July 9th, 2007
Recently, there have been several articles about new laws under consideration in the US that would pave the way for the development of follow-on biologics (also called biosimilars) that would provide competition for large molecule drugs known as biologics. In addition, a European panel recommended the approval of three biosimilar versions of erythropoesis stimulating agents.
Given the recent flurry of attention regarding biosimilars, I thought I would provide some perspective on our experiences in this area.
For those of you who have not been following this debate, it essentially centers on the fact that biologic medicines are fundamentally different from traditional, chemically-based products. They are, after all, genetically engineered and made from living cells, unlike traditional medicines. Biologics are complex and impossible to characterize fully. Other differences include the way they are manufactured and that all biologic medicines carry the potential for immunogenicity. Even small changes in how the biologic is made could have a significant impact on its safety and/or efficacy. Any new standards and policies that allow the development of follow-on biologics should therefore take into account how complex biologics are to ensure any biosimilars are safe and effective for patients.
In short, the concern is that follow-on biologics or biosimilars could act differently in the body from the innovator versions.
We know this first hand. When our Ortho Biotech unit made a change in the stabilizer of their biologic product, Eprex (epoetin alfa), in 1998 at the request of the European regulatory authorities, the company noticed an increase in reported immunogenetic responses, including a rare form of anemia called Pure Red Cell Aplasia — or PRCA — in patients receiving the product. It took a while, but after about five years at a cost of more than $100 million, we ultimately identified the most likely cause to be an interaction between uncoated rubber stoppers in pre-filled syringes and the new stabilizer, Polysorbate 80. This interaction resulted in organic compounds — called leachates — to be present in the product. When injected into the body, the leachates sparked the PRCA immune reaction in some patients.
As the production of follow-on biologics will no doubt involve many changes in the manufacturing process, there will always be the potential for subtle, but clinically meaningful difference in follow-on products. These products would be “similar” to a branded product, but they would not be the “same” and therefore, scientists do not consider them to be generics. Since laboratory testing isn’t enough to detect many of the clinically important differences in biologics, testing in humans will be necessary to ensure their safety and efficacy.
The development of a regulatory pathway that will enable the approval of follow-on biologics makes sense, and in general, we support the ongoing efforts in the US Senate to create a regulatory pathway for the approval of biosimilars. That said, given the potential risk to human health, there are some provisions in the current bill — such as interchangeability — that need further discussion since they potentially diminish the role of the physician and pose unnecessary risks to patients.