05 January 2016
Practice Group(s):
Biosimilars/Follow-on
Biologics
IP Litigation
Food, Drugs, Medical
Devices and
Cosmetics (FDA)
What Constitutes Interchangeability? AbbVie
Submits Citizen Petition to Suggest Requirements
By Jennifer M. Dienes, Maria E. Doukas, Margaux L. Nair, Christopher J. Betti, Ph.D.
On December 16, 2015, AbbVie submitted a citizen petition regarding the requirements
necessary to show interchangeability of a biosimilar product. This petition follows AbbVie’s
previous citizen petition and supplement regarding biosimilar labeling, as discussed in the
following: The Name Game: AbbVie’s Citizen Petition Regarding Biosimilar Labeling and The
Name Game Continues: AbbVie Files Supplemental Citizen Petition Raising Additional
Concerns Regarding Biosimilar Labeling. AbbVie’s citizen petition follows the FDA’s
approval of the first biosimilar, Zarxio®, in March 2015. See FDA Approves First Biosimilar:
Sandoz’s Zarxio®. However, Zarxio® was not approved as an interchangeable product. Id.
To date, no biosimilar has received approval as interchangeable with its reference product.
In its citizen petition, AbbVie proposes that the FDA require that applicants seeking
interchangeability meet the requirements of “Safety Standards for Determining
Interchangeability” set forth in section 351(k)(4) of the Public Health Service Act as amended
by the BPCIA for every condition of use for which the reference product is licensed. AbbVie
Citizen Petition at 1. AbbVie believes that these requirements should be met for each
condition of use regardless whether the biosimilar applicant is seeking licensure or intends to
labels its product for every such use. Id. AbbVie also requests that the FDA convene a Part
15 hearing to gain input from the public on the requirements for interchangeability. Id. at 1–
2.
I.
Summary of AbbVie’s Arguments
AbbVie argues that although the biosimilar designation is similar to the therapeutic
equivalence ratings assigned to generic small molecule drugs, biosimilars are different from
small molecule drugs in important ways. Id. at 2. Unlike small molecule drugs, AbbVie
asserts that “biological products present significant risks of immunogenicity, affecting both
patient safety and product efficacy.” Id. AbbVie cites to two FDA statements, one in 2007
and the other in 2015, that acknowledge potential risks of immunogenicity. Id. at 2–3.
AbbVie next asserts that it is impossible for one biological product to be the same as
another. Id. at 3. This is because, unlike small molecule drugs, which can be scientifically
guaranteed to have structural identity, there are no assurances that two biological products
are structurally identical because such identity cannot yet be demonstrated. Id. AbbVie
contends that these facts “lead to the conclusion that FDA should not find a biosimilar
biological product interchangeable with a reference product unless the agency has found the
two products interchangeable for every condition of use for which the reference product is
licensed, regardless of how the interchangeable biological product is labeled.” Id. (emphasis
in original). AbbVie believes that the FDA should clarify the statutory standard for
establishing interchangeability and specify that it differs from the standard for establishing
biosimilarity. Id. Further, a hearing should be convened pursuant to 21 C.F.R. Part 15 to
“consider the complexities of interchangeability” and the “implications of interchangeability
decisions in a multi-source product environment where multiple biosimilar biological products
What Constitutes Interchangeability? AbbVie Submits Citizen Petition to
Suggest Requirements
may have been found interchangeable with a single reference product, but not each other.”
Id.
II.
Biosimilar Interchangeability Decisions Are Intended
Therapeutic Equivalence Ratings for Small Molecule Drugs
to
Mimic
AbbVie asserts that the real-world effect of an interchangeable designation for a biosimilar
product is intended to mimic that of the therapeutic equivalence rating for a generic small
molecule drug. Id. at 4. A designation of interchangeability for biosimilars is akin to an “A”
rating for a small molecule drug, denoting therapeutic equivalence. Id. These designations
are supposed to guide pharmacists’ substitutions of generic or interchangeable products. Id.
The statutory language supports this by defining “interchangeable” as meaning “that the
biological product may be substituted for the reference product without the intervention of the
health care provider who prescribed the reference product.” Id. quoting 42 U.S.C. §
262(i)(3).
III.
Biological Products Are Fundamentally Different From Small Molecule
Drugs
Next, AbbVie argues that biological products are fundamentally different from small molecule
drugs because they are more likely to be immunogenic and biosimilars cannot be shown to
be the same as their reference products. Id. at 5. AbbVie emphasizes the risks involved
should a biological product cause an immunogenic response, including loss of efficacy and
neutralization of the body’s own naturally occurring proteins. Id. at 6. These effects are
highly variable and unpredictable and can lead to sometimes-fatal side effects in patients.
Id. According to AbbVie, immunogenicity can result from product-specific factors and
patient-specific factors, either of which can be exacerbated by switching between biological
therapies. Id. As evidence of problems caused by switching biological therapies, AbbVie
cites to the impact of switching patients whose Crohn’s diseases symptoms were well
controlled with infliximab to adalimumab, which in some patients caused loss of tolerance
and efficacy within one year when compared to patients who remained on infliximab. Id. at
7.
Additionally, AbbVie argues that biosimilar products cannot be proven to be the same as
their reference products, unlike small molecule drugs, which can be proven to be structurally
identical. Id. at 8. In fact, the nature of protein products makes it scientifically challenging to
compare one protein to another to establish safety and efficacy. Id. at 9. Further, it is
unlikely that a biosimilar could be demonstrated to be identical to a reference product. Id.
AbbVie concludes, “that biosimilar and reference products are similar, but not identical,
means one may not presume biosimilar and reference will have the same clinical effect in
each condition of use approved for the reference product.” Id.
IV.
A Biosimilar Should Only Be Designated as Interchangeable When It
Has Been Shown to Be Interchangeable for Every Reference Product
Condition of Use
AbbVie asserts several arguments in support of its proposal that a biosimilar product seeking
an interchangeable designation should have to show interchangeability for every reference
product condition of use. Id. at 9–15. AbbVie argues that state laws governing pharmacy
substitution of biological products direct the pharmacist to dispense a biosimilar product that
2
What Constitutes Interchangeability? AbbVie Submits Citizen Petition to
Suggest Requirements
has been found to be interchangeable with the reference product. Id. at 11. However,
“[n]either federal nor state law requires the pharmacist to determine whether the product to
be substituted is labeled for (let alone determined to be interchangeable for) the prescribed
use in question.” Id.
Thus, AbbVie concludes that these laws assume that an
interchangeable biosimilar is functionally the same a generic small molecule drug and is
therapeutically equivalent for all uses. Id. Because of this, AbbVie argues that the FDA
must ensure that biosimilars listed as interchangeable are in actuality interchangeable for all
indications and conditions of use for which the reference product is licensed. Id. If the FDA
does not take this approach, pharmacists might dispense a biosimilar that is not actually
interchangeable for a patient’s condition. Id.
AbbVie alleges that the statutory language supports its position. Id. at 12. Section
351(k)(4)(A) allows an interchangeability designation only if the biosimilar “can be expected
to produce the same clinical result as the reference product in any given patient.” Id.
(emphasis in original) quoting 42 U.S.C. § 262(k)(4)(A)(ii). “Any” means “one or some
indiscriminately of whatever kind” and “given” means “known; stated; [or] specified”; thus,
“any given” means “every” or “all.” Id. at 12. Therefore, the plain meaning of “any given
patient” is “all known, stated, or specified patients.” Id. Hence, the statutory language
requires that a biosimilar can only be deemed interchangeable if it can be expected to
produce the same clinical results as the reference product in all conditions of use for which
the reference product is approved. Id.
Further, the language of the interchangeability standard set forth in 351(k)(4)(A) is different
from the requirements for licensure of a non-interchangeable biosimilar set forth in
351(k)(2)(A). Id. at 13. A biosimilar applicant seeking approval of a non-interchangeable
product does not need to show biosimilarity for every reference product condition of use,
stating that the applicant must include clinical studies “to demonstrate safety, purity, and
potency in 1 or more appropriate conditions of use.”
Id. quoting 42 U.S.C. §
262(k)(2)(A)(i)(I)(cc). However, this language is absent from the interchangeability standard,
which adds language referring to the same clinical results in any given patient. Id. at 13.
Additionally, the language in section 351(k)(4)(B) requires that the applicant seeking an
interchangeable determination show the risk to patients of switching between the biosimilar
and the reference product without qualifying “use.” Id. AbbVie contends that “[i]t is hard to
see how this standard could be met unless the applicant had addressed ‘use’ of the
reference product broadly, i.e., in all approved reference product conditions of use.” Id.
AbbVie also concludes that this reading of section 351(k)(4) is consistent with section
351(k)(6), which provides a period of exclusivity for the first biosimilar product to be approved
as interchangeable as to any condition of use of the reference product. Id.
AbbVie asserts that the legislative history of the BPCIA supports its interpretation of the
statute. Id. at 14. Specifically, AbbVie points to several letters stating concerns over the
interchangeability determination and potential safety hazards that could be implicated
depending on how interchangeability is determined. Id. AbbVie also notes that the version
of the legislation that was passed by Congress used the phrase “any given patient” without
any language that would permit a selective showing of interchangeability. Id.
AbbVie acknowledges that its proposed requirement to consider all conditions of use
approved for the reference product means that the FDA would have to consider changes
made to either the reference product or the interchangeable biosimilar after an
3
What Constitutes Interchangeability? AbbVie Submits Citizen Petition to
Suggest Requirements
interchangeability decision has been made. Id. at 15. AbbVie contends that such an issued
determination should not be altered unless there are “significant scientific questions
regarding the continuing validity of the determination following a product change.” Id.
AbbVie believes that this should be “a rare occurrence.” Id.
V.
The Statutory Standards for Interchangeability and Biosimilarity Are
Different
As touched on above, the statutory requirements for showing biosimilar and
interchangeability differ. Id. To show interchangeability, a biosimilar applicant must show for
every condition of use licensed for the reference product that the product is biosimilar, is
expected to produce the same clinical result as the reference product in any given patient,
and, if the product is administered more than once to a patient, that risk in terms of safety
and efficacy of switching between the reference product and biosimilar is not greater than
simply using the reference product without any switching. Id.
AbbVie argues that interchangeability “must be interpreted to require more than biosimilarity”
and notes that section 351(k)(4)(A)(ii) requires that an applicant answer additional scientific
questions not required to show biosimilarity. Id. at 16. The first difference is that to be
interchangeable, a biosimilar product must have the “same clinical result” as the reference
product instead of merely “no clinically meaningful differences.”
Id.
Further,
interchangeability requires a showing that that the same clinical results are achieved for “any
given patient,” which is not required to show biosimilarity. Id. Next, there is a distinct
interchangeability requirement for a biosimilar product administered more than once to a
patient mandating an evaluation of the risks associated with switching. Id. at 16–17. These
requirements show that the licensure for interchangeability requires an “unprecedented level
of certainty.” Id. at 17. An applicant that meets this exacting requirement benefits from a
one-year period of exclusivity as the sole substitutable alternative to the reference product.
Id.
VI.
FDA Needs to Issue Guidance on Interchangeability and Should Hold a
Public Hearing
AbbVie concludes by noting that CDER has failed to issue its promised interchangeability
guidance. Id. at 18. AbbVie requests that any such guidance address the possibility of
having multiple interchangeable biosimilar products for a single reference product and the
implications of switching between those products during a single patient’s treatment. Id. at
19. AbbVie also asserts that given the amount of time since the FDA held public hearings in
2010 and 2012, another Part 15 public hearing should be held regarding the implementation
of the interchangeability provisions of the BPCIA. This will allow public input and ensure that
interchangeable biosimilars are introduced in a manner that “best serves the public interest
and the public health.” Id.
K&L Gates LLP will continue to monitor any developments, including any response the FDA
may provide, that arise from this citizen petition.
4
What Constitutes Interchangeability? AbbVie Submits Citizen Petition to
Suggest Requirements
Authors:
Jennifer M. Dienes
jennifer.dienes@klgates.com
+1.312.807.4219
Maria E. Doukas
maria.doukas@klgates.com
+1.312.807.4223
Margaux L. Nair
margaux.nair@klgates.com
+1.312.807.4280
Christopher J. Betti, Ph.D.
christopher Betti@klgates.com
+1.312.807.4313
Anchorage Austin Beijing Berlin Boston Brisbane Brussels Charleston Charlotte Chicago Dallas Doha Dubai Fort Worth Frankfurt
Harrisburg Hong Kong Houston London Los Angeles Melbourne Miami Milan Moscow Newark New York Orange County Palo Alto Paris
Perth Pittsburgh Portland Raleigh Research Triangle Park San Francisco São Paulo Seattle Seoul Shanghai Singapore Spokane
Sydney Taipei Tokyo Warsaw Washington, D.C. Wilmington
K&L Gates comprises more than 2,000 lawyers globally who practice in fully integrated offices located on five
continents. The firm represents leading multinational corporations, growth and middle-market companies, capital
markets participants and entrepreneurs in every major industry group as well as public sector entities, educational
institutions, philanthropic organizations and individuals. For more information about K&L Gates or its locations,
practices and registrations, visit www.klgates.com.
This publication is for informational purposes and does not contain or convey legal advice. The information herein should not be used or relied upon in
regard to any particular facts or circumstances without first consulting a lawyer.
© 2015 K&L Gates LLP. All Rights Reserved.
5