Other considerations for clinical studies are that the regulations are written with some flexibility, and although clinical studies have been required thus far, they are not mandated by the regulations. Perception from sponsors is that innovators make process changes all the time that impact structure and no clinical study is done because of good analytical characterization so why are biosimilars different? With solid analytical and functional data, we should continue to challenge regulators on the need for clinical studies.

1. BIOSIMILARS: REGULATORY
AND CLINICAL
CONSIDERATIONS
Alicia M. Baker, DRSc, MS
Executive Strategist
Head of Biosimilars Center of Excellence
Strategic Product Development Consulting
Eighteen biosimilars were approved by the FDA through the 351(k) pathway as of the end of March 2019, but the
regulatory pathway in the U.S. is still considered a new frontier, especially when compared to regulatory guidance
in the EU. With our global industry’s growing interest in developing biosimilars, it’s critical that sponsors have a
clear understanding of key clinical issues and develop a strategy for navigating today’s regulatory environment.
(Bio)similarities and Differences in Regulations
In the U.S., biosimilars are defined by the Biologics Price Competition and Innovation Act of 2009, also referred
to as BPIC Act. The EU defines biosimilars according to EU Directive 2004/27/EC. While each party has slightly
different wording, the spirit of the definitions is largely the same between the U.S. and the EU. The most notable
difference between the two is that the FDA will determine interchangeability in their regulatory review, while
the EMA will not comment on interchangeability, leaving it up to the individual member states. Currently, many
sponsors perceive that the interchangability designation in the U.S. is not necessary, however, if and when a
biosimilar achieves interchangability, it could change the landscape.
Both agencies agree that biosimilars must be systematically engineered to match the reference product.
Biosimilarity assessments are conducted against the innovator reference product at all levels of product
development. This includes physiochemical attributes, primary, secondary, tertiary, and quaternary structural
assessment, biological activity, preclinical in vivo biosimilarity, Phase I PK and safety, and Phase III efficacy and
safety. The impact on shelf life on all of the above is also critical.
Given that both biosimilars and their innovator reference products have inherent variability, it’s important to
decipher how these differences have a clinical impact. The characterization of the biosimilar will always be much
higher than that of a new biological entity and will always include reference product versus biosimilar.
Clinical Practice Considerations Based on Regulatory Guidance
During development, many key issues need to be considered based on current regulatory guidance.
For example, sourcing of the reference product is critical. In recent years, agencies have relaxed their position on
the reference products so that sponsors are not running separate studies with each country reference product.
Typically, a three-way bridging study in Phase I PK and/or PD study can compare the U.S. reference product,
EU reference product and the biosimilar product. However, there are ongoing discussions that using a single
sourced reference product throughout the span of development may be acceptable, rather than have to run Phase
1 bridging studies. It is certainly something to keep pushing with regulators for ease of development.
Getting a full range of indications in the reference’s label without conducting efficacy studies has been shown
possible by the approvals thus far. Here, extrapolation of indications beyond those studied is possible. Some
regulators will even be removing the word “extrapolate” from their guidance documents and regulations as
“extrapolate” means to apply to an unknown and this is not an unknown given the high similarity to the reference
product. We’ve seen recent approvals supported by regulatory guidance that is based on the overall totality of
evidence, an observation that assumes that the efficacy and safety of the biosimilar is justified. For example, with
the biosimilar, Inflectra®
, the sponsor was able to assume all the indications for the Remicade®
reference product.
That said, there still may be a delay of certain indication approvals for the biosimilar given IP issues. FDA will
be addressing this issue in upcoming guidance documents to provide additional clarity on how biosimilar
manufacturers can carve out indications from their labels where a reference drug maker may still maintain some
IP and subsequently how these indications can be efficiently added once that IP has lapsed.

2. Learn more at www.covance.com
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Other considerations for clinical studies are that the regulations are written with some flexibility,
and although clinical studies have been required thus far, they are not mandated by the regulations.
Perception from sponsors is that innovators make process changes all the time that impact structure
and no clinical study is done because of good analytical characterization so why are biosimilars different?
With solid analytical and functional data, we should continue to challenge regulators on the need for
clinical studies.
Exploring the Possibility of Interchangeability
Switching (or interchangeability) has also become a hot topic in biosimilars. The FDA published a recent
guidance document called “Considerations in Demonstrating Interchangeability With a Reference Product.”
Switching/interchangeability studies should be designed to determine whether alternating two or more times
between a biosimilar and its reference product impacts the safety or efficacy of the treatment course.
Product presentation differences, including the delivery device and container closure system, may also
affect the determination of interchangeability. Given the unique delivery devices and presentations associated
with biologics, this could potentially be a challenge. The requirements for interchangeability will vary
based on the product submitted, stressing the fact that no single data package exists for all proposed
interchangeable products.
If a sponsor is hoping that a Phase III pivotal equivalence trial could be designed to include switch data that will
be sufficient to support a regulatory designation of interchangeability, it’s more than likely that interchangeability
will not be granted with initial approval. However, there may be flexibility in the regulations. As FDA becomes
more comfortable with biosimilars, we predict that greater interchangeability may be possible in the near future.
As mentioned earlier, sponsor perception is that interchangability is not necessary, but when and if it is achieved,
the landscape may change.
Applying an End-to-End Vision
While early and clinical work often takes the spotlight, post-marketing pharmacovigilance should be considered
as well, as there’s confusion in naming of the biosimilars for adverse event (AE) drug reports. Possible post-
marketing solutions include applying appropriate measures to identify the product and batch number used
in patients as well as developing agency-driven risk-management plans to include specifically-focused post-
marketing studies.
With many key players in the global market, sponsors are wise to establish early engagement with regulatory
strategists to design an efficient proposition. From our experience, we’ve seen that early and frequent
engagement with regulatory agencies helps confirm development plans, evaluates the appropriateness of
the data being generating and aligns sponsors’ expectations for a more efficient development process.
At Covance we provide end-to-end services, and we have worked on 96 unique biosimilars and 152 biosimilars
projects. Covance has significant and broad biosimilars experience across the full spectrum of drug
development: CMC/bioanalytical, exploratory/preclinical, market access/reimbursement and clinical labs.
Contact us to discuss your biosimilars project needs.