FDA Advises Limited Clinical Testing for Biosimilars

Published on: 

The biosimilar pathway permits licensure based on less than full clinical data.

There are significant differences in developing biosimilars and innovator therapies, and a new approach requires a “cultural and cognitive transformation” by FDA reviewers, advisory committee members, and sponsors, says John Jenkins, director of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research. Large comparative clinical trials defeat the purpose of the abbreviated development program for biosimilars and risk raising costs and delaying patient access to an alternative therapy.

Instead, the biosimilar pathway permits licensure based on less than full clinical data, Jenkins pointed out at the Drug Information Association’s biosimilars conference in Washington, D.C. in October 2016. He and others agreed that some type of clinical testing is expected at this point to gain market approval for most biosimilars, but that FDA encourages sponsors to propose innovative study designs for these products that consider novel endpoints and unique patient populations. Jenkins added that FDA experts are available to discuss such approaches at a range of advisory meetings, and he urged sponsors to use these opportunities “wisely.”

Most important, he stated, is for biosimilar developers to submit complete applications to FDA that reflect pre-submission discussions with review staff. And all facilities listed in an application should be ready for inspection to avoid approval delays. A complete application should list all plants involved in producing the new product, and these facilities should be ready for inspection within the necessary timeframes and should be actively producing the product under review.

As of early October, FDA’s Biosimilar Product Development Program had 66 active projects involving approximately 20 different reference products. Seven companies have submitted at least 10 biosimilar applications to the agency, and four have been approved, reported Leah Christl, associate director for therapeutic biologics in OND.


The size and complexity of clinical studies for biosimilars, Christl explained, depends on the need for additional data to reduce any “residual uncertainty” about the similarity of the follow-on drug to a reference product after conducting extensive structural and functional characterization and preclinical animal studies. Under this “stepwise” approach for generating preclinical data, animal toxicity studies can address uncertainties about the safety of the proposed product, as can comparative clinical pharmacokinetic (PK) and pharmacodynamic (PD) studies. 

Steven Lemery, lead medical officer at OND’s Office of Hematology and Oncology Drug Products (OHOP), further explained that FDA expects at least one clinical immunogenicity study, but that a comparative clinical trial should be conducted only to address uncertainties stemming from earlier testing. The challenge, Lemery commented, is to keep the clinical trial small to avoid unnecessary costs and delays, yet have it large enough to produce useful and interpretable data. Too-large clinical studies risk diversion of patients and resources from other development programs and raise the prospect of false-negative results. Yet, Lemery acknowledged that additional immunogenicity data may make a biosimilar more acceptable to patients and prescribers.

Even with smaller clinical trials, biosimilar manufacturers face challenges in identifying clinical sites and investigators that understand their unique development issues and can attract a sufficient number of participants, pointed out Pfizer UK clinical operations program lead Vivienne Jenkins. Recruitment may be easier at sites in developing countries, but she noted that distant research programs also face difficulties in obtaining adequate and timely quantities of reference comparators due to import/export requirements and concerns about overage and waste. She advised that open market sourcing of reference products may be most appropriate for smaller Phase I trials due to shorter lead times and sponsor concerns about keeping study data confidential. For larger Phase III trials, though, direct sourcing from the reference product manufacturer can secure a more reliable and timely supply at a more predictable price, provided that the innovator is willing to provide its product.