Alexandria, VA—
In most cases, comparative efficacy trials supporting FDA approval of biosimilars are as rigorous as pivotal trials for new molecular entities, according to a new report.

In fact, according to the Institute for Safe Medicine Practices–led review, biosimilars were often tested in larger, longer, and more costly trials than the original products.

The report in JAMA Internal Medicine sought to answer concerns about how extensively biosimilars have been tested. It has been a decade since an abbreviated pathway was established for approval of biosimilar biologic products in the United States.

The study involved 23 biosimilars for 9 reference products approved by the FDA. The researchers explain that a “novel and frequent requirement for approval was a year-long comparative efficacy trial that included not only a comparison with the reference product but also a period in which some patients were switched between products.” 

That is in contrast to trials for most small-molecule generic drugs, which compare plasma concentrations over time in healthy volunteers, they advise.

The authors add that the issues identified most often by the FDA in biosimilar applications were problems in facilities or manufacturing processes.

Background information in the report notes that biosimilar biologic products were authorized in 2010, after the U.S. Congress established an expedited pathway for approval of clinically similar versions of approved products. The authors emphasize that, unlike for most small-molecule generic drugs, approval requirements for a biosimilar included animal studies and a comparative efficacy clinical trial.

The researchers analyzed evidence required to support a biosimilarity license application, examined the FDA evaluation process, and estimated the costs of the key clinical-trial evidence.

Included were all biosimilar biologic products approved from January 2010 through October 2019, using the publicly available FDA-review documents, disclosures from, and the published peer-reviewed literature. The costs of efficacy clinical trials were estimated using licensed proprietary software, the researchers write.

The following elements of each approved biosimilar were evaluated:
• The extent of human clinical testing to establish that the biosimilar had no clinically meaningful differences with the reference product, 
• Results of comparative animal studies, and
• FDA-cited application deficiencies.
Cited deficiencies involved either facility inspection, manufacturing or product quality, animal studies, laboratory analytical studies, phase I and/or immunogenicity studies, and/or phase III comparative efficacy trials, according to the report.

Results indicate that the 29 clinical trials that established  the efficacy of the biosimilar products were comparable to that of the reference products. Researchers point out that those enrolled a median (interquartile range [IQR]) of 504 (258-612) patients, had a median (IQR) estimated cost of $20.8 ($13.8-$35.3) million, and had a median (IQR) treatment duration of 52 (28-68) weeks.
Yet, substantial deficiencies temporarily halted the review of nine applications, with the most frequent deficits being five with failed facilities inspections and six with manufacturing process quality problems.

The study determined that the approved biosimilar submissions included 51 animal studies on species that included mice, rats, rabbits, dogs, and cynomolgus monkeys, with negative outcomes in two animal studies attributed to differences between human and test species. The FDA generally met the standard 12-month review deadlines or stopped the review clock when serious deficiencies were identified, the authors note.

“Further research is needed into whether less costly comparative efficacy trials could provide adequate evidence of biosimilarity and whether animal studies contribute useful scientific evidence,” the researchers conclude.
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