July 9th, 2007

Similar Biologics

molecules1.jpgRecently, 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.

2 Responses to “Similar Biologics”

  1. David Hamilton says

    Of course, branded biologics aren’t the “same” when produced in different facilities, either — just ask Genzyme about its so-far unapproved Myozyme manufacturing line in Boston. Oddly, though, I haven’t heard J&J or anyone else arguing that Genzyme needs to run clinical trials to ensure that the “new” Myozyme is the same as the “old” Myozyme — instead, everyone seems content to let Genzyme tinker with the process until it passes a battery of simpler and less expensive assays and convinces the FDA that different batches of the protein are equivalent.

    Why would it be a problem for would-be biogenerics makers to do exactly the same thing? Otherwise, I’m not sure why I’m not sure I see why different batches of Myozyme in this instance shouldn’t also be tagged as “biosimilars,” at least by the logic of this post.

  2. Ashritha (infoalcpl@gmail.com) says

    My colleagues and I have authored what we believe is India’s first ever complete mapping of the Biosimilars opportunity in India. The report is nowbeing made available to the general public.
    Various issues have been dealt with, such as:
    – Patent expirations
    – Regulatory frameworks
    – Infrastructure Requirements
    – Etc.
    If anyone is interested in this report, please contact me at (infoalcpl@gmail.com), and I would send you the brochure and other details.

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