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 Promotion of Biosimilars
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Speakers: Sheldon Bradshaw, Partner, Hunton & Williams LLP Bruce Leicher, Sr. Vice President and General Counsel, Momenta Pharmaceuticals, Inc. Andrew.
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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
• 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.
• 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.
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.
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.”
• 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.
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.
PROGRAMS PRECLINICAL/PROCESS DEVELOPMENT CLINICAL1 ANDA/BLA/NDA
FILED MARKETED
ComplexGenerics1
Enoxaparin Sodium Injection (Generic Lovenox®)*
GlatopaTM (Generic 20 mg/mL Copaxone®)*
M356 (Generic 40 mg/mL Copaxone®)*
Biosimilars
M923 Adalimumab (HUMIRA®)**
M834 Abatacept (ORENCIA®)
M511 Bevacizumab (AVASTIN®)
6 Early Stage Biosimilar Programs
Novel Drugs
Necuparanib - pancreatic cancer
hsIVIg (Hyper-sialylated IVIg)
SIF3 (Selective Immuno- modulator of Fc Receptors)
Anti-FcRn Antibody
Approved
ANDA Accepted
CTA Accepted/PK Study
Phase 2
1Clinical safety/efficacy trials have not been required for these complex generic drug applications
Momenta Product Portfolio: Broad Application of Thorough Characterization Across Complex Generics, Biosimilars, and Novel Drugs
*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
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“…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.”
Property of Momenta Pharmaceuticals and should not be reproduced or distributed
to any third party without Momenta’s prior approval.
• 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 CampaignJnJ 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
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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.
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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?
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Traditional “Brand” Messaging on Biosimilars
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“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.”
“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.”
In order to maximize benefits of the pathway, as policies and laws are developed and implemented, should we be emphasizing similarities or
differences?
Unsupported Comparative Claims are False and Misleading
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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?
• 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
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Can Current Messaging Survive a Biosimilar or Interchangeable Biologic Approval?
• Will existing commercial messaging survive approval of a biosimilar?
• Are they false and misleading?
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Questions
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A Citizen’s Petition on Biosimilar Labeling
Introduced by
Andy Papas, PhD, MBA
Vice President of Regulatory Affairs
NSF Health Sciences Pharma Biotech Consulting
Biosimilars: Advertising and Promotion
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 6-Mar-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
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, non-labeling 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