3 Big Biosimilar Questions At DIA 2016

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

It never fails to surprise me how different biosimilar conferences are from each other. This year, I attended three events: The World Biosimilar Congress, the GPhA Biosimilars Council Leading On Biosimilars, and, last week, DIA Biosimilars 2016. All three of these conferences included presentations and panel discussions on the broad (and often political) challenges facing the biosimilar space, including reimbursement, naming, interchangeability, education, and patient access. However, DIA Biosimilars 2016 was unique in that it carried attendees away from the broader discussions of commercialization challenges and policy. Instead, the conference drilled down into the nitty-gritty challenges of analyzing critical quality attributes (CQAs), generating clinical data, and predicting immunogenicity.

Question 1: Which Attributes Will Matter To Patients?

The FDA was a prominent voice during many of the panels at DIA. The FDA’s Steven Kozlowski, director of the biotechnology products, CDER, delved into the work facing both sponsors and the FDA when evaluating the CQAs of molecules. As technology has improved, the industry has become better able to identify, measure, and test the attributes of the different molecules. It is difficult to determine what mechanisms are in play within a molecule and which could ultimately impact the biosimilar’s performance in the body. Drugmakers must have a risk-based way to prioritize the myriad of attributes present within a molecule. Companies must then think about these attributes in terms of four potential outcomes: Can these attributes impact bioactivity, pharmacokinetics, safety, and immunogenicity? Kozlowski stated, “Only a small number of these attributes will likely matter in the patient. But part of the dilemma is determining which do.”

In the upcoming months, the FDA plans to release “The Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity” guidance, which Kozlowski argues will help companies approach statistical analysis of various CQAs. “You will not have the same rigorous statistics on every CQA,” he said. “You don’t have to perform equivalence testing on so many attributes that the power of your overall evaluation is tiny.” The FDA has been working with companies, many of which have come up with methods of evaluating CQAs. But there are many different views on the right ways to do this. The guidance is expected to provide a framework for companies.

Question 2: Is The FDA’s Statistical Approach Guidance Setting Biosimilars Up To Fail?

As Kozlowski acknowledged, there are many opinions surrounding the topic of this upcoming guidance. Sandoz’s CSO Martin Schiestl arguably gave one of the most important and challenging presentations at the conference. He homed in on what he described as the “controversial” topic of comparing analytical data. When comparing batch data from a biosimilar to the batch data of a reference product, a company is comparing the “means” of two different populations. However, as Schiestl stated, manufacturing processes (which often change throughout the life cycle of a biologic) are not controlled by means. As such, over time, the mean can shift after a process change. In turn, “a biosimilar, which must fit into the same data range as the reference product, ends up chasing a moving target,” Schiestl said. While pass/fail statistics have a place within clinical evaluations, he ultimately argued statistics should never be a pass/fail criterion in chemistry, manufacturing, and controls (CMC) comparability because biosimilar makers would be stuck “hunting ghosts.”

Question 3: Are Immunogenicity Concerns Valid?

Immunogenicity was a popular topic at this conference. One of the biggest fears about biosimilars is that switching from the reference biologic to the biosimilar will result in immunogenicity, or an unwanted immune response and adverse effects in patients. According to Hillel Cohen, executive director of scientific affairs at Sandoz, the concerns about immunogenicity, though primarily theoretical today, are at risk of evolving into a big barrier to biosimilar acceptance. Included in his presentation was a review of 102 different studies. These studies took place in a variety of patient populations and encompassed different study designs (i.e., parallel designs, single-switch, cross-over, and real-world observational studies). Following a review of this literature, Cohen concluded, “The vast majority of literature to date reveals there isn’t an increase of immunogenicity or safety concerns in the act of switching from a reference product to a biosimilar.”

Though there were two abstracts included in his lineup that raised some questions, he emphasized the importance for all stakeholders to rely upon the constantly growing database of literature to inform immunogenicity concerns. While we can’t dismiss theoretical concerns about switching, the vast majority of literature so far hasn’t revealed immunogenicity concerns. Of course, as Cohen stated, “We have to maintain an open mind to the data that will come, be it positive or negative. But given the state of the data where we are today, I don’t think people should say there are immunogenicity concerns.”