January 15, 2011 (Vol. 31, No. 2)

Building a Case for Side-by-Side Clinical Trials for Biosimilars and Originator Drugs

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.

Marie Rock, Ph.D.

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).


As with generics, the bioequivalency of biosimilars must be tested, but the complexity of biological drugs necessitates side-by-side clinical trials. The bioequivalency of biosimilars must be established through assays using antibodies to “extract” the biologic from the sample. Using a biologically derived technique to assess a biologically derived drug further complicates testing.

Biologic drug assays are highly diverse and results vary from test to test. For example, an assay that shows similar profiles between an originator and biosimilar does not necessarily indicate that the two are bioequivalent. If the antibody binds to the same molecular component in both the originator and the biosimilar, though it may be “seeing” the drugs in the same way, differences may still exist in the other parts of the drug.

On the other hand, an antibody may bind differently to an originator and biosimilar due to their unique glycosylation patterns. Though they may be bioequivalent, they cannot be considered biosimilar because the antibodies “see” them differently. These differences may affect the effectiveness of biosimilars and the way the body reacts to them.


Immunogenicity tests for generics are not necessary because small molecule drugs do not typically cause an immunogenic response. With biological drugs, the slightest presence of any impurities, degraded protein, or aggregates can trigger an antibody response. An antidrug antibody response can lead to a range of outcomes from neutralization of the drug’s therapeutic action to more serious consequences such as a cross-reaction with an endogenous protein.

Another challenge for biosimilars is that methods currently required for immunogenicity testing must meet more rigorous performance expectations than those that were in effect for the originator. For example, if the originator reported an immune response of 2% then, and if the same set of samples were tested on methods meeting current standards, a rate of 5% to 10% may have to be reported now. As a result, side-by-side testing is necessary for comparing rates of immunogenicity; otherwise, the follow-on may paradoxically appear to have a greater immune potential.

With the announcement that EMA will be adopting new biosimilar guidelines at the end of 2010, European pharmaceutical companies will most likely be required to perform separate clinical trials for different diseases addressed by the same antibody. The FDA should take a page from EMA and follow suit with a similarly cautious approach. The testing needed will be time-consuming and makes biosimilars a more expensive venture than generics.

Innovation of biosimilars should continue because it is precisely their complex nature that makes it so difficult to establish biosimilarity that also makes them valuable. Patients who take biologics may begin to experience decreased therapeutic efficacy as their immune system begins to adjust by producing antibodies against the biologic or the related impurities. Patients that become antibody positive to the originator have an option for an alternative therapy provided by the biosimilar. Since the biosimilar is not likely to be identical to the originator, there is a good chance that the antibodies to the originator will not interfere with the efficacy of the biosimilar.

Marie Rock, Ph.D. ([email protected]), is vp of the protein bioanalysis group of Midwest BioResearch, a subsidiary of WIL Research.

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