Industry Regulatory Experts Share Learnings From the Biosimilar Approval Process

During a panel on the second day of the 2017 AAM Biosimilars Council Conference, held in Washington DC, September 11-12, regulatory leaders from Pfizer and Sandoz shared their experiences with the development of their biosimilar products: epoetin alfa (Epogen) and etanercept (Erelzi), respectively.

Tracy Dianis, director, Global Regulatory Affairs Biosimilars, Pfizer Essential Health, brought up 3 key concepts with biosimilar development:

• The need to flip your mindset
• Narrating a holistic story
• Staying in tune with basic concepts

“Shifting your approach for the development program is a challenge,” Dianis said, “especially if you are trained for a long time in the development of originator molecules.”

Dianis told the audience that Pfizer launched the epoetin alfa biosimilar program prior to the Biologics Price Competition and Innovation Act of 2009 or the formal FDA guidance being issued. Product development included statistical analysis of analytical data, preclinical studies in rats, and clinical strategies that included pharmacokinetic and pharmacodynamic studies, in addition to extra clinical studies, Dianis said.

“We had a massive quantity of data to support the analytic and qualitative data. Through our discussions with the FDA, we ended on 2 attributes: mechanism of action and inherent quality of the molecule,” she added.

Another challenge of starting early was in the non-clinical space, she explained. “We didn’t know what the requirements would be. In case of epoetin alfa, we couldn’t do animal modeling; we leaned on our experiences of [the] originator biological space and also evaluated studies conducted for the reference.”

Pfizer ended up with 2 13-week toxicology studies, but Dianis stated that applying this study design in the comparative setting was challenging. “It really required ‘flipping our mindset’ to make sure we were thinking like a biosimilar and not an originator product developer,” she said.

The product, however, continues to face challenges—it was rejected by the FDA for a second time in June this year; the complete response letter cited issues with the potential manufacturing facility. The rejection followed a 14 to 1 recommendation by the Oncologic Drugs Advisory Committee just a month prior to approve the product.

Explaining the importance of the “totality of evidence,” she pointed to the value of highlighting data that demonstrated product biosimilarity to the reference product as well as the differences. “It is also important,” she continued “to develop a narrative on why the differences do not disqualify the existence of biosimilarity.” Teamwork should be at the core of the development program, according to Dianis, and the narrative should hold true across all the data packages submitted for FDA review. “Working in silos does not help in the biosimilar space…it requires close collaboration and needs the story to be woven through the data package.”

Dianis concluded by saying that while companies might focus their efforts in identifying and explaining new aspects of the biosimilar, traditional product development and compliance aspects retain their relevance.

Sharing the podium with Dianis was her counterpart from Sandoz, Cindy Cao, PhD, who stepped back in time to provide an overview of the regulatory approval steps faced by GP2015 (Erelzi). Prior to submission of the biologics license application on July 30, 2015, representatives from Sandoz met with the FDA for pre-investigational new drug discussions, which included conversations around a pediatric study plan as well as establishing a bridge between the US-licensed product and the EU-approved product.

The 2 parties also discussed, and agreed on, conducting safety and immunogenicity evaluations for patients who undergo a single transition from the reference (Enbrel) to GP2015. With respect to some issues with disulfide bonding studies, they continued to have conversations with the FDA. The team had to be open and ensured that their development program was driven by science, she said.

Following an advisory committee meeting on July 13, 2016, the FDA gave the product a green light on August 30, 2016. According to Cao, the following aspects were key to Erelzi’s success story:

• Early and continued discussions with the FDA: including important critical quality attributes
• Learning through development: monitoring batch-to-batch variations and sharing new product development observations with the FDA
• FDA’s flexibility and scientific approach

David Gaugh, RPh, senior vice president of regulatory sciences, AAM, who moderated the discussion, asked the panelists whether biosimilars are being held to higher standard than are originators.

“The reference product has had years of experience for routine manufacturing, especially in the context of statistical criteria,” Dianis responded. “In our case, even with multiple strengths, we are still very early in the process. [The FDA] are open to having the discussion, but the discussions can often be tougher because they want the product to be clean.”

Cao had a distinct perspective to share: she called biosimilar product development a moving target. “We do often observe differences over years with the reference product, but it’s not uncommon.”

Answering an audience question on differences in their experiences between the FDA approval process versus the European Medicines Agency, Dianis said that, with the epoetin alfa biosimilar, “EMA was a little more flexible than when we brought the program to the United States. Now [the differences] have evened out, but there are still some differences, statistical tiering being one of them.”

For Sandoz, on the other hand, the timings were flipped. “We filed with FDA prior to [European Union]; both authorities reviewed nearly simultaneously and our major learnings were similar with both bodies,” Cao said.