Vol.:(0123456789)

BioDrugs (2020) 34:159–170 https://doi.org/10.1007/s40259-019-00395-w

REVIEW ARTICLE

Identifying Key Benefits in European Off‑Patent Biologics and Biosimilar Markets: It is Not Only About Price!

Binita Dutta1 · Isabelle Huys1 · Arnold G. Vulto1,2  · Steven Simoens1

Published online: 2 December 2019 © The Author(s) 2019

AbstractBiosimilar medicines have shown similarity with the originator biologic and offer a similar clinical outcome generally at a lower cost. This paper identifies benefits of off-patent biologics and biosimilars, and illustrates these benefits with empirical data from Europe. We provide a narrative review of published literature on values and benefits of biosimilars in Europe. The results describe cost savings as the key driver stemming from the lower price of biosimilars, than that of originator products, and from price competition between biosimilar(s), originator, and next-generation products. Cost savings may then translate into a number of other associated benefits. The lower price of biosimilars and similar effectiveness to the originator biolog-ics improve cost effectiveness, implying that reimbursement can be granted or extended to other patient groups, or that the biologic therapy can be moved to an earlier line of treatment. Cost savings from biosimilars can be used to increase patient access to therapy or to increase the number of healthcare professionals. Finally, competition between off-patent biologics and biosimilars may stimulate an innovation in the formulation and development of next-generation biologics. Our paper illustrates that the benefit of off-patent biologics and biosimilars is not restricted to cost savings, but that these medicines may contribute to an expansion of medical treatment options for patients, hence concomitantly contributing to the long-term sustainability of the healthcare system. This review provides a broader view for clinical and economic decision makers and healthcare professionals on the added benefits of off-patent biologics and their use in clinical practice.

Key Points

Biosimilars are generally cheaper than originator biolog-ics and may also incite price reductions of originator bio-logics; however, the benefit of biosimilars is not limited to cost savings.

Competition in European off-patent biologics and biosimilar markets may expand access to the treatment, improve cost effectiveness of the treatment, increase the number of healthcare professionals, and stimulate an incremental therapeutic innovation.

1 Introduction

Biologics are being used in the treatment of the most seri-ous, life-threatening, and chronic diseases such as cancers [1], immune-mediated inflammatory conditions [2], diabetes mellitus [3], and fertility [4] and are likely to be of use in treating other diseases in the future. However, the clinical benefits of biologic therapy are offset by challenges related to affordability of and accessibility to biologic medicines [5].

Biosimilars are highly similar and clinically equivalent forms of originator biologics. Development of biosimi-lars is complex because biologics are large and complex molecules derived from living cells by a complex manu-facturing process. However, once assessed and licensed by an advanced regulatory agency, no meaningful difference between originator biologics and biosimilars is expected with respect to quality, safety and efficacy [5, 6]. Biosimi-lars are marketed following expiration of patent and exclu-sivities of the originator biologics. These medicines are generally less costly than the originator biologics, which may be due to an abbreviated clinical trial program, and

* Arnold G. Vulto a.vulto@gmail.com

1 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Louvain, Belgium

2 Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands

160 B. Dutta et al.

possibly also to a more advanced and efficient production process [7–10].

By 2018, 34 biologics have become off-patent and 15 more biologics are expected to reach the patent cliff in the next 5 years in Europe [11, 12]. Hence, there is an oppor-tunity for market access to biosimilars. As of May 2019, 59 biosimilars have been approved in Europe, six authori-zations have been withdrawn after approval, and there are six applications under evaluation for marketing approval [13]. These include growth factors (epoetins, filgrastim), hormones (follitropin-α, insulin glargine, somatropin, teriparatide), monoclonal antibodies and fusion proteins (adalimumab, infliximab, rituximab, etanercept), and low-molecular weight heparins (enoxaparin sodium).

European countries have implemented a variety of incentives and policies to promote market access and uptake of biosimilars. The principle reason behind this favorable market environment is that countries wish to capture the savings arising from the lower price of bio-similars in an era of restricted healthcare budgets, an increase in the burden of life-threatening diseases, early detection of these diseases, and an increase in the ageing population. Biosimilars are at least 15–45% less expensive than the originator biologics [14], although prices of bio-similars vary across European countries [15]. However, price evolution of off-patent biologics and biosimilars is rapid across European countries and discounts on selected biosimilars can reach up to 80% [16]. Cumulative sav-ings due to competition between originator biologics and biosimilars on eight key products (adalimumab, insulin glargine, etanercept, infliximab, rituximab, pegfilgrastim, trastuzumab, follitropin-α) are expected to reach €98 bil-lion by 2020 in the EU group of 5 (G5: Germany, France, Italy, Spain, and UK) and the USA [17]. In Europe, the Top-10 biologics sales are €16.5 billion based on 2017 sales figures [18]. Most of these biologics are off-patent in Europe and biosimilars to these biologics are available for clinical use. Assuming that the discount on off-patent biologics and biosimilars will be at least 50%, annual sav-ings could be as large as €8–10 billion by 2020.

The key driver for uptake of biosimilars is cost reduction relative to the originator biologics; however, in this paper we argue that there are other associated benefits stemming from this key driver. Some of these value propositions of biosimilars have already been outlined in a recent opinion paper [19]; however, it did not describe all the benefits of biosimilars supported by empirical evidence. The aim of this study is to provide an in-depth and structured review of the key driver and associated benefits of off-patent biologics and biosimilars and to illustrate these benefits with empirical data from Europe. Based on these results, a broader view is presented to policy and decision makers, the pharmaceuti-cal industry, and other stakeholders of different benefits of

off-patent biologics and biosimilars, thereby supporting their optimal use in society.

2 Methods

A comprehensive literature search was performed for a nar-rative review on the benefits of off-patent originator bio-logics and biosimilars, and of competition in the off-patent biologics and biosimilars market. MEDLINE and EMBASE were searched for studies published between January 2005 and November 2018, which encompassed the period during which biosimilars were first approved for use and launched in Europe [20]. Search terms were built on the concept of cost savings, economic evaluation, and other benefits of off-patent biologics and biosimilars beyond cost savings from payer, physician, patient, and market viewpoints. The search strings consisted of Medical Subject Heading (MeSH) and text terms for “biosimilar”, “reference, originator and off-patent medicines” and text terms for “value”, “lower price”, “price competition”, “supply chain benefit”, “access to treatment”, “competition”, “awarding reimbursement”, “extending reimbursement”, “earlier line of treatment”, “wrap around services”, “economic evaluation”, “off-patent biologics”, “cost effectiveness”, and “second generation ref-erence product”. The PubMed MeSH terms were appropri-ately modified in accordance with the EMBASE database. Given a paucity of published literature on benefits of off-patent biologics and biosimilars as this is an emerging field of research, the bibliographic reference lists of eligible stud-ies were also searched for other relevant sources such as the Generics and Biosimilar Initiative Journal (GaBI), which is not indexed in PubMed or EMBASE, and gray literature such as consultancy reports (IQVIA) and websites for the UK National Health Service (NHS), National Institute for Health and Care Excellence (NICE), and European Medi-cines Agency (EMA). Articles were selected for inclusion if they reported empirical data on benefits in the off-patent bio-logics and biosimilars markets in European countries. The search results from each database were limited to published references in the English language. Articles that reported on pharmaceutical or clinical aspects of off-patent biologics and biosimilars (such as bio-equivalence, immunogenicity, pharmacokinetics, or pharmacodynamic modelling) were excluded as such articles fell outside the scope of our lit-erature review. A broad overview of the search strategy is schematically presented in Fig. 1.

3 Results

Figure 2 schematically presents different benefits of off-pat-ent biologics and biosimilars for several stakeholders. This section defines and distinguishes between these benefits,

161Benefits of Off-Patent Biologics and Biosimilars in Europe

and includes an aggregate report on a number of empiri-cal studies illustrating each benefit in the European setting. The price of biosimilars in these studies are the ex-manu-facturing price or an average price weighted cost across EU G5 countries (France, Germany, Italy, Spain, and the UK). Results of empirical studies are outlined in Table 1.

3.1 Cost Savings from Biosimilars

Cost savings may accrue from the lower price of biosimilars, than that of their originator products and from the price com-petition between biosimilars, originator, and next-generation products. With respect to the former, our literature search identified eight empirical studies. Six of these studies carried out a hypothetical budget impact analysis of biosimilars and used it in a number of scenarios relating to the price differ-ence between the originator product and biosimilars, and to other parameters such as uptake, conversion rate, and time horizon [21–26]. One study calculated actual savings arising

from the introduction of biosimilar infliximab in a UK hos-pital [26]. A Spanish study computed actual savings accru-ing from competition between the reference, biosimilar, and new anti-tumor necrosis factor (TNF)-α products, and from therapeutic optimization [27]. All of these studies pointed to substantial savings in pharmaceutical costs, except for one study in which the budget increased when a new, alternative biologic entered the market during the time horizon of the budget impact analysis [28].

3.2 Improvement in Cost Effectiveness of Treatment

The lower price and similar effectiveness of biosimilars compared with the originator biologics improve the cost effectiveness of the biologic therapy [29–33], implying that reimbursement can be granted or extended to other patient groups.

Improved cost effectiveness of biosimilars may also allow biologic therapy to be used in an earlier line of treatment

STRATEGY NUMBER OF PUBLICATIONS SELECTED

European studies

(empirical evidence)

Additional 65 articles (n=180)

Names of all off-patent biologics and biosimilars approved in

Europe* (n=1175)

Reports: IQVIA, Deloitte

Guidelines: EMA/NICE

Journals not indexed in

PubMed (GaBI)

Names of biologics and

biosimilars (EMA list)*

Search terms on Biologics &

BiosimilarsAll articles on “Biologics & Biosimilars” on PubMed (n= 8360)

Human studies on Biologics & Biosimilars

Time horizon: Jan 2005 till Nov 2018 (n=4286)

Search terms in title or

abstract for “benefits” such as

“cost savings”, “saving”,

"economic evaluation”, etc.**

Selected (empirical studies in Europe) for a narrative review on

benefits of off-patent biologics and biosimilars

(n=46)

Human studies

Benefits of off-patent biologics and biosimilars (n=461)Selected articles based on title and abstract (n=115)

Excluded articles because

outside scope of study (n=134)

Fig. 1 A broad search strategy and different stages of narrative literature search. *IQVIA Report [20]; **see Sect. 2. EMA European Medicines Agency, GaBI Generics and Biosimilar Initiative Journal, NICE National Institute for Health and Care Excellence

162 B. Dutta et al.

and enable patients to access the biologic therapy at an early stage of disease. For instance, biosimilar filgrastim was moved to first-line cancer treatment in the UK as a result of its improved cost effectiveness when compared to alternative treatments [34]. This suggests that the cost effectiveness of originator biologics should be re-visited with new cost data on biosimilars.

3.3 Increase in Patient Access to Pharmacological Treatment

Cost savings from biosimilars can be used to increase patient access to biologic therapy. Several hypothetical budget impact studies have computed how many additional patients with the same disease or how many patients with a different disease can be treated with the money saved from biosimilars [22, 24]. A Swedish study showed that there was an increase in patient access to filgrastim treatment when restrictions to prescribe filgrastim for febrile neutropenia were relaxed fol-lowing the market entry of biosimilar filgrastim in a specific region [17, 35].

Cost savings from biosimilars may also serve to support patient access to other innovative treatments. Two simulation studies showed how access to targeted antineoplastic treat-ments could be expanded by drawing on savings generated by treating chemotherapy-induced febrile neutropenia with biosimilar filgrastim and by treating anemia with biosimilar epoetin alfa [21, 25].

3.4 Increase in the Number of Healthcare Professionals

Cost savings from biosimilars can be divided among stake-holders (such as payers, hospitals, and physicians) through so-called ‘gain-sharing arrangements’ with a view to pro-moting uptake of biosimilars [36], and could be reinvested in employing a greater number of healthcare professionals.

This efficient reallocation of savings can reduce the wait-ing time for patients and improve utilization of healthcare resources in a capacity-constrained hospital [26, 37].

3.5 Incremental Innovation of Biologics

Competition between off-patent biologics and biosimi-lars may stimulate innovations in formulation, route of administration (e.g., intravenous vs. subcutaneous), new approaches to promote patient adherence to the treatment, and development of next-generation biologics (e.g., fil-grastim, pegfilgrastim, and lipegfilgrastim). There are both tangible and intangible benefits from innovation in the for-mulation, which could be extended to patient flexibility, patient care, and productivity, hence resulting in an overall societal gain [38, 39]. However, reimbursement of incre-mental innovation varies across European countries, which might be detrimental relating to the uptake of improved off-patent biologics [39]. Moreover, incremental innova-tion of the originator biologic compared with the biosimi-lar may be expensive; hence, such innovations warrant an economic evaluation to demonstrate their cost effective-ness. These features may not be clinically superior or cost effective, and therefore it may not be a preferred choice for physicians to treat their patients at a higher cost [40, 41].

4 Discussion

Although the impetus for biosimilars development has been largely a reduction in the cost of biologics, there are other benefits emerging from the main argument of cost saving, which have been illustrated in this narrative review and supported by empirical data within Europe such as cost savings related to the use of biosimilars could be reallocated to increase access to biologic therapy for

Off-patent originator

biologic

Biosimilar Innovator biologic

Price competitionNew formulation

New administration routeNext generation biologics

Cost savings from off-patent and BioS competition

Physicians ProviderPayerPatients

• Treatment options of biologic vs

conventional therapy (increase cost-

effectivenesss of BioS)

• Wider treatment options within a

therapeutic class

• Autonomy to prescribe BioS

• Increase patient access to the same biologic

treatment

• Patient access to innovative therapies

• Improve patient access/ease of

use/adherence by use of next generation

biologics

• Moving therapy to an earlier line of therapy

(improve cost-effectiveness of BioS)

• Include reimbursement of BioS in new

indications

• Improve healthcare process and

infrastructure

• Increase in number of healthcare providers

• Add-on service for patient care

Fig. 2 Benefits of off-patent biologics and biosimilars for different stakeholders. BioS biosimilars

163Benefits of Off-Patent Biologics and Biosimilars in Europe

Tabl

e 1

Sum

mar

y of

stud

ies i

llustr

atin

g be

nefit

s of o

ff-pa

tent

bio

logi

cs a

nd b

iosi

mila

rs

Ben

efit

Stud

y no

.Ye

ar/s

ettin

gSc

ope

of th

e stu

dy re

leva

nt to

ben

efit o

f Bio

SSt

udy

desi

gnRe

sult

Cos

t sav

ings

fro

m B

ioS

1Ye

ar: 2

015

Setti

ng: E

U G

5 co

untri

esa

Estim

ate

the

econ

omic

impa

ct b

y co

nver

ting

orig

inat

or

(Neu

poge

n®) t

o B

ioS

(Zar

zio®

) filg

rasti

m fo

r the

trea

t-m

ent o

f che

mot

hera

py-in

duce

d fe

brile

neu

trope

nia

[21]

Sim

ulat

ion

study

on

hypo

-th

etic

al p

anel

of 1

0,00

0 pa

tient

s/14

-day

trea

tmen

t re

gim

en

Cos

t sav

ing

from

€3.

9 m

illio

n on

da

y – 4

to €

13 m

illio

n on

day

– 14

, as

sum

ing

100%

con

vers

ion

of

patie

nts f

rom

orig

inat

or to

Bio

S fil

gras

tim. O

ther

scen

ario

s in

this

stu

dy sh

owed

a si

mila

r out

com

e2

Year

: 201

7Se

tting

: 28

Euro

pean

co

untri

es

Estim

ate

cost

savi

ngs b

y in

trodu

cing

ritu

xim

ab B

ioS

(CT-

P10)

for p

atie

nts w

ith rh

eum

atoi

d ar

thrit

is a

nd

canc

er d

iagn

oses

[22]

Bud

get i

mpa

ct a

naly

sis

(1–3

 yea

rs)

Cos

t sav

ing

calc

ulat

ed o

n dr

ug ra

nged

fro

m €

90 m

illio

n to

€57

0 m

illio

n.

The

study

exp

lore

d 3

scen

ario

s3

Year

: 201

2Se

tting

: EU

G5

coun

tries

a

Estim

ate

cost

savi

ngs b

y co

nver

ting

orig

inat

or

(Neu

poge

n®) t

o B

ioS

(Zar

zio®

) and

peg

ylat

ed

(Neu

last

a®) fi

lgra

stim

for t

he tr

eatm

ent o

f che

mo-

ther

apy-

indu

ced

febr

ile n

eutro

peni

a in

pat

ient

s acr

oss

all t

umor

type

s. C

umul

ativ

e co

sts o

f Neu

poge

n® a

nd

Zarz

io®

wer

e co

mpa

red

with

the

cost

of a

sing

le d

ose

of N

eula

sta®

[23]

Sim

ulat

ion

study

/14-

day

treat

-m

ent r

egim

enC

ost s

avin

g ca

lcul

ated

for t

reat

men

t w

ith Z

arzi

o® o

ver N

eupo

gen®

and

N

eula

sta®

was

€45

7.84

and

€78

.50

4Ye

ar: 2

015

Setti

ng: 5

Eur

opea

n co

untri

es (G

er-

man

y, U

K, I

taly

, N

ethe

rland

s, an

d B

elgi

um)

Estim

ate

cost

savi

ngs b

y co

nver

ting

orig

inat

or in

flixi

mab

(R

emic

ade®

) to

Bio

S (R

emsi

ma®

), as

sum

ing

Bio

S di

scou

nt ra

nges

bet

wee

n 10

% a

nd 3

0% o

f orig

inat

or

pric

e [2

4]

Bud

get i

mpa

ct a

naly

sis (

1 ye

ar)

Cum

ulat

ive

cost

savi

ngs b

etw

een

€25.

79 m

illio

n an

d €7

7.37

mill

ion

acro

ss 6

lice

nsed

indi

catio

ns. B

oth

naiv

e (5

0%) a

nd sw

itch

(25%

) pa

tient

s wer

e in

clud

ed in

the

anal

ysis

5Ye

ar: 2

014

Setti

ng: E

U G

5 co

untri

esa

Estim

ate

cost

savi

ng b

y re

plac

ing

orig

inat

or (E

prex

®)

ESA

with

Bio

S (B

inoc

rit®

) [25

]Si

mul

atio

n stu

dy o

n hy

poth

eti-

cal p

anel

of 1

00,0

00 c

ance

r pa

tient

s with

che

mot

hera

py-

indu

ced

anem

ia

Tota

l esti

mat

ed sa

ving

was

€1

10.5

 mill

ion

and

€146

.1 m

illio

n in

100

% c

onve

rsio

n fro

m o

rigin

ator

to

Bio

S, u

nder

fixe

d an

d w

eigh

t-ba

sed

dosi

ng sc

enar

ios,

resp

ectiv

ely.

Va

riatio

ns in

dos

ing

sche

mes

and

tre

atm

ent s

cena

rios s

how

sim

ilar

cost

savi

ngs

6Ye

ar: 2

015

Setti

ng: U

K, t

each

-in

g ho

spita

l

Estim

ate

cost

savi

ng b

y in

trodu

cing

Bio

S in

flixi

mab

for

treat

ing

patie

nts w

ith IB

D [2

6]C

ase

study

(1 y

ear)

Cos

t sav

ing

of a

ppro

xim

atel

y €5

16,0

00 in

1 y

ear

164 B. Dutta et al.

Tabl

e 1

(con

tinue

d)

Ben

efit

Stud

y no

.Ye

ar/s

ettin

gSc

ope

of th

e stu

dy re

leva

nt to

ben

efit o

f Bio

SSt

udy

desi

gnRe

sult

7Ye

ar: 2

017

Setti

ng: E

U G

5 co

untri

esa

Stud

y fa

ctor

s infl

uenc

ing

the

adop

tion

of B

ioS

infli

xim

ab

in rh

eum

atol

ogy

and

IBD

in 6

diff

eren

t sce

nario

s [28

]B

udge

t im

pact

ana

lysi

s (5

 yea

rs)

In sc

enar

io a

naly

ses,

the

mar

ket

entry

of B

ioS

etan

erce

pt a

nd B

ioS

ritux

imab

was

als

o co

nsid

ered

. O

ver a

tim

e ho

rizon

of 5

 yea

rs, t

he

rheu

mat

olog

y bu

dget

dec

reas

ed in

G

erm

any,

Ital

y, S

pain

, and

the

UK

. Th

e bu

dget

for I

BD

fell

in It

aly

and

Spai

n bu

t inc

reas

ed in

Ger

man

y an

d th

e U

K d

ue to

the

avai

labi

lity

of a

ne

w b

iolo

gic,

ved

oliz

umab

. Sav

ings

in

crea

sed

whe

n B

ioS

infli

xim

ab

disc

ount

s gre

w to

75%

and

whe

n B

ioS

etan

erce

pt a

nd B

ioS

ritux

imab

w

ere

intro

duce

d8

Year

: 201

8Se

tting

: Spa

in,

terti

ary

hosp

ital

Stud

y co

st sa

ving

s fro

m th

e up

take

of n

ew d

rugs

, ant

i-TN

F-α

Bio

S, a

nd th

erap

eutic

opt

imiz

atio

n fo

r tre

atin

g pa

tient

s with

spon

dylo

arth

ritis

[27]

Retro

spec

tive,

obs

erva

tiona

l stu

dy (2

009–

2016

)C

umul

ativ

e co

st sa

ving

of €

798,

614

in 2

016.

Orig

inal

bio

logi

cs, n

ew

biol

ogic

s, an

d B

ioS

inci

ted

eco-

nom

ic c

ompe

titio

n su

ch a

s a lo

wer

lis

t pric

e, o

ffici

al d

isco

unts

, and

ne

gotia

ted

reba

tes.

Dis

coun

ts v

arie

d fo

r eac

h dr

ug, r

each

ing

a m

axim

um

of 3

1.9%

for B

ioS

infli

xim

ab. T

hese

fa

ctor

s effe

ctiv

ely

redu

ced

the

annu

al c

ost p

er d

rug

per p

atie

ntIm

prov

emen

t in

cos

t effe

c-tiv

enes

s of

treat

men

t

9Ye

ar: 2

018

Setti

ng: 9

Eur

opea

n co

untri

es

Cos

t effe

ctiv

enes

s of b

iolo

gic

ther

apy

com

pare

d w

ith

stan

dard

car

e [3

0]C

ost-e

ffect

iven

ess s

tudy

(5

year

s)U

se o

f Bio

S in

flixi

mab

ther

apy

was

m

ost c

ost e

ffect

ive,

with

the

high

est

leve

l of c

linic

al e

vide

nce.

Cos

t-eff

ectiv

enes

s rat

io c

alcu

latio

n w

as

repe

ated

by

decr

easi

ng th

e pr

ice

of

infli

xim

ab b

y 30

%, w

hich

resu

lted

in a

n IC

ER d

ecre

ase

in th

e ra

nge

of

19–3

0%10

Year

: 201

5Se

tting

: EU

cou

n-tri

es

Cos

t effe

ctiv

enes

s of o

rigin

ator

bio

logi

c tra

stuzu

mab

w

as re

view

ed fo

r a fi

rst-l

ine

inno

vativ

e th

erap

y fo

r m

etas

tatic

bre

ast c

ance

r in

the

EU [3

1]

Cos

t-effe

ctiv

enes

s stu

dy o

f or

igin

ator

bio

logi

c tra

stu-

zum

ab

30%

dec

reas

e in

pric

e of

tras

tuzu

mab

or

igin

ator

and

upt

ake

of B

ioS

at

this

pric

e ca

n m

ake

this

ther

apy

cost

effec

tive

by d

ecre

asin

g th

e IC

ER

valu

e fro

m €

63,1

37 to

€14

7,32

0 (p

er Q

ALY

, per

life

-yea

r gai

ned)

to

€29,

520

to €

68,8

80

165Benefits of Off-Patent Biologics and Biosimilars in Europe

Tabl

e 1

(con

tinue

d)

Ben

efit

Stud

y no

.Ye

ar/s

ettin

gSc

ope

of th

e stu

dy re

leva

nt to

ben

efit o

f Bio

SSt

udy

desi

gnRe

sult

11Ye

ar: 2

016

Setti

ng: N

ICE

guid

elin

es

Upd

ate

of tr

eatm

ent g

uide

line

in U

K fo

llow

ing

intro

duc-

tion

of B

ioS

infli

xim

ab [3

2]C

linic

al g

uide

lines

in th

e U

KA

dult

patie

nts w

ith n

on-r

adio

grap

hic

axia

l spo

ndyl

oarth

ritis

can

be

treat

ed w

ith in

flixi

mab

. Ear

lier t

his

indi

catio

n w

as re

stric

ted

for o

rigin

a-to

r infl

ixim

ab (R

emic

ade®

) due

to

high

cos

t12

Year

: 201

4Se

tting

: NIC

E gu

idel

ines

Upd

ate

of tr

eatm

ent g

uide

line

for t

he tr

eatm

ent o

f ane

-m

ia w

ith E

SA [3

3]C

linic

al g

uide

lines

in U

KU

se o

f Bio

S ep

oetin

alfa

for c

ance

r pa

tient

s with

che

mot

hera

py-in

duce

d an

emia

was

mos

t cos

t effe

ctiv

e (£

19,4

29 p

er Q

ALY

gai

ned)

13Ye

ar: 2

016

Setti

ng: E

U, I

MS

Insti

tute

repo

rt

Stra

tegi

c he

alth

aut

horit

ies i

n th

e U

K re

asse

ssed

the

exist

ing

guid

elin

es re

latin

g to

the

use

of G

-CSF

med

i-ci

nes [

34]

Clin

ical

gui

delin

es u

pdat

edIm

prov

emen

t in

the

cost

effec

tiven

ess

of B

ioS

filgr

astim

vs.

alte

rnat

ive

treat

men

t. G

-CSF

was

mov

ed to

fir

st-lin

e ca

ncer

trea

tmen

tIn

crea

se in

pa

tient

acc

ess

to p

harm

a-co

logi

cal

treat

men

t

4Ye

ar: 2

015

Setti

ng: 5

Eur

opea

n co

untri

es (G

er-

man

y, U

K, I

taly

, N

ethe

rland

s, an

d B

elgi

um)

Estim

ate

addi

tiona

l num

ber o

f pat

ient

s tre

ated

by

cost

savi

ngs i

ncur

red

by th

e us

e of

infli

xim

ab B

ioS

(Rem

sim

a®) a

cros

s 6 li

cens

ed in

dica

tions

[24]

Bud

get i

mpa

ct a

naly

sis (

1 ye

ar)

Ave

rage

bud

get s

avin

g of

€43

.13 

mil-

lion,

whi

ch c

ould

be

used

to tr

eat

3900

add

ition

al p

atie

nts w

ith B

ioS,

th

ereb

y in

crea

sing

pat

ient

acc

ess t

o TN

F-α

ther

apy

2Ye

ar: 2

017

Setti

ng: 2

8 Eu

rope

an

coun

tries

Estim

ate

addi

tiona

l num

ber o

f pat

ient

s with

rheu

mat

oid

arth

ritis

and

can

cer d

iagn

osis

who

cou

ld b

e tre

ated

by

the

cost

savi

ngs f

rom

ritu

xim

ab B

ioS

(CT-

P10)

und

er

diffe

rent

scen

ario

s [22

]

Bud

get i

mpa

ct a

naly

sis

(1–3

 yea

rs)

Savi

ngs i

n dr

ug c

osts

ass

ocia

ted

with

up

take

of t

he ri

tuxi

mab

Bio

S w

ould

al

low

trea

tmen

t of a

n ad

ditio

nal

7531

–47,

695

patie

nts,

depe

ndin

g on

th

e sc

enar

io1

Year

: 201

5Se

tting

: EU

G5

coun

tries

a

Estim

ate

num

ber o

f pat

ient

s with

mal

igna

nt tu

mor

s ac

cess

ing

ther

apeu

tic in

nova

tions

(ritu

xim

ab a

nd tr

as-

tuzu

mab

ther

apie

s) [2

1]

Sim

ulat

ion

study

on

hypo

-th

etic

al p

anel

of 1

0,00

0 pa

tient

s/14

-day

trea

tmen

t re

gim

en

Tota

l con

vers

ion

of p

atie

nts f

rom

or

igin

ator

to B

ioS

filgr

astim

can

ge

nera

te c

ost s

avin

gs o

f €3.

9–13

 mill

ion

(day

4 to

day

14)

, whi

ch

coul

d be

real

loca

ted

to tr

eat a

n ad

ditio

nal 3

47–1

213

B c

ell N

HL

patie

nts w

ith ri

tuxi

mab

ther

apy

or

an a

dditi

onal

132

–461

bre

ast c

ance

r pa

tient

s with

tras

tuzu

mab

ther

apy

5Ye

ar: 2

014

Setti

ng: E

U G

5 co

untri

esa

Estim

ate

num

ber o

f add

ition

al p

atie

nts w

ho c

ould

ac

cess

ther

apeu

tic in

nova

tion

(ritu

xim

ab fo

r B c

ell

NH

L, b

evac

izum

ab fo

r met

asta

tic c

olor

ecta

l can

cer,

and

trastu

zum

ab fo

r met

asta

tic H

ER2-

posi

tive

brea

st ca

ncer

) by

cost

savi

ngs g

aine

d by

con

verti

ng th

e us

e of

or

igin

ator

with

Bio

S ES

A (B

inoc

rit®

) in

anem

ic c

ance

r pa

tient

s [25

]

Sim

ulat

ion

study

on

hypo

thet

i-ca

l pan

el o

f 100

,000

can

cer

patie

nts w

ith c

hem

othe

rapy

-in

duce

d an

emia

Estim

ated

cos

t sav

ings

of €

146.

1 m

il-lio

n co

uld

be tr

ansl

ated

into

an

addi

tiona

l 12,

913

ritux

imab

, 517

1 be

vaci

zum

ab, o

r 490

8 tra

stuzu

mab

tre

atm

ents

for p

atie

nts w

ith B

 cel

l N

HL,

met

asta

tic c

olor

ecta

l can

cer,

and

met

asta

tic H

ER2-

posi

tive

brea

st ca

ncer

, res

pect

ivel

y

166 B. Dutta et al.

Tabl

e 1

(con

tinue

d)

Ben

efit

Stud

y no

.Ye

ar/s

ettin

gSc

ope

of th

e stu

dy re

leva

nt to

ben

efit o

f Bio

SSt

udy

desi

gnRe

sult

14Ye

ar: 2

014

Setti

ng: S

wed

en,

sout

hern

hea

lth-

care

regi

on

Cha

nge

in p

resc

ribin

g re

quire

men

ts/a

gree

men

t to

initi

ate

biol

ogic

trea

tmen

t for

pat

ient

s with

febr

ile n

eutro

peni

a [3

5, 4

2]

Cha

nge

in p

resc

ribin

g gu

idel

ine

Requ

irem

ent t

o ob

tain

an

agre

emen

t of

3 p

hysi

cian

s to

initi

ate

biol

ogic

tre

atm

ent f

or fe

brile

neu

trope

nia

was

no

long

er re

quire

d an

d in

divi

dual

ph

ysic

ian

has r

ight

to st

art t

reat

men

t w

ith th

e fil

gras

tim B

ioS

Incr

ease

in

num

ber o

f he

alth

care

pr

ofes

sion

als

6Ye

ar: 2

018

Setti

ng: B

elgi

um,

hosp

ital

Estim

ate

incr

ease

in n

ursi

ng st

aff b

y re

allo

catin

g fu

nds

as a

resu

lt of

cos

t sav

ings

gen

erat

ed b

y th

e us

e of

Bio

S in

flixi

mab

[26]

Cas

e stu

dy (1

 yea

r)C

ost s

avin

g by

switc

hing

orig

inat

or to

B

ioS

infli

xim

ab fo

r tre

atin

g pa

tient

s w

ith IB

D w

as d

iver

ted

to e

mpl

oy a

pa

rt-tim

e nu

rse

and

a fu

ll-tim

e nu

rse

to su

ppor

t pat

ient

s in

the

hosp

ital

15Ye

ar: 2

017

Setti

ng: U

K, u

nive

r-si

ty h

ospi

tal

Und

erta

ke a

“m

anag

ed sw

itchi

ng p

rogr

amm

e” in

143

pa

tient

s with

IBD

. Pat

ient

s tre

ated

with

orig

inat

or

infli

xim

ab w

ere

switc

hed

to B

ioS

infli

xim

ab C

T-P1

3,

whi

ch g

ener

ated

cos

t sav

ings

use

d to

hire

ext

ra h

ealth

-ca

re st

aff [3

7]

“Man

aged

switc

hing

pro

-gr

amm

e” u

sing

a g

ain-

shar

e ag

reem

ent b

etw

een

the

NH

S ho

spita

l tru

st an

d cl

ini-

cian

gro

up in

UK

By

inve

sting

12%

of t

he g

ross

savi

ngs,

7 IB

D sp

ecia

list n

urse

s, 0.

5 W

TE

cler

ical

supp

ort s

taff,

0.2

WTE

ph

arm

acist

s, an

d 0.

2 W

TE d

ietic

ians

w

ere

empl

oyed

to u

nder

take

pat

ient

ed

ucat

ion

rela

ting

to th

e sw

itch

to

Bio

S dr

ug, r

isk

man

agem

ent p

lan

(e.g

., ro

bust

phar

mac

ovig

ilanc

e an

d dr

ug tr

acea

bilit

y pr

oced

ures

) to

addr

ess p

oten

tial r

isk

due

to sw

itch-

ing

drug

, and

seco

ndar

y pa

tient

su

ppor

t ser

vice

s. G

ain-

shar

ing

and

ince

ntiv

izin

g he

alth

care

pro

fess

ion-

als f

rom

the

cost

savi

ng a

s a re

sult

of th

e re

duce

d dr

ug a

cqui

sitio

n co

st im

prov

ed h

ealth

car

e re

sour

ce a

llo-

catio

n, re

sulti

ng in

a b

ette

r ser

vice

an

d hi

gher

qua

lity

of p

atie

nt c

are

Incr

emen

tal

inno

vatio

n of

bi

olog

ics

16Ye

ar: 2

018

Setti

ng: N

ethe

rland

s, ho

spita

l pha

rmac

y an

d on

colo

gy d

ay

care

uni

t

Enro

l 126

pat

ient

s fro

m 6

hos

pita

ls a

nd c

ompa

re so

ciet

al

costs

bet

wee

n th

e IV

and

SC

form

ulat

ions

of o

rigin

ator

tra

stuzu

mab

(Her

cept

in®

) and

ritu

xim

ab (M

abTh

era®

) [3

8]

Inno

vatio

n in

form

ulat

ion

of

off-p

aten

t bio

logi

cs b

etw

een

IV a

nd S

C a

dmin

istra

tion

Resu

lts in

dica

ted

that

tota

l cos

ts o

f on

e ad

min

istra

tion

of S

C tr

astu

-zu

mab

wer

e 5%

low

er th

an th

ose

of IV

tras

tuzu

mab

. One

adm

inist

ra-

tion

of S

C ri

tuxi

mab

was

8%

less

ex

pens

ive

than

IV ri

tuxi

mab

, bot

h at

lis

t pric

es

BioS

bio

sim

ilars

, ESA

ery

thro

poie

sis-

stim

ulat

ing

agen

t, G

5 EU

-Gro

up o

f 5, G

-CSF

gra

nulo

cyte

col

ony-

stim

ulat

ing

fact

or, I

BD in

flam

mat

ory

bow

el d

isea

se, I

CER

incr

emen

tal c

ost-e

ffect

iven

ess

ratio

, IV

intra

veno

us, N

HL

non-

Hod

gkin

’s ly

mph

oma,

NIC

E N

atio

nal I

nstit

ute

for H

ealth

and

Car

e Ex

celle

nce,

QAL

Y qu

ality

-adj

uste

d lif

e-ye

ar, S

C s

ubcu

tane

ous,

TNF

tum

or n

ecro

sis

fact

or,

WTE

who

le ti

me

equi

vale

nta E

U G

5 co

untri

es: F

ranc

e, G

erm

any,

Ital

y, S

pain

, and

the

UK

167Benefits of Off-Patent Biologics and Biosimilars in Europe

patients who could not previously be treated, the biologic therapy could be moved to an earlier line of treatment, demand would be reallocated within a broader class of medicines, and there could be an increase in the number of healthcare staff. The benefits arising from the cost contain-ment have different impacts on various healthcare stake-holders and are schematically represented in Fig. 2. These benefits are inter-related; for example, improving the cost effectiveness of the biotherapeutic treatment may move therapy to an earlier line of treatment, widening patient access and thus resulting in a better health outcome for more patients. Cost savings by the use of lower-priced off-patent biologics and biosimilars could be reallocated to increase patient access to innovative therapies, thus foster-ing headroom for innovations and supporting holistic ben-efit of biotherapeutics. Hence, benefits associated with the use of off-patent medicines and biosimilars are integrated and not additive.

Competition between off-patent biologics and biosimi-lars stimulates incremental innovation by pharmaceutical companies. However, incremental innovation by the origi-nator manufacturing company could also be related to a strategic pricing policy put in place by the manufacturing company for the originator medicine before the launch of biosimilars, and developing next-generation products with better formulations and other add-on features could be a defense mechanism to save the market share of the origi-nator medicines. These innovations may not be clinically superior to the biosimilar or originator [40].

Our study has illustrated the key benefits in the Euro-pean off-patent biologics and biosimilars market with practical examples as derived from budget impact analy-ses, economic evaluations, and other studies. The short-comings of these studies, such as a limited range of cost parameters, assumptions used to populate the budget impact model regarding hypothetical drug pricing and bio-similars uptake, the limited range of sensitivity analysis, lack of local adaptation and validation of economic stud-ies, have been analyzed in the literature [5] and fell outside the scope of this study. The value of biosimilars may also be different across various regions of Europe. For Central and Eastern European countries, access to the originator biologics and biosimilars is a major challenge, whereas in Western European countries, the high price of these medi-cines is a major issue, which poses a financial burden to the healthcare system. Empirical studies illustrating ben-efits of biosimilars (Table 1) are based on hypothetical or descriptive studies from one or a few countries. The results cannot be generalized on the same parameters across all European countries.

The reimbursement system is different in each country and patients’ access to the biologic treatments may still be challenging, especially if there is a co-payment or limited

insurance coverage for these novel therapies. As a result, patients are less likely to have access to these expensive biologic treatments [43, 44]. The purchasing price of off-patent originators and biosimilars, which is regulated by the national authority, can also vary in different European countries, and within the same country prices may also be different if dispensed via ambulatory care or a retailer [15]. Additionally, there could be other factors such as a negoti-ated price between the manufacturers and hospitals, local tenders, existing contractual arrangements, and the price sensitivity of payers for biosimilars. Sometimes the price of the off-patent originator may also be lower  than that of biosimilars. Moreover, healthcare resources in Central and Eastern European countries are lower than in Western European countries [44]. An increase in patient access to pharmacological treatment is, therefore, likely to be a more relevant benefit in Central and Eastern European countries, where equity of access to the treatment is more of an issue than in other European countries. The current body of evi-dence illustrated in Table 1 is derived from hypothetical and descriptive studies in specific countries, thus inhibiting the generalizability of results. Due to the heterogeneity of the reimbursement systems and biosimilar policies between countries, benefits of off-patent biologics and biosimilars markets observed in one country cannot be extrapolated to another country. Therefore, there is a need to investigate and conduct a comparative analysis of benefits in off-patent originator biologics and biosimilars markets at a national, regional, and local level. Reimbursement assistance and innovative financial agreements may add to the overall ben-efits of the biologic therapy. Additionally, access to these biologic medicines can be improved by including them in the list of World Health Organization (WHO) essential medi-cines, based on their cost and clinical effectiveness data. This could be a supportive argument for off-patent origina-tor biologics and biosimilars being included in the national reimbursement lists of many countries. Furthermore, in an integrated health system, gain-sharing arrangements may be a potential solution to distributing cost savings from bio-similars, such as increasing the number of specialized nurses and support staff for a high-quality, cost-effective patient service, resulting in a favorable patient outcome [37]. These initiatives could also promote team-based approaches for a continuous process improvement in hospital settings.

Our literature search included benefits of the off-patent originator biologics and biosimilars market for which Euro-pean empirical data were available. Although additional drivers such as innovation in manufacturing technology, new branding, and marketing strategies exist, we did not find publicly available empirical data supporting these benefits.

Although our study has focused on those factors that contribute to the benefit of competition in the off-patent biologics and biosimilars markets, other factors exist that

168 B. Dutta et al.

undermine the attainment of benefits in this market. For instance, there has been a low uptake of biosimilars due to lack of confidence among physicians prescribing these medicines [45] and a ‘nocebo’ effect experienced by patients when switching originator medicines to biosimilars [46] in which patients anticipate negative consequences after switching to biosimilars from the originator biologic, which may lead to a negative implication on their health outcome. These barriers can be addressed by providing professional education with scientific evidence to prescribers, and imple-menting an awareness program regarding the use and poten-tial benefits of biosimilars for patients and other healthcare professionals.

Future studies are required to analyze and illustrate other benefits of competition in the off-patent biologics and bio-similars markets, such as a robust supply chain to avoid drug shortages, professional education for healthcare profession-als, and patient care pathways. Also, empirical research illustrating the various benefits of off-patent biologic medi-cines and biosimilars needs to move away from hypothetical studies to evidence generated from real-world data.

5 Conclusion

In this article we have reviewed benefits offered by off-patent biologic medicines and biosimilars, beyond cost contain-ment. These benefits may include improving patient access and affordability, moving biologic treatment to an earlier line of therapy, and provision of budget flexibility to fund novel therapies. Off-patent biologics and biosimilars may also cre-ate market competition and stimulate incremental innova-tion by the manufacturers. These benefits when executed in real-life scenarios could result in wider use of biologic treatments than the standard of care in inflammatory dis-eases and oncology.

Compliance with Ethical Standards

Funding This manuscript is supported by the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclu-sivity (MABEL).

Conflict of interest SS, IH, and AGV have conducted biosimilar re-search sponsored by Hospira (now Pfizer). SS was involved in a stake-holder roundtable on biosimilars sponsored by Amgen, Pfizer, and MSD, and has participated in an advisory board meeting for Pfizer. SS currently works with Pfizer, and works with Mundipharma and Cell-trion as a consultant, to carry out biosimilar research. AGV is involved in consulting, advisory work, and speaking engagements for a num-ber of companies, including AbbVie, Accord, Amgen, Biogen, EGA/Medicines for Europe, Fresenius-Kabi, Pfizer/Hospira, Mundipharma, Roche, and Sandoz.

Open Access This article is distributed under the terms of the Crea-tive Commons Attribution-NonCommercial 4.0 International License (http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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