Apr 20 2016 webinar COMBINED PRESENTATION …s3.proce.com/res/pdf/CHS/CHS2016AprHandout.pdf · ranibizumab (lucentis) 2015 2018 expired expired expired 2016 2019 2017 ... structure

Biosimilars ‐Managing the Products and the Potential for Confusion and MisinformationCHS Pharmacy Education Series

ProCE, Inc.www.ProCE.com 1

2016 Pharmacy Education Series

April 20, 2016Biosimilars ‐Managing the Products and

1

g gthe Potential for Confusion and Misinformation

Featured Speakers:

Ali McBride, PharmD, MS, BCPS, BCOP John Fanikos, RPh, MBAClinical Coordinator, Hematology/Oncology Director of Pharmacy BusinessDepartment of Pharmacy Brigham & Women’s HospitalUniversity of Arizona Cancer Center

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2016 Pharmacy Education SeriesApril 20, 2016Biosimilars ‐Managing the Products and

the Potential for Confusion and Misinformation

Featured Speakers:

Ali McBride, PharmD, MS, BCPS, BCOP John Fanikos, RPh, MBAClinical Coordinator, Hematology/Oncology Director of Pharmacy BusinessDepartment of Pharmacy Brigham &Women’s Hospital

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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 is a Consultant/Speaker for Hospira and Sandoz. Mr. Fanikos is a Consultant/Speaker for Baxalta, BD Rx, and Boehringer Ingelheim.

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.

Department of Pharmacy Brigham & Women s HospitalUniversity of Arizona Cancer Center

CE Activity Information & Accreditation

ProCE, Inc. (Pharmacist CE)

– 2.0 contact hours

Funding:This activity is self‐funded through CHSPSC

6

This activity is self funded through CHSPSC.



BIOSIMILARS - MANAGING THE PRODUCTS AND THE POTENTIAL FOR CONFUSION AND MISINFORMATION

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OBJECTIVES

• DESCRIBE THE CURRENT BIOTHERAPEUTICS LANDSCAPE, INCLUDING THE STATUS OF THE BIOSIMILAR PIPELINE IN THE U.S.

• DISCUSS OPERATIONAL STRATEGIES FOR INTRODUCTION, ROLL-OUT, AND MONITORING OF BIOSIMILAR PRODUCTS IN HEALTH SYSTEMS.

• DISCUSS THE CRITICAL ISSUES OF NAMING, INTERCHANGEABILITY, AND PHARMACOVIGILANCE WITH BIOSIMILAR PRODUCTS INCLUDING BIOPHARMACEUTICALS WITH A NARROW THERAPEUTIC WINDOWBIOPHARMACEUTICALS WITH A NARROW THERAPEUTIC WINDOW.

• OUTLINE STRATEGIES FOR PHYSICIAN AND OTHER STAKEHOLDER INTERACTION REGARDING BIOSIMILARS, INCLUDING STRATEGIES TO MANAGE MISINFORMATION.

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BIOLOGICAL (BIOLOGIC) DEFINITION

“BIOLOGICAL PRODUCT” MEANS:

• A VIRUS, THERAPEUTIC SERUM, TOXIN, ANTITOXIN, VACCINE, BLOOD, BLOOD COMPONENT OR DERIVATIVE, ALLERGENIC PRODUCT, OR ANALOGOUS PRODUCT, OR ARSPHENAMINE OR DERIVATIVE OF ARSPHENAMINE

• APPLICABLE TO THE PREVENTION, TREATMENT, OR CURE OF A DISEASE OR CONDITION OF HUMAN BEINGS (PUBLIC HEALTH SERVICE ACT SECTION 351(I))

• BIOLOGICAL PRODUCTS ALSO MEET THE DEFINITION OF EITHER A DRUG OR DEVICE UNDER SECTIONS 201(G) AND (H) OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT (FD&C ACT).

http://www.fda.gov/ICECI/Inspections/IOM/ucm122535.htm Accessed January 14, 2015

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BIOLOGIC AGENTS: EXAMPLESType of Biologic Example Example Indication

Monoclonal antibody Basiliximab Prophylaxis of acute organ rejection in renal transplants

Blood derivative Albumin Hypovolemia

Recombinant or purifiedproteins

C t ki I t f lf 2b M lCytokines Interferon alfa-2b Melanoma

Hormones Epoetin alfa Anemia due to CKD

Enzymes Pegloticase Treatment of refractory chronic gout

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WHY ARE BIOLOGICS IMPORTANT?

Schumock GT, Li EC, Suda KJ, et al. Am J Health Syst Pharm. 2015;72(9):717-736.

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THERAPEUTIC USES OF BIOLOGICS

1313114000

Analysis of 5% Sample of CMS Claims,2008 Outpatient Procedures BSA PUF

10633

7833

40824000

6000

8000

10000

12000

Num

ber

of C

laim

s

Other indications not listed:• Neurology• Gastroenterology• Dermatology

Data available at:http://cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/BSAPUFS/Outpatient_Proc.html

Excluded: ESAs (1.4 million claims), vaccines, IVIG

1118 855

0

2000

Cardiovascular Myeloid Growth Factors

Oncology Rheumatoid Arthritis

Macular Degeneration

Asthma

12



TOTAL US DRUG AND BIOLOGIC EXPENDITURES

• Annual growth in drug expenditures compared with previous year, 1999-2014. YTD = year to date.

Cha

nge

in E

xpen

ditu

res,

%

13

Schumock GT, et al. Am J Health Syst Pharm. 2015;72:717-736.

Ann

ual

Year

THE PATENT CLIFF AND GROWTH POTENTIAL FOR THE BIOSIMILARS MARKET

9.1

7.7

ADALIMUMAB (HUMIRA)

ETANERCEPT (ENBREL)

Global Sales 2013, US$ Billion EU Expiry Date

US Expiry Date

2018 2016

2015 20287.5

7.1

6.2

5.6

5.4

5.1

4.7

4 2

INFLIXIMAB (REMICADE)

INSULIN GLARGINE (LANTUS)

RITUXIMAB (MABTHERA)

BEVACIZUMAB (AVASTIN)

INTERFERON BETA-1A …

TRASTUZUMAB (HERCEPTIN)

GLATIRAMER ACETATE …

RANIBIZUMAB (LUCENTIS)

2015 2028

2015 2018

Expired Expired

Expired 2016

2019 2017

Expired Expired

Expired 2019

Adapted from IMS Health. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf

Accessed January 2016.

4.2

4.2

0 1 2 3 4 5 6 7 8 9 10

RANIBIZUMAB (LUCENTIS)

PEGFILGRASTIM (NEULASTA)2015 Expired

2016 2016

2015 Expired

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RATIONALE FOR BIOSIMILARS

• THE BIOLOGICS PRICE COMPETITION AND INNOVATION ACT WAS

ENACTED TO INCREASE COMPETITION WITH BIOLOGICAL

MEDICATIONS

• COMPETITION WILL LEAD TO:

• DECREASED PRICES (OR OVERALL EXPENDITURES)

INCREASED INNOVATION• INCREASED INNOVATION

Blackstone EA and Joseph PF. Am Health Drug Benefits. 2013;6(8):469-78.

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COST SAVINGS ASSOCIATED WITH BIOSIMILARS

• THE USE OF BIOSIMILARS IN THE EUROPEAN UNION AND THE UNITED

STATES MAY YIELD TOTAL SAVINGS OF $56 BILLION TO $110 BILLION

OVER THE NEXT FIVE YEARS (2016)

• RAND HAD REPORTED A COSTS SAVINGS OF 44.2 BILLION DOLLARS

TO THE US HEALTHCARE SYSTEM WITH BIOSIMILAR (2013)

• EXPRESS SCRIPTS ESTIMATED A COST SAVINGS OF 250 BILLION

(2013)

• EXPECTED COST SAVINGS MAY YIELD A SAVINGS OF 20-30%

http://drugtopics.modernmedicine.com/drug-topics/news/biosimilars-savings-may-reach-100-billion-2020 [Accessed 4/1/2016]Hirsch BR, Lyman GH. Biosimilars: Are they ready for primetime in the United States? Journal of the National Comprehensive Cancer Network. 2011; 9(8):934-943

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BIOLOGICS: A REGULATORY PERSPECTIVE351(a)Originator

351(k)Biosimilar

351(k)Interchangeable Biosimilar

351(a)Non-originator biologic

351(a)Next-generation “Bio-better”

Description First-to market biologic molecule; will likely be the

“Highly similar” to reference product;

A biosimilar deemedthat can be substituted for the

It is “another brand name” of an already approved

Biologic that has been altered to achieve improved will likely be the

reference productproduct; approved via Biosimilars pathway

substituted for the reference without permission from prescriber

already approved biologic

achieve improved clinical outcomes

Depth of data submitted to the FDA

“Standard” data package: efficacy and safety

Abbreviateddata package for comparability

Abbreviated data package for comparability; more information on efficacy and safety

“Standard” datapackage: efficacy and safety

“Standard” datapackage: efficacy and safety

Compared to N/A Yes Yes Yes or no Likely (standard of Compared to originator?

N/A Yes Yes Yes or no Likely (standard of care)

Implications Biosimilar pricing; explicit regulatoryoversight on comparison with reference; possible pharmacist substitution (for interchangeable)

Different pricingstructure; substitution issues

New entity

Adapted from: Lucio et al. Am J Health Syst Pharm. 2013; 70(22):2004-17

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GENERAL PRINCIPLES FOR DEMONSTRATING BIOSIMILARITY

• BIOSIMILARS APPROVED VIA AN ABBREVIATED PATHWAY

• DEMONSTRATION OF BIOSIMILARITY IS A COMPARABILITY EXERCISE

AND NOT A THERAPEUTIC EQUIVALENCE STUDY

• THE GOAL OF THE BIOSIMILARITY EXERCISE IS TO ESTABLISH THAT THE

CANDIDATE BIOSIMILAR IS NOT SIGNIFICANTLY DIFFERENT FROM THE

REFERENCE PRODUCT AND IS UNLIKELY TO HAVE ANY CLINICALLY

SIGNIFICANT DIFFERENCES

• SMALLER-SCALE DIRECT COMPARISONS AND EXTRAPOLATION ARE

USED

US FOOD AND DRUG ADMINISTRATION. GUIDANCE FOR INDUSTRY: SCIENTIFIC CONSIDERATIONS IN DEMONSTRATING BIOSIMILARITY TO A REFERENCE

PRODUCT. APRIL 2015 AVAILABLE AT:

HTTP://WWW.FDA.GOV/DOWNLOADS/DRUGSGUIDANCECOMPLIANCEREGULATORYINFORMATION/GUIDANCES/UCM291128.PDF

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REGULATORY PATHWAYS FOR DRUGS AND BIOLOGICS

Li EC, et al. J Manag Care Spec Pharm. 2015;21(7):532-39

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FDA SPECIFICATIONS FOR BIOSIMILARS

Biosimilar Product Specification Comparison with Reference

Formulation May be different

Delivery device/container May be different

Routes of administrationMay obtain licensure for fewer than all routes of administration for which reference product is licensed

May obtain licensure for fewer than all Indications for use

May obtain licensure for fewer than all conditions of use for which reference product is licensed

Strength Must be the same

US FDA. BIOSIMILARS: QUESTIONS AND ANSWERS IMPLEMENTATION OF BPCI ACT OF 2009. APRIL 2015. AVAILABLE AT:

HTTP://WWW.FDA.GOV/DOWNLOADS/DRUGS/GUIDANCECOMPLIANCEREGULATORYINFORMATION/GUIDANCES/UCM444661.PDF

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DEMONSTRATING BIOSIMILARITY: A STEPWISE APPROACH

• COMPARE PROPOSED BIOSIMILAR TO

REFERENCE IN TERMS OF:

1 STRUCTURE1. STRUCTURE

2. FUNCTION

3. ANIMAL TOXICITY STUDIES

4. HUMAN PHARMACOKINETICS (PK) AND

PHARMACODYNAMICS (PD)

5. CLINICAL IMMUNOGENICITY

6. CLINICAL SAFETY AND EFFECTIVENESS

• FDA INTENDS TO UTILIZE A “TOTALITY OF THE

EVIDENCE” APPROACH

US Food and Drug Administration. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. April 2015 Available at: http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

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BIOSIMILAR AND BIOLOGIC DEVELOPMENT

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Accessed Nov. 2014.

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STRUCTURE AND FUNCTION

• SERVE AS THE “FOUNDATION” OF BIOSIMILAR DEVELOPMENT

• USEFUL IN DETERMINING WHAT FUTURE STUDIES ARE NECESSARY• USEFUL IN DETERMINING WHAT FUTURE STUDIES ARE NECESSARY

• STRUCTURE• AMINO ACID SEQUENCE, HIGHER-ORDER STRUCTURES, GLYCOSYLATION,

PEGYLATION, ETC.• ANALYZE LOT-TO-LOT VARIABILITY

• FUNCTION• EVALUATE PHARMACOLOGIC ACTIVITY VIA IN VITRO OR IN VIVO

EXPERIMENTS• FUNCTIONAL EVALUATION THAT COMPARES CANDIDATE TO REFERENCE


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BIOSIMILAR MARKET

APPROVED BIOSIMILARS

• INFLIXIMAB (INFLECTRA)

• APRIL 7, 2016

• GLARGINE (BASAGLAR)

• DECEMBER 16, 2015

BIOSIMILARS IN DEVELOPMENT

• FILGRASTIM – APOTEX

• PEGFILGRASTIM – APOTEX

• ADALIMUMAB –ABBVIE

• RITUXIMAB

• FILGRASTIM-SNDZ (ZARXIO) • PEGFILGRASTIM

• BEVACIZUMAB

• TRAZSTUZUMAB

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BIOSIMILARS INTEGRATION INTO A HEALTH SYSTEM

• THERAPEUTIC EXCHANGE/P&T FORMULARY

• EDUCATION

• COST AND REIMBURSEMENT

• STATE BOARD OF PHARMACY

• ELECTRONIC HEALTH CARE RECORD INTEGRATION• ELECTRONIC HEALTH CARE RECORD INTEGRATION

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FORMULARY MANAGEMENT

• WHAT WAS THE DATA FOR THE APPROVAL OF THE BIOSIMILAR?

• IS THE CLINICAL EFFICACY AND SAFETY OF THE BIOSIMILAR A

CONCERN FROM THE PHASE I/III CLINICAL TRIAL?

• WILL PAYORS PAY FOR OFF LABEL USES OF THE BIOSIMILAR?

• ARE SIDE EFFECTS SIMILAR TO THE ORIGINATOR PRODUCT?

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FORMULARY MANAGEMENT: P&T QUESTIONS

• WHAT MODIFICATIONS NEED TO BE MADE TO EXISTING ORDER SETS AND PROTOCOLS TO INCLUDE BIOSIMILAR PRODUCTS?

• WILL CLINICAL STUDIES BE AFFECTED?

• WHAT EDUCATION WILL NEED TO BE PROVIDED TO PHYSICIANS, NURSES, AND OTHER CLINICIANS TO PREPARE FOR BIOSIMILAR ADOPTION?

• WHAT PATIENT EDUCATION MATERIALS WILL BE NEEDED TO SUPPORT BIOSIMILAR USE?

• WILL THERE BE IT ISSUES WITH EHR?

• WHAT IS THE FINANCIAL VALUE ASSOCIATED WITH USE OF A BIOSIMILAR?

• COMPARATIVE COST AND REIMBURSEMENT

• WILL 340B PRICING PLAY AN ISSUE

• IS THERE A CONCURRENT DRUG REPLACEMENT/PATIENT ASSISTANCE PROGRAM WITH THE BIOSIMILAR

• WILL PAYORS DETERMINE PREFERENCE?

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BIOSIMILAR REVIEW AND ADOPTION REQUIREMENTS

• UNLIKE GENERICS, INITIAL ADOPTION OF BIOSIMILARS TO HEALTH-

SYSTEM FORMULARIES WILL BE MORE COMPLEX

• PHARMACY & THERAPEUTICS COMMITTEE INVOLVEMENT

• DETAILED EVALUATION OF SAFETY AND EFFICACY

• MECHANISMS FOR PRESCRIBING, ADMINISTRATION, AND

DOCUMENTATIONOCUM N ON

• REQUIRES SUBSTANTIAL EDUCATION OF ALL CLINICIANS AND

PATIENTS

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BIOSIMILAR FORMULARY EVALUATION AND ADOPTION

• NOT A NEW PROCESS: HEALTH SYSTEMS HAVE EXISTING THERAPEUTIC STANDARDIZATION/FORMULARY MANAGEMENT EXPERTISE

• APPLICATION OF PREVIOUS EXPERIENCES WITH OTHER MOLECULES/DRUG CATEGORIES

• A REVIEW OF INDICATIONS AND OFF-LABEL USES WILL NEED TO BE EVALUATED

• IN ADDITION, A THOROUGH EVALUATION OF THE PHARMACOECONOMICIMPACT IN THE INPATIENT AND OUTPATIENT SETTING WILL ALSO NEED TOBE EVALUATED

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EDUCATION• HEALTH CARE PROFESSIONALS, PARTICULARLY THOSE ON P&T COMMITTEES, WILL BE VERY

INFLUENTIAL IN DRIVING THE ADOPTION OF BIOSIMILARS BY THE HEALTH CARE SYSTEMINFLUENTIAL IN DRIVING THE ADOPTION OF BIOSIMILARS BY THE HEALTH CARE SYSTEM

• HOWEVER, A LACK OF AWARENESS AND INFORMATION REGARDING THESE AGENTS ON THE PART OF HEALTH CARE PROFESSIONALS IS ONE OF THE MOST SIGNIFICANT PROBLEMS THAT MAY HINDER THE ADOPTION OF BIOSIMILARS

• A STUDY CONDUCTED IN 2011 AT THE 16TH ANNUAL CONFERENCE OF THE NATIONAL COMPREHENSIVE CARE NETWORK (NCCN) SURVEYED 277 HEALTH CARE PROFESSIONALS, INCLUDING PHARMACISTS (N = 38), PHYSICIANS (N = 129), AND NURSES (N = 71)

• THE STUDY FOUND THAT ONLY 13%, 8%, AND 12% OF THESE PROFESSIONALS

• CONSIDERED THEMSELVES TO BE “EXTREMELY FAMILIAR” WITH THE ABBREVIATED REGULATORY PROCESS FOR THE APPROVAL OF BIOSIMILARS

• WHEREAS 18%, 39%, AND 44% CONSIDERED THEMSELVES TO BE “NOT AT ALL FAMILIAR” WITH THIS TOPIC

P T. 2013 Jun; 38(6): 329–335JNCCN—Journal of the National Comprehensive Cancer Network 2011;9[Suppl 4]:S1–S22

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EVALUATION OF FORMULARY DECISIONS

J Natl Compr Cancer Network. 2011;9(Suppl 4):S1–S22

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SUMMARY OF FORMULARY CONSIDERATIONS FOR BIOSIMILARS

Formulary Evaluation Biosimilar Questions

Safety and Efficacy Product characteristicsClinical DataImmunogenicity

Manufacturer Considerations Medication availabilityHistory of shortages and recallsHandling PracticesSupply Chain

Hospital and Patient Consideration Packaging and labelingInterchangeabilityIndicationsNamingNamingInformation Technology

Economic Evalautions Patient Assistance Programs340b Pricing

Patient Education Biosimilar or Brand Name Information

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COST & REIMBURSEMENT

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REIMBURSEMENT

INPATIENT SETTING

• COSTS ARE BASED OFF OF DIAGNOSIS RELATED GROUPS (DRG)

• OFTEN ARE A GROUP OF PAYMENT MADE TO A HOSPITAL OR HEALTH SYSTEM TO COVER COST

• THESE ARE OFTEN CAPITATED COSTS OR CAPPED COSTS

• USUALLY A FLAT RATE IS PROVIDED FOR TREATMENT OR A PROCEDURE

COST REIMBURSEMENT IN THE INPATIENT SETTING IS MINIMAL

• P&T MEMBERS ARE ALWAYS LOOKING TO CUT COSTS IN THE FACE OF MINIMAL REIMBURSEMENT

• I.E., BRAND TO GENERIC EXCHANGES, IV TO ORAL CONVERSIONS…

• ONE OF THE KEY SITES FOR FORMULARY IMPLEMENTATION ARE FOUND TO BE IN THE INPATIENT SETTING.

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REIMBURSEMENT

OUTPATIENT SETTING• COSTS ARE BASED OFF OF BUY AND BILL POLICIES

• APC STANDS FOR AMBULATORY PAYMENT CLASSIFICATIONS

• SYSTEM FOR REIMBURSING ACUTE CARE FACILITIES FOR OUTPATIENT SERVICES (E.G., OUTPATIENT PROSPECTIVE PAYMENT SYSTEM OR OPPS)

• DEVELOPED BECAUSE OF SUCCESS OF DRGS

35

CMS CLARIFICATION FOR MEDICARE PART B

CMS Clarifies Biosimilar Coding and Reimbursement

Coding: Indicates the biosimilar will have its own unique Healthcare Common Procedure Coding Coding: Indicates the biosimilar will have its own unique Healthcare Common Procedure Coding System (HCPCS) code; however, CMS does not explain how subsequent biosimilars will be coded and does not address interchangeable biosimilars. CMS also states the existence of an identifier (ie, prefix or suffix) has no bearing on coding or reimbursement. CMS noted Zarxiowill be assigned a unique HCPCS code in the next quarterly HCPCS tape release in the coming weeks; the code will be available in the claims processing system on July 1, 2015, effective retroactively to the Food and Drug Administration (FDA) approval date

Payment: As specified by the Biologics Price Competition and Innovation Act of 2009 (BPCIA), biosimilars will be reimbursed at the biosimilar’s average sales price (ASP), plus 6% of the ASP for the innovator product. Before Zarxio’s ASP information is available, it will be reimbursed at

36

for the innovator product. Before Zarxio s ASP information is available, it will be reimbursed at 106% of its wholesale acquisition cost (WAC)

Coverage: CMS anticipates Zarxio will be covered generally through Part B, but it could also be covered under Part D in certain circumstances (for example, nursing homes or intermediate care facilities)



CMS CLARIFICATION FOR MEDICARE PART D

• CMS ALSO CLARIFIED RULES APPLYING TO BIOSIMILARS UNDER MEDICARE PART D IN A SEPARATE RELEASE. CMS ENCOURAGES PLANS TO CONTINUE TO USE EXISTING FORMULARY CHANGE AND FORMULARY REVIEW POLICIES TO PROMOTE APPROPRIATE USE OF BIOSIMILARS TO HELP CONTROL COSTS. OTHER IMPORTANT POINTS:BIOSIMILARS ARE NOT INTERCHANGEABLE WITH THEIR REFERENCE BIOLOGICAL PRODUCTS; AS SUCH, CMS ANTICIPATES THAT PART D SPONSORS’ PHARMACY AND THERAPEUTICS (P&T) COMMITTEES WILL REVIEW NEWLY APPROVED BIOSIMILARS

• BIOSIMILARS CAN BE ADDED TO A FORMULARY AT ANY TIME, BUT EXCHANGING THE REFERENCE PRODUCT WITH THE BIOSIMILAR IN THE FORMULARY WILL BE EVALUATED BY CMS ON A CASE-BY-CASE BASIS. A BIOSIMILAR AND REFERENCE PRODUCT WILL NOT BE CONSIDERED AS DIFFERENT DRUGS FOR PURPOSES OF SATISFYING THE 2 DISTINCT DRUGS REQUIREMENT FOR EACH OF THE SUBMITTED CATEGORIES AND CLASSES

• FOR LOW INCOME SUBSIDY (LIS) BENEFICIARIES BIOSIMILARS WILL STILL BE SUBJECT TO THE HIGHER • FOR LOW-INCOME SUBSIDY (LIS) BENEFICIARIES, BIOSIMILARS WILL STILL BE SUBJECT TO THE HIGHER MAXIMUM COPAYMENTS, $3.60 OR $6.60 IN 2015, DEPENDING UPON THE INDIVIDUAL’S SUBSIDY LEVEL

• BIOSIMILARS WILL NOT BE SUBJECT TO THE DISCOUNT PROGRAM ESTABLISHED TO CLOSE THE COVERAGE GAP UNDER PART D

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INDICATION EXTRAPOLATION: CHALLENGES FOR CLINICIANS

• FRAMEWORK AND DISCUSSION AT THE P&T COMMITTEE• FRAMEWORK AND DISCUSSION AT THE P&T COMMITTEE

• IT IS LIKELY THAT MANY WILL REJECT THE FRAMEWORK FOR

EXTRAPOLATION

• MAY NOT FEEL THAT THE “RISK” OF UNKNOWN IS WORTH THE “BENEFIT”

• PAYERS

• HOW WILL PAYERS MAKE THEIR COVERAGE DETERMINATIONS?

• COMPENDIA

• WILL THERE BE OFF-LABEL BASED UTILIZATION?

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BIOSIMILAR LEGISLATION

• THE HEALTHCARE REFORM LAW AMENDED THE PUBLIC HEALTH SERVICE (PHS) ACT TO CREATE AN ADDITIONAL APPROVAL PATHWAY TARGETED SPECIFICALLY AT TO CREATE AN ADDITIONAL APPROVAL PATHWAY TARGETED SPECIFICALLY AT BIOSIMILAR AND INTERCHANGEABLE BIOLOGICAL PRODUCTS (THE BIOLOGICS PRICE COMPETITION AND INNOVATION ACT OF 2009, OR BPCI ACT)

• ALLOWS THE SUBMISSION OF A BIOLOGICS LICENSE APPLICATION (BLA) FOR A BIOSIMILAROR INTERCHANGEABLE BIOLOGICAL

• REQUIRES A BIOSIMILAR APPLICANT TO DEMONSTRATE THAT THERE ARE NO CLINICALLY MEANINGFUL DIFFERENCES IN SAFETY, PURITY, AND POTENCY BETWEEN A BIOSIMILARPRODUCT AND A REFERENCE PRODUCT

• ALLOWS APPROVAL BY FDA OF A BIOSIMILAR PRODUCT AS “INTERCHANGEABLE,” AS SPECIFIED

U.S. Senate. Biologics Price Competition and Innovation Act. URL in reference listU.S. Congress. Sections 7001-7003 (Biologics Price Competition and Innovation Act of 2009) of the Patient Protection and Affordable Care Act (Public Law 111-148). URL in reference list 39

STATE BOARD OF PHARMACY AND LEGISLATION

• FDA CONTINUES WORK ON IMPLEMENTING BPCI ACT

• STATES HAVE CONSIDERED PROPOSALS TO RESTRICT SUBSTITUTION OF BIOLOGIC MEDICATIONS THAT ARE DEEMED SIMILAR/ INTERCHANGEABLE, BUT HAVE NOT BEEN CLEARED BY FDA FOR INTERCHANGE

• SUPPORTERS OF STATE PROPOSALS BELIEVE THE ULTIMATE DECISION ON SUBSTITUTION SHOULD BE LEFT TO THE PATIENT’S PRESCRIBING PHYSICIAN

• PERHAPS CONCERN FOR PATIENT SAFETY

• PERHAPS DESIRE TO PROTECT USE OF “ORIGINATOR” DRUG

• OPPONENTS BELIEVE STATE PROPOSALS ARE RESTRICTIVE AND INCONSISTENT • OPPONENTS BELIEVE STATE PROPOSALS ARE RESTRICTIVE AND INCONSISTENT WITH FORTHCOMING NATIONAL STANDARDS

National Conference of State Legislatures. Pro and con arguments on substitution (excerpt from Alabama legislative and media debate). URL in ref list.Generic Pharmaceutical Association. State initiatives. URL in ref list.Pollack A. New York Times. January 28, 2013. URL in ref list.

40



BIOSIMILAR LEGISLATION AND AUTOMATIC SUBSTITUTION

• FDA CONTINUES WORK ON IMPLEMENTING BPCI ACT

• STATES HAVE CONSIDERED PROPOSALS TO RESTRICT SUBSTITUTION OF BIOLOGIC MEDICATIONS THAT ARE DEEMED SIMILAR/ INTERCHANGEABLE, BUT HAVE NOT BEEN CLEARED BY FDA FOR INTERCHANGE

• SUPPORTERS OF STATE PROPOSALS BELIEVE THE ULTIMATE DECISION ON SUBSTITUTION SHOULD BE LEFT TO THE PATIENT’S PRESCRIBING PHYSICIAN

• OPPONENTS BELIEVE STATE PROPOSALS ARE RESTRICTIVE AND INCONSISTENT WITH FORTHCOMING NATIONAL STANDARDS

• WILL THERE INPATIENT/OUTPATIENT RESTRICTIONS

• WILL THERE BE DETAILING FOR COMMUNITY PHARMACY PRACTICES ONLY

41

STATE LEGISLATION BIOSIMILAR INTERCHANGEABILITY

• ANY BIOLOGICAL PRODUCT UNDER CONSIDERATION FOR SUBSTITUTION MUST FIRST BE APPROVED AS "INTERCHANGEABLE" BY THE U.S. FOOD AND DRUG ADMINISTRATION OR FDA. (ONE PRODUCT HAS GAINED FULL APPROVAL BY THE FDA AS A BIOSIMILAR (BUT NOT YET INTERCHANGEABLE) IN THE UNITED STATES AS OF MARCH 6, 2015)BIOSIMILAR (BUT NOT YET INTERCHANGEABLE) IN THE UNITED STATES AS OF MARCH 6, 2015)

• THE PRESCRIBER (SUCH AS A PHYSICIAN, ONCOLOGIST, PHYSICIAN ASSISTANT, ETC.) WOULD BE ABLE TO PREVENT SUBSTITUTION BY STATING “DISPENSE AS WRITTEN” OR “BRAND MEDICALLY NECESSARY.”

• THE PRESCRIBER MUST BE NOTIFIED OF ANY ALLOWABLE SUBSTITUTION MADE AT A PHARMACY. IN 2015 BILLS THE LANGUAGE COMMONLY IS ADJUSTED TO SAY "COMMUNICATE WITH." (THIS WOULD ALLOW A PHYSICIAN TO ASSESS AND COMPARE THE PATIENT EXPERIENCE.)

• THE INDIVIDUAL PATIENT MUST BE NOTIFIED THAT A SUBSTITUTE OR SWITCH HAS BEEN MADE. IN SOME CASES, STATE LAW WOULD REQUIRE PATIENT CONSENT BEFORE ANY SUCH SWITCH IS MADE.

• THE PHARMACIST AND THE PHYSICIAN MUST RETAIN RECORDS OF SUBSTITUTED BIOLOGIC MEDICATIONS.

• SOME STATE LEGISLATION PROVIDES IMMUNITY FOR PHARMACISTS WHO MAKE A SUBSTITUTION IN COMPLIANCE WITH BIOLOGICS STATE LAWBIOLOGICS STATE LAW.

• THE STATE MUST MAINTAIN A PUBLIC OR WEB-BASED LIST OF PERMISSIBLE INTERCHANGEABLE PRODUCTS.

• SOME LEGISLATION REQUIRES THE PHARMACIST TO EXPLAIN THE COST OR PRICE OF THE BIOLOGIC AND THE INTERCHANGEABLE BIOSIMILAR.

http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx [Accessed April 1st, 2016]

42



43

IT/EHR

I. ELECTRONIC HEALTH RECORDS

I. CERNER

II. EPIC

III. SUNRISE/SCM

II. NAMING OF BIOSIMILARS

I. MATCH THE NDC WITH THE DRUG ADMINISTERED

II. UTILIZATION OF MATCHED THERAPIES AND OUTCOMES

III. INVENTORY CONTROL

I. DECREASE NUMBER OF THERAPIES FOR AN INSTITUTIONS SUPPLY CHAIN

II. EVOLVING NUMBER OF THERAPIES WITH THE SAME INDICATION

III. MONITORING BETWEEN THERAPIES FOR OUTPATIENT/INPATIENT UTILIZATION

IV. NOTIFICATION TO PRESCRIBERS

I. OUTPATIENT

II. INPATIENT

44



CLINICAL STUDIES

• DEVELOPMENT OF CLINICAL STUDIES DOES NOT ALWAYS INCLUDE NEW THERAPIESN W S

• OFTEN STANDARD OF CARE (SOC) THERAPIES OFTEN ARE USED AS A COMPARATOR GROUP OR USED AS PART OF THE REGIMEN

• CURRENT STUDIES NOW CLASSIFY INCLUSION OR EXCLUSION WITH BIOSIMILARS

• EACH STUDY THAT NOW COMES OUT HAS TO BE EVALUATED FOR REVIEW OF THE CURRENT PROTOCOL AND EVALUATION FOR THESE THERAPIES

• IDS AND THE CLINICAL TRIAL DIRECTORS ARE NOW MADE OF THESE PRIOR TO REVIEW AND CLINICAL STUDY IMPLEMENTATION

45

REMS

• FDA REQUIRES REMS PROGRAMS FOR ALMOST 40 PERCENT OF NEW

G A O A S ACCO NG O S S N N GA ONDRUG APPROVALS, ACCORDING TO BRIEFS PRESENTED IN LITIGATION

ON THIS ISSUE

• BIOSIMILARS FOR A SPECIFIC DRUG CLASS WILL NEED TO EMULATE

REMS OF THE ORIGINATOR PRODUCT

• WILL THERE BE VARIANCES IN REPORTING THIS

CONTENT(ORIGINATOR TO BIOSIMILAR)( )

• MORE TO COME IN THE UPCOMING LECTURE…

46



• FACTORS TO CONSIDER FOR THE INTERCHANGEABILITY OF BIOSIMILARS AND PHARMACIST SUBSTITUTION OR INTERCHANGE OF

INTERCHANGEABILITY OF BIOSIMILARS

PHARMACIST SUBSTITUTION OR INTERCHANGE OF BIOLOGICAL PRODUCTS

• FORMULARY REVIEW PROCESS THAT CONSIDERS APPROPRIATE OFF-LABEL INDICATIONS FOR BIOSIMILARS

• KEY COMPONENTS OF A SUCCESSFUL PHARMACOVIGILANCE PROGRAM, INCLUDING PHARMACOVIGILANCE PROGRAM, INCLUDING ROLES THE PHARMACIST CAN ASSUME IN ENSURING SUCCESS.

GABI JOURNAL 2014;3:88-93

47

• THE BASIS FOR DRUG/BIOLOGIC PRODUCT SELECTION BY THE PHARMACIST

INTERCHANGEABILITY

• ORANGE BOOK - GENERICS

• PURPLE BOOK - BIOSIMILARS

• PATIENT & PRESCRIBER COMMUNICATION• NOTIFICATION VS. COUNSELING VS. WRITTEN

COMMUNICATION

• PROVISIONS TO EXCLUDE HOSPITALS/HEALTH-SYSTEMS WITH A FORMULARY SYSTEM

• DOCUMENTATION OF SUBSTITUTION

• DOES CURRENT PHARMACY PRACTICE LAW APPLY TO BIOLOGICS & BIOSIMILARS?• ARE THERE STATE BOARD OF PHARMACY ISSUES WE NEED TO

BE CONCERNED ABOUT?48



DEFINITION

EXTENDING INFORMATION AND CONCLUSIONS FROM ONE POPULATION TO MAKE INFERENCES IN ANOTHER TARGET POPULATION

INTERCHANGEABILITY

EXAMPLES: ACROSS DISEASES (TYPES, STAGE, ETC.), AGE GROUPS, IN COMBINATION WITH OTHER DRUGS, IMPAIRED ORGAN FUNCTION

PURPOSE (REGULATORY)

AVOID UNNECESSARY STUDIES OR REDUCE THE NUMBER OF STUDIES

LIMITED FEASIBILITY IN STUDYING THE TARGET POPULATION

INDUSTRY/REGULATOR EXTRAPOLATION TO REFERENCE’S LABELED INDICATIONS

EXTRAPOLATION OF DATA IS ALREADY AN ESTABLISHED REGULATORY EXTRAPOLATION OF DATA IS ALREADY AN ESTABLISHED REGULATORY PRINCIPLE

MANUFACTURING CHANGES WITH ORIGINATOR BIOLOGICS

HTTP://WWW.EMA.EUROPA.EU/DOCS/EN_GB/DOCUMENT_LIBRARY/SCIENTIFIC_GUIDELINE/2013/04/WC500142358.PDF

WEISE M, ET AL. BLOOD. 2014 OCT 8. PII: BLOOD-2014-06-583617. [EPUB AHEAD OF PRINT]

49

“BIOSIMILAR TO THE U.S.-LICENSED REFERENCE BIOLOGICAL PRODUCT AND CAN BE EXPECTED TO

INTERCHANGEABILITY DEFINITION

PRODUCE THE SAME CLINICAL RESULT AS THE REFERENCE PRODUCT IN ANY GIVEN PATIENT.”

“FOR A BIOLOGICAL 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 BIOLOGICAL PRODUCT SWITCHING BETWEEN USE OF THE BIOLOGICAL PRODUCT AND THE REFERENCE PRODUCT WILL NOT BE GREATER THAN THE RISK OF USING THE REFERENCE PRODUCT WITHOUT SUCH ALTERNATION OR SWITCH”

PHS ACT, SECTION 351(K)(4).

HTTP://WWW.FDA.GOV/DOWNLOADS/DRUGS/GUIDANCECOMPLIANCEREGULATORYINFORMATION/UCM216146.PDF.

ACCESSED JULY 2014

50



EVALUATION FOR EXTRAPOLATIONPHYSIOLOGIC & CLINICAL FACTORS

• CLINICAL EXPERIENCE WITH REFERENCE

BIOSIMILAR DATA PACKAGE

• PHYSIOCHEMICAL AND PRODUCT

• MOA & RECEPTORS FOR EACH

INDICATION

• DIFFERENCES IN SAFETY &

IMMUNOGENICITY BETWEEN PATIENT

POPULATIONS

• DEGREE TO WHICH FUNCTIONAL

FUNCTIONAL COMPARISON

• POTENTIAL UNCERTAINTIES

• ACCEPTABLE SAFETY PROFILE

INCLUDING IMMUNOGENICITY

• EXTRAPOLATE FROM HIGH- TO

LOW-RISK GROUPS FOR MOIETIES OF BIOLOGIC CAN BE

CHARACTERIZED AND COMPAREDIMMUNOGENICITY CONCERNS

• RECOGNIZE THAT ADDITIONAL

TESTS/STUDIES MAY BE

REQUIRED

Weise M, et al. Blood 2014 124:3191-3196

51

ONE SOURCE FOR A LIST OF BIOSIMILAR/INTERCHANGEABLE

PRODUCTS

THE PURPLE BOOK

WILL THIS BE TIED TO STATE PHARMACY PRACTICE LAWS (DRUG

PRODUCT SELECTION)?

FOR BIOSIMILARS, WILL THE DATA REGARDING THE

COMPARABILITY EXERCISE BE PUBLISHED (E.G., HIGHLY SIMILAR

WITH FINGERPRINT-LIKE SIMILARITY, HIGHLY SIMILAR, ETC.)

52



POSTPATENT BIOLOGICALS

BIOGENERICS

NAMING OF BIOSIMILARS

BIOGENERICS

SUBSEQUENT ENTRY PROTEIN

PHARMACEUTICALS

SECOND-GENERATION BIOLOGICALS

FOLLOW ON BIOLOGICALS FOLLOW-ON BIOLOGICALS

BIOSIMILARS

53

TEVA (US)FILGRASTIM (TBO-FILGRASTIM)

FULL NDA APPROVAL

CURRENT DRUG NAMES

SANOFI (US)ZALTRAP (ZIV-AFLIBERCEPT)

TYROSINE KINASE INHIBITORS NAMING CONVENTIONPONATINIB AND PAZOPANIB

WHO (OCT 2013)LEANING TOWARD “GENERIC + SUFFIX”

EU NAMINGALLOWS THE BIOSIMILAR TO USE THE SAME NONPROPRIETARY NAME AS REFERENCE

CAN LEAD TO UNMONITORED SUBSTITUTION

UK ADVISED PHYSICIANS TO PRESCRIBE BY BRAND NAME TO PREVENT AUTO-SUBSTITUTION

SANDOZ (20 5)SANDOZ (2015)

FILGRASTIM-SNDZ

“SHOULD NOT BE VIEWED AS REFLECTIVE OF THE AGENCY’S DECISION ON COMPREHENSIVE NAMING POLICY FOR BIOSIMILAR AND OTHER BIOLOGICAL PRODUCTS.”

54



KEY PREMISE IDENTIFY RELATIONSHIP BETWEEN THE BIOSIMILAR AND

DRUG NAMING

REFERENCE ORIGINATOR THERAPEUTIC CATEGORY

DOSING

DIFFERENTIATE PRODUCTS

AVOID “SOUND ALIKE” AND “LOOK ALIKE” ERRORS

FACILITATE EFFECTIVE PRODUCT TRACKING AND TRACING (ANTI-COUNTERFEITING) IMPORTANCE OF CONFIGURING IT SYSTEMS TO BE ABLE TO

TRACK SPECIFIC PRODUCTS

CAN THE USE OF CODES HELP PHARMACOVIGILANCE EFFORTS?

FDA GUIDANCE NEXSYMEO (REPLICAMAB-CZNM) IS BIOSIMILAR* TO JUNEXANT

(REPLICAMAB-HJXF) FOR THE 285 INDICATIONS LISTED

BIOSIMILAR MEANS THAT THE BIOLOGICAL PRODUCT IS APPROVED BASED ON DATA DEMONSTRATING 290 THAT IT IS HIGHLY SIMILAR TO AN FDA-APPROVED BIOLOGICAL PRODUCT, KNOWN AS A REFERENCE 291 PRODUCT, AND THAT THERE ARE NO CLINICALLY MEANINGFUL DIFFERENCES BETWEEN THE BIOSIMILAR 292 PRODUCT AND THE REFERENCE PRODUCT

55

EUROPEAN PHARMACOVIGILANCE

• MONITOR AND REPORT

• CORRECT ASSESSMENT OF SAFETY EVENT

• MEDICATION RECONCILIATION FOR ALL PROVIDERS

• CONSIDER TRANSITIONS OF CARE

• CURRENT DOSES TO BE CONSIDERED, HOW USED

• EVALUATION OF OUTCOME MEASURES

56



MANUFACTURING BIOLOGICS: SOURCES OF VARIATION

57

Adapted from Mellstedt H, et al. Ann Oncol. 2008;19:411-419.

ORIGINATOR MANUFACTURING PROCESS CHANGES

Pre-change

Post-change

5

4

3

Acidicvariants

Basicvariants

G2F

(1,6)G1F

Darbepoetin alfa Rituximab Etanercept

Capillary ZoneElectrophoresis

Cation ExchangeChromatography

Glycan MappingChromatogram

Post change

Post-change

Pre-change

Pre-change

Post-change

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

variants variants

G0

G2

Man5

G0F (1,3)G1F

• 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

Schiestl M, et al. Nat Biotechnol. 2011;29:310-312.

58



IMMUNOGENICITY CONCERNS

• ALL BIOLOGICS CONFER A RISK OF IMMUNOGENICITY

• RELATED TO PATIENT, DISEASE, AND PRODUCT FACTORS

• CONSEQUENCES INCLUDE NEUTRALIZING ANTIBODIES OR CYTOKINE RELEASE

SCIENTIFIC TOOLS FOR DETECTING IMMUNOGENICITY EXIST BUT THEY ARE • SCIENTIFIC TOOLS FOR DETECTING IMMUNOGENICITY EXIST, BUT THEY ARE NOT PRECISE

• CHANGES TO THE STRUCTURE OF THE PROTEIN INCREASE VARIATION IN IMMUNOGENICITY

• LOT-TO-LOT AND BETWEEN MANUFACTURERS

• VARIATIONS IN MANUFACTURING MUST BE MINIMIZED

• CLINICAL CONSEQUENCES:

• LOSS OR DIMINISHED EFFICACY OR SAFETY

• CASE REPORTS OF RARE BUT SERIOUS ADVERSE REACTIONS HAVE BEEN REPORTED

59

U.S. FDA. Immunogenicity Assessment for Therapeutic Protein Products. August 2014. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf

COMPARATIVE CLINICAL STUDIES

• CLINICAL IMMUNOGENICITY

• GOAL IS TO EVALUATE POTENTIAL DIFFERENCES IN INCIDENCE AND SEVERITY OF IMMUNE RESPONSES USING ENDPOINTS SUCH ASSEVERITY OF IMMUNE RESPONSES USING ENDPOINTS SUCH AS ANTIBODY FORMATION (BINDING, NEUTRALIZING), CYTOKINE LEVELS, ETC.

• FDA RECOMMENDS A COMPARATIVE PARALLEL STUDY

• 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• 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.

60



80

PRCA cases associated with Eprex

ONE CHANGE IN THE FORMULATION OF AN ESTABLISHED BIOPHARMACEUTICAL LED TO

UNPREDICTED IMMUNOGENICITY

Num

ber

of P

RCA

cas

es Substitute polysorbate 80

for HSA

20

40

60 Coated rubber syringe stoppers

Boven K, et al. Nephrol Dial Transplant. 2005;20 Suppl 3:iii33-40. Locatelli F, et al. Perit Dial Int. 2007;27(S2):S303-S307.

N

0

20

<1997 1998 1999 2000 2001 2002 200361

HOW TO WE CURRENTLY MITIGATE THIS RISK?

• THERE IS HIGH CONFIDENCE IN THE MANUFACTURING OF BIOLOGICAL PRODUCTSBIOLOGICAL PRODUCTS

• MOST CLINICIANS DO NOT EXPECT THERE TO BE DIFFERENCES WITH EFFICACY/SAFETY FROM LOT-TO-LOT

• MANUFACTURING PROCESS CHANGES ARE REGULATED: FDA GUIDANCE DOCUMENTS ADDRESS PROCESS CHANGES INTRA-MANUFACTURER

WHAT HAPPENS WITH INTER MANUFACTURER CHANGES?• WHAT HAPPENS WITH INTER-MANUFACTURER CHANGES?

• NEEDS TO BE REGULATED

• FDA NEEDS TO PROVIDE GUIDANCE

62



EUROPEAN BIOSIMILARS EXPERIENCE

Active Substance Products Approval

Epoetin alfaAbseamed

BinocritEpoetin Alfa Hexal

8/20078/20078/2007Epoetin Alfa Hexal 8/2007

Epoetin zetaRetacritSilapo

12/200712/2007

Filgrastim

AccofilBiograstim

Filgrastim HexalGrastofilNivestim

RatiograstimTevagrastim

Zarzio

9/20149/20082/2009

10/20136/20109/20089/20082/2009Zarzio 2/2009

Follitropin alfaBemfolaOvaleap

3/20149/2013

InfliximabInflectraRemsima

9/20139/2013

Insulin glargine Abasaglar/Abasria 9/2014

Somatropin Omnitrope4/2006

63

BIOSIMILARS

• NON-ONCOLOGIC INDICATIONS

• INFLIXIMAB

• ADALIMUMAB

• INSULIN GLARGINE (COMING TO A PHARMACY NEAR YOU)

• HEMATOLOGY/ONCOLOGY

• RITUXIMABRITUXIMAB

• BEVACIZUMAB

• TRAZSTUZUMAB

64



EXTRAPOLATION IN RITUXIMAB

• FROM “BIOSIMILARS: WHAT CLINICIANS SHOULD KNOW”• “EXTRAPOLATION OF EFFICACY AND SAFETY DATA TO OTHER INDICATIONS • EXTRAPOLATION OF EFFICACY AND SAFETY DATA TO OTHER INDICATIONS

OF THE REFERENCE PRODUCT THAT HAVE NOT BEEN INVESTIGATED DURING THE CLINICAL DEVELOPMENT OF THE BIOSIMILAR ALWAYS REQUIRES CONVINCING SCIENTIFIC JUSTIFICATION, WHICH SHOULD ADDRESS THE MECHANISM OF ACTION, TOXICITIES, AND IMMUNOGENICITY IN EACH INDICATION OF USE.”

• WITH A RITUXIMAB BIOSIMILAR CAN WE EXTRAPOLATE:• FROM NON-MALIGNANT USE (EG, RA) TO LYMPHOMA?

• FROM USE IN LYMPHOMA TO AUTOIMMUNE DISEASE?

• FROM SINGLE AGENT TO COMBINATION?

• FROM COMBINATION TO SINGLE AGENT?

Weise M, et al. Blood. 2012;120(26):5111-5117.

Zelenetz A. Presentation to NYAS March 2012.

65

INFLIXIMAB INFLIXIMAB IS A CHIMERIC MONOCLONAL ANTIBODY AGAINST TUMOUR

NECROSIS FACTOR ALPHA (TNF-Α)

INFLIXIMAB WAS APPROVED BY THE US FOOD AND DRUG ADMINISTRATION (FDA)

IN AUGUST 1998 AND BY THE EUROPEAN MEDICINES AGENCY (EMA) IN AUGUST IN AUGUST 1998 AND BY THE EUROPEAN MEDICINES AGENCY (EMA) IN AUGUST

1999

THE PATENTS ON REMICADE EXPIRE IN THE US IN SEPTEMBER 2018 AND IN EUROPE

IN FEBRUARY 2015

NUMEROUS LABELLED INDICATIONS

CROHN’S DISEASE

ULCERATIVE COLITIS ULCERATIVE COLITIS

RHEUMATOID ARTHRITIS IN COMBINATION WITH METHOTREXATE

ANKYLOSING SPONDYLITIS

PSORIATIC ARTHRITIS

PLAQUE PSORIASIS 66



CT-P13 (REMSIMA®, INFLECTRA®)

• CT-P13 (REMSIMA®, INFLECTRA®), THE FIRST BIOSIMILAR INFLIXIMAB, WAS APPROVED BY THE EMA IN ALL THE INDICATIONS GRANTED TO THE RMPTHE RMP

• APPROVAL WAS BASED ON AN EXTENSIVE AND COMPREHENSIVE COMPARATIVE PROGRAM, INCLUDING TWO PIVOTAL RANDOMIZED CONTROLLED TRIALS (RCTS) FOR RA AND AS

• PLANETRA [PROGRAMME EVALUATING THE AUTOIMMUNE DISEASE INVESTIGATIONAL DRUG CT-P13 IN RA PATIENTS]

• PLANETAS [PROGRAMME EVALUATING THE AUTOIMMUNE DISEASE INVESTIGATIONAL DRUG CT-P13 IN AS PATIENTS]

• THESE TWO STUDIES DEMONSTRATED EQUIVALENCE IN EFFICACY AND PHARMACOKINETICS (PK) BETWEEN CT-P13 AND RMP AND CONFIRMED THAT THE TWO AGENTS ARE HIGHLY COMPARABLE IN TERMS OF SAFETY.

Yoo DH, Oh C, Hong S et al. Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal Product. Expert Review of ClinicalImmunology 2015; 11:sup1, 15-24.

67

OVERVIEW OF INFLIXIMAB CLINICAL STUDIES

Protocol Design Objectives Treatment Study population

CT-P13 1.2 (pilot study) Prospective Phase 1, randomised double-blind, parallel-group, multiple single-dose intravenous (i.v.)

Primary: To determine Cmax, PK profiles of CT-P13 and Remicade at Weeks 0, 2 and 6 Secondary: PK profile, PD,

CT-P13 plus MTX or Remicade plus MTX

RA patients with active disease while receiving MTX Planned: 20 g ( )

infusion, multicentre y p

efficacy, and safety of CT-P13 in comparison to Remicade up to Week 102.

Randomised: 19 CT-P13: 9 Remicade: 10

CT-P13 1.1 PK equivalence (Study name: PLANET AS)

Prospective Phase 1, randomised, double-blind, multicentre, multiple single-dose i.v. infusion, parallel-group

Primary: To demonstrate comparable PK at steady state in terms AUCτ, Cmax,ss between CT-P13 and Remicade determined between Weeks 22 and 30. Secondary: long-term efficacy, PK and overall safety up to Week 54

CT-P13 or Remicade AS patients with active disease Planned: 246 (ratio: 1:1) Randomised: 250 CT-P13: 125 Remicade: 125

CT-P13 3.1 Prospective Phase 3, Primary: To demonstrate that CT- CT-P13 plus MTX or RA patients with active CT P13 3.1 Therapeutic equivalence (Study name: PLANET RA)

Prospective Phase 3, randomised, double-blind, multicentre, multiple single-dose i.v. infusion, parallel-group

Primary: To demonstrate that CTP13 is equivalent to Remicade, in terms of efficacy as determined by clinical response according to ACR20 at Week 30. Secondary: long-term efficacy, PK, PD, and overall safety up to Week 54

CT P13 plus MTX or Remicade plus MTX

RA patients with active disease while receiving MTX Planned: 584 (ratio: 1:1) Randomised: 606 CT-P13: 302 Remicade: 304

68



THE PLANET RA STUDY

• THE PRIMARY ENDPOINT, ACR20 RESPONSE AT WEEK 30, WAS EQUIVALENT BETWEEN TREATMENT GROUPS AND ACHIEVED IN 60 9% AND 58 6% IN ITT (N 606 95% CI 6% TREATMENT GROUPS AND ACHIEVED IN 60.9% AND 58.6% IN ITT (N=606, 95% CI −6% TO 10%) AND 73.4% AND 69.7% IN PP POPULATION (N=499, 95% CI −4% TO 12%) FOR CT-P13 AND INX, RESPECTIVELY

• EQUIVALENT RESULTS WERE ALSO SHOWN FOR ACR RESPONSES IN THE PP POPULATION AT WEEKS 14 AND 30 FOR CT-P13 AND INX, RESPECTIVELY

• MEAN IMPROVEMENTS FROM BASELINE FOR ADDITIONAL SECONDARY EFFICACY ENDPOINTS INCLUDING CDAI AND SDAI (CT-P13 (25.2 AND 25.8) VS INX (23.6 AND 24.4) AT WEEK 30, RESPECTIVELY) WERE EQUIVALENT AT WEEKS 14 AND 30 BETWEEN TREATMENT GROUPSTREATMENT GROUPS

• OVERALL, NO STATISTICALLY SIGNIFICANT DIFFERENCES IN RESPONSES BETWEEN THE TWO TREATMENT GROUPS WERE FOUND

Ann Rheum Dis. 2013 Oct; 72(10): 1613–1620.69

INFLIXIMABPLANETRA/PLANETAS

Incidence rate, n/N (%) Incidence rate, 100 PY

CT-P13 RMP CT-P13 RMP

All infections RA 127/302 (42.05%) 137/300 (45 67%)

39.97 43.62(45.67%)

AS 55/128 (42.97%) 49/122 (40.16%)

38.76 36.04

All serious infections

RA 13/302 (4.3%) 7/300 (2.33%)

4.09 2.23

AS 2/128 (1.56%) 3/122 (2.46%)

1.41 2.21

Malignancy RA 1/302 (0.33%) 4/300 0.31 1.27

and lymphoma

(1.33%)

AS 1/128 (0.78%) 0/122 0.70 0.00

Infusion-related reaction

RA 30/302 (9.93%) 43/300 (14.33%)

9.44 13.69

AS 11/128 (8.59%) 15/122 (12.3%)

7.75 11.03

70



INFLIXIMAB INTERCHANGEABILITY

• IN THE STUDY BY SOKKA AND COLLEAGUES

• 39 RA AND AS PATIENTS WERE SWITCHED FROM THE RMP TO BIOSIMILAR INFLIXIMAB AFTER A MEAN (SD) OF 4.1 (2.3) YEARS OF TREATMENT WITH THE RMP.

• PATIENTS’ SYMPTOM LEVEL AND DISEASE ACTIVITY ON AUC WERE SIMILARDURING INX AND INB, AND LOWER COMPARED TO VALUES BEFORE BIOLOGIC THERAPIES

• EFFECTIVENESS OF INB APPEARED SIMILAR TO INX OVER A MEDIAN OF 11MONTHS IN PATIENTS WHO SWITCHED FROM INX TO INB.

• NO IMMEDIATE SAFETY SIGNALS WERE OBSERVED LARGER CLINICAL • NO IMMEDIATE SAFETY SIGNALS WERE OBSERVED. LARGER CLINICAL COHORTS AND LONGER FOLLOW-UP ARE NEEDED TO CONFIRM SAFETY OF INB.

https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=25211271

INFLIXIMAB EUROPEAN APPROVAL

• EXTENSIVE ANALYTICAL TESTS SHOWED PHYSICOCHEMICAL AND STRUCTURAL COMPARABILITY EXCEPT FOR A SMALL DIFFERENCE IN THE PROPORTION OF A FUCOSYLATED FORMS. THE BIOSIMILAR AND THE REFERENCE INFLIXIMAB DEMONSTRATED COMPARABLE BINDING TO COMPLEMENT AND THE REFERENCE INFLIXIMAB DEMONSTRATED COMPARABLE BINDING TO COMPLEMENT RECEPTOR AND ALL TYPES OF FC-RECEPTORS EXCEPT FOR FCΓRIIIA/B, TRANSLATING INTO LOWER ADCC ACTIVITY. SIMILAR DIFFERENCES IN ADCC AND GLYCOSYLATION HAVE BEEN OBSERVED AS A RESULT OF CHANGES IN THE MANUFACTURING PROCESS OF THE ORIGINAL RITUXIMAB

• THE MAIN MODE OF ACTION IN ALL THERAPEUTIC INDICATIONS IS BINDING TO THE SOLUBLE AND/OR THE MEMBRANE-BOUND TNFΑ, WHICH WAS COMPARABLE IN THE BIOSIMILAR AND THE REFERENCE INFLIXIMAB

• SUPPLEMENTARY TESTS SHOWED SIMILAR INHIBITION OF DIRECT EFFECTS OF TNFΑ ON EPITHELIAL CELLS THAT PLAY AN IMPORTANT ROLE IN CROHN’S DISEASE

• THE BIOSIMILAR AND THE REFERENCE MEDICINE DISPLAYED A SIMILAR INDUCTION OF REGULATORY MACROPHAGES, WHICH ARE IMPLICATED AS A MODE OF ACTION OF INFLIXIMAB IN IBD

• BIOEQUIVALENCE AND COMPARABLE SAFETY, EFFICACY AND IMMUNOGENICITY OF THE BIOSIMILAR AND THE REFERENCE INFLIXIMAB WERE DEMONSTRATED IN TRIALS CARRIED OUT IN PATIENTS WITH ANKYLOSING SPONDYLITIS AND RHEUMATOID ARTHRITIS

72



BIOSIMILAR PHARMACOVIGILANCE

Risk Identification andcharacterization

Pharmacovigilance• Practical to encourage

healthcare provider reporting

• Real-time data• Ensure traceability

Pharmacovigilance• Practical to encourage

healthcare provider reporting

• Real-time data• Ensure traceability

Risk minimization• Healthcare provider

communication• Recalls and alerts• REMS?

Risk minimization• Healthcare provider

communication• Recalls and alerts• REMS?

FDA Approval

Healthcare Provider Responsibility for Reporting• Correct attribution of safety event• Maintenance of EMR• Bar code administration• Medication reconciliation• Consideration of transitions of care

Healthcare Provider Responsibility for Reporting• Correct attribution of safety event• Maintenance of EMR• Bar code administration• Medication reconciliation• Consideration of transitions of care 73

Zuñiga L, Calvo B. Pharmacoepidemiol Drug Saf. 2010 Jul;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.

INTERCHANGEABILITY• STANDARDS FOR DETERMINING INTERCHANGEABILITY

• MUST BE A BIOSIMILAR

• PRODUCES SAME CLINICAL RESULT AS THE REFERENCE IN ANY GIVEN PATIENT

• RISK OF SAFETY OR DIMINISHED EFFICACY DUE TO ALTERNATING OR SWITCHING BETWEEN BIOSIMILAR AND REFERENCE IS NO MORE THAN USING THE REFERENCE PRODUCT WITH NO SWITCHING

• WILL BE “DIFFICULT” IN THE INITIAL 351(K) APPLICATION DUE TO THE SEQUENTIAL NATURE OF THE ASSESSMENT

• APPROPRIATE TO BE “SUBSTITUTED FOR THE REFERENCE PRODUCT WITHOUT THE INTERVENTION OF THE HEALTH CARE PROVIDER WHO PRESCRIBED THE REFERENCE PRODUCT”

PHS Act, section 351(k)(4). http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf. Accessed May 2014.


74



INTERCHANGEABILITY STUDY DESIGN

• FDA INTERCHANGEABILITY CRITERIA: SWITCH BETWEEN REFERENCE (R) AND BIOSIMILAR (B) WITH NO CLINICAL CONSEQUENCESWITH NO CLINICAL CONSEQUENCES

• WHAT IS SWITCHING?R B B R B

B R R B R

R R

B B

A O S S GNS O OS• VARIOUS DESIGNS PROPOSED• STANDARD TWO-SEQUENCE, TWO-PERIOD

CROSSOVER

• BALAAM’S 4 X 2 CROSSOVER DESIGN

Chow SC, et al. Stat Med. 2013;32(3):442-448.

75

STRATEGIES FOR STAKEHOLDERS

• DEVELOP STAKEHOLDER ENGAGEMENT PLAN (BY STAKEHOLDER AND MARKET) TO BEGIN SHAPING MINDS/CHANGING BEHAVIORS

• EVALUATE THE FOLLOWING AS YOU DEVELOP YOUR ENGAGEMENT PLAN, FOR EACH STAKEHOLDER, BY MARKET:

• PHYSICIANS: TREATMENT GUIDELINES; PRESCRIBING INCENTIVES; IMPACT OF REAL-WORLD DATA/EXPERIENCE; IMPACT OF COST

• PAYERS: INFLUENCE ON POLICY AND ABILITY TO IMPLEMENT QUOTAS, TENDERS, ETC.; EXISTENCE AND USE OF TOOLS SUCH AS HTAS; WILLINGNESS TO ADOPT BIOSIMILAR BASED ON EXISTING/ REAL-WORLD DATA; IMPACT OF CREATIVE PRICING STRATEGIES

• PATIENTS: ABILITY TO INFLUENCE PRESCRIBING DECISION-MAKING; WAYS PATIENTS PATIENTS: ABILITY TO INFLUENCE PRESCRIBING DECISION MAKING; WAYS PATIENTS INTERACT WITH THE HEALTHCARE SYSTEM AND EACH OTHER (SOCIAL MEDIA), ETC.

76




• PROVIDE COMMERCIAL/MARKETING SUPPORT TO BIOSIMILAR

PRODUCT AS REQUIRED (BY STAKEHOLDER, MARKET)

• CONTINUE TO COMPETE BY PROVIDING VALUE-ADDED SERVICES

SUCH AS

• DEVICE IMPROVEMENTS

• CONVENIENCE

• SUPPORT SERVICES (EDUCATION, NURSE SUPPORT, ETC.) FOR HCPS AND

PATIENTS

http://www.quintiles.com/~/media/library/white%20papers/an-integrated-approach-to-biosimilar-development-amp-commercialization.pdf [Accessed April 1st, 2016]

77


• COUNTERING MISINFORMATION ON BIOSIMILARS

• THE MISINFORMATION IS GOING TO PREVENT FEAR AND DOUBT OVER

BIOSIMILARS.

• GOALS FOR CONTENT WOULD BE TO PREVENT SAFETY ISSUES AND

ALSO TAKE CONTENT FROM LARGER CLINICAL STUDIES

78



EXAMPLE OF MISINFORMATION

THE CHALLENGE OF BIOSIMILARS MELLSTEDT, NIEDERWIESER, ET.AL. ANN ONCOL 2008 19 (3) 411 419 (CONT )2008 19 (3): 411-419 (CONT.)

THE “CONCLUSIONS” SECTION OF THE MAIN ARTICLE CLARIFIES THE AGENDA OF THIS “LITERATURE REVIEW ” (WHICH HAS BEEN CITED 53 TIMES)

• “THERE ARE POTENTIAL CONCERNS REGARDING THE USE OF BIOSIMILARS IN PATIENTS WITH CANCER…”

• “…AUTOMATIC SUBSTITUTION SHOULD BE PROHIBITED…”

• “…EXTRAPOLATION OF CLINICAL DATA FROM ONE THERAPEUTIC INDICATION TO ANOTHER…WARRANTS CONCERN.”

79

SUMMARY

• NEW BIOSIMILAR THERAPIES ARE EXPECTED TO HIT THE MARKET OVER THE NEXT FIVE YEARS WITHIN MULTIPLE TREATMENT AREAS CURRENTLY PROGRESSING THROUGH PHASE I AND PHASE III STUDIES

• THE ROLE OF THESE NEW BIOLOGICS WILL BECOME IMPORTANT IN ADDRESSING THE CLINICAL STUDIES FOR EACH INDICATION, BUT UNDERSTANDING THE EXTRAPOLATION OF THE CONTENT FOR OTHER INDICATIONS WILL BE INCREASING IMPORTANT TO REVIEW

• ADDRESSING THE INTENT OF THERAPY, SUPPORTIVE CARE VERSUS THERAPEUTIC INTENT, WILL CONTINUE TO BE SCRUTINIZED AND QUESTION IN REGARDS TO TREATMENT OUTCOMES BASED ON STUDY WILL NEED TO BE REVIEWED

80



Biosimilars ‐Managing the Products d th P t ti l f C f i dand the Potential for Confusion and

Misinformation

April 20, 2016

81

Outline• Cacophony: Professional organizations, State regulation, and P&T Committee

Fi i l i li ti• Financial implications

• Case example

• Operational barriers

• Pharmacovigilance

• Transitions

• Summary

82



Who Is The Expert?

83

Biosimilars Position Statements From Stakeholder Medical Professions

“It is uncertain whether patients will respond to these drugs the same way they would to an original biologic, because biologics are very sensitive to manufacturing changes.”

‐‐‐American College of Rheumatology1

“No system should be adopted that would limit physician choice among biosimilar products or require substitution of products that have been designated interchangeable:”

‐‐‐American Society of Clinical Oncology2

“ The prescribing physician provides explicit permission to the pharmacist that a biosimilar may be used as a substitute to the original medication.”

‐‐‐American Academy of Dermatology3

“The pharmacy and the prescribing physician are to retain a permanent record in the

1. American College of Rheumatology. Position statement on biosimilars. http://www.rheumatology.org/Practice‐Quality/Administrative‐Support/Position‐Statements. Accessed November 13, 2015.2. American Society of Clinical Oncology. ASCO policy brief: biosimilars. http://www.asco.org/advocacy/policy‐statements. Accessed November 13, 2015.3. American Academy of Dermatology. Position statement on generic therapeutic & biosimilar substitution. https://www.aad.org/Forms/Policies/ps.aspx. Accessed November 13, 2015.4. National Psoriasis Foundation. Position statement on biosimilar substitution.. https://www.psoriasis.org/about‐psoriasis/treatments/statement‐on‐biosimilars Accessed November 13, 2015.

p y p g p y ppatient's medical record of the biosimilar substitution.”4

‐‐‐The National Psoriasis Foundation

84



Biosimilar Position Statements: Pharmacy Profession

“Support balance between bringing safe and effective drugs to market and maximizing patient access to affordable drugs.”

“Manufacturers should be allowed to use the same government‐approved name/international nonproprietary name as the reference product:”/ p p y f p

“The FDA should determine a two‐step process, with the first step determining the biosimilarity and the second step the interchangeability with the reference product.”

“Interchangeability should not be a requirement for approval.”

“The Academy opposes unnecessary requirements for prescriber notification of the product dispensed when the FDA has designated the products as interchangeable.”

1. Academy of Managed Care Pharmacy. AMCP position statement on biosimilar drug therapies. Available at: http://www.amcp.org/PositionStatements/. Accessed November 13, 2015.

85

American College of Rheumatology Position Statement 4/2016

• Biosimilars require a greater scrutiny in their evaluation than small molecule generics.

• Clinical data are necessary to ensure safety & efficacy and confidence for their use.

• Long‐term, post‐marketing data is necessary to monitor for less common but important adverse events.

• Surveillance studies are needed in children and adults, as toxicities and long‐term sequelae may be , g q ydifferent in these disparate populations.

• The decision to substitute a biosimilar product should only be made by the prescribing provider.

• In jurisdictions where substitution is lawful, the prescribing provider and the patient should be notified immediately when a substitution is made.

• Providers must retain the right to write “dispense as written”.

• The ACR does not endorse switching stable patients to a biosimilar for cost saving reasons without advance consent from the prescribing provider and knowledge of the patient.

• Biosimilars must have distinct names allowing them to be distinguished from each other for post‐marketing pharmacovigilance.

• Extrapolation of indications for biosimilars should not be routinely granted by the FDA.

• In 32 contrast, off‐label use of biosimilars may be appropriate when deemed by the prescribing provider to be clinically appropriate and in the best interests of the patient.

• FDA labels (package inserts) should clearly indicate whether a biosimilar is interchangeable with the reference (originator) biologic and delineate all indications for which a biosimilar is approved.

American College of Rheumatology. Available at: http://www.rheumatology.org/Practice‐Quality/Administrative‐Support/Position‐Statements.

86



Position paper from Health and Public Policy Committee to address escalating costs of prescription medications.g p pRecommendations: “Policy should aim to limit patient confusion between originator and biosimilar product.”“Policy should ensure safe use of biosimilar products”“Policy should promote the integration of biosimilar use into clinical practice”.

Daniel H. Ann Intern Med 2016: DOI:10.7326/M15‐2768.

Problems:Lack of price, cost, value transparencyRegulatory processLack of competitionPrice increasesLack of available biosimilars

87

NCCN Work Group Consensus Statement

Source: Zelentz, AD. JNCCN 2011;9{Suppl 4]:S1‐11.

88



NCCN Work Group Consensus and Recommendations

Source: Zelentz, AD. JNCCN 2011;9{Suppl 4]:S1‐11.89

As with other drugs, an institution’s P&T Committee should review biosimilar products for use in their own specific patient population.

NCCN Work Group Consensus and Recommendations

p p p p

Source: Zelentz, AD. JNCCN 2011;9{Suppl 4]:S1‐11. 90



Pharmacy and Therapeutics Committee

Source: Brigham and Women’s Hospital

91

Legislation on Biologics and Biosimilar Substitution, 2013‐2016

Common Features of State Legislation

•Must FDA approved as "interchangeable“ for substitution.•The prescriber prevents substitution by stating “dispense as written” or “brand medically necessary.”Th ib t b tifi d f•The prescriber must be notified of any substitution ("communicate with“).•Patient must be notified of a substitution or switch . •State law may require patient consent before any such switch is made.•RPh and MD must retain records of substituted biologic medications.•Immunity for pharmacists who make a

The National Conference on State Legislatures. Available at: http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx

Immunity for pharmacists who make a substitution in compliance with biologics state law.•The state must maintain a public or web‐based list of permissible interchangeable products.• RPh explain the price of the biologic and the interchangeable biosimilar.

92



Familiarity with Biosimilars and Related Legislation

Source: Zelentz, AD. JNCCN 2011;9{Suppl 4]:S1‐11.

93

The Purple Book• The “Purple Book” lists biological products and includes;

– Any biosimilar and interchangeable biological products licensed by FDA under the Public Health Service Act (the PHS Act).

– The date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act.

– To see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already‐licensed FDA biological product).

– Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.

• Separate lists for those biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm 94



Average Relative Price (average generic/brand)

94%

80%

90%

100%

%

Economics of Generic Drugs1‐2

52%

44%

39%

33%

26%23%

21% 20%

26%22%

20%24%

16%13%

11%

20%

30%

40%

50%

60%

70%

Ave

rag

e R

elat

ive

Pri

ce p

er D

ose

, %

11%9% 8%

6%

0%

10%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Number of Generic Manufacturers

1. Americas Health Insurance Plans. Generic Drug Savings in the US (4th Edition 2012). Available at: http://www.ahipcoverage.com/wp‐content/uploads/2012/08/2012‐GPHA‐IMS‐GENERIC‐SAVINGS‐STUDY.pdf. Accessed November 16, 2015.2. IMS Institute for Health Informatics. Medicine use and shifting costs of healthcare A review of the use of medicines in the United States in 2013. Available at: https://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMS%20Health%20Institute/Reports/Secure/IIHI_US_Use_of_Meds_for_2013.pdf. Accessed November 16, 2015. 95

Generic Drugs Capture Over 80% of Brand Drug Volume in 6 Months1‐3

1. Americas Health Insurance Plans. Generic Drug Savings in the US (4th Edition 2012). Available at: http://www.ahipcoverage.com/wp‐content/uploads/2012/08/2012‐GPHA‐IMS‐GENERIC‐SAVINGS‐STUDY.pdf. Accessed November 16, 2015.2. IMS Institute for Health Informatics. Medicine use and shifting costs of healthcare A review of the use of medicines in the United States in 2013. Available at: https://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMS%20Health%20Institute/Reports/Secure/IIHI_US_Use_of_Meds_for_2013.pdf. Accessed November 16, 2015.3. Graabowski , et al. Brief report : recent trends in brand‐name and generic drug competition. J Med Econ 2013:1‐8.

96



Misaligned IncentivesHospital Infusion Center Physician Office Hospital +/‐ Cancer Center

Providers

Reimbursement: ASP+6% Reimbursement: ASP+6% DRG or Exemption

Goal: Revenue enhancement Goal: Revenue enhancement Goal: Cost Containment

Drug Choice: Brand Drug Choice: Brand Drug Choice: Generic, g gBiosimilar, Equal outcome at lowest cost

Payor: Specialty Pharmacy Payor: Specialty Pharmacy Payor: Hospital Pharmacy

Benefit: Shift to Pharmacy Benefit: Shift to Pharmacy Benefit: Medical

Insurers

Vendors

Goal: Sales Goal: Sales Goal: Sales 97

Medicare Part B Biosimilar Biological Product Payment and Required Modifiers

milar Average

Sales Price of

Common HCPCS Code +

6% of the Average Sales =

Filgrastim‐sndz

Filgrastim

‐B Biosim Sales Price of all NDC codes

and payment limit

+Price of the Reference product

(Neupogen©)*

* Incentive to use Biosimilar

Modifier that identifies the manufacturer.

https://www.cms.gov/Medicare/Medicare‐Fee‐for‐Service‐Part‐B‐Drugs/McrPartBDrugAvgSalesPrice/Part‐B‐Biosimilar‐Biological‐Product‐Payment.html

Same Billing Code

Biosimilar HCPCS Code Product Brand names

Corresponding Required Modifier

Q5101 Injection, Filgrastim (G‐CSF), Biosimilar, 1 microgram

Zarxio© ZA‐Novartis/Sandoz

Example:

98



Supply Chain to Pharmacies and Patients

Category Pricing Marketshare

Brand Cost less

12 % of unit

0‐6% volume75% of $ volume

Generic Cost less 0.6%

85% ofunit volume15% of $ volume

Specialty Cost or 3% of p yCost plus

unit volume10% of $ volume

Source: Economic report on Retail and Specialty Pharmacies 2011‐2012.Available at: http://drugchannelsinstitute.com/products/industry_report/pharmacy/

99

Part B Drug Payment Model‐Proposed• Background

– Part B payments for drugs totaled $22 bil (8% ↑ since 2007)

– Growth driven by OP hospital setting

• Phase 1: Test change

– Control group

– Study group receives 2.5% ASP add‐on + $16.80 per drug per day paymentsetting

– ASP methodology flawed

• CMS proposing 2‐phase model– Whether modified ASP add‐

on payment in MD offices and Hospital OP strengthens financial incentive to choose higher value drugs

payment

• Phase 2: Use VBP tools

• Clinical decision support tools

• Value base pricing strategies (reference pricing, discounting coinsurance, etc).

• Participants– Whether alternative payment

approaches for Part B drugs:– Improves value– Improves outcomes– Reduces expenditures

https://www.federalregister.gov/articles/2016/03/11/2016‐05459/medicare‐program‐partb‐drug‐payment‐model#h‐51

• Physicians

• OP Hospitals

• DME suppliers

100



Part B Drug Payment Model‐ProposedPhase 1

Fall 2016

Phase 2 (Introduction of VBP)

2017 2018 2019 2020 2021

Rollout Full Implementation

Part B drugs/biologics areToolsVB Pricing Options

Description

* Flat fee issues per drug per day administered, $16.80 Phase 1, to be updated CY based on % increase in CPI.

Part B drugs/biologics are included that are priced under ASP and paid separately or via pass through.

VB Pricing OptionsReference pricing Equal pay for similar agents

Indications‐based pricing

Pricing based on effectiveness

Outcomes & risk sharing

Payers and vendor agreements linked to outcomes

Discounting Eliminate co‐insurance

Clinical Decision Support Standard med orders and tests (EBM)Preventive care and ADE alerts 101

Operational Barriers• MDs balk at off‐label use

– Lack of same FDA approvals

• Colony‐stimulating factors driven byColony stimulating factors driven by research protocols– IRB‐mandated amendments

• Treatments driven by order sets– Changes require IT resourcesg q

• Nomenclature in order entry system

• Clinician knowledge deficit

• Delivery systems and packaging102



Comparison of G‐CSF Agents1‐3

tbo‐filgrastim (Granix©)

filgrastim(Neupogen©)

filgrastim‐sndz (Zarxio©)

Indications •Nonmyeloid cancer patients receiving myelopsuppressive chemotherapy

•Nonmyeloid cancer patients receiving myelopsuppressive chemotherapy•AML patients receiving chemotherapy

•Nonmyeloid cancer patients receiving myelopsuppressive chemotherapy•AML patients receiving chemotherapy

•Cancer patients receiving BMT•Patients undergoing PBPC collection and therapy•Patients with severe chronic neutropenia

•Non‐myeloid cancer patients undergoing myeloblative chemotherapy followed by BMT •Patients undergoing PBPC collection and therapy•Patients with severe chronic neutropenia

Approval pathway BLA (2012) BLA (1991) Biosimilar (2015)

EU experience Biosimilar (2008) BLA (1991) Biosimilar (2009)

Dosage form and preparations

•300 mcg/0.5 mL in single‐use prefilled syringe •480 mcg/0.8 mL in single‐use prefilled syringe

•300 mcg/mL in a single‐use vial•480 mcg/1.6 mL in a single‐usevial

•300 mcg/0.5 mL in single‐use prefilled syringe•480 mcg/0.8 mL solution in single‐use prefilled syringe

1. Granix package insert. http://www.granixhcp.com/Pdf/prescribing‐information.pdf2. Zarxio package insert. http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe707775‐a0ae‐41b5‐a744‐28c41889fce8&type=display.3. Neupogen package insert. http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf

103

Colony Stimulating Factors

Source: Partners Healthcare Center for Drug Policy. Guidelines for Colony Stimulating Factors. Available at: http://handbook.partners.org/content/pdf/CDPGuidelines/Guidelines/CDP_ColonyStimulatingFactors.pdf

104



Drug Spend by Month

$250,000

$300,000

$50,000

$100,000

$150,000

$200,000

$0

Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Apr

G‐CSF TBO

Source: Brigham and Women’s Hospital, Pharmacy Department.

105

Nomenclature In Order Entry System

106



Manufacturer Drug Labeling and Packaging

107

Case• 49 YO F with Multiple Sclerosis (MS) maintained on Interferon Beta‐1A (Avonex©) IM 30 mcg every week.

• Third‐party prescription drug benefit change in injectable and infusion medications.

• Prescribed Interferon Beta‐1A (Rebif) IM 22 mcg three times per week.

• Dose increased to 44 mcg three gtimes per week.

• MRI images reveal expansion of lesions in CNS.

• Interferons are not all the same.

108



Pharmacovigilance• Academy of Managed Care Pharmacy (AMCP) convened a multidisciplinary task force.

• Goals: – Identify a system to monitor theIdentify a system to monitor the safety and effectiveness of biosimilar products after FDA approval.

–Provide consumers and clinicians with greater confidence in biosimilars.

–Determine the feasibility of launching a collective intelligence system to monitorintelligence system to monitor the safety and efficacy of biosimilars.

–Use available technologies, data sources, and observational research methods.

• Outcome:–Advisory council Task Force on Biosimilar Collective Intelligence

Systems J Manag Care Pharm. 2015;21(1):23‐34.

109

Post Marketing Surveillance‐Mini‐Sentinel Pilot

• The FDA Amendments Act mandated the development of an electronic surveillance system to track the safety of medications, biologics, and medical devices. once they reach the marketplace.they reach the marketplace. • In 2008, HHS and the FDA created the Sentinel Initiative.

• Actively managed post‐marketing monitoring system.

• Mini‐Sentinel pilot project integrates the FDA’s capabilities with those of multiple partners.

• Technical & methodologic support •Information for 50 million patientspatients.

• Data coordinating center can generate queries of disparate but standardized data sources for relevant product safety information.

• No longer limited to one healthcare system or one claims database.

Fanikos, J. J Thromb Thrombolysis 2016; 39:273‐287.

110



Transitions, Part One of Two

Issue• Insurers utilize step therapy or “fail first” policies that

require patients to try and fail one or more formulary‐covered medications before providing coverage for the originally prescribed non‐formulary or non‐preferred.

Practice• Step therapy or “fail first” tests use of a safe lower‐cost drug

before permitting more expensive drugs or services.

• When a patient changes insurers or a drug they are taking is• When a patient changes insurers or a drug they are taking is moved to a non‐preferred status, patients may be required to go through step therapy process again.

111

Options: • Permit a prescriber to override step therapy when

patients are stable, if the physician expects the treatment to be ineffective or cause harm based on the patients and disease characteristics

Transitions, Part Two of Two

patients and disease characteristics.• Require health plans to incorporate step therapy and

the override process in the preauthorization applications.

• Prohibit insurers from requiring patients to fail therapy more than once.

• Limit the initial step to 60 daysLimit the initial step to 60 days• Eliminate the need to repeat step therapy in a

successfully treated patient• When a health insurance plan changes formulary design,

the plan cannot limit or exclude coverage for a drug.

112



Administrative & operational support

Payers: Emphasis will be

Expansion

Ensure smooth

Building Strategies

Surveillance, Address therapeutic failures

placed on the strongestassurances of clinical safety and efficacy.

Focus on affordability and accessHeavily influenced by physician Patients: Increasingly concerned and

l

Vendors: Focus on long‐term relations ships and KOLs Highlight uncertainties

Counter detailEducate

Ensure smooth transitions

Physicians: Lack of experience with biosimilarsConservatism, Learning curve

Early vs Delayed vs Late AdoptionContain use to therapeutic use or small patient groupsEducation

y y p yguidance on biosimilarsvocal

113

Summary

• Numerous profession organizations statements, legislature in various stages. No

ifi d iunified voice.

• Finances and economics impacts decision making.

• Obstacles impede substitution.

Prepare to deal with and remove obstacles– Prepare to deal with and remove obstacles

– Be content with incremental gains

• Transitions of care represent problems

– Understand the different player perspectives114



U d t C tU d t C t PhPhUpdate on Current Update on Current Pharmacy Pharmacy Initiatives and StrategiesInitiatives and Strategies

116

Jerry H. Reed, MS, RPh, FASCP, FASHP

Corporate Director, Pharmacy Operations

Community Health Systems

117

Documents

Apr 20 2016 webinar COMBINED PRESENTATION …s3.proce.com/res/pdf/CHS/CHS2016AprHandout.pdf · ranibizumab (lucentis) 2015 2018 expired expired expired 2016 2019 2017 ... structure