Biosimilars, Part 3: Interchangeability

In recent editorials, I have discussed two major issues involved in biosimilars: intellectual property protection (see more "Biosimilars Approvals in the US: The Path Forward") and the comparability standard. Now, let's consider the third holy grail of biosimilars: interchangeability.

Under the new US biosimilars legislation, the FDA will decide whether or not to designate a biosimilar as interchangeable with its reference product. Under such a designation, the biosimilar may be substituted for the reference product without involving the prescribing physician. The stakes surrounding this determination are high. If a biosimilar is not designated as interchangeable with its reference product, the manufacturer will achieve little market penetration without actively promoting it to doctors. Most generics manufacturers, who don't even have a sales force, clearly are not prepared for that task.

Laura Bush

In the current regulatory environment, it seems likely that the FDA will be cautious in designating biosimilars as interchangeable. Yet in 1996, the FDA was the first to establish comparability as the standard for interchangeability for innovator biologics following manufacturing changes. In such cases, product labels don't change, and physicians and patients do not know that a manufacturing change has occurred. This brings us back to the standard used to approve a biosimilar. Given that comparability already is the interchangeability standard used by the FDA for innovator biologics, how can a biosimilar approved based on this same standard not be interchangeable?

Meanwhile in Europe, where the first biosimilar was approved in 2006, the law is silent on interchangeability. However, at least 15 countries have prohibited automatic substitution at the pharmacy level. Yet some countries have allowed it de facto through the use of tenders and other purchasing arrangements. (In Poland, for example, based on one year's bid, children were switched from Genotropin to Omnitrope, and then following the next year's bid, they were all switched back.)

There are other recent examples of regulators encouraging drug switching that are unrelated to biosimilars. Following news that the supply shortages of Genzyme's Fabrazyme (agalsidase beta) will continue for months, the EMA's Committee for Medicinal Products for Human Use (CHMP) recently recommended that physicians consider switching patients on low doses of Fabrazyme to alternative Fabry treatments, such as Shire's Replagal (agalsidase alfa). These switches are between products that could never pass the comparability test because they have different active ingredients.

Here in the US, too, regulators have facilitated drug switching by providing patient access to Replagal under a treatment protocol. Previously, the FDA did the same for VPRIV (velaglucerase alfa), another Shire drug that addresses a Genzyme product shortage. Of course, these latter substitutions involve the physician, and are in response to a critical drug shortage. Yet it is interesting to see that regulators do not seem to feel that the risks involved are high, in spite of known major differences between the products.

Thus, the interchangeability of biologics has been routine in the US for almost 15 years, as every FDA comparability determination results in a "new" postmanufacturing-change version of a product being treated (by the FDA, the innovator, and physicians) as fully substitutable with the premanufacturing-change product. Furthermore, the FDA, EMA, and physicians have felt it appropriate to substitute certain non-comparable products that have never even been compared in clinical trials. Thus, as the US enters the world of biosimilars, we should keep in mind the full extent of interchangeability that has been going on in this space for years.

Laura Bush is the editor in chiefof BioPharm International, lbush@advanstar.com