(© Michael Austin)
The Regulatory Battle Over Biosimilars
For over a year the U.S. Food & Drug Administration (FDA) held up approval of Massachusetts-based Genzyme’s new plant for Myozyme, a treatment already produced and marketed by the company for a rare neurological disorder called Pompe disease. Genzyme built its Framingham facility to handle increased demand. While neither Genzyme nor FDA would comment on the nature or cause of the delay, industry insiders—including Scott Gottlieb, resident fellow at the American Enterprise Institute in Washington, DC, and former Deputy Commissioner for Medical and Scientific Affairs, FDA—believe that at issue is whether the drug manufactured in the new plant is sufficiently similar to the product already on the market.
That’s just one example among many of the challenges companies and countries face in regulating biosimilars, also known as biogenerics or follow-on biologics. By any name, they are just generic versions of biological drugs.
On the legislative front, Europe took the lead by setting out a regulatory framework in 2003 and issuing its first guidelines in 2005. In contrast, it took until March 2008 for the U.S. Congress to develop a pathway toward regulating biosimilars. To some—notably groups that stand to gain from legislation that lets biosimilars move ahead—the U.S. delay is purely political, the result of a campaign by pharmaceutical companies to protect what William Haddad, president of New York-based Biogenerics, calls "perpetual patents." Likewise, in a statement about the action of the U.S. Congress, Kathleen Jaeger, chief executive officer of the Generic Pharmaceuticals Association, said, "At worst, it’s a step backwards that puts brand-company profits before patient needs." Nonetheless, the pharmaceutical issues go beyond corporate and political battles.
Assessing Similarity
Regardless of the impetus behind the regulations, or the lack of them, there is a scientific debate. It revolves around: How similar is similar enough? In order to qualify as a follow-on and not an entirely novel product, the follow-on must be similar in composition and in biological effect to the branded molecule. For a traditional small-molecule pharmaceutical, demonstrating both qualities is a relatively simple matter. Biosimilars, however, are exponentially more complex. A biotherapeutic may be a large, complex string of amino acids—a thousand or more times the size of a traditional drug—and the exact composition of these molecules is difficult to analyze and control. Moreover, small changes in processing could alter the basic amino-acid composition of the molecule, or it could alter the way the basic molecule is modified. The placement of sugar molecules, for example, can differ markedly from molecule to molecule—even for molecules made in the same facility under the same conditions.
How does the European Medicines Agency (EMEA) assess similarity? Well, it doesn’t exactly. To date the molecules approved by EMEA for follow-on status have been small, well-characterized drugs, such as recombinant human insulin. More complex molecules are currently under review, says Monika Betstetter, EMEA spokesperson. "It is true," she says "that we started off with relatively easy biologicals—definitely no antibody yet. Further guidelines will be developed as needed." She would not say which medicines are currently under review or how bioequivalence will be determined.
Observers expect that once FDA grapples with establishing criteria for equivalence between a branded and follow-on biological product, it will be "extremely conservative," says Gottlieb. He adds that the only possible exception will be the smaller, simpler molecules, like the ones already approved by EMEA. (For an even more complex issue, see sidebar "Seeking Stem-Cell Therapies.")
For both Europe and the United States, we can only wait to see how anything beyond a relatively easy biosimilar will be handled. It appears that the regulatory processes around the world will continue to evolve. Indeed, the complexity of biosimilars seems to create as much trouble for regulators as it does for manufacturers. In the meantime, those waiting to realize the cost benefits of biosimilars might be waiting a long, long time.
Seeking Stem-Cell Therapies
In the middle of January this year two remarkable, but supposedly unrelated things happened. Barack Obama was inaugurated as the United States’ 44th president, and FDA released a draft guideline governing the manufacture of cell- and tissue-based products, so-called "advanced therapies." These events might have led to a third event: The first-ever clinical trials with an embryonic stem cell–based therapy—in this case for spinal-cord injury—conducted by the California-based company Geron. Is this a coincidence? Anyone who knows for sure isn’t saying. What is known for sure is that the European Medicines Agency (EMEA) beat FDA to the draw.
The EMEA is very proactive, notes Marisa Papaluca-Amati, deputy head of the sector on clinical safety and efficacy at EMEA. The agency, she points out, already had guidelines on gene therapy in 1995, and the office "tracks innovation so that in 2001—the year specific requirements governing gene-based products was addressed legislatively—we were already poised to consider advanced therapies." The latest regulation [(EC) No1394/2007] on advanced-medicinal products, which also includes cell-and tissue-based products, came in effect in the European Union in January 2009, around the same time FDA issued its draft. In addition, the EMEA just created the Committee for Advanced Therapies (CAT). Composed of health professionals and patient representatives, CAT performs scientific evaluations of novel gene- and cell-based therapeutics and then suggests to EMEA guidelines to keep pace with the innovations.
Nonetheless, neither EMEA nor FDA guidelines on advanced cell and tissue therapies make any specific mention of embryonic stem cells. It is now clear—through the Geron decision—that the FDA guidelines pertain to embryonic stem cells. The EMEA guidelines do as well, says Papaluca-Amati, but the decision to move forward on those therapies is left up to the member states. "The legislation does not exclude embryonic stem cells," she says. "But member states may choose out of ethical considerations not to accept them or use any product derived from embryonic stem cells. Science should respect ethics."
