Promotion of Biosimilars
Speakers:
Sheldon Bradshaw, Partner, Hunton & Williams LLP
Bruce Leicher, Sr. Vice President and General Counsel,
Momenta Pharmaceuticals, Inc.
Andrew N. Papas, Vice President, Regulatory Affairs, NSF
Health Sciences Pharma Biotech Consulting
Jur Strobos, Of Counsel, Olsson Frank Weeda Terman Matz PC
Moderated by Susan Lee, Senior Associate, Hogan Lovells US
LLP
1
Biosimilars: Advertising and Promotion
Promotion of Biosimilars
and the First Amendment
Sheldon T. Bradshaw
Hunton & Williams LLP
October 2, 2015
sbradshaw@hunton.com
202-955-1575
2
The First Amendment
• What impact, if any, will the First Amendment have on
FDA’s application of traditional standards governing
advertising and promotional materials to Biosimilars?
• The tension between FDA’s policies and First Amendment
protections has come to a head a number of times over
the last two decades.
• The manner in which FDA regulates the dissemination of
truthful and non-misleading information is once again
squarely under the First Amendment spotlight.
October 2, 2015
sbradshaw@hunton.com
202-955-1575
3
WLF Litigation
• In a series of cases from 1998-1999, the Washington
Legal Foundation (“WLF”) challenged FDA’s policies
and regulations that restricted the dissemination of
truthful, non-misleading information.
• The federal district court for the District of Columbia
recognized that the First Amendment may, and in
certain specific instances does, protect a manufacturer’s
right to disseminate (and a physician’s right to receive)
truthful, non-misleading information regarding uses of
an FDA-approved drug outside of FDA’s approved
labeling.
October 2, 2015
sbradshaw@hunton.com
202-955-1575
4
Western States
• The Supreme Court recognized that pharmacies have
the right to promote drug compounding services under
the First Amendment.
• FDA sought public comment regarding the impact of the
First Amendment on its regulations.
• FDA expressly acknowledged that there may be tension
between certain aspects of the Agency’s authority and
judicial developments, and requested comments on
(among other issues) a manufacturer’s ability to
communicate information regarding off-label promotion.
October 2, 2015
sbradshaw@hunton.com
202-955-1575
5
Sorrell v. IMS Health, Inc.
• In 2011, the U.S. Supreme Court held that “[s]peech in
aid of pharmaceutical marketing . . . is a form of
expression protected by the Free Speech Clause of the
First Amendment.”
• Impact of Sorrell predicted by the dissenting Justices.
Justice Breyer writing for himself and two others warned
that “the same First Amendment standards that apply to
Vermont here would apply to similar regulatory actions
taken by other States or by the Federal Government
acting, for example, through Food and Drug
Administration (FDA) regulation.”
October 2, 2015
sbradshaw@hunton.com
202-955-1575
6
United States v. Caronia
• In 2012, the Second Circuit applied Sorrell to vacate the
criminal conviction of a sales representative who had
been prosecuted for “misbranding” based on truthful and
non-misleading off-label marketing claims.
• Court held that “the government cannot prosecute
pharmaceutical manufacturers and their representatives
under the FD&C Act for speech promoting the lawful,
off-label use of an FDA-approved drug” consistent with
the First Amendment.
October 2, 2015
sbradshaw@hunton.com
202-955-1575
7
Amarin Pharma, Inc. v. FDA
• In May 2015, the threat of FDA prosecution led Amarin
Pharma, Inc. and four physicians to file a lawsuit against
FDA to prevent FDA from prosecuting the company for
truthful, non-misleading statements regarding off-label
promotion of its FDA-approved drug product.
• On August 7, 2015, the United States District Court for the
Southern District of New York granted Amarin’s motion for
a preliminary injunction, concluding that Amarin had
demonstrated a likelihood of success on its claim that the
First Amendment protects truthful, non-misleading
manufacturer communications regarding off-label use.
October 2, 2015
sbradshaw@hunton.com
202-955-1575
8
Biosimilars – Implications for Labeling,
Advertising and Promotion of Biologics
FDLI Advertising and Promotion Conference
Bruce A. Leicher, Sr. Vice President and General
Counsel, Momenta Pharmaceuticals Inc.
October 2, 2015
Momenta Pharmaceuticals, Inc.
Corporate Info
• Founded in 2001; IPO 2004
• Located in Cambridge, MA
• ~250 employees; >75% in R&D
An Advanced Analytic Platform
• Expertise in high-resolution analytics,
biological characterization, and process
engineering
Driving Potential in Three Areas
• Complex Generics
• Biosimilars
• Novel Drugs
With a Track Record of Success
• Breakthrough success with
•
•
10
2010 generic Lovenox approval
2015 generic Copaxone approval
Momenta Product Portfolio: Broad Application of Thorough Characterization
Across Complex Generics, Biosimilars, and Novel Drugs
PROGRAMS
PRECLINICAL/PROCESS
DEVELOPMENT
CLINICAL1
ANDA/BLA/NDA
FILED
MARKETED
Enoxaparin Sodium
Injection (Generic Lovenox®)*
Complex
Generics1
GlatopaTM (Generic 20 mg/mL
Approved
Copaxone®)*
M356 (Generic 40 mg/mL
ANDA Accepted
Copaxone®)*
M923 Adalimumab
(HUMIRA®)**
CTA Accepted/PK Study
M834 Abatacept (ORENCIA®)
Biosimilars
M511 Bevacizumab
(AVASTIN®)
6 Early Stage Biosimilar
Programs
Necuparanib - pancreatic
cancer
Novel
Drugs
Phase 2
hsIVIg (Hyper-sialylated IVIg)
SIF3 (Selective Immunomodulator of Fc Receptors)
Anti-FcRn Antibody
1Clinical
11
safety/efficacy trials have not been required for these complex generic drug applications
*In collaboration
with Sandoz
**In collaboration
with Baxter
Scientific Principles Applied to the Review of Generic Lovenox are
Applicable to the Review of Biosimilar Candidates
“…Such a “totality of the evidence” approach can also be applied to assessing biosimilars,
since it seems possible to exceed a current state-of-the-art analytic characterization by
evaluating more attributes and combinations of attributes at greater sensitivities with
multiple complementary methods. There may be strategies that allow a “fingerprint”-like
identification of very similar patterns in two different products. Such strategies were used
in supporting the approval of a generic low-molecular-weight heparin product,
enoxaparin — which, though it differs from proteins in important ways, is structurally
complex. Although additional animal and clinical studies will generally be needed for
protein biosimilars for the foreseeable future, the scope and extent of such studies may be
reduced further if more extensive fingerprint-like characterization is used.”
14
Property of Momenta Pharmaceuticals and should not be reproduced or distributed
to any third party without Momenta’s prior approval.
Innovation to Thoroughly Define Biologics
Thorough Structural
Characterization
Control of
Manufacturing
Thorough Biological
Characterization
*
*
High resolution
physicochemical analytics
platform to thoroughly
characterize any product
15
Understanding the
nonlinear chemical and
biosynthetic reactions
that drive production
High resolution biology
applied pre-clinically and
in clinical settings
Momenta’s Goal: Interchangeable Biologics
Standard Approach
Product Knowledge
Brand
Biosimilar
Momenta Approach
Brand
Same
Biosimilar
Brand
Interchangeable
Same
Same
Same
Different
Unknown
Unknown
• Brand Drift
• Manufacturing
Change
Unknown
Different
Remove uncertainty. Qualify differences. Demonstrate equivalence.
• Thorough Product
Characterization
• Manufacturing Process Design
• Product Control and Quality
16
•
•
•
•
Increased POS for approval
Reduced clinical requirements
Opportunity for interchangeability
Improved commercial differentiation
Property of Momenta Pharmaceuticals and should not be reproduced or distributed
to any third party without Momenta’s prior approval.
Momenta is Committed to Enhancing Quality of Biologics
and Protecting Patient Safety
From contamination to characterization within a matter of weeks,
MNTA helped answer the complex question of the contaminant,
and published manuscripts that helped influence
the screening system for others to follow.
17
A History of Commercial Messaging to Deter
Biosimilar Innovation and Competition
Tactic
Message
Barriers to Competition
BIO CP - 2003
•
Generic biologics are
impossible
•
•
Prevent regulatory approval
Prevent/deter legislative pathway
Oppose Biosimilar
Pathway – 20072010
•
Biosimilars are unsafe even
if possible
Interchangeable biologics
are impossible/different
•
•
Prevent/deter pathway
Incorporate legislative features that
prevent/deter use of the pathway
• Mandatory clinical trials
• Complex IP exchange
Influence FDA
Guidance - 2011
•
Same messages
•
•
•
Emphasize differences (e.g., naming)
Mandate unnecessary clinical trials
Freeze scientific standards for similarity and
interchangeability
AbbVie CP I
•
Same messages
•
Delay biosimilars for 10 years
Naming Campaign
JnJ Citizen Petition
•
Biosimilars are different
and raise safety concerns
•
Amplifies anti-biosimilar commercial campaign
with providers, payers, patients and regulators
Restricted Access to
Reference Products
•
Biosimilar companies are
irresponsible
•
Prevents/delays initiation of development
AbbVie CP II
•
Biosimilars should be
named and labeled
differently
•
Interchangeable Biologics will “appear” different
and non-substitutable
18
•
Labeling Background
• Basic Principles and Questions
• Labeling must contain adequate directions for use
• Labeling must specify approved conditions or indications for
use
• Labeling may not be false or misleading
• Comparative and superiority claims in labeling and
promotional materials must be supported by substantial
evidence and adequate and well controlled clinical trials
But: Labeling forms the predicate for biosimilar and
interchangeable biologic promotion as well.
19
Differential labeling is Not Mandatory
•
The BPCIA is silent on labeling. The law itself does not require or preclude inclusion of
biosimilarity or interchangeability data in a label
• Interchangeable Biologics should include interchangeable designation
•
•
• Misleading to omit a positive designation at the Pharmacy and to Provivders
Potentially misleading to require negative statement of non-interchangeability
• Non-interchangeable biosimilars require a prescription and are not substitutable
The CP asserts “patient safety” risk?
• Assumes pharmacists will violate the law (substitution)
• Assumes physicians are inexperienced
• Familiar messaging to undermine confidence in biosimilars
• Goal is to disparage and deter physician adoption in a protected First Amendment CP setting
• Inconsistent with the BPCIA Goal of higher quality, more affordable, and more accessible biologics
• Adoption drives investment, innovation and quality
•
Biosimilar Applicant may or may not seek to include additional data or interchangeability
status
• As with any label, should be evidence based
• Additional data may be useful to demonstrate quality
•
Can anti-biosimilar messaging survive biosimilar and interchangeable biologic approvals?
20
Traditional “Brand” Messaging on Biosimilars
In order to maximize benefits of the pathway, as policies and laws are developed
and implemented, should we be emphasizing similarities or differences?
“Unlike generic medicines where the active
ingredients are identical, biosimilars are not likely to
be identical to the originator biologic. Biosimilar
development requires significant expertise,
infrastructure and investment to demonstrate safety
and equivalent efficacy and to ensure safe, reliable
supply of therapies for patients.”
“Safety is a priority for the development of all
medicines, but biologics raise safety considerations
above and beyond those of chemical drugs. This is
because biologics are more structurally complex medicines
than chemical drugs, and even slight changes in their
manufacture can cause undetected changes in the
biological composition of the product. These changes can in
turn affect the safety and effectiveness of the product in
patients. The EPREX example provides a further
rationale for not considering a follow-on product to be
interchangeable with an innovative product.”
21
Unsupported Comparative Claims are False
and Misleading
22
Mandatory Unique Naming Appears to be
Inconsistent with FDA Policy on Comparative Claims
•
A unique biosimilar name could make a label misleading or confusing in several ways:
• Does a unique name suggest a “clinically meaningful difference” when there is none?
• Does the answer differ for non-interchangeable biosimilars v interchangeable
biologics?
23
•
If a non-meaningful structural or functional difference in a biosimilar requires a
naming difference, will biologic manufacturing changes (brand or biosimilar) require
similar labelling changes?
•
Is it false and misleading to suggest that a biosimilar poses safety concerns when a
manufacturing change with similar differences may not have been tested to the same
standard as the biosimilar?
•
Is it false and misleading or confusing to patients to argue that biosimilars are more
different than the brand than the brand is to itself?
• The only well controlled studies and evidence and FDA Approval will demonstrate otherwise
Can Current Messaging Survive a Biosimilar or
Interchangeable Biologic Approval?
• Will existing commercial
messaging survive
approval of a biosimilar?
• Are they false and
misleading?
24
Questions
25
Biosimilars: Advertising and Promotion
A Citizen’s Petition on
Biosimilar Labeling
Introduced by
Andy Papas, PhD, MBA
Vice President of Regulatory Affairs
NSF Health Sciences Pharma Biotech Consulting
Disclosure Statement
• For the purpose of facilitating discussions on prospective labeling by
experts from varying viewpoints on this topic, NSF Pharma Biotech
Consulting introduces a recent recommendation for biosimilar
labeling via Company X’s citizen petition
• It should not be construed that NSF is representing Company X as a
client or adopts any or all of its proposed recommendations
regarding US biosimilar labeling
Background
• FDA approved Sandoz's 351(k) application to market Zarxio® on 6Mar-15 ('filgrastim-sndz'), first biosimilar drug approved in US
• Zarxio’s labeling: direct copy of reference biologic label (Neupogen)
with extrapolation of 4 indications
• Company X files Citizen Petition (CP)1 and a later supplement2 for
recommended biosimilar labeling
• To date, FDA has not issued draft guidance on labeling of
biosimilars but issued final guidance in Apr 2015 on Scientific
Considerations in Demonstrating Biosimilarity to a Reference
Product; Guidance for Industry
1: Docket No. FDA-2015-P-2000, 2-Jun-2015, Citizen’s Petition, 2-Jun-2015
2: Docket No. FDA-2015-P-2000-0007, 10-Aug-2015, Supplement to Citizen Petition, 10-Aug-2015
CP Requested Biosimilar Labeling
For product licensed under section 351(k) of the PHS Act, the approved
Rx drug labeling should contain:
• Clear statement that product is:
– A biosimilar3
– licensed for fewer than all of reference product’s conditions of use (if
applicable)
– licensed conditions of use were based on extrapolation (if applicable)
• Clear statement that FDA has not determined the biosimilar is
interchangeable with reference product (if applicable)
• Concise description of pertinent data developed to support
licensure, along with information to enable prescribers to distinguish
data from studies of biosimilar vs. studies of the reference product
3: As observed in EU, NZ, and CA
Key CP Points4
1. Sameness of Label, Requirement of Generic Drugs, Contrary to
BPCIA
2. Sameness [i.e., inflexible] Label Requirement - Misleading and
Violates FDCA and FDA Regulations
3. FDA Violated the APA5 When It Abandoned the Draft Scientific
Guidance Labeling Recommendations
4: FYI: No points are raised regarding pharmacoviligance reporting issues
5: Federal Administrative Procedures Act, 1946
Point 1
Sameness of Label, Requirement of Generic Drugs,
Contrary to BPCIA (Biologics Price Competition and
Innovation Act of 2009)
•
•
Approved label exactly that of the reference drug Neupogen
Includes all five of the Neupogen indications, four by extrapolation (sixth
approved after Zarxio approval)
Point 1 (cont.)
• “Same label” applied to Zarxio implies new FDA requirement
• Why BPCIA doesn’t support label sameness approach
– Biologics different from small molecule drugs; similar but not identical
– BPCIA created 2 tiered structure of biosimilarity: general biosimilar and
interchangeable
– BPCIA borrowed some ANDA provisions but didn’t borrow same label
requirement
– PREA amended to state non-interchangeable biosimilar is “a new active
ingredient” for purposes of pediatric research, but interchangeable
product is not
– In sum, characterizing feature of BPCIA deems biosimilars to be
different from their referents
• Therefore same labeling approach “legally” unsound
Point 2
FDCA misbranding violation occurs if label is false or
misleading; it omits material facts
• Material facts
– whether an omission is material “is determined by the degree to
which [the] information is objectively important, relevant, or
substantial to the target audience.”
– In other words, a material fact is one that reasonably would
influence “the intended audience.”
Point 2 (cont.)
• Biosimilar labeling must include information necessary to enable
informed prescribing and to dispel common misconceptions
– Survey of 400 US board certified physicians thought important that label
include all the elements being petitioned in this CP
Point 2 (cont.)
• Prescribers need to know whether a product is biosimilar and nature
and scope of its approval
– Zarxio was approved for 5 indications, 4 by extrapolation. Reference
product approved for 6th indication after Zarxio approval. None of these
facts can be derived from Zarxio’s label, resulting in materially
misleading biosimilar labeling
– In preamble accompanying the physician labeling draft rule, FDA stated
that “the basis for approval of the drug product, including the extent of
the product’s benefits,” should be included in labeling “to provide
practitioners with more accurate and specific information about a drug’s
efficacy that could help them to make informed prescribing decisions.”
Thus, FDA regulations provide for the basis for a drug’s approval to be
disclosed in its approved physician labeling
Point 2 (cont.)
• Prescribers need to know whether biosimilar is interchangeable with
reference product
– Prescribers may/not be able to tell whether biosimilar meets criteria of
being interchangeable
– Omitting that information is misleading and suggests that biosimilar could
be substituted for its referent which increases risk of inappropriate product
switching
• Prescribers need biosimilar-specific data and also need to know
whether data discussed in labeling are from biosimilar or from
reference product
– Immunogenicity – Zarxio’s label contained immunogenicity profile of
Neupogen® of 3% yet its profile was 0%. In addition, label also warned
that 3% result should not be compared to results reported by “other
filgrastim products”
– Prescriber likely to be confused and assume that 3% rate was that
observed for Zarxio; therefore source of data in label should be identified
Point 3
FDA Violated the APA When It Abandoned the Draft
Scientific Guidance Labeling Recommendations
• FDA published draft guidance on Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product; Guidance for
Industry in Feb 2012
• In final guidance of Apr 2015, FDA removed the earlier labeling
recommendation:
– “Labeling of a proposed product should include all the information
necessary for a health professional to make prescribing decisions,
including a clear statement advising that:
• This product is approved as biosimilar to a reference product for stated
indication(s) and route of administration(s).
• This product (has or has not) been determined to be interchangeable with
the reference product”
Point 3 (Cont.)
• Many discussions were held with public after issuance of draft
guidance and in the Agency’s view the draft guidance was “well
received”
• Yet in Apr. 2015, FDA published final guidance with this entire
section removed
• APA requires “unwavering” obligation on agencies to provide a
reasoned explanation for their policies
• FDA cannot abandon that proposal without comment, leaving
regulated entities and other key stakeholders to guess its “unspoken
thoughts”
Supplement to Citizen Petition
1. FDA Purple Book5
– On 30-Apr-2015, Senate HELP Committee chairman plus others
requested FDA via letter to explain why first approved biosimilar label
contained no statement regarding the product’s interchangeability status
• Under what circumstances should label disclose it had not been found interchangeable?
– On 22-Jun-2015, FDA responded that omitted interchangeability would
not be needed on biosimilar label because information could be found in
Purple Book
– Assertion - FDA defends material omission in Zarxio’s Package Insert
on grounds that relevant information can be obtained from another, nonlabeling source
• Ironic twist - without “biosimilar” in label, prescriber would not know to consult biosimilar
Purple Book
5: FDA’s Purple Book: “Licensed Biological Products with Reference Product Exclusivity and Biosimilarity
or Interchangeability Evaluations”
Supplement (cont.)
– FDA regulations6 explicitly state that prescription drug labeling found "on or within
the package" (in other words, the package insert) must contain all of the
information that prescribers require to administer the drug to their patients safely
and effectively.
2. Amarin Pharma Inc. v. FDA
– FDA letter sent to DOJ on 8-Jun 2015, includes FDA statement on permissible
marketing of Vascepa®:
– Communication should not state or imply that studies conducted using products
other that Vascepa were studied of Vascepa itself…
– Similarly in brief filed with court on 23-Jun-2015, DOJ (on behalf of FDA)
asserted that it would be “misleading for Amarin to suggest or imply …that
studies using products other than Vascepa were studies of Vascepa itself”
3. Information provided demonstrating additional stakeholder support
for the CP’s recommended labeling
6: 21 CFR 201.100(c)(1)
FDLI Key Discussion Points
• What information is needed by prescribers/pharmacists regarding
biosimilar labeling
– Should biosimilar or interchangeability declaration be required in prescribers
label?
– Should the clinical data supporting licensure of biosimilar be required in label?
• What information is needed by patients?
• Can/should the Purple Book serve as surrogate communication
vehicle?
Contact Information:
Andy Papas
apapas@nsf.org
Biosimilars: Advertising and Promotion
Application of Traditional
Standards to Biosimilar
Labeling
Jur Strobos MD
Attorney at Law
Olsson Frank Weeda Terman Matz PC
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
42
Overview
• Proposed Alternative Views of Labeling
– Copy Reference Label – ‘Genericized’
– Include Provisos
• Evidentiary standards for claims
– Comparison Claims
• How is a biosimilar actually different?
– Examples from filgrastim sndz
– Statutorily permissible differences
• What is truth?
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
43
Labeling
• Efficacy (indication/usage/clinical studies)
• How and Why (dosing, administration, how
supplied, clinical pharmacology)
• Safety (contraindications, warnings,
precautions, adverse reactions,
interactions, special populations,
nonclinical pharm/tox, overdose)
• Proprietary information (mfg, name, etc.)
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
44
Generic Drugs
• All components of labeling other than
proprietary information are copied
– But, none of the copied information was
generated by the generic sponsor
• Unique clinical or other information
generated by sponsor NOT on the label
– Mfg, bio-availability,1 -equivalence,1
extrapolation of use
• Is this truthful? Or, dictated by 505(j)2, 3?
(“bioequivalence”); 2§505(j)(2)(A)(iv) (“same
therapeutic effect”); 3§505(j)(2(A)(v) (“same” “labeling”)
1§505(j)(2)(A)(iv)
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
45
Recent Citizen’s Petition:1
Add Four Provisos to Label
• Product is “biosimilar” (or “interchangeable”)
• Product is NOT biosimilar for certain
specified uses
• Labeled Indication/Usage based on
extrapolation
• Include summary of data actually generated
by the sponsor of the biosimilar
1Docket
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
No. FDA2015-P-2000
46
How Is BPCIA Different?
• “Biosimilar”1 or “highly similar”2
– No “clinically meaningful” differences3
– Any differences are “clinically inactive”2
• Has to specify “mechanisms of action for
the condition or conditions of use” “to the
extent known for the reference product.”4
• “Same” labeling re how to use.
• But, elsewhere, does not specify “same”
labeling PHS §351(k)(2)(A)(i)(I); PHS §351(k)(2)(A)(i)(I)(aa); PHS
1
October 2, 2015
2
§351(i)(2)(A); 3PHS §351(i)(2)(B); 4PHS §351(k)(2)(A)(II)
jur.strobos@ofwlaw.com
240-472-9665
47
Statutory Evidentiary Standards
• Efficacy data:
– “[S]ubstantial evidence” based on “adequate
and well-controlled investigations, including
clinical investigations”1
• Other data:
– “Adequate tests” to support “conditions” “in
the labeling”2
• “Reasonable evidence”3
• “Some basis to believe”4
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
1FDCA
§ 505(d)(5), (7)
§ 505(d)(1)
321 CFR § 201.57(c)(6)
421 CFR § 201.57(c)(7)
2FDCA
48
Comparative Claims
• Comparisons of efficacy must be
supported by substantial evidence1
• Comparisons of safety must also be
supported by substantial evidence
– E.g., “frequency, severity or character of
adverse reactions”2
121
CFR § 201.57(c)(3)(v)
221 CFR § 201.57(c)(7)(iii)
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
49
Data to Establish Biosimilarity1
• Analytical studies (physico-chemical)
• Nonclinical
• Clinical
– PK/PD, immunogenicity, maybe other
• Sufficient to support 1 or more conditions for use
• Same mechanism of action if known
• BPCIA does not require substantial evidence
of comparative efficacy or safety for approval
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
1PHS
§351(k)(2)(A)(i)
50
Filgrastim sndz
Comparability Data
•
•
•
•
•
Analytical (CMC)
Immunogenicity
Pharmacology/Toxicology
Clinical Pharmacology
Clinical/Statistics
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
51
Analytical
• Are these
differences
clinically
active?
• Statistically
meaningless1
1FDA
Briefing Document at page
17-12; Addendum at 1-7
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
52
Immunogenicity/PK/PD
• Comparison of Anti-Drug Antibodies
– Differences within limits of assay accuracy
• Comparison of Neutralizing Antibodies
– No positives for either
• PK variability less than required for
generics
• No identified PD differences within
historically published variability
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
53
Clinical Safety and Efficacy
• Open label (EP06-301)
– Does not meet criteria of substantial evidence
• Comparative (EP06-302)
– 1:1 N≈200
– Met retrospective noninferiority margin
– Does not meet criteria for substantial evidence
• Given size/design, were these studies
probative? Necessary?
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
54
Conclusion
• Comparative claims to other marketed
products – whether relative safety or
efficacy – are inherently efficacy claims1
– Must be supported by “substantial evidence”
– BPCIA does not require substantial evidence
to support a finding of biosimilarity (or
interchangeability)
• The words “similar” or “not similar” are
comparative claims
October 2, 2015
121
CFR § 201.57(c)(3)(v); 21 CFR § 201.57(c)(7)(iii)
jur.strobos@ofwlaw.com
240-472-9665
55
Conclusion II
• BPCIA requires extrapolation of indications
for a biosimilar based on mechanism of
action, and other limited data
• These data do not include substantial
evidence
• Statements related to support or lack of
support for specific indications could be
construed as a comparative claim
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
56
If BPCIA precludes the agency from
requiring substantial evidence to support
a finding of biosimilarity, can FDA require
labeling that contains unsubstantiated
comparative claims?
Or permit comparative promotional
claims?
October 2, 2015
jur.strobos@ofwlaw.com
240-472-9665
57
Questions?
58