Washington Editor

ROCKVILLE, Md. - The question of whether a biologic is actually a manufacturing process that would be nearly impossible to copy is being tossed around by scientists and industry experts this week in a meeting moderated by the FDA.

While there doesn't appear to be strong opposition to the prospect of follow-on biologics, controversy surrounds potential guidelines for those products and whether preclinical and late-stage clinical studies would be necessary to get them to market. In contrast, pharmaceutical generic makers are required to show equivalence to innovator products, a task that does not require extensive clinical trials. During the past several years, the FDA said it has received numerous inquiries as to how a company can scientifically demonstrate that a protein pharmaceutical product (or follow-on biologic) is similar enough to an approved product to obtain licensure without conducting certain clinical trials. Because of the scientific complexity of protein pharmaceutical products (not including second-generation products), the FDA said it would initiate a dialogue with stakeholders on the issue.

The agency expects to release draft guidance on the subject in the coming year. In the first of a two-day meeting on the proposed products, representatives from the Washington-based Biotechnology Industry Organization and Pharmaceutical Research and Manufacturers of America (PhRMA) warned regulators that protein products are more complex and complicated than small-molecule generic drugs.

"Because a follow-on manufacturer can never exactly duplicate the innovator's process, and because differences in process may result in differences in the protein product and its clinical effects, FDA must continue to apply consistent regulatory standards for all manufacturers, and FDA must insist on receiving the full complement of data necessary to demonstrate safety and effectiveness," Sara Radcliffe, BIO's managing director, scientific and regulatory affairs, told the panel.

A full complement would include all data necessary to demonstrate the safety and effectiveness of the label being claimed, Radcliffe said, adding that all regulatory requirements must be based on sound science. Meanwhile, Caroline Loew, PhRMA's vice president scientific and regulatory affairs, said even a slight difference in manufacturing processes might cause significant differences in the resulting product. No one knows that better than Genentech Inc., of South San Francisco, and partner XOMA Ltd., of Berkeley, Calif., makers of Raptiva (efalizumab, formerly Xanelim), an FDA-approved treatment for chronic moderate to severe plaque psoriasis in adults age 18 or older who are candidates for systemic therapy or phototherapy. (See BioWorld Today, Oct. 29, 2003.)

The partners were well on their way to filing a biologics license application in late 2001 when they transitioned from small-scale to large-scale manufacturing and ran into a problem with differences in materials. The BLA ultimately was delayed when the FDA requested a pharmacokinetic study to confirm the equivalence between materials used for testing and manufacturing. (See BioWorld Today, Oct. 8, 2001.)

"So we conducted another Phase III," Robert Garnick, Genentech's senior vice president, regulatory affairs, quality and compliance, told the panel.

Indeed, John Dingerdissen, vice president of worldwide manufacturing, global biologics supply chain for Malvern, Pa.-based Centocor Inc., a Johnson & Johnson company, said the biologics manufacturing process cannot be fully appreciated without visiting a manufacturing facility. J&J supports follow-on biologics with appropriate FDA guidelines, he said. Generic or potential follow-on makers don't appear to oppose potential FDA guidelines.

Representing Cincinnati-based Duramed Research Inc., Carole Ben-Maimon, company president and chief operating officer, said biogenerics are pharmaceutically therapeutic equivalents of innovator products that can be developed without referencing an innovator's processes, specifications or clinical data. "For established products, therapeutic equivalency can be demonstrated using in vitro studies, clinical outcomes, surrogate markers and pharmacokinetics," Ben-Maimon said. "We do not need proprietary information to create a biogeneric."

She said biogenerics should not require full preclinical and clinical programs because such data supporting the innovator product would be in the public domain.

The FDA is expected to conduct a second meeting on follow-on biologics in January.

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