Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 1
2017 Pharmacy Education Series
February 15, 2017Navigating Biosimilars
Featured Speakers:
Ali McBride, PharmD, MS BCPS, BCOP Sue V. Ie, PharmDClinical Coordinator Hematology/Oncology Fellow, Health Information and Clinical OutcomesDepartment of Pharmacy Community Health Systems Professional Services CorporationThe University of Arizona Cancer Center
2
Submission of an online post‐test and evaluation is the only way to obtain CE credit for this webinar
Go to www.ProCE.com/CHSRx
Webinar attendees will also receive an email with a direct link to the web page
Print your CE statement of completion online– Credit for live or enduring (not both)
Deadline: March 17, 2017
CPE Monitor (applicable to pharmacists and pharmacy technicians)– CE credit automatically uploaded to NABP/CPE Monitor upon completion of post‐test and
evaluation (user must complete the “claim credit” step)
Online Evaluation, Self-Assessmentand CE Credit
Attendance Code
Code will be provided at the end of today’s activity
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 2
How to Ask a Question
Locate menu bar on your computer desktop
Click orange arrow button to open menu box
Type question into question box
Click Send
Do not close menu box
– This will disconnect you from the Webcast
Please submit questions throughout presentation
ClickNo!
Click
Enter question
3
Accessing PDF Handout
Click the hyperlink that is located directly above the question box
Do not close menu box
– This will disconnect you
from the Webcast
No!
Clickhyperlink
4
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 3
2016 Pharmacy Education Series
5
It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. McBride has served in an advisory role for Pfizer and as a speaker for Sandoz. Dr. Ie does not have any relevant commercial and/or financial relationships to disclose.
Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature.
February 15, 2017Navigating Biosimilars
Featured Speakers:
Ali McBride, PharmD, MS BCPS, BCOP Sue V. Ie, PharmDClinical Coordinator Hematology/Oncology Fellow, Health Information and Clinical OutcomesDepartment of Pharmacy Community Health Systems Professional Services CorporationThe University of Arizona Cancer Center
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist and Pharmacy Technician CE)
– 2.0 contact hours
6
Funding:This activity is self‐funded through CHSPSC.
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 4
Biosimilars: A Brief Review of Therapies in Treatment
ALI MCBRIDE, PHARMD, MS BCPS, BCOP
7
Learning Objectives
1. Summarize the current Biosimilar Arena
2. Review the clinical data regarding new biosimilars on the market
3. Evaluate FDA Guidance on Biosimilar Interchangeability and Naming
8
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 5
What Is a Biologic?
A biological product that is demonstrated to be “highly similar” to an FDA‐licensed biological product (reference product)
May rely on certain existing scientific knowledge about the safety, purity, and potency of the reference product
New licensure pathway permits a “biosimilar” biological product to be licensed based on less‐than‐full complement of product‐specific, nonclinical and clinical data
9
What Is a Biologic?Technical definition from US Code of Federal Regulations◦ “Any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man"
Derived from living sources◦ Various cultures of bacteria or viruses◦ Human or animal sources
Biologics do not always have therapeutic intent
For now, think of biologics as “therapeutic proteins”
10
10
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 6
Biologic ProductionProcess important for biologics production
Production process for biologics has more steps and is more complex than process for traditional drugs
HTTP://BIOSIMILARSOURCE.COM/BIOSIMILARS.HTM
11
11
Generic Equivalents as Defined in the “Orange Book”
FDA stipulates that “pharmaceutically equivalent” drug products must be formulated to:◦ Contain the same amount of active ingredient in the same dosage form◦ Meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity)
Products are therapeutic equivalents only if:◦ They are pharmaceutical equivalents◦ They can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling
FOOD AND DRUG ADMINISTRATION. CENTER FOR DRUG EVALUATION AND RESEARCH. ORANGE BOOK: APPROVED DRUG PRODUCTS WITH THERAPEUTIC
EQUIVALENCE EVALUATIONS.12
12
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 7
General Classes of Biologics
Monoclonal antibodies
Complex sugars
Blood derivatives
Vaccines
Recombinant or purified proteins, such as: ◦ Cytokines◦ Thrombolytic agents◦ Enzymes
13
13
Biologic Manufacturing Process Changes
Despite these differences, when the products are within a prespecified acceptable range, the products are marketed with no change in label
If large alterations occur, analytical studies (and possibly additional clinical studies) are required to compare post‐change product with existing pre‐change product
Capillary ZoneElectrophoresis
Cation ExchangeChromatography
Glycan MappingChromatogram
Pre‐change
Post‐change
Post‐change
Pre‐change
Pre‐change
Post‐change
54
3
2
1
6
7
Time, min Time, min Time, min
18 22 26 30 34 38 42 46 14 18 22 26 30 10 15 20 25 30 35 40
Acidicvariants
Basicvariants
G0
G2
G2F
Man5
G0F(1,6)G1F
(1,3)G1F
Darbepoetin alfa Rituximab Etanercept
Schiestl M, et al. Nat Biotechnol. 2011;29:310‐312.
14
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 8
ICH Q5E: Regulatory Guidance for Changes in Manufacturing of Biologics
Over the life of a biopharmaceutical changes are inevitably introduced into manufacturing◦ Improve yield
◦ Changes in sourcing of components
◦ Changes in production scale
Manufacturing changes are governed by ICH Q5E regulation recognized by both the FDA and EMA. ◦ Guidance aims to minimize the drift inherent in a reference product
◦ The regulations provide guidance to conduct a comprehensive assessment on the impact to the product
Key requirements include:◦ Analytics should be selected and optimized to maximize the likelihood of detecting potential differences
◦ Apply more than one analytical procedure to evaluate the same quality to maximize the detection of potential differences
◦ Evaluate critical control points in the manufacturing process that affect product characteristics
US Food and Drug Administration. Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
Product to a Reference Product. Nov 2016 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf
15
Biologic Manufacturing Changes –Demonstration of Comparability
FDA. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073476.pdf. Accessed Nov 2016
“The demonstration of comparability does not necessarily mean that the quality attributes of the pre‐change and post‐change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product.”
16
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 9
Regulatory Pathways for Drugs and Biologics
Li EC, et al. J Manag Care Spec Pharm. 2015;21(7):532‐39 17
Biosimilar Development Approach
Adapted from McCamish M et al. Clin Pharmacol Ther. 2012; 91:405‐17.
Develop highly similar biologic
Test and confirm Interchangeability
Postmarketing Monitoring
Test and confirm biosimilarity
• Analytical methods for structure/function
• Cell lines• In vitro/vivo models• Substance pilot and final scale
• Formulation and final drug product
• Human clinical trials• Consideration of clinically sensitive endpoints
• Clinically sensitive patient population
• Immunogenicity• Efficacy and safety
• No explicit FDA guidance• Will be “difficult” to do in the initial 351(k) application
• Assessment of rare but serious adverse effects
• Active and/or passive surveillance methods
• Follows previous guidance
FDA Approval
18
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 10
Biosimilar and Biologic Development
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Feb 15, 2012 (accessed 2015 Oct 30).
351(a)
351(k)
19
Four Assessments of Analytical Characterization
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30).
Studies of Structure and Function:Residual Uncertainty
Not similar
Similar
Highly similar
Highly similar with fingerprint‐like similarity
No further development through 351(k)
Additional information needed: analytical,
comparative PK/PD, etc.
High confidence; appropriate for targeted clinical studies
Very high confidence; appropriate for moretargeted clinical studies
High
Low
20
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 11
Human Pharmacokinetics and Pharmacodynamics
“Fundamental” for demonstrating biosimilarity
Both PK and PD will be necessary
◦ PK: patient population considerations
◦ PD should study measures that
◦ Are relevant to clinical outcomes
◦ Can be quickly assessed with precision
◦ Have the sensitivity to detect clinically meaningful difference
Ideally correlate exposure to clinical outcomes
Use crossover and parallel designs
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30).21
Comparative Clinical Studies
Efficacy and safety: specific clinical trial design will depend on what residual questions remain◦ Clinical studies should be designed to demonstrate neither decreased nor increased activity
◦ Use clinically relevant and sensitive endpoints in the right population
◦ Biosimilar sponsor to justify comparability delta
Schellekens H. NDT Plus. 2009; 2(suppl 1):i27‐i36.22
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 12
Indication Extrapolation Framework
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf (accessed 2015 Nov 4).
Weise M et al. Blood. 2014; 124:3191‐6.
Patient Factors• Similarity of biologic disposition: PK/PD
• Organ function• Age, ethnicity, etc.
Disease Factors• Clear MOA?• Similarity of disease (e.g., histology, stage, pathophysiology, etc.)
• Single vs. combo therapy• Clinical manifestation
Endpoint Factors• Efficacy and toxicity• Short‐term vs. long‐term
• Sensitivity of surrogate outcomes
Quantitative Evidence of BiosimilarityIn vitro, preclinical, epidemiological studies, diagnostic studies, clinical trials, and
observational studies
Indication Extrapolation DeterminationNo extrapolation; extrapolation to some indications; extrapolation to all indications
23
Source of Names and NumbersOriginator Manufacturer ◦ Reference Product (Trade Name)
• United States Adopted Names (USAN)◦ The generic name (Reference Name)◦ Provided by AMA◦ Generally adopted by FDA
United States Pharmacopeia (USP)◦ Monographs and consistency concerns
Institute for Safe Medication Practices (ISMP)◦ Consults on Naming Clarity and Safety concerns ◦ Advocates for Labeling standards
Food and Drug Administration (FDA)◦ Ultimately approves product name◦ Assigns National Drug Code (NDC)
Centers for Medicare & Medicaid Services (CMS) ◦ Assigns HCPCS codes ◦ Codes usually the same between biosimilars & originator
HCPCS=Healthcare Common Procedure Coding System 24
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 13
The Dilemma of Biosimilar Naming
Biosimilars should have the exact same INN as the reference product
Biosimilars should have a distinct INN to differentiate from reference
and other biosimilars
Pros• Communicate that these products are “highly similar”
• Facilitate adoption and substitution of interchangeable biologics
Cons• Hard to trace for pharmacovigilance
Pros
• Improved pharmacovigilance• Recognize as distinct productsCons
• Confusion about whether they are “interchangeable”
• May impede adoption• Issues with substitution
Traynor K. Am J Health‐Syst Pharm. 2014; 71:446‐7.
Carroll J. Manag Care. 2013; 22:6‐7.25
Importance of a Naming StrategyGoal:
◦ Identify relationship between the “biosimilar” and “reference” / “originator”◦ Therapeutic category
◦ Dosing ◦ Differentiate products
◦ Support pharmacovigilance (PV)
◦ Intended product administered to patient
◦ Outcomes and ADEs attributed to correct product
◦ Avoid “sound alike” and “look alike” errors
◦ Facilitate effective product “track and trace” (anti‐counterfeiting)
26
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 14
Biosimilar Naming
FDA PROPOSED SUFFIX FDA PROPOSED SUFFIX
UniqueDevoid of meaningFour lowercase letters of which at least three are distinctNonproprietaryAttached to the core name with a hyphenFree of legal barriers that would restrict its usage
Be false or misleadingInclude numerals and other symbols aside from the hyphen attaching the suffix to the core nameInclude abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or orderContain or suggest any drug substance name or core namelook similar to or be capable of being mistaken for the name of a currently marketed product Look similar to or otherwise connote the name of the license holderBe too similar to any other FDA-designated nonproprietary name suffix
27
Naming OptionsOptions◦ Totally different names from originator
◦ Preferred by most originator pharmaceutical companies
◦ Same USAN name as originator
◦ EU policy
◦ Unique suffix attached to originator’s USAN
◦ Error prone because some computer fields truncate long names
◦ Facilitates listing adjacent to reference in formulary data bases
◦ Supported by WHO, ISMP, HOPA
◦ Unique prefix attached to originator’s USAN
◦ Precedent with tbo‐filgrastim
◦ Current FDA position
◦ Open comment period on using meaningful suffix
◦ Current precedent for 2 Sandoz products:
◦ Filgrastim‐sndz Zarxio ®
◦ Etanercept‐szzs Erelzi ®
◦ Infliximab‐dyyb Inflectra ®
28
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 15
FDA Draft Guidance on Naming
Goal: facilitate pharmacovigilance and prevent inadvertent substitution
INN with an added random four‐letter suffix for all biologics (including reference products)◦ replicamab‐cznm
◦ replicamab‐hixf
Benefits◦ Common INN will group similar biologics in electronic systems
◦ Having suffix for all products reduces perception that biosimilar is inferior to reference product
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf29
Biologic Naming: Residual concerns
Suffix “devoid of meaning” does not mean it should be confusing
Communicating the naming to providers◦ Purpose for names
◦ Pharmacovigilance and reporting
Interchangeable biosimilars: how will they be named?◦ Different name?
◦ Same name?◦ Same suffix as reference?
◦ No suffix for reference AND interchangeable biosimilar?
30
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 16
Biosimilar Product Labeling: Basic Principles
Reference biologic is found to be safe and effective as per the originator’s registration trials
Biosimilar manufacturer demonstrates that the biosimilar is “highly similar” to the reference, with no clinically meaningful differences
What about:◦ Minor differences in inactive components?
◦ Differences in stability or storage?
◦ Differences in conditions of use?
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf 31
FDA Draft Guidance on Biosimilar Labeling
Clearly identifies the product as a biosimilar
Incorporates relevant data and information from the reference◦ Clinical trial data
◦ Adverse effects
With appropriate product‐specific modifications◦ Conditions of use
◦ Administration, preparation, storage
◦ Safety information that does not preclude demonstration of biosimilarity
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf
32
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 17
FDA Draft Guidance on Biosimilar Labeling
Approaches to product identification◦ Biosimilar product name
◦ Reference product name
◦ Core name
May include information from studies for specific indications for which the biosimilar is not seeking approval
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf
33
FDA: Interchangeability
The biological product is biosimilar to the reference product
It can be expected to produce the same clinical result as the reference product in any given patient
For a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alteration or switch
A product with an interchangeable designation may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htmhttp://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx.
34
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 18
Biosimilar Implementation
35
Biosimilar Pharmacovigilance
Zuñiga L et al. Pharmacoepidemiol Drug Saf. 2010; 19:661‐9. Felix T et al. Nat Biotechnol. 2014; 32:128‐30. Casadevall N et al. Expert Opin Biol Ther. 2013; 13:1039‐47.
Pharmacovigilance
• Practical to encourage healthcare provider reporting
• Real‐time data
• Ensure traceability
Risk minimization
• Healthcare provider communication
• Recalls and alerts
• FDA REMS?
Risk Identification andCharacterization
FDA Approval
Healthcare Provider Responsibility for Reporting• Correct attribution of safety event• Maintenance of electronic medical record• Bar code administration• Medication reconciliation• Consideration of transitions of care
36
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 19
The P&T Committee Will Be Integral to the Biosimilar Implementation Process1
The review process will be different than that used for a generic small‐molecule drug
P&T Committees will likely establish institutional policies around therapeutic substitution
1. Zelenetz AD, Ahmed I, Braud EL, et al. JNCCN J Natl Compr Cancer Netw. 2011;9(SUPPL. 4). 37
Considerations for Formulary Selection of Biosimilars
Griffith N et al. Hosp Pharm. 2014; 49:813‐25.
• Clinical data• Range of
indications• Immunogenicity
concerns• Potential for
therapeutic interchange
• Number of similar agents on formulary
• Pharmaco‐vigilance requirements
• Supply reliability• History of drug
shortages• Supply chain
security• Anti‐counterfeit
measures• Patient assistance
programs• Reimbursement
support
• Product packaging and labeling
• Bar coding • Compatibility
with CSTDs,* robotics
• Product preparation and administration
• Storage requirements
• Economic considerations Hospital Payer Patient
• Payer policies• Transitions of care• IT and medication
system changes• Educational
requirements
Efficacy/SafetyManufacturer Considerations
Product Considerations
Hospital and Patient Factors
*CSTDs = closed system transfer devices
38
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 20
Formulary Selection Considerations:Efficacy and Safety
Clinical data and populations studied in FDA approval
Range of indications
Presence of biomarker to assess efficacy and safety
Experienced vs. de novo patients◦ Immunogenicity concerns due to switching
Griffith N et al. Hosp Pharm. 2014; 49:813‐25.39
Formulary Selection Considerations: Manufacturer Considerations
Expertise manufacturing biologics
Supply reliability
Supply security and anti‐counterfeit measures
Patient assistance programs
Reimbursement support programs
Griffith N et al. Hosp Pharm. 2014; 49:813‐25.40
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 21
Pharmacy & Therapeutics Committee Membership and Functions1
Pharmacy & Therapeutics Committee
Committee Chair(Chief of Pharmaceutical Services)
Member secretary
Hospital administration• Dean• Hospital director
Pharmacy• Pharmacists
Clinical• Physicians• Nurses and physician assistants
Committee members
1. Tyler LS, Cole SW, May JR, et al. Am J Heal Pharm. 2008;65(13):1272‐1283. doi:10.2146/ajhp080086. 41
Formulary Selection Considerations:Product Considerations
Product packaging and labeling from safety perspective
Bar coding
Compatibility with closed system transfer devices (if NIOSH hazardous drug)
Preparation and administration considerations
Storage requirements
Dosage forms meet needs of patient populations
Griffith N et al. Hosp Pharm. 2014; 49:813‐25.42
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 22
Formulary Selection Considerations:Payer, Provider, and Patient Factors
Economic considerations◦ Payer
◦ Provider
◦ Patient out‐of‐pocket cost – impact on adherence
Management of transitions of care◦How many products in “preferred” status
◦ Consistency of product provided
43
CMS Billing Guidance, April 2015
CMS Payment◦ Utilize same HCPCS code as Reference Drug
◦ Initial: 106% AWP
◦ Then: Biosimilar ASP + 6% Reference ASP
◦ Reference Product: ASP + 2.3% (varies)
CMS release:
◦ “…unique opportunity to achieve measurable cost savings and greater beneficiary access to expensive therapeutic treatments for chronic conditions.”
◦ “CMS is considering policy options for coding of additional biosimilars and will release further guidance in the future”
◦ Expects price to be 15 – 30% lower than reference product
http://mobile.biopharma‐reporter.com/Markets‐Regulations/US‐CMS‐releases‐new‐info‐around‐biosimilar‐pricing‐uptake?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright#.VSPTi_nF‐Gl
44
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 23
CMS Biosimilar Modifiers
Biosimilars will share the same HCPCS code, but with a modifier that identifies the manufacturer of the specific biosimilar product
https://www.cms.gov/Medicare/Medicare‐Fee‐for‐Service‐Part‐B‐Drugs/McrPartBDrugAvgSalesPrice/Part‐B‐Biosimilar‐Biological‐Product‐Payment.html
Biosimilar HCPCS Code Product Brand namesCorresponding Required Modifier
Q5101 Injection, Filgrastim (G‐CSF), Biosimilar, 1 microgram
Zarxio ZA ‐ Novartis/Sandoz
Q5102 Injection, infliximab, biosimilar, 10 mg
Inflectra ZB ‐ Pfizer/Hospira
45
Patient / Co‐Pay Assistance ?
Most originator drugs have PAP
Most “biosimilar drugs” are produced by companies that have PAP programs
To be competitive, providers should insist on at least the same level of support as with the originator drug.
46
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 24
Current Biologics on the Market
Generic Brand Indication
Human insulin Several Diabetes mellitus
Interferons: , , Several Several
Epoetin alfa Darbepoetin alfa
Procrit® , Epogen®, Aranesp®
Anemias
FilgrastimPegfilgrastimSargramostim
Neupogen®Neulasta®Leukine®
Febrile neutropenia
Trastuzumab Herceptin® Her2Neu cancers
Rituximab Rituxan® Lymphomas, NHL
CetuximabBevacizumab
Erbitux®Avastin®
EGFR‐expressing cancers
47
47
Annual Sales of Biologic Agents
HTTP://PATENTDOCS.TYPEPAD.COM/FILES/TEN‐YEAR‐POTENTIAL‐SAVINGS‐FROM‐BIOSIMILARS‐IN‐CALIFORNIA.PDF48
48
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 25
7‐5‐2016 US Federal Court (Amgen vs Apotex) requires biosimilar manufacturer to give notice to reference manufacturer and wait 180 days before bringing the drug to market.
Drug (examples) Patent Expires
Lovenox 2012
Neupogen 2013
Epogen 2013
Lantus 2014
Interferon beta 1‐a 2015
Neulasta 2015
Synagis 2015
Humira 2016
Rituximab 2016
Erbitux 2016
Remicade 2018
Avastin 2019
Herceptin 2019
Aranesp 2024
Etanercept (Enbrel) approved 9‐2016, delayed market release to 3‐2017
www.biopharminternational.com/federal‐court‐weighs‐biosimilar‐patent‐dance
PATENT “CLIFF”
49
NAVIGATING BIOSIMILARS
Sue V. Ie, PharmDFellow, Health Information and Clinical OutcomesCommunity Health Systems Professional Services CorporationFebruary 15, 2017
50
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 26
Disclosures • None
51
Outline • Biosimilar naming and interchangeability status
• Biosimilar pipeline
• Formulary status of biosimilars at CHSPSC
• Reimbursement and billing of biosimilars
• Legal aspects of biosimilars
• IT integration of biosimilars
• Pharmacovigilance and immunogenicity of biosimilars
52
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 27
BIOSIMILAR NAMING AND INTERCHANGEABILITY
Guidance from the FDA, January 2017
53
FDA releases nonproprietary
naming guidance for biologics,
Jan. 2017
http://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf
Applies to each originator biological product, related biological product, and
biosimilar product
54
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 28
FDA releases nonproprietary
naming guidance for biologics,
Jan. 2017
Core name
Four lowercase
letter suffix**
Proper name
**unique, devoid of meaning, four lowercase letters of which at least three are distinct, nonproprietary, attached to the core name with a hyphen, and free of legal barriers that would restrict its usage
http://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf 55
FDA releases nonproprietary
naming guidance for biologics,
Jan. 2017
• Application
– Ordering, prescribing, dispensing, recordkeeping, and
pharmacovigilance
• Purpose
– Facilitate pharmacovigilance
– Facilitate accurate identification to HCPs and patients
– Minimize inadvertent substitution of any products that
have not been determined to be interchangeable
Interchangeable productsNonproprietary name suffix TBD
http://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf 56
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 29
FDA releases long-awaited draft
biosimilar interchangeability
guidance,Jan 12, 2017
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf 57
FDA releases long-awaited draft
biosimilar interchangeability
guidance,Jan 12, 2017
• Interchangeability = no immunogenicity concerns
– Meets the standards in section 351(k)(4) of the PHS Act and may be substituted for the reference product without the intervention of the HCP who prescribed the reference product
• FDA requirements for interchangeability will vary based on the product submitted, including:
– Product complexity
– Product‐specific immunogenicity risk
• Switching studies
– Used to determine whether alternating between a biosimilar and its reference product two or more times impacts the safety or efficacy of the treatment course
– Not needed if product only intended to be administered once
• Extrapolated data may be used to support interchangeability for multiple indications if there is adequate scientific justification to do so
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf 58
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 30
BIOSIMILAR PIPELINE
59
FDA Approved Biosimilars
• FDA has approved four biosimilars under section 351(k)
of the Public Health Service Act (PHS Act)
– Sandoz’ Zarxio® (filgrastim‐sndz)
– Pfizer and Celltrion’s Inflectra® (infliximab‐dyyb)
– Sandoz’ Erelzi® (etanercept‐szzs)
– Amgen’s Amjevita® (adalimumab‐atto)
• 351(i) of the PHS Act allows interchangeable
biosimilars to be substituted for their reference
product at the pharmacy level
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm
Refer to the FDA’s Purple Book for lists of licensed biological products and their biosimilar and interchangeable status.
60
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 31
Expected Benefits of
Biosimilars in the U.S.
• Long‐term cost savings potential for payers, health
systems, hospitals, and patients
• Increased accessibility for patients
• “Patent cliff”
– Oncology (mAbs)
– Diabetes (insulin)
– Rheumatoid arthritis (mAbs)
61
Almost 50 distinct
biosimilarscurrently in
development
http://www.marketwatch.com/story/these‐new‐drugs‐might‐never‐get‐a‐chance‐to‐save‐the‐us‐250‐billion‐2016‐07‐20http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf 62
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 32
Biosimilars in Europe have
resulted in substantial
savings and increased
patient access
http://www.marketwatch.com/story/these‐new‐drugs‐might‐never‐get‐a‐chance‐to‐save‐the‐us‐250‐billion‐2016‐07‐20http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf
Use of biologic treatments has increased by as much as 100% since they first became available in the EU
63
http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf64
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 33
Obstacles to Biosimilar
Adoption in the U.S.
• Extensive and continuous education needed
• Reimbursement is complicated and varies widely
• Information systems will require tweaks to signify
originator biologic vs biosimilar products
• Patent loading and “patent dance” by pharmaceutical
companies
65
BIOSIMILARSFORMULARY STATUS
66
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 34
Guidance for Use of
Inflectra®
• CHSPSC, LLC Formulary Management
Committee physicians have recommended
Inflectra Category A status
• Equal availability of both Inflectra
and Remicade to acute care, outpatient
infusion centers, and physician practices
67
Guidance for Use of
Inflectra®
Establish processes within your
business offices that when clinically
appropriate as assessed by the prescriber (Physician Practice) and/or
medical staff (Acute Care), to evaluate
the prior authorization
requirements for Inflectra and
Remicade and consider these in
determining prescribing, especially in
qualifying new patient starts
68
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 35
Biosimilars –CHSPSC
Formulary Status
• Zarxio and Inflectra do NOT have interchangeable
status
Biosimilar ReferenceProduct
CHSPSC Formulary Status
Zarxio® (filgrastim‐sndz)
Neupogen(filgrastim)
Category B
Inflectra® (infliximab‐dyyb)
Remicade(infliximab)
Category A
69
Inflectra vs. Remicade
Formulary Assessment
• Same dosage forms and strengths available
• Same indications with exception of pediatric ulcerative
colitis due to market exclusivity for Remicade for that
indication until September 2018
• Same dosing and drug interactions
• Similar efficacy and adverse effects expected
• Similar patient assistance programs
Inflectra Category A formulary status recommended
Both Remicade and Inflectra available—perform local reimbursement assessment
70
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 36
REIMBURSEMENT AND BILLING OF
BIOSIMILARS
71
Coverage for Inflectra
• Coverage varies across commercial payers, Medicare,
and Medicaid and by treatment site of care
• Providers should confirm payer policies prior to
treating patients with Inflectra
Confidential CHS‐specific costs are available on the CHSPSC Corporate Pharmacy intranet and through your local Regional Pharmacy Directors. These may be used locally in your determinations.
72
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 37
CMS Reimbursement
https://www.cms.gov/Medicare/Medicare‐Fee‐for‐Service‐Part‐B‐Drugs/McrPartBDrugAvgSalesPrice/2017ASPFiles.html 73
HCPCSCode
Short Descriptor
Long Descriptor SI APC HCPCSCode Effective Date
Modifier Modifier Effective Date
Q5101 Inj filgrastimg‐csf biosim
Injection, Filgrastim (G‐CSF) Biosimilar, 1 microgram
G 1822 03/06/2015 ZA‐Novartis/ Sandoz
01/01/2016
Q5102 Inj., infliximab biosimilar
Injection, Infliximab, Biosimilar, 10 mg
K 1846 04/05/2016 ZB‐Pfizer/Hospira
04/01/2016
Table 5 – Biosimilar Biological Product Payment and Required Modifiers
CMS Pub 100‐04 Medicare Claims Processing, Transmittal 3557, July 1, 2016
As a reminder, OPPS claims for separately paid biosimilar biological products are required to include a modifier that identifies the manufacturer of the specific product. The modifier does not affect payment determination, but is used to distinguish between biosimilar products that appear in the same HCPCS code but are made by different manufacturers.
74
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 38
Controversial CMS Payment Policy
• Coding
– All biosimilars sharing the same reference product
will have a single billing and payment code, or Q‐
code
– Biosimilars are required to have a modifier
designating the product and the manufacturer,
e.g., Inflectra = Q5102/ZB
• Reimbursement
– Single payment rate for all biosimilars by blending
the volume‐weighted Average Sales Price (ASP) for
each biosimilar and 6% of the reference product’s
ASP
– Same model as for multi‐source generic drugs
75
Controversial CMS Payment Policy
• Issues and concerns with this
methodology
– Biosimilars are single‐source drugs and
fundamentally different from generics
– Conflicts with the BPCIA of 2009 and the
351(k) abbreviated licensure pathway
– Potentially misleading since biosimilar
products can have different approved
clinical indications
– Modifier inadequate for distinguishing
between approved clinical indications
76
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 39
Commercial Payers
• Precertification or prior authorization
commonly required
77
AnthemPrior Authorization
https://www11.anthem.com/shared/noapplication/f0/s0/t0/pw_g258718.pdf?refer=ahpfooterhttps://mediproviders.anthem.com/Clinical%20Pharmacy%20Policies/PHARM_ALL_Infliximab.pdf
78
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 40
Anthem 2017 Formulary
https://www11.anthem.com/pharmacyinformation/ 79
Checklist for Clean
Claims
Has insurance been verified?
Is this a covered service?
Were the specific payer requirements followed?
If applicable, is the referral authorized?
Is medical necessity documented?
Is all of the required information included on the claim?
Are the correct codes (diagnosis, CPT, HCPCS, and modifier) reported?
Are the billed units accurate and consistent with the Q code descriptor?
If reporting any discarded drug, was it properly documented?
If a separate and distinct E/M service was provided, is it identified with modifier 25?
Modified from Janssen CarePath 2016 Billing Guide for REMICADE® (infliximab) 80
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 41
Physician Office Sample Claim Form:
CMS-1500
x
Doe, John, S
123 Main Street
Anytown AS
10101
01 01 50 X Doe, John, S
123 Main Street
Anytown AS
10101
000‐00‐0000
Medicare
Dr. Smith 123 456 7890
K50 00
123 456 7890
123 456 7890
123 456 7890
01 04 16 01 04 16 11 96413 A 1
01 04 16 01 04 16 11 96415 A 1
01 04 16 01 04 16 11 Q5102 ZB A 40
Item 24D. Indicate appropriate CPT and HCPCS codes, including the InflectraQ‐code and “ZB” HCPCS modifier to specify Inflectra
Item 21. Specify appropriate ICD‐10‐CM diagnosis code(s)
Item 19. If additional information is required to describe Inflectra (e.g., NDC), this info may be captured in Item 19
Item 24E. Enter reference to the diagnosis for the CPT and HCPCS codes
Item 24G. Specify the units. For example, 10 units = 100 mg of infliximab biosimilar (Inflectra). To bill 400 mg, enter 40 units
Modified from Pfizer enCompass Billing and Coding Guide for INFLECTRA®. December 2016 81
Hospital Outpatient
Sample Claim Form: UB-04
Modified from Pfizer enCompass Billing and Coding Guide for INFLECTRA®. December 2016
01‐01‐50 M
Anytown Hospital456 Main StreetAnytown, AS 10101
John S. Doe
K50.00
Medicare
0260 IV therapy 96413 01‐04‐16 1
FL 67. Specify appropriate ICD‐10‐CM diagnosis code(s)
FL 43.Describe procedure
Form Locator (FL) 42. Specify revenue codes FL 44.Specify appropriate CPT and HCPCS codes and moifiers, including, the “ZB” HCPCS modifier to specify Inflectra
FL 46. Specify the units. For example, 10 units = 100 mg of infliximab biosimilar (Inflectra). To bill 400 mg, enter 40 units
123 Main StreetAnytown AS 10101 US
0260 IV therapy 96415 01‐04‐16 1
0636 Drugs requiring detailed coding – Q5102/ZB 01‐04‐16 40INFLECTRA
82
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 42
PATIENT ASSISTANCE
PROGRAMS83
Indigent Care Options
Both Remicade and Inflectra offer similar
patient assistance programs
• For patients with private or commercial insurance
– Eligible patients pay just $5 per infusion
– $20,000 maximum program benefit per calendar year
https://www.pfizerinflectra.com/patient‐resourceshttps://remicade.janssencarepathsavings.com/
Monday-Friday, 9 AM to 8 PM ET
84
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 43
Pfizer enCompass
Program
• A reimbursement and patient support program
• Access Counselors services:
– Investigate patient insurance benefits and coverage
details for Inflectra
– Navigate prior authorization requirements
– Assist with coding and billing challenges
– Support the claims and prior authorization appeals
processes
– Identify affordability options to help appropriate patients
who need financial assistance get started with Inflectra
treatment
For additional information, contact a Pfizer enCompassAccess Counselor at:
1‐844‐722‐6672Monday‐Friday, 9 AM to 8 PM ET
Modified from Pfizer enCompass Billing and Coding Guide for INFLECTRA®. December 2016 85
Lutheran Shared Services Center –
Indigent Drug Program
• Contacts
Christina (Chrissy) [email protected]
Manager, Business OfficeLutheran Health Network
86
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 44
LEGAL CONSIDERATIONS
State Laws and Legislation
87
State Laws and Legislation
http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx
As of January 2017, 38 states have considered establishing state standards for substitution of a “biosimilar” prescription product to replace an original biologic product.
88
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 45
Typical Provisions of
State Legislation
FDA “Interchangeable” Designation
Prescriber Preference “DAW”
“Notification” vs “Communication”
Patient Notification
Record Retention
Immunity for Pharmacists
Web List of Permissible Interchanges
Cost or Pricing Explanation
http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx89
Summary of Biologics and
Biosimilar State Laws
• Available on the NCLS State Law and Legislation
Related to Biologic Medications and Substitution of
Biosimilars website
http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx90
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 46
NCLS Prescription
Drug Database
http://www.ncsl.org/research/health/prescription‐drug‐statenet‐database.aspx
• New and updated bills: All state legislative material is
updated for actions through Monday of the current week.
91
NCLS Prescription
Drug Database
http://www.ncsl.org/research/health/prescription‐drug‐statenet‐database.aspx92
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 47
TECHNICAL CONSIDERATIONS
93
Reimbursement Charge Master
• Each biosimilar will require their own charge code
• Check to see if a charge code has already been setup
using the AUTO CDM prompt
94
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 48
EHR and CPOE
Requirements
• Reasons for changes
– Consistency in display of drugs and drug names
– Indication of biologic reference product vs. biosimilar vs.
interchangeable product to ensure prescribers know
what they are ordering and if a product has been
substituted
– Pharmacovigilance requirements
• Changes needed for information systems
– Pharmacy dispensing system
– Order sets
– CPOE
– eMARs
– Policies and guidelines
– Inventory systems (e.g., bar coding)
95
PHARMACOVIGILANCE AND IMMUNOGENICITY
96
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 49
Pharmacovigilance • Biosimilar approval clinical trials may have a smaller
safety database
• Monitor and identify biosimilar safety issues, e.g.,
immunogenicity, adverse effects such as potential
infections
• Extrapolation of indications
• Immunogenicity
– Biological molecules antibiodies decrease effectiveness
– Switching concerns between different biosimilars and
the reference product
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000Approv.pdf
COMPLEXITY
Small molecule drug
Small biologic
Large biologic
While the FDA considers naming and traceability, also consider proactive changes to ADR reporting requirements to minimize and proactively address these concerns.
97
Immunogenicity of Remicade and
Inflectra
• Infliximab and biosimilar infliximab‐dyyb
demonstrated similar incidence of antidrug antibodies
that reduced the efficacy of the drug
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000Approv.pdf 98
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 50
QUESTIONS?
"Baseball is ninety percent mental. The other half is physical.“
Yogi Berra
99
101
Jerry H. Reed, MS, RPh, FASCP, FASHP
Senior Director, Pharmacy Services
Community Health Systems
Update on Current Pharmacy Initiatives and Strategies
Navigating BiosimilarsCHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 51
102