By Nitisha Pyndiah, PhD
To follow up our previous part 1 about the analytical data required to demonstrate interchangeability, let’s look into the clinical studies required.
What clinical studies are required to demonstrate interchangeability?
To demonstrate interchangeability, FDA recommends using the residual uncertainty approach to identify the next steps to resolve the uncertainty. Once analytical characterization has been performed, non-clinical and clinical studies are conducted to address any specific residual uncertainty (for instance, immunogenicity that may arise in patients due to minor structural differences identified during the analytical characterization)
Postmarketing data from a licensed biosimilar will generally not be sufficient to demonstrate interchangeability without an appropriately designed, prospective, controlled switching study.
In FDA’s draft guidance about demonstration of interchangeability, FDA recommended switching studies with the aim to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable and the reference product is not greater than the risk of using the reference product without such alternation or switch.
Furthermore, in certain case scenarios, if there is residual uncertainty regarding interchangeability based on an immunogenicity-related adverse event, a sponsor may need to obtain licensure as a biosimilar product and collect postmarketing data before interchangeability can be demonstrated.
The draft guidance entitled, Considerations in Demonstrating Interchangeability with a Reference Product, also highlights that if a patient has an adverse reaction during the course of a switching study, the fact that the patient had been receiving both reference product and proposed interchangeable product may lead to carryover effects, thus determining which product was responsible for the reaction may be difficult. Differences identified between the non-switching and the switching arm would lead to the conclusion that the proposed product is not interchangeable regardless of which product either reference or proposed interchangeable product or switching from one product to the other was at the origin of this difference.
FDA highlighted that the agency would be flexible on the design of the switching studies and will address product-specific scientific matters on a case by case basis when sponsors/applicants sought advice from FDA. As for biosimilars, developers of interchangeable products are highly advised to contact FDA early in their development.
An interchangeable product developer has two main options regarding switching studies:
- A dedicated switching study
- An integrated study also referred to as ‘2 in 1’ studies (Figure 1)
The dedicated switching study design as its name suggests is a study to demonstrate interchangeability once biosimilarity has been demonstrated using another clinical study. The integrated study, on the other hand, refers to a single study which is used to ‘support the demonstration of no clinically meaningful differences between the reference product and the proposed product for biosimilarity’ in a first part and incorporates a switching study in the second part (Figure 1 at bottom of the page).
For the switching study, the lead-in period with the reference product should be long enough to allow a steady state of pharmacokinetics before randomization to the switching part of the study. At least three switches are required for the switching arm, meaning that there should be at least two separate exposure periods to both the reference product and the proposed interchangeable product.
At the end of these switches, the last switching interval should be from the reference product to the proposed interchangeable product and be long enough to allow for the washout of the reference product corresponding to at least three or more half-lives of the product. Following this last step, the pharmacokinetics of the proposed interchangeable product will be assessed and compared in the switching arm and the non-switching arm.
There has been a lot of attention regarding switching studies and trying to understand whether switching studies may have a negative impact on patients. A recent publication (Cohen, H.P., et al. Drugs (2018)), analyzing the data from 90 studies that enrolled 14,225 unique patients, reported that in most of the studies, no immunogenicity, safety and efficacy differences were reported after switching from reference product to biosimilar. This recent report brings hope to patients and healthcare providers regarding unchanged safety and efficacy of the interchangeable products. Indeed, interchangeable products may have a major economic impact on healthcare costs as regulators, pharmacists, patients and payors work towards reducing the cost of biologics treatments.
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Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.
Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.