The FDA has often emphasized the importance of companies “telling the biosimilar story” in order to successfully file for market approval. But what these biosimilar stories look like, or how they even took shape, is not often regularly shared. Luckily, I had the opportunity to hear two of these stories at the 2017 Biosimilars Council Leading on Biosimilars Conference. In a presentation on regulatory best practices, Cindy Cao, U.S. biopharmaceutical regulatory affairs expert from Sandoz, did a fabulous job telling the story of Sandoz’s development of its biosimilar, Erelzi (etanercept).
But in addition to Sandoz’s story, which I discussed in the first of this two-part article, Tracy Dianis, director of global regulatory affairs, biosimilars, at Pfizer, took to the podium to highlight the company’s regulatory journey for its biosimilar of Epogen (EPO). What I particularly admired about Dianis’ presentation was her candidness about the cognitive and cultural transition that needed to occur in her own mindset, as well as within Pfizer, in order to embrace biosimilar development.
Biosimilars & Big Pharma: Not An Innate Transition
If we look at the successes in the biosimilar industry today, many of them have been accomplished by the Big Pharma companies. When I first began writing about biosimilars, I interviewed an executive from Biogen who emphasized the natural transition it was for the company to enter into the biosimilar space. I believe the phrase used was: “We know how to do this stuff.” Indeed, the Big Pharma players entering the biosimilar space have the people and the development and commercial experience to bring drugs to market. Couple all this with the well-known name and long-term reputation as a successful drug maker, and it would seem these larger companies have all they need to jump effortlessly into the biosimilar space.
But after hearing Dianis’ biosimilar story, it’s clear that entering the biosimilar development realm is not an innate and swift transition — regardless of any company’s history with successful drug development. As Dianis acknowledged, “Biosimilars and biologics are two different animals. If you’re like me, you trained in the originator process for many years. It really took a conscious effort to flip our mind-sets to the biosimilar step-wise approach. We had to actively ask ourselves: Are we thinking with the biosimilar mind-set, or are we following and continuing what we’re used to in the originator space?”
As has been reiterated on many occasions, a key difference between the development of originator and biosimilar drugs is the emphasis on the analytical foundation. While originator drugs rely on extensive clinical trials to demonstrate safety and efficacy, the brunt of the biosimilar maker’s work is using advanced analytics to get down into the weeds, if you will, of the reference molecule.
As such, when it came to tackling EPO, one of the most notable challenges for members of the Pfizer team was recognizing the breadth of the analytical similarity package. “I don’t think this level of rigor was applied in the analytical space until we entered the biosimilar paradigm,” Dianis said. And when tackling the glycosylated EPO molecule, Pfizer was faced with an expensive analytical endeavor that generated a large amount of data. This data, in turn, needed to be interpreted and put together into a seamless biosimilar story.
Another challenge in managing this data was the fact that the Pfizer development team began working with the FDA prior to the release of FDA guidances. In these early days, there was uncertainty around what the FDA would consider appropriate to support a demonstration of biosimilarity — for instance, in the realm of animal modeling. Similarly, when Pfizer began working with the FDA, the agency had not yet communicated the now-well-known Critical Quality Attributes (CQAs) tiering system nor the level of statistical rigor they expect to see within each tier. As such, in the beginning, the team found itself with a lengthy list of CQAs in tier one, which, over time and after more discussion with the FDA, was whittled down to only two.
These questions about how much would be enough to demonstrate biosimilarity also extended into the clinical program. For instance, the Epogen reference molecule is approved for both intravenous (IV) and subcutaneous (SC) administration. SC administration is considered to be the most sensitive for detecting differences in safety. Pfizer chose to study safety and efficacy in the chronic kidney disease population, which traditionally receives treatment through IV administration in U.S. dialysis centers. “We weren’t really sure what the bar was going to be with the FDA,” Dianis said. “We also weren’t sure what the bar would be for adoption and acceptance of the biosimilar by the healthcare professionals once we were approved. As such, we chose to do studies with both IV and subcutaneous administration.”
Cultural Transformation Key To The Biosimilar Journey
Though a number of scientific challenges arose during the development of EPO, there was also a cultural transformation that had to occur within Pfizer in order to successfully tell its biosimilar story. Though the literal act of writing a story is a lonely activity (says the poet), successfully “weaving together” Pfizer’s biosimilar story required new levels of collaboration within the company.
As Dianis described, during her years working on originator programs, she often found that work was carried out independently amongst the different departments. The CMC group and the clinical group rarely worked together unless something quirky came up during development that needed to be discussed between different groups. Ultimately, “We worked on independent tracks, then came together at the end to support the wheel,” she described. But entering biosimilar development, which relies upon the step-wise approach to demonstrating biosimilarity, required breaking out of these more-traditional silos. For instance, thanks to EPO’s complex glycosylation profile, one of the company’s primary tasks was to interrogate the glycosylation data. But in order to tell the story of how the company approached that data, the team needed to become comfortable weaving across the different scientific and technical areas that contributed to the totality of evidence.
As she summarized, “We built it together — the interrogation of the glycan structures. The consistency of the functional data translated to the pharmacokinetic and the pharmcodynamic data being consistent all the way through to our comparable safety and efficacy studies. The differences observed in the physico-chemical profile were carried through and interrogated all the way through the totality of the evidence.”
On the macro level, it’s regularly said there needs to be more communication amongst the many biosimilar stakeholders — companies, the government, payers, patients, and physicians. And, generally speaking, companies need to enhance their communications and collaborations across departments to successfully “tell the biosimilar story.” Embracing communication may seem like common sense. But from Dianis’ story, it’s clear that the biosimilar development process is as much a challenge from an organizational standpoint as it is a rigorous scientific undertaking.
As Dianis put it best, “In the biosimilar space, you can’t tell a story in silos. In order to take a step-wise approach to establishing biosimilarity, you really need to weave the story though the entire data package, across the various modules and applications. This requires close collaboration across the teams and embracing cross-functional discussions.”