The U.S. Food and Drug Administration (FDA) will issue new regulations governing the approval of biosimilar drugs later this year. This topic has captured the attention of many in and around the healthcare industry. Scientists, regulatory agencies, pharmaceutical companies, patients and healthcare providers find themselves in a situation where they all have something to gain, but not without controversy.
Even the most enthusiastic supporters of biological therapeutics agree that no matter how rigorous the physiochemical characterization, the biological nature of the drug as well as the production process leaves room for differences that may have profound effects upon the protein's safety and efficacy.
In the late 1990's, a small change in the formulation of Eprex, which was not done by a follow-on manufacturer, but by the originator, resulted in a severe immunogenic response, leaving some patients with the inability to make red blood cells. Despite being approved for safety and efficacy for years, the change in formulation forced nearly 200 patients to get frequent blood transfusions for survival. Fortunately, a collaboration of American and European medical experts and regulatory bodies intervened and reduced the incidence of pure red-cell aplasia due to Eprex by more than 80 percent. The event heightened the concern regarding the complex nature of the biologic production process, and demonstrated that even in the hands of the most careful and experienced companies mishaps can occur.
The current landscape of biosimilar approval: Where are we now?
Approval of biosimilars, otherwise known as follow-on biologics (FOBs), in the United States has been handled under the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act), passed in 1984 to regulate the approval of small-molecule drugs and their generic counterparts. However, the protocol outlined by Hatch-Waxman does not take into account the crucial differences between chemically and biologically derived drugs.
A biosimilar pathway has been in effect in the European Union since 2005. In an effort to better regulate biosimilars in the United States, President Barack Obama signed into law the Patient Protection and Affordable Care Act in March 2010. Section 7002 of the act provides a regulatory pathway for the creation of FOBs and stipulates that the FOB must be "highly similar" to the originator with "no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency of the product."
Unlike small-molecule drugs and their generics, it is not always possible to chemically and technically characterize biologics and FOBs. As a result, the determination of a "highly similar" assessment is based on the nature of the biologic and a possible harmful immunological response.
Small and simple vs. large and complex
The nature of the production process and the end product is well defined for small-molecule drugs. All chemically synthesized drugs can be scientifically characterized because of their chemically definable structure. Every drug has a defined weight and melting point and can be tested using crystallization and chromatography, which produce precise quantitative data. The production process of generic drugs is reproducible, which makes developing a generic a feasible task. Pharmaceutical companies can simply obtain the originator patent information from the U.S. Patent and Trademark Office or information in published literature. With the chemical formula in hand, creating a generic becomes an intricate but solvable stoichiometric problem.
Unlike small-molecule drugs, biologic drugs are large, complex molecules that are difficult to characterize and define using tests. Biologics are produced using recombinant technology and are generally proteins, which can be very complex. Choices made during production can influence the nature of the FOB including the cell type (animal or plant), development of the genetically modified cell, purification process 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 under patent protection. It is impossible to produce FOBs that are identical to the originators, hence the benchmark of "highly similar" in Section 7002.
The approval pathway for generics: Bioequivalency
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" and works in the same way in the same amount of time as the name brand originator.
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. Drug absorption and concentration are tested using chromatography. If the concentration and absorption of the generic meets statistical requirements set by the originator, then the generic is considered to be bioequivalent.
Another advantage in the approval process of a generic drug is that pharmaceutical companies generally do not need to test for safety or efficacy. Pharmaceutical companies submit chemistry, manufacturing and control documents to prove that their products have the same active ingredient and follow the same quality manufacturing standards. Because the purity and safety of the originator is thoroughly tested and documented, additional testing for the generic is unnecessary and costly.
The challenges associated with FOB approval
Fewer advantages are afforded to biopharmaceutical companies developing biosimilars than those producing generic drugs. Because some manufacturing details about the originator are kept confidential and because biologics have an unpredictable nature, it is impossible to develop a follow-on that exactly replicates the active molecule of the originator. Variables such as protein folding, aggregate formation and glycosylation can affect the performance and efficacy of the biologic. As a result, regulators require clinical trials to provide analytical evidence of biosimilarity. Two of the most important and most difficult aspects of FOB clinical testing are providing evidence of bioequivalency (purity and potency) and immunogenicity (safety).
Bioequivalency
As with generics, the bioequivalency of biosimilars must be established through assays using antibodies to "extract" the biologic from the sample. Because antibodies can be limited in quality or not commercially available, the producer of the biosimilar may have to generate antibody reagents themselves.
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 FOB does not necessarily indicate that the two are bioequivalent. If the antibody binds to the same molecular component in both the originator and the FOB, 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 FOB due to their unique glycosylation patterns and other conformational differences. Though they may be bioequivalent, they cannot be considered biosimilar because the antibodies "see" them differently. These differences may affect the effectiveness of FOBs and the way the body reacts to them.
Ideally, antibody assays should be designed to recognize both the originator and the FOB in the same way. By establishing a standard curve with reference material—in this case the originator—researchers can assay concentrations of the originator and the FOB. The originator can be obtained in its market form, but it cannot be used as an assay calibrator due to the quantities and purified amounts required for assay calibration. The practical approach is to use the FOB drug as a calibrator for the standard curve.
Immunogenicity
Immunogenicity tests for generics are not necessary because small molecule drugs may lack bioavailability or potency, but do not cause an immunogenic response. With biological drugs, the slightest presence of any impurities, degraded protein, or aggregates can trigger an antibody response. An anti-drug 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.
Prior to recent regulatory developments, many biopharmaceutical companies compared results of their FOB immunogenicity tests to literature published on the originator. Biopharmaceutical companies now need to do immunogenicity testing using side-by-side analytical tests for more stringent performance criteria.
Why go through all the trouble?
Along with bioequivalency and immunogenicity testing, biopharmaceutical companies need to establish FOB efficacy through biomarker development. All of this testing is time consuming and makes FOBs a more expensive venture than developing a generic. But despite the challenges, FOBs may have major therapeutic benefits for patients.
Innovation of FOBs 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 FOB. Since the FOB is not likely to be identical to the originator, there is a chance that the antibodies to the originator will not interfere with the efficacy of the FOB. Biopharmaceutical companies are driven to produce FOBs for several very important reasons—there's a strong possibility of efficacy, a reduction in development costs and the establishment of a therapeutic alternative for patients. ddn
Marie Rock is the vice president of the Protein Bioanalysis group of Midwest BioResearch, a WIL Research company in Skokie, Ill.
