their regulatory status and their use...definition of a biosimilar 1. = a copy of a biologic (which...
TRANSCRIPT
Bruno Flamion, MD, PhD
Professor of Physiology & Pharmacology, University of Namur, Belgium
Past Chair of the European Medicines Agency (EMA) Scientific Advice Group
Past Chair of the Committee for Reimbursement of Medicines in Belgium
(CTG/CRM)
Biosimilars
Their regulatory status and their use
History of biological products (or “biologics”)
• 1890 serum therapy (von Behring)
• 1921 discovery of insulin (Banting & Best)
• 1983 Humulin®, first recombinant drug (Genentech/Eli
Lilly)
• 1986 muromomab, first (murine) monoclonal Ab
• 1989 epoietin alpha (Epogen®), first therapeutic
glycoprotein (Amgen)
• 1994 abciximab, first chimeric monoclonal Ab
• 1996 daclizumab, first humanized monoclonal Ab
• 1997 rituximab (Mabthera®); 1998 trastuzumab
(Herceptin®); 1999 infliximab (Remicade®)
• 2002 adalimumab (Humira®), first human monoclonal Ab
• 2004 bevacizumab (Avastin®), cetuximab (Erbitux®)
• …. (explosion of biologics)
2
Definition of a biosimilar
1. = a copy of a biologic (which cannot be exactly the same for
biological reasons) but not a simple copy (“intended copy”).
2. The biosimilar copy must have successfully completed a
comparability exercise vs the originator (“the reference
product”).
3. During that exercise the biosimilar must pass a number of
qualifications, assays, non-clinical tests, and also (at least in the
EU) clinical tests.
4. This exercise must meet strict regulatory requirements, for
instance those set up by the European Medicines Agency (EMA)
or, more recently, the FDA
5. The goal is to ensure that using the biosimilar instead of the
reference product entails a very low (negligible) likelihood of
clinically significant difference. 4
5
EMA-like regulation « Simple copy » or
generic regulation
No regulation
European Union (EMA) since 2005 Mexico China *
USA (FDA) since 2012 Peru Russia
WHO since 2009 Chile
Canada India
Australia …
Japan
South Korea, Taiwan
South Africa, Jordan
Turkey, Brazil (new)
Regulations vary across the world
* Out of 382 biologics on the market in China, 361 are simple copies
How to make a similar biological product?
Biologics have a complex manufacturing process that makes them difficult to copy; the end product is not to exactly the same as the originator
Cloning into DNA vector
Transfer into host cell expression
Different cell culture processes
Different purification and formulation
protocols
Coding gene mutation
Dörner T, et al. Ann Rheum Dis. 2013;72(3):322-328. Ahmed I. Clinical Therapeutics 2012; 34(2):400–419
10
• A political decision was made in 2004 to allow official copies of existing biological products
based on a reduced dossier
in parallel with the “generic” concept
taking advantage of experience with the comparability of biotech products after a change in manufacturing process
• The goal was (is) purely pharmaco-economical
• There is no official definition of a biosimilar in the EU
From Joerg Windisch, CSO Sandoz
The size matters…
Biologicals are micro-heterogeneous mixtures of several isoforms,
each of which may differ in terms of potency, half-life and
immunogenicity
Rudd, P. M., et al. (1997) The glycosylation of the complement regulatory
protein, human erythrocytes CD59. J. Biol. Chem. 272:7229.
… but also the intrinsic heterogeneity (e.g. glycoforms)
11
Example of biological product complexity
2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600
K
pyro-E O
D
G
G
D
O
D O
O
• Methionine oxidation (2 x 2)
pyro-E • Pyro-Glu (2)
• High mannose, G0, G1, G2 (5)
• Sialylation (5)
D
D
D • Deamidation (3 x 2)
G
G
• Glycation (2 x 2)
(9600)2≈ 108
potential variants
K
C-term Lys (2)
Modified from: Koszlowski, S. & Swann, P. (2006) Adv. Drug Delivery Revs. 58, 707-722
EMA requirements for biosimilar approvals
*** Including receptor binding assays (affinity, reversibility),
epitope analysis (for a MAb), bioassays…)
***
15
Number of manufacturing changes approved for –
mabs/-cepts in rheumatology
From Schneider CK et al.,
Ann Rheum Dis 2013; 72:315
Comparability Exercise for existing products
Physicochemical characteristics of subsequent products do not have
to be identical but « highly similar »” (they may be slightly improved)
The latest versions
of Remicade are
« biosimilars » of the
previous versions
Comparability Exercise vs Biosimilarity
Comparability (change in manufacturing
process)
Biosimilarity
Thorough internal
knowledge by manufacturer
No internal knowledge
Extensive analytical data
Low need for clinical data
Extensive analytical data
High need for clinical data
Noninferiority tests Therapeutic equivalence
If the comparison fails at any stage,
the products cannot be declared
biosimilar 16
1 Omnitrope (somatropin) Sandoz (Novartis) Authorized
2 Valtropin (somatropin) – [yeast] Biopartners Authorized
3 Alpheon (interferon alfa) BioPartners Negative
4 Binocrit (epoetin alfa) Sandoz (Novartis) Authorized
5 Epoetin alfa Hexal (epoetin alfa) Hexal (Novartis) Authorized
6 Abseamed (epoetin alfa) Medice Authorized
7 Silapo (epoetin zeta) Stada Authorized
8 Retacrit (epoetin zeta) Hospira Authorized
9 Insulin Marvel Short (human insulin) Marvel Life Sci Negative
10 Insulin Marvel Intermediate (human insulin) Marvel Life Sci Negative
11 Insulin Marvel Long (human insulin) Marvel Life Sci Negative
12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorized
13 Biograstim (filgrastim) CT Arzneimittel Authorized
14 Tevagrastim (filgrastim) Teva Authorized
15 Zarzio (filgrastim) Sandoz (Novartis) Authorized
16 Filgrastim Hexal Hexal (Novartis) Authorized
17 Biferonex (interferon beta-1a) BioPartners Negative
18 Nivestim (filgrastim) Hospira Authorized
Biosimilars at the European Medicines Agency (1)
1
3
4
5
6
7
2006
2007
2007
2008
2009
2010
2-withdrawn
These 3
products are
identical !!
19 Remsima (infliximab) Celltrion Authorized
20 Inflectra (infliximab) Hospira Authorized
Biosimilars at the European Medicines Agency (2)
8 ** 2013
9 21 Ovaleap (follitropin alpha) Teva Authorized
10 22 Gastrofil (filgrastim) Apotex Authorized
Biosimilars under evaluation
** Marketed in Norway, Portugal, Ireland, Finland, Eastern Europe;
pending patent issues in other EU States
23 Bemfola (follitropin alpha) Finox Biotech AG Authorized 11 2014
MAb In all indications !!
24 Abasaglar (insulin glargine) Lilly-Boehringer Authorized 12
1 insulin at EMA – NB. Celltrion’s trastuzumab approved in S. Korea (January 2014)
7 Jan 2014: FDA Oncology Advisory Committee supported “Zarxio” as biosimilar
NB. At FDA: Basaglar (not a biosimilar – 505(b) procedure FDA-approved
Identical
products
FDA Guidance (2012) and issues
Q/S/E stepwise approach (like EU); decision
based on “the totality of evidence”
The extent of clinical study required depends
on remaining uncertainty after in vitro and
animal testing (some biosimilars could be
approved without a need for clinical trials)
FDA is obliged to rule also on the
interchangeability of each biosimilar (yes or
no): “product expected to produce the same
clinical outcome as the reference product in
any given patient”
The biosimilar company has to reveal the
details of its manufacturing methods to the
originator…
Will FDA use the same INN?
NB. FDA accepted the Remsima biosimilar
application in August 2014
20
22
• The biosimilar concept is purely pharmacoeconomic
• Without a reduction in regulatory requirements, this concept is not tenable
• How can regulatory requirements be reduced without undue risks (unacceptable loss of efficacy, or unexpected immunogenicity) ?
23
Methods agreed by regulators to ensure efficacy and
safety of biosimilars with less patients than originator
1. At least one accurate PK study (if possible, PK/PD data)
2. Less patients but enough statistical power to detect differences if they exist:
• more homogeneous population *
• “in principle, the most sensitive endpoints” *
• reasonable equivalence margins (➙ leads to some additional uncertainty)
3. Extrapolation of indications if the mechanism of action, safety and immunogenicity are expected to be similar in these indications
4. Reinforced Risk Management Plan (RMP)
* For anti-TNF, RA is a sensitive population (perhaps more sensitive
than IBD or psoriasis)
* In oncology, it is preferable to use early stage cancer patients and
a « response rate » endpoint rather than survival rates
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
Results of CT-P13 (infliximab) Phase III equivalence trial
• N= 606. Primary efficacy endpoint: ACR20 response at week 30
• Safety: Treatment-emergent adverse events were seen in 35.2% of patients
treated with CT-P13 and 35.9% of patients treated with INX
• Immunogenicity: Equivalent levels of anti-infliximab antibodies were detected in
both treatment arms at week 14 and week 30
Yoo DH, et al. Ann Rheum Dis. 2013;72(10):1613-1620.
184/302 178/304 182/248 175/251
Treatment difference =
2% (95% CI: 6%, 10%)
Treatment difference =
4% (95% CI: -4%, 12%)
CT-P13
60.9 58.6
73.4 69.7
INX
PP Population ITT Population
Res
po
nse
Rate
, %
Evolution of Remicade (EU): Efficacy
1999 2000 2001 2002 2003 2004 2005 2006
RA: signs
and symptoms
Fistulizing
CD maintenance
Ankylosing
Spondylitis
Luminal CD
maintenance
Early RA
Psoriatic
Arthritis
Moderate/
Severe
Psoriasis
Ulcerative
Colitis
RA:
joint damage
Crohn’s
Disease
RA:
physical function
Basis for extrapolation of
indications for Remsima®
/Inflectra®, together with PK
data in AS
+ Post-approval
commitment for a Ph III
trial in Crohn’s disease
26
The clinical issues are not different from other biosimilars
but extrapolation may be “technically” more difficult
Very complex
production
Very complex
mechanism of action
Biosimilar MAbs in oncology
Complex
(oncology)
indications
EMA/CHMP. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2013/06/WC500144124.pdf
Increased immunogenicity of biosimilars?
28
Immunogenicity & traceability
1. Immunogenicity in humans cannot be predicted from
animal data absolute need for comparative clinical
trials including tests for neutralizing Abs and PK/PD data
2. How long ?
Usually 1 year pre-licensing if chronic use is intended; the
post-marketing RMP is crucial thereafter
3. Adequate traceability is mandatory. The recommendation
is to identify the product (in case of, e.g., hypersensitivity)
by INN + brand name + manufacturer + batch number (+
country of origin)
NB. Some complain that the SmPC of the biosimilar is identical to
that of the originator (except a simple mention in 5.1: « X is a
biosimilar – detailed information available on website of EMA ».)
29
Interchangeability
1. Can a patient be switched from an originator to a
biosimilar during (chronic) treatment? – and vice-versa
2. Studies designed to demonstrate that switching (back and
forth) does not entail any additional risk would be long,
costly and probably unreasonable (cf. ongoing issue at
FDA)
Recent initiative towards interchangeability
• NOR-SWITCH
study
• 800 patients
• started recruiting
in November
2014
31
Interchangeability
1. Can a patient be switched from an originator to a
biosimilar during (chronic) treatment? – and vice-versa
2. Studies designed to demonstrate that switching (back and
forth) does not entail any additional risk would be long,
costly and probably unreasonable (cf. ongoing issue at
FDA)
3. In Europe, demonstrated biosimilarity would imply
interchangeability – but the decision is up to each
Member State.
4. In Belgium, FAMHP excludes biologics from INN
prescription and forbids automatic substitution of biologics
by pharmacists
1. The biosimilarity concept means a “low likelihood of
clinically significant differences”
2. According to (EU, FDA…) regulators, a product can be
called biosimilar only if it has successfully gone through
the stepwise (Q/S/E) “comparability exercise” (i.e.,
strong regulatory oversight) and is thus considered of
high quality, safe, and efficient
Take-home messages (1)
3. The focus of the clinical part of the biosimilar exercise
is on PK/PD and the use of sensitive populations and
endpoints to detect any potential difference
4. Extrapolation of indications is key to the biosimilar
concept but needs to be justified in all cases — and
explained to clinicians!
Take-home messages (2)
5. Detection of immunogenicity and a good Risk
Management Plan are key elements of safety — so far
there has been no safety issue with any biosimilar
product
6. Traceability should be ensured by prescribing under
brand names and keeping good records
7. Interchangeability is a national (or local) issue — in
most of Europe, automatic substitution by pharmacists is
not allowed – involving the prescriber is preferable
Take-home messages (3)
8.Clinicians, supported by national and local (hospital)
decision makers, could give away some “prescription habits”
in favour of lower prices
9.Infliximab biosimilars, impacting on well-defined medical
specialties (rheumatologists, gastroenterologists,
dermatologists) and high cost situations, will be a good test
Take-home messages (4)