Biosimilars: Experts Discuss Possible Interchangeability Guidance Changes and Reducing Phase 3 Requirements

With a mountain of challenges to creating sustainable biosimilars markets, particularly in the US, experts on Friday at the Medicines for Europe’s 16^th annual biosimilars conference in London discussed possible regulatory changes that could help open the doors for more competitors.

Rumors of upcoming changes to the US Food and Drug Administration’s (FDA) draft guidance on interchangeability were discussed briefly by Leah Christl, FDA’s associate director for therapeutic biologics, who said that there have been some news articles saying that the standard for interchangeability could change, though that is not possible because it is a legal standard.

However, the data elements necessary to support an interchangeability designation may change between the draft and final guidance, Christl noted.

Martin Schiestl, chief scientific officer at Sandoz, told to Focus in an interview: “The biggest hurdles or requirements in the interchangeability guidance are those that require a US reference product and the requirement for switching studies, which are quite challenging … there is a risk that even if everything is perfect, the outcome could be negative because of technical problems.”

In addition to the soon-to-be-released biosimilar policy roadmap, Christl also highlighted upcoming guidance from FDA and noted that the agency has moved from a 10-month review clock to a 12-month review clock, though there will be more transparent milestones:


Phase 3 Trial Reduction

Schiestl, meanwhile, detailed certain areas where the US and EU could further harmonize their regulations, particularly on guidance related to statistical methodologies and critical quality attributes, as well as with the further reduction of clinical data necessary to support biosimilar applications in certain circumstances.

The reduction of clinical data “is a discussion that’s just starting,” Schiestl said, noting that many experts are thinking about the criteria to enable this next big leap in the adapting regulations, “which would be a biosimilar antibody without a comparative Phase 3 safety and efficacy trial.”

He noted that there are currently several examples of biosimilars, such as pegfilgrastim, that can come to market without Phase 3 trials, though there is an opportunity for others with “less immunogenicity or no immunogenicity.”

Earlier on Friday, Gillian Woollett, senior vice president at Avalere Health, also discussed how conducting some Phase 3 studies for certain biosimilars may be unethical because they have become repetitive and do not offer any new data.

“At some level it’s patronizing to do these trials, and we need to recognize there are some phenomenal financial agendas at play here,” Woollett said.

But Elena Wolff-Holz, chair of the European Medicines Agency’s biosimilar products working party, made the case that Phase 3 clinical trials are necessary in some cases, especially for biosimilars that are first in a class.
Shifts or drifts in originators that can lead to artificially better or worse looking biosimilars – “what exactly that means, this is the work we need to do,” she said.

Niklas Ekman, vice-chair of EMA’s biosimilars working party, also noted: “When we discuss the possibility of waiving clinical trials – there’s added pressure on the analytical side … and transparent pre-planning for statistical approaches needs to be better.”

Schiestl further explained to Focus that there must be enough scientific data to make this conclusion that Phase 3 trials can be skipped, and only in certain circumstances – “meaning the quality comparison is good enough to allow skipping a Phase 3 trial, also that there’s a sensitive enough PK model … it must be grounded in scientific data.”

And even with tweaks to FDA’s interchangeability draft guidance, a reduction of Phase 3 requirements and further harmonization of regulations across borders, it’s unclear how much the US biosimilars market will open up as a result.

Numerous conversations at the conference centered on the idea that biosimilar companies are struggling to gain their place in the US (despite the nine FDA approvals of biosimilars, only one biosimilar has mustered more than 10% market share). Some even suggested that these barriers and struggles in the US are intentional – that biopharma companies rely heavily on the US profits from their blockbuster reference products and therefore want to do everything in their power to prevent competition.

Intentional or not, as more biologics come off patent over the next several years, time will tell if these initial struggles to gain market share in the US were just a blip on the radar.

And Schiestl said he remains optimistic with regard to the adaptive regulations, particularly as regulators “began with a very conservative approach and now with time, experience and knowledge,” have become more efficient. “Hopefully we’ll see more biosimilars without Phase 3 trials,” he added.