Do Biosimilars Require Clinical Trials?

FDA has mapped out a development pathway for biosimilars that relies primarily on structural analysis and preclinical and clinical pharmacology studies to document similarity to a reference product, with clinical testing utilized largely to assess residual safety or immunogenicity issues. Now research experts are proposing more limited clinical trials for follow-on therapies in some situations, particularly for critical oncology drugs and for highly targeted treatments for rare conditions where limited patient populations already call for streamlined clinical testing.

While some clinical trials may be warranted to assess remaining meaningful differences between a biosimilar and reference product, large trials may be less appropriate where in vitro, pharmacokinetic (PK), and pharmacodynamic (PD) studies can demonstrate therapeutic equivalence. This issue was discussed at the recent biosimilars conference sponsored by the Drug Information Association (DIA), where Parexel Consulting Vice President Cecil Nick and others examined where clinical data can contribute to the assessment of immunogenicity, safety and efficacy in a follow-on product, and where such studies may be unnecessary or would fail to address the right questions.

As of Sept. 30, 2017, FDA had approved seven biosimilars, including the first oncology treatment, through its “step-wise” approach for assessing analytical similarity. With more leading oncology therapies losing patent protection in the next five years, Julie Ann Rosenberg, development asset lead for oncology biosimilars at Pfizer Essential Health, questioned the need to repeat the large clinical trials conducted by innovators to gain FDA approval of multiple indications for key oncology therapies such as bevacizumab (Avastin). She noted that large clinical comparison studies for biosimilars that enroll hundreds of patients would divert resources from developing new therapies and delay and raise costs for treatment with biosimilars.

Richard Markus, Vice President for Development for Amgen Biosimilars, outlined how Bayesian methodology and Frequentist statistical approaches can improve the precision of estimates from clinical studies and justify smaller, tighter clinical trials for biosimilars, particularly where high-quality structural analyses, functional assays, animal testing, human PK and PD studies, and clinical immunogenicity assessment first reduce residual uncertainty about product similarity, he explained. 

The rise of personalized medicine, moreover, provides a model for market approval of highly targeted therapies based on limited clinical studies that assess molecular biomarkers. Similarly, FDA encourages development programs for pediatric treatments and for rare diseases that build on existing information and focus clinical studies on what attributes remain important to assess, pointed out Sue Lim, medical officer for therapeutic biologics and biosimilars in the Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER). She noted that FDA and sponsors have considerable knowledge of reference product safety, and that a biosimilar with the same cell line and formulation as the reference product may not need a large trail to determine similar immunogenicity. 

FDA and sponsors will be addressing these and other proposals for streamlining biosimilar development through added support provided by the Biosimilar User Fee Amendments (BsUFA II) enacted in August, noted Leah Christl, OND Associate Director for Therapeutic Biologics. User fees will fund additional FDA staffers to help draft and finalize guidance documents and the scheduling of more frequent advisory meetings with sponsors of biosimilar development programs, including proposals for novel methods to address complex development issues. FDA has committed to provide timely assessments of innovative clinical study protocols intended to prove biosimilarity and/or interchangeability.