The primary focus ofthe Food and Drug Administra­tion, industry and counselpreparing for the advent of follow-on biologics inthe United States has been the legal and regulatory framework governing the ap­proval of such products asbiosimilars under the Biolog­ ics Price Competition and Innovation Act of 2009 ("BP­CIA''). However, the BPCIA further provides that the FDA may determine that a biologic product is also in­terchangeable with (and thus,under Federal law,freely substitutable for) its reference product. As stakeholders anticipate the potential for "generic biologics,'' the FDA has released a Draft Guidance outlining considerations for applicants seeking to demonstrate interchangeabil­ ity. This Draft Guidance sheds some light on the bur­ dens sponsors of proposed interchangeable biological products ("interchangeables") will (and will not) face along the path to interchangeable licensure.


On Jan. 18,2017, the FDA released Considerations in Demonstrating Interchangeabili With a Reference Product (''the Draft Guidance''),  outlining the FDA's recommendations to sponsors seeking to demonstrate interchangeability under the BPCIA. The Draft Guid­ ance is focused on therapeutic protein products, and is intended to provide an overview of the scientific consid­ erations and information the FDA will evaluate when determining interchangeability. Most notably, as dis­cussed below, the Draft Guidance indicates that spon­ sors will likely be required to conduct a clinical study assessing the risks associated with switching between the proposed interchangeable and the reference prod­uct.


Interchangeability Under the BPCIA

The BPCIA establishes an abbreviated pathway to li­ censure for biological products shown to be either bio­ similar to, or interchangeable with, an FDA-licensed biological reference product.3Incontrast to biosimilars, an interchangeable may be substituted by a pharmacist for its reference product without the intervention of the prescribing health care provider (i.e., even if the refer­ ence product is prescdbed).3 The BPCIA further pro­ vides significant exclusivity incentives for the first ap­ proved interchangeable for a given reference product.4 A product may be designated as interchangeable un­ der the BPCIA if it is sufficiently shown that the prod­ uct is biosimilar5 to the reference product and further "can be expected to produce the same clinical result as the reference product in any given patient"6 Addition­ ally,where the product is administered more than once


1Available     at GwdancecomplianceRegulatorylnformation/Guidances/ UCM537135.pdf.

z See ff 7002-7003, amending Section 351(k) of the Public

Health Service Act, codtfied at 42 U.S.C. 262(k).

3 42 u.s.c.262(i)(3).

4 See 42 u.s.c.262(k)(6).

5 Biosimilarity is defined in the BPCIA to mean "the biologi­

cal product is highly similar to the reference product" and "there are no clinically meaningful differences between the biological product and the reference product interms of the safety, purity, and potency of the product." See 42 U.S.C. 262(i)(2).

8See 42 u.s.c.262(k)(4)(A).







to an individual, it must be shown that "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."7


Interchangeability Under the Draft Guidance

The Draft Guidance outlines the data the FDA ex­ pects will generally be required to demonstrate that a proposed interchangeable is clinically equivalent to the reference product and has no switching risk. Consistent with prior industry guidance for demonstrating biosimi­ larity,8 the Draft Guidance recommends a stepwise ap­ proach to progressively identify and address "residual uncertainty" about clinical outcomes and switching risk.9

To show clinical equivalence "in any given patient," the Draft Guidance indicates that sponsors are ex­ pected to demonstrate that the proposed interchange­ able product should produce the same clinical result in

all of the reference product's licensed conditions of use.10 Notably, the Draft Guidance states that such

showing "will likely not involve additional clinical stud­ ies" beyond those required to support the other ele­ ments of interchangeability.11 Rather, the Draft Guid­ ance contemplates that evidence in support of this ele­ ment can include an evaluation of the evidence generated to support biosimilarity, such as identifica­ tion and analysis of structural and immunogenic differ­ ences between the reference product and the proposed interchangeable product. Sponsors are recommended to include a scientificjustification as to why any differ­ ences "do not preclude" a determination of clinical

equivalence in any given patient. 12

With respect to switching risk, however, the "FDA expects that applications generally will include data

from a switching study or studies in one or more appro­ priate conditions of use."13 The Draft Guidance pro­

vides fairly specific input on the design of such studies, as discussed below.


Analytical  Framework  and Key Considerations

Several factors that may influence the data needed to support a demonstration of interchangeability within this framework are emphasized.

Extent of Comparative Characterization: The Draft Guidance contemplates that comparative analytical evi­ dence generated to support biosimilarity will also be


7 42 u.s.c. 262(k)(4)(B).

8 See, e.g., Scientific Considerations in Demonstrating Bio­ sirnilarity to a Reference Product, available at http://

GuidanceComplianceRegulatorylnformation/Guidances/ UCM291 128.pdf.

9 Draft Guidance at 5.

10 Id. at 3.

11Id. at 3-4.

12 Id. at 3.

13Id. at 4.


relevant to the determination of interchangeability.14 While noting that "there is a continuum of comparative analytical data" that could support a demonstration of biosimilarity, the Draft Guidance states several times that clinically relevant "fingerprint-like" analytical similarity may permit a "more selective and targeted approach" to demonstrating interchangeability, includ­ ing required clinical studies.15

Product Complexity: The degree of structural and functional complexity of the proposed interchangeable may also influence the sponsor's burden; as an ex­ ample, the Draft Guidance states that "products ex­ pected to have a single target" may pose less uncer­

tainty regarding interchangeability than "those acting on multiple or less-defined biological pathways. "16

Immunogenieity Risk: The Draft Guidance also states that risk assessments for the proposed interchangeable and clinical experience with the reference product re­ garding immunogenicity can affect the data required to support a demonstration of interchangeability, noting that "products with a documented history  of inducing detrimental immune responses may require more data to support interchangeability than products with an ex­

tensive documented history that immunogenicity does not impact clinical outcomes."17

Considering the foregoing factors together, the FDA will determine whether "residual uncertainty'' remains with respect to clinical equivalence. If so, the FDA may determine that, for example, postmarketing data of the product as a licensed biosimilar will also be reuired to support a demonstration of interchangeability. 8

Postmarketing Data: While postmarketing data may be considered or required to support interchangeability, the Draft Guidance indicates that postmarketing data will not be accepted as a substitute for a switching study. The Draft Guidance acknowledges that "in cer­ tain circumstances, postmarketing data from a licensed biosimilar product may be helpful as a factor when con­

sidering what data is necessary. "19 However, the "cur­

rent thinking" of the FDA "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 suf­ ficient to support a demonstration of interchangeabil­ ity."20


Switching Studies

As noted, for those products intended to be adminis­ tered to an individual more than once, a suitable switch­ ing study or studies will likely be required. Fairly de­ tailed recommendations for the design and analysis of such studies, including endpoints, sample sizes, patient populations and analytical parameters, are provided at Section VI.A of the Draft Guidance.

Whereas sponsors may rely in part on studies com­ paring a proposed product to a non-U.S.-licensed com-


14Id. at 5-6.

15 Id. at 6.

16Id. at 7.

17Id. at 7.

18Id. at 7-8.

19 Id. at 8.

20 Id. at 8.







parator product to demonstrate biosimilarity 21  the






"strong1y recommends" that sponsors' use a U.S.-licensed reference product in any switching study to support a determination of interchangeability.22 The Draft Guidance further provides recommendations for integrated studies of biosimilarity and switching risk for sponsors considering a single study to establish in­ terchangeability.23


Product Presentation-Container Closure

Systems and Delivery Devices

In addition to the analyses outlined above the Draft Guidance recommends that sponsors underte a com­ parative analysis of the proposed interchangeable prod­ uct's "presentation,'' defined to refer to the "container closure system and/or delivery device constituent part of the product."24 Noting repeatedly that biologic prod­ ucts are administered to a variety of end users, that the tasks involved in administration "can vary considerably depending on the type of presentation and its design characteristics," and that interchangeable products can be substituted without health care provider intervention or additional training, the Draft Guidance states that "it is important that sponsors carefully consider the pre­ sentation of the proposed interchangeable product rela­ tive to the reference product" to address the potential risk of "use-related  error."25

In particular, the Draft Guidance recommends that spons«;>rs generally should not seek licensure for a pre­ sentation for which the reference product is not li­ censed. "For example, if the reference product is only marketed in a vial and a prefilled syringe, a sponsor should not seek licensure for the proposed interchange­ able product for a different presentation, such as an auto-injector."26

The Draft Guidance further outlines a "threshold" presentation anal.fsis to evaluate the potential for errors in product use.2 Sponsors are advised to conduct a line-by-line labeling comparison, a visual and tactile physical comparison and a comparative task analysis to identify differences in "external critical design attributes"--those features that directly affect the per­ formance of critical tasks.28 If such differences are found in the final design of the proposed interchange­ able product, the Draft Guidance recommends that sponsors conduct a "comparative use human factors" study to assess differences in the use error rate between the reference product and the proposed interchange­ able product.2 Although considerations for such stud­ ies are outlined in the Appendix to the Draft Guidance, the FDA "expects that such additional studies will likely not be needed for many interchangeable products.1130


21 Id. at 15.

22 Id. at 16.

23 Id. at 12.

24 Id. at 16-18.

25 Id. at 17.

2s Id.

27 Id. at 19-20.

28 Id. at 20.

29 Id. at 22-23.

30 Id. at 17.


  • ased on the Draft Guidance, it appears that the FDA

will generally expect sponsors to provide:

  • a comparative analysis of the data generated to es­ tablish biosimilarity;
  • a switching study;
  • scientific justification for extrapolating supporting data from the studied condition of use to any additional conditions of use for which the reference product is li­ censed; and
  • a comparative threshold analysis of product pre­

The most notable feature of the Draft Guidance is the switching study requirement for products intended to be administered more than  once. The FDA has appar­ ently concluded that "the risk in terms of safety or di­ minished efficacy of alternating or switching between use" of the proposed interchangeable and the reference product will generally only be adequately assessed by a clinical trial. The suggested design of the switching studies provided in the Draft Guidance is relatively ro­ but and potentially resource intensive for sponsors. Gomg forward, sponsors may be incentivized to con­ d_uct an integrated study of biosimilarity and switching nsk to reduce the overall burden of interchangeable li­ censure, or, if required clinical studies are extensive to simply work towards its own Biologic License Appllca­ tion ("BIA'') to take advantage of longer exclusivity.

Conversely, the Draft Guidance indicates that addi­ tional clinical trials (beyond those required to establish biosimilarity) likely will not be required to establish that a proposed interchangeable product "can be ex­ pected to produce the same clinical result as the refer­ ene product in any given patient." Although the Draft Guidance contemplates analysis of clinical outcomes in various patient populations, one could interpret the rec­ ommendations to emphasize clinical parity in each of the reference product's licensed conditions of use. The recommendations provided in this regard  appear largely coextensive with those provided to establish bio­ similarity. Some stakeholders may have expected or ap­ preciated further clarity on the extent of analyses re­ quired in different patient populations and subpopula­ tions.

In contrast to the arguably limited recommendations provided for demonstrating clinical equivalence, the Draft Guidance places substantial emphasis on presen­ tation, providing a relatively detailed template for spon­ sors to identify and minimize risks of use-related error arising from external critical design attributes. This el­ ement of interchangeability may not have been readily apparent from the statute, and may represent an oppor­ tunity for innovators and reference product manufac­ turers to implement additional barriers (including so­ called "soft IP" barriers, such as trademarks and design patents)  to interchangeable  licensure and competition.

The Draft Guidance is subject to public comment be­ fore finalization by the FDA. Comments should be sub­ mitted by March 20, 2017, and should be identified with reference to the following Docket Number: FDA-2017- D-0154.

LIFE SCIENCES LAW & INDUSTRY REPORT    ISSN   1935-7257                                                                                                   BNA      3-17-17

Reproduced with pennission from Life Sciences Law &Industry Report, 11LSLR 06,03/17/2017.Copyright c 2017

by The Bureau of National Affairs, Inc. (BOC>-372-1033)