By Lynn C. Tyler
Just shy of seven years after the Biologics Price Competition and Innovation Act (BPCIA or Act) became law and created a pathway for biosimilars to reach the US market, the FDA has released a draft guidance on a key provision of the Act. The draft guidance is titled, “Considerations in Demonstrating Interchangeability With a Reference Product” (Guidance). The standard for determining whether a biosimilar is interchangeable with n originally-licensed or “reference” product is important because “the bio[similar] product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” Guidance at 2.
In light of the importance of the Guidance, this article will closely follow its structure and language, highlighting most if not all of the general rules. Those interested in the nuances and explanations are urged to review the full Guidance, as anyone contemplating pursuit of the interchangeable designation for a product is certain to do in any event.
- General Principles
The Guidance includes a section titled “General Principles” which summarizes the approach FDA will take to decide if a biosimilar is interchangeable with its reference product. As with the biosimilarity decision, FDA will consider the totality of the evidence when evaluating interchangeability.
To support a demonstration of interchangeability, the BPCIA provides, among other things, that a sponsor must show that the proposed product “is biosimilar to the reference product.” Where a product is first licensed as a biosimilar, that licensure may be referenced to support a showing for this statutory criterion for demonstrating interchangeability. In other words, previously-approved biosimilars can later be upgraded to interchangeable status.
In addition, the BPCIA provides that an application for an interchangeable product must include information sufficient to show that the proposed interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient.” The Guidance states that the data and information to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use may vary depending on the nature of the proposed interchangeable product and may include, but need not be limited to, an evaluation of data and information generated to support a demonstration of a biological product’s biosimilarity, such as:
- The identification and analysis of the critical quality attributes
- The identification of analytical differences between the reference product and the proposed interchangeable product, and, in addition, an analysis of the potential clinical impact of the differences
- An analysis of mechanism(s) of action in each condition of use for which the reference product is licensed, which may include the following.
- The target receptor(s) for each relevant activity/function of the product
- The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target receptor(s)
- The relationship between product structure and target/receptor interactions
- The location and expression of target receptor(s)
- The pharmacokinetics and biodistribution of the product in different patient populations
- The immunogenicity risk of the product in different patient populations
- Differences in expected toxicities in each condition of use and patient population (including whether the expected toxicities are related to the pharmacological activity of the product or to off-target activities)
- Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed
Where applicable, the data and information should include a scientific justification as to why any differences that exist between the reference product and the proposed interchangeable product, with respect to the factors described, do not preclude a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. The data and information may also include a scientific rationale to extrapolate data and information supporting a demonstration of interchangeability in an appropriate condition of use to the remaining conditions of use for which the reference product is licensed.
In addition, the BPCIA provides that another criteria for interchangeability is a finding that information in the application is sufficient to show that “for a biological 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 states that FDA expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use.
II. Factors Affecting the Amount and Type of Data Needed to Demonstrate Interchangeability
Section V of the Guidance discusses several factors that impact the amount and type of data and information needed to support a determination of interchangeability.
A. Product-Dependent Factors.
The first set of factors discussed are “product dependent” factors:
- Product Complexity and the Extent of Comparative and Functional Characterization
Like an earlier guidance document on biosimilarity, the Guidance recommends that sponsors use a stepwise approach generating data and information to address residual uncertainty about demonstrating interchangeability during product development. At each step, the sponsor should evaluate the extent to which there is residual uncertainty about the interchangeability of the proposed product with the reference product, and identify next steps to try to address that uncertainty.
Such information would include, in part, a showing that the proposed interchangeable product meets the highly similar standard for demonstrating biosimilarity. The product’s degree of structural and functional complexity may also influence the data and information needed to support a demonstration of interchangeability. The extent to which data and information provided by advanced analytical approaches helps to reduce residual uncertainty about interchangeability depends on the degree of analytical similarity between the products and the strength of the evidence for the clinical relevance of the analytical data.
- Product-Specific Immunogenicity Risk
Clinical experience with the reference product and comprehensive product risk assessments (e.g., regarding immunogenicity) may also affect the data and information needed to support a demonstration of interchangeability. For example, products with a documented history of inducing detrimental immune responses may require more data to support a demonstration of interchangeability than products with an extensive documented history that immunogenicity does not impact clinical outcomes.
- Totality of Factors to Consider in Assessing the Data and Information Needed to Support a Demonstration of Interchangeability
The two factors above need to be considered together to inform a consideration regarding residual uncertainty about the data and information needed to support a demonstration of interchangeability.
B. Biosimilar Product Postmarketing Data That May Impact the Data Needed to Support a Demonstration of Interchangeability
The Guidance states that FDA’s current thinking is that postmarketing data collected from products first licensed and marketed as a biosimilar, without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies, generally would not be sufficient to support a demonstration of interchangeability.
III. Data And Information Needed To Support A Demonstration Of Interchangeability
A. Design and Analysis of a Switching Study
- Study Endpoints
The primary endpoint in a switching study or studies should assess the impact of switching or alternating between use of the proposed interchangeable product and the reference product on clinical pharmacokinetics and pharmacodynamics (if available), because these assessments are generally most likely to be sensitive to changes in immunogenicity and/or exposure that may arise as a result of alternating or switching.
- Study Design and Analysis
a. Dedicated Switching Study Design
A study with a lead-in period of treatment with the reference product, followed by a randomized two-arm period—with one arm incorporating switching between the proposed interchangeable product and the reference product (switching arm) and the other remaining as a non-switching arm receiving only the reference product (non-switching arm)—may be appropriate when designing a switching study. Considerations for the design and analysis of such a study are:
- Sample size: The sample size of the switching study should generally be based on PK considerations (inter-subject variability in AUCtau or Cmax should be primary considerations) and should be appropriately justified.
- Number and duration of switches: The number and duration of switches between the reference product and the proposed interchangeable product should take into consideration the clinical condition to be treated, the therapeutic dosing of the product, and the duration of the exposure interval to each product that would be expected to cause the greatest concern in terms of immune response and resulting impact on safety and efficacy, if any.
PK, PD, and immunogenicity sampling: To capture the full PK profile, intensive PK sampling should be performed during the last switch interval following the dose after which at least three half-lives of the reference product have elapsed. Trough PK sampling should be conducted after each switch to ensure that steady state is attained. The timing of PD and immunogenicity sampling should be appropriately justified.
b. Integrated Study Design
If a sponsor is considering a study design using a single study intended to (1) support a demonstration of no clinically meaningful differences between the reference product and the proposed product for biosimilarity and (2) evaluate the impact of switching or alternating between the reference product and the proposed product for interchangeability, an integrated, two-part study design may be appropriate.
- Study Population
The study population for switching studies should be adequately sensitive to allow for detection of differences in pharmacokinetics and/or pharmacodynamics, common adverse events, and immunogenicity between the switching and non-switching arms.
- Condition of Use To Be Studied
Sponsors should consider choosing a condition of use that would support subsequent extrapolation of data to other conditions of use. In addition, it is important to note that a sponsor may obtain licensure only for a condition of use (or uses) for which the reference product is licensed.
- Route of Administration
If a product is approved for more than one route of administration, sponsors should study the route of administration that will best assess how a patient’s immune response will impact the clinical performance of the proposed interchangeable product, including changes in safety risk and efficacy.
- Extrapolation of Data
If the proposed product meets the statutory requirements for licensure as an interchangeable product under the Act based on, among other things, data and information sufficient to demonstrate interchangeability in an appropriate condition of use, the sponsor may seek licensure of the proposed product as an interchangeable product for one or more additional conditions of use for which the reference product is licensed. The sponsor would need to provide sufficient scientific justification for extrapolating data to support a determination of interchangeability for each condition of use for which the reference product is licensed and for which licensure as an interchangeable product is sought. The Guidance then lists several issues to be addressed in the scientific justification.
IV. Use Of A U.S.-Licensed Reference Product In A Switching Study Or Studies
According to the Guidance, using a non-U.S.-licensed comparator product generally would not be appropriate in a switching study.
V. Developing Presentations For Proposed Interchangeable Products
When developing a product for licensure as interchangeable under the Act, it is important for sponsors to consider carefully the presentation of the proposed interchangeable product relative to the reference product. A sponsor developing an interchangeable product generally should not seek licensure for a presentation for which the reference product is not licensed.
Therefore, FDA recommends that sponsors analyze the presentations of a proposed interchangeable product to identify differences in design compared to the presentations licensed for the reference product using the threshold analysis outlined in the Guidance. After discussing the threshold analyses, the Guidance discusses the potential outcomes of those analyses and types of potential studies necessary to show interchangeability in light of any differences.
VI. Postmarketing Safety Monitoring
According to the Guidance, robust postmarketing safety monitoring is an important component in ensuring the safety and effectiveness of biological products, including biosimilar and interchangeable products.
Postmarketing safety monitoring for interchangeable products should first take into consideration any particular safety or effectiveness concerns associated with the use of the reference product and its class, the proposed interchangeable product in its development and clinical use (if marketed outside the United States), the specific condition of use and patient population, and patient exposure in the interchangeability development program. Postmarketing safety monitoring for an interchangeable product should also have adequate pharmacovigilance mechanisms in place. Rare but potentially serious safety risks may not be detected during preapproval clinical testing because the size of the population exposed likely will not be large enough to assess rare events. In particular cases, such risks may need to be evaluated through postmarketing surveillance or studies. In addition, as with any other biological product, FDA may require a postmarketing study or a clinical trial to evaluate certain safety risks.
The Guidance concludes with an Appendix discussing comparative use human factors studies. To support a demonstration of interchangeability under the Act, a comparative use human factors study should be designed to provide data supporting that the use error rate for the proposed interchangeable product is not worse than the use error rate for the reference product when used by patients and caregivers (as applicable) in representative use scenarios and use environments. The comparative use human factors studies described in the Guidance would generally be simulated-use studies where the participants, who are representative of the patients and caregivers, are asked to simulate the use of the product presentations (container closure systems and/or delivery device constituent parts) without actually administering the product.
 Lynn Tyler is a partner is the Indianapolis office of Barnes & Thornburg LLP. He concentrates his practice in intellectual property litigation and FDA counseling.