8/14/2017 FOLLOW-ON BIOLOGICS: HOW BIOSIMILAR ARE THEY? STEPHANIE A. KLEPSER, PHARM.D. OPTIMED SPECIALTY PHARMACY OBJECTIVES OBJECTIVES

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1 FOLLOW-ON BIOLOGICS: HOW BIOSIMILAR ARE THEY? STEPHANIE A. KLEPSER, PHARM.D. OPTIMED SPECIALTY PHARMACY OBJECTIVES Explain how biosimilars differ from small molecule generic drugs. Discuss the FDA approval process for biosimilar medications. Explain what additional requirements must be met for a biosimilar to establish interchangeability. Describe some of the logistical challenges that will need to be addressed as biosimilars hit the market. OBJECTIVES Explain how biosimilars differ from small molecule generic drugs. Discuss the FDA approval process for biosimilar medications. Explain what additional requirements must be met for a biosimilar to establish interchangeability. Describe some of the logistical challenges that will need to be addressed as biosimilars hit the market. 1

2 TERMINOLOGY Biologic Product A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product applicable to the prevention, treatment, or cure of a disease or condition of human beings. HISTORY 1717: Process of variolation was introduced in England Involves putting puss/scabs from a patient with smallpox into a healthy patient through the nose or skin 1813: The Vaccine Act of 1813 First federal law to regulate any medical substance Later repealed in s: Discovery of human diphtheria vaccine Lead to the discovery of multiple live and heatkilled vaccines 1796: Edward Jenner discovers first smallpox vaccine Immunity to smallpox was achieved through deliberate infection with cowpox 1879: Louis Pastuer prepares the first laboratory-prepared vaccine Used weakened chicken cholera bacteria to immunize chicken against the disease 1902: Biologics Control Act In response to St. Louis Tragedy Implemented federal regulations of biologic products Objective was to ensure safety, purity, and potency HISTORY 1906: Federal Food and Drugs Act Outlawed adulterated and misbranded foods and drugs (did not mention biologics) Sherley Amendment in 1912 prohibited labeling medications with false therapeutic claims 1941: Blood fractionation techniques wellestablished Albumin was used to treat burn victims at Pearl Harbor Manufacturing standards for blood fractionation products established during WWII 1949: Poliovirus successfully grown in human tissue cell culture Led to explosion of vaccine and biologic research 1938: Food Drug and Cosmetic Act Replaced 1906 Act Gave congress authority to oversee safety of food, drugs and cosmetics Biologic products considered to be drugs under this act 1944: Public Health Service Act Biologic Control Act was incorporated into section 351 of this act Gave Laboratory of Biologics Control the authority to license biological products (later became part of NIH) 1954: First licensed polio vaccine approved 2

3 HISTORY 1972: Control of biologics moved from the NIH to the FDA Bureau of Biologics Review the safety, efficacy, and labeling of all future and previously licensed biologics Today known as the Center for Biologics Evaluation and Research (CBER) 2010: Patient Protection and Affordable Care Act signed into law by President Obama Included the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) Abbreviated pathway for biosimilar approval (section 351(k) added to the PHS Act) March 6, 2015: First biosimilar approved in the USA Sandoz s Zarxio (filgrastim) biosimilar to Amgen s Neupogen 1984: Drug Price Competition and Patent Term Restoration Act Hatch-Waxman Act Created abbreviated pathway for the approval of generic medications based on bioavailability and bioequivalence Safety and efficacy is assumed to be equivalent Did not address biologic products 2014: The FDA Purple Book is available Listing of all biologics products and biosimilars licensed by the FDA January 2017: FDA publishes Nonproprietary Naming of Biological Products Guidance as well as draft guidance on Considerations in Demonstrating Interchangeability with a Reference Product TERMINOLOGY Follow-on Biologic A general term used to describe biologic products only marketable after expiration of the reference-product patent(s) Includes biosimilars, biobetters, and biogenerics TERMINOLOGY Biosimilar A biologic product may be demonstrated to be biosimilar if: data show that the product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency 3

4 TERMINOLOGY Biobetter (or biosuperior ) Whereas biosimilars aim to establish similarity, biobetters aim for superiority in one or more aspect of their clinical profile Work against same target protein, but may include structural or functional changes or improved formulations to improve safety and/or efficacy They are too dissimilar to receive biosimilar designation and must go through full FDA approval in the US (i.e. BLA) The term biobetter has no legal or regulatory recognition May also be referred to as biosuperiors May be misleading since they are never compared directly with the reference product and are instead evaluated via placebo-controlled studies BIOBETTERS TERMINOLOGY Biogeneric A follow-on biologic portrayed or used as though it is an identical, interchangeable generic equivalent of a reference product. Currently only used in lesser or non-regulated international markets where generic equivalence may be presumed. No biogenerics exist in US markets 4

5 SMALL MOLECULE DRUGS VS. BIOLOGIC PRODUCTS Small Molecule Drugs Low molecular weight Organic or chemical synthesis Fewer critical process steps Well-characterized Known structure Homogenous drug substance Not usually immunogenic Biological Products High molecular weight Made with/from live cells/organisms Many critical process steps Less easily characterized Structure may or may not be completely known Heterogeneous mixtures (may include variants) Often immunogenic SMALL MOLECULE DRUGS VS. BIOLOGIC PRODUCTS OBJECTIVES Explain how biosimilars differ from small molecule generic drugs. Discuss the FDA approval process for biosimilar medications. Explain what additional requirements must be met for a biosimilar to establish interchangeability. Describe some of the logistical challenges that will need to be addressed as biosimilars hit the market. 5

6 NOVEL SMALL MOLECULE VS. NOVEL BIOLOGIC APPROVAL Novel Small Molecule Drug Approved via Food, Drug, and Cosmetic Act (FDCA) New Drug Application (NDA) Benefit-risk profile and efficacy must be demonstrated Novel Biologic Product Approved via Public Health Service Act (PHSA) Biologics License Application (BLA) Benefit-risk profile and efficacy must be demonstrated Pfizer Biosimilars: Biosimilars in the US Health Care Landscape (Nov 2016) GENERIC SMALL MOLECULE VS. BIOSIMILAR APPROVAL Generic Small Molecule Drug Approved via Food, Drug, and Cosmetic Act (FDCA) Abbreviated New Drug Application (ANDA) via Hatch-Waxman Bioequivalence must be demonstrated Biosimilar Approved via Public Health Service Act (PHSA) Biosimilar Biologics License Application (BPCI Act) Must demonstrate high similarity to reference product AND no clinically meaningful differences Pfizer Biosimilars: Biosimilars in the US Health Care Landscape (Nov 2016) BIOSIMILAR VS. GENERIC APPROVALS Bioequivalence: Generic Drug The rate and extent of absorption to NOT show a significant difference from the listed drug, Comparable to a brand/reference listed drug product in dosage form, strength, OR route of administration, quality and performance characteristics, and intended use. In lieu of animal, clinical, and bioavailability studies, The only extent bioequivalence of absorption must does NOT be show a demonstrated. significant difference and any difference in rate is intentional or NOT medically significant Biosimilar Data show that the product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, AND There are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency 6

7 BIOSIMILAR APPROVAL Totality of Evidence approach Goal is NOT to re-establish therapeutic benefit of the biosimilar Goal is to demonstrate lack of clinically meaningful differences WHAT ABOUT INSULIN? Small Molecule Drugs Biological Products Low molecular weight High molecular weight Organic or chemical synthesis Made with/from live cells/organisms Fewer critical process steps Many critical process steps Well-characterized Less easily characterized Known structure Structure may or may not be completely known Homogenous drug substance Heterogeneous mixtures (may include variants) Not usually immunogenic Often immunogenic Molecular weights: Aspirin ~ 180 g/mol Atorvastatin ~ 558 g/mol Bovine Insulin ~ 5733 g/mol Insulin Glargine ~ 6063 g/mol Adalimumab ~ 144,190 g/mol WHAT ABOUT INSULIN? Small Molecule Drugs Biological Products Low molecular weight High molecular weight Organic or chemical synthesis Made with/from live cells/organisms Fewer critical process steps Many critical process steps Well-characterized Less easily characterized Known structure Structure may or may not be completely known Homogenous drug substance Heterogeneous mixtures (may include variants) Not usually immunogenic Often immunogenic Manufacturing process: Recombinant DNA technology Grown in yeast, bacteria 7

8 WHAT ABOUT INSULIN? Small Molecule Drugs Low molecular weight Organic or chemical synthesis Fewer critical process steps Well-characterized Known structure Homogenous drug substance Not usually immunogenic Biological Products High molecular weight Made with/from live cells/organisms Many critical process steps Less easily characterized Structure may or may not be completely known Heterogeneous mixtures (may include variants) Often immunogenic WHAT ABOUT INSULIN? Insulin meets the definition of a biologic product Historically, some natural source proteins were regulated as a subset of drugs under section 505 of the FDCA The first recombinant human insulin was approved in 1982 under the FDCA Subsequent insulin products have followed suit There are no insulin products approved via the PHS Act No reference biologic = no mechanism for biosimilar approval Generic insulin is not possible since insulin is not a small-molecule chemical drug Section 505(b)(2) of the FDCA does allow for an abbreviated approval process based on the previously approved products safety and efficacy ( follow-on biologics ) March 23, 2020: An approved application for a biologic under section 505 of the FDCA shall be deemed to be a license for a biologic product under section 351 of the PHS Act OBJECTIVES Explain how biosimilars differ from small molecule generic drugs. Discuss the FDA approval process for biosimilar medications. Explain what additional requirements must be met for a biosimilar to establish interchangeability. Describe some of the logistical challenges that will need to be addressed as biosimilars hit the market. 8

9 BIOSIMILAR INTERCHANGEABILITY Currently, a pharmacist CANNOT automatically substitute a biosimilar for the reference product Prescriber must write exact name of the product to be dispensed e.g. If Remicade is written, Inflectra cannot be substituted without prescriber consent and vice versa Section 315(i) of the BCPIA includes a provision allowing for the approval of interchangeable biologics If deemed interchangeable, the biosimilar could be substituted for the reference product without prescriber intervention HOW IS INTERCHANGEABILITY ESTABLISHED? Section 351(k)(4) of the BCPI Act: The FDA will determine a biologic product to be interchangeable with the reference product if: It is biosimilar to the reference product It can be expected to produce the same clinical result as the reference product in any given patient For a 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 is not greater than the risk of using the reference product without such alteration or switch HOW IS INTERCHANGEABILITY ESTABLISHED? Draft guidance was released by the FDA for comment January 2017 Considerations in Demonstrating Interchangeability With a Reference Product FDA has not finalized formal guidance regarding how to demonstrate interchangeability As such, current biosimilar manufacturers have not pursued this designation 9

10 INTERCHANGEABILITY IN THE USA A total of 45 states have considered legislation addressing biosimilar substitution, and 35 states now have laws in place. TYPICAL FEATURES OF BIOSIMILAR STATE LEGISLATION FDA Approval Prescriber Decides Notification vs. Communication Patient Notification Records Immunity Web lists Cost/pricing A biologic must be approved as interchangeable in order to be considered for substitution. The prescriber can prevent substitution by stating DAW. Earlier bills require active notification, later bills allow the information to be communicated to the prescriber via dispensing records. Some states require patient notification when a switch has been made; some even require patient consent to switch. The pharmacist and physician must retain records of the substituted product. Some states provide immunity to pharmacists who substitute in compliance with biologics state law. The state must maintain public records of permissible interchangeable products. Some states require pharmacist to explain the cost of the reference product vs. the biosimilar, and some require that the substituted product must have the lowest cost. BIOSIMILAR SUBSTITUTION IN MICHIGAN: HB 4812 Originally passed the House of Representatives containing language that would require pharmacists to notify the prescriber if an interchangeable biosimilar is substituted. The Senate Health Policy Committee approved the bill, but removed the notification requirements. The House of Representatives was not supportive of the changes and the bill has not moved forward. 10

11 INTERCHANGEABILITY WORLDWIDE OBJECTIVES Explain how biosimilars differ from small molecule generic drugs. Discuss the FDA approval process for biosimilar medications. Explain what additional requirements must be met for a biosimilar to establish interchangeability. Describe some of the logistical challenges that will need to be addressed as biosimilars hit the market. BIOSIMILAR NOMENCLATURE The nonproprietary name designated for each originator biological product, related biological product, and biosimilar product will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters. 11

12 BIOSIMILAR NOMENCLATURE filgrastim-jcwp Neupogen (filgrastim) Amgen Remicade (infliximab) Janssen Enbrel (etanercept) Amgen Humira (adalimumab) Abbvie filgrastim-bflm Zarxio (Sandoz): filgrastim-sndz Inflectra (Pfizer): infliximab-dyyb Renflexis (Merck): infliximab-abda Erelzi (Sandoz): etanercept-szzs Amjevita (Amgen): adalimumab-atto APPROVED INDICATIONS Biosimilars may not receive all the same FDA-approved indications as the reference biologic, especially when orphan conditions are involved. Humira has ten FDA-approved indications; Amjevita has seven. Remicade is FDA approved for Pediatric UC; Inflectra is not. How will clinicians keep track as more products come to market? WILL BIOSIMILARS BE ABLE TO OFFER MUCH COST SAVINGS? 12

13 WILL BIOSIMILARS BE ABLE TO OFFER MUCH COST SAVINGS? Will biosimilar manufacturers be able to compete with the reference product on: Copay reduction programs Patient Assistance Programs (PAPs) Rebates NONTHERAPEUTIC SWITCHING Payer Formulary Patient Preference Patient Financials Pharmacy Reimbursement Product Availability NONTHERAPEUTIC SWITCHING To Switch Not to Switch Delivery Mechanism/Device Cost Ancillary Support Services Immunogenicity Non-transparent cost implications Prescriber vs. Payer vs. Pharmacy vs. Patient Preference 13

14 PATENT WARS Biologic manufacturers may have multiple patents in place protecting various aspects of their product: Drug/formulation Manufacturing process Delivery system CONCLUSION Biosimilars introduce a new therapeutic option for patients requiring a biologic product. Biosimilars may provide some cost-savings, but will not be to the same degree as small-molecule generics. Legal and logistic concerns still need to be addressed as these agents enter the market. ANY QUESTIONS? 14