Transcript Title

Biosimilars – An NHS perspective
Maggie Dolan
Regional Pharmacy Procurement Specialist
South East Coast
Introduction
Currently 2012 –
Pharmacy Advisor South East Coast
medicine procurement /contracting / medicine optimisation
work on behalf of provider trusts and commissioners
Surrey and Borders Partnership NHS Foundation Trust
Career history
Chief Pharmacist - Edinburgh Sick Children's Hospital 1993-1999
Chief Pharmacist – West Lothian Integrated Trust 1999- 2005
Pharmacy Advisor National Services Scotland 2005- 2012
National procurement of Medicines
Health Emergency Planning
Patient Access Scheme
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Aim
 The changing medicines landscape
 driving patient access to medicines
 the Biosimilar Medicine Challenges
 questions to consider
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Medicines are changing
Value of generic medicines to the
NHS Health Economy
£12.2bn saved in 2012-13. That is the extra cost if all community
pharmacy scripts had been fulfilled as a brand.
Generic usage is 75.20% of all scripts in primary care
Secondary care spend on generics £250m /annum
Contracting delivered a £30million cost saving to Trusts across
England
Branded to Generic – point of savings
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Generics - Supporting patients access to
life changing medicines
 Generics at transition – 70-90% price reduction
 Biosimilars
- 20-40% ?
 More competitive pricing / wider availability
Cash releasing contracting
invest in new medicines / treat more patients
Biologics growth continues to outstrip growth rate of
total pharma, showing a steep hike from 2013
Such a trend is putting additional financial pressure on
healthcare budgets
Biologics – Share of sales
Global market trends
Sales and Growth
6.6%
250
12%
10%
8%
150
6%
100
4%
50
12.6%
Growth, LCUS$
200
Sales, US$ billions
9.8%
49.8%
21.2%
Japan
0%
2008
2009
2010
2011
Biologics Sales
2012
2013
2014
ROW
2.7%
US
10.2%
8.9%
62.9%
Biologics Growth
Total Pharma growth
Source: IMS Health, MIDAS, MAT Q2 2014, Rx; Brazil and Mexico Non Retail Sales are included; Share of growth in LC$
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EU5
Biologics – Share of growth
2%
0
Pharmerging
15.3%
Europe illustrates importance of biologic therapies
Europe Top 10 products 2009-14
2009
2010
2011
2012
2013
2014
1
LIPITOR
LIPITOR
LIPITOR
HUMIRA
HUMIRA
HUMIRA
2
SERETIDE
SERETIDE
SERETIDE
SERETIDE
SERETIDE
ENBREL
3
PLAVIX
HUMIRA
HUMIRA
ENBREL
ENBREL
SERETIDE
4
ENBREL
ENBREL
ENBREL
LIPITOR
HERCEPTIN
HERCEPTIN
5
HUMIRA
HERCEPTIN
HERCEPTIN
HERCEPTIN
MABTHERA
REMICADE
6
HERCEPTIN
LOVENOX
LOVENOX
LOVENOX
REMICADE
AVASTIN
7
LOVENOX
AVASTIN
AVASTIN
MABTHERA
LOVENOX
MABTHERA
8
ZYPREXA
ZYPREXA
MABTHERA
REMICADE
AVASTIN
LOVENOX
9
PANTOZOL
PLAVIX
REMICADE
AVASTIN
LUCENTIS
LYRICA
10
SYMBICORT
REMICADE
ZYPREXA
SPIRIVA
LYRICA
LUCENTIS
Small molecule products
Biologic products
Source: IMS Health, MIDAS, MAT June 2014. Rx bound. Europe doesn’t include Russia and Turkey.
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It’s the loss of exclusivity that drives biosimilar
interest
All these products will lose patent protection in EU by 2020
(
Global Sales (MAT 06/2014), US$ billion
10.8
US expiry date
2018
2016
2014
2015
2015
2028 (extended)
2015
2018
Expired
2018
Expired
Expired
2019
2019
Interferon Beta-1A (Avonex, Rebif)
2015
2016
Trastuzumab (Herceptin)
2014
2019
2017
2014
2015
2015
2016
2016
Adalimumab (Humira)
9.2
Insulin Glargine (Lantus)
8.3
Etanercept (Enbrel)
7.9
Infliximab (Remicade)
6.4
Rituximab (Mabthera)
6.3
Insulin Aspart (Novomix, Novorapid)
5.9
Bevacizumab (Avastin)
5.5
5.3
Total
~ US$ 79
billion
4.6
4.5
Glatiramer Acetate (Copaxone)
Pegfilgrastim (Neulasta)
4.5
0
EU expiry date
Ranibizumab (Lucentis)
5
10
Source: IMS MIDAS, 06/2014, Rx bound, IMS Patent focus
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Not considered existing biosimilars
such as Epoetin Alfa expired in EU, but
still patent protected in the US
Expected UK launch dates
Infliximab
Insulin Glargine
Dalteparin
2015
Pegfilgrastim
2016
Enoxaparin
Etanercept
Trastuzumab
2017
2018
Rituximab
Adalimumab
UK Anti-TNF Spend
IMS HPA June 2014
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Anti –TNF spend
IMS HPA June 2014
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Uptake of biosimilars across Europe
Why slow acceptance / uptake
Biosimilar but not identical - confusing
Clinical trial data vs characterisation of structure and function
to judge safety and efficacy
Understanding of the scientific concepts of the development and
licensing of biosimilars
Resolution- a well informed NHS , peer debate and
pharmacovigilance
PMSG Biosimilars Group
Purpose
To devise a strategy to ensure the NHS makes best use of
Biosimilar
medicines which has patient safety as a priority
whilst Tasks
supporting a robust Biosimilar market
Membership – 4 Nations
NICE , CMU, Trusts , Commissioners – CCGs , NHSE
Specialist Pharmacy Services - Regional Procurement, QA,
MI
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Assess Pipeline – engage with suppliers
Understand barriers to uptake
Provide resources for NHS/ patient educational opportunities
Support clinical engagement and contracting
Collect data on uptake / implementation
Pharmaceutical Industry Sector Board - Biosimilars
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NHS Scotland Biosimilar Procurement Strategy
Implementation Challenges
Supply Chain
Forecasting
Storage and Distribution
Homecare /Outsourced
Outpatients
Supply Chain;
Funding Model; Governance
Substitution
Strategy for Experienced vs.
Naive Patients
Naming of Biosimilars
e.g. Remicade®/ Remsima® /
Inflectra®
Compounding
Dose Banding;
Goods vs. Service Contracts
Clinical Acceptance
Therapeutic Similarity Across
Licensed Indications
Market Defence Strategies
Benefit Sharing CCGs/NHSE
Assessment of Biosimilars in the UK
(evidence based choice)
Scottish Medicines
Consortium (SMC)
NICE
All Wales Medicines
Strategy Group
(AWMSG)
Biosimilars- protein based medicines
 EMAa biosimilar is a medicine which is similar to a biological
medicine which has already been authorised ,used in general at
the same dose to treat the same disease
 FDA
a biosimilar is a biological product which is highly similar to a
US licenced product not withstanding differences in clinically
inactive components, for which there are no clinically meaningful
differences from the originator
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Why ‘biosimilar’ not ‘bioidentical’?
 Microheterogeneity
 An effect of the inherent variability of the biological system used for
manufacture1
 Resulting product is a mixture of different forms of the same protein2
 Post-translational modifications3
 Glycosylation, methylation, oxidation, deamination
 May occur after a change in cell line or manufacturing process
 Resulting product is highly similar, but not identical to the originator
 Make complex molecules, such as mAbs and –cept fusion proteins,
particularly difficult to replicate
But...originator products are also subject to variability4
1. Weise M, et al. Nat Biotechnol 2011;29:690-3. 2. European Commission. What you need to know about biosimilar medicinal products.
A consensus information document. [Accessed September 2014].
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf 3. Dörner T, et al. Ann Rheum Dis 2013;72:322-8. 4.
Schneider CK. Ann Rheum Dis 2013;72:315-8.
Biologics Manufacturing Process
Numerous ways to manufacture the same biologic
Different process = Different product
Process changes are the norm
Originator product variability
All currently licenced mAbs and -cept
fusion proteins used in rheumatology
have had changes in manufacture after
their initial approval
Figure adapted from reference
Schneider CK. Ann Rheum Dis 2013;72:315-8.
Regulatory requirements
Generic drugs
Quality
assessment
To provide information on the
quality of the medicine
Pharmacokinetic
assessment
To demonstrate that the
generic formulation the same
levels of active substance in
the body
EMA. Generic medicines. [Accessed August 2014]. http://www.ema.europa.eu/
Regulatory requirements
Biosimilars
Quality
comparison
Non-clinical
comparison
Clinical
comparison
To compare molecular structure and
functionality of biosimilar and
originator. Involves comprehensive
analytical characterisation, receptor
binding studies and bioassays –
ADCC binding
Pk toxicity
To provide confidence that any
differences seen in the quality
comparison do not impact safety
and efficacy of the biosimilar
European Commission. What you need to know about biosimilar medicinal products. A consensus information document. [Accessed September 2014].
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
Regulatory requirements
Characteristic
EMA requirement
Primary amino acid sequence
Must be identical to the reference product
Potency
Must match the reference product
Route of administration
Must match the reference product, but the device used
can be different
Higher order structures, post-translational
modifications and other potential variants
Must be as similar as possible to the reference product,
with adequate analysis to ensure no effect on efficacy,
safety or immunogenicity
Adapted from Dörner T, et al. Ann Rheum Dis 2013;72:322-8.
Regulatory requirements
Clinical study parameter
EMA requirement
Pharmacokinetics
Single-dose, comparative human studies
Pharmacodynamics
Combine with PK studies where a clinically relevant PD
endpoint is available. Otherwise, non-clinical evaluation
required
Efficacy
Highly-sensitive, dose-comparative PD studies may be
sufficient. Otherwise, at least one adequately powered
equivalence trial
Safety
At least one adequately powered equivalence trial
Immunogenicity
Must be assessed during the safety trial
Adapted from Dörner T, et al. Ann Rheum Dis 2013;72:322-8.
Comparability & Analytics of biologics
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The goal of the comparability exercise (existing biologics) is to ascertain
that pre- and post-change drug product is comparable in terms of
quality, safety, and efficacy.
The product should be evaluated at the process step (s) most appropriate
to detect a change in the quality attributes.
Not designed to show they are identical, merely highly similar
The battery of tests should be carefully selected / optimised to maximise
the potential for detecting relevant differences in the quality attributes
The nonclinical and clinical studies include PK, PD, clinical efficacy,
specific safety, immunogenicity and pharmacovigilance.
If assurance of comparability shown via analytical studies alone then
nonclinical /clinical studies not warranted.
However, where differences observed, may need a combination of
quality, nonclinical, and/or clinical studies.
These scientific principles are exactly the same for a
biosimilar molecule
Reference product variability
- the Goal Posts
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Once “goal posts” are established an iterative process is used to fully
evaluated by physicochemical and biological characterisation vs originator.
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Essentially the goal posts have been set by the originator
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If attributes fall outside established “goal posts,” various process steps are
modified to produce product attributes that are within originator variability.
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Depending on the extent of the biosimilar/originator overlap, preclinical and
clinical development can be abbreviated compared to developing a novel
biologic.
Outcome of the biosimilars
licensing process…
European Medicines Agency (EMA):1
“Like the reference medicine, the biosimilar has a degree of natural
variability. When approved, its variability and any differences between it and
its reference medicine will have been shown not to affect safety or
effectiveness. An authorised biosimilar is generally used at the same dose
to treat the same conditions.”
An authorised biosimilar can be therefore be
considered to be clinically equivalent to the originator
product despite trivial differences in molecular
structure.
These minor molecular differences are comparable
with the level of variation found within originator
product2 following a manufacturing change.
1. EMA. Questions and answers on biosimilar medicines (similar biological medicinal products) EMA/837805/2011.
2. Schiestl M, et al. Nat Biotechnol 2011;29:310-2.
Extrapolation of indications –
the totality of the evidence
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Extrapolation is possible based on the overall evidence of
comparability provided from the comparability exercise and with
adequate scientific justification - decided by EMA.
This includes at least one clinical study (if same MOA) in the
most sensitive population measuring the most sensitive clinical
endpoint(s) ie RA
Principles apply to biosimilars AND biologics pre and post-change
For infliximab extrapolation was based on the comprehensive
characterisation / comparison of the physicochemical, binding
and functional characteristics of the biosimilar vs innovator
Similar effects seen in a wide range of in-vitro / ex-vivo
functional assays, including experimental models tailored to IBD
Preliminary clinical data also indicated similar response to CT-P13
compared with historical data on Remicade.
Indication extrapolation: conclusion
As long as the necessary considerations are
taken into account, extrapolation of data to other
indications of the reference product, and thus
formal lack of a clinical trial in the respective
clinical indication, does not imply less
reassurance as regards efficacy and safety of the
biosimilar
Weise M, et al. Blood 2012;120:5111-7.
Immunogenicity must be assessed
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The Clinical trials were designed to evaluate residual
uncertainty in relation to safety and/or immunogenicity
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Analytical or animal data cannot predict immune responses
in humans  human immunogenicity data required
Immunogenicity influenced by patient/ disease/ product
Patient and disease factors are known so focus was on
potential product-related factors
Clinical end points / trials - far less sensitive than analytics
at picking up even moderate differences between products
Trials >6/12 needed but long-term data and
pharmacovigilance essential
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Post-marketing surveillance
At the time of marketing authorisation application a
comprehensive plan must also be submitted detailing
further safety studies in a post-authorisation setting,
including the following aspects:
•
Safety in indications licensed for the reference product that are
claimed based on extrapolation of efficacy and safety data,
including long-term safety data unless otherwise justified
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Occurrence of rare and particularly serious adverse events
described and predicted, based on the pharmacology, for the
reference
EMA. Guideline on similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues.
EMA/CHMP/BMWP/403543/2010
The IBS Position statement
A point in time in the evolution of biosimilars
An infliximab statement rather than biosimilars per se
Currently anti- tnfs have widely differentiating characteristics
and efficacy
eg Etanercept / certolizumab not licenced for IBD in EU
EMA have licensed CT-P13 (Remsima / Inflectra ) and for all
indications of the originator (Remicade)
Asumption these biosimilars will be as effective as the originator
across rheumatology ,gastroenterology and dermatology
indications– Only pharmacovigilance will tell
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Conclusions
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Clinician engagement vital
But a paradigm shift in thinking is required
 Clinical Trials vs Analytics
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Remicade is a biosimilar of itself and Inflectra / Remsima are a
biosimilars of Remicade
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A phased entry will be required but with defined milestones
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This is the first of many so we need to get it right
The contracting challenge
Biosimilar- pricing----- comparable discount on originator
Remicade pricing – volume price matrix –IMPACT?
Clinical intention ?
Regional impact ?
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Questions
Are current biologic molecules biosimilars of themselves ?
Will biosimilars be seen as a new treatment options in class
rather that “generics” ?
Will they be substituted in existing patients ?
Will they be accepted as therapeutically interchangeable in
terms of clinical data ?
Can the NHS / branded pharma afford the NHS not to use
biosimilars ?
ONLY TIME WILL TELL – Thank you for listening
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