2016 11 17 aaps_337 denver vulto biosimilars interchangeability vs16k16agv
TRANSCRIPT
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.
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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.
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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
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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
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
10
Joint Symposium AAPS /
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
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
13
Joint Symposium AAPS /
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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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
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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
29
Joint Symposium AAPS /
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)
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Vezer et al. Current Med Res Opinion 2016
Authorized manufacturing changes for therapeutic
monoclonal antibodies (mAbs) in European Public
Assessment Report (EPAR) documents
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
36
Joint Symposium AAPS /
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)
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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)
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Founded by Huub Schellekens, Arnold Vulto and Lasia Tang
www.gabionline.net (16d08) www.gabi-journal.net
Founded in 2008 by Schellekens, Tang & Vulto)
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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
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
48
Joint Symposium AAPS /
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
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
50
Joint Symposium AAPS /
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
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GaBI will be happy to publish
your biosimilar studies
54