The answer, like most things, is “it depends.” An important question remains to be answered: Are Congress and the FDA really going to declare “interchangeability” between an innovator biologic medication and a follow-on biologic? With interchangeability, you’d have a situation much like that with most current generic drugs. Brands will have a short time to recoup costs and will be competing with generics that can be substituted by a pharmacist without the intervention of the doctor.
Just a few short years ago FDA said that it “has not determined how interchangeability can be established for complex proteins.” The Biotechnology Industry Organization (BIO) states that “the current state of science is not sufficient to establish interchangeability for complex follow-on biologics.”
Follow-on biologics have already been approved, but not as interchangeable products
An explosion of generic drugs has resulted from the generic pathway established in 1983 by the Hatch-Waxman Act: Section 505(b)2 of the Food, Drug, and Cosmetics Act (FDCA), which allows for an abbreviated new drug application (ANDA).
According to FDA Guidance for Industry: Applications Covered by Section 505(b)2, an ANDA is “an application…where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.” In other words, the generic manufacturer can rely on published literature and the FDA’s finding that the original branded drug is safe and effective. The ANDA pathway generally does not require costly Phase III studies, but it was not written to apply to biologics.
In 2004, FDA stated that it could not reach a final decision concerning the approval of Omnitrope, a follow-on recombinant human growth hormone (rhGH) manufactured by Sandoz, through the 505(b)2 ANDA process (the application used Pfizer’s Genotropin as its reference). FDA felt that it was an issue that had to be settled by Congress because there was so much uncertainty in the scientific and legal issues surrounding biologics.
A response that continues to raise more questions, years later
Ordered by a federal district court to hold a hearing on the ANDA, FDA approved Omnitrope in 2006 but issued a 53-page “decision letter” addressing petitions from Pfizer, BIO, and Genentech requesting that FDA not allow this ANDA for a biologic (protein) product. At the very beginning of the letter, FDA spells out several items that its response does NOT address, including:
- Interchangeability—Omnitrope was designated as a “BX” generic; these are “drug products for which the data are insufficient to determine therapeutic equivalence”
- Scientific issues with protein products, especially those not well-characterized by currently available analytical techniques (rhGH was considered by FDA to be “extensively and adequately characterized”)
In addition, Sandoz had conducted three original Phase III trials in pediatric patients with growth failure. So this decision did not establish a precedent.
Fast-forward five years
The Biologics Price Competition and Innovation Act, signed into law in 2010, attempts to provide a pathway to interchangeability for biologic medications in general, despite the fact that—as far as I know—researchers have not solved the issues wisely avoided by FDA in 2006. The law as written states that the follow-on biologic must show data from “analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive compounds.”
For FDA to declare a follow-on biologic “interchangeable,” the manufacturer must show that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the [follow-on] biologic product and the reference product [innovator or brand] is not greater than the risk of using the reference product” alone.
Follow-on = Me-too?
Right now, it seems to me that the only way to demonstrate interchangeability (lack of additional risk) would be through large, costly Phase III studies. The price of entry into manufacturing biologics is high, so the steep discounts seen for generics will not materialize (follow-on biologics could easily be 80%-90% of the price of the original). And given the fact that it may be reckless, in the current state of knowledge, to declare a follow-on biologic “interchangeable” (allowing substitution without the knowledge of the physician), will patients and physicians choose a 10% discount for a “biosimilar”?
So the situation won’t be remotely comparable to generics, if science prevails. You’ll be looking at biologics that are based on an innovator product, priced at 90% of the original, with no automatic substitution. Unlike chemical “me-toos” (new brands in a class, such as statins), follow-on biologics will not be able to promote better efficacy or safety. I think for now, biotech innovators have little to worry about, and follow-on biologic manufacturers face an uphill battle.

