Patents for the first wave of blockbuster protein drugs have already expired and dozens more — worth billions in potential generic sales — are due to expire by 2010. However, FDA has yet to issue any comprehensive guidance on generic biopharmaceuticals. Barring an act of Congress, it will be at least three years before follow-on biologicals are approved in the U.S., most experts agree.
Ironically, some follow-on biologics are already made and sold in the U.S., in fact if not in name. Approved years ago under procedures established for small molecules, human growth hormone, insulin, interleukins and interferons are available, as are versions of therapeutic proteins modified with polyethylene glycol (PEG) residues to improve pharmacokinetics.
Part of the challenge that FDA faces is the sheer complexity of biomolecules. Creating a generic small-molecule drug is straightforward. Even when structural or process route data aren’t available, a competent chemist can usually reverse-engineer chemical drugs in a matter of days. Once a GMP manufacturing process is in place, generics houses apply for Abbreviated New Drug Applications (ANDAs), which means no clinical trials.
Proteins, however, are nowhere near that easy to duplicate. In addition to primary structure (amino acid sequence), biochemists must worry about secondary, tertiary and quaternary structures which may coexist in any combination. Even their primary structures are not straightforward, since they encompass post-translational modifications (PTMs) such as glycosylation, acetylation and several dozen other chemical transformations unique to the cell line in which each protein is manufactured.
Speaking at last fall’s ISPE annual meeting in Scottsdale, Ariz., Dennis Fenton, VP for manufacturing at Amgen (Thousand Oaks, Calif.), observed, “Each manufacturer must make its own cell line, and each manufactured cell line is unique.” Even when biogenerics developers are lucky enough to find that they generate PTMs in similar quantities and familiar patterns, almost any process variable—nutrient composition, culture time, downstream separations—can affect the locations and distributions of PTMs.
Until FDA and Congress act — probably some time this year — manufacturers of generic versions of approved biopharmaceuticals must, like Sandoz, wait in regulatory limbo. Last September, the company sued FDA when the Agency was unable to reach a decision, after two years, on a new drug application for Omnitrope, the Sandoz version of human growth hormone. According to Sandoz, Omnitrope is almost an exact copy of similar HGH products already marketed in the U.S. FDA argued that it had simply not completed its review and is not purposely delaying.
The stakes for follow-on proteins are high. Generic challenges to some of biotech’s biggest blockbusters — such as Amgen’s anemia drugs Epogen and Aranesp, which combine for more than $5 billion in annual sales — will have the same impact as generic small-molecule drugs for branded medicines. A recent study by URCH Publishing (London) estimated that the global market for “biogenerics” could be as high as $5.4 billion, or as low as $0.8 billion, by 2010, depending on how quickly FDA moves to issue guidance. According to DataMonitor (London), “at-risk” biologicals currently enjoy $20 billion in annual sales.
Science is improving, but far from perfect
A session held at the Scottsdale ISPE meeting featured Fenton of Amgen, Suzanne Sensabaugh, senior director for global biogenerics for generic giant Teva Pharmaceuticals (North Wales, Pa.), and Kathleen Clouse, Ph.D., acting director of FDA’s division of monoclonal antibodies in CDER’s Office of Biotechnology Products. The discussion promised to be contentious, but ended with the participants reaching common ground. They agreed that the science for establishing the bioequivalence of follow-on biologicals is improving, as are controls for verifying safety and efficacy, but that they are far from perfect. Bottom line: NDAs for follow-ons must be considered individually.
The ultimate issue is not whether chemical equivalence is possible, but rather what type and degree of chemical equivalence FDA will demand as a first-pass judgement on similarity. As Fenton noted, detailed process characterization will be critical to product quality for biosimilars, but the complexity of biologics and the structural impact of process steps makes characterization difficult. “Is it possible to produce the same product by two different methods?” questioned FDA’s Clouse. “In theory, yes. But it’s very hard.”
|A computer-generated illustration of human growth hormone (HGH). Courtesy of Janos Rohan.
Assuming that a follow-on is deemed by some criteria to be “similar” to the originator product, there remains the question of the types of bioassays for assuring regulators that the proteins are behaving similarly. Assuming that a biosimilar arrives at this point in the regulatory process, nobody knows how much clinical testing, if anything, FDA will require. Estimates range from small safety/efficacy studies (ideal) to full-blown Phase III trials.
Good analytical methods, from chromatography to peptide mapping to nuclear magnetic resonance (NMR), are available for characterization, Clouse noted, but these “give average data, and may not be able to prove bioequivalence.” Thus, there will likely be a need for additional clinical trials to prove the safety and efficacy of follow-on products, she said.
Regardless of process, product can equal product, Sensabaugh argued. In other words, products that are slightly different analytically can behave essentially the same in patients, despite the fact that they were manufactured by different companies, through different processes, at different locations. Sensabaugh noted that six structurally identical and equivalent HGH products — from Eli Lilly’s Humatrope to Teva’s Tev-Tropin—are on the market today, having been approved in an earlier era under regulations for small-molecule drugs (see "Product Equals Product," below).