3.13.2 Potential benefits of improved analytical methods 3.13.3 Potential benefits of new

Biosimilarity: The FDA Perspective

132 In addition, many of the linked amino acids can have modifications attached. These attachments can be small (only a few atoms) or very large (similar in size to the rest of the protein). One commonly observed attachment is the addition of complex groups of sugar molecules, called oligosaccharides. Attachments occur at very specific locations on the protein and, like folding, can have a great impact on the therapeutic function of the protein. A protein can thus be represented as a long chain with 20 different types of links with different possible attachments on the links.

To further complicate matters, biological drugs are not composed of structurally identical units. Instead, they are a mixture of products with slightly different features. This is referred to as microheterogeneity and can be represented as a mixture of very similar chains that differ in a few links or in a few of the attachments. The protein chains themselves can then be linked or aggregated (i.e., clumped). It is a challenge to analyze and characterize the composition of such a mixture. Even with currently available analytical technologies, some uncertainty regarding the actual structure of a biologic usually remains. Simple measurements of biological activity, such as enzyme activity, may provide additional information about a product. But there is currently no way to, a priori, understand how the product will perform in patients (e.g., distribution in the body, immune responses against the product). As a result, nonclinical or clinical studies are necessary to assess the safety and the effectiveness of the product.

3.13.2 Potential benefits of improved analytical methods

Advances in analytical tests during the last two decades have driven progress in biopharmaceutical manufacturing, but there is still room for significant improvement. New or enhanced analytical technologies and measurement systems and standards that can more accurately and precisely assess the HOS and the attachments of biological drugs would provide additional assurance of the quality of biological drugs in at least three specific ways: • Improved analytical methods would enable quicker and more confident assessments of the potential effects of changes in the manufacturing process, the equipment, or the raw materials. • At present, the manufacturers and the FDA are hampered by the inability to measure fully structural differences that could be caused by changes in the manufacturing process. Since these unknown structural differences could change the properties of the product, the FDA might only approve a manufacturing change after seeing the results of studies of the product in animals or humans. This can significantly slow the implementation of innovative process improvements and impede the

The FDA regulatory guidance

manufacturer’s ability to react to changes in raw material supplies, which could reduce the availability of the drug to patients who need it. Improved analytical methods could reduce the requirements for the animal and/or human studies for evaluation of manufacturing changes. In addition, for products that have abbreviated pathways for approval, improved analytical methods could facilitate comparison of products and detection of differences between manufacturers. • The development of analytical methods that can evaluate the quality of the biologic throughout the manufacturing process would provide a superior system for ensuring product quality.

This would enable increased productivity and improved quality control during the manufacturing process. Improved analytical methods would increase general knowledge in the field of biopharmaceuticals.

The FDA intends to heavily rest its regulatory decisions based on the knowledge of improved analytical methods; this poses a direct challenge to the industry to come up with novel methodologies that will be robust and more reassuring of the structural variability. The FDA has proven this resolve several times by approving complex products, both biological- and nonbiological based on analytical similarity demonstration, allowing the sponsors to launch these products without any testing in patients. The FDA has been legally challenged but won the argument and has frequently stated that a robust analytical similarity demonstration is more useful that targeted clinical trials. This philosophy and this resolve of the FDA are critical to understand.

A good example of how the increased knowledge can inform both regulatory decision making and product design is that of therapeutic proteins like mAbs that affect a patient’s immune system to kill tumor cells, and some that do not. One reason for this difference was discovered only after the development of an analytical technique that enabled scientists to characterize the structure of the sugar chains attached to the antibodies. It was discovered that antibodies with certain sugar chains were more consistently able to direct an immune system to kill tumor cells than antibodies with different sugar chains. The FDA initially used this knowledge to require monitoring and control of these sugar chains to ensure consistent clinical benefit to patients. But this knowledge has also enabled the industry to design new mAb products with enhanced tumorkilling activity. These discoveries have led to a great emphasis on the glycan patterns of mAbs and an appreciation why a biosimilar product must emulate all binding and activity characteristics of the reference product, regardless of the specific relevance of the mode of action. For example, the ADCC activity, although not directly related to drugs like TNF blockers, is required to be matched to obtain the FDA approval of the extrapolation of multiple indications. These topics are discussed in detail in later chapters. 133