Phil Johnson MS RPh

Safe School Meds, Principle Partner

Moffitt Cancer Center, Director of Pharmacy (Retired)

Biosimilar Drugs: Opportunities and Issues

The Community Oncology Alliance ConferenceMoving Forward on Payment Reform

April 23, 2015

Disclosures

• I have no financial relationships relevant to this program.

Learning Objectives

• Describe the molecular and manufacturing differences between biological versus traditional small-molecule drugs.

• Explain the regulatory landscape of biosimilars in the USA and Europe.

• Assess the factors to consider relevant to the interchangeability of biosimilars and indications for use.

• Discuss safety issues and key components of a successful pharmacovigilance program.

• Discuss financial implications with the advent of biosimilar drugs.

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

First Biotechnology Process

Yeast Fermentation 4,000 BC• Budweiser

• Amstel

• Heineken

• St. Pauli Girl

• Molson

Are these equivalent or interchangeable?

Biologics vs. Small Molecule Drugs

Mellstedt H. EJC Supplements 2013;11:1-11.

Small Molecule Synthesis: Aspirin

Manufacturing of Small Molecules

1. Chemical process based on a series of controlled and predictable chemical reactions

2. Process is standardized between manufacturers

3. Final structure easily verified

4. Contaminants are quantifiable

Biologic Categories

• Monoclonal antibodies• Complex sugars • Blood derivatives• Vaccines• Recombinant or purified proteins

– Cytokines– Thrombolytic agents– Enzymes

Biosimilar Manufacturing

• Several major steps included in development– Modifying the selected gene of interest– Inserting the desired gene into a specific host cell – Replicating cell line and increased protein

expression– Harvesting protein products from the cell– Purifying the selected protein

• More patents on the process than on the drug

Biosimilar Manufacturing

http://www.pharmqd.com Accessed 2014 Oct 16.

Similarities and Differences “Similar” vs. Reference Product

BIOSIMILAR Specification Comparison with REFERENCE

Formulation May be different

Delivery device/container May be different

Routes of administration Licensure depends on application

Conditions of use Licensure includes all indications for reference product (recent precedent)

Strength Must be the same

Specific potential molecular differences

Amino acid substitution N- and C-terminal modifications Mismatched disulfide bonds Post-translation modifications folding

Carboxylation FormylationGlycosylation Methylation Phosphorylation

PEGylation

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259809.htm

Are biosimilar drug issues new ?Which, if any, are relevant to current discussion?

• Human Growth Hormone – First to be substituted

• Human Insulin – Many choices, little hesitation to interchange

• Interferon Alpha 2a, 2b, Beta, Gamma– Payer directed formulary equivalence / interchange

• Influenza Vaccine– Multiple manufacturers; you provide what you can get

• Heparin – Harvested, purified, equivalence by batch

• Low molecular weight heparin (LMWH) – Significant dosing issues when interchanged

• Anti-infectives– Therapeutic Class representative for sensitivity tests

• CMS considered erythropoietin and darbepoetin “Functional Equivalents”

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

Hatch-Waxman Amendments to Federal Food Drug and Cosmetic Act (FDCA)-

1984

• Allowed generic firm to use safety and efficacy data of innovator drug after expiration of patents and exclusivities

• A generic must have the same indications, strength, purity and quality as the original product.

• It must be prepared in the same formulation and be bioequivalent

• Increased availability of generics• 1984 12% prescriptions were generic

• 2012 80% prescriptions were generic

Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 1984 Stat. 1538 (codified as amended in scattered sections of 21 & 35 U.S.C.).

Evolution of Biosimilar Approval Pathway in U.S.

• Two federal laws for the approval of pharmaceuticals– Food, Drug, and Cosmetic Act (FDCA)

• New drug application (NDA)• Abbreviated NDA (ANDA)

– Public Health Service Act (PHSA)• Biologics license application (BLA)

• Most biologics approved under PHSA– “Hatch Waxman Act” of 1984 does not apply

– Biologics Price Competition and Innovation Act (BPCI) of 2009 created an abbreviated FDA approval pathway for biosimilars

• Full interpretation and implementation still pending

• According to the FDA, “drugs” are different from “biologics”

Zelenetz AD et al. J Natl Compr Canc Netw. 2011; 9(Suppl 4):S1–S22.

FDA Approval Pathways

†FDCA = Federal Food Drug and Cosmetic Act ¥PHSA = Public Health Service Act

Drugs• Small-molecules• Approved via FDCA

Biologics• Approved via PHSA¥

New Drug Application

(NDA)505(b)(1)

Safety and Efficacy must be

demonstrated

Abbreviated New Drug

Application(ANDA)

505(b)(2)

Bioequivalence must be

demonstrated

Biologics License Application

(BLA)351(a)

Safety and Efficacy must be

demonstrated

Biosimilar Biologics License

Application351(k)

Must demonstrate that it is highly

similar to 351(a) reference

Interchangeable biosimilars

require more data

Many types of biologic products

Reference or Originator

Biosimilar Interchangeable Biosimilar

New biologic approved via

BLA

Depth of data submitted to the FDA

“Standard” data package

Abbreviated data package

Abbreviated data package, more information on efficacy and safety

“Standard” data package; efficacy and safety on its own merit

Compared to reference?

N/A Yes Yes Not Required

Current example in USA

FilgrastimNeupogen ®

Filgrastim-sndzZarxio ®

Not Yet Tbo-filgrastimGranix ®

Guideline on Similar Biological Medicinal Products (Oct 05)

Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active

Substance: Quality Issues (June 06)

Overarching

Quality

Annexes EpoetinJuly 2006

G-CSFJune 2006

InsulinJune 2006

HGHJune 2006

GeneralApplicableto allBiosimilars

Specific:Product data requirements

Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active

Substance: Nonclinical & Clinical Issues (June 06)

Nonclinical& Clinical

Heparin LMWH & Others Draft

13 biosimilar marketing authorizations have been granted

EMA Model: Biosimilars Regulations www.ema.europa.eu

EMA=European Medicines Agency

The Naming Game

History of NamingSelected Terms Used to Describe “Generic” Biologics

• Post patent biologicals• Biogenerics • Subsequent entry protein pharmaceuticals• Second-generation biologicals• Follow-on biologicals • Follow-on protein products • Bio-betters• Biosimilars

Source of Names and Numbers

• Originator Manufacturer (Reference Product)– Trade Name

• Unites States Adopted Names (USAN)– Provide by AMA– Generally adopted by FDA– The generic name (Reference Name)

• United States Pharmacopeia (USP)– Monographs and consistency concerns

• Institute for Safe Medication Practices (ISMP)– Naming clarity / Safety concerns – Labeling standards

• Food and Drug Administration (FDA)– Ultimately approves name– Assigns National Drug Code (NDC)

• Centers for Medicare & Medicaid Services (CMS) – Assigns HCPCS codes which could be the same between

biosimilarsHCPCS=Healthcare Common Procedure Coding System

Reference Slide

Recent Naming Events (Precedents ?)

• Prefix vs Suffix– Granix (tbo-Filgrastim), Full NDA approval– Zaltrap (ziv-aflibercept)– Zarxio (Filgrastim-sndz) (FDA “placekeeper name”???)

• Tyrosine Kinase Inhibitors naming convention– PONATinib and PAZOPanib

• WHO (Oct 2013)– Leaning toward “Generic + Suffix”

• EU naming– Allows the biosimilar to use same non-proprietary name as reference

• HER-2 targeted Kadcyla (ado-trastuzumab emtansine)• Trastuzumab: 8mg/kg loading; 6mg/kg q 3 weeks maintenance

• Ado-trastuzumab: no loading; 3.6mg/kg q 3 weeks

• FDA rejected “trastuzumab emtansine” and added prefix “ado”

• ISMP Alert 4-17-13: Use both brand and full generic name to avoid confusion

• International Medication Safety Network (IMSN) Alert 5-8-14: USAN and WHO did not approve FDA name, leading to international confusion

• Confusion documented as leading to overdoses of ado-trastuzumab

• FDA working on naming resolution

“IMSN Alert – Risk of confusion between the names trastuzumab-emtansine and trastuzumab”, May 8, 2014, IMSN Alert “Confusion regarding the generic name of the HER2-targetd drug KADCYLA (ado-trastuzumab emtansine)”, April 17, 2013 NANALERT

Importance of a Naming Strategy• Goal:

– 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)

Naming Options• Options

– Totally different names from originator• Preferred by 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

– Unique prefix attached to originator’s USAN• Precedent with some new drugs• Supported by ISMP and Hematology/Oncology Pharmacy

Association (HOPA)

– Current FDA position with Sandoz Filgrastim• Assigned “PLACEHOLDER” name

State initiatives: warranted or not?

State Legislation Statusas of October 2014

http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx

State Proposals Are Driven By BPCI Act…

• Biologics Price Competition and Innovation Act of 2009– Allows approval by FDA of a biosimilar product as

“interchangeable”• Must demonstrate NO clinically meaningful differences in safety, purity, and

potency

• 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 with forthcoming national standards

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

Frequent Features of State Legislation

http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx

• Any biological product under consideration for substitution must be certified and listed as approved for substitution by the FDA • No products have gained such approval as biosimilars in the United States

• Prescriber would be able to prevent substitution by stating “dispense as written” or “brand medically necessary”

• Prescriber must be notified of any allowable substitution made at a pharmacy

• Individual patient must be notified that a substitute or switch has been made; in some cases, state law requires patient consent before any such switch is made

• Pharmacist and the physician must retain records of substituted biologic medications

• State must maintain a public list of permissible interchangeable products

Enacted State LegislationOctober 2014

• Florida, HB 365 (2013), Chapter 2013-102 http://www.flsenate.gov/Session/Bill/2013/0365/BillText/er/PDF

• North Dakota, SB 2190 (2013) http://www.legis.nd.gov/assembly/63-2013/documents/13-0511-04000.pdf?20131023091537

• Oregon, SB 460 (2013), Chapter 342, 2013 Laws, https://olis.leg.state.or.us/LIZ/2013R1/Measures/Text/SB0460/Enrolled (contains sunset clause)

• Utah, SB 78 (2013), http://le.utah.gov/~2013/bills/sbillenr/sb0078.pdf (contains sunset clause)

• Virginia, SB 1285, (2013), Chapter 544 (contains sunset clause), http://lis.virginia.gov/cgi-bin/legp604.exe?131+ful+CHAP0544

Amendment Enacted by State of Florida (Key Points)• Section 1. Subsection (6) of section 465.019, Florida 18 Statutes, is

AMENDED to read:• (6) In a Class II institutional pharmacy, an institutional formulary system

may be adopted with approval of the medical staff for the purpose of identifying those medicinal drugs, and proprietary preparations, biologics, biosimilars, and biosimilar interchangeables that may be dispensed by the pharmacists employed in such institution. …shall establish policies and procedures for the development of the system in accordance with the joint standards of the American Hospital Association and American Society of Hospital Pharmacists for the utilization of a hospital formulary system…..

• Section 2. Section 465.0252, Florida Statutes, is created to read: • 465.0252 Substitution of interchangeable biosimilar products. • (3) A pharmacist who practices in a class II or modified 54 class II institutional

pharmacy shall comply with the notification provisions of paragraph (2)(c) by entering the substitution in the institution's written medical record system or electronic medical record system.

http://www.flsenate.gov/Session/Bill/2013/0365/BillText/er/PDF

Where is this going? ...Considerations For Pharmacy

• Familiarize yourself with state and federal laws – Much may hinge on future FDA determinations of

biosimilarity and interchangeability– Some laws are being adopted with sunset clauses and

may expire before applications/determinations occur– Seek amendments that reward existing good practice

• Closely follow your state Board of Pharmacy’s guidance– Is there a need to reconcile biosimilar substitution with

existing state laws on substitution of generic drugs?

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

Antibody Formation: “Immunogenicity”

• Potential increases with amino acid sequence changes• Immune responses have different consequences

– Neutralize the molecule, making it therapeutically ineffective– Hypersensitivity reactions– No clinical effect– Rare but serious autoimmune responses can be life-

threatening• Pure red cell aplasia (PRCA) with anti-epoetin antibody

• Immunogenicity of biologic drugs is unpredictable, unforeseeable– Scientific tools for detecting immunogenicity exist, but in some

cases they are undeveloped

Kessler M et al. Nephrol Dial Transplant. 2006; 21:v9-v12.Chirmule N, et al. AAPS J. 2012;14(2):296-302

Factors Affecting the Immunogenicity of Proteins

Chirmule N, et al. AAPS J. 2012;14(2):296-302

• Disease Factors– Immune dysregulation– Inflammatory responses

• Patient Factors– Major histocompatibility complex background

• Product Factors– AA sequence, structure, etc.– Impurities– Formulation– Route of administration– Dose

Is dosing an issue?

• Molecular size differs among biosimilar drugs– Will “gram” based dosing be equivalent?

• Should “international unit” dosing be required?– “Vial contains 123 mcg (equivalent to 250 units) per mL”– Should “units” only be required when molecular size

difference is greater than __?__ %– Erythropoietin is 34,000 daltons, typical dose = 10,000 units– Filgrastim is 18,800 daltons, typical dose = 300 mcg

• Should all prescribing and dosing be based on units?• Should dose equivalent be based on originator dosing?

– What if the originator stops production?

• Should pharmacy advocate for standards or just monitor the emerging market?

Are Companion Diagnostics Interchangeable ?

• FDA Guidance for Industry and FDA Staff, August 6, 2014• For regulators (and payers ?)

– Determine which patients will benefit– Decrease the chance of a drug being used off-label …

• For drug makers– Easier to obtain approval …

• Key points in guidance:– "in most circumstances, an IVD companion diagnostic device and its

corresponding therapeutic product should be approved or cleared

contemporaneously by FDA for the use indicated in the therapeutic product

labeling."

– In cases where the drug cannot be used safely or effectively without the

companion diagnostic (CDx), FDA will not approve it.

– FDA will, however, approve some drugs without a CDx in certain circumstances.• Therapy is intended to treat a serious or life-threatening disease

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf

13 Drugs with FDA Required Companion Diagnostics

Approximately 80 companion tests are in use• Erbitux (cetuximab)• Vectibix (panitumumab)• Exjade (deferasirox)• Gilotrif (afatinib)• Gleevec/Glivec (imatinib mesylate)• Herceptin (trastuzumab)• Perjeta (pertuzumab)

• Kadcyla (ado-trastuzumab emtansine)

• Mekinist (trametenib)• Tafinlar (dabrafenib)• Tarceva (erlotinib)• Xalkori (crizotinib)

• Zelboraf (vemurafenib)

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm

Will CDx apply to a single drug or a therapeutic class ?

Will this effect interchangeability ?

Biosimilar Pharmacovigilance:Role of the Pharmacist

• Monitor and report – Adverse events: FDA MedWatch– Medication errors

• Correct assessment of safety event– What was ordered vs. what patient received ?

• Maintenance of EMR• Bar code administration

• Medication reconciliation for all providers• Consider transitions of care

Does coding help differentiate ?• NDC and HCPCS codes can support differentiation

• Billing claims data can be a useful in pharmacovigilance– Outcomes

– Adverse Events

• Problems with using billing data– NDA: Leuprolide Acetate (depot formulations)

• Lupron Depot: intramuscular injection• Eligard: subcutaneous injection• 2013 HCPCS code:• J1950: Injection, leuprolide acetate (for depot suspension), per

3.75 mg– BLA: Epoetin alfa

• Procrit® and Epogen®• 2013 HCPCS codes:• J0885: Injection, epoetin alfa, (for non-ESRD use), 1000 units• J0886: Injection, epoetin alfa, 1000 units (for ESRD on dialysis)

Biosimilar Pharmacovigilance

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.

Pharmacovigilance• Define monitoring parameters• Easy reporting methods• Real-time data• Ensure traceability

Risk minimization• Healthcare provider feedback

and communication• Recalls and alerts• REMS?

Constant Monitoring to Identify and Characterize Safety Risk

• Naming standards• Integration into electronic medical

record (EMR)• Drug codes: HCPCS, NDC, etc.• Prospective registries

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

Interchangeability Definition• Interchangeability definition

– “Biosimilar to the U.S.-licensed reference biological

product … expected to 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 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 2014 Nov 13.

• Biological products approved by FDA and dates of approval

• Approval pathway: e.g., 351(a), 351(k)• Lists if a biosimilar is interchangeable• Defines exclusivity period

FDA “Purple Book”

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 2014 Oct 16.

“Documented” Practice Standards

Decision Domains Supporting Use

Restricted Formularies and Clinical Pathways

Evidence Rated

Compendia

Biosimilar labeled

indications

Are Indications Interchangeable ?

• Provider Formulary and P&T committee– Is the “risk” of unknown worth the “benefit”– Ability to monitor and report (pharmacovigilance)– Multiple providers (especially oral chemo)– What evidence will they require to support

interchange

• Payers– How will payers make their coverage

determinations?– Compendia therapeutic class representatives

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

Generics vs Biosimilars

CMS Billing Guidance, April 2015

• CMS Payment– Initial: 106% AWP– Then: Biosimilar ASP + 6% Reference ASP

• 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

Bottom Line• CMS OPPS Reimbursement for 2015

– Filgrastim 5mcg = $4.99• ASP = $4.7075• 6% = $0.2824

– tbo-filgrastim 5mcg = $3.920 (106% WAC)– If new biosimilar is priced 20% less:

• ASP = 3.7660 + 0.2824 = $4.0484 payment• Margin = 7.5%

– For 300 mcg dose• $282.450 payment for reference drug (Neupogen®)• $242.904 payment for biosimilar• 6% reference same for both = $16.944

• Cost difference: 282.45 - 225.96= $56.49

– Assumptions:• Your cost = ASP• Your regional OPPS reimbursement is the same as National

Patient / Co-Pay Assistance ?

• Most originator drugs have PAP• Most “biosimilar drugs” are produced by

companies that have PAP programs– Granix (TevaCore.com)– Zarxio (Will announce at product launch)

• To be competitive, providers should insist on at least the same level of support as with the originator drug.

Patent Cliff (selected items)

Drug 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

Embrel 2028

Impact onPrice

Response From

Originators

Result

Prior to biosimilar entry, originators had already introduced price discounts

Biosimilar EPOs are priced at ~ 20% less than the originator brands

Originators responded to limit biosimilar uptake

Questions on the quality, safety, and efficacy of biosimilars

Advising clinicians against switching EPO products

Questioning the adequacy of EU pharmacovigilance systems to effectively monitor biosimilars in clinical practice

Clinicians comfortable with the introduction of biosimilars

No unexpected safety concerns identified in 24 months

Extensive “Post Authorization Safety Studies” have been undertaken by the biosimilar manufacturers to monitor safety of their products in the market

European EPO Commercial Experience

Branded EPOs are switched to biosmiliars on tenders today (interchangeability)

75% cost reduction announced during FIP 2010 World Conference

EU payors are driving biosimilar uptake if funding mechanisms give them influence

AGENDA

• What are biosimilar drugs?• Regulatory issues• Safety concerns and Pharmacovigilence• Indications for use• Financial implications• Summary / Key Points

Summary• Biosimilar use and regulation exists in Europe and is being

defined in the U.S.

– Naming to be determined

– Interchangeability to be determined

• Pharmacists must lead Pharmacovigilence efforts

– Monitoring and Reporting Adverse Events

– Dosing Issues

– Coding Issues

– Companion Diagnostic Issues

• What / Who will determine use ?

– Cost alone

– Payer Formulary

– Provider Formulary

Questions ?