmaceutical industry was actively pursuing follow-on biologics, manufacturers and regulators needed to be able to compare biologics produced by different manufacturing processes. Before an innovator company could change its manufacturing process (e.g., to scale up production or improve efficiency), FDA required assurance that the modifications would not adversely affect product quality, safety, or efficacy. Without this assurance, a manufacturer would have to undertake a completely new development program that resulted in a second product.

In 1996, the agency published a guidance about the concept of comparability. This guidance required that products' quality attributes after a process change be "highly similar" to the attributes the product had as a result of the original process. The agency also called for process understanding sufficient to predict that differences in quality attributes would not decrease the product's safety or efficacy.

Manufacturers were expected to negotiate which criteria and operating ranges they would measure before and after a process change to establish the comparability of the pre-and postchange products. Comparability could generally be established through analytical testing and biological assays, according to the guidance, but nonclinical and clinical data would be required in some instances (3).

One could argue that any biopharmaceutical for which a manufacturing-process change has been approved using comparability can be the reference for a follow-on biologic because its quality characteristics and process criteria are well defined and testing can demonstrate product similarity. Indeed, the knowledge gained by evaluating comparability and approving process changes has influenced Europe's procedure for approving follow-on biologics considerably, says Schneider.

Although European regulators apply similar principles to innovators' process changes and approving follow-on biologics, one important difference stands out. Throughout the development phase, an innovator accumulates a history of its product, its manufacturing process, and the drug's clinical performance. In contrast, the maker of a follow-on biologic must reverse-engineer the innovator's manufacturing process and establish its own data history. It cannot compare its product with the innovator's at each step of development; it can only compare the two end products.

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