London, 28 September 2016 onward distribution · 2017. 5. 23. · fast as seen for small molecule...

Biosimilars: the current state of affairs

Confidential to RJW & partners Ltd - not for

onward distribution

London, 28 September 2016


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



onward distribution

Neil Johnson, RJW & partners Ltd

Biosimilars: why is regulatory approval

still not enough to achieve sales?

3


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?


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


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


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 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


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)


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.


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


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


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.


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?


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%



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


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


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


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


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


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


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


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


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


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


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



onward distribution

Ad Rietveld, RJW & partners Ltd

Are biosimilars what payers have been

waiting for?

27


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


Survey results


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


Biosimilars could save €100bn

over the next 5 years (US + EU)1

1 Delivering on the Potential of Biosimilar Medicines, IMS

Survey results


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


Survey results


National pricing and reimbursement policies

are not seen as obstacles for biosimilar uptake


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


International Healthcare Spending as a % of GDP

Source: OECD Health Data 2015

32


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


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


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


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


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


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


lower priced

biosimilar

€952

€718

Biosimilar Remsima (2013)

Original product (Remicade)

Biosimilar Inflectra (2013)

€300

€445


€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


first biosimilar

No biosimilar

available

€510.29

17% discount vs


both biosimilars

Biosimilar Remsima (2013)

Original product (Remicade)

Biosimilar Inflectra (2013)

€150

€234.33

€300

€350


€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


€561


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


€434

€382

Price for 100mg (1 vial)

Remsima and Inflectra

(biosimilars)

Remicade


€179

€252


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


€148

Price for 1 pre-filled syringe

(50mg/1ml)

Benepali (biosimilar)

Enbrel

€174

€211


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.


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.



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.



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


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.


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?



onward distribution

How to ensure that evidence for

biosimilars is relevant to payers

Chloe Brown, RJW & partners Ltd

49


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


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?


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.


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


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


• Plaque psoriasis


Source: Gabionline.net


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


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


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).

http://syndicatedanalyticslibrary.imshealth.com/news/PharmaQueryNews/14537#anchor14537



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




EMA Guidance on infliximab

Infliximab

Reference

product

indications

• Ankylosing spondylitis



• 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


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


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


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


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.


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


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


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


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.


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


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


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Thank you!

71

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