What's the Catch?
There are many reasons why the approval pathway for follow-on biologics and NBCDs should differ from those of small-molecule
compounds. Most small-molecule drugs are low-molecular-weight organic compounds that can be easily characterized and have
a known active moiety. In contrast, biologics and NBCDs are complex therapies that are manufactured using living organisms
or chemically synthesized proteins. They are far more complex than most small-molecule chemical drugs and can possess not
only primary structures, but secondary and tertiary structures as well. Because biologics and NBCDs are more difficult to
characterize, unwanted or unplanned immune responses might occur, leading to a loss of efficacy or severe side effects. For
these reasons, the Hatch-Waxman Act guidelines may suffice for generic approval of small molecule compounds without safety
concerns, but they do not properly consider complex drugs.
As Dr. Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research (CDER) has observed, "Unlike small molecule
drugs, whose chemical composition can easily be determined to be the same as an approved product, the very nature of protein
products makes comparisons of one protein to another, including establishing safety and efficacy, more scientifically challenging.
Because of the variability and complexity of [these] molecules, current limitations of analytical methods, and the difficulties
in manufacturing a consistent product, it is unlikely that, for most proteins, a manufacturer of a follow-on protein product
could demonstrate that its product is identical to an already approved product. Therefore, the section 505(j) generic drug
approval pathway, which is predicated on a finding of the same active ingredient, will not ordinarily be available for protein
Per Dr. Woodcock's observations, generic versions of biologics and NBCDs are typically shown to be similar to, but not identical to the reference product. As such, it is highly unlikely that the active substances are identical between the reference and
follow-on product. Additionally, analytical techniques are not available to establish biopharmaceutical equivalence between
generics and their biological or NBCD counterpart. Therefore, additional considerations are needed when determining an approval
pathway for generic versions of biologics and NBCDs to ensure that safety, efficacy, and immunogenicity concerns are appropriately
One such example can be seen with the glatiramoid class of drugs, including Copaxone, which is manufactured by my company,
Teva. Copaxone is classified as a complex, chemically synthesized heterogeneous mixture of polypeptides with immunomodulatory
activity. The actual active sequences, or structures (epitopes) responsible for the efficacy and safety of the product, are
unknown. It is currently impossible to isolate and identify the active amino acid sequences in Copaxone, even using the most
technologically sophisticated multidimensional separation techniques. Furthermore, Copaxone's mechanisms of action, and their
specific effects on the immune system, are still not fully elucidated.
When Teva pursued development of a new glatiramoid product—protiramer—the company found that even slight changes in the manufacturing
process led to systemic toxicity and caused extensive fibrosis, organ damage, eosinophilia, and death in animals. These signs
were never observed in similar preclinical studies involving lower molecular weight glatiramer acetate. Given the inability
to fully characterize the active ingredients of Copaxone, any purported generic version must be studied in preclinical testing
and full-scale, placebo-controlled clinical trials with measured clinical endpoints (such as relapse rate and disability accumulation)
in MS patients to establish safety, efficacy, and immunogenicity.