Biosimilars were briefly (albeit unofficially) known as biogenerics, then follow-on biologics, before the current nomenclature was adopted. The U.S. FDA website defines biosimilars as “biological prescription drugs that are demonstrated to be ‘highly similar’ (biosimilar) to or ‘interchangeable’ with an FDA-approved biological product.” Yet some experts believe the designation can apply solely based on chemical similarity, approval mechanism, or a combination of chemistry and medical indication.
The 2009 biosimilars market for the U.S. and Europe is estimated at $150 million, according to Datamonitor’s recent report Pharmaceutical Key Trends 2011—Biosimilar Market Overview. But with 30 biologics—with annual sales of $51 billion—losing patent protection before 2015, biosimilars should experience explosive growth with sales reaching $3.7 billion by 2015. Worldwide revenues for all biologics in 2008 were $123 billion.
Although this article is about biosimilars, it is useful to discuss them within the context of the gamut of follow-on biologics (here meant descriptively and intuitively, not in any official sense) that include biobetters (a.k.a., biosuperiors) and innovator biologics that in some way resemble an approved molecule.
For our purposes, biosimilars are drugs that strive to be identical in every measurable way to an approved biological. Next-generation improvements in drug properties (e.g., pharmacokinetic advantages through PEGylation or drug-device combinations) are biobetters, while changes resulting in altered drug function result in new biological entities, or innovative drugs.
The relative significance of the three follow-on classes becomes apparent when global pharmaceutical markets are divided into emerging (“pharmerging”), European-style single-payer, and the more complex U.S. system.
In emerging markets (e.g., Russia, South America, Eastern Europe), where consumers generally pay for their own medicines, biosimilars will dominate based on price. In these nations, loyalty to domestic manufacturers and brands combined with high commercial entry barriers suggest that breaking in will likely follow a branded-generic model that relies heavily on manufacturing and distribution partnerships.
Western Europe has already shown its accommodation to biosimilars by approving 14 of them, compared with just four in the U.S. Here the operative term is value. Biobetters and innovative biologicals must demonstrate some combination of testable patient benefit and pricing advantages.
Not surprisingly, and despite the paucity of stateside approvals, the U.S. has become the testing ground for discovery, manufacturing, regulatory approval, and reimbursement for the three follow-on classes, particularly biosimilars. Not everyone agrees that success will be automatic.
Developers of biosimilars face significant hurdles, as the 2010 U.S. healthcare legislation legalized them but ignored the thorny issues of science and regulation.
If regulators insist that key studies compare the candidate, head to head, against a reference product licensed specifically in their jurisdiction, streamlining and coordinating development programs to work across jurisdictions will be difficult. “We spend considerable time trying to justify the use of only one reference product past a early certain stage of the clinical program,” says Bruce Babbit, principal consultant with Parexel International.
The second issue involves the degree to which biosimilar developers can import clinical results from the innovator’s development program for secondary indications. For example, rituximab was originally indicated for cancer and later for rheumatology. If a developer’s data for the first indication is convincing, how much clinical development for the second (or third) indication will be required?
Ideally, if sponsors can demonstrate a high level of physicochemical similarity, repeating the innovator’s entire clinical program should be unnecessary. Reaching this level of trust, however, could take many years and many approvals.
Complicating matters is the comparability, or lack thereof, between reference studies conducted a decade before and modern practice, which may be built on evidence from postapproval studies or pharmacovigilance.
“The clinical trial challenges will be significant,” Babbit adds. “It would not surprise me if FDA holds more frequent meetings with biosimilar developers than with other biologics developers, particularly around chemical manufacturing and controls. It will be a slow-moving process, and the agency will not commit to Phase III from the outset.”
As companies and regulators gain experience the system will relax by virtue of experience and familiarity. The question is: Will anyone be left standing at that point?