BIOSIMILARS: CHALLENGES AND OPPORTUNITIES

Transcription

1 BIOSIMILARS: CHALLENGES AND OPPORTUNITIES SATURDAY/4:30-5:30PM ACPE UAN: L01-P 0.1 CEU/1.0 hr Activity Type: Knowledge-Based Learning Objectives for Pharmacists: Upon completion of this CPE activity participants should be able to: 1. Describe the current FDA approval process for biosimilar agents. 2. Describe additional requirements for FDA approval of biosimilar agents. 3. Assess new biosimilar agents for interchangeability. 4. Identify opportunities provided by biosimilar agents. 5. Identify challenges related to biosimilar agents. Speaker: Shane Madsen, PharmD, BCPS Shane Madsen is the Ambulatory Clinical Pharmacy Manager at the University of Iowa Hospital & Clinics. He is an active member of the Johnson County Pharmacy Association, Iowa Pharmacy Association, and the American Society of Health-System Pharmacists. Shane serves as a preceptor for students from the University of Iowa, College of Pharmacy, as well as PGY1 and PGY2 residents at UIHC. Speaker Disclosure: Shane Madsen reports that he is a P&T Committee Member with Wellmark. Off-label use of medications will not be discussed during this presentation.

2 Biosimilars: Challenges & Opportunities Shane Madsen, Pharm.D., BCPS Disclosure Shane Madsen reports: - he is member of the Pharmacy & Therapeutics Committee for Wellmark 1

3 Learning Objectives Upon successful completion of this activity, participants should be able to: - describe the current FDA approval process for biosimilar agents. - assess new biosimilar agents for interchangeability. - identify opportunities provided by biosimilar agents. - identify challenges related to biosimilar agents. Definitions 1 Biological product (i.e., biologic): - Large, complex molecule used to diagnose, prevent, treat, and cure diseases and medical conditions - Often produced using live organisms Bacteria, animal cells, plant cells Biosimilar: - Biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved biological product Interchangeable product: - Biological product that meets criteria for biosimilar and shown to: produce the same clinical result in any given patient (if administered more than once), have no additional risk in switching between reference product and interchangeable product 1. FDA Biosimilar and Interchangeable Products. Biosimilars/ucm htm#biological. Last accessed Jan 8,

4 Biologic Landscape Biologic landscape 2016 U.S. healthcare and medication spend 2 - $3.3 trillion in total healthcare spend - $328.6 billion in prescription drug spend This does not account for medically-billed medications Biologics = 38% of prescription drug spend in <2% of patients receive biologics Biologics = 70% of drug spend growth from CMS National Healthcare Expenditure Fact Sheet. Last accessed Jan 8, Rand Corporation. Biosimilar Cost Savings in the United States: Initial Experience & Future Potential

5 Biologic landscape 2016 Top 10 Branded Medicine by Sales 3 include: - #1 Humira (adalimumab) $13.6 billion - #3 Enbrel (etanercept) $7.4 billion - #4 Lantus (insulin glargine) $5.7 billion - #5 Remicade (infliximab) $5.3 billion - #10 Neulasta (pegfligrastim) $4.2 billion 3. Frellick, M. Top-Selling, Top-Prescribed Drugs for Medscape. Oct 2, Last accessed Jan 8, Humira*,% Enbrel*,% Remicade*,% Neulasta* Lovenox Biologic landscape Estimated that patents will be lost on medications accounting for $67 billion by Already lost patent 5 : Neupogen % Epogen Rituxan Herceptin % Avastin % * On the 2016 list of top-selling medications % FDA-approved biosimilar in US 4. Jarrett S, Dingermann T. Biosimilars Are Here: A Hospital Pharmacist s Guide to Educating Health Care Professionals on Biosimilars. Hosp Pharm. 2015;50(10): FDA Purple Book: CDER. pplications/biosimilars/ucm pdf. Last accessed Jan 8,

6 Biologics Price Competition & Innovation Act of 2009 Introduction of biosimilars in the U.S. Biologics Price Competition & Innovation Act of Part of Patient Protection & Affordable Care Act (i.e., Affordable Care Act, Obamacare) in Introduced and defined biosimilars and interchangeable products in U.S. - Amended Public Health Service (PHS) Act Added section 351(k) related to biosimilars and interchangeable products Section 351(a) is original section for biologics - Developed process to transition biologics previously approved through Food, Drug, & Cosmetics Act to PHS by e.g., insulin products, low-molecular weight heparin products 6. FDA. Biosimilars: Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. April Stevenson JG, Popovian R, Jacobs I, et al. Biosimilars: Practical Considersations for Pharmacists. Annals of Pharmacotherapy. 2017;51(7):

7 Introduction of biosimilars in the U.S. Biologics Price Competition & Innovation Act of Modified exclusivity period for innovator products - Required notification to manufacturer of reference product including materials submitted to FDA - Developed procedure for patent dispute resolution - Required FDA to develop biosimilar user fee program Implemented in Modified definition of biological product FDA. Biosimilars: Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. April FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April 2015 BPCI Act 8 Vaguely written law led to delay in FDA guidance Unlike European biosimilar regulations and Hatch- Waxman Act for generics: - No codified regulations - Non-binding guidance documents First finalized guidance document in April 2015 (5 years later) - No list of required data / documents to submit Case-by-case review based on biologic / biologic class 8. Falit BP, Singh SC, Brennan TA. Biosimilar Competition In the United States: Statutory Incentives, Payers, and Pharmacy Benefit Managers. Health Affairs. 2015;34(2):

8 BCPI Act Guidance documents 9 - Final Guidance Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (finalized 4/2015) Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (finalized 4/2015) Biosimilars: Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of 2009 (finalized 4/2015) Formal Meetings Between the FDA & Biosimilar Biological Product Sponsors or Applicants (finalized 11/2015) Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (finalized 12/2016) - Draft Guidance Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (draft 8/2014) Biosimilars: Additional Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of 2009 (draft 5/2015) Considerations in Demonstrating Interchangeability With a Reference Product (draft 1/2017) Statistical Approaches to Evaluate Analytical Similarity (draft 9/2017) 9. FDA Biosimilars Guidance. Last accessed Jan 8, BCPI Act Exclusivity modifications 6,13 - Reference product exclusivity 12 years total from first licensure before approval of biosimilar 4 years from first licensure before biosimilar application can be submitted 6 months additional exclusivity for approved pediatric studies Separate 7 year period of exclusivity for orphan drug designation - Biosimilar exclusivity NONE - Interchangeable product exclusivity Up to 12 months for first interchangeable product 6. FDA. Biosimilars: Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. April FDA. Draft: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act. Drafted published August

9 Biosimilars Biosimilar Biosimilar 11 - Approved through PHS Act, section 351(k) - Reference product usually FDA-approved can use non-fda approved, if proof of direct relationship to FDA-approved product - Must demonstrate: that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency 11. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April

10 Biosimilar Biosimilar 11 - clinically meaningful difference not defined could include differences in safety purity potency 11. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April Biosimilar Biosimilar application 11,12 - FDA highly recommends dialogue in planning phase - No absolute requirements on what is submitted - Case by case decision dependent upon agent / class - Approved through totality of evidence standard - Application will likely contain data from: Analytical studies structure / function Animal studies PK/PD, toxicities, immunogenicity Human clinical studies MOA, immunogenicity, PK / PD, efficacy - FDA can decide to not require any of these or require more 11. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April FDA. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. December

11 Biosimilar Biosimilar application must include: - Proof of: Biosimilarity Same MOA Same route of administration Same dosage form Pre-filled syringe = auto-injector = vial / syringe May need to have human factors studies Lyophilized powder the above Emulsions suspensions Same concentration Good manufacturing practices 15. FDA. Draft: Additional Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Draft published May Original product vs biosimilar study burden Original Product 351(a) Study Burden Additional Clinical Studies Clinical Pharmacology Animal Analytical Biosimilar 351(K) Study Burden Additional Clinical Studies Clinical Pharmacology Animal Analytical 10

12 Biosimilar Extrapolation can be used - Clinical and non-clinical safety and efficacy studies 6 Not required for all approved indications Must be able to demonstrate no difference across indications for: MOA PK / PD Immunogenicity Toxicities - Cannot extrapolate across routes of administration if different from reference product s approved indications - Can chose to apply for fewer indications 6. FDA. Biosimilars: Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. April Development of biosimilar candidate Select cell line Expand the cell line Protein production & purification Establish safety range for QA in replication process Identify critical quality attributes of reference product impacting safety and efficacy 10. Vulto AG, Jaquez OA. The process defines the product: What really matters in biosimilar design & production. Rheumatology. 2017;56:iv14-iv29. 11

13 Biosimilar vs. generic Biosimilar generic 7 - Not interchangeable - Not an identical match to reference product Actual variance between lots of reference product - Large, complex biologics vs small, simple molecule Biologics: Large protein structures that have numerous folds with secondary, tertiary, and quaternary structures Produced in living organism Small changes in production environment = potential large changes in end product Example: erythropoietin product in Europe Greater chance for immunogenicity Small, molecule generics: Small, simple structures Manufactured with chemical synthesis 7. Stevenson JG, Popovian R, Jacobs I, et al. Biosimilars: Practical Considersations for Pharmacists. Annals of Pharmacotherapy. 2017;51(7): Interchangeable Products 12

14 Interchangeable products Biological product that meets criteria for biosimilarity and shown to: - produce the same clinical result in any given patient, and - (if administered more than once), have no additional risk in switching between reference product and interchangeable product Switching studies Would allow for interchange between reference product and interchangeable product w/o new order - state law may limit this in practice Guidance document not final - draft released January 2017 By law, could be granted interchangeable product initially, but not recommended by FDA at this time 14. FDA. Draft: Considerations in Demonstrating Interchangeability With a Reference Product. Draft published January FDA. Draft: Additional Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Draft published May Interchangeable products Immunogenicity is major concern - Switching studies will be required for any drug expected to be administered > 1 time Should assess 2 switches Should assess PK / PD markers Use of non-fda approved reference product not likely to be allowed 14. FDA. Draft: Considerations in Demonstrating Interchangeability With a Reference Product. Draft published January FDA. Draft: Additional Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Draft published May

15 Interchangeable products Extrapolation still allowed - Heightened scrutiny of differences between products - Heightened scrutiny of differences across indications Product presentation - More scrutiny in delivery device Educational needs for patients / caregivers - Not likely to approve auto-injector for pre-filled syringe 14. FDA. Draft: Considerations in Demonstrating Interchangeability With a Reference Product. Draft published January FDA. Draft: Additional Questions & Answers Regarding Implementation of the Biologics Price Competition & Innovation Act of Draft published May Hatch-Waxman Act vs. BCPI Act Hatch-Waxman Act BCPIAct Medication type Small, molecules Biologics Requires bioequivalence Yes No Formal rules for application Yes No, guidance documents Patent & product resource Orange Book Purple Book CDER and CBER Patent exclusivity for nonoriginator product Yes 180 days Biosimilar: No Interchangeable product: up to 1 year Adapted from: 8. Falit BP, Singh SC, Brennan TA. Biosimilar Competition In the United States: Statutory Incentives, Payers, and Pharmacy Benefit Managers. Health Affairs. 2015;34(2):

16 Naming of biosimilar product No final guidance - Draft published January 2017 Brand names allowed Nonproprietary name - Concern for Ability to identify patient safety issues Substitution errors Clarity for pharmacists & other healthcare providers in ability to interchange - Will have core name from reference product + 4 letter suffix 4 letters are devoid of meaning e.g., infliximab-dyyb (Inflectra) - Will apply to previously approved biologics as well 16. FDA. Draft: Nonproprietary Naming of Biological Products. Draft published January Package labeling No guidance document States that it is a biosimilar to the reference product - INFLECTRA (infliximab-dyyb) is biosimilar* to REMICADE (infliximab) for the indications listed. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDAapproved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Utilizes clinical data from reference product FDA discourages inclusion of comparative trials with biosimilar and reference product 7. Stevenson JG, Popovian R, Jacobs I, et al. Biosimilars: Practical Considersations for Pharmacists. Annals of Pharmacotherapy. 2017;51(7): Inflectra [package insert]. Yeonsu-gu, Incheon; Republic of Korea : Celltrion;

17 Current State No approved interchangeable products 9 approved biosimilar products Nonproprietary Name Brand Name Date Approved filgrastim-sndz Zarxio March 2015 infliximab-dyyb Inflectra April 2016 etanercept-szzs Erelzi August 2016 adalimumab-atta Amjevita September 2016 infliximab-abda Renflexis May 2017 adalimumab-adbm Cyltezo August 2017 bevacizumab-awwb Mvasi September 2017 trastuzumab-dkst Ogivri December 2017 infliximab-qbtx Ixifi December FDA. Biosimilar Product Information. /Biosimilars/ucm htm. Last accessed January 8,

18 Decreased healthcare spending Estimated 20-40% price decrease with biosimilars 19 - Early experience in U.S. filgrastim market ~24% 21 Congressional budget office estimated $25 billion in savings in first 10 years 20 ( ) - Not likely to be fully realized due to delay in implementation 2017 Analysis by Rand Corporation 21 - Estimated $54 billion savings from Hirsch BR, Lyman GH. Biosimilars: A cure to the U.S. health care cost conundrum. 2014;28: Congressional Budget Office. Cost estimate S 1695 Biologics Price Competition and Innovation Act of June 25, Rand Corporation. Biosimilar Cost Savings in the United States: Initial Experience & Future Potential Remicade: A Case Study in How U.S. Pricing and Reimbursement Curb Adoption of Biosimilars Drug Channels. Last accessed January 24, Biologic drugmakers use patents, suits to thwart generic competition USA Today. Last accessed January 8, Merck-Samsung Remicade Biosimilar Accelerates Price War - Bloomberg Last accessed January 24,

19 Challenges to realizing spending decrease Delayed implementation / guidance Manufacturer hesitancy - Reliance on guidance documents vs rules - Patent lawsuits have delayed & discouraged entry - High cost and high complexity in manufacturing process - Required to share cutting-edge technology or process innovations - Lack of exclusivity for 1 st biosimilar Challenges to realizing spending decrease Contracting strategies by manufacturers of reference product Acceptance of biosimilars providers, pharmacists, patients - General safety - Extrapolating to indications not studied - Switching patients 18

20 Challenges to realizing spending decrease Reimbursement barriers for medically-billed biologics - Medicare has blended reimbursement for biosimilars, but originator product has individual reimbursement No interchangeable products - State laws prohibiting / developing roadblocks for automatic substitution even with interchangeable products As of December 1, 2017; 35 states had rules (includes Iowa) - Cumbersome process to change to biosimilars Challenges in practice Education gap on biosimilars & regulations Pharmacist Provider Nurses Clerical staff Patient Potential for error with multiple products with essentially same nonproprietary name 19

21 Challenges in practice Budget - Most cost-beneficial for inpatient may insurance approval for outpatient use Provider uneasiness with switching - Reimbursement Patient education - Same drug, different devices Role of the pharmacist Become the expert in new, complex arena Education - Patient: insurance may require different product than clinic staff provided administration education Ask questions Provide detailed education to ensure appropriate use - Other healthcare professionals Explain the approval process Product differences 20

22 Role of the pharmacist Finances - Know reimbursement differences - Know out-of-pocket cost differences for patient Medication safety - Be cognizant of biosimilar products and naming - Administration errors due to lack of education - Financial errors dispense a product that will not be reimbursed - Error and ADR reporting is critical Regulatory - Interchangeability - State law - EHR documentation Take Home Points Biologics are complex molecules with complex manufacturing process Biologics are significant driver of prescription drug spend Biosimilars have the potential to bend this cost curve Guidance for biosimilars and interchangeable products is non-binding Biosimilar generic There are significant challenges in incorporation of biosimilars to U.S. market Pharmacists can play a key role in the success of this incorporation 21

23 Questions? 22