Last November’s FDA public hearings on the approval pathway for biosimilars further highlighted the growing divide and upcoming challenges associated with deeming a biosimilar “highly similar” to the originator. This language comes from the Patient Protection and Affordable Care Act signed by President Obama in March 2010.
Although it’s the first piece of regulatory legislation for biosimilars in the U.S., the Act fails to provide exactly how a highly similar determination is made. This lack of specificity has led to one of the most contentious questions surrounding biosimilar approval discussed at the hearing: How in-depth must clinical trials go?
Supporters of full-blown side-by-side clinical trials of both the originator and the biosimilar argue that this approach better ensures patient safety. Opponents argue that extensive clinical testing may be unnecessary if a biosimilar is shown to be highly similar to a reference product’s published data.
The latter group’s argument is founded upon the generic approval pathway established for small molecule drugs by the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) passed in 1984.
By following Hatch-Waxman’s guidelines, generic drug companies are spared the costs of expensive clinical trials because all they need to prove is that their drug’s active ingredient is “bioequivalent”, which requires demonstrating the equivalent concentrations in the bloodstream over the same period of time.
In addition, since the generic drug is the same molecule, all of the additional information regarding safety and metabolism has been proven and accepted by the FDA in the submission provided by the originator. This economic advantage given to small molecule generic manufacturers cannot be applied to biosimilars.
Unlike small molecule drugs and their generics, it is impossible to precisely characterize biologics and biosimilars chemically and technically. As a result, the determination of a highly similar assessment is based on the nature of the biologic and a possible harmful immunological response. Complex characteristics of biologics call for a thorough case-by-case set of clinical trials of both the originator and the biosimilar using current analytical methods and expectations.
Generic Drug Approval
The well-defined, predictable nature of small molecule drugs combined with the rigorous testing done by originators gives generic manufacturers the ability to bypass several costly steps. As long as the pharmaceutical company can provide proof that their products have the same active ingredient and follow the same quality manufacturing standards, then safety and efficacy clinical trials are also unnecessary for the generic.
As a result, generic drug manufacturers are only required to prove bioequivalency by testing their own drug along with the originator’s drug and showing that the generic gives the same profile in the bloodstream. One measure of a generic drug’s bioequivalency is its bioavailability––the amount of the drug in the bloodstream, the time it takes to get there, and the time it takes to exit the body. If the concentration and absorption of the generic meets statistical requirements compared to the originator, then the generic is considered to be bioequivalent.
Biosimilar Approval Challenges
Unlike small molecule drugs, biologic drugs are large complex molecules and scientific characterization of biologics doesn’t produce absolute, well-defined metrics. Variables such as protein folding, aggregate formation, and glycosylation can affect the performance and efficacy of the biologic. Choices made during production can also influence the nature of the biologic including the choice of the cell type, development of the genetically modified cell, purification processes, and formulation of the therapeutic protein. Because of these complexities, originator companies still have problems replicating their own production process despite years of experience with the drug. Furthermore, these complexities make exact replication of the originator’s active molecule nearly impossible.
The analytical methods used to test biological drugs are constantly improving in the hopes of better quantifying their complex characteristics. Many of these techniques and technologies were not available during the development of the originator. Data published on originators that opponents of full-blown clinical trials would like biosimilar manufacturers to compare their drug against is outdated.
As a result, thorough side-by-side clinical trials of the originator and the biosimilar are needed in order to provide analytical evidence of biosimilarity. Two of the most important and most difficult aspects of biosimilar clinical testing are providing evidence of bioequivalency (purity and potency) and immunogenicity (safety).