It’s the law and science.
The regulatory world of biological drugs is more complex and perhaps less clear than for the world of small molecule drugs. This is particularly true in the U.S. where, for historical reasons, biologics and small molecule drugs are regulated under separate statutes, the Public Health Services Act (PHSA) 351 and the Food Drug and Cosmetic Act (FDCA) 505, respectively.* The underlying science for biologics is also in some ways more complex than for small molecule drugs. It is the intersection of the legal framework and the science that makes generic drugs the “same” as their reference products and biosimilars “similar” to theirs.
At the time that the Hatch-Waxman amendments were passed in 1984, the concept of therapeutic equivalence was already well developed and generally understood by pharmaceutical chemists, industry, and regulators. Therapeutic equivalence is defined as pharmaceutical equivalence and bioequivalence. Stated more simply, the active substance in the drugs is the same and they are distributed throughout the body to the same extent and within the same amount of time. Thus, when creating an abbreviated approval pathway for generic drugs in the Hatch-Waxman legislation, the scientific basis for the abbreviated pathway was not at issue. The same cannot be said for the creation of an abbreviated approval for biosimilars.
Biologics regulated under the PHSA were not included in the Hatch-Waxman generic pathway, in part, because at the time the science for these products was not sufficiently advanced for different, unrelated manufacturers to make reliable copy versions. Over the next couple of decades, science advanced, biotechnology became more commercialized and the number of biotechnology-derived biologic medicines continued to grow.
Scientists, forever the optimists, began to see the feasibility of making copies of existing biotechnology products. At the same time, biotech entrepreneurs realized that the patents on some of the earlier biotech products would be expiring. Thus the concept of a biosimilar was born.
However, unlike the regulatory pathway for generic drugs, there has not been consensus on the scientific criteria for biosimilars. Therefore, creating a pathway—in the U.S. and elsewhere—has tried to work out the science at the same time as the legal and regulatory standards.
The differences between small molecule drugs and biologics are the basis for the differences in the regulatory standards for their respective abbreviated pathways.
Due to the greater size (10 to 1000 times, typically) and complexity of biologics and the heterogeneity of biological processes, current science does not allow one to make “identical” copies of a biologic or even to analyze them to the level of precision that is possible for small molecule generic drugs that are the “same” as their reference listed drug. In fact, as analytical techniques improve, more and more differences at the molecular level are seen between similar biologics produced by different manufacturers. So for the forseeable future, biosimilars will remain “similar”, and not the “same”, as their reference products, and authorizing law, regulation and guidance should reflect this. Thus in the U.S., generic drugs are approved under the FDCA 505(j) and biosimilars will be approved under the PHSA 351(k), reflecting the statutory and scientific distinctions between a generic drug and a biosimilar.
*Without digressing too much, some products that would scientifically be considered biologics are regulated as “drugs” under the FDCA instead of as biologics under the PHSA due to largely historical reasons.