2017 pharmacy educations3.proce.com/res/pdf/chs2017febhandout.pdfnavigating biosimilars chs pharmacy...

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

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Deadline: March 17, 2017

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2016 Pharmacy Education Series

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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

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Funding:This activity is self‐funded through CHSPSC.



Biosimilars: A Brief Review of Therapies in Treatment

ALI MCBRIDE, PHARMD, MS BCPS, BCOP

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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

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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

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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”

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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

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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

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General Classes of Biologics

Monoclonal antibodies

Complex sugars

Blood derivatives

Vaccines

Recombinant or purified proteins, such as: ◦ Cytokines◦ Thrombolytic agents◦ Enzymes

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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.

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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

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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.”

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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

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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)

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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

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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



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

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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



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)

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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

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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 ®

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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?

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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

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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

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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.

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Biosimilar Implementation

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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



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

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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




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




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

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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

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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

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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



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

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Annual Sales of Biologic Agents

HTTP://PATENTDOCS.TYPEPAD.COM/FILES/TEN‐YEAR‐POTENTIAL‐SAVINGS‐FROM‐BIOSIMILARS‐IN‐CALIFORNIA.PDF48

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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”

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NAVIGATING BIOSIMILARS

Sue V. Ie, PharmDFellow, Health Information and Clinical OutcomesCommunity Health Systems Professional Services CorporationFebruary 15, 2017

50



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

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BIOSIMILAR NAMING AND INTERCHANGEABILITY

Guidance from the FDA, January 2017

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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





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



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



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



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



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)

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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



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

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http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf64



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

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BIOSIMILARSFORMULARY STATUS

66



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



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



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



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



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



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



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



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



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



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



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



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



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



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



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



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



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



102