More than 25 years after Hatch-Waxman, no legal pathway for approval of generic biologic drugs exists. But if that redoubtable Democrat, Rep. Henry Waxman of California, has his way, an abbreviated approval process for biogenerics may be created soon. Waxman is proposing the Access to Life-Saving Medicine Act.
Introduced in mid-February, the legislation lays out a framework for clinical trials for what the public and legislators call generic biopharmaceuticals that includes tax credit incentives, short approval times, and limitations on the filing of patent lawsuits. It also preserves a period of exclusivity for the first generic biologic approved.
The proposed law is not met with joy from the Biotechnology Industry Organization, which represents the biopharmaceutical industry. "The issue is always safety and effectiveness, and we're not certain the law as it now is written adequately addresses those issues. The complexity of biopharmaceuticals is far greater than that of other drugs," says Sara Radcliffe, VP for scientific and regulatory affairs of BIO.
The FDA has already announced that it would consider generic versions of biotechnology medications "similar" to, but not interchangeable with, brand-name versions. In statements to the Pharmaceutical Research and Manufacturers of America at its annual meeting in March, FDA Commissioner Andrew von Eschenbach said that the FDA recognizes "that the end point would be what could be best described as similarity. Similarity in the sense that when a doctor gives you the product, it will achieve an effect that is similar to the effect that we expected from the innovative ... compound," according to the Associated Press.
FDA officials have said in the past that they do not have the legal authority or necessary guidelines to approve biogenerics, which both the BIO and the agency call "follow-on" biologics or "biosimilars."
The Generic Pharmaceutical Association disagrees. According to the GPhA, the agency already has that right under Hatch-Waxman's section 505(b)(2), which allows for differing dosages and rates of absorption than branded drugs. Under that provision, an applicant must submit testing only with regard to the differences, instead of requiring full preclinical and clinical testing.
Regardless whether the FDA already has the authority, the proposed law authorizes it to determine the efficacy of biogeneric applications product by product, by reviewing clinical trial data. An applicant must demonstrate that there are no clinically meaningful differences between the two products and show that the new product shares the "principal molecular structural features of the reference product and the same mechanism of action, if known," says William Warren, a partner in the law firm Sutherland Asbill & Brennan in Atlanta.
That's tough to do, say opponents. Radcliffe says that biologics are so complex that it is impossible to analyze them in a laboratory as one would analyze chemical drugs. "Determination of biosimilarity requires clinical trials," says Radcliffe. That's what makes the current system of abbreviated pathway for generics approval, including section 505(b)(2), irrelevant.
A lot at stake
There is a lot of money at stake. Biologics are typically 20 times as expensive per patient per day as other drugs. And since the early 1980s, their use has soared. More than 150 are on the market, many treating prevalent and deadly diseases. According to IMS Health, biologic drug product sales jumped 17.1 percent in 2005, with sales of $52.7 billion worldwide. That market is expected to reach $90 billion within two years.
That's a big reason why the proposed new law makes sense, says William Hauser Jr., MD, a regional medical director for Aetna. In a letter of support to Waxman, Hauser noted that the average cost of biotech drugs is $45 PMPD compared to $1.66 PMPD for synthetic drugs. "Our cost for these drugs is enormous," says Hauser, "more than two and a half billion dollars a year. Even a small reduction would be significant."
"The science is available for an abbreviated pathway for biogenerics," agrees Paul Wallace, MD, medical director for health and productivity management programs at Kaiser Permanente. "What we need is the political will."
Insulin and human growth hormone
Some biopharmaceuticals are simpler to create than others — insulin and human growth hormone being the two prime examples. According to Bryan Liang, MD, executive director of the Institute of Health Law Studies at California Western School of Law in San Diego, it is possible for manufacturers to re-create simpler and older biotech drugs such as insulin and human growth hormone fairly easily.
"They are made up of a relatively small number of proteins and molecules that scientists have already mapped out and can safely mimic," he says, adding that with more complicated medicines, that probably isn't possible yet. According to Liang, some biotech drugs, including monoclonal antibodies that treat cancer, are too complex to re-create without extensive cost-prohibitive trials.
It appears that insulin has brought this issue to a head. Six years ago the FDA said it would issue guidelines for approval of generic insulin. But on Feb. 10, the agency announced that guidance would not be forthcoming, at least not for a while, because it favors broader guidelines that would cover all biologics. Four days later Congress reacted with the Access to Life-Saving Medicine Act.
"An approach to improving access and reducing costs is the use of generic drugs, if they are proven to be medically safe and effective," says Larry Deeb, MD, president of medicine and science at the American Diabetes Association.
The insulin market 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 a human growth hormone named Omnitrope, made by Sandoz, a Novartis subsidiary. When Omnitrope was approved, Novo Nordisk stock dropped 1.8 percent over concerns that insulin could not be far behind.
The degree of complexity in HGH molecules is comparatively low, as is the case with insulin. "That shows that this approach is scientifically feasible," said Waxman in announcing his legislation. The problem, said Waxman, is that notwithstanding the approval of an Omnitrope equivalent, the FDA will not issue statutory pathways for generic versions of biotech drugs to enter the market after relevant patents have expired. That is why he is sponsoring legislation to force the FDA to act.
Eleven governors recently expressed concern to the FDA about the cost to their Medicaid programs. "The cost ... is enormous," says Aetna's Hauser. "We need a new approach and this could be it. It allows the FDA to develop safe and effective biosimilar drugs."