The Biotechnology Industry Organization's written comments on FDA development of a guidance for follow-on proteins will include examples of biologic mishaps resulting from manufacturing process changes.

During an FDA public workshop on follow-on proteins Sept. 14, BIO argued that changes in the biologic manufacturing process can result in unexpected alterations of the final product.

Consequently, the complexity of the biologic manufacturing process requires extensive data derived during product development to assure appropriate safety and efficacy of the biologic, BIO said.

FDA requested specific examples of innovator changes to the manufacturing process that required developmental data to confirm safety and efficacy.

"Can you give us an example where developmental data had a real impact on the type of change...without that data you wouldn't have never known about [product variant] through any of your analytical testing?" FDA Division of Therapeutic Proteins Deputy Director Barry Cherney, PhD, asked.

BIO is "going to submit written comments to the docket and we would be happy to give more detail then," Managing Director-Scientific & Regulatory Affairs Sara Radcliffe said. Comments are due by Nov. 12.

FDA is also interested in hearing more information on the effect of manufacturing changes.

"You and other speakers have made the point often that minor changes to products can dramatically alter product quality and potentially affect product safety and efficacy," Division of Therapeutic Proteins Director Amy Rosenberg, MD, said.

"We at FDA are only aware of a very small subset of those changes," Rosenberg said. "In previous industry meetings, we have asked industry to share those with us on a more robust basis. Is BIO committed to helping us understand how some of the small changes can potentially affect the product?"

"Absolutely," Radcliffe replied.

Several manufacturers, including Pfizer and Genentech, presented case studies at the workshop.

FDA raised concerns that innovators would have the agency establish a higher regulatory hurdle for follow-on biologics than is required for the innovator product.

"For post-approval changes, manufacturers routinely change master cell banks, they may make formulation changes, and they never demonstrate comparability. How can you justify a full-blown clinical study would need to be done for a follow-on biologic?" FDA Division of New Drug Chemistry II Chemist Janice Brown asked.

"Given the extensive amount of information out there on innovator products, some that have been on the market for 10 years, with well known both therapeutic effects and adverse effects, is there anything in all of that data, published and potentially available for study of the innovator's product, that would...allow for any lesser degree of study in order to gain approval?" Rosenberg asked.

"That is something you'd have to assess on a case-by-case basis," Pharmaceutical Research & Manufacturers of America VP-Scientific & Regulatory Affairs Caroline Loew responded.

[Editors' note: The regulatory hurdles facing follow-on biologics will be discussed during an Oct. 6-7 web-based audioconference sponsored by "The Pink Sheet," in partnership with Polidais LLC. For information, please visit ¹ http://www.drugdevicedialogue.com/ or call 800-332-2181].

FDA also expressed concerns about the level of immunogenicity testing that should be required prior to approval of a follow-on biologic.

"There are many factors that would cause even a simple protein to have immunogenic properties," Rosenberg said.

Adequate immunogenicity testing can be conducted after the follow-on product is on the market, said Carole Ben-Maimon, president of Barr's Duramed subsidiary.

PhRMA disagreed: "We should be applying very substantial standards for follow-on products because we know it's such a complex area," Loew said.

- Adam Eckstein

BIO Comments On Follow-On Biologics Will Include Manufacturing Anecdotes

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