1. Biosimilars: What to Expect

2. Joshua A. Meeks Pharm D. Encompass Rx
EncompassRx –

3. Disclosures
Joshua A. Meeks, Pharm D, is employed by Encompass Rx specialty pharmacy and declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this activity, including grants, employment, gifts, or stock holdings.

4. Learning Objectives
Review recently approved specialty medications and recognize emerging specialty therapies
Evaluate the impact of new and emerging specialty medications on patients and payers
Develop strategies to manage costs and facilitate appropriate access to specialty medications
Recognize the role of specialty pharmacies and pharmacists in educating patients and managing specialty medications
Define biosimilars and recognize the role of biosimilars in the specialty market
Assess potential issues and barriers associated with biosimilars

5. Spending on biologic medicines grew by 9
Spending on biologic medicines grew by 9.6% to 28% of the total spending in 2013, up from 21% in 2008, with most of the growth due to significant innovations in cancer and autoimmune diseases.

6. Today’s Market Top Selling Drugs by Sales (2015) Sales in Millions 1
Humira
14,012 2
Harvoni
13,864 3
Enbrel
8,697 4
Remicade
8,355 5
Rituxan
7,115 6
Lantus
7,029 7
Avastin
6,751 8
Herceptin
6,603 9
Revlimid
5,801 10
Sovaldi
5,276

7. Biologics make up 29% of total global pharmaceutical sales Specialty and biologics drugs to make up majority of pipeline
This Trend expected to continue along with rate of biosimilar approvals in the US. This signifies the need of biosimilars in the US as more and more biologics enter the market and make up majority of the specialty drugs. Biosimilars will offer cost savings.

8. What is a biologic? A macro molecule derived from natural components
Extremely sensitive to environmental changes which may alter their chemical structure and functionality
Batch to batch variation in products
Derived from bacteria, yeast, human cells, etc
Sensitive to changes in temperature, pressure, light, etc
1MORROW T, Felcone LH. Defining the difference: What Makes Biologics Unique. Biotechnology Healthcare. 2004;1(4):24-29.
2Food and Drug Administration. Biosimilars.
(Accessed 2015 November 7)

9. Complex Manufacturing
Cell culture
Genetically engineer cell to produce desired product and create cell line
Recovery and Purification
Harvest desired component and purification
Formulation to Distribution
Much more complex than generic small molecule drugs in that these 1st 2 steps require a great deal of tedious development.
Basically have the cell engineered to produce the protein or ab that you desire by pulling that dna sequence and introducing it into a host cell then replicating it. The desired component is then harvested and purified extensively to then be packaged accordingly
So we can see here and from the manufacturing procedures that small changes in the procedure can alter the structure ever so slightly which can in turn impact the function or immunogenicity of the product
2Food and Drug Administration. Biosimilars.

10. Comparison of small mol vs. biologic and Zarxio size vs EPO vs mab’s

11. What is a biosimilar?
A biologic shown to be “highly similar” to the reference biologic AND has “no clinically meaningful differences in safety and effectiveness” from the reference product
Offer less costly options that are proven to be safe and effective as the reference product
Must have same MOA, dosage form, route of administration, and dosage strength as the reference product
1MORROW T, Felcone LH. Defining the difference: What Makes Biologics Unique. Biotechnology Healthcare. 2004;1(4):24-29.
2Food and Drug Administration. Biosimilars.
(Accessed 2015 November 7)

12. Biosimilar Approval Pathway
Biologics
Approved under the Public Health Service Act (1944)
In 2010, Affordable Care Act amended the PHS Act and create an abbreviated pathway for biosimilar approvals much like the ANDA pathway for generic drugs
Non-biologics
Approved under the Food, Drug, and Cosmetic Act
The Hatch-Waxman amendment of established procedure for generic drug approvals
Different approval pathways for traditional drugs and biologics and abbreviated pathway created to pave the way for biosimilars just as Hatch-Waxman paved way for traditional generic drugs
US Food and Drug Administration. Biosimilars. 27 August Available at:

13. Public Health Services Act
Biosimilar Application 341(k) Analytical studies, Animal data, & Clinical data (Each stage is head-to-head comparison to reference product)
Biologics License Application 351(a) Full evaluation of drug (Pre clinical R&D, Phase I,II, & III clinical trials)
The different pathways of the 2 applications
Is Insulin considered a biosimilar?
US Food and Drug Administration. Biosimilars. 27 August Available at:

14. Biologics Price Competition & Innovation Act
Created abbreviated licensure pathway for biologics to be approved as biosimilar
Biosimilars application must include biosimilarity data derived from:
Analytical Studies (Structural and Functional Analyses)
Animal Studies (Toxicity, Pharmacodynamics, Pharmacokinetics)
Clinical Studies (Human pharmacology, immunogenicity, and clinical comparison data)
Interchangeability is separate application after biosimilar approval
Much like inferiority studies of which everything is compared to the reference product
Food and Drug Administration. Scientific ConsiderationsinDemonstratingBiosimilarity to a Reference Product. Guidance for Industry. 2015; April..

15. FDA defines interchangeability as….
“An interchangeable biological product is expected to produce the same clinical result as the reference product in any given patient, and for a product that is given to a patient more than once, the risk in terms of safety and effectiveness of alternating or switching between the interchangeable and the reference product is not greater than the risk of using the reference product without alternating or switching.”
What’s missing? No specific guidance as to what manufacturers need to demonstrate interchangeability as opposed to just biosimilarity
US Food and Drug Administration. Biosimilars. 27 August Available at:

16. Interchangeability
The FDA has issued information regarding the standard of “interchangeability”
Must demonstrate the expectation of providing the same clinical response as the reference product in any given patient
Switching between the reference product and biosimilar must not exhibit any diminished effect to the patient in regards to safety and efficacy
If the FDA deems a biosimilar as “interchangeable” with the reference product, it may substitute the reference product without the authorization of the prescriber
1st and foremost must demonstrate biosimilarity – Initial approval
Example if switching from brand Humira and switching to interchangeable biosimilar, the patient should experience highly similar efficacy and side effect profile
Food and Drug Administration. Biosimilars Questions & Answers Regarding the Impllementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. 2015; April..

17. Biosimilar = generic. Biosimilar = Interchangeable
Biosimilar = generic??? Biosimilar = Interchangeable??? Interchangeable biosimilar = generic ???

18. The FDA issues Industry guidance on labeling for Biosimilar products
Biosimilars Labeling
March 31, 2016
The FDA issues Industry guidance on labeling for Biosimilar products
1st and foremost must demonstrate biosimilarity – Initial approval
Example if switching from brand Humira and switching to interchangeable biosimilar, the patient should experience highly similar efficacy and side effect profile
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

19. Biosimilars Labeling Biosimilar Approval/licensure date
Biosimilarity Statement
*(defines biosimilar)
1st and foremost must demonstrate biosimilarity – Initial approval
Example if switching from brand Humira and switching to interchangeable biosimilar, the patient should experience highly similar efficacy and side effect profile
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

20. Biosimilars Labeling
“FDA recommends that in the biosimilar product labeling, applicants incorporate relevant data and information from the reference product labeling, with appropriate product specific modifications.”
“Data from clinical studies designed to support a demonstration of biosimilarity are not likely to be relevant to a health care practitioner’s considerations regarding safe and effective use of the biosimilar product and potentially may cause confusion, resulting in an inaccurate understanding of the risk-benefit profile of the product.”
1st and foremost must demonstrate biosimilarity – Initial approval
Example if switching from brand Humira and switching to interchangeable biosimilar, the patient should experience highly similar efficacy and side effect profile
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

21. Biosimilars Labeling
“Therefore, based on a demonstration of biosimilarity, biosimilar product labeling should include a description of the clinical data that supported safety and efficacy of the reference product as described in the FDA-approved product labeling for the reference product.”
Due to the potential for differences in clinical study parameters, we think that including comparative clinical data in biosimilar product labeling would be confusing or even potentially misleading to healthcare providers,” Leah Christl, the FDA's associate director for therapeutic biologics, wrote in a blog post. “Ultimately, the comparative data are useful for the FDA to make a decision about biosimilarity, but are not likely to be relevant to a healthcare provider's prescribing considerations.” 
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

22. Biosimilars Labeling
Proprietary name should be used in package labeling
Except….
Clinical studies or data (safety and efficacy data) derived from studies in which the reference product is described AND
Biosimilarity statement
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

23. When to use the core name?
Biosimilars Labeling
When to use the core name?
In BBW, CI’s, AE’s, and precautions….
This is labeling that identifies where risk applies to both reference and biosimilar products
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

24. Biosimilars Labeling
Data for Indications approved for the reference product but not the biosimilar product will not be included in the labeling
Immunogenicity statement in subsection of “ADVERSE REACTIONS” section
Interchangeability?
This is labeling that identifies where risk applies to both reference and biosimilar products
Do you think this product labeling will increase prescriber uptake of biosimilars or decrease? What’s your take?
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

25. It serves the same purpose as the Orange book….except for Biologics
Purple Book
It serves the same purpose as the Orange book….except for Biologics
Lists all approved biologics approved under 351(a) of the PHS Act as well as their approval dates and and patent expirations
Lists the dates that biosimilars of the reference products were approved
Will also list products approved as biosimilars and interchangeability status
Purple book is biologic equivalent of the traditional drug orange book
As more and more biosimilars approved it will be the main resource for pharmacists to determine interchangeability or just biosimilarity of a product
Food and Drug Administration. Biosimilars Questions & Answers Regarding the Impllementation of the Biologics Price Competition & Innovation Act of Guidance for Industry. 2015; April..

26. What if a biosimilar is not approved as interchangeable with the reference product?
How will payers treat this product?
Will payers be more likely to cover the interchangeable product and have the other biosimilars as non-formulary?

27. Perception of Payers Interchangeability?
Would you treat an interchangeable biosimilar different from a non-interchangeable biosimilar?
Interchangeability?

28. Your Perception Efficacy Safety Cost Savings
Would you treat an interchangeable biosimilar different from a non-interchangeable biosimilar?

29. Likelihood of substitution with biosimilar?
Your Perception
Likelihood of substitution with biosimilar?
15% cost savings?
30%?
Interchangeability?
Would you treat an interchangeable biosimilar different from a non-interchangeable biosimilar?

30. Perception of Prescribers
150 board certified specialty practitioners (GI, DERM, RA, Onc., Endo.)
Efficacy then safety were most important factors for prescribers followed by costs
Also more likely if pt is biologic naïve and if developed by major pharm company
Ultimately believe managed care will determine prescribing significantly

31. On March 6, 2015, the FDA approved the 1st Biosimilar in the US
Zarxio (Sandoz)
FDA approved biosimilar to Amgen’s Neupogen for all 5 labeled indications
FPI essentially identical

32. Zarxio Launched September 3rd and markets at a 15% discount compared to the reference product Neupogen
Zarzio Launched 2009 in Europe with same initial 15% discounted price and now average discount of Neupogen biosimilars in Europe is 20-30% cost savings
Why only 15% discount? Biologics still require clinical studies to an extent to prove biosimilarity which still requires significant funding
Does anyone know the approximate discount on tradition generic drugs?

33. Concerns Developing AB’s to reference product….what about biosimilar?
Most reference products patients have tried and failed and have moved on to new products. Will prescribers switch patients back to reference product biosimilar?
This is labeling that identifies where risk applies to both reference and biosimilar products
Do you think this product labeling will increase prescriber uptake of biosimilars or decrease? What’s your take?
Food and Drug Administration. Labeling for Biosimilar Products. Guidance for Industry. 2016, March 31..

34. Zarxio aka filgrastim-sndz
Instead of using shared non proprietary names for biosimilars, the FDA has suggested adding a 4 letter suffix to the end of the non proprietary name
FDA still debating if interchangeable biosimilars will have a unique 4 consonant suffix or share the same suffix as its reference counterpart
FDA establishing guidance not mandates
Eventually will provide mandates to create uniformity
Will need to distinguish interchangeable products especially regarding billing to account for utilization and pharmacovigilance
Lets’ chat, some groups advocating for the same non-proprietary name for all the biosimilars of a reference product…why?
Same – different names may inadvertently cause skepticism of prescribers/pts to utilize biosimilars as it may cause the perception that they are not the same or have different efficacy
Different names – sames names may cause perception that they are identical..which they are not, this also causes problems in pharmacovigilence and ae monitoring, different names may also reduce incorrect substitutions
“FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations”
FDA’s proposed Rule: “Designation of Official Names and Pro per Names for Certain Biological Products” Filed August 27, Accessed October 7, 2015.

35. On April 5, 2016, the FDA approved the 1st MAB Biosimilar in the US
Infelctra (Hospira/Pfizer)
FDA approved biosimilar to Janssen’s Remicade for 7 of 8 labeled indications
Remicade – Janssen 1998
Janssen claims exclusivity is until 2018 – inflectra will go thru litigations and most likely be a while until it enters the market
Excludes pediatric UC

36. Infliximab-dyyb Approved for all but 1 indication – pediatric UC
Only comparison studies were with RA and AS
Why only pediatric exclusion?
Pediatric exclusivity for UC until 2018 for Remicade

37. Growth of filgrastim biosimilars in Europe
Gradual process of biosimilar acceptance and development.

38. Growth of filgrastim biosimilars in Europe
Increasing access to medication
When comparing our market to Europe’s and trying to predict the traction and acceptability, we need to identify the difference in populations. We have a much more diverse melting pot if you will, when compared to Europe which plays a major role in how biosimilars may affect patients of different genetic makeup ie under or overexpression of certain genes

39. Increased access may offset total savings due to biosimilars
Increase in access to biologic regimens
Cost savings related to biosimilars in combination with reduced costs of reference products to compete
As much as a 50% increase in access of GCSF medications reported in Europe since introduction of biosimilars leading to the evidence of increased access to biologic therapy due to biosimilars
Increased access may offset total savings due to biosimilars

40. Estimated Cost Savings of Biosimilars
Project potentially $250 billion in savings over next 10 years if 11 of the likeliest biosimilars enter the market
Express Scripts
Estimate 10 year savings to be only $25 billion
Congressional Budget Office
Express Scripts projection predicts more of a best case scenario where as CBO a significantly lower estimate

41. Dependent Variables Acceptance of prescribers and patients
Reference product push-back
Final FDA mandates
Acceptance of extrapolation
Also rate of utilization of providers and patients
Reference product manufacturers may cause delays with litigation and attempts to extend patents
Extent of additional clinical and non-clinical research required by FDA to show biosimilarity and interchangeability
FDA may need to accept extrapolation for other indications to not only expedite approval of biosimilar products but also maximize cost savings (additional clinical trials increase costs of development)
13 Andrew W. Mulcahy, Zachary Predmore, and Soeren Mattke, “The Cost Savings Potential of Biosimilar Drugs in the United States,” RAND Corporation, 2014,

42. Extrapolation
Infliximab (Remicade) biosimilar approved in Europe in 2013 for all 8 indications by Celltrion/Hospira
Marked the 1st MAB biosimilar approved
Pre-approval clinical studies were done for RA and AS indications only then extrapolated data as basis for approvals for the other 6 indications
Post-marketing studies confirming biosimilarity and extrapolation for other indications
Weise M, Kurki P, Wolff-holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):

43. Biologic manufacturers update the manufacturing process throughout the life cycle of the drug
Regulations are set in place to ensure that despite changes in the manufacturing process, the product remains
highly similar and
will predictively
reproduce the same
clinical and safety
results
This data displays support to an extent of biosimilar extrapolation and it’s use in current manufacturing practices for reference products
In regards to changes in manufacturing procedures and processes
1McCamish M, Woollett G. The Continuum of Comparability Extends to Biosimilarity: How Much Is Enough and What Clinical Data Are Necessary?Clinical Pharmacology and Therapeutics. 2013;93(4): doi: /clpt
2Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72(3):315-8.

44. Manufacturing process changes are the norm
The determination of comparability within these regulations have not been primarily based on clinical and non-clinical data but rather physicochemical and analytical comparisons
Manufacturing process changes are the norm
Batch to batch biosimilarity, not identical
If this is the case, historical data supports the quality and predictability of biosimilars
1McCamish M, Woollett G. The Continuum of Comparability Extends to Biosimilarity: How Much Is Enough and What Clinical Data Are Necessary?Clinical Pharmacology and Therapeutics. 2013;93(4): doi: /clpt
2Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72(3):315-8.

45. On November 5, 2015, the FDA rejects Hospira’s EPO Bisomiliar application
Details of FDA rejection not available yet but may imply that more complex biologics may be tougher to get approved than originally thought
Retacrit was approved in Europe in 2008

46. SANDOZ Currently 5 biosimilar products in clinical trials in the US
Humira, Enbrel, Rituxan (2), Epogen (2), Neulasta
6 of 7 in phase III trials
Had first biosimilar approval in the US with Zarxio (filgrastim)

47. Filgrastrim Reference product: Neupogen (Amgen) (Sandoz)
FDA approved biosimilar 3/2015
(Apotex/Intas)
FDA accepted application in 2/2015
8 Filgrastim biosimilar products currently approved in Europe

48. Epoetin Alfa Peg-filgrastim Reference product: Neulasta (Amgen)
(Apotex)
FDA accepts application 12/2014
Epoetin Alfa
Reference product: Procrit (Janssen) & Epogen (Amgen)
(Hospira)
FDA rejects application 11/2015
(Sandoz)

49. Biosimilars & Medicare
Less than 1% of the retiree population >65 utilize biologics
However, 7-7.5% of healthcare spending for this population is represented by biologics

50. CMS Addresses Biosimilars
CMS may add biosimilars and/or remove reference product from formulary at any time
Excludes approvals under 351(k) from the CGDP during coverage gap
Biosimilars still considered subject to higher maximum copays
Biosimilars still considered subject to higher maximum copays
Transitional supply for when single product either reference or biosimilar is on formulary and patient on the opposite
Centers for Medicare & Medicaid Services (CMS) ASP NDC HCPCS Crosswalk. 30 September Available at: /Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2014ASPFiles.html. Accessed December 19, 2014.

51. Product Reimbursement under Medicare B
Initially CMS ruled that Medicare will pay 106% of WAC until ASP data is available for the Biosimilar product
Once ASP available, reimbursement will be ASP of biosimilar products + 6% of ASP for reference product
Designed to drive biosimilar prescribing
Changed from the 95% of AWP to more closely resemble the actual market cost
Large sleeper discounts to providers before
ASP method stabilized medicare b expenditures

52. State Regulations on Biosimilars
Address substitution regulations of FDA approved interchangeable biosimilars
Requirements of notification of substitution to prescriber and/or patient
Proof of medical necessity requirements (Tennessee)
Record keeping of substitutions
Available at: Accessed November 16, 2015.

53. Overview of present state legislatures regarding biosimilar rulings
Available at: Accessed November 16, 2015.

54. Georgia Pharmacy Law
Pharmacist may substitute an interchangeable biologic product
Shall dispense the lowest retail priced interchangeable product in stock
Must record substitution on original Rx with identity of biosimilar and it’s manufacturer
2015 Ga. Laws 2-42 tit.26, ch.4, art. 1.

55. Georgia Pharmacy Law continued…
Must indicate substitution on auxiliary label
Brand necessary still dictates reference product prescribed must be dispensed
Must communicate to prescriber that substitution has occurred with identity and manufacturer of interchangeable product
2015 Ga. Laws 2-42 tit.26, ch.4, art. 1.

56. Pharmacovigilence
Must be able to identify the product(s) the patient has received
Must have consistent, effective naming system in place to avoid substitution errors and correct dispensing of the prescribed product (INN and distinct brand name)
*humanized vs chimeric – less immunogenicity, newer biologics are humanized therefore will see less risk of immunogenicity in later biosimilars
Examples
1Pineda C, Caballero-uribe CV, De oliveira MG, et al. Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a point of view. Clin Rheumatol. 2015;34(4):
2Grampp G, Felix T. Pharmacovigilance Considerations for Biosimilars in the USA. BioDrugs. 2015;29(5):

57. Pharmacovigilence
System in place for reporting adverse events and effectively determining whether such event occurred from biosimilar or reference product
State laws on substitution record keeping
*humanized vs chimeric – less immunogenicity, newer biologics are humanized therefore will see less risk of immunogenicity in later biosimilars
Examples
1Pineda C, Caballero-uribe CV, De oliveira MG, et al. Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a point of view. Clin Rheumatol. 2015;34(4):
2Grampp G, Felix T. Pharmacovigilance Considerations for Biosimilars in the USA. BioDrugs. 2015;29(5):

58. What to expect moving Forward….
Final specific FDA considerations in demonstrating interchangeability
Biosimilar naming
More states enacting regulations regarding biosimilars
More Biosimilars approved
Education is Key!!!

59. Make Me a Match Remicade Cimzia Plegridy Opdivo Stelara Cosentyx
Praluent
Ulcerative Colitis
Crohn’s Disease
Rheaumatoid Arthritis
Psoriatic Arthritis
Psoriasis
Multiple Sclerosis
Ankylosing spondylitis
Oncology
Familial Hypercholesterolemia
Type II Diabetes
Remicade – 8 indications
Cimzia - PsA, RA, AS, CD
Opdivo – NSCLC, metastatin melanoma, BRAFV mutations
Cosentyx – PP, PsA, AS