Last year, FDA approved a follow-on version of human growth hormone, Sandoz's "Omnitrope," under its 505(b)(2) process, but only after years of testing and review. The agency implemented a case-by-case approach that called for Sandoz to conduct considerable physicochemical testing to demonstrate structural similarity to the innovator drug, Pfizer's "Genotropin." Sandoz had to provide pharmacology, toxicology, and bioavailability data. Clinical efficacy and safety data from comparative controlled trials were needed to establish that the active ingredients in Omnitrope and Genotropin have highly similar structures and analogous PK and PD parameters. FDA also required long-term trials of the new product, but they were less extensive clinical studies than those conducted by the innovator.

Similarly, Biogen (now Biogen Idec) used peptide maps and glycoform characterizations to demonstrate that its follow-on "Avonex" (interferon β1a) had a similar structure to the original product. Multiple bioassays were needed to demonstrate comparable bioactivity, and PK data was required to show comparable product distribution and clearance. Positive results from these tests allowed Biogen to rely on data from an earlier efficacy study.

For assessing structural changes in biotechnology products, clinical trials are not always the best approach, according to some experts. While FDA may ask for additional PK studies to evaluate differences following manufacturing changes, the agency seldom demands large outcomes studies. And if trials are not needed, Woodcock commented, it may be unethical to require them.

A related issue is whether preclinical and clinical testing can demonstrate that a follow-on biologic should be rated therapeutically equivalent to an innovator product. Conventional generic drugs that demonstrate bioequivalence and "sameness" do not require a physician's intervention for substitution at the pharmacy. But FDA officials have found that while a new biologic may be similar to the innovator, they are not sufficiently the same to be substitutable. The European Union talks only of "biosimilars," emphasizing that these products are not generic copies.

Documenting the comparability of biologics is quite challenging, said Siegel at the March Senate hearing, but "ensuring interchangeability is essentially impossible." Even with the added studies, Omnitrope did not get a therapeutically equivalent rating from FDA.

To demonstrate substitutability, Woodcock said that the follow-on sponsor may need studies showing that repeated switches between the innovator and the follow-on have no negative effects. Such hurdles to documenting substitutability are prompting generics makers to talk of biotechnology "interchangeability." This less-precise term implies similarity that falls short of therapeutic equivalence and may require a physician's prescription for substitution.

Cutting costs

Whether a follow-on can be rated equivalent or substitutable is an important issue because it can have a significant impact on the sales and prices of follow-ons. And, it is the prospect of reduced prices on expensive biotechnology therapies that is driving the push for legislation authorizing FDA approvals of follow-ons. The pharmacy benefit manager (PBM) Express Scripts unveiled a report in February 2007 projecting savings of some $70 billion over 10 years from biogenerics. Another study put the savings for Medicare at $14 billion. A coalition of generics makers, payers, PBMs and patient advocates claim that follow-ons can save lives by making new life-saving drugs affordable for many patients.

Consulting firm Avalere Health, however, estimates savings of only $3.6 billion over 10 years. This analyst claims it will take years for manufacturers to develop and for FDA to approve new follow-ons, and these products will cost more to test and produce. If they're not interchangeable, moreover, physicians will be slow to prescribe them. But payers say that even prices only 10% lower will save millions of dollars on drugs that cost more than $100,000 per year. The United States spends more than $3 billion a year on insulin, and state Medicaid agencies are searching for any savings they can find.