Ask the Experts: Incorporating Biosimilars in the ...€¦ · relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner

Ask the Experts: Incorporating Biosimilars in the Medication-use Process

Presented as a Live Webinar

Tuesday, March 1, 2016 12:00 p.m. – 1:00 p.m. EDT

On-demand Activity

Live webinar recorded and archived to be watched at your convenience Available after April 20, 2016

www.ashpadvantage.com/BiosimsNow

Planned by ASHP Advantage and supported by independent educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Sandoz, a Novartis company.


Activity Overview In this activity, the faculty will discuss approaches for integrating biosimilars into the medication-use process, using practical examples to illustrate factors to consider in the decision-making process. The content for this activity is based on questions raised by participants in a recent educational symposium on this topic.

Learning Objectives At the conclusion of this application-based educational activity, participants should be able to

• Apply operational principles to the review of a biosimilar for formulary consideration.• Describe the clinical data paradigm used to review a biosimilar for formulary consideration.• Examine the issues related to switching between a biosimilar and the reference product.

Continuing Education Accreditation ASHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #0204-0000-16-443-L04-P for the

live activity and ACPE activity #0204-0000-16-443-H04-P for the on-demand activity).

Participants will process CPE credit online at http://elearning.ashp.org/my-activities. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity.

Webinar Information Visit www.ashpadvantage.com/go/biosimsnow/webinar to find

• Webinar registration link• Group viewing information and technical requirements• CPE webinar processing information

Additional Educational Activities in this Initiative Additional educational information on this topic can be found at www.ashpadvantage.com/BiosimsNow.

• On-demand archive of the 2015 Midyear activity “Biosimilars—The Time Is Now: Challenges andOpportunities for Pharmacists” (1.5 credit hours)

• Engaging the Experts interviews with the faculty• Two e-newsletters• On-demand archive of this webinar (1.0 credit hour)

Copyright © 2016, American Society of Health‐System Pharmacists, Inc. All rights reserved.

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http://elearning.ashp.org/my-activities

http://www.ashpadvantage.com/go/biosimsnow/webinar

http://www.ashpadvantage.com/BiosimsNow


Faculty Edward C. Li, Pharm.D., M.P.H., BCOP Associate Professor University of New England College of Pharmacy Portland, Maine

Edward C. Li, Pharm.D., M.P.H., BCOP, is Associate Professor in the Department of Pharmacy Practice at the University of New England College of Pharmacy in Portland, Maine.

Dr. Li earned his Doctor of Pharmacy degree from Philadelphia College of Pharmacy and his Master of Public Health degree from University of New England (UNE). He completed a pharmacy practice residency at University of Wisconsin Hospital and Clinics and an oncology pharmacy practice residency at University of Maryland School of Pharmacy, both accredited by ASHP.

Dr. Li is a board-certified oncology pharmacist who maintains a practice with New England Cancer Specialists, the region’s largest oncology group located in Scarborough, Maine. He also works with New Century Health, a leading innovator of quality and cost management programs, to develop cancer treatment pathways. Before joining UNE, he was Oncology Pharmacy Manager at National Comprehensive Cancer Network, a not-for-profit organization whose clinical practice guidelines in oncology are the standard of care in the United States.

Dr. Li’s research focuses on cancer pharmacoepidemiology, pharmacoeconomics, and evaluations of health policy issues as they relate to oncology practice.


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James G. Stevenson, Pharm.D., FASHP Professor, Department of Clinical Pharmacy University of Michigan College of Pharmacy President, Hospital & Health System Services Visante, Inc. Ann Arbor, Michigan

James G. Stevenson, Pharm.D., FASHP, is Professor in the Department of Clinical Pharmacy at University of Michigan College of Pharmacy in Ann Arbor and President of Hospital and Health System Services for Visante, Inc.

Dr. Stevenson received his Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees from Wayne State University in Detroit, Michigan. From 1999-2014 he served as Chief Pharmacy Officer in the University of Michigan Health System. During that same time period he was Associate Dean for Clinical Sciences at the College of Pharmacy, assuming the additional responsibilities of Chair of the Department of Clinical, Social, and Administrative Sciences from 2011-2014. In 2014 he assumed his current position for Visante, a medicines management consulting company. Before joining the University of Michigan Health System, Dr. Stevenson served as Director of Pharmacy Services at West Virginia University Hospitals and Detroit Receiving Hospital and University Health Center and as Executive Director of Pharmacy Services for the eight-hospital Detroit Medical Center. Previous academic appointments were at West Virginia University and Wayne State University.

Dr. Stevenson is a fellow of ASHP, and he is widely recognized as a leader in pharmacy. He was named Pharmacist of the Year by both the Michigan Society of Health-System Pharmacists and the Michigan Pharmacists Association. He received the 2015 Excellence in Innovation Award from the Michigan Pharmacists Association for a state-wide patient safety initiative. In addition, he was honored with the Distinguished Alumnus Award by Wayne State University College of Pharmacy and the Joseph Oddis Leadership Award by Michigan Society of Health-System Pharmacists. Dr. Stevenson served on the ASHP Board of Directors and is currently Treasurer of the Hospital Pharmacy Section of International Pharmaceutical Federation. He received the 2010 John W. Webb Lecture Award for extraordinary dedication to fostering excellence in pharmacy management, as well as the 2013 ASHP Award for Distinguished Leadership in Health-System Pharmacy Practice.

Dr. Stevenson’s specific areas of expertise include pharmacy practice management, pharmacy informatics, and medication safety.


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Disclosures In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Standards for Commercial Support, ASHP requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g. employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on the content.

All faculty and planners for ASHP education activities are qualified and selected by ASHP and required to disclose any relevant financial relationships with commercial interests. ASHP identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity. Anyone who refuses to disclose relevant financial relationships must be disqualified from any involvement with a continuing pharmacy education activity.

• Edward C. Li, Pharm.D., M.P.H., BCOP, declares that he has served on an advisory board andspeakers bureau for Hospira and an advisory board for Pfizer Inc. He has also served on advisoryboards for Merck and Sandoz and has divested himself of these relationships.

• James G. Stevenson, Pharm.D., FASHP, declares that he has served as a consultant for Amgen Inc.and is an employee of Visante, Inc.

• All other planners report no financial relationships relevant to this activity.


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Edward C. Li, Pharm.D., M.P.H., BCOP

University of New England College of PharmacyPortland, Maine

James G. Stevenson, Pharm.D., FASHP

University of Michigan College of PharmacyVisante, Inc.Ann Arbor, Michigan

Planned by ASHP Advantage and supportedby independent educational grants from

Boehringer Ingelheim Pharmaceuticals, Inc. and Sandoz, a Novartis company

Ask the Experts: Incorporating Biosimilars in the Medication‐use Process

Disclosures

• Edward C. Li, Pharm.D., M.P.H., BCOP, declaresthat he has served on an advisory board andspeakers bureau for Hospira and an advisoryboard for Pfizer Inc. He has also served onadvisory boards for Merck and Sandoz and hasdivested himself of these relationships.

• James G. Stevenson, Pharm.D., FASHP, declaresthat he has served as a consultant for Amgen Inc.and is an employee of Visante, Inc.

• All other faculty and planners report no financialrelationships relevant to this activity

Learning ObjectivesAt the conclusion of this educational activity, participants should be able to• Apply operational principles to the review of a

biosimilar for formulary consideration.• Describe the clinical data paradigm used to

review a biosimilar for formularyconsideration.

• Examine the issues related to switchingbetween a biosimilar and the referenceproduct.

Rate your current knowledge of biosimilars and issues related to integrating them into your health system.

a. Am very confident in my knowledgeb. Have good understanding with some residual

questionsc. Am beginning to understand issues, but still

have questionsd. Have not yet considered biosimilars

Today’s Outline• Introduction and review

– Data required by FDA for biosimilar approval– Current status of biosimilar naming and interchangeability– Biosimilar pipeline– Formulary review

• Questions– Theme 1: Considerations in P&T review of biosimilar

filgrastim– Theme 2: What clinical data should be reviewed for clinical

decision making?– Theme 3: Issues with biosimilar switching

Introduction: Biosimilar Data Package

Adapted from McCamish M et al. Clin Pharmacol Ther. 2012; 91:405‐17.

Develop highly similar biologic

Test and confirm Interchangeability

Postmarketing Monitoring & Policies

Test and confirm biosimilarity

• Analytical methods for structure/function

• Cell lines• In vitro/vivo models• Substance pilot and final

scale• Formulation and final drug

product

• Human clinical trials• Consideration of clinically

sensitive endpoints• Clinically sensitive patient

population• Immunogenicity• Efficacy and safety

• No explicit FDA guidance• Will be “difficult” to do in

the initial 351(k)application

• Pharmacovigilance (riskidentification andcharacterization)

• Risk minimization ifnecessary

FDA ApprovalFDA Approval

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http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf.

Feb 15, 2012 (accessed 2015 Oct 30).

351(a)

351(k)

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FDA Proposed Guidance on Naming

• INN with an added random four‐letter suffix for all biologics(including reference products)– replicamab‐cznm– replicamab‐hixf

• Benefits– Ability to differentiate products for pharmacovigilance purposes;

some biosimilars may be licensed for fewer indications than the reference product

– Common INN will group similar biologics in electronic systems– Having suffix for all products reduces perception that biosimilar is

inferior to reference product

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf. August 2015 (accessed 2016 Feb 2).

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Interchangeability Update

• Interchangeability relates to switching (noimmunogenicity concerns)

• State biosimilar laws use interchangeabilitydesignation as the basis for pharmacistsubstitution

• Awaiting FDA interchangeability guidanceregarding what data are required– Set to be released in 2016

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm417290.pdf. Jan 22, 2016 (accessed 2016 Feb 2).

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Current Biosimilars(?) in the U.S.

Product U.S. ApprovalPathway

U.S. Biosimilar

EU Biosimilar

Enoxaparin 505(b)(2)-abbreviated pathway under FDCA

No Yes

tbo-filgrastim 531(a) No Yes

Filgrastim-sndz 531(k) Yes Yes

Insulin glargine 505(b)(2) No Yes

JS

Biosimilar Development in the U.S.

Brand Name (U.S. or EU)

INN ManufactureraBLA

submittedFDA

approval

Zarxio filgrastim-sndz Sandoz 7/2014 3/2015

Remsima infliximab Celltrion 8/2014

pegfilgrastim ApotexSandoz

12/201411/2015

Retacrit epoetin zeta Hospira 1/2015

Grastofil filgrastim Apotex 2/2015

etanercept Sandoz 10/2015

adalimumab Amgen 11/2015

http://www.gabionline.net/Biosimilars/News (accessed 2017 Feb 2).JS

Manufacturer Considerations

Considerations for Formulary Selection of Biosimilars

Griffith N et al. Hosp Pharm. 2014; 49:813‐25.

• Clinical data• Range of indications• Immunogenicity

concerns• Potential for

therapeuticinterchange

• Number of similaragents on formulary

• Pharmacovigilancerequirements

• Supply reliability• History of drug

shortages• Supply chain

security• Anti‐counterfeit

measures• Patient assistance

programs• Reimbursement

support

• Product packaging and labeling

• Bar coding • Compatibility with

CSTDs,* robotics• Product

preparation and administration

• Storagerequirements

• Economicconsiderations Hospital Payer Patient

• Payer policies• Transitions of care• IT and medication

system changes• Educational

requirements

Efficacy/Safety Product Considerations

Hospital and Patient Factors

*CSTDs = closed system transfer devices

JS

See enlargement, p. 15


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http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf


http://www.gabionline.net/Biosimilars/News

What are your thoughts about reviewing a biosimilar filgrastim for formulary consideration?

a. Formal P&T review is unnecessary; handle likea generic

b. Abbreviated P&T review will sufficec. Full P&T committee review is requiredd. Unsure

JS

Theme 1: Considerations in P&T review of biosimilar filgrastim

“What sort of uptake is expected for biosimilar

filgrastim-sndz compared with reference filgrastim?” “What are the main

considerations in the formulary evaluation of biosimilar filgrastim?”

“If 14 days of biosimilar filgrastim is cheaper than

pegfilgrastim, will (should?) the P&T

committee switch over to biosimilar filgrastim?”

JS

Biosimilars Market Uptake in Europe

Assessing biosimilar uptake and competition in European markets 2014. www.imshealth.com. October 2014 (accessed 2016 Feb 2).

Perc

ent o

f Tre

atm

ent D

ays,

201

3

JS

Factors Impacting Uptake of Biosimilars

• Range of indications• Price, reimbursement• Position within prescription drug plans

(patient out‐of‐pocket costs)• Dosage forms available• Supply reliability

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Biosimilar Filgrastim: Analytical Tests for Comparability

Rathore AS et al. Anal Bioanal Chem. 2014; 406:6569‐76.

Category Test Objective

Quantitative analysis of various product-related impurities

RP-HPLC Product-related impurities (oxidized and reduced product)

SE-HPLC high-molecular-weight impurities (aggregates)

Reducing and non-reducingSDS PAGE

high- and low-molecular-weight impurities

Quantitative analysis of various host cell-related impurities

ELISA HCP quantitation

2D gel electrophoresis HCP identification and measurement of isoelectric point and molecular weight

UPLC-MS HCP identification and measurement of molecular weight

Picogreen assay Quantitation of double-stranded DNA

Structural integrity analysis

CD spectroscopy Secondary structure

Fluorescence spectroscopy Secondary structure

UPLC-mass spectroscopy Intact mass analysis, peptide mapping, and identification of disulfide linkage positions

Functional analysis In vitro-bioassay Biological activity

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Physicochemical and Biologic Comparability of a Biosimilar Filgrastim

Sörgel F et al. BioDrugs. 2010; 24:347‐57.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/

OncologicDrugsAdvisoryCommittee/UCM428780.pdf. Jan 7, 2015 (accessed 2016 Feb 2).

N-terminal sequencing confirmed identical primary structureReceptor binding affinity

Surface Plasmon Resonance

Spectroscopy

Secondary & tertiary structures

Peptide Mapping Far UV CD spectra

Biosimilar contained lower amounts of variants and impurities via RP-HPLC.Stability was the same via forced degradation and analyzed via RP-HPLC, SEC, and in vitro bioassay.

Conclusion: “[the biosimilar] is similar to its reference product with regard to protein structure, size, mass, charge, hydrophobicity, and bioactivity.

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www.imshealth.com

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428780.pdf

PK/PD Comparison of a Biosimilar Filgrastim with Reference



Pharmacokinetic and Pharmacodynamic Analysis

While lower, the biosimilar Cmax and AUC were within the standard equivalence boundaries of 80–125%

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Summary of Filgrastim Clinical Studies

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428780.pdf. Jan 7, 2015 (accessed 2016 Feb 2).

Name Type N Design

EP06-101 PK/PD, safety 32 Randomized, double-blind, 2-way crossover; healthy subjects

EP06-103 PK/PD, safety 28 Randomized, double-blind, 2-way crossover; healthy subjects; 2 doses per group



EP06-302 Safety, efficacy 204 Randomized, double-blind, active control; breast cancer patients

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EP06‐302: Biosimilar Filgrastim Phase III RCT• Randomized, double‐blind study• Population: patients with breast cancer receiving

adjuvant/neoadjuvant TAC chemotherapy• Four treatment arms: Biosimilar (B), Reference (R)

Blackwell K et al. Ann Oncol. 2015; 26:1948‐53.

Arm 1

Arm 2

Arm 3

Arm 4

Ran

dom

ize

Cycles 1 through 6

B B B B B B

B R B R B R

R B R B R B

R R R R R R

n=48 per arm

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EP06‐302: Biosimilar Filgrastim Phase III RCT

• Primary endpoint– Mean duration of severe neutropenia (DSN) after cycle 1– One‐sided 97% CI ANCOVA for non‐inferiority– Difference of 1 day was the cut‐off for clinical significance

• Secondary endpoints– Number of patients reporting fever– Incidence of febrile neutropenia (FN) – Hospitalization due to FN– ANC nadir depth– Time to ANC recovery– Filgrastim antibody formation, adverse effects

Blackwell K et al. Ann Oncol. 2015; 26:1948‐53.EL

EP06‐302: Efficacy Results (Cycle 1)

Filgrastim-sndz Reference Statistics

Mean DSN, days (SD)

1.17 days (1.11)

1.20 days (1.02)

Lower limit of the 97.5% CI of -0.26 days

Depth of ANC nadir, count

0.30 × 109/L (range: 0−8.87)

0.25 x 109/L (range: 0−8.39)

Time to ANC recovery, days (SD)

1.79 days(0.97)

1.68 days (0.81)

Incidence of FN, % (n)

4.7% (5 patients)

1.9% (2 patients)

Blackwell K et al. Ann Oncol. 2015; 26:1948‐53.EL

SD = standard deviation.CI = confidence interval.

EP06‐302: Efficacy Results


Number of Patients (%) with at Least One Occurrence

Secondary Endpoint

Pooled non-alternating

(B + R)n=86

Pooled alternating

(B-R + R-B)n=89

Biosimilarnon-

alternatingn=40

Referencenon-

alternatingn=46

Fever episode 8 (9.3) 12 (13.5) 6 (15.0) 2 (4.3)

FN 2 (2.3) 6 (6.7) 2 (5) 0

Hospitalization due to FN

2 (2.3) 1 (1.1) 2 (5) 0

Infection 6 (7.0) 9 (10.1) 2 (5) 4 (8.7)

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EP06‐302: Safety Results


0

10

20

30

40

50

60

70

Bone Pain Asthenia Diarrhea Arthralgia

% o

f pat

ient

s

Arm 1 (n = 53) Arm 2 (n = 54) Arm 3 (n = 55) Arm 4 (n = 52)

“No patient developed binding or neutralizing antibodies against G-CSF in any arm at any time during the study.”

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Filgrastim‐Pegfilgrastim Financial Analysis

Product ASP (480 mcg)

ASP (14 days)

Reimburse-ment

Margin* Break-evenwith

Pegfilgrastim

Filgrastim (reference) $483.36 $6,767.04 $7,173.06 $406.02 8 days

tbo-filgrastim $369.60 $5,174.40 $5,484.86 $310.46 10 days

Biosimilar $465.12 $6,511.68 $6,917.70 $406.02 8 days

Pegfilgrastim N/A $3,828.10 $4,057.78 $229.69 N/A

https://www.cms.gov/apps/ama/license.asp?file=/McrPartBDrugAvgSalesPrice/downloads/2016‐January‐ASP‐Pricing‐File.zip. Effective Jan 16, 2016 (accessed 2016 Feb 2).

ASP = average sales price.*Assumes acquisition price is equal to ASP.

JS

Formulary Consideration Points• Biosimilar filgrastim is comparable to reference

filgrastim– Preclinical data– PK/PD and duration of severe neutropenia– Allows extrapolation to other indications

• Based on ASP, 14 days of biosimilar filgrastim is stillmore expensive than pegfilgrastim– While the margin is better with filgrastim products,

pegfilgrastim is used for convenience on outpatient side– Use of filgrastim products less than 8 days for FN prophylaxis

will result in cost savings (but with loss of efficacy)– Inpatient use should focus on using the lowest‐price product

JS

“A biosimilar’s efficacy is questionable because its studies do not assess the same efficacy endpoints as reference studies.”

a. Agreeb. Neutralc. Disagreed. Unsure

JS

Theme 2: What clinical data should be reviewed for clinical decision

making?

“There are questions about interchangeability of these products. The FDA statute has 2 separate

paths, one "biosimilar" and one "interchangeable." But what is the evidence surrounding therapeutic

substitution of the reference product to the biosimilar, from the biosimilar to the reference

product, or from one biosimilar to another biosimilar, particularly in terms of the

immunogenicity concern?”

“What types of clinical data are

clinical pharmacists looking for to be comfortable with

biosimilars?”

EL

Human Pharmacokinetics and Pharmacodynamics

• “Fundamental” for demonstrating biosimilarity• Both PK and PD will be necessary

– PK: patient population considerations– PD should study measures that

• Are relevant to clinical outcomes• Can be quickly assessed with precision• Have the sensitivity to detect clinically meaningful difference

• Ideally correlate exposure to clinical outcomes• Use crossover and parallel designs

http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2016 Feb 2).

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https://www.cms.gov/apps/ama/license.asp?file=/McrPartBDrugAvgSalesPrice/downloads/2016-January-ASP-Pricing-File.zip

http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

Clinical Pharmacist: What to assess with PK/PD studies?

• Were these studies used as part of thebiosimilar data package submitted to FDA?– Assess endpoints and correlation to clinical

outcomes– Are the products comparable?

• Can these data be extrapolated to apopulation in which you are considering use?

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Comparative Clinical Studies• The goal of comparative clinical studies is to assess

whether the biosimilar is different than the reference, not to demonstrate safety and efficacy

Long-term outcomes

Short-term outcomes

Pharmacologic action

Administerbiologic

Survival (DFS, OS)

Response rate

HER2 degradation; ADCC; inhibit

MAPK/PI3K/Akt

ReferenceTrastuzumab

Survival (DFS, OS)

Response rate

HER2 degradation; ADCC; inhibit

MAPK/PI3K/Akt

Biosimilar Trastuzumab

Clinical Pharmacist: What to assess with comparative clinical studies?

• Clinical data and populations studied in FDAapproval

• Range of indications• Presence of biomarker to assess efficacy and

safety• Experienced vs. de novo patients

– Immunogenicity concerns due to switching

Griffith N et al. Hosp Pharm. 2014; 49:813‐25.EL

Extrapolation of Indications• Extrapolation of data from a clinical trial in one

disease to support approval for additional indications• Factors to be considered

– Clinical experience with the reference product– Mechanism(s) of action in each indication– Target receptors– Product structure and target/receptor interactions– Pharmacokinetics in different patient populations– Differences in the safety/immunogenicity profile between

indicationsWeise M et al. Blood. 2014; 124:3191‐6.

http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm428

732.pdf (accessed 2015 Dec 26).EL

Monoclonal Antibody Example: Infliximab

Feagan BG et al. Biologicals. 2014; 42:177‐83.

Heavy chain

Light chain

Fc region

Fab region

• Inhibition of receptor-ligand binding

• Inhibition of extracellulardomain shedding

• Reverse signaling (apoptosis)

• Activating vs. inhibitory functions

• Examples: ADCC, endocytosis of immune complexes, CDC, inhibiting activation of lymphocytes

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ADCC = antibody‐dependent cell‐mediated cytotoxicity.CDC = complement‐dependent cytotoxicity.

Indication Extrapolation Framework

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf. March 19, 2013 (accessed 2016 Feb 2).

Weise M et al. Blood. 2014; 124:3191‐6.

Patient Factors• Similarity of biologic

disposition: PK/PD• Organ function• Age, ethnicity, etc.

Disease Factors• Clear MOA?• Similarity of disease

(e.g., histology, stage, pathophysiology)

• Single vs. combo therapy• Clinical manifestation

Endpoint Factors• Efficacy and toxicity• Short‐term vs. long‐

term• Sensitivity of surrogate

outcomes

Quantitative Evidence of BiosimilarityIn vitro, preclinical, epidemiological studies, diagnostic studies, clinical trials, and

observational studies

Indication Extrapolation DeterminationNo extrapolation; extrapolation to some indications; extrapolation to all indications

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http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm428732.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf

Initial experience and evidence with biosimilar infliximab indicates which of the following?

a. Biosimilar is MORE immunogenic than thereference

b. Biosimilar is LESS immunogenic than thereference

c. Immunogenicity is concern when switching fromref to the biosim

d. Comparable immunogenicity of biosimilar, evenwith switching

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Theme 3: Issues with biosimilar switching

“I'd like to learn more about how prescribing of anti-rheumatic biologics will be changed by the introduction of biosimilars. In particular, I'd like

to know more about the biosimilar antigenic similarities and differences, such as, would a

patient that had a infusion reaction to Remicade (infliximab) be expected to have the same reaction with biosimilar infliximab. Or, if a patient has developed anti-drug antibodies,

will those antibodies bind the biosimilar.”

“Can this be treated like warfarin - start a patient on one and

keep them on with no change during their

treatment?”

EL

Framework for Switching

Rx for B

Back/forth

Sequential

Rx for R

B B B B B B

B R B R B R

R R R B B B

R R R R R R

Rx for R B B B B B B

Substitution

Sw

itchi

ngN

ot S

witc

hing

R = Reference B = Biosimilar

Inte

rcha

ngea

ble

mea

ns t

hese

ou

tcom

es a

re t

he s

ame

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Immunogenicity Concerns• All biologics confer a risk of immunogenicity

– Related to patient, disease, and product factors– Possible consequences include neutralizing antibodies or cytokine

release– Scientific tools for detecting immunogenicity exist, but they are not

precise• Changes to the structure of the protein increase variation in

immunogenicity– Lot‐to‐lot and between manufacturers– Variations in manufacturing must be minimized

• Possible clinical consequences– Loss or diminished efficacy or safety– Rare but serious adverse reactions have been reported

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf. August 2014 (accessed 2016 Feb 2).

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Interchangeability in the EU• EMA does not have a role; policy left up to individual

countries• Many countries have rules prohibiting substitution• France has recently provided for limited pharmacy level

substitution– At treatment initiation (physician must specify naïve patient)– Biosimilar must belong to same biologic group– Substitution is not specifically prohibited by the physician– Agence nationale de securite du medicamet et des produits de

sante (ANSM) created list of substitutable similar biologics• UK’s National Institute for Health and Care Excellence

(NICE) issued a ruling recommending that patients shouldbegin treatment with the least expensive drug available –projected to increase new starts on biosimilars

http://www.gabionline.net/Sponsored‐Articles/Legislations‐on‐biosimilar‐interchangeability‐in‐the‐US‐and‐EU‐developments‐far‐from‐visibility. Jan 6, 2015.

http://www.reuters.com/article/us‐pharmaceuticals‐britain‐biosimilars‐idUSKCN0V41UT. Jan 26, 2016 (both accessed 2016 Feb 2).JS

The Nor‐Switch Study

• Cost of biosimilar infliximab significantly less thanreference in Norway

• Government funding study to evaluate theinterchangeability in patients with existing inflammatory bowel disease (IBD)

• Active switching of patients on reference product tobiosimilar and assessment of safety/efficacy parameters

• Anticipated completion January 2017http://www.pharmatimes.com/Article/15‐02‐

23/Celltrion_Remicade_biosimilar_gathers_momentum_in_EU.aspx. Feb 23, 2015 (accessed 2016 Feb 2).

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http://www.gabionline.net/Sponsored-Articles/Legislations-on-biosimilar-interchangeability-in-the-US-and-EU-developments-far-from-visibility

http://www.reuters.com/article/us-pharmaceuticals-britain-biosimilars-idUSKCN0V41UT

http://www.pharmatimes.com/Article/15-02-23/Celltrion_Remicade_biosimilar_gathers_momentum_in_EU.aspx

Immunogenicity Studies

Week 14 Week 30 Week 54

Biosim Ref Biosim Ref Biosim Ref

PLANET-RA 25.4% 25.8% 48.4% 48.2% 52.3% 49.5%

PLANET-AS 9.1% 11% 27.4% 22.5% 22.9% 26.7%

Ben‐Horin S et al. Expert Rev Gastroenterol Hepatol. 2015; 9(suppl 1):27‐34.

Proportion of patients with anti‐drug antibodies (ADAs) to biosimilar or reference infliximab in randomized controlled studies for RA or AS

• Development of ADAs can lead to loss of efficacy• Similar rates between biosimilar and reference in prospective studies• Cross‐immunogenicity in vitro tests showed similar immunogenicity• Totality of the data should instill confidence in extrapolating

immunogenicity across indications

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RA = rheumatoid arthritis.AS = ankylosing spondylitis.

Infliximab Biosimilar Switching

• Retrospective multicenter study of 6 hospitalsin Korea in patients with mild to moderate IBD

• 36 out of 110 adults receiving biosimilarswitched from reference to biosimilar

• Efficacy was maintained in most patients whoswitched

• No antibody or long‐term assessmentsperformed

Jung YS et al. J Gastroenterol Hepatol. 2015; 30:1705‐12. JS

Infliximab Biosimilar: Switching in Pediatric Patients

• Prospective study in 3 Polish academic centers; 32 patients withulcerative colitis or Crohn’s Disease switched from reference to biosimilar due to lack of availability of reference product

• Patients presenting with active disease before switching tobiosimilar achieved a clinical remission after receiving the biosimilar

• Patients maintained remission after 2 doses of biosimilar• At the end of follow‐up

– Two patients lost therapeutic response– One patient had an infusion reaction– No significant differences between reference and biosimilar in mild

adverse eventsSieczkowska J et al. J Crohns Colitis. 2016; 10:127‐32.

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Switching: Early Inferences

• Switching of biologics has been around fordecades (e.g., erythropoiesis‐stimulatingagents, myeloid growth factors)

• Switching of biosimilar monoclonal antibodiesseems feasible– No initial loss of efficacy– Similar safety

• Longer‐term studies are needed for definitiveanswer

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Summary• FDA has taken an approach similar to the EMA in the

regulatory approval process for biosimilars• Approval includes clinical studies of PK/PD, efficacy,

safety, and immunogenicity• Multiple factors need to be considered in the formulary

review process, including clinical, operational, and economic

• Uptake of biosimilars in the EU has been variable, with increased activity around substitution and switching

• FDA will be releasing future guidance on interchangeability

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Rate your current knowledge of biosimilars and issues related to integrating them into your health system.

a. Am very confident in my knowledgeb. Have good understanding with some residual

questionsc. Am beginning to understand issues, but still

have questionsd. Have not yet considered biosimilars


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Useful Resources for Pharmacists

• ASHP Resource Center on Biosimilars– http://www.ashp.org/menu/PracticePolicy/ResourceCenters

/Emerging‐Sciences/Biosimilars.aspx (accessed 2016 Feb 2).

• American Journal of Managed Care Resource Center– http://www.ajmc.com/resource‐center/biosimilars (accessed

2016 Feb 2).

• Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health‐system pharmacists. Am J Health‐Syst Pharm. 2013; 70:2004‐17.


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http://www.ashp.org/menu/PracticePolicy/ResourceCenters/Emerging-Sciences/Biosimilars.aspx

http://www.ajmc.com/resource-center/biosimilars


http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf.

Feb 15, 2012 (accessed 2015 Oct 30).

351(a)

351(k)

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Biosimilars Market Uptake in Europe

Assessing biosimilar uptake and competition in European markets 2014. www.imshealth.com. October 2014 (accessed 2016 Feb 2).

Perc

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atm

ent D

ays,

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http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf

www.imshealth.com

Physicochemical and Biologic Comparability of a Biosimilar Filgrastim



N-terminal sequencing confirmed identical primary structureReceptor binding affinity

Surface Plasmon Resonance

Spectroscopy

Secondary & tertiary structures

Peptide Mapping Far UV CD spectra

Biosimilar contained lower amounts of variants and impurities via RP-HPLC.Stability was the same via forced degradation and analyzed via RP-HPLC, SEC, and in vitro bioassay.

Conclusion: “[the biosimilar] is similar to its reference product with regard to protein structure, size, mass, charge, hydrophobicity, and bioactivity.

EL

PK/PD Comparison of a Biosimilar Filgrastim with Reference



Pharmacokinetic and Pharmacodynamic Analysis

While lower, the biosimilar Cmax and AUC were within the standard equivalence boundaries of 80–125%

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Self-assessment Questions 1. When applying operational principles for considering a filgrastim biosimilar for formulary, which of

the following statements is true?

a. Administering biosimilar filgrastim in the outpatient setting is significantly less expensive thanpegfilgrastim.

b. The use of filgrastim products for less than 8 days will result in significant cost savings andtherefore this should be the preferred outpatient strategy.

c. Formulary decisions for both the inpatient and outpatient settings should be based on whatproduct can be acquired for the lowest price.

d. While pegfilgrastim’s margin for Medicare is less than for 14 days of filgrastim products (ifacquisition price is equal to the average sales price), pegfilgrastim is still likely to be used in theoutpatient setting because of patient convenience.

2. The goal of biosimilar comparative clinical studies is to

a. Demonstrate that the biosimilar is safe and effective.b. Describe the clinical differences between the biosimilar and reference product in efficacy and

safety.c. Assess whether the biosimilar is different than the reference product based on clinically

sensitive endpoints.d. Document the cost savings associated with use of the biosimilar compared with the reference

product.

3. Which of the following scenarios is an example of switching?

a. The prescriber writes a prescription for the reference product in a de novo patient, and thepharmacy dispenses the biosimilar.

b. The prescriber writes a prescription for biosimilar A in a de novo patient, and the pharmacydispenses biosimilar B.

c. A patient who has been taking a reference biologic for the past year now receives the biosimilardue to the patient’s insurance coverage policy.

d. A patient who has been taking pegfilgrastim as an outpatient for febrile neutropenia prophylaxisreceives biosimilar filgrastim during an extended hospital stay.

Answers

1. d2. c3. c


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Documents

Ask the Experts: Incorporating Biosimilars in the ...€¦ · relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner