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

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.

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

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)

Biosimilar products evaluated in the EU

Omnitrope somatropin Sandoz Genotropin Approval Apr-06Valtropin somatropin BioPartners Humatrope Approval Apr-06Alpheon interferon alfa-2a BioPartners Roferon-A Refusal Jun-06Abseamed SandozEpoietin alfa Hexal HexalBinocrit MediceSilapo HospiraRetacrit StadaInsulin Rapid Marvel soluble insulinInsulin Long Marvel isophane insulinInsulin 30/70 Mix Marvel biphasic insulinTevagrastim TevaRatiograstim/Filgrastim Ratiopharm RatiopharmBiograstim CT ArzneimittelFilgrastim Hexal HexalZarzio SandozNivestim 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

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)

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)

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

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

The biosimilar concept

Stepwise development approach

sufficient evidence of comparability at each stage

quality

non-clinical

PK/PD

efficacy/safety

Comparability tools

High

Low Probable clinical relevance

of differences found

Sensitivity to product differences

Reference Biosimilar

Reference Biosimilar

Reference

Reference

Biosimilar

Biosimilar

A

B

The biosimilar concept

Holistic review process

biosimilarity

conclusion based on

all parts of the dossier

taken together

EMA Guidelines for Biosimilar ProductsOverarching 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

InsulinsEMEA/CHMP/BMWP/32775/2005

(Under revision)(2011)

IFN-betaBeta (draft)

CHMP/BMWP/652000/2010

IFN-alphaEMEA/CHMP/BMWP/

102046/2006

LMWHEMA/CHMP/

BMWP/86572/2010

SomatotropinsEMEA/CHMP/BMWP/94528/2005

GM-CSFEMEA/CHMP/BMWP/31329/2005

FSHCHMP/BMWP/671292/2010

mABEMA/CHMP/

BMWP/403543/2010(Draft)

EpoietinEMEA/CHMP/

BMWP/301636/08

EMA and FDA differences in evaluation of the biosimilarity

EMA FDASimilar 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

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

Step 1: Orthogonal bioassays addressing multiple functions

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.)

Scenarios in step-wise decision making in non-clinical development of biosimilars

Step 1 is OKStep 2 is OK

Step 1 is OKStep 2 some concerns (e.g. new formulation,

relevant sensitive models exist)

Step 1: differences foundStep 2: risks and concerns

Clinical development

Step 3: in vivo models and

additional data

Differences between requirements from FDA, EMA,

PMDA and Indian Agency

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

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)

Example of PK or PD failure

PK soluble insulin

test

PD isophane insulin

test

EPAR, EMA website

Example of PK & PD success

EPAR, EMA website

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).

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

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).

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

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

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

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

Justification for the margin size

Placebo Reference product

18% 42%

24%

Margin for equivalence 12%

Prior knowledge: EPAR, literature and symposia

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)

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

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

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

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 studiesinterventional

• long-term or repeated treatment (e.g. continuation of pivotal trial)

• systematic antibody testing

• other (extrapolated) indication, route of administrationnon interventional (registries)drug utilisation surveys

Clinical requirements: Risk Management Plan

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

“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

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

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.”

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.”

SubstitutabilityNew 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.

Questions and thanks for your participation