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Phase 3 Trials May Be Unnecessary for Biosimilars, Paper Argues


“It is now time to reassess whether the current clinical development paradigm really makes sense from a scientific and economic perspective while millions of patients still have limited or, more often, no access to life-changing/life-saving [monoclonal antibodies],” writes Francois-Xavier Frapaise, MD, PhD.

Phase 3 clinical trials that compare proposed biosimilars with their reference molecules are a cornerstone of the regulatory approval process. However, writing in BioDrugs, Francois-Xavier Frapaise, MD, PhD, argues that as analytical methods for understanding the structure—function relationship of biotherapeutics have advanced, large and expensive phase 3 trials for biosimilars may no longer provide the most meaningful information on the equivalence of biosimilars and their reference products.

Frapaise writes that the primary structure of proteins and possible post-translational modifications can be reliably characterized by a variety of methods, including peptide mapping by liquid chromatography—mass spectrometry. Bioactivity of proteins can be assessed by measuring cell uptake and proliferation, among other methods. A variety of techniques, such as binding analysis by surface plasmon resonance, allow for assessment of target binding. Protein content and concentration can be reliably measured, and the presence of high–molecular-weight species or aggregates can be readily detected. Furthermore, a variety of means exist to assess higher-order structures, and to measure charge distribution, glycosylation, and process-related impurities.

Not only have analytical methods progressed in their level of sophistication, writes Frapaise, but developers are also better equipped to understand the structure—activity relationships of biologic medicines; for example, developers are now well aware that the glycan profile can impact a product’s safety.

According to Frapaise, comparative phase 1 pharmacokinetic and pharmacodynamic studies, which are generally large in size and expose volunteers to the investigational compounds for up to 1 year, can address the question of immunogenicity without the need for a phase 3 study.

In fact, he argues, phase 3 trials pose a variety of challenges, and have inherent limitations. They are not powered to detect meaningful differences in safety profiles, says Frapaise, and when numerical differences in adverse events are present, these imbalances are difficult to interpret. Detecting differences in efficacy is also challenging, he says, in trials that enroll approximately 500 to 800 patients.

“It is also worth noting that the chances of observing differences in immunogenicity in [rheumatoid arthritis] patients, many of them receiving methotrexate—an immunosuppressant—are, at best, remote,” he adds.

Therefore, a different approach to confirming biosimilarity could be the use of postmarketing studies and real-world data, he argues. Taking such an approach could ease the financial burden and time requirement for biosimilar development.

Read more about real-world evidence in biosimilars.

“It is now time to reassess whether the current clinical development paradigm really makes sense from a scientific and economic perspective while millions of patients still have limited or, more often, no access life-changing/life-saving [monoclonal antibodies],” concludes Frapaise. In many cases, he says, chemistry, manufacturing, and controls information and meaningful phase 1 studies will leave little residual uncertainty about the biosimilarity of products, and properly designed postapproval studies could be “more appropriate” than phase 3 trials.


Frapaise FX. The end of phase 3 clinical trials in biosimilars development? BioDrugs. 2018;32(4): 319-324. doi: 10.1007/s40259-018-0287-0.

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