Sponsors of biosimilars must demonstrate similarity, not safety and efficacy, FDA officials reiterated as they discussed ways to do that at an advisory committee meeting Wednesday.

The reference biologic has already established safety and efficacy, Marjorie Shapiro, of the FDA's Division of Monoclonal Antibodies, told the Pharmaceutical Science and Clinical Pharmacology Advisory Committee. The biosimilar, in turn, must show similarity to that reference drug.

Of course, that raises the question of how similar is similar. To help sponsors answer that question, the FDA is encouraging them to use various analytical approaches to create a "fingerprint" that shows a high level of similarity to the reference biologic. To do that, sponsors will need to look at a combination of characteristics that demonstrates a high certainty that they have identified the proper fingerprint.

Shapiro admitted that the FDA doesn't know yet what that fingerprint analysis looks like, but reviewers will know it when they see it, she said. So far, the agency has yet to receive an analytical package for a proposed biosimilar.

"We're still learning," Shapiro said, noting that sponsors could come in with a novel approach. She advised sponsors to go heavy on the analytics on the front end, as that's likely to reduce their clinical trial burden down the road.

The FDA's insistence on proof of similarity vs. safety and efficacy has created tension with innovator drugmakers and patient advocacy groups. Several groups raised the issue at a hearing the FDA held on biosimilars in May. Seemingly the most insignificant changes in manufacturing, packaging, handling and storing of biologics can have unintended consequences that can be life threatening, Dolph Chianchiano, of the National Kidney Foundation Inc., testified at that meeting. (See BioWorld Today, May 14, 2012.)

Genzyme Inc.'s Robert Mattaliano, speaking on behalf of the Pharmaceutical Research and Manufacturers of America, echoed that sentiment at Wednesday's advisory committee meeting. Sponsors and reviewers alike need to understand how small changes may have unintended clinical consequences, he said, adding that "patient safety should be paramount." Stressing the complexity of biologics, Mattaliano pointed out that each lot of an innovative biologic may have to go through as many as 50 tests to ensure its quality and consistency.

The FDA is giving biosimilar sponsors a lot of flexibility as to what analytical tools they use to show similarity. But each tool could produce different results, Mattaliano said, using the metaphor of the blind man describing an elephant. "There's a lot of subjectivity here that we're all struggling with," he noted.

While he agreed with the FDA's case-by-case approach rather than a one-size-fits-all, Mattaliano urged caution. "Our lenses are improving, but they're not yet crystal clear," he said. The scientific community should be humble about what it doesn't know, because being wrong could have serious consequences, he warned.

Acknowledging the importance of patient safety, Sandoz GmbH's Mark McCamish said the big issue is patient access. With biologics 22 times more expensive than small-molecule drugs in the U.S., "price is an issue that limits access," he said, speaking on behalf of the Generic Pharmaceutical Association.

Within a few years, access could be an even bigger issue, he added, as seven of the top 10 drugs prescribed in the U.S. are expected to be biologics.

While the FDA continues to pave its new biosimilar pathway, the rest of the world is moving on down the highway. Just last month, South Korea approved the first biosimilar monoclonal antibody (MAb) – Celltrion Inc.'s Remsima, a follow-on of Johnson & Johnson's Remicade (infliximab), which is indicated for rheumatoid arthritis. Remsima will be marketed in Asia and South America by the end of the year, and Celltrion, along with its partner Hospira Inc., has filed for market authorization in Europe, where the biosimilar will be launched as Infectra, according to GlobalData.

While Remsima is the world's first official biosimilar MAb, Dr. Reddy's Laboratories launched Reditux, a biosimilar of rituximab (MabThera, Roche AG and Biogen Idec Inc.), in India in 2007 under unapproved biosimilar guidelines. (See BioWorld Today, Jan. 6, 2011.)