«PrevThe Progressive Librarian: 10 ways to be more forward-thinking NextWhat you don’t know can hurt you – how to manage the Patent Troll risk»

The U.S. may be arriving late to the biosimilar market, but it can make up the lost time through a speedier adoption of the follow-ons.

"I think the pendulum is swinging to the other direction" when it comes to adoption, Siegmund Gutman, a partner at Proskauer Rose LLP, told BioWorld Today. The EU may have taken the lead in developing the market, but it hasn't been quick on the uptake, he noted. The U.S., facing the pressure of higher drug prices, could be much faster in adopting biosimilars, especially when the FDA opens the pathway for interchangeables.

Robert Cerwinski, a partner at Goodwin Procter LLP, agreed, saying an acceleration in the uptake of biosimilars is very likely in the U.S., but it's tough to predict the rate of that acceleration. Interchangeability, which allows for automatic substitution, will be a major factor.

The EU path has no separate development for interchangeables and leaves biosimilar substitution up to the individual member states. The lack of interchangeability in many EU countries has been a natural barrier to biosimilar adoption there, Cerwinski told BioWorld Today. As a result, biosimilars haven't eroded the EU market share of several reference biologics as fast as many experts had expected.

For a follow-on to be deemed interchangeable in the U.S., it must by law produce the same clinical results as the reference drug in any given patient. The risk, in terms of safety or diminished efficacy, of switching between an interchangeable and reference biologic must not be greater than from consistent use of the reference product. While the FDA has said that switching trials likely would be necessary to demonstrate interchangeability, it hasn't mapped out the path forward for interchangeables.

Industry and U.S. lawmakers have been pushing for guidance on interchangeability for a few years. In questioning the FDA's Janet Woodcock at a Senate subcommittee hearing last year on biosimilars, Sen. Chris Murphy (D-Conn.) pressed for a date when the long-promised guidance would be delivered.

Woodcock declined to make a commitment. "We're working very hard," she said instead. Although she assured Murphy that interchangeability is scientifically possible, Woodcock expressed concerns that continued switching between molecules could trigger an immune response – something that's been seen among various reference epoetin products. The FDA needs to make sure the interchangeability guidance is "bulletproof," she said. (See BioWorld Today, Sept. 18, 2015.)

Testing the Waters

As the agency continues to develop its guidance, some biosimilar sponsors appear to be testing the waters for interchangeability, as several clinical trials have a crossover element. For instance, the ongoing phase III study of Coherus Biosciences Inc.'s biosimilar candidate to Humira (adalimumab, Abbvie Inc.) assigns some of the plaque psoriasis patients initially randomized to Humira to the biosimilar at week 16. All patients will be switched to the biosimilar at week 24, according to ClinicalTrials.gov. EMD Serono Inc., part of Merck KGaA, has a similar component in an ongoing phase III trial of its Humira biosimilar candidate.

As part of the development of its rituximab biosimilar, Sandoz Inc. is conducting a phase III trial to identify potential safety risks of transitioning from the U.S.-licensed Rituxan or the EU-approved Mabthera to its proposed biosimilar as compared with continuing treatment with the reference biologic produced by Roche AG and Biogen Idec Inc.

Even if such studies aren't enough to meet future FDA interchangeability guidelines, they will address concerns about switching patients from the innovator to that particular biosimilar, which could help the sponsor differentiate its biosimilar and encourage faster uptake in what may be a crowded market.

That concern has been a factor slowing the uptake of biosimilars in the EU. Doctors have been reluctant to switch patients with chronic diseases from a biologic that's working for them to a biosimilar – unless economic considerations force it, Cerwinski said.

While such data could assuage doctors' and patients' worries, it also could help get U.S. payers on board with a particular biosimilar. Of course, the data will only be useful if the FDA allows sponsors to share the information.

Looking forward, many experts expect payers to drive the uptake of biosimilars in the U.S. In many instances, payers will force patients to switch to a discounted biosimilar, Stacie Ropka, of Axinn Veltrop and Harkrider LLP, told BioWorld Today. Given their role, she expects payers will be educating patients and doctors about biosimilars as much, if not more than, biosimilar sponsors and the FDA.

Meanwhile, several questions could still trip up biosimilars in the U.S. based on the complexities and variability of biologics. The biosimilar path "is more or less a pass/fail result," said David Fox, a partner at Hogan Lovells LLP. "You're either a biosimilar or you're not." He likened the FDA's path to a field goal in football. A team gets the three points whether the football sails through the center of the goal post or barely shaves the post.

While that may work when using a biosimilar instead of the reference product, it could be worrisome when switching occurs between biosimilars that have not been evaluated against each other. Similar questions arise with interchangeables, Fox told BioWorld Today. For example, could a biosimilar be interchangeable with the reference biologic for some indications but not others? And would two follow-ons deemed interchangeable with the originator be interchangeable with each other? These are all questions the FDA has yet to answer.

Lessons Being learned

While the motivation for biosimilars is better patient access through reduced prices, the follow-ons offer other benefits as well. As the FDA and industry work through the questions of developing the new path, they're learning valuable lessons that could improve the quality and efficiency of biologics manufacturing and give them a better understanding of the mechanisms of biologics in general.

"While it's too early to tell, lessons learned from the development of biosimilars may have future impacts on the world of biologic manufacturing," said Geoffrey Eich, executive director of Amgen Inc.'s biosimilars division.

Jennifer Campbell, director of Merck Millipore's worldwide biosimilars program, expects biosimilars to drive the move toward flexible, single-use manufacturing technology that is more efficient for smaller volumes. As the biosimilar market takes shape, the innovator is likely to retain about half its market share, with three or four biosimilars splitting the other half, Campbell said at a roundtable discussion on manufacturing that was hosted last year by the Tufts Center of the Study of Drug Development. (See BioWorld Today, Oct. 20, 2015.)

With each sponsor having a smaller share of the market and some biosimilar sponsors offering several different follow-ons, companies will need that flexibility and efficiency of scale, she explained.

Other lessons are to be learned from the science of biosimilars. Rigorous science is required to develop and make high-quality biologics, Eich told BioWorld Today. As a developer of both innovative biologics and biosimilars, Amgen, of Thousand Oaks, Calif., has found that the research required for biosimilar development and the process of reverse engineering is strengthening its biology and technical expertise.

Another future benefit of biosimilars in the U.S. is the innovation they will spur by forcing the sponsors of reference products to invest in finding and developing the next generation of biologics, with the promise of better treatments and cures. "You can already see the impact of innovation with meaningful benefit to patients in most settings where biosimilars are entering," Eich said.

Biotechnology "is still very young, yet we are transforming diseases with severe morbidity or mortality toward manageable or even curable conditions. So the technology and its application for patients are always going to be advancing," he added. And with those advances will come a new spate of biosimilars.

This article is an excerpt from the insightful new report, Biosimilars: U.S. Market Opportunities and Critical Strategies 2016, from Thomson Reuters BioWorld.

Click here to download a free copy of the full report, which also looks at:

  • Wait continues as new market teeters on brink of explosion
  • Conventional wisdom floundering in backlog of FDA biosimilars reviews
  • Legislative riddles hand courts vital role in shaping biosimilar path
  • Payment policies can make or break the emerging market
  • Makers of blockbuster biologics ready for biosimilar competition
  • Patient engagement is key to building a biosimilar market
  • Biosimilar uptake in the U.S. could outpace adoption in the EU

Thomson Reuters will host an upcoming webinar, “Driving Biosimilar Success: Insights from the Industry’s Leading Experts,” on Wednesday, June 15, 2016 from 11 am ET (8 am PT). Scott Foraker, Vice President & General Manager, Biosimilars of Amgen Inc. and Mari Serebrov, Regulatory Editor - Thomson Reuters BioWorld will discuss the core competencies needed to succeed in today’s biosimilars landscape, and best practices. Further information, including how to register, may be found here.