In the first part of this series, we looked at where the EMEA (the EU equivalent of the FDA) got it right in terms of the regulatory pathway to biosimilars, without putting patients at risk. Their process is rigorous, testing both the structural (does the protein structure match?–unlike some current US proposals, in which differences in the very amino acid structure are considered “minor”) and functional (does it work in large numbers of patients without causing immune reactions?) aspects of proteins. The attitude is “approve only if” the biosimilar meets tough standards that show that it is indeed comparable to the innovator protein.
Put simply, the EMEA got the regulations right because they got the science right.
Certain US proposals–most notably by Henry Waxman–are tilted in favor of approval. When a biosimilar comes forward, the legislation is written in such a way that the prevailing attitude is “approve unless” some extraordinarily lenient guidelines are breached.
Biosimilars are not the same as generic drugs–not even close.
In the general guidance published by the EMEA, it is clearly stated that the generic approach is scientifically not appropriate for biosimilars. Biosimilars cannot be assumed to have the same efficacy and safety profile as the innovator protein–and neither can they be deemed identical simply by statutory fiat, as the Waxman proposal currently attempts to do.
“Due to the complexity of biological/biotechnology-derived products, the generic approach is scientifically not acceptable for these products.”
– EMEA, Guideline on Similar Biological Medicinal Products (CHMP/437/04), adopted October 2005
Many supporters of biosimilars legislation applaud the EU for having pioneered a regulatory approval pathway. However, the actual approval of biosimilars–and along with it the approbation of the U.S. biosimilars supporters–often founders on the shores of science: that is, the simple fact that the EU looks at the relevant science. When testifying before the Senate Committee on Health, Education, Labor, and Pensions in March 2007, Nicolas Rossignol, the European Commission Administrator, EC Pharmaceutical Legislation, stated that:
“The rationale for creating [a] new licensing route is that biologics similar to a reference product [i.e., the innovator product or brand] do not usually meet all the conditions to be considered as a generic. [emphasis in original] Although the EU ‘generic’ route remains legally open to biologics…, this is more a theoretical possibility than a practical way forward given the current state of science. It is clear for EU regulators today that the complexity of biological molecules, the fact that they are produced in living organisms and their sensitivity to changes in the manufacturing process make it virtually impossible for applicants to produce an identical copy of a reference biological product. In other words, the licensing route for biosimilars is based on the principles that biologics are not chemical drugs, [and] the generic approach is, in the quasi-totality of cases today, very unlikely to be applicable to biologics: biosimilars are not ‘biogenerics’.” [emphasis mine]
I’m sure Schumer and Waxman had expected someone from the EU to be on their side. After all, to a certain type of “intellectual,” isn’t Europe better in all things? But here was a representative of the EU all but telling them that their proposal was reckless. There were those pesky facts again, when Waxman and Schumer obviously wanted only to slap down pharma companies and tell their constituents that they had wrangled cheap drugs for them. Rossignol continued to pick apart their bill in an extremely polite way.
After elaborating on the reasons for the EU’s 11-year period of data exclusivity (Waxman recently wanted NO data exclusivity, and some proposals were as short as 5, when the break-even cost for biologics, given the cost of VC capital, is about 12 to 15 years), Rossignol continued his withering testimony, turning next to provisions in the Waxman-Schumer bill that merely overlooked–by fiat–science stating that shortcuts to biosimilars were rarely available.
“The type of amount of pre-clinical data are not predefined in legislation but are determined on a case-by-case basis, on the basis of the relevant scientific guidelines. This approach reflects the wide spectrum of molecular complexity among the various products concerned, ranging from relatively simple molecules such as insulin to far more complex ones. Thus, the requirements to demonstrate safety and efficacy of a biosimilar are essentially class-specific. In theory, a biosimilar application could therefore range from being almost as ‘abridged’ as a generic application (with very limited non-clinical/clinical studies), to being nearly as complete as a full stand-alone application.” [emphasis mine]
This is not what this committee wanted to hear–rather what they wanted to hear was something along the lines of, “Yeah, we make biologics in the bathtub in Europe, they’re almost free for everyone, the birds are always singing, and the sky is always blue.” Instead they heard from an EU/EMEA representative that the task is difficult and requires getting scientists involved–not merely making political calculations.
Schumer introduced Mr. Rossignol with as stunning a bit of hypocrisy as can be imagined:
“As it stands today, the EU has a highly-regulated process in place that has arguably been unnecessarily burdensome to competitors and has only resulted in two approvals to date. This process was not established by the legislation that was passed by the European equivalent of Congress, however. The statute that created a pathway to biosimilars in the EU was written in broad language which gave Europe’s equivalent of the FDA discretion to flesh out the details. [in other words, they gave the damn scientists too much freedom to do that science-y thing of complicating everything…]
So when we think about this model, I agree that we should pass legislation that would give the FDA the discretion to establish a scientific approval process as they see fit. But why would the United States of America deprive the FDA of the ability to draft its own regulations [in other words, simple and one-size-fits-all], and force them to swallow a complex set of regulations that has been created by another system of government [the complexity of the regulations is a result of the science, not the whim of the government; only simplicity could be “forced” on the production of biosimilars by the whim of the government]? A system of government, I might add, that has price controls [given the healthcare debacle, which must result in rationing and price controls if passed, along with Medicare already paying at about 70% of the rate of private insurance, so that doctors and hospitals lose money on Medicare patients and pass the cost along to those covered by the so-called ‘rapacious’ insurance companies, the hypocrisy here should leave you without words, no matter where you stand politically] and a generic drug market that is not as robust as our own.”
To be fair, it appears that Schumer has taken his name off of Waxman’s bill, but that does not change the complete hypocrisy (“we don’t want to regulate too much”) in the statement above. Waxman’s newer bill is largely the same as the one he introduced during the 2007 session; I see no substantive difference when it comes to the understanding of the science involved.
Similar is not identical.
The EU begins with the premise that a biosimilar is just that–similar to the innovator or pioneer protein, but not identical. The EU shows a proper deference to gaps in our scientific knowledge of proteins. Some simple, foundational premises are laid out in the EMEA Guideline on Similar Biological Medicinal Products (CHMP/437/04, adopted October 2005):
First, biologics are not chemical drugs.
“Biological medicinal products are usually more difficult to characterize than chemically derived medicinal products. In addition, there is a spectrum of molecular complexity among the various products…Moreover, parameters such as the three-dimensional structure [crucial to a fully functioning protein, but not well-characterized — my note], the amount of acido-basic variants or post-translational modifications [what happens to the protein after it is formed from DNA/RNA, including various chemical reactions and folding into the proper 3D shape — my note]…can be significantly altered by changes, which may initially be considered to be ‘minor’ in the manufacturing process. Thus, the safety/efficacy profile of these products is highly dependent on the robustness and monitoring of quality aspects.”
Second, there may be subtle differences between a biosimilar and the innovator product. The EU recognizes that:
“…it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference [innovator] products, which may not become fully apparent until great experience in their use has been established [emphasis mine].”
The EU is stating clearly that because follow-on biologics are similar, but not identical to, innovator biotech proteins, testing is needed to detect subtle differences: pre-clinical testing, clinical testing, and post-marketing testing (surveillance or Phase IV) to ensure safety and efficacy in the broader population. The EMEA guidelines are based on current science–not wishful thinking, the desire to save money alone, or statutory pronouncement.
Next time: More on getting the science right, class-specific guidelines for biotech medications, and the absolute necessity for full-on Phase III testing for almost all, if not all, biosimilars.