Iman Barilero, PhD, PharmD Associate Director, European Regulatory Affairs

Current Regulations and Guidelines in Current Regulations and Guidelines in Europe on Approval of Similar Biological Europe on Approval of Similar Biological

Medicinal Products “Biosimilars”Medicinal Products “Biosimilars”

Malaysia National Regulatory SeminarMalaysia National Regulatory Seminar Subang Jaya, Selangor, 6-7 September, 2005Subang Jaya, Selangor, 6-7 September, 2005

Iman Barilero, PhD, PharmDAssociate Director, European Regulatory Affairs

Global Regulatory Policy and IntelligenceJohnson & Johnson Pharmaceutical R&D, United Kingdom

September 7, 2005

Driving forces for emerging biosimilars

The potential increase for the biopharmaceutical market, as innovative science is targeting a huge range of diseases from growth deficiency to arthritis, to multiple sclerosis, to cancer and orphan diseases, etc

The patents of several biopharmaceuticals have expired, or are about to expire opening a new market sector

Pressure to reduce healthcare expenditure and increase patient access to treatment will drive the development of cheaper biosimilars

How will emerging biosimilars be evaluated by regulators, pharmacists and physicians?

Scientific framework development Biopharmaceuticals as compared to chemical low molecular weight drugs:

o Size and Complexity High molecular weight with complex three-dimensional structure

o Production process Recombinant DNA technology with complex manufacturing process Produced by living organisms, therefore often heterogeneous Small changes in the process may affect safety and efficacy

o Characterization and analytical methods Difficult to characterize completely by physico-chemical analytical methods or bioassays Current analytical methods do not detect all product variations that can affect clinical

efficacy, side effects or immunogenicityo Biological activity

Depends on reproducibility of the production process, in-house standards, and maintaining cold chain integrity

o Immunogenicity Proteins known to induce a specific immune response with clinical implications

Regulatory framework development

Regulatory authorities in the EU (EMEA), the USA (FDA) and scientific community have recognized that biosimilars (as new biopharmaceuticals) differ from generic low molecular weight drugs in several important ways (scientific considerations)

Not possible at present for two different manufacturers to manufacture two identical biopharmaceuticals (similar at best)

Can a generic approach be used for marketing approval of biosimilars?

The legal and regulatory principles of ‘essential similarity’ (EU) or ‘bioequivalence’ (USA) cannot be applied to biosimilars

Regulatory status in EuropeSeptember 2005

Review of Pharmaceutical legislation in EU since 2001 after proposal from EU Commission

Part of the New Medicines Legislation in EU (comes into force in 2005)

The first legal basis in the EU for biosimilars has been established1

– Directive 2004/27/EC of 31 March 2004 (amending Directive 2001/83/EC): to come into force in EU members states by 30 October 2005

– Directive 2003/63/EC of 25 June 2003 (Annex I): already came into force in EU member states on 1 July 2003

There is a clearly defined legal/regulatory framework in the EU

1http://pharmacos.eudra.org/F2/review/index.htm

Legal framework for biosimilars (1)

Directive 2004/27/EC – Article 10.4

– Where a biological medicinal product which is similar to a reference biological product does not meet the definition of a generic medicinal product

– Owing to, in particular, differences in raw material or differences in manufacturing processes

– The results of appropriate pre-clinical tests or clinical trials must be provided, in accordance with the relevant criteria stated in Annex I and the related detailed guidelines

Concept of ‘biosimilarity’ from concept of ‘essential similarity’

Legal framework for biosimilars (2) Directive 2003/63/EC - Part II, Section 4 of Annex I

– Information required for ‘essentially similar‘ products (generics) not sufficient

– Data requirements

Pharmaceutical, chemical, and biological data (+ Quality comparability studies)

Bio-equivalence and bio-availability data

Other comparative data (on a case by case basis) Toxicological, other non-clinical Appropriate and clinical data

– Extrapolation of efficacy and safety to other indications to be justified or demonstrated separately

– The general principles are (to be) addressed in agency guideline

The same reference product should be used in all studies

The Centralised Procedure is obligatory for biopharmaceuticals and biosimilars

Recognition of high standard data package to evaluate biosimilars based upon fundamental criteria of quality, safety, and efficacy

Reference product to be authorized in the EU

The new legislation places a strong emphasis on safety when assessing and approving biosimilars

Framework for general and product specific case-by-case approach to assess biosimilars, taking into account current scientific knowledge and guideline to be developed by agency

Key aspects of the new EU legislation on biosimilars (1)

Key aspects of the new EU legislation on biosimilars (2)

When developing a biosimilar, it is important for the Marketing

Authorization Holder (MAH) to consider whether each

individual indication should be studied

The Committee for Human Medicinal Products (CHMP) of the

EMEA will decide what kind of tests and data will be needed to

assess the safety and efficacy of biosimilars

– EMEA/CHMP scientific advice

EMEA/CHMP guidelines on Comparability

EMEA/CHMP guidelines on comparability

Since 2002 EMEA/CHMP have been developing a set of guidelines on "comparability issues" covering

– Quality

– Preclinical

– Clinical aspects

Applying to

– Change to a manufacturing process of a biological medicinal product

– Similar biological medicinal products "biosimilars"

EMEA/CHMP guidelines on comparability

www.emea.eu.int

Need for biosimilar guidelines

Need to support legislation

– Annex I *: General (Overarching) Guideline

– “The general principles to be applied are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency.”

Need to focus on Comparability Exercise versus Reference Product

– Specific Quality / Safety / Efficacy guidelines

* 2003/63/EC, Annex I, Part II, Section 4

Dr John Purves, EMEA – DIA Euro meeting Lisbon, 8 March 2005

EMEA/CHMP new biosimilar guidelines

16 November 2004, the EMEA issued new guidance documents for the development and approval of biosimilar products

– EMEA/CHMP overarching guideline to address general principles for development of biosimilars

– Four concept papers that will lead to product-class specific guidelines for four biosimilar products (insulin, somatropin, epoetin, G-CSF)

– Plan to revise existing EMEA/CHMP guidelines on Comparability

separation of biosimilarity and comparabilityguidelines for biotechnology-derived proteins

More comprehensive and evolving EMEA/CHMP guidelines for biosimilars taking into consideration the clinical and regulatory

experiences to date

Comparability guidelines: separation of comparability and biosimilarity

Biosimilar biotech-

derived proteins

CHMP-BWP

Comparability of biotech-derived proteins: Quality ICH Q5E

Biosimilar biotech-derived proteins: S&E CHMP BMWP

Comparability of biotech-

derived proteins

S&E (?)

Quality issues (non)- clinical issues

Guidelines on Comparability

Dr Pekka Kurki, Chair CHMP Biosimilar WP – DIA Euro meeting Lisbon, 8 March 2005

Biosimilar guidelines

Biosimilar biotechnology-

derived proteins(S&E)

Product-class-specific annexes

Somato-tropins

Epoietins Insulins rhG-CSF Others?


Biosimilar guidelines – current status (1)

Overarching guideline on biosimilars (EMEA/CHMP/437/04) released November 2004 for public consultation by February 2005

Guideline on similar biological medicinal products containing biotechnology derived proteins as active substance

– Quality (EMEA/CHMP/49348/05) released March 2005 for public consultation by June 2005

– Non-clinical / Clinical (EMEA/CHMP/42832/05) released June 2005 for public consultation by October 2005

Biosimilar guidelines – current status (2)

Product-class specific guidelines on biosimilars - (non)clinical annexes

– Insulin (EMEA/CHMP 32775/05) released May 2005 for public consultation by October 2005

– Somatropin (EMEA/CHMP/94528/05) released May 2005 for public consultation by October 2005

– Erythropoietin (EMEA/CHMP/94526/05) released June 2005 for public consultation by October 2005

– Granulocyte colony stimulating factors (EMEA/CHMP/31329/05) released June 2005 for public consultation by October 2005

Biosimilar overarching guideline (EMEA/CHMP/437/04)

Outline concepts and basic principles (Annex I, Part II, Section 4)

– In principle, concept of “biosimilarity” applicable to any biological product . In practice, highly purified products, which can be thoroughly characterised (some biotech products)

– Due to the complexity of biotechnology derived products the generic approach is scientifically not appropriate

– Biosimilar considerations: analytical methods, ability to characterize the product, manufacturing process, clinical and regulatory experience

Choice of Reference Product

– Authorized in EU

– Similar in molecular and biological terms

– Same reference product used in quality, safety and efficacy studies

– Same pharmaceutical form, strength and route of administration Specific biosimilar product given to patient should be clearly identified to support

Pharmacovigilance monitoring post-marketing

Biosimilar quality guideline (EMEA/CHMP/49348/05)

Specific for rDNA derived proteins Full quality dossier (CTD Model 3) Extensive comparability exercise Main issues

– Comparison to EU Pharmacopoiea standard as reference is not sufficient

– Drug substance/product

– State-of-art analytical methodology to characterize both biosimilar and reference products

– Biosimilar process should be well developed, i.e. avoid additional comparability exercises

– Product produced with final manufacturing process to be used in clinical trials (close to batches intended for marketing)

– Differences to be addressed in the (non)clinical program

Biosimilar (non)clinical guideline (EMEA/CHMP/42832/05)

Guideline on general principles

– Toxicological and other non-clinical

– Clinical equivalence

– Safety studies

– Immunogenicity

– Pharmacovigilance and risk mangement

Product class specific Guidelines

– As above, additional detail: case-by-case

Biosimilars (non)clinical guideline Principles (1)

Extensive comparability studies required to show similarity in terms of quality, safety and efficacy

Company should justify the approach taken during the development of the product and contact EMEA for scientifc and regulatory advice

Full quality dossier and equivalent safety and efficacy profiles Same EU reference product for all aspects of the comparability studies Same pharmaceutical form, strength and route of administration Data requirements are guided on a case-by-case basis by

– Type of product and claimed therapeutic indication(s)

– Extent of characterisation possible by analytical methods (complexity of molecule, state of the art analytical procedure)

– Observed / potential differences between biosimilar and originator, and the impact on quality, safety, and efficacy

– Clinical experience with substance class

Biosimilars (non)clinical guideline Principles (2)

The more complex the production process, the more scientific studies required to establish ‘similarity’

The required clinical data for the comparability study with test product as produced with the final manufacturing process …. (otherwise justification and adequate additional data needed)

Extrapolation to other indications

– Extrapolation of efficacy and safety to other indications of the reference product must be justified or demonstrated separately

– Justification dependent on e.g.

Clinical experience with the reference product

Whether same mechanism of action involved

Whether immunogenicity is disease specific, dependent on route of administration or duration of treatment

Dr Martina Weise, BfArM, Member CHMP Biosimilar WP – DIA Annual Meeting, Washington, June 2005

Biosimilars (non)clinical guidelines Non-clinical studies (1)

Should be performed before going into clinical development

Should be designed to detect differences in response and not the response per se

Their design requires a clear understanding of the product characteristics

– Physico-chemical and biological studies should be reviewed from the point of view of potential impact on efficacy and safety

– Approach taken will need to be fully justified in the non-clinical overview

General principles to be followed and tailored to the specific product on a case-by-case (as per product class specifc guidelines)

– Pharmacodynamics studies

– Toxicological studies

Dr Hans-Karl Heim, Non-clinical Assessor, BfArM– EGA Meeting on Biosimilars, London, May 2005


• Pharmacodynamics studies

• In vitro studies: a battery of receptor binding studies or cell-based assays

many of which may already be available from quality-related bioassays

in order to assess if any differences in reactivity are present and to determine the likely causative factors

• In vivo studies: animal studies should be designed to maximise the information obtained

preferably compare reference and claimed ‘biosimilar‘ products in the pharmaceutical form intended to be used in the clinical trials

be performed in (a) relevant species

employ state of the art technology


• Limitted Toxicological studies

Repeat dose toxicity study

• at least one study in relevent species, including toxicokinetic and immunological measurements

• study duration should be sufficiently long to detection of relevant differences in toxicity

Specific safety concerns (e.g. local tolerance, antigenicity)

• might be addressed in the same repeat dose study

Biosimilars (non)clinical guidelines Clinical studies (1)

The clinical comparability exercise is a stepwise procedure

Comparative PK study

– Absorption and clearance and/or half life (e.g elimination rate may be different)

– Equivalence margin must be based on clinical judgement (acceptance range for generics may not be applicable)

Clinical efficacy

– In principle, confirmatory comparative trial(s) to demonstrate therapeutic equivalence and assay sensitivity (ICH E9, ICH E10)

– Equivalence margins justified primarily on clinical grounds (review of the clinical trials performed with reference drug)

Biosimilars (non)clinical guidelines Clinical studies (2)

Comparative PK/PD studies may suffice if

– The reference product is well characterised

PK and PD

Relationship PK – PD – clinical effect (exposure/effect)

– PD marker(s) accepted surrogate marker(s) for efficacy (most relevant PD marker to be tested)

– Equivalence margin pre-defined and justified

– Comparison within the linear/”sensitive” part of the dose-response curve (more than one dose may be needed)

Biosimilars (non)clinical guidelines Clinical safety and pharmacovigilance

Pre-licensing

– Clinical safety data always required, even if efficacy is shown to be comparable

– Sufficient number of patients to compare common ADRs between reference and claimed ’biosimilar’ products: type, severity, frequency

– Risk specification and pharmacovigilance plan part of the application dossier, as per EU legislation and guidelines

– Pharmacovigilance systems/procedures should be in place (traceability as per current EU guidelines)

Post-marketing

– Benefit/risk assessment on ongoing basis

– Risk management programme may be required if rare but serious adverse reactions (e.g Epoetin/PRCA)

Biosimilars (non)clinical guidelines Immunogenicity (1)

Factors affecting immunogenicity

– The immune response against therapeutic proteins differs between products ……

– There is considerable inter-individual variability in antibody response in terms of different antibody classes, affinities, and specificities

– Data should be collected from a sufficient number of patients (and Data should be collected from a sufficient number of patients (and appropriate duration) to characterise the variability in antibody appropriate duration) to characterise the variability in antibody responseresponse

Consequences of an immune response

– An immune response to the product may have a significant impact on its clinical safety and efficacy…….


Principles for evaluation of immunogenicity

– The immunogenicity of a similar biological medicinal product must The immunogenicity of a similar biological medicinal product must always be investigatedalways be investigated

– Normally an antibody response in humans cannot be predicted from animal studies

– Only clinical trials are decisive to reveal immunogenicity

– The assessment of immunogenicity requires an optimal antibody testing strategy

– Characterisation of the observed immune response, as well as evaluation of the correlation between antibodies and pharmacokinetics or pharmacodynamics, relevant for clinical safety and efficacy in all aspects


Testing – The applicant should present a rationale for the proposed

antibody-testing strategy– Testing for immunogenicity should be performed by state of the

art methods …– The screening assays should be validated and sensitive enough– An assay for neutralising antibodies should be available for

further characterisation of antibodies detected by the screening assays

– The periodicity and timing of sampling for testing of antibodies should The periodicity and timing of sampling for testing of antibodies should be justifiedbe justified

– In case of chronic administration, one-year follow up data will be required pre-licensing.

– In view of the unpredictability of the onset and incidence of immunogenicity, long term results of monitoring of antibodies at long term results of monitoring of antibodies at predetermined intervals will be required predetermined intervals will be required (post-marketing)

Points to consider (1)

Today, EU legal/regulatory framework is in place to approve biosimilars Essential similarity does not apply to biosimilars Product complexity/limitation of analytical methods – major factor Current and evolving EMEA/CHMP guidelines to support biosimilar applications

Case by case approach and product-specific approach for the "biosimilar situation" although general principles apply

Importance of ongoing regulatory experience with the assessment of biosimilar applications via the CHMP scientific advice

Importance of clinical experience with biologics (2–3 years after market approval to adequately validate risk/benefit profile)

A post-licensing risk management program (ongoing B/R assessment, PSURs, Phase IV trials, Registries?) will be a crucial element of the approval process if safety concerns

Points to consider (2)

Immunogenicity is still a ‘black box’ because onset and incidence are difficult to predict

Most of the severe immune-mediated adverse events are rare and may only become evident post-approval

The question occurs all along the life cycle of the product, and particularly when

– A change is introduced to the manufacturing process, the formulation, the storage conditions, etc….

– A new manufacturer proposes a "biosimilar" product Importance of progress made with quality tools and methods Choice of antibody assays and their standardisation are important

for comprehension and interpretation of the "immunogenicity profile" at any stage of the life cycle of a product

Issue of tracking biosimilar products given to patients to ensure post-marketing surveillance?

Emerging biosimilars

Evolving and rapidly expanding field following different rules and dynamics than generic drugs

Awareness Education Alertness

The way forward ?

How to build a collaborative approaches with stakeholders, experience sharing

– those who have experience should share it

• unexpected immunogenicity

• assay strategies for different product classes

– role for Eur. Pharmacopoiea and OMCLs?

• standards (antibodies, assays)

– Conferences, public meetings (e.g EMEA/DIA WS on biosimilar guidelines, Dec 8-9, 2005, Paris)

Opening the immunogenicity ‘black box’? Any further guidance is warranted?

– assays?

– risk management?

The way forward ?


Iman Barilero, PhD, PharmD Associate Director, European Regulatory Affairs

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