Abbreviated Biologics Applications for biosimilar products are governed by 42 U.S.C. § 262. Section 262(k) requires an applicant seeking approval for a biosimilar product to submit information “demonstrating that”:
(I) the biological product is biosimilar to a reference product based upon data derived from—
(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;
(bb) animal studies (including the assessment of toxicity); and
(cc) a clinical study or studies . . . that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;
(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;
(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;
(IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and
(V) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
42 U.S.C. § 262(k)(2)(A)(i) (emphasis added).
In addition to demonstrating conformity with the reference product labeling, route of administration, dosage form, strength, etc., the aBLA must demonstrate that the proposed product is “biosimilar” to the reference product based on (1) analytical studies, (2) animal studies, and (3) at least one clinical study.
The statute provides the following definition of biosimilarity:
The term “biosimilar” or “biosimilarity”, in reference to a biological product that is the subject of an application under subsection (k), means—
(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
(B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
42 U.S.C. § 262(i)(2) (emphasis added).
Demonstrating Biosimilarity
Unlike the well-understood methods for proving “bioequivalence” in the case of small molecule drug products, there is no pre-defined or universal means for demonstrating biosimilarity. Due to the broad variety of biological products, FDA’s biosimilarity assessments have largely become case-by-case determinations. In fact, FDA may reach the conclusion that one or more of the information categories required by the statute to prove biosimilarity is not necessary. See 42 U.S.C. § 262(k)(2)(A)(ii) (“[FDA] may determine . . . that an element described in clause (i)(I) is unnecessary in [an aBLA] application.”
Because of the fact-specific nature of demonstrating biosimilarity, applicants are encouraged “to meet with FDA to present their product development plans and establish a schedule of milestones that will serve as landmarks for future discussions with [FDA].” Guidance for Industry – Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015) at 4. FDA expects that the proposed biosimilar product will differ in some respects from the reference product and, therefore, emphasizes that its review is based on a “totality-of-the-evidence” which may show that the difference are not “clinically meaningful.” Id. at 8.
FDA likewise emphasizes that the purpose of the biosimilar application is “not to independently establish the safety and effectiveness of the proposed product.” Id. at 7. Accordingly, to minimize the amount of time and resources devoted to proving biosimilarity, FDA recommends that applicants follow a “stepwise approach” to their development work. Id. A stepwise approach begins “with extensive structural and functional characterization of both the proposed product and the reference product, which serves as the foundation of a biosimilar development program.” Id.
FDA points out that “rigorous structural and functional comparisons that show minimal or no difference between the proposed product and the reference product will strengthen the scientific justification for a selective and targeted approach to animal and/or clinical testing to support a demonstration of biosimilarity.” Id. In other words, favorable structural and functional comparisons may help minimize the scope and quantity of animal and human clinical testing that may be required to show biosimilarity. In fact, “FDA encourages sponsors to consult extensively with the Agency after completion of comparative structural and functional analyses (before finalizing the clinical program) and throughout development as needed.” Id. at 8 (emphasis added).
Finally, FDA notes that “a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product.” Id. at 18. Moreover, “FDA expects a clinical study or studies designed to establish statistical evidence that the proposed product is neither inferior to the reference product by more than a specified margin nor superior to the reference product by more than a (possibly different) specified margin.” Id. at 20.
Abbreviated Biologics License Applications for Interchangeable Products
In addition to information and data required under Section 262(k) to obtain approval for a biosimilar product, an applicant may submit additional data in order to gain approval for an interchangeable product. See 42 U.S.C. § 262(k)(2)(B) (“An application . . . may include information demonstrating that the biological product meets the standards [for an interchangeable product]”). As noted above, an interchangeable biological product is akin to a generic drug product in that it is considered to provide therapeutic equivalence with the reference product. However, demonstrating interchangeability requires substantially more evidence than demonstrating biosimilarity.
In order to demonstrate interchangeability with the reference product, the applicant must submit information and data “sufficient to show that”:
(A) the biological product—
(i) is biosimilar to the reference product; and
(ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) 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.
42 U.S.C. § 262(k)(4)(A) – (B) (emphasis added).
Demonstrating Interchangeability
As with demonstrating biosimilarity, FDA considers the totality of the evidence and encourages applicants to consult frequently with FDA. See Guidance for Industry – Considerations in Demonstrating Interchangeability with a Reference Product (May 2019) at 9 (“FDA recommends sponsors intending to develop a proposed interchangeable product to meet with FDA to discuss their proposed product development plan”).
Although the “data and information necessary [to interchangeability] may vary depending on the nature of the proposed product,” FDA identifies the following general categories of information relevant to its review:
• 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 or mechanisms of action in each condition of use for which the reference product is licensed, which may include the following:
- The target receptor or receptors for each relevant activity/function of the product
- The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target receptor or receptors
- The relationship between product structure and target/receptor interactions
- The location and expression of target receptor or receptors
• An analysis of any differences in the expected pharmacokinetics and biodistribution of the product in different patient populations for which the reference product is licensed
• An analysis of any differences in the expected immunogenicity risk of the product in different patient populations for which the reference product is licensed
• An analysis of any differences in expected toxicities of the product 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) for which the reference product is licensed
• Information on 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.
Guidance for Industry – Considerations in Demonstrating Interchangeability with a Reference Product (May 2019) at 4.
As a result of the heightened standard of proving interchangeability with the reference product, FDA advises:
A switching study or studies will generally be expected to demonstrate 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. . . .’
Id. at 9.
FDA explains that the “switching study is typically designed to assess whether switching between the reference product and the proposed interchangeable product will present risk in terms of safety or diminished efficacy that is greater than using the reference product without such switching.” Id. As a practical matter, “[i]f an apparent difference in clinical response in terms of safety or diminished efficacy is noticed between the switching and non-switching arms of the study . . . , it would raise concerns as to whether the proposed interchangeable product is interchangeable.” Id. at 10.
In order to overcome these concerns and minimize the cost of development, “FDA has outlined a flexible approach regarding the design of a switching study” and expressed its willingness to “address program-specific scientific matters . . . on a case-by-case basis in interactions with sponsors.” Id. Accordingly, FDA encourages applicants to “have early discussions with FDA about their product development plans.” Id.
Exclusivity for First Interchangeable Biological Product
As an incentive to undertake the additional burden of proving interchangeability, the first applicant to receive approval is awarded a period of exclusivity against other applicants seeking approval of an interchangeable for the same reference product. This exclusivity is similar to the 6-month exclusivity awarded to first filers of an ANDA, which is provided as an incentive to challenge Orange Book listed patents.
The exclusivity for a first interchangeable biological product does not have a fixed effective period. Rather, the duration of the exclusivity may be adjusted depending on whether the manufacturer of the interchangeable product is sued for patent infringement. FDA creates the exclusivity by delaying approval of subsequent applications seeking approval of an interchangeable product.
After FDA has licensed the first interchangeable product “for any condition or use,” FDA will not approve a subsequent biological product as an interchangeable based on the same reference product “until the earlier of”:
(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;
(B) 18 months after—
(i) a final court decision on all patents in suit in an action instituted [by the reference product owner against the manufacturer of the interchangeable]; or
(ii) the dismissal with or without prejudice of an action instituted [by the reference product owner against the manufacturer of the interchangeable]; or
(C)
(i) 42 months after approval of the first interchangeable biosimilar biological product if [the manufacturer of the interchangeable has been sued by the reference product owner] and such litigation is still ongoing within such 42-month period; or
(ii) 18 months after approval of the first interchangeable biosimilar biological product if the [the manufacturer of the interchangeable has not been sued by the reference product owner].
For purposes of this paragraph, the term “final court decision” means a final decision of a court from which no appeal (other than a petition to the United States Supreme Court for a writ of certiorari) has been or can be taken.
42 U.S.C. § 262(k)(6)(A) – (C).
Accordingly, the statute endeavors to provide at least an 18-month exclusive time period to launch and begin commercializing the interchangeable product. That exclusive period may be extended into the future if the manufacturer of the interchangeable product is sued for patent infringement. The objective is to provide the reference product owner and the manufacturer of the interchangeable product time to resolve any patent infringement issues, while still giving the manufacturer of the interchangeable product the intended benefit of the exclusivity period.