“EU regulatory and clinical development framework for biosimilars” Explains the current EU experience and practices relating to the submission and approval of biosimilars

1. IFPMA/AIPM Biotherapeutics Workshop, Moscow
EU regulatory and clinical development
framework for biosimilars
15-16th
May 2013
Dr Alex Kudrin, Medical Assessor in Biologicals, MHRA, London, UK

2. Disclaimer
• This presentation is given in personal capacity and
represents only the author’s personal views and does not
represent policies or recommendations of MHRA, EMA,
FDA, any other companies and regulatory bodies
mentioned in this presentation.
• No confidential data is disclosed.
• All relevant references and links are from public domain.

3. Biosimilars’ adoption will expand, but will
remain modest to 2016
• Market of biologics will
continue to expand due
to new, superior products
and earlier access;
• Spending on biosimilars
will increase but will
constitute only 2% of total
biologic spending;
• Biosimilar adoption is
expected to be modest
due to remaining patent,
market exclusivity and
lack of substitution

4. Lessons learned from first wave of biosimilars in EU
• Current EU biosimilar market:
- EPOs – 60%
- GSFs – 20%
- GHs – 20%
• Uptake of EPOs, filgrastims and GHs was highly variable
between EU countries (EPOs - 90% in Norway; <7% in Italy)
• Discounting of both reference and biosimilar products is
considerable: e.g. Eprex – 82% discount
• The dynamics is affected by pricing and extent of decision
making by physicians (e.g. GHs)

6. Biosimilar products evaluated in the EU
Omnitrope somatropin Sandoz Genotropin Approval Apr-06
Valtropin somatropin BioPartners Humatrope Approval Apr-06
Alpheon interferon alfa-2a BioPartners Roferon-A Refusal Jun-06
Abseamed Sandoz
Epoietin alfa Hexal Hexal
Binocrit Medice
Silapo Hospira
Retacrit Stada
Insulin Rapid Marvel soluble insulin
Insulin Long Marvel isophane insulin
Insulin 30/70 Mix Marvel biphasic insulin
Tevagrastim Teva
Ratiograstim/Filgrastim Ratiopharm Ratiopharm
Biograstim CT Arzneimittel
Filgrastim Hexal Hexal
Zarzio Sandoz
Nivestim filgrastim Hospira Neupogen Approval Jun-10
Approval
Aug-07
Dec-07
Jan-08
Sep-08
Feb-09
Approval
Approval
Withdrawal
Approvalfilgrastim
filgrastim
Eprex
Eprex
epoietin alfa
epoietin zeta
Marvel Humulin
Neupogen
Neupogen
Since 2006: 14 biosimilars (2 somatrotropins, 5 EPOs and 7 GM-CSFs were
approved in EU
>40 EMA SA by Q4 2012

9. Next biosimilar targets
• Pegfilgrastim (Neulasta)
• Interferon beta (Avonex, Rebif)
• Insulin glargine (Lantus)
• Etanercept (Enbrel)
Monoclonal antibodies:
• Infliximab (Remicade) application under assessment
• Trastuzumab (Herceptin)
• Bevasizumab (Avastin)
• Rituximab (MabThera)
• Cetuximab (Erbitux)
• Adalimumab (Humira)
• Palivizumab (Synagis)

10. Definitions
 Biological substance: produced by or extracted from a
biological source and for which a combination of physico-
chemical-biological testing and the production process and
its control is needed for its characterisation and the
determination of its quality
 Similar biological medicinal product (SBMP or “biosimilar”):
a new biological medicinal product claimed to be similar to
a reference medicinal product authorised in the EU
Does not meet the definition of a generic product “owing to,
in particular, differences relating to raw materials or
differences in manufacturing processes” (Directive
2004/27/EC)

11. Biosimilar: Definition
• Reference is approved in EU or at least in one of EU countries
• Biosimilarity development pathway involving relevant orthogonal analytical
comparability methods, non-clinical and clinical models utilised from the
outset rather than in opportunistic fashion
• Quality TTP should be achieved (atypical glycosylation profile and presence
of impurities should be justified)
• An authorised biosimilar is generally administered via the same route of
administration
• The same dose (posology) as the reference products in indications approved
for a reference medicinal products
• Primary structure identical to the reference biological product
• Like the reference medicine, the biosimilar has a degree of natural variability
• Biosimilar and reference products have independent life cycle fate
• Quality, non-clinical, and clinical attributes are sufficiently similar yet might
not be identical between the biosimilar and the reference product
• More data is required as ‘essential similarity’ cannot be met

12. Biosimilars and “biobetters”
Attributes Biosimilars “Biobetters”
Experience Number of precedents No cases described so
far
Quality Similar TPP Different or atypical TPP
PK / PD Similar to reference Exaggerated or atypical
Efficacy Similar to reference Enhanced efficacy
Safety Similar to reference Similar / improved
Immunogenicity Similar to reference Similar / improved
Route of administration The same as for
reference
The same or different
Additional indications Potentially new
indications
Different or new
indications
Regulatory path Biosimilar New Active Substance

13. The biosimilar concept
 Stepwise development approach
sufficient evidence of comparability at each stage
 quality
 non-clinical
 PK/PD
 efficacy/safety

14. Comparability tools
High
Low Probable clinical relevance
of differences found
Sensitivity to product
differences
Reference Biosimilar
Reference Biosimilar
Reference
Reference
Biosimilar
Biosimilar
A
B

15. The biosimilar concept
 Holistic review process
biosimilarity
conclusion based on
all parts of the dossier
taken together

16. EMA Guidelines for Biosimilar Products
Overarching Guidance (CHMP/437/04)
Under revision: EMA/CHMP/BMWP/572643/2011
Concept and basic principles for biosimilar development
Product Specific Annexes to Non-/Clinical Guidelines
Quality Guideline (Draft)
EMA/CHMP/BWP/247713/2012
Non-/Clinical
Guidelines
(Under revision)
EMA/CHMP/BMWP/572828/2011
Insulins
EMEA/CHMP/BMWP/32775/2005
(Under revision)
(2011)
IFN-beta
Beta (draft)
CHMP/BMWP/652000/2010
IFN-alpha
EMEA/CHMP/BMWP/1
02046/2006
LMWH
EMA/CHMP/
BMWP/86572/2010
Somatotropins
EMEA/CHMP/BMWP/94528/2005
GM-CSF
EMEA/CHMP/BMWP/31329/2005
FSH
CHMP/BMWP/671292/2010
mAB
EMA/CHMP/BMWP/
403543/2010
(Draft)
Epoietin
EMEA/CHMP/
BMWP/301636/08

17. EMA and FDA differences in evaluation of the
biosimilarity
EMA FDA
Similar TTP Highly similar TTP
Risk driven non-clinical package NHP data still needed for biosimilar MABs
PK/PD study PK/PD study (address any differences
between US and EU commercialized
batches of the reference product)
Therapeutic equivalence study Might be waived in some cases
RMP in all cases REMS in exceptional circumstances
Not appropriate Switching data

18. Stepwise process
• Step 1: Orthogonal in vitro functional assays
• Step 2: Determination of the need for animal studies
• Step 3: Conduct of the relevant animal studies

19. Step 1: Orthogonal bioassays addressing multiple
functions

20. Step 2: Determination of the need for in vivo
studies
Relevant in vivo model:
• Species (NHP, transgenic or transplant model)
• Design: sensitivity and variability
Factors to consider if relevant in vivo models available:
• Presence of quality attributes not detected in reference (e.g.
PTMs);
• Presence of quality attributes in higher amounts than those in
the reference (e.g. impurities)
• Relevant differences in formulation (excipients etc.)

21. Scenarios in step-wise decision making in non-
clinical development of biosimilars
Step 1 is OK
Step 2 is OK
Step 1 is OK
Step 2 some concerns
(e.g. new formulation,
relevant sensitive
models exist)
Step 1: differences found
Step 2: risks and concerns
Clinical
development
Step 3: in vivo
models and
additional data
Differences between
requirements from FDA, EMA,
PMDA and Indian Agency

22. Clinical requirements
The clinical comparability exercise:
a stepwise approach
1. PK/PD studies: in all cases
2. Clinical efficacy/safety trial(s)
o PK/PD may be sufficient to establish clinical comparability
regarding efficacy if PD marker is an accepted surrogate marker
for efficacy (e.g. insulin)
o efficacy in an appropriate model (assay sensitivity)
o safety & immunogenicity always necessary

23. Clinical requirements
Pharmacokinetics
 not a standard bioequivalence study!
 comparison of absorption and elimination (Cl, T1/2)
 choice of the design and equivalence margins to be justified
Pharmacodynamics
 to be justified!
 relevance of the PD marker
 choice of the population (re assay sensitivity)
 choice of the study design, duration, dose (in the steep part of
the dose response curve, preferably several doses)

24. Example of PK or PD failure
PK soluble
insulin
test
PD isophane
insulin
test
EPAR, EMA
website

25. Example of PK & PD success
EPAR, EMA
website

26. PK studies in healthy normal volunteers
• Ethical challenges
• Provide with lesser variability and greater sensitivity
• Immunocompetent host
• Preferred in single dose settings
• Optimal to gain initial clinical insight into PK/PD similarity
• Should be avoided in situations when subjects are likely to
develop immunogenicity but may require product in the future
• Avoid when high risk of immunogenicity or serious AEs (e.g.
PML).

27. PK study design
• Preferred: single dose in HV with full characterisation of PK
profile including late elimination phase (e.g. 5 half-lives)
• Non-mediated clearance
• Parallel / crossover (e.g. etanercept)
- If not possible:
• Single dose in patients
• Multiple dose in patients

28. Sampling times
• In SD studies: should cover whole PK profile,
including late elimination phase
• Sufficient sampling time-points around predicted Cmax
• In MD studies:
- Ideally, first dose (most sensitive comparability) and
last dose (for elimination)
- Otherwise, first dose and steady state (e.g. during 4-8
cycle NHL treatment with rituximab – after 6 cycle or
in CLL: cycles 2-6 after 4 cycle).

29. PK parameters
• In SD studies:
- Primary: AUC(0-∞)
- Secondary: Cmax, Tmax, Vd, T1/2
- For subcutaneous route: Cmax should be co-primary; partial AUCs
as secondary
• In MD studies:
- Primary: truncated AUC(0-t) after first dose and AUC(0-T) over
a dosage interval at steady state;
- Secondary: Cmax and Ctrough at steady state

30. Statistical tests
• Primary
- Equivalence margins of 80-125%
- Justification of any widening (including the impact on safety
and efficacy) – if slightly outside without any impact on efficacy
might be accepted.
• Secondary
- Descriptive statistics with ratio / difference and 90%CIs –
discussion of results

31. Clinical efficacy
Adequately powered randomised (double-blind) parallel
group equivalence trial in the most sensitive and
preferably well-known model
 choice of the equivalence margin to be justified!
Example : Adalimumab or infliximab biosimilar
Primary endpoint: equivalence of ACR20 or DAS28
Both include some indices which are subjective, e.g. number of tender joints
(DAS28, ACR20), patient assessment of pain, and physician and patient
global assessments of disease activity (ACR20)
ACR20 represents the change in activity over time (20% improvement)
New
 1 efficacy/safety study with one route
 1 bridging multiple-dose PK/PD study with the other route

32. Patient population and dose selection
• Homogenous and most sensitive to reduce variability
attributed to disease, target expression, concomitant
therapies
• No requirement to test all approved dose regimens
• Most sensitive dose should be chosen
• Low dose is more sensitive to study target-mediated
clearance (because the mechanism is less likely to be
saturated)
• High dose more appropriate in general to study non
specific clearance and address safety differences

33. Justification for the margin size
Placebo Reference product
18% 42%
∆24%
Margin for equivalence 12%
Prior knowledge: EPAR, literature and symposia

34. General principles in immunogenicity
• The assay should be in place from Phase I study
• Sensitive and specific assay: for both reference and biosimilar
• Validated screening, confirmation and neutralisation assays
• Justification of periodicity and timing of sampling
• Sensitive patient population and subgroup analyses (exposure
related, immunosuppression status related, across indications,
AE-related, loss of efficacy, PK/PD modelling)
• Monitoring of immunogenicity without switching up 12 month
• Switch-associated immunogenicity data (not required in EU)
• EU: descriptive evaluation of immunogenicity
• US: one-sided margin for immunogenicity (larger study)

35. Extrapolation of indications
• It is possible to extrapolate therapeutic similarity
• Justification will depend on MOA, own clinical experience, and
available literature data
• Depends on the strength of knowledge around MOA (e.g. poor
understanding of Fc-receptor binding pattern and functionality)
• MABs with both immunomodulatory and anti-tumour MOA:
quality, non-clinical database, potency assay(s) and in-vitro
assays that cover the functionality of the molecule
• In some cases extrapolation is more challenging: e.g. rituximab

37. Extrapolation: Outcomes
• Reliant on the totality of biosimilarity exercise and
satisfactory results of clinical studies and functional
cellular assays
• The preferred option is to grant all indications rather
than just few core indications with shared MoA
• Scenario with rituximab is the most complex

38. Pharmacovigilance of biosimilars: principles
• Reference and biosimilar have independent from each other life cycles
• No need to reiterate reference safety profile but safety burden
associated with reference products is still attached
• Pre-approval PV database will be limited and rarely exceed 500-700
patients
• RMPs for all new products including biosimilars are mandatory
• RMP / Postmarketing PV activities will be expected in all cases
• Risk management is closely linked with education of patients and
prescribers
• Biosimilar companies will have to deal with poor education around use
of reference products
• Closer monitoring of patients following the switch: 0-6 months and up
to 1 year for the adequacy of response, AEs / complications, and
immunogenicity
• Postmarketing observational studies / registries will be expected in
some cases

39. Pharmacovigilance Plan
 Important identified and potential risks based on the reference
product – especially rare ADRs
 Planned activities outside routine PV
• Traceability of batches
• Monitoring of safety and risks in sub-populations (pregnancy, paediatric etc.)
• Enhanced safety monitoring in indications based on extrapolation
• Immunogenicity and switcheability
• Risk for off-label use
Post-authorisation safety/efficacy studies
interventional
• long-term or repeated treatment (e.g. continuation of pivotal
trial)
• systematic antibody testing
• other (extrapolated) indication, route of administration
non interventional (registries)
drug utilisation surveys
Clinical requirements: Risk Management Plan

40. Product labelling
 Same as the reference product, including
 same ADRs
 same PK/clinical efficacy study results
 However, a few additional wording possible, e.g. description of
study results
“During clinical studies 541 cancer patients and 188 healthy volunteers were
exposed to Filgrastim ratiopharm. The safety profile of Filgrastim ratiopharm
observed in these clinical studies was consistent with that reported with the
reference product used in these studies”.
 Specific statement in section 5.1 (Pharmacodynamic properties)
<(Invented) Name> is a biosimilar medicinal product. Detailed information is
available on the European Medicines Agency website; www.emea.europa.eu

41. “Changing one medicine for another that is
equivalent” (WHO)
 Interchangeability: medical practice in a clinical
setting, on the initiative or with the agreement of
the prescriber
 Substitutability: dispensing at the pharmacy level
without requiring consultation with the prescriber
 Automatic substitution: obligation of substitution
due to national or local requirements

42. Switching / interchangeability data
• FDA: no precise study design, might be waived if high
level of biosimilarity is declared
• EMA: no pre-approval requirements but post-
marketing PV monitoring of switch-associated
phenomena

43. Substitutability
 The rules for substitution are within the
remit of the EU national authorities
 Most EU member states have already taken action.
 In the UK, MHRA recommendation (Feb-2008)
“When prescribing biological products, it is good practice to
use the brand name. This will ensure that automatic
substitution of a biosimilar product does not occur when the
medicine is dispensed by the pharmacist.”

44. Substitutability
 At EU level, same labelling for all erythropoietins
(2010):
 SmPC (Special warnings): “In order to improve
the traceability of ESAs, the trade name of the
administered ESA should be clearly recorded (or
stated) in the patient file” .
 Patient leaflet: “<Brand name> is one of a group
of products that stimulate the production of red
blood cells like the human protein erythropoietin
does. Your healthcare professional will always
record the exact product you are using.”

45. Substitutability
New EU pharmacovogilance directive (2010/84/EU)
 Some medicinal products are authorised subject to additional
monitoring. This includes all medicinal products with a new
active substance and biological medicinal products, including
biosimilars, which are priorities for pharmacovigilance.
 Member states shall ensure, through the methods for
collecting information and where necessary through the follow-
up of suspected adverse reaction reports, that all appropriate
measures are taken to identify clearly any biological medicinal
product prescribed, dispensed, or sold in their territory which is
the subject of a suspected adverse reaction report, with due
regard to the name of the medicinal product, and the batch
number.

46. Questions and thanks for your participation