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1 Opportunities, Challenges and Clinical Adoption of Biosimilars: Updates for Specialty Pharmacy Tracey McGuire RPh, MSA Director of Specialty Drug Management MedImpact Healthcare Systems, Inc. Randolph, New Jersey Pharmacy Accreditation Pharmacy Times Continuing Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 1.0 contact hour (0.10 CEU) under the ACPE universal activity number L01- P. The activity is available for CE credit through May 5, Faculty Disclosure Tracey McGuire RPh, MSA, has no relevant financial relationships with commercial interests to disclose.

2 This activity is sponsored by Pharmacy Times Continuing Education and supported by an educational grant from Sandoz. Learning Objectives Compare differences between the development and approval process for biosimilar as compared to small molecule generic agents Explore the regulatory challenges to uptake of biosimilars for therapeutic use in clinical practice Identify the implications surrounding formulary uptake and clinical adoption of biosimilar agents Generics Generics are small-molecule pharmaceutical products that are chemically and therapeutically equivalent copies of the original small molecule They are chemically synthesized through predictable and well-defined chemical processes Low complexity of manufacturing Crommelin D, et al. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci. 2005;11(1):11-7.

3 Biosimilars Biologics are much larger and more complex molecules than conventional medications Cannot be fully characterized Cannot be identical versions of the reference drug Exhibit high molecular complexity making the process of development and regulatory approval complicated Variations in biosimilars are inherent due to lack of knowledge of how the innovator drug is processed and the cell line used for the reference drug Biosimilars can only be highly similar to the reference biologic product they were compared to, but have allowable differences Biosimilars also have no clinically meaningful differences in terms of safety, purity, and potency from the reference product ticbiologicapplications/biosimilars/ucm htm. Accessed 2/15/2016.; Stevenson J.G. Am J Manag Care. 2015;21(16 Suppl):S320-S330.; Hoffman JM, et al. Accessed February 26, 2016.; Christl,L, OND Therapeutic Biologics and Biosimilars Team, CDER, FDA. s/therapeuticbiologicapplications/biosimilars/ucm pdf. Accessed February 6, 2016 Key Differences between Small Molecule and Biologic Drugs Overview of the Main Differences Between Small Molecule and Biologic Drugs Small Molecule Produced by chemical synthesis Low molecule weight Well-defined structure Mostly process dependent Completely characterized Stable Mostly non-immunogenic Biological Produced by living cell structures High molecular weight Complex, heterogeneous structure Strong process dependent Impossible to fully characterize the molecule composition and heterogeneity Unstable, sensitive to external conditions Immunogenic Reprinted with permission. Declerck P. Biologicals and biosimilars: a review of the science and its implications. Generics and Biosimilars Initiative Journals (GaBI Journal). 2012;1(1)1: Manufacturing Biologics Biological agents, including biosimilars require complex processes for manufacturing, product testing, and for evaluation of safety and efficacy Drug Substance Upstream manufacturing process Downstream manufacturing process Conversion to Drug Product Sterile assurance Manufacturers may use different protein sources, bioreactors of multiple scales, and extraction and purification processes Manufacturing production complexities could lead to substandard biosimilars, thus requiring manufacturers to demonstrate that their production process has robust validation FDA website. Accessed April 5, 2016.; Mellstedt H, et al. Ann Oncol. 2008;19(3):

4 Regulatory Pathway Generic Biosimilars Abbreviated Pathway Regulated according to the Federal Food, Biologics Price Competition and Innovation Drug, and Cosmetic Act that was enacted in (BCPI) Act of 2009 established an abbreviated This act was modified in 1984 under licensure pathway or biosimilars. the Hatch-Waxman Act to allow for the Manufacturers seeking biosimilar approval expedited approval of genetic medications must file a 351(k) application with the FDA. through and Abbreviated New Drug Since 2012, the FDA has issued, and Application (ANDA) process. subsequently revised, draft guidance documents outlining the general approach it will use in determining biosimilarity to a reference product. Testing Requirements Phamracokinetic studies demonstrating bioequivalence A totality of the evidence approach is used. Manufactureres should use a stepwise approach to demonstrate biosimilarity. This approach can include a comparison of the proposed products and the reference product regarding structure, function, animal, toxicity, human pharmacokinetics and pharmacodynamics, clinical immunogenicity, and clinical efficacy and safety, as well as effectiveness. Christl L, et al. ns/biosimilars/ucm pdf. Accessed February 6, 2016.; enerics/default.htm. Accessed April 5, Clinical Factors Impacting Uptake of Biosimilars Quality Concerns Complexities in manufacturing The Indication Extrapolation Conundrum Could be difficult to justify when the mode of action is complex and involves multiple receptors or binding sites 12 Immunogenicity Nomenclature Interchangeability Concerns Key to encouraging manufacturers to file biosimilar product applications Give prescribers more confidence in using biosimilars Weise M, et al. Blood. 2014;124(22): ; Scott C. Accessed April 6, 2016.; Accessed April 5, Indication Extrapolation If a manufacturer meets the requirements for biosimilarity in one indication, the results may be extrapolated to other indications for which the reference drug is approved but the sponsor has to affirmatively make that case Orphan indications granted to the reference subsequently cannot be added to the biosimilar for 7 years Infliximab- FDA approval received on April 5, 2016 for all indications except pediatric ulcerative colitis due to orphan indication Accessed February 28, 2016.; Inflectra [package insert]. Lake Forest, IL: Hospira, a Pfizer Company; 2016.

5 Nomenclature In August 2015, the FDA issued a draft guidance and a proposed rule on its plans to change the nonproprietary naming conventions for all biologics Proposal to use the nonproprietary name of the originator product along with a distinct four-letter suffix devoid of meaning for originator products and biosimilars Only the first biosimilar has currently had a placeholder nonproprietary name imposed, but does not match the configuration the FDA proposed in its rule Accessed April Interchangeability A sponsor of a biosimilar can apply for an interchangeability designation either at initial approval or subsequent to its approval as a biosimilar One year of exclusivity is granted once an interchangeable biosimilar is approved Manufacturers must demonstrate that the drug can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch As of early 2016, the FDA had yet to issue final guidance for interchangeability cations/therapeuticbiologicapplications/biosimilars/ucm htm. Accessed February 15, State Legislative and Regulatory Activity The focus on biosimilar entry combined with concerns regarding interchangeability has prompted some states to take legislative measures All products considered for substitution must be approved by the FDA as interchangeable The prescriber may prevent substitution by writing DAW (dispense as written) The prescriber must be notified of any allowable substitution made at the pharmacy The individual patient must be notified that a substitution was made (and in some states, patient consent would be required) The pharmacist and physician must retain records of substituted biologic medications Singh SC, et al. Am J Manag Care. 2015;21(16 Suppl):S331-S339.

6 State Legislation Map As of Jan. 4, 2016, there were bills or resolutions filed in 31 states related to biologics and/or biosimilars and a cumulative total of 18 states and Puerto Rico have been signed into law Reprinted with permission from National Conference of State Legislatures. State laws and legislation related to biologic medications and substitution of biosimilars Accessed February 26, Regulatory challenges may impact formulary uptake Formularies may be driver of biosimilar uptake to over come difference in state regulations related to interchangeability Requires P&T Review Payer challenges across lines of businesses make it difficult to drive utilization through formulary benefit design Medical reimbursement challenges for providers from administering the biosimilar Manufacturers may bypass abbreviated pathway and produce biobetters, which are also based on originator products Larrick AK. Accessed February 6, 2016.; Lucio SD, et al. Am J Health Syst Pharm. 2013;70(22): Payer Regulatory Challenges Medicaid rules, as they are applied to differently by state, and by fee-for-service (FFS) versus managed Medicaid programs represent a significant challenge to payers working across multiple states and program types Medicare Part D rules which dis-incentivize biosimilars when members are in the donut hole Commercially-insured businesses traditionally had more latitude in benefit design and use of management controls (eg, policies to address copay subsidy programs). Some legislatures are intruding on this independence (eg, oral parity laws) Larrick AK. Accessed February 6, 2016.; ASPE Reasearch Brief, Essential Health Benefits: Comparing Benefits in Small Group Products and State and Federal Employee Plans, ed. U.S. Department of Health & Human Services (2011).

7 Provider Regulatory Challenges Medicaid rules, as they are applied to differently by state, and by fee-for-service (FFS) versus managed Medicaid programs represent a significant challenge to providers working across multiple states and program types MCOs will need to account for and manage the inconsistencies in Medicare Part D, Part B and Medicaid coverage of office-administered biosimilars The lack of subsidy in the donut hole for biosimilar versus the innovator Delay in J-code differentiation within their strategy and advocacy MLN Connects Provider enews. MLN/MLNMattersArticles/Downloads/SE1509.pdf. Accessed February 22, Clinical Adoption of Biosimilars Biosimilars represent a new paradigm of practice, and as such, it is hard for clinicians to adopt and accept that which they do not understand Variables that impact prescribing and that will influence the level of comfort physicians and other clinicians have with the use of biosimilars Physician considerations: Patient preference Duration of action Expectations of therapy The disclosed manufacturer Reimbursement and discounts under buy and bill Patient and Provider education materials European Union experience and learning(s) Payer Adoption of Biosimilars Payer considerations for employing biosimilar benefit designs and/or voluntary initiatives: Regulatory guidance Ability to employ a consistent benefit across population Cost savings potential Acceptance by clinical community

8 Conclusion Biosimilars require a rigorous development and approval process compared to small molecule generic agents Regulatory differences between states pose challenges to the uptake of biosimilars Payer and provider challenges may impact formulary uptake and clinical adoption of biosimilar agents Additional Resources Purple Book: aredevelopedandapproved/approvalapplications/therapeuticbiolog icapplications/biosimilars/ucm htm Biosimilars: on/guidances/ucm htm FDA Basics Webinar, June 17, 2013: Biological Products: Part 1 FDA Basics Webinar August 19, 2013: Biological Products, Part 2: Biosimilar Biological Products CE Course: FDA Overview of Biosimilar Products