their regulatory status and their use...definition of a biosimilar 1. = a copy of a biologic (which...

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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

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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

Economic push: EPO price competition in Germany

6

Economic push: use of filgrastim in Europe

7

Variable uptake of biosimilar G-CSF in Europe

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…)

***

14

The comparability exercise (ICH, 2004)

http://www.ich.org

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

EMA guidelines for biosimilar development

17

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

Why is there (still) a debate on

biosimilars?

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

Some Take-Home

Messages

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)

Thank You !!

[email protected]