Pathway: State Implications

Transcription

1 Implementation of a U.S. Biosimilar Pathway: State Implications Women In Government, Midwestern Regional Conference Des Moines, Iowa Kimberly Greco Director, Regulatory Affairs Amgen Inc. July 20, 2012

2 The health care reform law of 2010 authorized FDA to approve copies of biologic medicines An Act Entitled : The Patient Protection and Affordable Care Act. Page Biologics Price Competition and Innovation Act of 2009 (BPCIA) SEC APPROVAL PATHWAY FOR BIOSIMILAR BIOLOGICAL PRODUCTS. 2

3 Amgen makes innovative medicines and intends to make biosimilars Amgen supports a responsible, science-based pathway for biosimilars that meets our guiding principles of: Patient safety Sound scientific analysis Continued focus on the development of new therapies 3

4 Biologics have transformed the treatment of patients with many serious diseases Cancer Hemophilia Diabetes Rheumatoid arthritis Kidney disease Psoriasis Biotechnology harnesses the cell information and processes to make medicines. Biotech medicines are based on protein produced by cells. 4

5 Biologics are larger & more complicated than chemical drugs Small Molecule Biologics Acetylsalicylic acid ~180 daltons 21 atoms Insulin 51 amino acids ~5,800 daltons 788 atoms Somatropin 191 amino acids ~22,000 daltons 3091 atoms IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms Images not to scale. Image and data sources: and Genazzazi, AA et. al. (2007) Biosimilar Drugs: Concerns and Opportunities. Biodrugs 2007; 21 (6) ppg Aspirin comprehensive prescribing information Insulin product information /i2767pis.Par.0001.File.tmp/i2767pis.pdf. 3. OMIM. omim.org/entry/ Davies DR, Padlan EA. Three-dimensional structure of immunoglobulins. Ann Rev Biochem. 1975;44:

6 Making Copies The differences between chemical & biotech medicines also matter when making copies Chemical Drugs Simple chemical ingredients Uniform, predictable structure and easy to characterize Defined chemical process Biotech Medicines Large, complex proteins Heterogeneous and difficult to characterize Expressed in biological system Generics Identical active substance Identical biological activity Only question is rate and extent of absorption Bioavailability study adequate for approval Biosimilars Similar, not identical active substance Biological activity may vary Necessary to identify differences and determine which differences matter clinically Bioavailability study alone not adequate for approval Biosimilars are not generics 6

7 No two biologics will be identical when expressed from different living cells Biosimilars are similar......but not identical to the original medicine The challenge with biosimilars is knowing which differences matter clinically. 1 Health Canada Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), 2010/03/05

8 Legal and Regulatory Status in the U.S. Legal basis for approval Food, Drug & Cosmetics Act (FDCA) Provision for generic approvals (1984) E.g. Hatch-Waxman for drugs Mainly for chemical drugs 505(b)(2) offers a pathway for FDCA proteins, e.g. Omnitrope. (A few biological products were approved via FDCA, and thus the 505(b)(2) and ANDA routes are available if scientifically appropriate.) Public Health Service Act (PHSA) Majority of biologics approved under this act PHSA did not have provisions for abbreviated approvals Congress approved legislative pathway for biosimilars, amending PHSA enacted into law in 2010 (PL ) (BPCIA was passed as part of the Affordable Care Act) 8 8

9 U.S. biosimilar pathway amends the Public Health Service Act and defines key requirements Application Requirements Guidance Documents Patent Provisions Standard of Approval Data Protection Transition from FDCA to PHSA Interchangeability User Fees Medicare Part B Reimbursement Data Source: Patient Protection and Affordable Care Act. Available at 9

10 BPCIA implementation has implications for states in two notable areas Attribution of Adverse Events Informing benefit-risk profile and ensuring accurate and efficient attribution of adverse events throughout product lifecycle Application of interchangeability Determining what role the FDA designation of a product as interchangeable will have for the practice of pharmacy

11 We know from Europe, accurately attributing adverse events is essential for patient safety Eprex (epoetin alfa) NeoRecormon (epoetin beta) Amgen believes three levels of traceability for all biologics, including interchangeable products, are essential to allow health authorities to trace an event to its root cause**: Drug class Individual manufacturer s product Manufacturer s lot number Eprex (epoetin alfa) NeoRecormon (epoetin beta) Aranesp (darbepoetin alfa)* Eprex (epoetin alfa) NeoRecormon (epoetin beta) Aranesp (darbepoetin alfa)* Dynepo (epoetin delta) (withdrawn) Mircera (peg-epoetin beta) Ratioepo (epoetin theta) Biopoin (epoetin theta) Binocrit (epoetin alfa) Abseamed (epoetin alfa) Epoetin alfa Hexal (epoetin alfa) o Silapo (epoetin zeta) o Retacrit (epoetin zeta) = Full marketing authorization = Biosimilar authorization #1 (Aug 2007) o = Biosimilar authorization #2 (Dec 2007) According to The United States Patent and Trademark Office s on-line search tool at and accessed on June 29, 2011, the following marks are registered or otherwise listed with that office: Aranesp is a registered trademark of Amgen, Inc. Mircera is a registered trademark of Hoffmann-La Roche Inc. CORPORATION NEW JERSEY Dynepo is a registered trademark of Aventis Pharma Holding GmbH CORPORATION FED REP GERMANY The following list of marks may be registered with jurisdictions outside of the United States: NeoRecormon, Biopoin, and Ratioepo * Please see full US safety information, including boxed warnings for Aranesp (darbepoetin alfa) at the end of this presentation or at Some products are marketed in different jurisdictions under different brand names. Data Source: European Public Assessment Reports published on EMA Website. Available at Withdrawal statement for Epoetin Delta available at ** Morrison A, Walker C, Fox A. PharmacoVigilance Review. 2009;3(4):

12 Biologics are often very sensitive, e.g. to manufacturing, handling and the environment A change in any of the many steps in manufacturing a biologic medicine, container closure, storage, etc. could change the characteristics of the end product. Feed 2 Alkali 3 Bioreactor Motor: RPM 2,4 Gases 4 : N 2, O 2, CO 2 Many changes won t matter. Some changes could have implications for the patient, such as: Probe outputs: temperature, ph, dissolved oxygen 2 Cell and growth media 2 -- neutralizing the medicine -- Changing the pharmacokinetics -- cross-reacting with native proteins N 2 = nitrogen; O 2 = oxygen; CO 2 = carbon dioxide; RPM = revolutions per minute. 1. Amgen Inc. An Introduction to Biotechnology. Accessed February 10, Martin I, et al. Trends Biotech. 2004;22: Langheinrich C, et al. Biotechnol Bioeng. 1999;66: Rodrigues C, et al. Biotechnology Advances. 2011;29:

13 All biologics present distinct challenges in attribution of adverse events Molecular Size AE Latency Crossover Period Acetylsalicyclic acid ~180 daltons 21 atoms IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms Product Concentration Anti-drug Antibodies Detected X Time after patient dosing Graphs for illustration purposes only; not actual data points 0 Product Concentration Cross-over Period X Time after patient dosing Anti-drug Antibodies Detected Images not to scale

14 Both Federal and State authorities have important roles in successful biosimilar policy Tracking requirement on product label/ insert Federal Jurisdiction Pharmacist notification obligations Effective Tracking & Tracing Unique product names State Jurisdiction Physician record keeping requirements Patient access to information 14

15 U.S. biosimilar pathway amends the Public Health Service Act and defines key requirements Application Requirements Guidance Documents Patent Provisions Standard of Approval Data Protection Transition from FDCA to PHSA Interchangeability User Fees Medicare Part B Reimbursement Data Source: Patient Protection and Affordable Care Act. Available at 15

16 A determination of interchangeability is distinct from a finding of biosimilarity Biosimilarity Highly similar and absence of clinically meaningful differences Interchangeability 1) Biosimilar 2) Expectation of same clinical result in any given patient 3) No additional risk to safety or efficacy as a result of a switch(es) Beyond the scientific assessment, there are significant practical challenges to interchangeability; traceability is one. 16

17 FDA clearly distinguishes interchangeable biologics from biosimilars Interchangeability a higher standard Under the BPCI Act, biosimilars will also have an opportunity to meet a higher standard of similarity to a reference product interchangeability reflecting an FDA assessment that pharmacists can make substitutions between biologics without the prescriber s intervention. Biosimilar substitution inappropriate The Agency will also develop standards to ensure that products not deemed interchangeable are not inadvertently substituted for a reference product without the prescriber s consent. Source: Developing the Nation's Biosimilars Program. Steven Kozlowski, M.D., Janet Woodcock, M.D., Karen Midthun, M.D., and Rachel Behrman Sherman, M.D., M.P.H. N Engl J Med 2011; 365: August 4, Amgen Policy Presentation 17

18 FDA must determine how similar is similar enough to be interchangeable. Switching studies have a role How many patients? Who is any given patient? But questions remain. How many switches? How to track and evaluate outcomes? 18

19 States regulate product substitution State pharmacy practice acts and related regulations and regulatory actions govern substitution of one product for another by a pharmacist without the involvement of the prescriber; Interchangeability is a scientific determination by FDA. Substitution at the retail pharmacy presents different issues than in an institutional setting, although most state substitution laws apply broadly to the practice of pharmacy. Reference: Patient Protection and Affordable Care Act. Available at 19

20 Current state generic drug substitution policies vary Permissive: Generic substitution is permissive (not mandatory) in most states. Dispense as Written: applies in variety of forms in states Exceptions: A few states restrict or prohibit substitution for specified drugs. Orange Book: Many states specifically rely on the Orange Book to identify FDCA-approved drugs that may be substituted. Other states are closely tied to the Orange Book, but not specifically linked to it, in setting the standards for substitution. A few states give discretion to the pharmacist to decide what should be substituted. Amgen Policy Presentation 20

21 States take different approaches to generic substitution and the Orange Book AK HI WA OR NV CA ID AZ UT MT WY CO ND SD NE KS OK MN WI IA IL MO AR MI MI OH IN KY TN NH VT NY PA WV VA NC SC ME CT NJ DE MD DC M A RI NM MS AL GA State product selection laws that require use of the Orange Book. TX LA FL Source: The Pharmacist s Letter. State Regulations on Generic Drug Substitution. Updated April How will science-based principles apply to biologic substitution in the states? Amgen Policy Presentation 21

22 In summary: Biosimilars are similar, not identical to products they copy. made of very large and complex molecules that can cause an unwanted immune response highly sensitive to the manufacturing process and seemingly minor changes can have clinical implications. Implementing comprehensive, reliable tracking and tracing is important for all biologics and states have a role State pharmacy practice acts require updating to address interchangeable biologics and biosimilars. 22

23 Questions R1-V1 23