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 products."

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.