Six years ago, the Food & Drug Administration said it would soon issue guidelines for approval of generic insulin, treating the drug (along with human growth hormone, or HGH) as an exception. On Feb. 10, the agency announced that guidance would not be forthcoming, at least not for a while. Four days later, Congress reacted with proposed legislation that forced the FDA's hand.
 Sara Radcliffe |
But Sara Radcliffe, VP for scientific and regulatory affairs of the Biotechnology Industry Organization (BIO), which represents the industry, said, "No one is arguing that there is no potential value in financially available forms of insulin. The pressing issue is safety and effectiveness. The complexity of biopharmaceuticals is far greater than that of other drugs. While insulin relies on small nonglycosylated proteins, it doesn't mean it is simple to make an insulin product."
And "even small differences in these products can cause differences in effectiveness and unexpected side effects," agreed Kelley Davenport, director of corporate communications for Amgen, whose share of the biopharmaceutical market approaches $10 billion annually, according to IMS Health.
Several generic drugmakers have already begun developing generic versions of biopharmaceuticals because patents on brand drugs have expired, or are soon about to.
The insulin market in this country is dominated by Eli Lilly (Humulin), Novo Nordisk (Novolin), and Sanofi-Aventis (Lantus). Humulin and Novolin have already lost much of their patent protection.
In June 2006, the FDA approved Omnitrope (somatropin recombinant), an HGH made by Sandoz. The degree of complexity in HGH molecules is comparatively simple, as is the case with insulin. "That shows that this approach is scientifically feasible," said Rep. Henry Waxman (D, Calif.).
The legislation―sponsored by Charles Schumer (D, N.Y.), Hillary Rodham Clinton (D, N.Y.), Waxman, and colleagues―is named the Access to Life-Saving Medicine Act. It would essentially expand Waxman-Hatch to include biologics. It does recognize, however, that because biotech drugs are produced from living cell cultures, their generic versions are more chemically complicated than those of traditional drugs. So the proposed law establishes a stipulation for case-by-case approval of the products.
In February, 11 governors contacted the FDA, demanding that it ease the way for the production and sale of generic insulin. "Biological drugs are so expensive that we need to push the FDA on this," said Sen. David Vitter (R, La.) in a public statement supporting the new legislation, adding that diabetes is crippling his state's Medicaid program.
The problem, say Waxman and others, is that, notwithstanding its approval of an Omnitrope equivalent, the FDA won't issue statutory pathways for generic versions of biotech drugs to enter the market after relevant patents have expired. That's why he is sponsoring legislation to force the agency to create abbreviated pathways for biogenerics.
When Omnitrope was given the green light, Novo Nordisk stock dropped 1.8% over concerns that insulin could not be far behind. But in a public statement, Novo Nordisk's president, Martin Soeters, said that although he expects to see inexpensive generic human insulin on the market in 2008 or 2009, "the new generation of insulins is so clearly superior and there is such a change in attitude by doctors and patients toward it that they will not go back."
Novo Nordisk officials should be more worried, said generic manufacturers, because the science behind biologics is not as complex as brand manufacturers say it is. "We have the knowledge necessary to understand and deal with it," said Bruce Downey, chairman of Barr Laboratories, a large generic manufacturer. "At this point, given the political pressure, it's just a matter of time."
Insulin is among the most readily accessible biopharmaceuticals to generic substitution, say scientists. "The least complex regulatory situation would involve nonglycosylated proteins for which a generic is shown to have the same sequence as the pioneer protein, when a generic and protein are unqualifiedly the same," said David Dudzinski, M.D., a physician and attorney who has written extensively about the regulatory and scientific environment surrounding generic biopharmaceuticals.
"Potential examples include insulin and HGH," said Dudzinski. "Generics in this class could be approved with the minimal amount of safety and efficacy evidence within the 505(b)(2) process." He is referring to a section of the 1984 Waxman-Hatch Act that does not require bioequivalence to a brand drug, allowing for differing dosages and rates of absorption than the branded drugs. Under that provision, an applicant must submit testing only with regard to the differences, instead of full preclinical and clinical testing. Depending on a resulting FDA rating, an approved 505(b)(2) drug may be treated as interchangeable with the branded drug. Or a physician may be required to specially prescribe the substitution.
The FDA permits a few biologics to be regulated as drugs under 505(b)(2), including insulin, growth hormone, glucagon, calcitonin, and hyaluronidase, said William Warren, a partner with the law firm Sutherland Asbill & Brennan in Atlanta. But "there exists no standard approval pathway for generic versions of biologics," he said. "Of concern are unanticipated immunogenic responses, such as reactions to unique glycosylation patterns produced by differing organisms."
An example of potential problems is Eprex, an antianemia biologic Johnson & Johnson markets in Europe. Several patients using the product developed an allergic reaction following a minor manufacturing change in 1998 that created an interaction between the product and rubber stoppers used in syringes. Johnson & Johnson has since corrected the problem.
That exemplifies what the controversy surrounding generic biologics comes down to: the chemical complexity of drugs derived from living organisms and the unforeseen consequences implied by such complexity. That and money, of course.
Biologics are typically 20 times more expensive than other drugs. The biologic market accounted for $32.8 billion in 2005, the fastest-growing sector of the prescription drug market. It is predicted to exceed $60 billion by 2010. People with diabetes spend $3.3 billion a year on insulin, much of which is covered by Medicare, Medicaid, and private insurers. Some market analysts claim the price of insulin could fall by 25% if generic versions became available.
Radcliffe argues that biologics are so complex, it is impossible to analyze them in a laboratory as one would chemical drugs. BIO, in fact, never uses the term biogeneric, preferring follow-on biologics or biosimilars.
Notwithstanding the given difficulty, proponents of a clearly delineated abbreviated pathway for approval of generic insulin define the issue in terms of life and death. "Biologics treat some of the most devastating diseases; no one should be denied access to them because they're too expensive. This is particularly true of insulin," said Schumer in announcing the new legislation. "Generic biologics are a safe and affordable lifesaving alternative."
THE AUTHOR is a writer based in Gettysburg, Pa.
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