Dr Bill Richardson Biosimilars in Perspective - Regulation - Presenter Disclosure Information
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Dr Bill Richardson
Biosimilars in Perspective – Regulation
Presenter Disclosure Information:
Currently employed by NDA Group as Medical Adviser
Previously employed by MHRA as Medical Assessor
This speaker has no conflicts of interest
Introduction
o Background - Regulation of biological
medicines in the EU
o Experience with biosimilar medicines
in the EU
o Biosimilar medicines for the
management of rheumatoid disease
2
Background
Biological medicines are derived from living
organisms:
A biological substance is a substance that is produced by or extracted
from a biological source and that needs for its characterisation and the
determination of its quality a combination of physico-chemical-biological
testing, together with the production process and its control. The
following shall be considered as biological medicinal products:
immunological medicinal products and medicinal products derived from
human blood and human plasma; advanced therapy medicinal products
(Directive 2001/83/EC ).
3
Background
4
Background
o Biological medicines
o Vaccines
o Blood products
o Enzymes
o Hormones
o Immunomodulators
o Antibodies
5Regulation of Biological Medicines
Aspirin Insulin Antibody
C 9 H 8 O4 51 amino acids ~5000 amino acids
MW 180 g/mol (Da) 5808 Da 144190 Da
6Regulation of Biological Medicines
Since 1995 - EU Regulations (EC 726/2004) require all
recombinant biological medicines to be authorised centrally
by the European Commission
o Applicants submit data to the European Medicines Agency to
demonstrate
o Quality
o Efficacy
o Safety
o EMA committees assess the data in detail and make
recommendations to the European Commission
o The EC issues legally binding decisions on marketing
authorisation
7Regulation of Biosimilar Medicinal Products
The regulatory requirements are similar to those for an innovative
product but:
o The product is not required to be identical to the reference product –
only similar in all important respects
o Some variability must be accepted for biological medicines
o Complex large protein molecules
o Many also have specific structural complex carbohydrates
attached
o Product critically dependent on conditions of manufacture
o This variability exists even within one brand of a biological
medicine
o No requirement for the same biological system to be used in
manufacture
o Not always necessary to conduct clinical trials in all indications for the
reference product in order to obtain marketing authorisation for use in
all indications
8Regulation of Biosimilar Medicinal Products
o Biosimilar is compared to the reference product:
o Quality characteristics (physicochemical, biological,
analytical tests)
o Non-clinical (non-human) characteristics
o Clinical trials
o Independent product and process development
o Reference product must be used for all parts of comparability
exercise
o Reference product must be a medicinal product authorised in the
Community, on the basis of a complete dossier (CHMP/437/04) –
under revision
9Dossier Requirements for Biosimilars
CTD Module Originator Biosimilar
3
4
Cross reference
5
Cross reference
Cross reference – Integrated Comparability Exercise –
class specific product specific
Safety and Efficacy Quality, Safety and Efficacy
10Development Timelines
o Timelines:
o Longer process to develop the cell line and
manufacturing process to achieve similarity
o Shorter pre-clinical and clinical development
programmes if similarity is achieved
11Development Timelines
Year 1 2 3 4 5 6 7 8
Development of an Originator Product
Tox RD Tox
Phase I/POC Phase II Phase III
Cell PI PI PII PII PIII
line process IMP process IMP process
dev Dev supply Dev supply Dev
Development of a Biosimilar Product
PC
Phase I Phase III
PI PIII PIII
Cell line Process
IMP process IMP
development development
supply Dev supply
Product Characterisation
Martin Schiestl: WHO/KFDA Workshop on implementing
WHO guidelines on evaluating similar biotherapeutic products
Seoul, 24 – 26 August 2010
12Time to positive opinion issued by
the European Medicines Agency (days)
Biosimilar Review is not Accelerated
13Biosimilar Medicinal Products – EU experience
Active Reference Authorisation Marketing
Substance Product Indication Medicine Name date Authorisation Holder
Pituitary Dwarfism
Genotropin Prader-Willi Syndrome
somatropin 1995 Turner Syndrome Omnitrope 12/04/2006 Sandoz GmbH
Anaemia
Eprex Cancer Medice Arzneimittel
epoetin alfa 1980s Chronic Kidney Failure Abseamed 28/08/2007 Pütter GmbH & Co. KG
Binocrit 28/08/2007 Sandoz GmbH
Epoetin Alfa Hexal 28/08/2007 Hexal AG
Retacrit 18/12/2007 Hospira UK Limited
Silapo 18/12/2007 Stada Arzneimittel AG
Cancer
Neupogen Haematopoietic Stem Cell Transplantation
filgrastim 1991 Neutropenia Tevagrastim 15/09/2008 Teva GmbH
Ratiograstim 15/09/2008 Ratiopharm GmbH
Biograstim 15/09/2008 AbZ-Pharma GmbH
Zarzio 06/02/2009 Sandoz GmbH
Filgrastim Hexal 06/02/2009 Hexal AG
Hospira UK Ltd.
Nivestim 08/06/2010
filgrastim Neupogen Neutropenia Grastofil 18/10/2013 Apotex Europe BV
Psoriatic Arthritis
Rheumatoid Arthritis
Ulcerative Colitis
Crohn Disease
Psoriasis Celltrion Healthcare
infliximab Remicade Ankylosing Spondylitis Remsima 10/09/2013 Hungary Kft.
Inflectra 10/09/2013 Hospira UK Limited
follitropin Gonal-f
alfa 1995 Anovulation Ovaleap 27/09/2013 Teva Pharma B.V.
14First Biosimilar mAb Submission
o Infliximab (Remicade) Marketing Authorisation
application
o Remsima (Celltrion)
o Inflectra (Hospira)
o Tumour necrosis factor-α (TNFα) inhibitor
o Approved indications: Rheumatoid arthritis, Ankylosing
Spondylitis, Ulcerative Colitis, Psoriatic Arthritis, Crohn’s
Disease, Psoriasis
15Biosimilar infliximab
o Comparability with reference product (Remicade)
o all major physicochemical characteristics and
biological activities of Remsima were similar
o activities of Remsima in experimental models were
similar
o 2 pivotal clinical studies:
o pharmacokinetic study in patients with ankylosing
spondylitis (AS) (Study CT-P13 1.1)
16Biosimilar infliximab
N = 125 patients per group
Observation interval 30 weeks
17Biosimilar infliximab
o Comparability with reference product (Remicade)
o all major physicochemical characteristics and
biological activities of Remsima were similar
o activities of Remsima in experimental models were
similar
o 2 pivotal clinical studies:
o pharmacokinetic study in patients with ankylosing
spondylitis (AS) (Study CT-P13 1.1)
o efficacy and safety study in patients with active rheumatoid
arthritis (RA) (Study CT-P13 3.1)
o To demonstrate that Remsima is equivalent to Remicade, in terms of
efficacy as determined by clinical response according to ACR20 at
Week 30 (300 patients per group).
18Biosimilar infliximab
o Comparability with reference product (Remicade)
o Clinical safety
o The nature and incidence of adverse drug reactions was
generally similar
o No new safety concerns
o Immunogenicity profile of the two products up to 54 weeks
and the impact of antibodies on efficacy and safety was
similar
o Numerical imbalance in serious adverse events was
observed in the study CT-P13 3.1 with a higher number of
serious infections, including active tuberculosis.
19Biosimilar infliximab
Summary of infections in the whole clinical programme
20Biosimilar infliximab
o Risk Management Plan
o Uncertainties requiring follow up
o Imbalance in serious infections, including active
tuberculosis.
o Long term safety
o Long term immunogenicity
o Interchangeability with Remicade
o Efficacy and safety in extrapolated indications (e.g.
psoriasis, IBD)
o Potential differences in very rare adverse reactions (e.g.
lymphomas)
21Biosimilar infliximab
o Risk Management Plan
o Studies planned to examine uncertainties
o Long-term observational cohort study in RA
o Participation in EU RA registries (BSRBR/RABBIT)
o Registry study in Crohn’s and ulcerative colitis
o Randomised controlled trial in Crohn’s disease
22Biosimilar infliximab
o Risk Management Plan
o Risk minimisation measures
o The major risks with TNF-inhibitors are serious infections,
including tuberculosis, hepatitis, opportunistic infections;
heart failure; hypersensitivity reactions; infusion reactions;
demyelination; lupus.
o Educational programme for prescribers
o Opportunistic infections and TB
o TB screening
o Hypersensitivity reactions/Infusion reactions
o Lymphoma/malignancies
o Patient alert card
o Immunisations in children/risk of infection
o How to trace which product is responsible – treatment
record keeping (brand names/batch numbers)
23Contentious issues o International non- proprietary names (INNs) o Extrapolation of indications o Interchangeability of biosimilars
Naming - INN
o Proposal
o Distinct INN for all biologicals
o Biosimilars to have a specific ‘qualifier’ added
o Pro:
o Enhance traceability and pharmacovigilance
o Prevent unwanted switching in countries with INN
prescribing
o Con:
o May create confusion with regard to similarity
o INN prescribing prone to (more) prescriptions errors
o Traceability already assured by LOT number and unique
brand nameExtrapolation of indication
o Will biosimilars automatically be granted all indications
approved for the reference product?
o Will approved biosimilars be able to develop new indications
beyond those approved for the originator?
26Interchangeability
o Are EU approved biosimilars interchangeable?
o No EMA/CHMP ‘official’ answer or designation
o No request for ‘switching’ studies
o National competent authorities decide on a national basis
o Left to the discretion of the prescribing doctor
"The decisions on interchangeability and/or substitution rely on national
competent authorities and are outside the remit of the EMA/CHMP. Member
States have access to the scientific evaluation performed by the CHMP and all
submitted data in order to substantiate their decisions."*
*(Page 33/33 of EMA Procedural advice for users of the centralised procedure
for similar biological medicinal products applications - EMA/940451/2011).
27Interchangeability / Switching
28Thanks for listening
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