2016 11 17 aaps_337 denver vulto biosimilars interchangeability vs16k16agv

Interchangeablity of Biologicals and Biosimilars:

Perceptions and Clinical Reality in Europe

Arnold G. Vulto PharmD PhD FCP

Professor of Hospital Pharmacy & Practical Therapeutics

ErasmusMC Hospital Pharmacy

Rotterdam / The Netherlands

Denver, November 17, 2016

Vs16k16

Conflict of Interest Statement

I declare no personal financial interest in any pharmaceutical bussiness

I entertain friendly relationships with all innovative and generic / biosimilar

companies (AbbVie, Amgen, Biogen, EGA, Mundipharma, Pfizer/Hospira,

Roche, Sandoz)

As a co-founder I have a societal – but not financial - interest in the advocacy

of cost-effective treatments via the Generics & Biosimilar Initiative (GaBI)

My employer – Erasmus University Hospital - receives any honoraria

(advisory boards, speakers honoraria) if they let me speak at scientific or

commercial meetings.

2

My personal motto as a hospital pharmacist

My drive is optimal treatment for all patients at an affordable cost

Science gives us the best possible description of the world.

It is emotion that is distorting view.

3

Agenda

Biosimilars: a new drug development paradigm

And therefor: new definitions needed

Europe, many countries

Importance of national regulators opinion

The information gap

How to raise trust

Summary and take home messages

4

Joint Symposium AAPS /

EUFEPS / JBF / USP

What are biosimilars?

How I see biosimilars as of November 2016

A biosimilar is a pharmaceutical product, that as such has been licensed by

e.g. EMA or FDA via the WHO regulatory pathway (=minimum global

standard)

EMA definition of a biosimilar

It is a version of an already licensed rec-DNA drug product, for which

similarity has been proven in an extensive comparability exercise,

encompassing physical, chemical, biological and pharmacological

properties, including efficacy and safety

This excludes all kinds of bio-questionables in existence in other regions of

the world that have not been endorsed via the WHO pathway as a biosimilar.

Reference to such products as if biosimilars may be inferior is thus WRONG.

A new drug development paradigm, based on a

“comparability excercise” and different from traditional

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Clinical trials

PK / PD

Pre-clinical

Analytical

traditional biosimilar

(McAmish et al. CPT 2013)

Confidence is provided by the (upside down)

“totality of evidence”

Uwe Gudat (Merck AG) DIA Biosimilars

Meeting Brussels, November 2016

Characteristics of biosimilar development and licensing

Emphasis on physico-chemical comparison with sophisticated techniques and

in-vitro models, much more sensitive to detect differences than any clinical trial

Most prescribers have no knowledge of these techniques

Confirmation of similarity in a small clinical trial in a sensitive indication and

end-point

Unlike large clinical trials to prove efficacy and safety

Extrapolation of indications based on scientific principles like mode of action

Addressed in post-licensing “risk management plans” (EU)

EMA has no say over national implementation, like interchangeability

8

Prescribers are unfamiliar with this paradigm

Biosimilars are not identical but similar

What are then the differences and what could be the consequence?

A deep understanding of bioequivalence and “biosimilarity” is not easy

Biosimilars are standing on the shoulders of 10 – 15 years of

experience of innovator medicines

Physicians don’t like uncertainty

Therefore additional education essential

Agenda





The information gap

How to raise trust


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EUFEPS / JBF / USP

Framing the discussion:

confusing definition issue / words to avoid

Switching is both:

Change from one treatment / molecule to another

Change from reference product to biosimilar

(also coined non-medical switching).

Better word transitioning: only for biosimilar (Dörner, 2016)

Interchangeability: EMA differs fundamentally from FDA

Very confusing: population versus individual level

Substitution:

Why discuss? We don’t do it (with few exceptions).

Using these words is framing the discussion (see: Lakoff / YouTube)

Weise et al. Nature Biotechnology 29, 690–693 (2011)

Dörner et al Ann Rheum Dis doi:10.1136/annrheumdis-2016-209166 11

Agenda





The information gap

How to raise trust


13


EUFEPS / JBF / USP

32 separate countries

One Medical Agency = EMA

Common regulation for GMP,

GDP, etc

Health Care “local competency”

Funding

Pricing

What is available

• All countries have some form of

“solidaric” health care system

There is not one Europe

Courtesy Per Troein, IMS health

Selection of 23 Biosimilars licensed in the EU

(list of 1/2/2016)

19 products in EMA licensing pipeline (15/11/2016)

Adalimumab (3x, Amgen, Samsung, ???)

Etanercept (2x; Sandoz, Shire)

Insulin glargine (2x; a.o. Samsung/MSD)

Insulin lispro (1x; Sanofi-Genzyme)

Peg-filgrastim (4x)

Rituximab (2x; Celltrion, Sandoz)

Teraparatide (2x)

Trastuzumab (3x; a.o. Mylan, Samsung)

Europe has unified licensing, but not unified access

Legislation is only part of the story

There exists a formal legal framework (i.e. EMA)

Versus a less formal local interpretation with many variations

Acceptance of a biosimilar is dependent on how different stakeholders act

Physicians, patients, pharmacists, 3rd party payers, policy makers

Essential to buy in “ownership” from stakeholders like prescribers (e.g. via

guidelines) and patients(-organisations)

“The” biosimilar does not exist

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Three classes of therapeutic proteins (biologicals);

are perceived differently by prescribers

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Class 1: substitution products

Hormones like growth factors or insulin

Effect visible / measurable in hours or days

Interchangeability less of an issue

Class 2: proteins with a specific pharmacological effect

Like TNF-alfa inhibitors

Effect only visible after some time, but not in all patients

Interchangeability under debate

Class 3: proteins with a less clear measurable clinical effect

“Targeted therapies” in oncology

The effect is a statistical chance some time in the future (survival)

Biosimilar uptake as % of accesible market (2014; IMS)

Transitioning of EPO in the first year did not increase

immunogenicity (Italy)

Ingrasciotta et al.

BioDrugs

29(2015)275

Second Class:

Therapeutic proteins with a pharmacological action

These proteins do not mimic a biological function, but act mostly as a

pharmacologcial antagonist e.g. binding a circulating protein or

blocking a receptor

The clinical effect may be visible and measurable within days or weeks

In a proportion of patients

Currently licensed biosimilars (Nov. 2016) infliximab and etanercept

With extensive “extrapolated indications”

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Savings can be considerable:

The case of infliximab-biosimilar in Norway

In February 2014, Norway negotiated a 39% discount on the innovator list

price on exclusivity basis: all new patients will start on infliximab biosimilar

Renegotiation 2015: 69% discount; no switching

Renegotiation 2016: 61% discount

Market uptake

March 2014 >12 %

March 2015 >50 %

November 2016 >95%

(Steinar Madsen, EU-DIA Biosimilar Meeting Brussels , November 2016)

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Prices and savings with biosimilar Infliximab in Norway

Steinar Madsen, EU DIA Biosimilar Meeting November 2016 23

What were the succes factors in Norway:

Multi stakeholders approach

An advisory board with most of the (clinical) opinion leaders and patient

organisations were involved in deciding on the pre-tender conditions

To start with, only new patients will receive the biosimilar

New tender again for NEW patients (existing patients will not be changed)

(Based on good experience many patients have been transitioned)

Gain sharing: savings will be invested in:

Treating more patients for less money

Trials in support of unresolved areas like extrapolated indications and

controlled switching (NorSwitch trial)

This is a win-win for everybody (Torfinn Aanes, National Procurement Board)

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25

Denmark

Sweden Finland

Norway

But all physicians know: clinical effect is declining,

the target is moving, biosimilar will be blamed….

26 Juillerat, P. et al. (2014)

RA

Senabre-Gallego, JM. et al. (2011)

IBD

Third class:

therapeutic proteins with a remote clinical effect

These protein drugs provide a statistical chance on benefit some time

in the future (e.g. trastuzumab, rituximab).

For these we need deep trust in the principles of similarity.

On what is the purported clinical effect based?

Can we expand the use in other types of cancer?

Doctors may be very reluctant to accept clinical similarity of these

molecules (“You can’t gamble with patients’ lives”)

As yet, these are theoretical questions, as no biosimilar of this type

has been granted EU marketing authorisation yet. 27

Agenda





The information gap

How to raise trust


29


EUFEPS / JBF / USP

Screenshot April 2015

Dutch Medicines Evaluation Board new position

on biosimilars (April 2015)

• New patients can be treated with a biosimilar right away.

• Uncontrolled exchange between biologicals (whether originators or

biosimilars) must be avoided. In other words, a patient must receive

adequate clinical monitoring and clear instructions.

• If a patient is treated with a biological, detailed product and batch

information must be recorded in the patient file to guarantee the

traceability of the product in the event of problems.

Dutch Medicines Board:

Active support for patients

and patient organisations

April 2016

FIMEA position on interchangeability (2015)

35

Vezer et al. Current Med Res Opinion 2016

Authorized manufacturing changes for therapeutic

monoclonal antibodies (mAbs) in European Public

Assessment Report (EPAR) documents

Agenda





The information gap

How to raise trust


36


EUFEPS / JBF / USP

Patient perspectives on Biosimilars

Survey (on-line) among European IBD-patients (2014-2015)

1181 respondents, only 38% “had heard of biosimilars”

25% had no concerns

47% had concerns on efficacy, 40% on safety

66% want to know to be treated by reference product or biosimilar

Conclusion:

Most patients not familiar with biosmilars, many have doubts

Patients wish to be informed and involved in decision making

Peyrin-Biroulet et al. ECCO-JCC (2016)

Doi: 10.1093/ecco-jcc/jjw138; online 31/7/2016 37

Players in the Information Debate

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Innovative companies have high stakes

Have invested for years in a strong prescriber relationship

Now innovators have joined the biosimilar bandwagon, they can exploit

this advantage double

Some companies may send “mixed messages”

The biosimilar industry was reluctant with high quality scientific information;

it came too late or it was impossible to find

Smaller marketing budgets

They have to build a relationship with prescribers

Celltrion radically changed the landscape with CT-P13

What we learned: Price competition alone will not make the difference (Cf.

Troein (IMS): biosimilar growth hormone and Infliximab in Scandinavia)

39

Top-10 Pharma-companies (2015 Rx sales)

and strategy in the biologicals market

Moorkens et al. ISPOR 2016

The close relationship between innovator and

health care professionals

Academic research departments are supported by innovator industry

Clinical trials performed with a reference product or innovative medicine

provide a loyal user base

Procurement deals for hospitals can include multiple products with the

reference product being one.

How to overcome?

Education and easy access to impartial information

But: who takes this up, where to find? (GaBI)

Support investigator initiated trials with biosimilars.

We perceive an information gap

EMA’s EPAR (100+ pages) is difficult to find / read / understand for a

healthcare professional

Need support to understand the comparability excercise

No access to risk management information / PSUR’s

It is a snapshot in time and is not updated

Research findings should be published and made accesible

With 2nd class biosimilars more research data are early available

Chapeau Celltrion!

Clinical trials scattered and not always easily accesible

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Umbrella initiative to build trust in cost-effective treatments:

One-stop website with comprehensive information on generics

and biosimilars

Peer reviewed open access scientific journal

Scientific symposia

Educational meetings

Patient information

2008:Closing the information gap (www.gabionline.net)

42

Founded by Huub Schellekens, Arnold Vulto and Lasia Tang

http://www.gabionline.net/

www.gabionline.net (16d08) www.gabi-journal.net

Founded in 2008 by Schellekens, Tang & Vulto)

http://www.gabionline.net/

http://www.gabi-journal.net/



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Results: The positions of the European regulators and medical

societies are slowly converging. While many questions were

answered, productive discussions identified areas of disagreement

and uncertainties. The results of these discussions will inform

debate and decision-making in the participants’ organizations and

home countries.

Conclusions: The picture of biosimilars is becoming clearer, and

stakeholders are beginning to understand better the basis of

biosimilar development, on one hand, and the reasons for

concerns, on the other hand. Different stakeholders – patients,

doctors, pharmacists, payers – need different information. Above

all, this must be a collaborative exercise.

Biosimilars create uncertainty with prescribers

Innovative medicines

Offer a clear advantage – whether real or not

Promise a solution for a therapeutic problem

And hence, the physician is prepared to take a certain risk

Biosimilars

Don’t offer prescriber and patient a clear therapeutic advantage

May offer a modest price advantage for the patient / 3rd party payer

They may carry – as with any other new drug – some risk

Reversal of the “burden of change” mostly without compensation

Doctors and patients don’t like trouble with their medicines

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The market place makes it even more confusing

Innovative companies have high stakes

Are seeding doubt among prescribers and patients with “you never know”.

Have invested for years in a strong prescriber relationship

The biosimilar industry initially was reluctant with high quality scientific

information; it came too late or it was impossible to find

Smaller marketing budgets

Traditionally, they did not have a relationship with prescribers.

It is an uneven playing field

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Agenda





The information gap

How to raise trust


48


EUFEPS / JBF / USP

How to build trust in biosimilars?

Reduce the information gap

Regulators can communicate their knowledge

actively to medical professionals:

“The past 10 year there has not been a

single serious incident with biosimilars”

The assessment system worked as expected

Raised mistrust was not justified and we learned better in the meantime

Avoid trouble around transition

Convince prescribers on the (financial) advantages for the society,

without compromising quality of treatment.

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Agenda





The information gap

How to raise trust


50


EUFEPS / JBF / USP

In summary

Biosimilars follow a new drug development paradigm

Once licensed, they have the same high quality, equal to any other

biotech drug and can be prescribed without reservation for new patients

and to transition existing patients

Europe has a unified licensing system with decentralised market access

There exist formal and informal barriers towards market acceptance

Critical to have support from stakeholders; requires a lot of education

Biosimilars may contribute to an affordable health care for all

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Take home message

Communication on principles and terminology around biosimilars is essential.

Avoid terminology with negative emotional values

All Stakeholders need to be educated

Prescribing doctors

Dispensing and procuring pharmacists

Policy makers (government, third-party payers)

Patients

Make inpartial information easy available / accesible in local language

Decision to change prescribing by doctors dependent on

Incentives (like INN-prescribing systems) and avoiding reversal of burden

Acceptance of societal values (like lower cost, quality of care) 52

Thank you for your attention

Contact: [email protected] 53

GaBI is supporting you.

Please support GaBI.

GaBI will be happy to publish

your biosimilar studies

2016 11 17 aaps_337 denver vulto biosimilars interchangeability vs16k16agv

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