Average clinical efficacy testing cost millions of dollars more for phase 3 biosimilar studies than for pivotal studies of originator products, authors report.
Most comparative efficacy trials conducted to obtain FDA approval for a biosimilar had a tendency to be larger, longer, and more costly than clinical trials required for originator products, according to a study of US biosimilar approvals prior to November 2019.
Investigators analyzed public records of FDA reviews and approvals of the biologic license applications, clinical trial data from the ClinicalTrials.gov website, and published peer-reviewed articles in this study of the evidence required to prove a biosimilarity claim and costs of phase 1/3 comparative clinical trials.
The need for comparative clinical efficacy studies is a subject of fierce debate currently, with numerous investigators, biosimilar development companies, and even regulators calling into question the value produced from these trials. Comparative trials are generally the final stage in a biosimilar development plan, which begins with manufacturing facility inspections and laboratory analytical studies of the proposed biosimilar agent, before moving on to animal studies and, finally, efficacy studies.
These comparative studies for biosimilars generally require larger patient populations than even the pivotal (confirmatory) trials for originator products because of the high equivalency standards and large patient population sampling needed to demonstrate biosimilarity, according to authors of the report.
“Given that pivotal trials for new molecular entities provide the primary and essential new scientific evidence that will guide the treatment of thousands to millions of future patients, an ethical and policy question arises about whether numerous, larger, and more costly trials should be conducted to demonstrate that no meaningful differences exist from a proven treatment,” the authors wrote.
Clinical Trials for Biosimilars vs Originators
Between January 2015 and October 2019, 23 biosimilars had received approval from the FDA referencing 9 originator products. For 21 of those 23 products (91%), there were 24 phase 3 clinical trials that evaluated comparative efficacy and may also have included a follow-up study to evaluate switching between biosimilars and reference products.
Investigators estimated that the median cost for the 24 phase 3 trials for biosimilars was $27.6 million vs a median of $19 million for 138 pivotal (confirmatory) trials from 2015 to 2016 that supported the approval of 59 originator agents.
Additionally, researchers found that phase 3 trials for biosimilars tended to enroll a higher number of patients (median 538 [372-644]) compared with pivotal efficacy trials of originator products (median 446 [205-678]), from 2005 to 2012.
Phase 3 biosimilar efficacy trials were also conducted for longer periods of time than originator efficacy trials, with 100% of the ones for biosimilars lasting longer than 26 weeks compared with 35% of pivotal trials for originator approvals (2005 to 2012) taking that long.
Investigators cautioned that, “these comparisons provide a useful context, but they are not exact comparisons given that the previous findings included biologic products and small-molecule drugs and that phase 3 trials were usually but not always required for marketing approval.”
Animal Trial Requirements
The 23 approved biosimilars included in the study had a total of 51 animal studies, with 1 to 7 experiments conducted for each product. Species used in the studies included mice, rats, rabbits, dogs, and macaque monkeys.
Although animal studies are required by the Biologics Price Competition and Innovation Act for a biosimilar to receive approval, investigators found that animal studies “did not appear to provide useful scientific information given that human data were available both for the reference product and in clinical trials for the biosimilar product.”
Animal studies are not required by the European Medicines Agency for a biologic to be approved.
The authors concluded that additional research is needed to determine whether less costly and time-consuming studies of bioequivalence, more use of real-world data, or employment of other methods could provide sufficient scientific evidence to demonstrate biosimilarity.
Moore TJ, Mouslim MC, Blunt JL, Alexander GC, Shermock KM. Assessment of availability, clinical testing, and US Food and Drug Administration review of biosimilar biologic products. JAMA Intern Med. Published online October 5, 2020. doi:10.1001/jamainternmed.2020.3997