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Patient Safety is Job 1 in Biosimilar Drug Development

By Mari Serebrov
Washington Editor

If patient advocacy groups have their way, it could be a lot harder and take longer for biosimilars to come to market.

While the groups want the price breaks the follow-on drugs might offer, they are concerned about safety. 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 Friday at the FDA's hearing on three proposed biosimilar guidances. (See BioWorld Today, Feb. 10, 2012.)

To avoid such consequences, patient group after patient group urged the FDA to mandate clinical trials for all biosimilars. "We recognize that increases costs," Andrew Spiegel, of the Colon Cancer Alliance, told the FDA panel. But that's better than getting a drug that doesn't work, he said.

Richard Dolinar, of the Alliance for Safe Biologic Medicines, echoed those feelings. "Patient safety must be the non-negotiable priority in developing a framework" for approving biosimilars.

Some drugmakers, especially those known for generics, countered that biosimilars need only to demonstrate similarity – not safety and efficacy. If similarity is established, there's no need for further requirements, noted James Roach, of Momenta Pharmaceuticals Inc.

But Kristin Van Goor, representing the Pharmaceutical Researchers and Manufacturers of America, sided with the patient groups about the need for clinical testing to prevent unpredictable consequences stemming from minor changes. The biosimilar path must be based on a rigorous evaluation of those differences, she said.

Some differences can't be avoided, added Jay Siegel, of Johnson & Johnson's Janssen R&D Inc. But allowing avoidable differences would expose patients to avoidable risks, he said.

The safety debate extended to extrapolating similarity to unrelated indications and pediatric populations rather than requiring more testing. Some differences may not be a problem in one indication, Siegel said. However, they could be clinically meaningful in another.

Karl Heinz Emmert, of Merckle GmbH, part of the Teva Group, argued that extrapolation to other indications is justified because it's based on the totality of the evidence rather than the mechanism of action. And since a biosimilar would not be a new active ingredient, he said 351(k) applicants should not be required to do pediatric studies.

The FDA has proposed the totality-of-the-evidence approach, on a case-by-case basis, to determine what, if any, additional animal or human trials would be needed to demonstrate biosimilarity. Immunogenicity studies likely are to be required for almost all biosimilars, Rachel Sherman, director of the Office of Medical Policy at the FDA's drug center, has said. But she added, "We do not want companies repeating studies that do not need to be done."

The naming of biosimilars is another safety issue that was raised at the hearing. Several patient and industry groups encouraged the FDA to require unique names for biosimilars to facilitate pharmacovigilance. Naming is a quality issue, Chianchiano said, that would help hold manufacturers accountable for their products.

If a common nonproprietary name were used, patients wouldn't know which drug they're getting, Dolinar said. That could be a problem, especially if the patient has an adverse reaction.

Michelle Rohrer, of Genentech Inc., a member of the Roche Group, suggested the FDA adopt a standardized naming system using unique suffixes and prefixes to indicate each biosimilar and interchangeable drug. Unique names are critical, she said, because biosimilars are not identical.

Sara Radcliffe, of the Biotechnology Industry Organization, agreed, saying that without unique names, the FDA would be implying that biosimilars are the same.

Making the case for a common name, Heinz Emmert said having a variety of trade names across different countries could hinder global pharmacovigilance. He pointed out that unique names are not needed for a track-and-trace system – that can be done by the batch number and with a unique NDC code.

Although in the past, the FDA has seemed to favor unique names, agency staff at Friday's hearing raised the possibility of overdosing or misdosing if different names were used, as a patient could inadvertently be prescribed two versions of the same biosimilar.

Another safety issue discussed was interchangeability. The proposed guidances don't define a way to establish interchangeability. While patient groups were vocal against interchangeability, some companies argued that biosimilarity and interchangeability should be one and the same.

Throughout the hearing, the FDA was given a long list of suggestions for changes and steps going forward, including:

guidances on interchangeability, labeling, naming and promoting of biosimilars;

having a track-and-trace system in place before the first biosimilar is approved;

requiring postmarket pharmacovigilance of all biosimilars;

rethinking the definition of "protein";

excluding immunoglobulin products from the biosimilar path;

developing a patient education campaign about biosimilar issues, including lay summaries of guidances;

creating an "Orange Book" for biosimilars;

protecting trade secrets of the innovator biologic;

rethinking the use of non-U.S. comparators. Neal Parker, of Abbott, questioned the legality of this, citing the wording of the Biologics Price Competition and Innovation Act, which requires biosimilars to reference U.S. approved biologics.

The FDA will continue to accept comments and suggestions through May 25.