Biosimilars: The Health- System Pharmacy · PDF fileBiosimilars: The Health-System Pharmacy...

©2014 Novation Confidential.1

Steven Lucio, PharmD, BCPS

January 29, 2015

Effectively Managing Specialty Therapies: A Forum for Payers

Biosimilars: The Health-

System Pharmacy Perspective


Key Questions to Be Addressed

• To what extent do hospitals view biosimilars as a viable alternative

for the management of biologic drug costs?

• What are the greatest hurdles to biosimilar adoption?

• How are hospitals preparing for the introduction and subsequent

evaluation of biosimilars?

• What physician education and other clinical strategies are being

employed to elevate interest in biosimilars?



By 2019….


Understanding the Biosimilar Paradigm

1. Demystifying the science and comprehending the regulation

2. Reviewing the European market and model

3. Leveraging the Pharmacy and Therapeutics Committee and the

therapeutic interchange infrastructure

4. Learning by example – the “non-biosimilar” biosimilar, tbo-

filgrastim

5. Monitoring the payer response



The Principles of Biologic Manufacturing

• As compared to small molecule drugs, all biologics products,

whether originator reference or biosimilar, are:

• More structurally complex

• More difficult to manufacture and demonstrate variability in

their production

• And are more likely to elicit immunogenic responses

• Clinicians, including pharmacists and physicians, do not dwell on

these particular aspects of pharmaceutical manufacturing on a day

to day basis

• Education on these elements is ongoing, but more training is

required


Biologic Medications Are More Complex Than

Generics

Aspirin

C9H8O4

Rituximab

C6416H9874N1688O1987S44

Filgrastim

C845H1343N233O243S9

www.drugbank.ca, accessed March 20, 2013


Biologic Manufacturing Is More Complex

www.pharmaceutical-technology.com, accessed Feb.28, 2014

©2014 Novation Confidential.7©2014 Novation Confidential.7

Biologic Manufacturing Complexity

Mellstedt H, et al. Ann Oncol. 2008;19:411-419.


Biologic Manufacturing Variability

Nature Biotechnology 2011;29:310-312


Biologic Manufacturing Changes Are Not

Uncommon (EMA Example)

Ann Rheum Dis 2013;72:315-318

0 10 20 30 40

Benlysta

Ilaris

Rilonacept Regeneron

Cimzia

Simponi

RoActemra

Orencia

Humira

Enbrel

Remicade

MabThera

©2014 Novation Confidential.10©2014 Novation Confidential.10


Biologics Can Generate Immune Responses

• Large globular proteins that can induce a range of immune responses

• Factors contributing to immunogenicity:

• Post-translational modifications

• Higher order structure

• Aggregation

Product Antibody

formation (%)

Erythropoietin < 1

Factor VIII 15-52

Factor IX 1-2

Interferon α 44

Interferon β < 5

IL1 Ra 2

Growth hormone 1-2

Infliximab 17-60

Nephrol Dial Transplant 2006;21[Suppl 5]:v4-v8, Nat Rev Drug Discov 2012;11:527-540, J Investig Allergol Clin Immunol 2008;18:335-342


What Is a Biosimilar? Is it a Generic Biologic?


• No, because of the complexity, manufacturing variability and

potential for immunogenicity associated with biologics

• A biosimilar is:

• A follow-on biologic that meets extremely high standards

for comparability to an originator biologic drug, and

• Approved via an abbreviated process for use in the same

indications as the originator product with no clinically

meaningful differences in safety, purity, and potency



Understanding Biosimilar

Legislation



Biologics Price Competition and Innovation Act

of 2009

• Signed into law on Mar. 23, 2010

• Created the 351(k) or “biosimilar” pathway

• Granted FDA authority to approve “highly similar” versions of previously approved biologics

• “Abbreviated” process

• Biosimilars must demonstrate safety, purity and potency


Approval Pathways (Small Molecules)

Product

type

Application

type

Application

pathway

Clinical

studies

Application

requirements

Drug

(Food Drug

and

Cosmetic

Act)

New Drug

Application

(NDA)

505(b)1 YesFull evaluation of

safety and efficacy

505(b)2 Yes

Studies do not have

to be done by the

application sponsor

Abbreviated New

Drug Application

(ANDA)*

505(j) No

Approval based upon

bioequivalence

determination

*Created by Hatch-Waxman Amendments

Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-2017.


Approval Pathways (Biologics)

Product

type

Application

type

Application

pathway

Clinical

studies

Application

requirements

Biologic

(Public

Health

Service Act)

Biologics

License

Application

(BLA)

351(a) Yes

Full evaluation of

purity, safety and

potency

Biosimilar

Application

(established

2010)

351(k) Yes

Yes, but abbreviated

process (one clinical

trial)



Interpreting the “Pyramid”

Clinical

Animal Studies

Clinical Immunogenicity

Clinical Knowledge (e.g., Post-Market Experience)

Human Pharmacokinetics and Pharmacodynamics

Structural and Functional Characterization

The more work

you do here…

…the less you

should have to do

here.

Adapted from FDA Webinar: Biosimilar Biological Products


Interpreting State Legislation Related to

Biologics and Biosimilar Substitution

http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed Nov. 25, 2014.



The Regulatory Unknown

• What will biosimilars be named? (e.g. non-proprietary name)

• What will be the requirements for biosimilar interchangeability?

• Will the Food and Drug Administration allow for extrapolation of indications?

• When will the Food and Drug Administration make these decisions?

• How will the patent litigation process impact the timing of product launches?


Biosimilar Patent Litigation Process

Within 20 days of FDA accepting a biosimilarapplication for review, access to BLA information and manufacturing processes must be provided to the reference product sponsor and patent owner.

Sensabaugh SM. Drug Inf J. 2011;45:155-162



What Can We Learn From Europe?

“A clear understanding of the

scientific principles of the

biosimilar concept

and access to unbiased

information on licensed biosimilars

are important for physicians to

make informed and appropriate

treatment choices for their

patients”

EMA = European Medicines Agency. Weise M, et al. Blood. 2012;120:5111-5117.



Biosimilars Approved in Europe

Inflectra (infliximab; Hospira), first biosimilar monoclonal antibody approved

September 10, 2013

JNCCN 2011;9:934-943, IN VIVO Biosimilars Report, October 2010; www.forbes.com, June 28, 2013, Hospira press release, September 10, 2013

Drug NameDate First

ApprovedSuppliers

Somatropin Apr. 2006 Sandoz Gmb, Biopartners GmbH

Epoetin alfa Aug. 2007 Hexal AG, MEDICE Pharma GmbH & Co.

KG

Epoetin zeta Dec. 2007 STADA Arzneimittel AG, Hospira

Filgrastim Sept. 2008 Ratiopharm GmbH, CT Arneimittel, Teva,

Sandoz, Hexal AG, Hospira

Incentives for Biosimilars in Different

European Countries

Nat Rev Drug Discov. 2014;13:99-100


Germany France Italy UK Sweden

High generic

usageYes No No Yes Yes

Quotas Yes No Yes No No

Reference

price system

for biosimilars

Yes No No No No


1st and 2nd Generation Product Shares Epoetin

and Filgrastim Markets in Q4 2011

Therapy Germany UK France Sweden Italy

Epoetin (market share by revenue)

Aranesp® 60.8% 70.7% 68.6% 67.6% 41.2%

Eprex® 12.9% 26.0% 26.8% 10.7% 52.0%

Biosimilars 26.3% 3.2% 4.6% 21.7% 6.8%

Filgrastim (market share by revenue)

Neulasta® 73.5% 57.1% 77.0% 58.6% 59.4%

Neupogen® 14.6% 5.1% 11.2% 13.7% 24.9%

Biosimilars 11.9% 37.8% 11.8% 27.7% 15.7%

Nat Rev Drug Discov. 2014;13:99-100


The Dilemma of Limited Data

• Objective: To compare the efficacy and

safety of erythropoietic stimulating

agents (ESAs), including biosimilars, to

treat anemia in adults with CKC

• All proprietary ESAs prevent blood

transfusions but information on biosimilar

ESAs is less conclusive.

• “In general, data for biosimilar ESA

formulations are sparse and very low

quality, and are not suitable to inform

patients and health providers about the

balance of their benefits and risks”

Cochrane Database Syst Rev 2014 Dec 8;12:CD010590


Increasing Complexity of Biosimilar Evaluation

Feagan BG, et al. Biologicals. 2014;42:177-183.


What “Else” Can We Learn From Europe?

• “Biosimilars have been on the European Market for several years and have performed as expected in all licensed indications, including extrapolated indications.”

• “In our view, generation of redundant or merely ‘comforting’ data should not be requested. Instead extrapolation should be based on sound and objective scientific criteria.”

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



Weise M, Bielsky MC, De Smet K, et al. Blood. 2012;120:5111-5117; FDA. Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference

product, draft guidance, February 2012.

Use of Biosimilars in Extrapolated Indications

• Consideration of extrapolation across indications must be scientifically sound, requires:

• Similarity with reference product convincingly demonstrated,

• Relevant mechanism of action and/or receptor are the same in extrapolated indications,

• Safety profile of biosimilar properly characterized and acceptable

• May vary by product – filgrastim vs. epoetin vs. infliximab vs. ritixumab



Health-System Pharmacy

Formulary Management

Strategies



Important Issues for P & T Committees

• Addition of biosimilars to health system formularies will be a much

more involved process compared to small molecule generics

• Involvement of Pharmacy and Therapeutics Committee

required

• Review will include a more detailed evaluation of safety and

efficacy

• Mechanisms for prescribing, administration and

documentation will be more complex than generic products



Therapeutic Interchange Application Strategies

• The infrastructure for formulary evaluation and therapeutic interchange

already exists within healthcare organizations

• Existing examples

• Low molecular weight heparins

• Carbapenem antibiotics

• Echinocandin antifungals

• Insulins

• Tacrolimus and other transplant medications

• Topical thrombins

• Tumor necrosis factor – alpha inhibitors

• Erythropoietin stimulating agents

• Somatropin (human growth hormone)

• IVIG



Elements of a Drug-Evaluation Document

• Brand and generic names

and synonyms

• FDA approval information,

including data and FDA

rating,

• FDA-approved indications

• Potential non-FDA

approved indications

• Dosage forms and storage

• Recommended dosage

regimens

• Pharmacokinetic

considerations

• Use in special populations

• Pregnancy category

• Comparisons of the drug’s

efficacy, safety,

convenience and costs

• Clinical trial analysis and

critique

• Medication safety

assessment and

recommendations

• Financial analysis,

including

pharmacoeconomic

assessments



Formulary Management: Key Questions

• What was the approval history

of the biosimilar?

• What information is available

concerning the clinical efficacy

and safety of the biosimilar?

• E.g., FDA review document,

published trials, European

data, AMCP dossier, expert

organization guidelines

• Will the biosimilar product be

endorsed only for labeled

indications or for off-label

indications as well?

• What is the existing level of

adverse events with the

originator product?

• How will you ensure

appropriate

pharmacovigilance with the

biosimilar?



Formulary Management: Key Questions

(Continued)

• What modifications need to be made to existing order sets and protocols to

include biosimilar products?

• What education will need to be provided to clinicians to prepare for biosimilar

adoption?

• What patient education materials will be needed to support biosimilar use?

• What is the financial value associated with use of a biosimilar?

• Comparative cost and reimbursement



Tbo-filgrastim, “The non-biosimilar biosimilar”


The Tbo-filgrastim Example

• Could not be marketed until November 2013

• However, approved as a biosimilar in EU (TevaGrastim)

• Authorized September 15, 2008

Granix® (Teva)

• Approved August 2012 in the US via a biologics license application (BLA) or 351(a), not the 351(k) biosimilars pathway

• Approved for only one of the indications for which Neupogen(filgrastim; Amgen) is licensed

Comparative Properties

Neupogen (filgrastim) package insert. Thousand Oaks, CA: Amgen; 2012 May; Tbo-filgrastim package insert. North Wales, PA: Teva Pharmaceuticals USA; 2013 May.


Amgen G-CSF Teva G-CSF

Brand name Neupogen Granix

Generic name Filgrastim Tbo-filgrastim

Application type BLA BLA

Ingredient r-metHuG-CSF r-metHuG-CSF

Molecular Weight 18,800 daltons 18,800 daltons

Protein length 175 amino acids 175 amino acids

Expression system E. coli E. Coli

Dosages 300 mcg, 480 mcg 300 mcg, 480 mcg

Dosage forms Vial and syringe (both PF) Syringe (PF)

Storage conditions 2° to 8°C 2° to 8°C

Comparative Properties

Neupogen (filgrastim) package insert. Thousand Oaks, CA: Amgen; 2012 May; Tbo-filgrastim package insert. North Wales, PA: Teva Pharmaceuticals USA; 2013 May.


Indications Neupogen® Granix®

Cancer patients receiving myelosuppressive

chemotherapyYes Yes

Patients with acute myeloid leukemia receiving

induction or consolidation chemotherapyYes No

Cancer patients receiving bone marrow transplant Yes No

Patients undergoing peripheral blood progenitor cell

collection and therapyYes No

Patients with severe chronic neutropenia Yes No

Pregnancy category C C

Data for use in pediatrics Yes No


Tbo-filgrastim Clinical Trial Data


Mean Absolute Neutrophil Counts (XM02-02)



Post-Marketing Data with Tbo-filgrastim

• ASCO Annual Meeting 2014 Abstract from Teva

• Review of European Union Periodic Safety Update Reports

• Analyzed safety data from clinical trials and post-marketing sources from

September 15, 2008 to March 31, 2013

• Cumulative exposure to tbo-filgrastim ~ 4,474,929 patient days

• 254 tbo-filgrastim case reports and 461 adverse reactions

• Most commonly occurring terms = allergic type reactions (11), interstitial

pneumonia (4) and splenomegaly (2)

• Conclusions: No new safety risks identified

J Clin Oncol 32,2014 (suppl; abstr e17540)



Aetna Clinical Policy Bulletin: Hematopoietic Colony-Stimulating Factors (CSFs)

Aetna Approval Criteria



Anthem Approval Criteria


https://www.anthem.com/provider/noapplication/f0/s0/t0/pw_b157349.pdf?na=pharminfo, accessed June 6, 2014


Caremark Tbo-filgrastim Coverage

Granix clinical rational, available at : http://www.caremark.com/portal/asset/FEP_Rationale_Granix.pdf; accessed June 6, 2014

• Cancer patients receiving myelosuppressive chemotherapy

• Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy

• Cancer patients receiving bone marrow transplant

• Patients undergoing peripheral blood progenitor cell collection and therapy

• Patients with severe chronic neutropenia


BCBS – Coverage Across Various States

• Illinois

• GRANIX – Tier 4

• Neupogen – Tier 5 (prior authorization)

• Michigan

• GRANIX (preferred brand)

• Montana

• Neupogen (preferred brand)



Where Do We Stand with

Biosimilar Development?



Filings Accepted by FDA

http://www.novartis.com/newsroom/media-releases/en/2014/1835571.shtml;FDA Law Blog, April 2, 2014;

www.hpm.com/pdf/blog/REMICADE%20-%20Celltrion%20DJ%20Complaint.pdf; Celltrion press release, August 11, 2014; The Pink

Sheet Daily, December 19, 2014; www.forbes.com, January 7, 2015.

• Sandoz – filgrastim (Zarxio)

• Oncologic Drugs Advisory Committee Meeting (Jan. 7)

• Recommended for approval with all

indications of the reference product

• Possible approval date – March 2015

• Celltrion – infliximab

• Filed for approval; possible approval in summer 2015

• Likely to be substantial patent challenges related to this product

• Apotex – pegfilgrastim

• Announced December 17, 2014

• Possible approval in August 2015



Oncologic Drugs Advisory Committee

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


Comparison of Clinical Response

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



Summary

• Health system pharmacists eagerly await the

introduction of biosimilars

• However, many hurdles to adoption exist

including:

• Lack of familiarity with the nuances of biologic

manufacturing

• Limited understanding of regulatory

requirements and the remaining need for

clarification of outstanding issues

• Competition for attention and resources with

other critical concerns

• Degree of cost savings not defined

• Desire for confirmatory data (i.e. comfort data)

persists



Biosimilar Opportunities

• Several factors should support a

willingness to consider biosimilars and

help facilitate their adoption

• Need for financial relief for high cost

drugs will not abate

• Desire for alternatives to limited

distribution, originator products given

recent decisions of branded suppliers

• Opportunity to expand influence of

specialty pharmaceuticals

• Existence of formulary management

infrastructure already in place to

support and sustain therapeutic

interchange where clinically

appropriate



Conclusions

• The biosimilar approval mechanism will offer a process for the

introduction of clinically similar, less-expensive biologics.

• However, biosimilar adoption will be more complex and will require

substantial education of pharmacists, physicians, patients, and many

other stakeholders.

• Health care organizations will need to invest greater resources to

evaluate and use biosimilars.

• The biosimilar market will continue to be influenced by numerous

regulatory decisions, legal rulings and marketing approaches.

• Limited uptake of initial biosimilar opportunities could greatly minimize

the potential for success of subsequent more complex products.


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