How These Biosimilar Unknowns Could Impact Manufacturers

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

One of the best parts of covering the biosimilar space is the fact that so much has yet to unfold. As the U.S. jumps into the fray with its own biosimilar policies and regulations, drugmakers are faced with new questions, many of which have yet to be answered. These questions span from where the FDA will land in terms of biosimilar naming and interchangeability, to how to navigate the varying needs of global regulators. During my time covering biosimilars, I’ve grown well-versed in some of these arguments, including those around naming, labeling, and reimbursement. But several discussions in the past few months have added new layers of complexity to these issues.

How The Biosimilar Suffix Will Evolve Over Time

There are a lot of opinions on how biosimilars should be treated once on the market. There has been a loud outcry against the FDA’s current proposal to include a random, four-letter suffix on a biosimilar name. In fact, that naming policy was one of the most frequently discussed issues at the GPhA Biosimilars Council’s Leading on Biosimilars conference. But during the regulatory risks and realities panel, the experts from Mylan, Pfenex, and Sandoz steered the conversation away from the well-known arguments on whether or not this policy is necessary. It may seem that, once the FDA releases its final guidance on naming, the battle against the suffix will forever be lost. But this doesn’t have to be the case.

Hillel Cohen, executive director of scientific affairs at Sandoz, argued the biosimilar industry should push for an “intellectually honest” assessment of the impact of the suffix on pharmacovigilance. “As a group, we have to push the FDA to do an evaluation on whether pharmacovigilance has gotten better or worse in three to five years if they are going to go down the path of unique suffixes for biosimilar pharmacovigilance,” Cohen asserted. Should random suffixes cause greater confusion or more mistakes, in turn making pharmacovigilance worse, biosimilar players could insist the FDA alter its naming policy.

The naming issue could also get more complicated once interchangeability moves from a theoretical to an actual regulatory designation. In the next three to five years, I’d imagine there will be at least one biosimilar deemed interchangeable on the market. This raises the question of whether an interchangeable biosimilar will need to change its suffix to match that of the reference biologic. (It has yet to happen, but the FDA originally planned to outfit reference product names with suffixes, as well.) One of the ways around having to change the biosimilar suffix, Cohen suggests, is by listing interchangeability status in the Purple Book. The book could list the suffix and tell the pharmacist whether it’s a biosimilar or interchangeable. This method could eliminate the inevitable confusion that would result from altering suffixes.

Perhaps one of the most interesting questions addressed the role manufacturing changes could play in naming. Both biologics and biosimilars encounter a number of manufacturing and process changes. One audience member asked why different suffixes couldn’t be given to biosimilars (and biologics) after a manufacturing change to improve traceability. To implement such a policy, however, would lead to challenges determining which changes were major enough to warrant a suffix. Another challenge would be creating an additional, acceptable suffix after each change. As Cohen said, “The FDA looks at suffixes really, really, really closely — even more closely than I’m implying. It’s going to be a challenge for companies in five or six years to come up with suffixes.”

Abbreviated Clinical Development: What To Expect

The notion of abbreviating the already-abbreviated biosimilar development pathway is quite controversial. Though a European regulator at the DIA event last month suggested the EU is well on its way to embracing shorter development pathways for certain biosimilars, the FDA is still growing accustomed to the review of biosimilars. This isn’t to say there won’t be flexibility depending on the data submitted. In fact, the FDA repeatedly urged attendees at the recent DIA Biosimilars 2016 event to follow a step-wise motion rather than the “shotgun approach” when presenting data to the agency to ensure a company doesn’t end up doing more work than might be necessary.

But so far, all the biosimilars currently approved in the U.S. supplied patient efficacy data to support their approval. As Pfenex’s CMO Hubert Chen described at the GPhA conference, “If you look at the patient population, the endpoints, and sample sizes, you will be hard-pressed to distinguish differences between what was required to approve the biosimilar and the originator.”

But there have been several instances that suggest the FDA is supportive of clinical biosimilar assessments based on pharmacokinetics and pharmacodynamics (PK/PD) and immunogenicity. For instance, pure-play biosimilar company Coherus boasted an abbreviated development program for its Neulasta biosimilar, which is currently under review by the FDA. The company carried out a PK/PD assessment in healthy subjects and was permitted to perform an immunogenicity assessment in healthy subjects as well. Neulasta’s abbreviated development was rationalized because of the treatment’s well-established clinical profile. However, it’s important to note that not all molecules will be able to achieve these kinds of development programs, because of the lack of PK/PD knowledge or how they’re administered. (You would be hard-pressed to find healthy subjects lining up to get an injection in the eye for a PK/PD assessment of a Lucentis biosimilar and an institutional review board that would find this ethical.)

One of the biggest educational challenges is retraining physicians to understand the different role large clinical efficacy studies play in biosimilar development. In particular, it needs to be articulated that, in biosimilar development, more clinical development does not necessarily mean the biosimilar is more similar to its reference. For instance, less clinical data could very well imply the analytics demonstrated the molecule was already a close match to the reference product. Chen argued, “We need to be more proactive in educating stakeholders to realize quantity of data does not necessarily equate to a higher quality biosimilar.”