Biosimilar Drugs: Opportunities and Issues

Biosimilar Drugs: Opportunities and Issues
The Community Oncology Alliance Conference Moving Forward on Payment Reform April 23, 2015 Biosimilar Drugs: Opportunities and Issues Phil Johnson MS RPh Safe School Meds, Principle Partner Moffitt Cancer Center, Director of Pharmacy (Retired)

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
Chemical process based on a series of controlled and predictable chemical reactions Process is standardized between manufacturers Final structure easily verified 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
Accessed 2014 Oct 16.

Similarities and Differences “Similar” vs. Reference Product
BIOSIMILAR Specification Comparison with REFERENCE Formulation May be different Delivery device/container 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 Formylation Glycosylation Methylation Phosphorylation PEGylation

Are biosimilar drug issues new
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”

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 % prescriptions were generic % prescriptions were generic Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No , 1984 Stat (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 created an abbreviated FDA approval pathway for biosimilars Full interpretation and implementation still pending According to the FDA, “drugs” are different from “biologics” HATCH WAXMAN info: A genuine compromise: patent term restoration for innovators coupled with rapid approval of generic products on patent expiry Main approval procedure (ANDA) designed for small-molecule, chemically-synthesized drugs Active ingredients must be “the same” No clinical trials except for bioequivalence studies in healthy subjects, based on pre-existing FDA regulations and long-established scientific principles No requirement for therapeutic equivalence evaluations, but FDA had well-established process already in place for making them -- there was a backlog of activity that Hatch-Waxman unleashed FDA guidance delayed on multiple occasions After 3 years and litigation, a growth hormone product was approved by FDA in 2006 But FDA was explicit that product was: not a generic biologic, not equivalent to innovator, not a pathway for future approvals Became clear legislation was required to clarify approval process Public Health Service Act NOT Food, Drug, and Cosmetic Act A clear regulatory framework for approval of biologic generics does not yet exist. In a casesome considered a test of FDA policy, the agency denied Sandoz’ application for their Omnitrope, a copy of Pfizer’s somatropin product, Genotropin.86,87 The case clearly indicates that current regulations are not adequate to address approval of biologic generics. Guidance from the FDA on the regulatory issues regarding biologic generics was highly anticipated in summer 2004, but it has been delayed.88 According to one FDA official, the planned guidance was not (OLD) innovative, but will represent an important step forward.89 The FDA has sought to make the Ultimately, legislative action may be necessary to fully clarify the approval process for biologic guidance development process more public, and an open meeting is planned for early ,91 generics. - announcement of a White Paper “in the next months”, draft guidance ALL ALONG – could do full development program documents and a third public forum - nothing happened • The US Omnitrope-story: - 2004: FDA declined that a decision could be made due to “unresolved - 07/2003: 505(b)(2) Omnitrope application scientific and legal issues” - 09/2005: Sandoz files a lawsuit against the FDA for failure to take action on its pending application act on the application - 04/2006: Court ordered the FDA to comply with its statutory obligation to - 06/2006: FDA approval Zelenetz AD et al. J Natl Compr Canc Netw. 2011; 9(Suppl 4):S1–S22.

FDA Approval Pathways Drugs Biologics Small-molecules
Approved via FDCA Biologics Approved via PHSA¥ New Drug Application (NDA) 505(b)(1) Abbreviated New Drug Application (ANDA) 505(b)(2) Biologics License Application (BLA) 351(a) Biosimilar Biologics License Application 351(k) Must demonstrate that it is highly similar to 351(a) reference Safety and Efficacy must be demonstrated Bioequivalence must be demonstrated Safety and Efficacy must be demonstrated Interchangeable biosimilars require more data †FDCA = Federal Food Drug and Cosmetic Act ¥PHSA = Public Health Service Act

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 Not Required Current example in USA Filgrastim Neupogen ® Filgrastim-sndz Zarxio ® Not Yet Tbo-filgrastim Granix ®

EMA Model: Biosimilars Regulations
Overarching Guideline on Similar Biological Medicinal Products (Oct 05) Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (June 06) General Applicable to all Biosimilars Quality Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical & Clinical Issues (June 06) Nonclinical & Clinical Specific: Product data requirements Annexes Epoetin July 2006 G-CSF June 2006 Insulin June 2006 HGH June 2006 Heparin LMWH & Others Draft 13 biosimilar marketing authorizations have been granted EMA=European Medicines Agency

The Naming Game

History of Naming Selected 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 Since biologic products cannot be replicated in the exact way chemical compounds can be, the term “generic” is not entirely appropriate and a variety of other terms are used, including “postpatent biologics,” “follow-on biologics,” “biosimilars,” and “biogenerics.” The FDA appears to prefer the term follow-on biologics, and defines these drugs as, “a protein product with the same amino acid sequences and a similar enough production process and overall structure to appear on its face to be very similar to an already approved product or products.” The number of different terms used to refer to generic biologics serves to illustrate the complexity of the issue. For simplicity, we refer to these products as biologic generics. A clear regulatory framework for approval of biologic generics does not yet exist. In a case some considered a test of FDA policy, the agency denied Sandoz’ application for their Omnitrope, a copy of Pfizer’s somatropin product, Genotropin.86,87 The case clearly indicates that current regulations are not adequate to address approval of biologic generics. Guidance from the FDA on the regulatory issues regarding biologic generics was highly anticipated in summer 2004, but it has been delayed.88 According to one FDA official, the planned guidance was not innovative, but will represent an important step forward.89 The FDA has sought to make the guidance development process more public, and an open meeting is planned for early ,91 Ultimately, legislative action may be necessary to fully clarify the approval process for biologic generics. b Since biologic products cannot be replicated in the exact way chemical compounds can be, the term “generic” is

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 biosimilars Reference Slide HCPCS=Healthcare Common Procedure Coding System

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 : Use both brand and full generic name to avoid confusion International Medication Safety Network (IMSN) Alert : 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 Status as of October 2014

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 list U.S. Congress. Sections (Biologics Price Competition and Innovation Act of 2009) of the Patient Protection and Affordable Care Act (Public Law ). URL in reference list

Frequent Features of State Legislation
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 Legislation October 2014
Florida, HB 365 (2013), Chapter North Dakota, SB 2190 (2013) Oregon, SB 460 (2013), Chapter 342, 2013 Laws, (contains sunset clause) Utah, SB 78 (2013), (contains sunset clause) Virginia, SB 1285, (2013), Chapter 544 (contains sunset clause),

Amendment Enacted by State of Florida (Key Points)
Section 1. Subsection (6) of section , 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 , Florida Statutes, is created to read: 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.

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?

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):

Factors Affecting the Immunogenicity of Proteins
Disease Factors Immune dysregulation Inflammatory responses Patient Factors Major histocompatibility complex background Product Factors AA sequence, structure, etc. Impurities Formulation Route of administration Dose Chirmule N, et al. AAPS J. 2012;14(2):

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

13 Drugs with FDA Required Companion Diagnostics Approximately 80 companion tests are in use
Erbitux (cetuximab) Kadcyla (ado-trastuzumab emtansine) Vectibix (panitumumab) Mekinist (trametenib) Exjade (deferasirox) Gilotrif (afatinib) Tafinlar (dabrafenib) Gleevec/Glivec (imatinib mesylate) Tarceva (erlotinib) Xalkori (crizotinib) Herceptin (trastuzumab) Zelboraf (vemurafenib) Perjeta (pertuzumab) 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
Constant Monitoring to Identify and Characterize Safety Risk Pharmacovigilance Define monitoring parameters Easy reporting methods Real-time data Ensure traceability Risk minimization Healthcare provider feedback and communication Recalls and alerts REMS? Naming standards Integration into electronic medical record (EMR) Drug codes: HCPCS, NDC, etc. Prospective registries Zuñiga L, Calvo B. Pharmacoepidemiol Drug Saf Jul;19:661-9. Felix T, et al. Nat Biotechnol ;32: Casadevall N, et al. Expert Opin Biol Ther. 2013;13:

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). guidancecomplianceregulatoryinformation/ucm pdf. Accessed 2014 Nov 13.

FDA “Purple Book” 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 Accessed 2014 Oct 16.

Decision Domains Supporting Use
“Documented” Practice Standards Restricted Formularies and Clinical Pathways Evidence Rated Compendia Reference biologic labeled indication 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

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

Bottom Line CMS OPPS Reimbursement for 2015 Filgrastim 5mcg = $4.99
ASP = $4.7075 6% = $0.2824 tbo-filgrastim 5mcg = $ (106% WAC) If new biosimilar is priced 20% less: ASP = = $ payment Margin = 7.5% For 300 mcg dose $ payment for reference drug (Neupogen®) $ payment for biosimilar 6% reference same for both = $16.944 Cost difference: = $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 Lantus 2014 Interferon beta 1-a 2015 Neulasta Synagis Humira 2016 Rituximab Erbitux Remicade 2018 Avastin 2019 Herceptin Aranesp 2024 Embrel 2028

European EPO Commercial Experience
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 Impact on Price Response From Originators 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 Result

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 Pharmacists will play a key role in evaluating biosimilars for inclusion in a formulary. A number of product and manufacturer parameters will need to be weighed during this process, including parameters related to the assessment of product safety and efficacy, and manufacturer considerations. Pharmacists will also need to review healthcare system and patient considerations, including economic considerations (eg, cost and coverage concerns) and issues surrounding use of biosimilars and references products following transitions of care between the inpatient and outpatient setting.

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