Post on 19-Sep-2020
Biosimilars: the current state of affairs
Confidential to RJW & partners Ltd - not for
onward distribution
London, 28 September 2016
Biosimilars: the current state of affairs
A workshop by RJW&partners
Biosimilars: the current state of affairs 2
Workshop Agenda
Time Subject Presenter
14.00 - 14.10 Opening and introductionsAd Rietveld, RJW &
partners (Chair)
14.10 - 15.00
Session 1: Why is regulatory approval
of biosimilars still not enough to drive
sales?
Neil Johnson, RJW &
partners
15.00 - 15.50Session 2: Are biosimilars what payers
have been waiting for?
Ad Rietveld, RJW &
partners
15.50 - 16.20 Coffee All
16.20 - 17.10Session 3: How to ensure the evidence
for biosimilars is relevant to payers?
Chloe Brown, RJW &
partners
17.10 - 17.30 Summary of the workshopAd Rietveld, RJW &
partners
17.30 End of workshop
Biosimilars: the current state of affairs
Confidential to RJW & partners Ltd - not for
onward distribution
Neil Johnson, RJW & partners Ltd
Biosimilars: why is regulatory approval
still not enough to achieve sales?
3
Biosimilars: the current state of affairs 4
Short answer: biosimilars are not generics.
Longer answer:
Physicians need to become familiar and comfortable with the biosimilar concept
and the clinical evidence supporting them.
Health authorities need to reassure themselves that biosimilars are
interchangeable with the original/reference product.
At the same time, they need to persuade prescribers about the patient and health
care expenditure benefits of biosimilars.
It all takes time.
Why is regulatory approval still not enough to
achieve sales?
Biosimilars: the current state of affairs 5
Several major biologicals have already lost
exclusivity, or will do so in the next few years
Source: company websites
2015 2016 2017 2018 2019 2020
Humira (adalimimab)
Enbrel (etanercept)
Avastin (bevacizumab)
Herceptin (trastuzumab)
Gleevec (imatinib)
Revlimid (lenalidomide)
Expired 2015
Expired 2014
Expired 2015
US LOE
Europe LOE
Biosimilars: the current state of affairs 6
This should be the ‘Perfect Storm’ for biologicals:
loss of exclusivity meets cost containment
Biologicals1
Predicted $290bn global sales in 2020
48% of sales is from 11 biologics that
face loss of exclusivity (LOE) by 2022
> 700 biosimilars approved or pending
approval globally
1 Winning with Biosimilars, Opportunities in Global Markets, Deloitte2 Delivering on the Potential of Biosimilar Medicines, IMS
Cost containment
Elderly populations growing – big users
of biologics
Demand for therapies increasing
Growth in specialty drug spending
Pressure on drug prices and health care
expenditure
Biosimilars could save €100bn
over the next 5 years (US + EU)2
Biosimilars: the current state of affairs 7
But biosimilars are not generics
Similar but not
chemically identical
Bioequivalent and
identical to original
High development
costsLess costly to develop
Substitution is usually
not automatic
Automatic substitution
in most situations
Efficacy and safety not
known without data
Efficacy and safety
same as original brand
Biosimilars Generics
Biosimilars: the current state of affairs 8
Biosimilars are just that - similar
Monoclonal antibodies produced in
vitro undergo defined processes from
transcription to post-translational
modifications.
These processes yield heterogeneity
of the expressed monoclonal protein,
contributing to immunogenicity.
Despite this, studies have not found
substantial differences between
biosimilars and reference products in
terms of pharmacokinetics,
pharmacodynamics or immunogenicity.
This suggests that the primary
(nonproprietary) amino acid sequence
is of the utmost importance in defining
the antibody characteristics.
Source: Dorner & Kate, 2015
Biosimilars: the current state of affairs 9
Because they are not identical, biosimilars must show they are therapeutically similar
to reference products in order to gain regulatory approval.
The approval of this infliximab biosimilar and Remicade is based on two trials
(PLANETRA in rheumatoid arthritis, and PLANETAS in ankylosing spondylitis).
The studies showed no clinically meaningful differences in the efficacy or
pharmacokinetic profiles of the two products.
In addition, data from extension studies showed that in patients switched from
Remicade to the biosimilar, efficacy was sustained and similar to those maintained
on the biosimilar.
Although regulatory trials were only performed in rheumatoid arthritis and ankylosing
spondylitis, efficacy and safety for other indications was assumed and, in 2013, the
EMA granted approval for all indications for which Remicade is approved.
Biosimilar approval in clinical practice:
Remsima/Inflectra (CT-P13, infliximab biosimilar)
Biosimilars: the current state of affairs 10
But there were some differences in PLANETAS
Transition data from the PLANETAS extension study showed some differences in
adverse events:
There were similar rate of adverse events between the transition and
maintenance groups (4.8% vs 4.4% respectively).
But fewer patients experienced more than 1 adverse event during the second
year with continuation of CT-P13 compared to those transitioning to CT-P13
from Remicade (48.9% vs 71.4%).
These differences highlight the fact that biosimilars are not identical to the reference
product and some variation in the clinical profile might emerge.
Biosimilars: the current state of affairs 11
France, Germany, Netherlands, Poland, Spain, Sweden, UK
USA
Russia
One payer from each country with national payer role, either HTA
or pricing/reimbursement; the US payer was a pharmacy director
with a large, national health plan.
We examined attitudes towards biosimilars and how they thought
the environment would evolve.
We wanted to get some perspectives from payers
so conducted a small survey across 9 markets
Biosimilars: the current state of affairs 12
Most payers do not expect biosimilars to take
significant market share in the next 5 years
Source: RJW & partners research, 2016
25% 25% 25%30%
25%
10%
80%
25%
0%
20%
40%
60%
80%
100%
% share of patent expired market
Q: what do you expect the market share for
biosimilars to be in the next 5 years?
10%
50%*
*depending on how long the product has been available
Biosimilars: the current state of affairs 13
No mandatory INN prescribing or
generic substitution in UK but physician
training, cost controls and software
(ScripSwitch) drive high generic uptake.
With biosimilars, physician concern over
clinical equivalence limit the uptake.
The UK has tended to be more
conservative with biosimilar uptake
compared to eg Germany and Sweden.
Also, the MHRA position (2008) is that
biosimilars ‘are not to be presumed
identical’ because of structural
variations from the original molecule.
The UK estimate may seem exceptionally high but is not
unrealistic
Source: IMS, 2012
84%
30%
73%
0%
20%
40%
60%
80%
100%
Generics Biosimilars G-CSFbiosimilar
% of off-patent drug prescribing in UK
But it depends on the product e.g. the uptake of biosimilar G-CSF has been
very high.
Biosimilars: the current state of affairs 14
Several factors could drive the uptake of biosimilars
Advocacy – whether clinicians are prepared to speak-up for biosimilars
Prescriber comfort level with biosimilars – safety concerns
Brand loyalty and defensive strategies by manufacturers of originator brands
National policies regarding the pricing/access process or substitution of biosimilars
Maturity – biosimilars are still a relatively new concept
Why could uptake be limited in some situations?
Biosimilars: the current state of affairs 15
RJW survey asked about the main obstacles for
biosimilars in achieving market penetration
Clinical
advocacy
Defensive
strategy by
originator
Clinician
safety
concerns
National
policies
France
Germany
Netherlands
Poland
Russia
Spain
Sweden
UK
USA
% responses 67% 56% 44% 11%
Source: RJW & partners research, 2016
Biosimilars: the current state of affairs 16
Clinician advocacy was seen as the biggest barrier
“Clinicians use issues of quality and batch problems, but
they should know better”
Netherlands
“Clinicians are wary and prefer to wait for studies showing
equivalence”
UK
Biosimilars: the current state of affairs 17
At around 50%, uptake of biosimilars is relatively high in Germany1.
Substitution might be possible under generic substitution policy (Aut idem Regelung).
However, high uptake is most likely due to the local efforts of insurers to promote
biosimilar use, for example:-
The extent to which local payers promote
biosimilars is an important driver
1 Spoors & Kusel, 2015
70%
16%
0%
20%
40%
60%
80%
Bremen Saarland
In Bremen, insurers have
encouraged biosimilar uptake using:
Prescription quotas
Physician education sessions
Publication of data on safety and
efficacy
In Saarland there were no such
efforts1.
% of prescribing that is biosimilars
Biosimilars: the current state of affairs 18
Switch studies are designed to find out if
biosimilars can replace reference products
Switch studies are designed to
help to overcome concerns about
interchangeability.
These can be conducted in
several different ways but all
involve replacement of the
reference drug with a biosimilar.
The aim is to show that switching
does not lead to a loss of efficacy
or an decrease in tolerability.
Source: Dorner & Kate, 2015
Biosimilars: the current state of affairs 19
Use of biosimilar infliximab CT-P13 (Remsima/Inflectra)
varies widely across Nordic countries
Norway Denmark
SwedenFinland
Source: Løvik Goll, update on NOR-SWITCH study, April 2016
Biosimilars: the current state of affairs 20
The Norwegian Medicines Agency
(NoMA) funded a switch study to find out
if Remicade and Remsima are
interchangeable.
The NOR-SWITCH study assesses the
clinical impact of switching from
Remicade to Remsima in patients with
the inflammatory conditions shown.
500 patients across all indications are
being switched to Remsima, with
disease worsening as the primary
endpoint.
No data available yet but the study
reports very soon.
The NOR-SWITCH study is intended to find out whether
switching to an infliximab biosimilar is appropriate
Diagnosis distribution
Source: Løvik Goll, update on NOR-SWITCH study, April 2016
Biosimilars: the current state of affairs 21
The PRospective Observational cohort
Study on patients with Inflammatory
bowel disease receiving Therapy with
BIOsimilars (PROSIT-BIO) reported data
on patients with ulcerative colitis (n=174)
and Crohn’s disease (n=223).
Efficacy was similar in the three groups:
Patients switched from Remicade to
Remsima (93 patients)
Patients receiving a biosimilar who
were anti-TNFα naïve (217 patients)
Patients receiving a biosimilar who
had previously received biologics (87
patients)
Safety was also similar.
An Italian switch study shows similar outcomes
with an infliximab biosimilar
95%92% 91%
0%
20%
40%
60%
80%
100%
Switched:Remicade to
Remsima
anti-TNFnaïve
Previousbiologic
% patients responding
Remsima
Biosimilars: the current state of affairs 22
Remicade was initially considered by NICE
to be too costly to be cost-effective in
ankylosing spondylitis.
Infliximab biosimilars (Remsima/ Inflectra)
launched in 2015 at a 10% discount but
the manufacturers subsequently offered
further (confidential) discounts to the NHS.
NICE recommended using the least costly
treatment first ie biosimilars ahead of
Remicade1. NICE is supporting local
payers in implementing the advice.
Discounts for the biosimilars are high in
other markets: in France up to 45%, while
in Norway the hospital tender price for
Remsima is reported to be a 72% discount
to Remicade2.
Price reductions have to be big enough to
encourage payers to adopt them
£0
£100
£200
£300
£400
Remicade Remsima/Inflectra
Real price
UK NHS price/100mg vial
-10%
-40%?
1 NICE TA383, 20162 Løvik Goll, update on NOR-SWITCH study, April 2016
Source: BNF, 2016
Biosimilars: the current state of affairs 23
Uptake can ultimately be high, but it depends
HGH G-CSF
Denmark 34% 57%
Finland 9% 87%
France 12% 35%
Germany 9% 51%
Italy 8% 53%
Poland 99% 71%
Portugal 0% 83%
Spain 19% 73%
Sweden 18% 91%
UK 5% 73%
Averages 21% 67%
Source: IMS data
While biosimilar uptake may not be as
fast as seen for small molecule
generics, it can still be high.
Only one human growth hormone
(HGH) biosimilar exists since 2006 and
the initial device not easy to use.
Uptake has been slow.
In contrast, there are 8 G-CSF
biosimilars (5 since 2009) and
penetration has been high, exceeding
90% in Sweden.
The variation across markets shows
that much depends on the product and
country situation.
% of treatment days attributable to biosimilars
Biosimilars: the current state of affairs 24
Acceptance of clinicians is key and there is
evidence this is happening
0%
20%
40%
60%
80%
100%
A survey of the European
Crohn’s and Colitis Organisation
found that attitudes of clinicians
towards biosimilars has
changed.
While most were sceptical in
2013 this had shifted significantly
in the most recent survey in
2015.
% of respondents
2013 2015
Little or no confidences in biosimilar Mabs
Believe biosimilars are interchangeable
Biosimilars: the current state of affairs 25
The prize for health care systems is a big one
At big discounts,
many more patients
gain access to
therapy
Significant gains in
population health
Big savings on drug
budgets
Biosimilars: the current state of affairs 26
The rising costs of health care, and demands from patients for the most effective
treatments will drive towards acceptance of biosimilars.
Clinician concerns and brand loyalty remain a factor in uptake but we think this will
change - similar concerns were seen when generics were introduced.
Health authorities and payers are starting to encourage uptake - initiatives are in
place in many countries.
In situations where appropriate education and quotas are in place, the uptake of
biosimilars has been high.
Widespread substitution of all biosimilars is unlikely to be seen in the near term but
over time, the uptake of biosimilars is likely to be strong.
Summary: realising the benefits will take time and
some effort by authorities
Biosimilars: the current state of affairs
Confidential to RJW & partners Ltd - not for
onward distribution
Ad Rietveld, RJW & partners Ltd
Are biosimilars what payers have been
waiting for?
27
Biosimilars: the current state of affairs 28
We interviewed payers: they see
biosimilars as a way to manage rising costs
Payers across markets see
biosimilars as a vital tool to
contain rising pharmaceutical
expenditure
“Biosimilars and other generics would be a
significant way of rising cost control. The
mainstream approach will be replacement of the
domestic product, as well as price negotiation and
risk sharing.” Payer , US
“Biosimilars are one of the most important ways to
control the rising costs of biological therapies. The
other way is the negotiating committee and cost-
effectiveness control of newer drugs.” Head of
HTA, Russia
“Biosimilars will be important to negotiate the
prices of new biological therapies - ideally we
would also agree with physicians associations (at
federal as well as on regional level) on minimum
prescribing quotas for biosimilars.” Former Head
of G-BA, Germany
Source: RJW & partners research, 2016
Survey results
Biosimilars: the current state of affairs 29
Oncology and immunology are areas where
biosimilars are expected to make an impact
0
1
2
3
4
5
6
7
8
9
Oncology Immunology Diabetes Cardiovascular Respiratory
Source: RJW & partners research, 2016
Biosimilars could save €100bn
over the next 5 years (US + EU)1
1 Delivering on the Potential of Biosimilar Medicines, IMS
Survey results
Biosimilars: the current state of affairs 30
Payers estimate biosimilar discount levels to
be 10 - 40% of the originator product price
90%
80%
70%
60%
Participants estimate of the current
level of discount for biosimilars
compared to reference products
10 - 40%
“At least 25%, average about 30%.
This is conditioned by the provisions
of the Act on Reimbursement.” Ex-
MOH, Poland
“I guess between 10 and 30%,
depending on the disease area and
amount of competitors.” Ex-CVZ,
Netherlands
“Good Question – I would estimate
this at 40%.” Director Catalan HTA
Agency, Spain
Reference Product Biosimilar
Source: RJW & partners research, 2016
Survey results
Biosimilars: the current state of affairs 31
National pricing and reimbursement policies
are not seen as obstacles for biosimilar uptake
Source: RJW & partners research, 2016
67%
56%
44%
11%
0%
20%
40%
60%
80%
Clinical advocacy Defensive strategy byoriginator
Clinician safetyconcerns
National policies
Main obstacles to uptake of biosimilars
(% of payers, N=9)
“Clinicians use issues of quality and
batch problems, but they should know
better” Netherlands
“Clinicians are wary and prefer to wait
for studies showing equivalence” UK
Survey results
Biosimilars: the current state of affairs
International Healthcare Spending as a % of GDP
Source: OECD Health Data 2015
32
Biosimilars: the current state of affairs
Typical breakdown of health care costs of a wealthy
western nation: the Dutch health care budget 2015
Primary care
11%
Unspecified 2%
Home care 7%
Education 3%
Mental health care
8%
Ambulances 2%
Pharmaceutical
care 14%
Secondary care 50%
Other 3%*
*incl. cross border treatments
Payers see drugs as obvious targets for
cost containment
33
Biosimilars: the current state of affairs 34
Biologics are very much on the radar screen of
payers - top-selling drugs in 2014
Rank Product CompanySales (billion US$,
2014)Biologic?
1 Humira Abbvie 11.8 Yes
2 Lantus Sanofi 10.3 Yes
3 Sovaldi Gilead 9.4
4 Abilify Otsuka 9.3
5 Enbrel Amgen 8.7 Yes
6 Crestor AstraZeneca 8.5
7 RemicadeJohnson &
Johnson8.1 Yes
8 Nexium AstraZeneca 7.7
9Rituxan /
MabtheraRoche 6.6 Yes
10 Avastin Roche 6.1 Yes
Source: 247WallStreet.com 2016
Biosimilars: the current state of affairs 35
The biggest selling biologicals in 2014 have
indications in immunology and oncology
Rank Product Sales (billion US$) Indication
1 Humira 12.5
Rheumatoid arthritis, plaque psoriasis, Crohn's
disease, ulcerative colitis, psoriatic arthritis, ankylosing
spondylitis, poly-articular juvenile idiopathic arthritis
2 Remicade 9.7Rheumatoid arthritis, psoriatic arthritis, Crohn's
disease, ulcerative colitis, plaque psoriasis
3 Rituxan 8.7
Rheumatoid arthritis, non-Hodgkin lymphoma,
Chronic lymphocytic leukemia, granulomatosis with
polyangiitis, microscopic polyangiitis
4 Enbrel 8.5
Rheumatoid arthritis, poly-articular juvenile idiopathic
arthritis, psoriatic arthritis, ankylosing spondylitis.
plaque psoriasis
5 Lantus 7.5 Diabetes
6 Avastin 7.0
Glioblastoma, metastatic colorectal cancer, non–
small cell lung cancer, metastatic kidney cancer,
advanced cervical cancer, platinum-resistant ovarian
cancer
7 Herceptin 6.8 Breast cancer, metastatic stomach cancer
Source: cellculturedish.com
Biosimilars: the current state of affairs 36
Some of these major biologicals have already lost
exclusivity, or will do so in the next few years
Source: company websites
US LOE
Europe LOE
2015 2016 2017 2018 2019 2020
Humira (adalimimab)
Enbrel (etanercept)
Avastin (bevacizumab)
Herceptin (trastuzumab))
Expired 2015
Expired 2014
The global biologics market is expected to exceed $390 billion by 2020
with biosimilars accounting for 28 percent of the total market.*
*IMS
Biosimilars: the current state of affairs 37
Price differential of originator vs biosimilar products
We looked at current prices of originator and biosimilar products in EU5
markets to assess the level of discount applicable for biosimilar products
vs originators:
Filgrastim: Neupogen and biosimilars which were approved from 2008
onwards
Infliximab: Remicade and biosimilar products Remsima and Inflectra
(both approved in 2013)*
Etanercept: Enbrel and biosimilar product Benepali
To understand the impact of the launch of biosimilar products on the
previous price of the originator product, we also looked at the price
history of these same examples in detail for France
*Flixabi approved in 2016 but price
information not yet available
Biosimilars: the current state of affairs 38
Germany: Biosimilars are introduced at considerably
lower prices than the originator products
Source: rote-liste.de, public prices with tax
Dates beside biosimilar names refer to EMA approval
Filgrastim30M units/0.5ml, 1 pre-filled
syringe
Infliximab100mg powder, 1 vial
Etanercept
50mg/1ml, 1 syringe
€50
€100
€150
€200
€100
€200
€400
€500
€200
€400
€600
€1000
€800
First biosimilar (Filgrastim Hexal, 2008)
Original product (Neupogen)
Second biosimilar (Nivestim, 2010)
Public price Public price Public price
€178
€123
First biosimilar (Benepali, 2016)
Original product (Enbrel)
31% discount vs for
originator product for
available biosimilars
€361
19% discount vs
originator product
€767
25% discount vs
originator product for
lower priced
biosimilar
€952
€718
Biosimilar Remsima (2013)
Original product (Remicade)
Biosimilar Inflectra (2013)
€300
€445
Biosimilars: the current state of affairs 39
€615.88
€53.30
Spain: Current prices of originator and biosimilar
products
Dates beside biosimilar names refer to EMA approval
Filgrastim30M units/0.5ml, 1 pre-filled
syringe
Infliximab100mg powder, 1 vial
Etanercept
50mg/1ml, 1 syringe
€25
€50
€75
€100
€50
€100
€200
€250
€200
€400
€600
€1000
€800
First biosimilar (Ratiograstim, 2008)
Original product (Neupogen)
Second biosimilar (Zarzio, 2009)
Public price Public price Public price
€53.30
€45.04
Original product (Enbrel)
15% discount vs
originator product for
first biosimilar
No biosimilar
available
€510.29
17% discount vs
originator product for
both biosimilars
Biosimilar Remsima (2013)
Original product (Remicade)
Biosimilar Inflectra (2013)
€150
€234.33
€300
€350
Biosimilars: the current state of affairs 40
€76.50
€96.15€96.15
Impact of introduction of biosimilar on price of
originator product in France: filgrastim
€10
€20
€30
€40
€50
€60
€80
€70
€120
€110
€100
€90
Price per
syringe (MSP)
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
First Biosimilar
introduced at 20%
discount
€81.73
Originator price
decrease of 15%
Lowest priced
biosimilar, at 25%
discount to originator
Notification of prices in Journal Officiel
Prices have not
changed since 2012
Price for 1 pre-filled syringe
(30Munits/0.5ml)
Ratiograstim (biosimilar)
Neupogen
Nivestim (biosimilar)
Further price cuts planned for 2 biosimilars
will take discount level to 25% discount in
2017
Biosimilars: the current state of affairs 41
€561
Impact of introduction of biosimilar on price of
originator product in France: Infliximab
€50
€100
€150
€200
€250
€300
€400
€350
€600
€550
€500
€450
Price per
100mg (MSP)
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Original product price
reduced to match prices
of biosimilars
Biosimilars introduced at
10% discount to
previous originator price
All infliximab prices
have decreased to
the same level
€536€509
€483
Notification of prices in Journal Officiel
€434
€382
Price for 100mg (1 vial)
Remsima and Inflectra
(biosimilars)
Remicade
Biosimilars: the current state of affairs 42
€179
€252
Impact of introduction of biosimilar on price of
originator product in France: Etanercept
€50
€100
€150
€200
€250
€300
€400
€350
€600
€550
€500
€450
Price per
syringe (MSP)
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Original product price
decreased by 3%
following introduction of
biosimilar
Biosimilar introduced at
18% discount to
originator price
€226€219
Notification of prices in Journal Officiel
€148
Price for 1 pre-filled syringe
(50mg/1ml)
Benepali (biosimilar)
Enbrel
€174
€211
Biosimilars: the current state of affairs 43
The interviewed payers seem rather too pessimistic
as current experience already shows a high growth
IMS data and Quintiles Knowledge Connect
Biosimilar sales in the EU-5
As of September 2015, the biosimilars
market in the EU5 stood at US $490
million, a massive increase since 2007
when the market was just being
established.
Biosimilars: the current state of affairs 44
Uptake levels of older biosimilars indicate that
market shares can be in the range of generics
Growth
HormoneFilgrastim
Denmark 34% 57%
Finland 9% 87%
France 12% 35%
Germany 9% 51%
Italy 8% 53%
Poland 99% 71%
Portugal 0% 83%
Spain 19% 73%
Sweden 18% 91%
UK 5% 73%
Averages 21% 67%
Source: IMS data (2013)
Biosimilar uptake may not be as fast as
seen for small molecule generics, but
these figures indicate that they ultimately
can reach similar levels.
In Germany, some payers have
encouraged biosimilar uptake using:
Prescription quotas
Physician education sessions
Publication of data on safety and
efficacy
In Norway, the authorities have promoted
switch studies to prove interchangeability
of biosimilars
The UK’s NICE has recommended that
infliximab biosimilars, Remsima and
Inflectra, should be used ahead of the
originator Remicade.
% of treatment days attributable to biosimilars
Biosimilars: the current state of affairs 45
Variation across markets points at the country
situation as one of the main obstacles for uptake
Growth
HormoneFilgrastim
Denmark 34% 57%
Finland 9% 87%
France 12% 35%
Germany 9% 51%
Italy 8% 53%
Poland 99% 71%
Portugal 0% 83%
Spain 19% 73%
Sweden 18% 91%
UK 5% 73%
Averages 21% 67%
Source: IMS data (2013)
The country situation with
respect to funding and price
setting rules may be the main
determining factor for the
success of biosimilars.
Unlike the European regulatory
system for marketing approval
for biosimilars, pricing and
funding systems are nationally
decided on with considerable
variation across countries.
A lower price is a necessary
condition for uptake but only
generates usage if
accompanied by other
measures.
% of treatment days attributable to biosimilars
Biosimilars: the current state of affairs
There appears to be a link between the presence of
cost-sensitive users and biosimilar penetration
Country Process Mandatory discount? Cost-sensitive users?Filgrastim
penetration
France Normal P&MA
process No
Hospitals yes,
community no 35%
Germany No early benefit
assessment
No
Subject to Festbeträge
Insurer-driven cost
consciousness
Richtgrossen system
51%
Italy Normal P&MA
process
Price set at least
20% below the
originator
Regional driven cost
consciousness 53%
Spain Normal P&MA
process
Price set 30%
below originator
Regional driven cost
consciousness
Hospitals yes,
community no
73%
UK In the context of
MTA process No
CCGs need to stay
within budget 73%
Sweden
Cost
minimization
approach
No County councils
responsible for budget 91%
46
Biosimilars: the current state of affairs 47
The US may be lagging behind Europe in the
biosimilar registrations but will catch up quickly
According to Reuters, UnitedHealth Group, the largest health insurer in the US, has
become the latest insurer to announce plans to stop covering Sanofi’s Lantus (insulin
glargine) from 2017. Reuters reports that the insurer will instead place Eli Lilly’s
biosimilar insulin glargine Basaglar (which is due to be launched in December 2016)
on tier 1 of its formulary (which contains products that have the lowest out-of-pocket
costs for insured members).
In addition, Reuters reports that UnitedHealth Group plans to exclude Amgen’s
Neupogen (filgrastim) from its formulary and will instead cover Novartis’ biosimilar
Zarxio (filgrastim-sndz).
Similar plans to cover biosimilar versions of insulin glargine and filgrastim, instead of
the original biologics products, were recently announced by CVS Caremark.
Biosimilars: the current state of affairs 48
In conclusion: Price and uptake of biosimilars is in
essence linked to just four factors
Cost-sensitivityPrice controlsTrust
Do stakeholders
believe the benefits
and risks to be the
same as for the
originator
molecule?
If a device is
needed for
administering the
product, do
stakeholders
experience the
device as handy as
the one used with
the originator
product?
Are biosimilar
prices regulated
eg. a % discount
versus the
originator
product?
Do regulations
include price
reduction of the
originator
product?
Do regulations
foresee in price
negotiations for
the biosimilar
and/or the
originator
product?
Are users cost-
sensitive eg. do they
have a budget to
adhere to?
Are there
copayments for
patients that make
patients look for
lower-priced
options?
Are measures in
place that promote
lower-priced
products or even
make use
mandatory eg.
substitution rules?
Competition
Are there
sufficient numbers
of alternatives to
create price
competition?
Biosimilars: the current state of affairs
Confidential to RJW & partners Ltd - not for
onward distribution
How to ensure that evidence for
biosimilars is relevant to payers
Chloe Brown, RJW & partners Ltd
49
Biosimilars: the current state of affairs
Evidence requirements for European regulatory approval for biosimilars have been in
place longer than other regions and have been thoughtfully established
Overarching guidelines
Product-specific guidance
Payers seem unlikely to require additional clinical evidence for a biosimilar in
approved indications for which the reference product is already reimbursed
Payers could benefit from evidence that would overcome resistance of providers to
use biosimilars
In indications of the reference product for which there are no clinical data of
comparability of the biosimilar
Substitution of a biosimilar for the reference product or another biosimilar
Economic evidence could conceivably show a biosimilar to be cost-effective in
indications/ positioning where the reference product is not
How might the evidence required for regulatory
approval need to be supplemented for payers?
50
Biosimilar evidence is not scrutinised by national
level payers in all European countries
Biosimilar P&R path Countries Comment on evidence review/ requirements
Standard process
France All products reviewed by Transparency Commission
Biosimilars given ASMR V (no improvement)
Sweden All products reviewed by TLV
Cost-minimisation model required
UK All products reviewed by SMC & AWMSG - cost minimisation is
accepted. NICE only review as part of MTA
Spain Standard process despite creation of reference pricing groups for
biosimilars
Greece All products reviewed by Ministry of Health and Social Solidarity
Specific biosimilar process
Belgium Specific guidelines for biosimilar submission under class 2
Switzerland Specific guidelines for biosimilar submission
Abbreviated process
Germany Biosimilars do NOT undergo AMNOG
Italy Faster access only if pre-specified price discount applied
Netherlands Allocated to reference price group
Poland Similar to generic process
Austria
Source: Foxon et al. ISPOR 20th Annual Meeting, May 2015
Biosimilars: the current state of affairs 52
The principles of evidence requirements for a biosimilar approval in the EEA are laid
out in the overarching guidelines
Comparability studies are needed to generate evidence substantiating the similar
nature of the biosimilar product and the chosen reference product authorised in EEA
in terms of quality, safety and efficacy
A stepwise approach is taken to characterisation and comparison
Physicochemical and biological
Non-clinical in vivo
Pharmacokinetics and pharmacodynamics
Clinical studies
The extent and nature of the clinical studies required depend on the level of evidence
of comparability demonstrated in previous steps
The requirements for clinical studies depend on the potential for difference between
similar products and their implications for safety and efficacy
These differ between different product types
What are the principles of evidence requirements
for biosimilar authorisation?
Biosimilars: the current state of affairs 53
What evidence is needed in each indication?
EMA overarching guideline states
“If biosimilarity is demonstrated in one indication, extrapolation to other
indications of the reference product could be acceptable with appropriate
justification”
Circumstances in which indication-specific data may not be needed for regulatory
purposes:
Product interacts with single receptor and impact is same in all indications
Active substance only has one active site that is relevant in all indications
The studied therapeutic indication is likely to be sensitive to differences relevant
to all aspect of safety and efficacy.
It is possible for different biosimilar products to have different evidence packages and
potentially a different range of indications
Would payers/ prescribers make a distinction between different biosimilars on
the basis of approved indications?
However, payers may find evidence in additional indications relevant to justify use of
lower cost biosimilar to prescribers/ providers.
Biosimilars: the current state of affairs 54
Background: Biosimilar products in EEA (1)
Active substance Biosimilars available Range of indications
Somatropin Omnitrope (2006) • Pituitary dwarfism
• Prader Willi syndrome
• Turner syndrome
Epoetin alfa Abseamed (2007)
Binocrit (2007)
Epoetin alfa Hexal (2007)
• Anaemia
• Cancer
• Chronic kidney failure
Epoetin zeta Retacrit (2007)
Silapo (2007)
• Anaemia
• Autologous blood transfusion
• Cancer
• Chronic kidney failure
Filgrastim (G-CSF) Biograstim (2008)
Tevagrastim (2008)
Ratiograstim (2008)
Zarxio (2009)
Filgrastim Hexal (2009)
Nivestim (2010)
Grastofil (2013)
Accofil (2014)
• Neutropenia after chemotherapy or
myeloablative therapy
• Mobilisation of peripheral blood
progenitor cells (PBPCs)
• Congenital or idiopathic neutropenia
• Persistent neutropenia in HIV
Source: Gabionline.net
Biosimilars: the current state of affairs 55
Background: Biosimilar products in EEA (2)
Active substance Biosimilars available Range of indications
Infliximab Remsima (2013)
Inflectra (2013)
Flixabi (2016)
• Ankylosing spondylitis
• Crohn’s disease
• Psoriatic arthritis
• Psoriasis
• Rheumatoid arthritis
• Ulcerative colitis
Follitropin alfa Ovaleap (2013)
Bemfola (2014)
• Anovulation (IVF)
Insulin glargine Abasaglar (2014) • Diabetes
Etanercept Benepali (2016) • Axial spondyloarthritis
• Psoriatic arthritis
• Plaque psoriasis
• Rheumatoid arthritis
Source: Gabionline.net
Biosimilars: the current state of affairs 56
EMA Guidance relevant to filgrastim
Filgrastim
Reference
product
indications
• Neutropenia after chemotherapy or myeloablative therapy
• Congenital or idiopathic neutropenia
• Persistent neutropenia in HIV
• Mobilisation of peripheral blood progenitor cells (PBPCs)
Nature • Non-glycosylated protein produced in E coli (filgrastim)
EMA guidance on
rhG-CSF* (2006)
Recommended clinical model for efficacy – allows for extrapolation to other
indications with same MoA
• Prophylaxis of severe neutropenia after cytotoxic chemotherapy in a homogeneous
patient group (tumour type, stage, chemotherapy).
• 2 arm comparison vs reference product using chemotherapy known to induce
neutropenia (or 3-arm with placebo)
• Primary endpoint: duration of severe neutropenia (<0.5 x 109 /l)
Alternative models, including pharmacodynamic studies in healthy volunteers, may be
pursued for the demonstration of comparability, if justified
Recommended clinical safety data
• Data after repeated dosing preferably in a comparative clinical trial.
• Total exposure = conventional chemotherapeutic treatment course
EMA concept
paper (2015)
Guideline revision in progress to update in line with scientific advice given.
Clinical waivers possible since structure, physicochemical nature and biological activity of
G-CSF are well characterisable and PD parameters of clinical relevance are available.
Source: www.ema.europa.eu* Also applies to glycosylated protein produced in CHO
(lenograstim), for which no biosimilars available
Biosimilars: the current state of affairs 57
All filgrastim biosimilars have the full range of
indications despite different approaches in trials
Biosimilar Clinical Trials
Biograstim
Tevagrastim
Ratiograstim
PK and PD
• 2 comparative single dose studies in healthy volunteers
Efficacy:
• Randomised, placebo & active controlled in breast cancer with chemo
Safety:
• Randomised, active controlled in lung cancer with chemo (Pt-based)
• Randomised, active controlled in NHL with chemo (CHOP)
Nivestim PK and PD
• 2 comparative studies in healthy volunteers, of which one repeat dose
Efficacy & safety
• Randomised active-controlled in breast cancer treated with doxorubicin and docetaxel
Zarxio
Filgrastim Hexal
Grastofil
Accofil
PK and PD
• 4 comparative studies in healthy volunteers, of which 1 or 2 repeat dose
Efficacy and Safety
• Non-comparative single arm repeat dose study in breast cancer with chemo
Labels in EPAR and US label (Zarxio) indicate same indications as Neupogen
Biosimilars: the current state of affairs 58
Decisions of national payers have not been affected
by clinical evidence package of filgrastim biosimilars
All biosimilar filgrastim products have been treated similarly by national level payers in countries
where biosimilars go through standard reimbursement procedure
The reference product (Neupogen) is reimbursed/ recommended across all indications
Irrespective of clinical evidence package in patients
1) Randomised efficacy and safety studies vs Neupogen in cancer patients receiving chemo
(Tevagrastim, Ratiograstim)
2) Single randomised study vs Neupogen in patients with cancer receiving chemo (Nivestim)
3) Open label safety study in cancer patients receiving chemo (Zarxio, Accofil)
France
Reimbursed at 100% across all indications for reference product (Neupogen) in
hospital and ambulatory sectors
ASMR V – no benefit
UK (SMC)
Recommended for use in all indications for reference product
UnitedHealth Group plans to exclude Amgen’s Neupogen (filgrastim) from its formulary and
will instead cover Novartis’ biosimilar Zarxio (filgrastim-sndz).
Biosimilars: the current state of affairs 59
Large US health insurance companies also seem
unconcerned by limited clinical evidence
UnitedHealth Group, the largest health insurer in the US, and CVS Caremark have
both announced intention to cover Zarxio (filgrastim-sndz) on tier 1 of formulary and
exclude Amgen’s Neupogen (filgrastim)
The US wholesale list price for the 300mcg syringe of Zarxio is $275.66, and the
480mcg $438.98, a 15% discount to Neupogen’s costs at $324.30 and $516.45,
respectively, according to Reuters.
Source: Reuters reported in PharmaTimes online and IMS PharmaNews
Biosimilars: the current state of affairs 60
EMA Guidance on infliximab
Infliximab
Reference
product
indications
• Ankylosing spondylitis
• Rheumatoid arthritis
• Psoriatic arthritis
• Psoriasis
• Crohn’s disease
• Ulcerative colitis
Nature • Chimeric human-murine monoclonal antibody to TNFα produced in CHO
• 4 polypeptide chains, one glycosylation site
EMA guidance
on biosimilar
monoclonal
antibodies
(2012)
Comparative clinical studies between biosimilar and reference product
should be conducted. Extrapolation to other indications is possible.
Step 1: Show comparability of PK in sufficiently sensitive and homogeneous
population.
• Studies in patients may be a better option than healthy volunteers
• Only required to investigate PK profile in multiple clinical indications, if
distinct therapeutic areas (eg autoimmunity and oncology)
• PD markers may provide pivotal proof of comparability if dose-
response and acceptable surrogate for patient outcomes
Step 2: Clinical efficacy studies, if required, should be randomised, parallel
group, preferably double-blind, equivalence trials vs reference
• Use most sensitive patient population and clinical endpoint to detect
product-related differences, if present
Safety
• Long-term immunogenicity/safety data may be required post-authorisation
Source: www.ema.europa.eu
Biosimilars: the current state of affairs 61
All infliximab biosimilars had only been studied in
rheumatology indications at time of approval
Biosimilar Clinical Trials
Remsima
Inflectra
(CT-P13)
PK and safety immunogenicity and supportive efficacy
• Comparative multiple dose study in ankylosing spondylitis (PLANETAS)
Efficacy and Safety:
• Randomised, double-blind, parallel group comparison with Remicade in
rheumatoid arthritis (PLANETRA)
Planned/ in progress
• Randomised, double-blind cross-over comparison with Remicade in
active Crohn’s disease
Flixabi PK and supportive immunogenicity study
• Comparative multiple dose study in healthy volunteers (3 arm vs EU and
US sourced Remicade)
Efficacy & safety
• Randomised, double-blind, parallel group comparison with Remicade in
rheumatoid arthritis
Biosimilars: the current state of affairs 62
Most regulatory authorities have extrapolated
approval of Remsima/Inflectra to all indications
Country/
regulator
RA AS Ps PsA CD UC
EMA √ √ √ √ √ √
USA √ √ √ √ √ √
South Korea √ √ √ √ √ √
Colombia √ √ √ √ √ √
Turkey √ √ √ √ √ √
Canada √ √ √ √ X X
Japan √ X X X √ √
Source: Dorner and Kay. Nature Review Rheumatology, 2015
Drugs @FDA
Biosimilars: the current state of affairs 63
Reasons for non-extrapolation of indications for
Remsima/Inflectra were different
Canada
Extrapolation to rheumatology and dermatology indications, but NOT to
inflammatory bowel diseases (IBD)
Rationale – differences in properties, including antibody-dependent cell-
mediated cytotoxicity (ADCC), which might be an important aspect of activity in
inflammatory bowel diseases.
Japan
Extrapolation to inflammatory bowel diseases, but not AS, Ps, PsA
Rationale – indications protected by a period of exclusivity
The Canadian view could be indicative of objections that may need to be
countered to introduce biosimilars at regional and local levels
Biosimilars: the current state of affairs 64
NICE decision in the UK favoured infliximab
biosimilars
The SMC initially recommended use of Inflectra and Remsima in the same indications
for which Remicade was recommended (i.e. RA, Crohn’s, psoriasis, psoriatic arthritis
BUT NOT ankylosing spondylitis or ulcerative colitis).
Evidence in RA study was accepted as showing similarity of efficacy and safety
Cost minimisation study showing cost-savings was accepted
The SMC advice in ankylosing spondylitis or ulcerative colitis was superseded by
NICE MTAs across anti-TNFs in these indications, which recommended use of
infliximab.
NICE guidance in ankylosing spondylitis was in favour of biosimilar (lower cost)
infliximab
“Infliximab is recommended only if treatment is started with the least
expensive infliximab product. People currently receiving infliximab should be
able to continue treatment with the same infliximab product until they and their
NHS clinician consider it appropriate to stop.”
The ICER for biosimilar infliximab was still above usual threshold for cost-
effectiveness, but lower price on tendering was taken into account.
Biosimilars: the current state of affairs 65
French national decision-maker is signalling that
open to interchangeability as well as extrapolation
All three products (Remsima, Inflectra and Flexabi) have been reviewed by the
Transparency Commission
The nature of the clinical evidence package has been discussed
The numerical differences have been mentioned
Opinions have all indicated that products are considered comparable by EMA and
recommendations for reimbursement/ use similar to those for reference product have
been made across all labelled indications, with restrictions on use in psoriasis.
Accepted for use in hospital in all indications for reference product
(Remicade)
ASMR V – no benefit
In the opinion on Flixabi, the Transparency Commission also indicated that formal
exclusion of interchangeability no longer justified. Switching can be envisaged if:
Patient informed of possible change
Patient followed up
Actual product given can be traced
Biosimilars: the current state of affairs 66
Evidence of safety on switching is highly relevant to
payers
Regulatory clinical trials for biosimilars, when conducted, are usually parallel group
studies
EU biosimilar guidelines state:
“Evaluation does not include recommendations on whether a biosimilar should
be used interchangeably with its reference medication
“Substitution policies are within the remit of EU member states”
In the US, Biologics Price and Competition Act states that if a biosimilar agent is
determined to be “interchangeable”, a pharmacist would be allowed to substitute for its
reference product without consulting the prescribing physician.
Studies demonstrating lack of issues on switching could be useful to
National payers, in policy making on substitution
Regional and local payers, to overcome objections of physicians to switching
Biosimilars: the current state of affairs 67
Study designs to support switching/
interchangeability
Source: Dorner and Kay. Nature Review Rheumatology, 2015
Could be addressed by real world
evidence
Approach used in PLANETRA and
PLANETAS extension studies
Approach being used in post-launch
study of Crohn’s Disease
Biosimilars: the current state of affairs 68
The NOR-SWITCH study uses a randomised
transition from Remicade to Remsima/Inflectra
Biosimilar
Reference drug
The Norwegian Medicines Agency (NoMA) is encouraging a substitution culture
by promoting clinical studies to show that Remicade and Remsima/ Inflectra
are interchangeable.
The NOR-SWITCH study was designed to assess the safety and efficacy of
switching from Remicade to Remsima in patients with rheumatoid arthritis,
spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn's disease and
chronic plaque psoriasis.
It is a randomised double-blind study in 500 patients across all indications. Half
the patients will be switched to Remsima and the others remain on Remicade,
with occurrence of disease worsening as the primary endpoint; the study
reports this year.
Biosimilars: the current state of affairs 69
Extension to regulatory studies of Remsima/
Inflectra has shown feasibility of switching
Clinical studies for Remsima/ Inflectra
PLANETAS in Ankylosing Spondylitis patients
PLANETRA in Rheumatoid arthritis patients
Both included an extension study after 1 year in which patients on reference product
(Remicade) switched to biosimilar for a 1 year and patients on biosimilar continued on
biosimilar for a year.
Both demonstrated comparability between groups in
Safety
Efficacy
Anti-drug antibody levels
Biosimilars: the current state of affairs
How might the evidence required for regulatory approval need to be
supplemented for payers?
Little point in conducting parallel group studies vs reference product in additional
indications beyond those required for regulatory approval.
Additional studies should focus on concerns/ objections raised by physician societies
that can limit payers’ ability to promote switching to biosimilar products:
Extensions to regulatory studies can include switching from reference product to
biosimilar
Studies in additional indications should also address switching between
reference product and biosimilar
Data from real world studies and registries are helpful to address concerns of
rare AEs
Simple health economic modelling may be useful to show a biosimilar to be cost-
effective in indications/ positioning where the reference product is not
Conclusion: Payers are more concerned by
interchangeability than biosimilarity
70
Biosimilars: the current state of affairs
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71