FooD
and Drug
FDLI’s
P o li c y F O R U M
How Should FDA Use Naming
and Labeling to Communicate
Information About Biosimilars?
Erika F. Lietzan
Partner, Covington & Burling LLP, Washington, DC
Michael S. Labson
Partner, Covington & Burling LLP, Washington, DC
Emily A. Alexander
Associate, Covington & Burling LLP, Washington, DC
V o l u m e 1 , Iss u e 2 1 / /
november 9, 2011
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F D L I ’ s f o o d a n d d r u g p o li c y f o r u m
Michael D. Levin-Epstein, J.D., M.Ed.Aliza Yudkoff Glasner, Esq.
Editor-in-ChiefEditor
E d it o r i a l A d v i s o r y B o a r d
William Vodra (Chair)
Joseph L. Fink III (Vice Chair)
Senior Counsel, Arnold & Porter LLP
Professor of Pharmacy, University of Kentucky
Associations
American Enterprise Institute
Medical Device Manufacturers Association
Scott Gottlieb, Fellow
Brendan Benner, Director of Public Affairs
Consumer Healthcare Products Association
Personal Care Products Council
David Spangler, Senior Vice President, Policy & International Affairs
Drug Information Association
Mark Pollak, Senior Executive Vice President
PhRMA
Lisa Zoks, Director of Marketing and Communications
Lori Reilly, Vice President, Policy and Research
International Dairy Foods Association
United Fresh Produce Association
Peggy Armstrong, Vice President of Communications
Robert Guenther, Senior Vice President of Public Policy
Individuals
Christina L. Anderson
Carolina Heavner
Senior Legal Counsel, Medtronic, Inc.
Senior Associate, K&L Gates LLP
Marice Ashe
Mary Clare Kimber
Executive Director, Public Health Law and Policy
Manager, Regulatory Policy, Plasma Protein Therapeutics Association
James E. Dillard III
Patricia Maloney
Senior Vice President, Altria Client Services, Inc.
Director, Medical Regulatory Affairs, Quest Diagnostics
Sandra Eskin
Director, Food Safety Campaign, The Pew Charitable Trusts
Gary Messplay
Partner, Hunton & Williams LLP
Eric Feldman
Deputy Dean for International Affairs & Law Professor,
University of Pennsylvania
Tim Schmidt
Paul Franz
Sheila D. Walcoff
Vice President and Associate General Counsel,
The Procter & Gamble Company
Founding Principal, Goldbug Strategies LLC
Attorney, Johnson Controls
Pamela Wilger
Lawrence Gostin
Corporate Food Safety & Regulatory Affairs, Cargill
Professor of Global Health Law and Director of the O’Neill Institute,
Georgetown University
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Ta b l e o f C o n t e n t s
I.Introduction..................................................................................................1
Policy Recommendations................................................................................ 1
II.Background...................................................................................................2
III.Issues in Dispute.........................................................................................2
IV.Research and Response.........................................................................7
V.Impact of Policy Recommendations.............................................8
VI. Conclusion.....................................................................................................9
Sources......................................................................................................................9
About the Author............................................................................................11
About the Policy Forum..............................................................................11
About FDLI...........................................................................................................12
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How Should FDA Use Naming and Labeling to
Communicate Information About Biosimilars?
Erika F. Lietzan, Partner, Michael S. Labson, Partner and Emily A. Alexander, Associate, Covington & Burling LLP,
Washington, DC*
I . I N T RODUC T I ON
In March 2010, as part of the comprehensive healthcare reform legislation, Congress enacted the Biologics Price Competition
and Innovation Act of 2009 (BPCIA).1 The BPCIA amended the Public Health Service Act (PHSA) and other statutes to grant
the Food and Drug Administration (FDA) the authority to approve biosimilars—biological products that are “highly similar”
to innovative biological products “notwithstanding minor differences in clinically inactive components” and that have no
“clinically meaningful differences” from those innovative products in terms of safety, purity or potency.2 The BPCIA also grants
FDA the authority to deem a biosimilar as “interchangeable” with the reference product, which means that the product “may
be substituted for the reference product without the intervention of the health care provider who prescribed the reference
product.” 3 In order to garner this designation, an applicant must establish that the product “can be expected to produce the
same clinical result as the reference product in any given patient.” For products that are administered more than once, the
sponsor must meet an additional requirement: “the risk in terms of safety or diminished efficacy of alternating or switching
between” the proposed interchangeable biosimilar and the reference product must not be “greater than the risk of using
the reference product” alone.4
The BPCIA does not expressly address the nonproprietary or proprietary naming of biosimilars, or their labeling. These
decisions are left in the first instance to FDA, although some provisions of existing law—like the requirement that the
labeling of a drug (including a biological product that is a “drug”) may not be false or misleading5—apply and will be
relevant. FDA’s decisions regarding the naming and labeling of biosimilars will have a significant impact on patient safety
and will influence stakeholder behavior (e.g., physician prescribing habits, payer and formulary decisions, and industry
approaches to promotion) as well as other bodies of law (e.g., state substitution laws and state tort law). This article explores
various naming and labeling questions that must be resolved by FDA as it begins to approve biosimilars and suggests ways
in which the agency might address them.
1
P o li c y R e c o m m e n d a ti o n s
FDA should:
•Expeditiously issue guidance or regulations on how biosimilars will be named and labeled.
• Work with national and international stakeholders to develop a consistent methodology to ensure that
biosimilars have nonproprietary names that are distinguishable from those for reference products.
•
Seek public comment on the multitude of issues that could be addressed in the labeling of biosimilars, with
the goal of creating rules that will result in clear communication to healthcare professionals regarding the
attributes of biosimilars and the basis for approval of each biosimilar product.
* The views expressed herein are solely those of the authors and do not necessarily reflect the views of the firm or its clients.
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I I . BAC K GROUND
Some earlier biosimilar bills considered in the legislative process included provisions addressing the naming and labeling
of biosimilars or interchangeable biosimilars. A bill introduced by Representative Eshoo in March 2008, for example, would
have required FDA to
ensure that the labeling and packaging of each biological product licensed under this subsection bears a
name that uniquely identifies the biological product and distinguishes it from the reference product and
any other biological products licensed … following evaluation against such reference product.6
In contrast, a bill introduced by Representative Waxman in February 2007 would have required FDA to designate the same
official name for a “comparable” biological product as its reference product, if FDA acted to designate any official name. 7
Few bills explicitly addressed the labeling of biosimilars, and those that did included only general provisions. For example,
the 2007 Waxman bill would have required FDA to “provide for the label of the comparable biological product to include a
statement that the biological product is interchangeable with the reference product for the conditions of use prescribed,
recommended, or suggested in the labeling for which interchangeability has been established,” if such a statement was
requested by a biosimilar applicant.8
While biosimilar legislation was being debated in Congress, FDA expressed some views on how biosimilars should be
named and labeled, as discussed in more detail below. But the BPCIA as enacted fails to include any provisions related
to the labeling and naming of biosimilars or interchangeable biosimilars. FDA and other stakeholders have started initial
discussions of these issues. For example, in November 2010, FDA held a public hearing and opened a docket seeking
comment on the agency’s implementation of its new biosimilar authority. As part of the docket, FDA posed a series of
questions related to many different topics, including naming and labeling, and numerous stakeholders weighed in on these
issues.9 The focus to date, however, has been on naming, and FDA and other stakeholders have not yet engaged in any
significant debate on how biosimilars should be labeled.
2
I I I . I SSUES I N D I SPU T E
A.Naming
At the most basic level, the nonproprietary name of a drug or biologic serves to identify the specific pharmaceutical product.
But the name can also provide other information to healthcare professionals, patients and other stakeholders. A name can
identify the class to which the product belongs (e.g., the nonproprietary names for monoclonal antibodies end with “mab”),
as well as its potential relationship to other related products. The name of a product can also affect prescribing, distribution
and substitution practices, and the name plays a key role in the reporting of adverse events.
The primary debate regarding the naming of biosimilars focuses on whether a biosimilar should be required to have a
nonproprietary name that is distinct from that of its reference product. Two overarching public health considerations will be
particularly relevant to this decision: 1) how the naming of biosimilars will affect pharmacovigilance, and 2) how the naming
of biosimilars will affect substitution.
Initial signals from FDA suggest that a concern over effective pharmacovigilance looms large and that the agency is
considering requiring distinct nonproprietary names. In June 2007 during the height of Senate negotiations over biosimilars
legislation, the Secretary of Health and Human Services sent a letter to Senator Kennedy describing the administration’s
views on biosimilars legislation and stated that the legislation should require distinct nonproprietary names for biosimilars.10
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This view was reiterated in a 2008 letter from FDA to Congress.11 In the October 2010 Federal Register notice in which the
agency sought comment on its implementation of the BPCIA, FDA seemed to indicate that the agency was considering
requiring a reference product and a biosimilar to share a common nonproprietary name stem, while employing a suffix
or prefix to distinguish the biosimilar. FDA asked “if each product were given a unique nonproprietary name, should a
distinguishing prefix or suffix be added to the nonproprietary name for a related biological product that has not been
demonstrated to be biosimilar, a biosimilar product, or an interchangeable product to facilitate pharmacovigilance?”12
Finally, in an August 2011 New England Journal of Medicine article, several key FDA personnel working on implementing the
BPCIA stated that “[t]racking adverse events associated with the use of reference and biosimilar products will be difficult if
the specific product or manufacturer cannot be readily identified, and appropriate strategies must be developed to ensure
the implementation of robust, modern pharmacovigilance programs for biologics.”13
Other regulatory authorities around the world have similarly acknowledged that biosimilars should be distinguishable
from their reference products through unique nonproprietary names or brand names. For example, the Japan Ministry
of Health, Labor and Welfare has stated that “the nonproprietary names and brand names of follow-on biologics should
be readily distinguishable from the nomenclature of originator biodrugs and other follow-on biologics.” Japan’s biosimilar
guidance specifically provides that “Follow-on 1” (or 2, 3, etc.) must be added as a suffix to the nonproprietary name of the
reference product. And “BS” should be added to the end of the product’s brand name.14 The World Health Organization
(WHO) recommends that biosimilars have unique brand names.15 And although the European Medicines Agency (EMA)
does not have the same authority over naming as FDA does, all of the biosimilars approved in the European Union have
been distinguishable by brand name or by both brand name and nonproprietary name. The EMA has emphasized that
being able to distinguish between related products is critical to a robust pharmacovigilance system16:
It should be recognised that, by definition, similar biological medicinal products are not generic medicinal
products, since it could be expected that there may be subtle differences between similar biological
medicinal products from different manufacturers or compared with reference products, which may not
be fully apparent until greater experience in their use has been established. Therefore, in order to support
pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly
identified.
3
How biosimilar naming conventions will affect FDA’s ability to ensure effective and efficient pharmacovigilance for biosimilars
is perhaps the most important consideration in the naming debate. When a patient experiences an adverse event, it will be
critical to know which product the patient was taking and (because some immunogenic reactions can have a long latency
period) whether the patient was switched at any time in the past from a related product. If an adverse event cannot be
tracked to the responsible product, it will be difficult for regulatory authorities and other stakeholders to take appropriate
action. This could result in unwarranted caution about an entire class of related products (when, for example, the adverse
event actually resulted from an isolated manufacturing change implemented by one sponsor). This caution could lead
to regulatory action with respect to the whole class, possibly denying patients access to life-saving medicines that are in
fact unaffected by the issue in question. Alternatively, the inability to differentiate between products could result in failure
to identify quickly an emerging problem with a product. Specifically, the background rate of a given adverse event for a
product and product class can typically be estimated by analyzing past data, including premarket data. But if one product
is associated with a sharp increase in a specific adverse event, and these data are analyzed as part of the adverse events of
the class as a whole, the increase could be misinterpreted as a relatively minor increase in the background rate. This in turn
could lead to a delay in detecting the safety signal with respect to the one affected product and, in turn, avoidable and
potentially quite serious adverse reactions. In response to these concerns, some stakeholders contend that adverse events
can be accurately traced to the correct product through use of other product identifiers, such as national drug code (NDC)
and manufacturer and brand name. These pieces of information will undoubtedly aid in pharmacovigilance, but adverse
event reports rarely include details like NDC, as one FDA official suggested at the November hearing.
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In addition to facilitating pharmacovigilance, distinct names for biosimilars can play a role in ensuring that these products
are not subject to inadvertent substitution. FDA has previously recognized that inappropriate substitution of biologics
represents a public health threat, and naming may represent an opportunity for the agency to help address this concern. For
example, the agency stated in its 2008 letter to Congress that its “paramount concern is that patients not be exposed to an
avoidable safety risk by being switched to a product not known to be interchangeable with the product they are currently
receiving” and that “patients should not be switched from the innovator biological product to a follow-on biological product
(or vice versa) without the express consent and advice of the patient’s physician.” 17 The EMA and Health Canada have also
both cautioned against the substitution of biosimilars, stating, for example, that “[s]ince biosimilar and biological reference
medicines are similar but not identical, the decision to treat a patient with a reference or a biosimilar medicine should be
taken following the opinion of a qualified healthcare professional.” 18
Because biosimilars will be similar to, but not the same as, their reference products, and because biosimilars will have been
the subject of different premarket testing programs than their corresponding reference products, physicians may want
to choose which biological product a patient receives. (This issue is closely linked with the labeling question because a
physician may not have sufficient information to differentiate between the products if the labeling of the reference product
and the biosimilar are nearly identical.) Moreover, once a biosimilar is approved, both the biosimilar and the reference
product may “drift,” or subtly change over time from their characteristics at the time the biosimilar was shown to meet the
approval standard, as a result of independent, minor changes in the manufacturing processes for both products. Although
FDA and sponsors may be able to monitor for this phenomenon, it could affect a prescriber’s decision to select a particular
biologic.
The concern over inadvertent substitution may be less relevant if a biosimilar has been deemed interchangeable. Some
interchangeable biosimilars may ultimately be subject to automatic substitution (an outcome that will be determined by
state law, rather than FDA action, given that states have authority over substitution laws), but interchangeability ratings
may come only after the biosimilar has been on the market for some time, if at all (in order to allow the sponsor to gather
a significant amount of postmarket data). Changing the nonproprietary name after the product has been on the market
could create confusion for healthcare professionals and patients. The situation could become particularly complicated if
the reference product gains approval for a new indication and the biosimilar sponsor has not yet shown interchangeability
for that indication. Moreover, the analytical profiles of an interchangeable biosimilar and its reference product could
drift apart after the time when interchangeability was established. This in turn could result in slightly different safety and
efficacy profiles. It may therefore be beneficial to distinguish between the products over the long term, regardless of an
interchangeability determination.
4
Some stakeholders have argued that the use of different nonproprietary names for interchangeable biosimilars will reduce
potential market impact and patient access. The use of a common stem, with distinguishing prefixes or suffixes (an option
which FDA has clearly considered), represents one approach to mitigating this concern. The common stem would signal
to healthcare professionals and patients that the products are related, while the distinguishing prefix or suffix would signal
that they are not the same product and permit effective pharmacovigilance. And the common stem would allow pooling
of adverse events across a product class.
B.
Labeling
Unlike generic drugs, biosimilar biological products are not subject to a statutory requirement that their approved labeling
be the same as the approved labeling of their reference products. FDA therefore faces a number of important decisions
regarding how the approved labeling of biosimilars should be used to communicate information about these products
to healthcare professionals. This section discusses key biosimilar labeling issues faced by FDA and the ways in which the
agency can use biosimilar product labeling to inform stakeholders about biosimilarity in general and the basis of approval
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for individual products more specifically. It recommends that FDA use a transparent process that provides a meaningful
opportunity for public input, before making any decisions on these critical issues.
We focus here in the first instance on the approved professional labeling, or package insert. The term “labeling” broadly
means “all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2)
accompanying such article.” 19 This definition includes both the professional labeling that is FDA approved (i.e., the package
insert) and promotional labeling that is created and disseminated by the product sponsor.
The package insert “is the primary mechanism through which FDA and drug manufacturers communicate essential,
science-based prescribing information to health care professionals.”20 It represents “a compilation of information based
on a thorough analysis of the” application.21 FDA regulations include detailed descriptions of what information should be
included in each section of the package insert.22 These regulations were revised in 2006 in order to improve readability and
consistency, to enhance the utility of labeling for healthcare professionals and to protect patient safety.23
The package insert also forms the basis for permissible promotional labeling and advertising. As an initial matter, it limits the
uses for which a product may be promoted. A drug is misbranded if it lacks “adequate directions for use,” 24 and according to
FDA, an approved drug that is marketed for an unapproved use by definition does not include adequate directions for use.
In addition, a drug is misbranded if its labeling (including promotional labeling) is “false or misleading,” and FDA often relies
on the information in the package insert to determine whether promotional material is false or misleading. In other words,
a company’s promotion must be consistent with, and not contrary to, the package insert. Because the approved package
insert sets the parameters for permissible advertising and promotion of biosimilars, and because (unlike generic drugs)
biosimilars may be actively promoted to healthcare professionals, patients and payers, the decisions that FDA makes now
about its general approach to biosimilar labeling could have a significant impact on the biologics marketplace.
Foreign regulatory authorities have generally concluded that the labeling of a biosimilar should be specific to the biosimilar,
and thus differ from that of the reference product. Health Canada, for example, explained in guidance that “[u]nlike generic
pharmaceutical drugs, the sponsor of [a biosimilar, there known as a subsequent entry biologic (SEB)] will not be able to
utilize the [product monograph (PM)] of the reference biologic drug in its entirety as that of its own product.” Instead, the
labeling will include: 1) a statement indicating that the product is an SEB; 2) key data on which the decision for market
authorization was made; 3) tables showing the results of the comparisons between the SEB and reference biologic drug; 4)
information on the indications approved for use; 5) no claims of bioequivalence between the SEB and reference biologic
drug; and 6) no claims of clinical equivalence between the SEB and the reference biologic drug.25 The EMA has stated more
generally that “[t]he name, appearance and packaging of a biosimilar medicine differ to those of the biological reference
medicine.” 26 And EU biosimilar labeling (the Summary of Product Characteristics) typically reflects these differences by, for
example, explicitly stating that the product is a biosimilar, comparing the safety and clinical profile of the biosimilar and the
reference product, and explicitly disclaiming reference product routes of administration for which the biosimilar does not
have approval.
5
FDA must also address how the package insert will describe the basis for approval. The core issue is whether, to what extent
and how information in the reference product package insert (gleaned from studies of the reference product, the raw
data from which remain confidential in the reference product application) can and should be reflected in the biosimilar
package insert. The agency faces important legal as well as policy questions as it considers this issue, and the legal questions
are beyond the scope of this paper. Agency precedent for follow-on products approved under FDCA section 505(b)(2) is
somewhat inconsistent on this issue of citations to the reference product. The package insert for Omnitrope, a recombinant
human growth hormone approved on the basis of a showing that it was highly similar to the innovative product Genotropin,
refers to Genotropin only as “another somatropin product” and refers to somatropin generally. It does not identify which
specific product the information in the package insert (e.g., information about adverse events) was derived from.27 In
contrast, the package inserts for other 505(b)(2) products occasionally use the brand name of the reference product and
identify which product was the source of which information.28
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FDA also faces the question whether and how to differentiate between indications supported by clinical data and indications
approved through extrapolation (if, in fact, it decides to permit extrapolation). Again, in view of the core information function
of package inserts, it would be reasonable (and probably consistent with physician expectations) to require the package
insert to explain the nature of the evidence supporting each indication’s inclusion. Health Canada took a similar approach
in the product monograph for Omnitrope:
There are no clinical trials conducted with Omnitrope in adult [growth hormone deficiency (GHD)]
patients. The use of Omnitrope in adult GHD patients is supported in consideration of the similar product
quality characteristics of Omnitrope and Genotropin® and the similar pathophysiology of adult GHD
to GHD in children. In addition, comparative non-clinical, human pharmacokinetic/pharmacodynamic,
and clinical efficacy and safety studies in children … have been conducted to demonstrate comparable
clinical profiles between Omnitrope and the reference product.29
It seems reasonable to require the package insert to include a disclaimer for any indications for which the biosimilar
applicant has not established biosimilarity or at least any indication as to which the biosimilarity exercise failed (if indeed
such a product can still be approved as biosimilar).
Another open question is whether and to what extent the agency should use the biosimilar package insert to communicate
advice to healthcare professionals about the implications of possible substitution of biosimilars that have not been found
interchangeable. FDA has already identified inappropriate substitution of biologics as a potential public health concern,
asking, for example, in its Federal Register notice “What safeguards should the agency consider to assist the healthcare
community when prescribing, administering, and dispensing biological products to prevent unsafe substitution of
biological products?”30 There is some precedent for a warning about substitution and switching that could raise patient
safety issues: insulin products approved in the United States and Europe are labeled with a warning that any change in
brand should be made cautiously and only under the supervision of a physician. The EMA has also used biosimilar product
labeling to warn healthcare professionals about similar public safety issues. After two patients in a clinical study investigating
erythropoiesis stimulating agents (ESAs) experienced pure red cell aplasia (PRCA), the EMA amended the Summary of
Product Characteristics to include a statement warning healthcare professionals of the importance of traceability: “In order
to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be
clearly recorded (or stated) in the patient file.” 31 The patient Package Leaflet was also amended to warn patients to “[t]ake
special care with other products that stimulate red blood cell production: [Biosimilar name] is one of a group of products
that stimulate the production of red blood cells like the human protein erythropoietin does. Your healthcare professional
will always record the exact product you are using.”32 According to the EMA, the agency “considered it important that
accurate medication histories are maintained for patients treated with epoetins, recording the trade name or the scientific
name with the name of the manufacturer.” 33
6
The issues discussed above represent some of the major labeling issues presented by biosimilars. But there are other decisions
to be made. For example, should the biosimilar applicant be required to prove (or extrapolate proof of ) every reference
product indication, and if so, may it exclude an indication that is still protected by a reference product patent? Will there
be any expectation that the biosimilar applicant seek to prove, or extrapolate proof of, indications added to the reference
product package insert following initial approval of the biosimilar? How should drift in the reference product’s quality
characteristics, or in the biosimilar product’s quality characteristics, subsequent to the biosimilarity finding be handled?
Should the individual sections of the biosimilar package insert (such as the “Adverse Reactions” section) include information
specific to the reference product alone (such as adverse reactions specifically observed during use of the reference product
but not yet observed with respect to the biosimilar product)? Should the Clinical Studies section describe the clinical studies
of the reference product, the clinical studies (if any) that supported approval of the biosimilar product, or both? All of these
decisions raise important scientific, public policy and legal issues.
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I V . RESEARCH AND RESPONSE
A. Expeditiously issue guidance or regulations on how biosimilars will be named and labeled.
If FDA decides that biosimilars should have distinct nonproprietary names, the question then becomes how the agency can
accomplish this goal. Under section 508 of the FDCA, the agency has the authority to designate the official name of a drug,
including a biologic that meets the definition of a drug, through rulemaking. The FDCA provides that this name will be the
“established name” of the product, in lieu of the official title of the drug or ingredient in an official compendium (e.g., the
United States Pharmacopoeia) or the “common or usual name” of the drug.34 Since the early 1980s, however, FDA has rarely
employed this authority.
Accordingly, the more likely scenario is that biosimilar nonproprietary names will be selected by the United States Adopted
Name (USAN) Council. The USAN Council is composed of five members: one each from the American Medical Association
(AMA), the United States Pharmacopeial (USP) Convention, the American Pharmacists Association and FDA, and one
member-at-large. Today, unless FDA takes “positive action by publishing an official name under section 508 of the act, a
drug name adopted by the USAN Council will be the drug’s ‘established name.’” 35 In written comments to FDA, the AMA
expressed its initial view that biosimilar products should have distinct nonproprietary names and that interchangeable
biosimilars may not necessarily require a distinct name. The other members have not yet publicly expressed their opinions.
FDA should consider using its role on the Council to advocate for a particular naming convention for biosimilars. If FDA were
unsuccessful at convincing the other members, the agency may need to resort to official name rulemaking as discussed
above.
Whether the USAN Council or FDA is ultimately responsible for selecting nonproprietary names for biosimilars, FDA should
work with other stakeholders to promote a consistent approach to the naming of biosimilars. For example, USP has thus
far issued very few monographs for biologics, but as this changes, FDA may want to work with USP in order to ensure that
the monographs do not inadvertently frustrate attempts by the agency to address its pharmacovigilance and inadvertent
substitution concerns through naming conventions for biosimilars.
7
A threshold question is whether the labeling of a biosimilar will be the same as the labeling of its reference product. FDA
has said very little on this question publicly, but the available—though not entirely analogous—precedents from the FDCA
context suggest the approved labeling will be different. Moreover, it would be more consistent with the core informational
function of approved labeling to treat each product as a fully independent biological product, described by its own
approved package insert, which must then be maintained and updated over time (for example, as a result of productspecific pharmacovigilance, or as a result of evolution in the product through manufacturing changes and “drift” in product
characteristics).
Beyond the threshold question of labeling sameness, FDA faces specific questions about the precise content of biosimilar
package inserts. The first might be whether the agency should use the package insert to explain the concept of biosimilarity,
or whether this information generally should be communicated through another means. In view of the fact that the package
insert is the primary means by which FDA and sponsors communicate information to prescribers about drug products, it
would make sense for FDA to require each biosimilar package insert to state clearly that the product is a biosimilar and
perhaps to require a brief explanation of the meaning of biosimilarity. It would also be reasonable to require the package
insert to identify the reference product.
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B. Work with national and international stakeholders to develop a consistent methodology
to ensure that biosimilars have nonproprietary names that are distinguishable from those for
reference products.
FDA should also consider how it can work with regulatory agencies around the world, and other international stakeholders,
to establish consistent standards for biosimilar naming or to create an efficient mechanism to designate a nonproprietary
name for a proposed biosimilar. As discussed above, many regulatory authorities have already recognized the need to
distinguish biosimilars from reference products in some fashion, but the results are often ad hoc and as more biosimilars
are approved, the results could be inconsistent. A consistent global approach will help to reduce healthcare professional
and other stakeholder confusion regarding biosimilars and will allow a biosimilar sponsor efficiently to seek review of a
nonproprietary name for a product that it proposes to market in numerous countries.
As it implements its biosimilar authority, FDA may be poised to play a key role in this coordination process. The WHO’s
International Nonproprietary Name (INN) Expert Group could also play a role. Although the WHO has already announced
its view that biosimilars should have distinct trade names (as opposed to distinct nonproprietary names), INNs and USANs,
as well as other foreign nonproprietary names, have historically been identical in almost all cases. If individual regulatory
agencies continue the current trend of requiring distinct names, the INN Group may feel some pressure to adopt the same
convention.
C. Seek public comment on the multitude of issues that could be addressed in the labeling
of biosimilars, with the goal of creating rules that will result in clear communication to
healthcare professionals regarding the attributes of biosimilars and the basis for approval of
each biosimilar product.
These issues should be vetted through a transparent process that includes an opportunity for meaningful public comment.
Although FDA already held a public meeting and opened a docket related to the implementation of the BPCIA, the agency
did not invite comments on the package insert, and stakeholders generally did not address the package insert. Additional
public comment will allow stakeholders to submit detailed proposals representing a multitude of different perspectives,
including those of physicians, pharmacists, patients, payers, and innovative and biosimilar companies. A transparent process
could further improve these stakeholders’ understanding of and confidence in FDA’s approval of biosimilars and will present
another opportunity for the agency to educate relevant players on the agency’s approach to this new class of products.
As part of this implementation process, FDA should consider commissioning a study focused on healthcare professional
understanding of the meaning of biosimilarity, as well as the ways in which the agency can most effectively communicate
critical information to all stakeholders.
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V . I MPAC T O F PO L I CY RECOMMENDA T I ONS
As FDA works to implement the BPCIA, the agency should strive deliberately and expeditiously to resolve questions
about naming and labeling of biosimilars. Innovative companies, biosimilar sponsors, healthcare professionals, and other
stakeholders, including other regulatory agencies around the world, will benefit from clear guidance from FDA on these
issues. Moreover, some of the naming and labeling questions may need to be answered before other issues related to
biosimilars can be addressed by FDA and by other stakeholders. For example, whether FDA uses a product’s labeling to
communicate information about interchangeability may affect how state substitution laws will need to be amended to
address the substitution of interchangeable biosimilars. Similarly, how biosimilars will be named may affect the design
of any pharmacovigilance system put into place for biosimilars. FDA should therefore strive to resolve some of the major
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naming and labeling questions in a timely manner. Of course, some labeling issues may be raised by, and certain labeling
decisions will turn on, the contents of particular biosimilar applications, so some of these issues may not be able to be
resolved immediately or in a broadly applicable manner.
V I . CONC L US I ON
The implications of FDA’s decisions regarding the naming and labeling of biosimilars will be far-reaching. Patients, physicians,
pharmacists, payers, states, foreign regulatory authorities and other stakeholders will all look to FDA’s decisions on these
issues to inform their own actions.
SOURCES
1Patient Protection and Affordable Care Act, Pub. L. No. 111-148, Title VII, Subtitle A.
2PHSA § 351(i)(2).
3
PHSA § 351(i)(3).
4
PHSA § 351(k)(4).
5
FDCA § 502(a).
6
H.R. 5629, 110th Cong. (2008).
7
H.R. 1038, 110th Cong. (2007).
8
Id.
9
Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments,
75 Fed. Reg. 61,497 (Oct. 5, 2010).
10
Letter of Michael O. Leavitt, Sec’y of HHS, to Sen. Kennedy (June 26, 2007).
11
Letter of Frank M. Torti, M.D., M.P.H., to Rep. Pallone, Chairman, Subcomm. on Health, H. Comm. on Energy &
Commerce (Sept. 18, 2008) (hereinafter “FDA Letter”).
12
75 Fed. Reg. at 61,499.
13
Steven Kozlowski et al., Developing the Nation’s Biosimilar Program, 365 New Eng. J. Med. 385, 387-88 (2011).
14
Japan Ministry of Health, Labor and Welfare, Guidelines for the Quality, Safety and Efficacy Assurance of Followon Biologics (Notice to Directors, Health Bureaus, Prefectural Government) (Mar. 2009).
15
WHO Expert Committee on Biological Standardization, Guidelines on Evaluation of Similar Biotherapeutic
Products (SBPs) § 12 (2009).
16
EMA Committee for Medicinal Products for Human Use, Guideline on Similar Biological Medicinal Products 4
(2005).
17
FDA Letter, supra note 11.
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18
See EMA, Questions and Answers on biosimilar medicines (similar biological medicinal products),
EMEA/74562/2006 Rev. 1 (Oct. 2008), available at http://www.ema.europa.eu/docs/en_GB/document_library/
Medicine_QA/2009/12/WC500020062.pdf; see also Health Canada, Questions & Answers To Accompany the
Final Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs),
available at http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/01-2010-seb-pbuqa-qr-eng.php#q15.
19
FDCA § 201(m).
20
Requirements on Content and Format of Labeling for Human Prescription Drugs and Biologics; Requirements for
Prescription Drug Product Labels, 65 Fed. Reg. 81,082 (Dec. 22, 2000).
21
Id.
2221 C.F.R. § 201.57.
23
Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 71 Fed.
Reg. 3922 (Jan. 24, 2006).
24
FDCA § 502(f ).
25
Health Canada, Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry
Biologics (SEBs) § 2.5 (May 2010).
26
EMA, Questions and Answers on biosimilar medicines (similar biological medicinal products), EMEA/74562/2006
Rev. 1 (Oct. 2008), available at http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_
QA/2009/12/WC500020062.pdf.
27
Omnitrope Prescribing Information (July 2011).
28
See, e.g., Pexeva Prescribing Information (January 2011) (stating that “PEXEVA® (paroxetine mesylate) is an orally
administered psychotropic drug with a chemical structure related to paroxetine hydrochloride (Paxil®)” and that
“[i]n pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of
9089 patients receiving drug and 4 of 3187 patients receiving placebo”).
29
Health Canada, Omnitrope Product Monograph (April 2009).
30
75 Fed. Reg. at 61,499.
31
See EMA, Binocrit, Procedural steps taken and scientific information after the authorisation (updated Aug. 18,
2010).
32
Id.
33
Id.
34
FDCA § 502(e).
35
47 Fed. Reg. 31,008, 31,009 (July 16, 1982).
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About the Authors
Emily Alexander is an Associate in the food and drug practice group in the Washington, DC, office of Covington & Burling LLP.
She provides regulatory advice and strategic guidance to pharmaceutical, biotechnology and medical device companies,
as well as related trade organizations, on applicable federal, state and local law. At this time, she focuses on, among other
things, the regulation of biosimilars and biologics in the United States and foreign jurisdictions, including issues related to
data exclusivity, naming and labeling. She has published articles and given speeches on the Biologics Price Competition and
Innovation Act of 2009 and was involved in various types of advocacy leading up to the passage of the act.
Michael S. Labson is a Partner at the law firm of Covington & Burling LLP in Washington, DC. His practice spans the full range
of pharmaceutical and medical device regulation. He provides strategic advice in dealing with FDA and other agencies.
He has litigated a variety of cases in the life sciences area, has general trial and appellate experience and works actively
on legislative matters. Mr. Labson’s recent work has involved issues such as clinical trial conduct; FDA dispute resolution;
user fees; orphan drug, pediatric and market exclusivities; product promotion; anti-kickback compliance; Medicaid rebates;
drug samples; GMP and quality system requirements; FOIA; imports and exports; drug pedigrees; life cycle planning;
pharmacovigilance; and Rx/OTC switches. He also has expertise on DEA and controlled substances issues and child-resistant
packaging requirements. Mr. Labson graduated magna cum laude from Harvard College and magna cum laude from
Harvard Law School, where he was an Editor and Treasurer of the Harvard Law Review. Following law school, he clerked for
the Honorable David M. Ebel on the U.S. Court of Appeals for the Tenth Circuit in Denver, Colorado.
Erika Lietzan is a Partner in the law firm of Covington & Burling LLP in Washington, DC, practicing in its food and drug group
and government affairs group. She specializes in U.S. and ex-U.S. regulation of drugs and biological products. Her areas of
special focus at this time include biosimilars; the Hatch-Waxman amendments and BPCIA; data and market exclusivities; WHO
initiatives relating to drugs and biologics; comparative effectiveness and health outcomes research; supply chain issues (e.g.,
counterfeiting, pedigrees, importation and online pharmacy); drug safety (e.g., risk management and pharmacovigilance);
and interactions with healthcare professionals (e.g., samples, grants, advertising and promotion, and PhRMA Code). She
speaks and publishes regularly on these topics. Ms. Lietzan currently works with a number of trade associations and ad
hoc coalitions, as well as many of the country’s major biopharmaceutical companies and many smaller companies. Among
other things, she provides compliance and strategic advice (including with respect to proposed corporate transactions);
assists in regulatory, legislative and policy advocacy in the U.S. and around the world; serves as an expert in litigation both
domestically and abroad; counsels and advocates in the course of criminal and congressional investigations; and prepares
clients for regulatory meetings and legislative hearings. For two years, Ms. Lietzan was Assistant General Counsel of PhRMA.
She is past chair of the Biotechnology Committee of the American Bar Association, and she is an elected member of the
American Law Institute. Ms. Lietzan serves as a Director, Food and Drug Law Institute Board.
11
A b o u t t h e F OOD AND DRUG P o li c y F ORUM
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The Forum welcomes articles on cutting-edge state, national and international policy issues related to food and drug law.
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Each issue of the Forum presents an important policy topic in the form of a question, provides background information
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The Food and Drug Law Institute, founded in 1949, is a non-profit organization that provides a marketplace for discussing food
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FDLI’s Mission is to provide education, training, and publications on food and drug law; act as a liaison to promote networking as
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