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.
Eukaryotic cells are typical expression systems for therapeutic proteins, including follow-on biologics.
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).
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).
HeLa cells, which are used for research purposes, are heterogeneous and difficult to characterize.
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
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.