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FDA officials agree that large comparative clinical trials defeat the purpose of the abbreviated development program for biosimilars.
Large comparative clinical trials defeat the purpose of the abbreviated development program for biosimilars, according to FDA officials, and studies that merely replicate the safety and efficacy findings of the innovator product risk raising costs and delaying patient access to an alternative therapy. Instead, the biosimilar pathway permits licensure based on less than full clinical data, pointed out John Jenkins, director of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research. Speaking at the Drug Information Association’s biosimilars conference in Washington, D.C. last week, Jenkins and others agreed that some type of clinical testing is expected at this point to gain market approval for most biosimilars, while emphasizing significant differences in developing biosimilars and innovator therapies. This new approach, Jenkins pointed out, requires a “cultural and cognitive transformation” by FDA reviewers, advisory committee members and sponsors.
As of early October, FDA’s Biosimilar Product Development Program had 66 active projects involving about 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-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 data 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 to assess titers, persistence, impact on PK, clinical sequelae and neutralization. A comparative clinical study, however, should be conducted only to address uncertainties stemming from earlier testing, and it should focus on cardinal adverse events, while also assessing the primary endpoint and immunogenicity.
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. Some equivalence studies enroll more than 500 patients, which may defeat the intent of establishing a streamlined biosimilar pathway. In the future, comparative studies for biosimilars may have only two arms with less than 100 participants. 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 sponsors 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. Investigators tend to prefer involvement in research on exciting new treatment advances, as opposed to follow-on therapies. That leads sponsors to non-academic sites, which often have less experience and require more staff training, she noted. Patient recruitment similarly is difficult for these products and can benefit from study protocols that set appropriate inclusion/exclusion criteria and carefully define an appropriate patient population.
Recruitment may be easier at sites in developing countries, but Jenkins 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 1 trials due to shorter lead times and sponsor concerns about keeping study data confidential. For larger phase 3 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.
FDA encourages sponsors to propose innovative study designs for biosimilars, with novel endpoints and unique patient populations, said John Jenkins. He noted that FDA experts are available to discuss such approaches at a range of advisory meetings, and he urged sponsors to use these opportunities “wisely.” Biosimilar developers should request the type of meeting that fits their needs and provide the agency with complete data packages in advance to ensure productive outcomes. Most important, Jenkins added, is 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.