Biosimilars and biobetters in the pipeline. Overall there are 427 biosimilars, 367 biobetters and 117 reference products. US/EU protein reference products are nearly all recombinant proteins. Vaccines, blood derived, cellular, cultured tissues and other types of biologics are not included. Credit: Ronald Rader, Biotechnology Information Institute, Rockville, Maryland. http://www.biosimilars.com/

Although US Food and Drug Administration (FDA) officials mapped out a draft guidance for biosimilar products early this year, opinions over what regulatory standards should be adopted remain sharply divided. Biosimilar manufacturers, innovator companies and other stakeholders aired their views during a public hearing, convened May 11, at the FDA White Oak Campus in Silver Spring, Maryland. Some seek standards that sound every bit as stringent as required for innovator drugs and are also calling for biosimilars manufacturers to be barred from learning proprietary details from reference products. Others envision biosimilars much as generics are for small-molecule drugs—simple, if inexact, equivalents to be used interchangeably among patients. How deeply these stakeholders are divided and the many details about which they worry seem guaranteed to delay further FDA efforts to build a workable review system for these products (Nat. Biotechnol. 30, 297–299, 2012).

Organizations representing patient groups largely welcome the price-lowering potential of biosimilars. But some of these groups are urging FDA to set very high standards for such products to meet. “Clinical trials are crucial; [there should be] no shortcut to safety,” says Alexey Salamakha of the Global Healthy Living Foundation based in Upper Nyack, New York. “We recognize it increases the cost,” says Andrew Spiegel of the Washington, DC–based Colon Cancer Alliance, who nonetheless urges FDA to “mandate clinical testing” for biosimilars.

Science should dictate the “level and degree” of clinical trials to support biosimilars, says Everett Neville of Express Scripts in Washington, DC, but such trials “should not be a barrier to these products.” Kristin Bass of the Washington, DC–based Pharmaceutical Care Management Association urges FDA not to “delay unnecessarily bringing lower cost products to patients.” She argues that the FDA pathway for evaluating and approving changes that innovator companies now routinely introduce into their own reference products “paves the way for biosimilars.”

But Neal Parker of Abbott Laboratories in Abbott Park, Illinois, sees that pathway as mostly closed to companies developing biosimilars. Parker argues that federal law forbids companies from drawing on pivotal data assembled to vet biosimilar products outside the US. The FDA should also take great care to keep those companies—as well as FDA reviewers—from any access to proprietary data that innovators developed to support their reference products. “Nothing authorizes access to trade secrets of innovator products to biosimilar companies,” he says.

One of the most contentious issues is whether to allow interchangeability—the automatic substitution of an innovator product for a follow-on product. For instance, Dolph Chianchiano of the New York–based National Kidney Foundation urges the agency to not to grant biosimilars “interchangeability” status automatically when approved. In contrast, Marcie Bough of the American Pharmacists Association in Washington, DC, suggests that the label on a biosimilar product might refer to the “reference product and say whether it's interchangeable,” she adds. “We need more information to manage prescription orders for biosimilar products.”

Given potential safety concerns with different manufacturer versions of brand biologics, such as Eprex (epoetin α), such leniency might be impractical because even the name of 'biosimilars' is proving contentious. “Get away from the generics mindset,” says Michelle Rohrer of Genentech in S. San Francisco, California. “Unique names are critical,” she adds, recommending a system with four distinct categories—one for the innovator drug, another for related candidates that are under biologic license application review, yet another for biosimilars and a fourth for biosimilars that are deemed interchangeable with their respective innovator products.

Others argue for a simpler system, one in which suffixes are used to distinguish innovator products from biosimilars, and company names are also included for the sake of tracing prescribed products back to their manufacturers. Others go even further. Patrick Vink of Mylan in Canonsburg, Pennsylvania, recommends collapsing those categories once a biosimilar meets FDA standards for interchangeability. Karl Heinz Emmert of Teva, headquartered in Petah Tikva, Israel, says that, because biosimilars are being developed to “behave the same as reference products,” there should be “no assumption of [their] inferiority” and they should not be held to “a 'higher standard' of interchangeability.”

Vink further recommends that FDA establish a “dedicated Office of Biogenerics” to handle the anticipated workload, whereas Mark McCamish of Sandoz International in Holzkirchen, Germany, urges FDA to allot adequate “resources” for reviewing these products. The recently passed Senate version of the Prescription Drug User Fee Act V supported such provisions in a bill that was then sent to the full House for consideration. Some 427 biosimilars are under development, along with an additional 367 'biobetters' in a field of 117 reference products, according to Ronald Rader of the Biotechnology Information Institute in Rockville, Maryland.