Joan O'Callaghan of the HPRA provides the regulatory perspective for biologic and biosimilar medicines in Ireland

1. Biosimilars: Regulatory
Perspective in Ireland
Joan O’Callaghan
IPPOSI Breakfast Seminar: Biologics and Biosimilars in Ireland
5th April 2016

2. Overview
• Biological medicines
• Biosimilar medicines
• Biosimilar approval process
• Pharmacovigilance of biological medicines
• Interchangeability
05/04/2016 2

3. Biological Medicines

4. What is a biological medicine?
• Biological medicines contains active
substances made by a biological process or
are derived from a biological source.
• Broad term and examples include
– Hormones (e.g. insulin)
– Enzymes (enzyme replacement therapy)
– Monoclonal antibodies (targeted treatment)
– Blood derived products (clotting factors)
– Animal derived products (e.g. heparin, vaccines)
405/04/2016

5. What is a biological medicine?
• Biological medicines provide effective
treatments for a wide variety of serious
conditions. Examples include
– Diabetes mellitus (Lantus®)
– Rheumatoid Arthritis (Humira®)
– Cancer (Herceptin®)
– Multiple Sclerosis (Tysabri®)
05/04/2016 5

6. What is a biological medicine?
• Most biological medicines are
produced from the cell cultures of
living organisms
• Often the cells have been engineered
in order to produce a therapeutic
molecule or group of molecules,
usually proteins
05/04/2016 6

7. Biological medicines have a complex
manufacturing process
05/04/2016 7
Source: Slide by Nanna Aaby Kruse, Mediacademy, Oct 2011

8. Biological Medicines and Chemical Medicines
05/04/2016 8

9. Biological Medicines and Chemical Medicines
Biological medicines Chemical Medicines
Large complex structure
Inherent natural variability
Synthesis in living organisms-
difficult to reproduce
No two batches likely to be
identical
More likely to cause an immune
reaction due to size and structure
Generally given by
injection/infusion
Generally prescribed by specialists
Small simple structure
Single well defined chemical
structure
Made by combining chemical
ingredients
Reproducible manufacturing
process
Unlikely to cause immune reaction
due to small size
Often taken orally
Prescribed by GPs and/or
specialists05/04/2016 9

10. Relative complexity of chemical and
biological medicines!
05/04/2016 10

11. Biological Medicines
• Biological medicines have revolutionised
the treatment of many diseases including
cancer, rheumatoid arthritis, psoriasis,
inflammatory bowel disease and diabetes
• Biological medicines are high cost and use
is often limited
• Patents of many ‘blockbuster’ biological
medicines have expired or are nearly
expired
05/04/2016 11

12. Sales and patent expiry
05/04/2016 12

13. Biosimilar medicines

14. What is a biosimilar medicine?
A biosimilar is a biological medicine that is
highly similar to another biological medicine
(reference product) that has already been
approved for use in patients
A biosimilar is not a generic
05/04/2016 14

15. Biosimilars v’s Generics
• Generic medicines are
usually small molecule
‘chemical’ medicines
• A generic medicine is an
exact copy of a reference
medicine
• It is not possible to make an
exact copy of a biological
medicine
05/04/2016 15

16. Biosimilar medicines
• Only comes on market after
patent of reference product has
expired
• Encourages competition which
can lead to price reductions and
improve patient access to high
cost medicines
05/04/2016 16
“Similar but not
identical”
.

17. Biosimilar medicines in Europe
Active
substance
Reference
product
Biosimilars
Epoetins Eprex Absamed, Epoetin Alfa Hexal,
Binocrit, Retacrit, Silapo,
Etanercept Enbrel Benepali
Filgrastim Neupogen Filgrastim Hexal, Biograstim,
Ratiograstim, Grastofil,
Tevagrastim, Nivestim,
Zarzio, Accofil
Follitropin GONAL-f Ovaleap, Bemfola
Infliximab Remicade Remsima, Inflectra
Insulin glargine Lantus Absaglar
Somatropin Genotropin Omnitrope
05/04/2016 17

18. Biosimilar approval process

19. Biosimilar approval process
 Manufacturers must demonstrate
to regulators that biosimilars have
similar quality, safety and efficacy
to the reference product and there
are no clinically meaningful
differences between the two
 Tailored approach which involves a
comparability exercise against the
reference product
 First step: quality comparability
 Second step: pre-clinical
comparability
 Third step: clinical comparability
05/04/2016 19

20. Quality comparability
• Quality testing is cornerstone of
biosimilarity
• Large number of physiochemical
and biological tests
• Quality comparability exercise must
show biosimilar is highly similar to
reference
• Potential impact of any (minor)
quality differences on safety and
efficacy must be addressed
05/04/2016 20
Quality
Clinical

21. Pre-clinical comparability
 Pre-clinical studies are required for all new
medicines. Involves testing in cell culture and
in animals in order to determine safety profile
prior to use in humans
 For biosimilars preclinical studies relate to
mechanism of action of medicine and could
uncover subtle differences between reference
and biosimilar
 Testing in animals may not always be
necessary
05/04/2016 21

22. Clinical comparability
 Clinical trials are designed to see if
clinically meaningful differences exist
between reference and biosimilar
 Generally includes data on
pharamacokinetics,
pharmacodynamics, safety and
efficacy
 Testing for immunogenicity required
05/04/2016 22

23. Indication extrapolation
• Clinical data may not be
required for the biosimilar
in all indications
• Must be scientifically
justified
• Similar approach is used to
justify post-approval
changes for other
biological medicines
• Approved on case by case
basis
05/04/2016 23

24. Pharmacovigilance

25. Pharmacovigilance
 Science of monitoring, evaluating and
preventing drug-related adverse events
 Clinical safety of all biologicals must be
monitored on an on-going basis after
approval
 New medicines including biosimilars are
subject to additional monitoring for a
certain time period after authorisation
 Patients should report side effects to the
HPRA and/or their healthcare
professional
05/04/2016 25

26. Traceability of biological medicines
05/04/2016 26
Biological medicines exhibit
variability: therefore biological
medicines with the same
international non-proprietary
name (INN) should not be
considered identical
Prescribe, dispense
and record using
brand name
Changes in manufacturing
processes can affect
likelihood of medicine
causing an immune
reaction
Adverse reaction reports
should include brand name
and batch number

27. Information for patients on
the approval process of a
medicine

28. Information for patients
European Medicines Agency website: ‘Find
Medicine’ section
• Summary of assessment available
• Further information: Package leaflet etc.
05/04/2016 28

29. HPRA Guideline on biosimilars
• Regulation
• Product information
• Prescribing
• Dispensing
• Traceability
05/04/2016 29

30. Interchangeability

31. 3105/04/2016
Interchangeability, substitution and
switching
 Interchangeability: medical practice of
changing one medicine for another
that is expected to achieve the same
clinical effect in a given clinical setting
and in any patient (prescriber is
involved)
 Substitution : practice of dispensing
one medicine instead of another
equivalent and interchangeable
medicine at the pharmacy level without
consulting the prescriber
 Switching: decision from treating
physician to exchange one medicine
for another medicine with the same
therapeutic intent in patients who are
undergoing treatment.

32. Substitution in Ireland
• ‘Generic substitution’ allows for
most chemical medicines to be
substituted for each other at the
pharmacy level
• Biological medicines are excluded
from ‘generic substitution’
• Pharmacists cannot ‘substitute’ a
reference medicine for a
biosimilar or vice versa unless
there is prescriber agreement
05/04/2016 32

33. HPRA position on interchangeability and
switching
05/04/2016 33
If it is planned to change the
medicine a patient receives from a
reference to a biosimilar medicine
or vice versa, the treating physician
should be involved; this should
involve discussion between the
prescriber/patient and
prescriber/dispensing pharmacist
• Ongoing engagement between prescribers, dispensers
and those with responsibility for procurement
• Stakeholder engagement to ensure optimal use of
resources and ensure the best patient outcomes
• Switching back and forth not recommended as
currently availability of data on the impact of this is
limited

34. International policies
• Tendering process determines which brand of biological
medicine is used in hospitals
• High uptake of infliximab biosimilar (new patients and
switching)
Denmark
• Pharmacist substitution possible if brand is given an ‘a’ flag
following evaluation by the reimbursement body
• Prescriber and patients retain right to decline substitution
Australia
• Category for ‘interchangeable biological product’ (no
medicine approved in this category to date)
• Legislation to allow pharmacist substitution of
‘interchangeable biological products’ passed in 16 states
United
States
05/04/2016 34

35. Regulatory Science Ireland:
Biosimilars Research Project

36. Regulatory Science Ireland
05/04/2016 36

37. RSI: Biosimilar Project
• Research activities: HPRA and UCC
• Supported by: HPRA, UCC and IPHA
• Industry Advisors: Merck, AbbVie, Novartis
• Objectives
• Peer reviewed scientific publications (practical
considerations for healthcare professionals)
• Survey perspectives and understanding of
biosimilars
• Comparative studies of international models for
providing safe and effective use of biosimilars
• Develop training materials and online resources
• Outreach activities
05/04/2016 37

38. RSI Biosimilar Project
Publications to date
• Biosimilar Medicines: Opportunities and
Challenges in the clinical use and supply of
Biosimilars (IPN and HPN)
• Biosimilar Medicines: Recent Developments
(HPN)
Prescriber survey
• Knowledge, behaviours and attitudes towards
biological medicines specifically biosimilars
05/04/2016 38

39. Any questions?
joan.ocallaghan@hpra.ie