Many innovator companies and follow-on manufacturers agree that human clinical trials should be a requirement for the regulatory
approval of biosimilars. Differences in cell lines and manufacturing processes, and biological drugs' inherent heterogeneity,
are grounds for considering a follow-on biologic as a different product from the original drug. Clinical testing must include
a robust evaluation of safety, confirm efficacy, and be carried out in the appropriate patient population, says Gail Wasserman,
senior vice-president of development at MedImmune (Gaithersburg, MD).
When an innovator seeks approval for a process change, it is not necessarily required to perform clinical trials if analytical
testing can establish the similarity of the pre-and postchange versions of its drug. Yet innovators argue that the standards
should be different for a follow-on biologic because it is produced with different raw materials through a different process.
A follow-on manufacturer does not have the innovator's historical and clinical data, they argue, and must develop its own.
Although sophisticated analytical techniques have emerged, they cannot fully characterize protein drugs' complex structure.
The industry does not yet have the understanding to relate the analytical testing alone to clinical performance, says Wasserman.
A minor change in a biological drug's structure could have significant clinical consequences, thus clinical testing should
In addition, analytical testing cannot easily predict immunogenicity, says Jeffrey R. Mazzeo, biopharmaceutical business director
at Waters (Milford, MA). For example, characterization methods can measure protein aggregation, but scientists cannot be sure
whether aggregates will cause an immune response in the body. Nor can they predict whether aggregation will occur after an
injection is administered. Although analytical testing can detect contaminants, it cannot readily identify and quantitate
individual host-cell proteins, which could potentially be immunogenic, says Mazzeo.
For these reasons, the most definitive way to establish a biosimilar's safety, efficacy, and comparability to a reference
drug is through clinical testing in humans. "Given where we are with testing today, there's no way around it," says Mazzeo.
"They're going to have to do a head-to-head trial against the innovator product and demonstrate that the safety profile and
the efficacy are the same."
The Biotechnology Industry Organization (BIO) asserts that Johnson & Johnson's (New Brunswick, NJ) experience with its Eprex
drug demonstrates the need for clinical testing during the approval process for follow-on biologics. In 1998, the European
health authorities asked the company to stop using human serum albumin (HSA) as a stabilizer for Eprex, which had been marketed
for 10 years with no reports of immunogenicity problems. The company replaced HSA with polysorbate 80, which caused uncoated
rubber stoppers in single-use Eprex syringes to leach plasticizers into the drug. The plasticizers stimulated an immune response
that resulted in pure red-cell aplasia, a severe form of anemia (4).
"The Eprex case shows that one protein can be different from another in ways that cannot be detected in the laboratory but
are seen only by the body's exquisitely sensitive immune system," says a statement on BIO's website. "If one change to a well-established
complex manufacturing process, made by the manufacturer who has intimate knowledge of the process, can cause a problem with
immunogenicity, surely the risk is even greater with an entirely new manufacturer and process—as will be the case with follow-on
Although innovators and makers of follow-on biologics generally agree about the need for clinical testing, they disagree about
the extent of testing that should be required. Follow-on manufacturers argue for a limited amount of clinical studies, but
many innovators assert that full clinical-trial programs should be mandated because the drugs' inherent variability means
that follow-ons must be considered new products, according to Mazzeo.
Yet some industry professionals are not convinced that clinical trials should be required for the approval of follow-on biologics.
They argue that manufacturers of these drugs should not be held to higher standards than are innovator companies. Given that
complicated biological drugs such as the influenza vaccine are approved every year in the US under the Public Health Service
Act without clinical trials, they argue that requiring clinical trials for follow-on biologics would be unnecessarily burdensome
to follow-on makers (6).
At most, some argue, the requirements for approving follow-on biologics should be the same as those for approving new biologics.
The comparability standard that innovators meet to obtain approval for manufacturing-process changes could be applied to follow-on
biologics. The standard has already been used to approve processes as different as a follow-on manufacturer's would likely
One example involves Biogen Idec's Avonex multiple-sclerosis treatment. A joint venture between Rentschler Technology (Laupheim,
Germany) and Biogen Idec developed BG9015, a beta-interferon product, and tested it in clinical trials. After the joint venture
failed, Biogen Idec developed the cell line for Avonex, also a beta interferon, and created a manufacturing process for the
biological at a new facility in a different country. Biogen Idec submitted Avonex for FDA approval, relying on the clinical
studies of BG9015. FDA approved the product after determining that Avonex was comparable with BG9015 on the basis of biological,
biochemical, and biophysical analyses and pharmacokinetic studies in humans (7).
Because BG9015 was produced by a joint venture, Biogen Idec had access to manufacturing information and important intermediates
required to make the product. The maker of a follow-on biologic, however, would seek to compete with the innovator and would
not have this advantage (8).