Tony Hagen is senior managing editor for The Center for Biosimilars®.
Biosimilar orphan drugs might not be cheaper than innovator orphan products, owing to multiple factors, but modifications to regulatory policy could change this, a presenter said at the Terrapinn Festival of Biologics Basel 2020.
Orphan drugs are often significantly more costly than other biologics, and the presumption might be that biosimilar orphans could bring down the cost of these agents significantly, but the realities undermine that theory, said Roman Drai, MD, PhD, research and development director with Geropharm of Saint Petersburg, Russia.
However, it’s possible that with some modifications in evidence requirements by regulators, the cost of developing biosimilar orphans could be bought down significantly, and this savings could be passed on to patients, Drai said at the Terrapinn Festival of Biologics Basel 2020.
Under ordinary circumstances, competition helps to spur innovator companies to develop better drugs, with patients reaping the benefit, Drai said. “An innovator company might produce first-in-class and best-in-class drugs if they have someone pushing behind them, such as a biosimilar company.”
This doesn’t necessarily happen with orphan drugs, and the costs of development are the reason, Drai said. The costs of developing orphan drugs may be 4 times higher than costs for nonorphan drugs, he said. “The cost for ultra-orphan drugs could be 12 to 20 times higher.”
Orphan drugs are priced high in large part because they are intended for rare conditions and a small population of patients is eligible for treatment with these drugs. Further, the high costs of development must be offset within the same product exclusivity window as applies to common originator and biosimilar drugs, depending on patents, Drai said. This need for a return on investment is factored into the price of orphan drugs.
Another reason for the high cost of developing orphan drugs, both biosimilars and originators, is that for pharmacodynamic (PD) and pharmacokinetic (PK) studies, roughly 40 patients would be needed, but residual uncertainty needs to be resolved via efficacy, safety, and immunogenicity studies, and for this as many as 380 patients would be needed, he said. “You could not just enroll 50 patients to compare with a biosimilar; this is not enough to exclude the uncertainty.”
For that combined patient population (N = 420), an estimated $7.74 million would be needed to perform the PK/PD, efficacy, safety, and immunogenicity studies in Russia—roughly 7 times higher than for nonorphan drugs. In addition, those confirmatory studies would come after more basic studies to establish pharmaceutical and comparative quality and to perform comparative nonclinical evaluation.
Time is another factor that adds to the cost. Enrollment is prolonged because it isn’t easy to get patients to switch to a biosimilar for an orphan drug study, and enrollment may have to be conducted across multiple geographic zones to get the minimum number of patients. An immunogenicity study alone might stretch out to 12 months, Drai said.
Getting past these issues is possible with some structural changes in the way this development work is traditionally performed, he said. This can be accomplished by lowering residual uncertainty prior to phase 3 studies: Phase 3 studies could be waived altogether, they could be postponed until after marketing authorization, and a smaller-than-usual number of patients could be enrolled for phase 3 studies, Drai said, suggesting 3 alternatives.
The prerequisites for allowing such a bypass would be as follows: the existence of a simple molecular structure; high binding affinity between the molecule and antigen; low disulfide bridges; and moderate hydrophobicity, or molecular attraction to water. If these conditions are met, the phase 3 studies could be deemed unnecessary, Drai said.
Further, identifying biomarkers could ease the process by providing surrogate clinical end points for helping understand the drug’s mechanism of action, he said.
“We need to have smart approach to orphan biosimilars and develop guidelines for orphan biosimilars,” he said. “This would lower costs, and often a biosimilar orphan drug could cost less than an originator and it would make the therapy available all over the world.”