Locke Lord QuickStudy: Proving Biosimilar Interchangeability – New FDA Guidance Provides Important Considerations for Making that Proof

May 15, 2019

On May 10, 2019, the United States Food and Drug Administration (FDA) issued a new draft Guidance entitled Considerations in Demonstrating Interchangeability With a Reference Product.

This new FDA Guidance provides important considerations for biosimilar applicants desiring to prove that a biosimilar product satisfies the requirements for receiving an interchangeability designation under Section 351(k)(4)(A) - that the applied for biologic product is:

“biosimilar to the reference product;”
“can be expected to produce the same clinical result as the reference product in any given patient;” and
“for a biosimilar product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

The Guidance is generally broken down into five main sections regarding the scientific considerations for demonstrating interchangeability:

(I) data and information needed to support an interchangeability demonstration;

(II) considerations for the design and analysis of a switching study or studies;

(III) considerations regarding the comparator product in a switching study or studies;

(IV) abbreviated considerations for developing presentations, container closure systems and delivery device constituent parts for the proposed interchangeable product and

(V) postmarketing safety monitoring considerations.

This QuickStudy provides the highlights of the guidance, however, industry sponsors seeking to show interchangeability should review the entire guidance in full.

(I) Type and Amount of Data to Support Interchangeability Demonstration.
Data and information for establishing interchangeability are beyond what is required for biosimilarity (see Section VII of Guidance entitled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product). The Interchangeability Guidance divides the types of factors impacting the data needed to support an interchangeability designation into Product-Dependent Factors and Post-Marketing Data.

Regarding Product-Dependent Factors, FDA first discusses the Product Complexity and the extent of comparative and functional characterization. As required for biosimilars, FDA recommends a step-wise approach during product development to show that the proposed interchangeable product is “highly similar” to the reference product. This would include consideration of the product’s degree of structural and functional complexity – for example, a single target receptor product would need less clinical data than a product with multiple targets or less-defined pathways. Also, FDA recognizes that there are a number of analytical methods for making the “highly similar” showing (e.g., change variants and glycoforms), and that advances in analytics may allow for better comparisons.

FDA then discusses Product-Specific Immunogenicity Risk. Reference products with a documented history of inducing detrimental immune responses may require more data for interchangeability than products without such a documented history.

The third product-dependent category discussed is the Totality of Factors. Under this category, FDA provides two examples showing the case-by-case nature of the required demonstration.

Regarding the Post-Marketing Data, FDA comments that their current thinking is that post-marketing data from products first marketed as biosimilars are insufficient to support an interchangeability demonstration without an appropriately designed switching study(ies). However, FDA does recognize that appropriate post-marketing data can reduce the uncertainty about interchangeability and will evaluate that data as part of the totality of evidence in making an interchangeability determination. FDA encourages sponsors to discuss their plans for use of post-marketing data as evidence of interchangeability with FDA.

(II) Considerations for the Design and Analysis of Switching Study or Studies.
The Guidance explains that the main purpose of the switching study(ies) is to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between the use of the proposed interchangeable product and the reference product is not greater than using the reference product without switching. The switching study should evaluate changes in treatment that result in two or more alternating exposures or switch intervals.

For products only administered once, a switching study is generally not needed. Products administered more than once, however, will generally require switching studies or FDA will expect justification of why one is not needed.

The design of the switching study will be impacted by how the proposed interchangeable will be used in clinical practice, taking into account scenarios of most clinical concern. The switching study should report response in terms of safety or diminished efficacy through assessment of differences in immunogenicity and pharmacokinetics (“PK”) and/or pharmacodynamics (“PD”) as compared to not switching. 

FDA outlines a flexible approach regarding switching study designs and encourages early discussions about the clinical plan. The Guidance also includes as an attachment, an example of a Switching Study Design. The flexible approach includes consideration of Study End Points, Study Design and Analysis, Study Population, Conditions of Use to be Studied, Route of Administration, and Extrapolation of Data.

Study End Points – The primary endpoint in a switching study should assess the impact of switching or alternating between the proposed interchangeable and reference products on clinical PK and PD (if available). FDA considers PK and PD endpoints more sensitive at detecting changes in exposure or activity. In addition, the switching study should descriptively assess immunogenicity and safety. The study may also incorporate efficacy endpoints, but at therapeutic doses many such endpoints are generally less sensitive to detect changes from switching or alternating.

Thus, when PD endpoints sensitive to change are identified, a PD analysis in addition to PK analysis is generally considered more useful in evaluating the impact of switching. 

Study Design and Analysis – FDA identifies two main study designs in the guidance – (i) Dedicated Switching Study Design and (ii) Integrated Study Design.

(i) Dedicated Switching Study Design – considerations include (a) sample size (based on PK considerations) with inter-subject variability in AUCtau and Cmax as primary considerations but prior immunogenicity information should also be considered; (b) number and duration of switches taking into account clinical condition with lead-in period sufficient to establish adequate baseline, at least two separate switch intervals, in switching arm final switch should be from reference to interchangeable product, and comparative assessment during final exposure period with washout period of at least 3 or more half-lives; (c) PK, PD and immunogenicity sampling should capture full PK profile with trough PK sampling to ensure steady state attainment; (d) tudy analysis using 90% confidence interval for geometric mean ratio of AUCtau (IV and SC data) and Cmax (SC data) within 80-125% range, with Ctrough and Tmax as secondary endpoints; and  (e) safety, immunogenicity and efficacy descriptively assessed as secondary endpoints – safety could reasonably evaluate adverse events and immunogenicity should include anti-drug antibody (ADA), neutralizing antibody (NAb) incidence, and ADA and NAb titer.

(ii) Integrated Study Design – integrated two-part study, subjects in reference product arm should be re-randomized in second part of study to continue or switch to interchangeable product. Study needs to be adequately powered.

Study Population – should be patients who are adequately sensitive in order to detect switching differences. If healthy subjects are proposed, then discussions with FDA about rationale should occur before submitting a proposed protocol.

Conditions of Use to be Studied – Only for condition(s) of use for which reference product is licensed.

Route of Administration – if product has more than one route, use the route that will best assess changes in clinical performance from switching.

Extrapolation of Data – available for additional uses for which a reference product is licensed—extrapolation should consider mechanism(s) of action (target receptor(s), binding, dose/concentration response, relationship between product structure and target receptor and location and expression of target receptor); effects of patient population differences on PK, biodistribution, immunogenicity and toxicity; any other safety and efficacy factors for each condition of use.

(III) Comparator Product Considerations.
If a sponsor seeks to use data from a comparison of the proposed interchangeable to a non-US-licensed comparator product, sponsor will need to provide adequate data to establish a “bridge” between the non-US-licensed comparator and the US-licensed reference product to justify relevance of data. Moreover, because the comparator in a switching study acts as both the active-switching arm and the control non-switching arm, the type and extent of “bridging” data may be different or more extensive than in other contexts.

(IV) Presentation Considerations.
Interchangeable product should have same presentation (i.e. container closure system and any delivery device system) as the reference product. Otherwise, a different presentation should be discussed with FDA. The interchangeable application should include all necessary CMC information relevant to the presentation.

(V) Postmarketing Safety Monitoring.
Finally, the Guidance explains that robust post-marketing safety monitoring is an important part of ensuring that biologic and interchangeable products are safe and effective and to evaluate serious safety risks not detectable through smaller population size of preapproval clinical testing. Such post marketing studies should focus on the particular safety or effectiveness concerns of the reference product, the proposed interchangeable product, the specific condition of use and patient population and patient exposure. 


As the biosimilar industry matures and companies seek more and more licenses for interchangeable products, this new guidance provides important information and high level considerations for how to establish interchangeability. Each product will have to stand on its own merit and good communication with FDA at all stages will be a key to obtaining a successful license on an interchangeable.
The Locke Lord IP Pharmaceutical and Biotechnology team stands ready to assist clients with their needs in handling matters related to biosimilars. Should a prospect aBLA applicant have any questions or concerns about the above issues or any other areas related to biosimilars or patent litigation, please contact the authors.