An introduction to the regulatory framework of Biotechnology - Business Aspects of... · An introduction to the regulatory framework of Biotechnology ... Biotechnology is the use

An introduction to the regulatory framework

of Biotechnology

Business Economics of Biotechnology

8 November 2012

Marc Martens

2© Bird & Bird LLP/LSTS 2012

Section 1 – Introduction

Section 2 – Biotechnological medicinal products

Sub-Section 1 – Medicinal productsmarketing authorisation

abridged proceduresRegulatory Data

Protection

Sub-Section 2 – Biological medicinal products, biosimilars

Sub-Section 3 – Cells tissues ATMPs

Section 3 - GMOs

Section 4 - Conclusion

Table of contents




Biotechnology

Biotechnology is the use of living organisms, or products of living organisms, for human benefit, to make a product or solve a problem

● Scope is extraordinarily broad, as to origins and technologies involved

Applications historically used for ages, and still used today

● Selective breeding, fermentation, …


Types of biotechnology : helicopter view (1)

Different types of biotechnology

● Microbial

● Agricultural• Genetically modified cultures

• Molecular pharming

● Animal• Transgenic animals as sources of antibodies (bioreactors)

• Aquaculture

● Forensic (DNA Fingerprinting)

● Bioremediation (e.g. oil degrading bacteria)

● Medical

All types are interdependent (>same scientific sources)


Types of biotechnology : helicopter view (2)

● WHITE biotechnology• Industry

● RED biotechnology• Medicine

● GREEN biotechnology• Agriculture


Genetic engineering through molecular

biology and Analysisthrough

bioinformatics

Environmentaland aquaticapplications

Drug development

Agricultural biotechnology

Detection

Pharmaceuticals and Healthcare

Regulatoryapproval / Oversight

Schematic view

Physiology (human, animal, plant)

MathematicsMolecular and

cell biologyImmunology

Statistics MicrobiologyBiochemistry

PhysicsChemical

engineering

Computer Science

Genetics

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Physiology (human, animal, plant)

MathematicsMolecular and

cell biologyImmunology

Statistics MicrobiologyBiochemistry

PhysicsChemical

engineering

Computer Science

Genetics

Genetic engineering through molecular

biology and Analysisthrough

bioinformatics

Schematic viewPharmaceuticals and Healthcare

Detection

Regulatoryapproval / Oversight

Agricultural biotechnology

Drug development

Privacy/ Data protection/

Criminal law

Pharmaceutical law/Social security law /

Patients’ rights

Public bodies (EU: EMA, EFSA, etc.

National: FAHMP, FASFC, ethics

committees etc.)

GMO regulations / consumer protection

Pharmaceutical law / Clinical

trials

GMO regulations / consumer protection

Environmentaland aquaticapplications

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Depending on the product, the intended application, or finality, different regulatory frameworks can apply

● crucial to consider those aspects in the earliest stages of product development

Some areas subject to Health, Environmental as well as Ethicalconcerns

Some areas of biotechnology are highly regulated


Phyto-pharmaceutical

product

Importance of product qualification

Medical device

e.g. Directives90/385/CEE

and 93/42/CEE

Foodstuff(possibly GMO)

Numerousregulations

and directives

Cosmetics

e.g. Directive 76/768/EEC

Food additive

e.g. Directive 89/107/CEE

Chemicalproduct

e.g. Regulation1907/2006,

Directive 67/548/EEC

Medicinalproduct

e.g. Directive 2001/83/EC,

Regulation 726/2004

Product

e.g. Directive 91/414/EEC


Section 2 – Red biotechnology Biotechnological medicinalproducts



Section 2 – Biotechnological medicinal products



Protection

Sub-Section 2 – Biological medicinal products, biosimilars

Sub-Section 3 – Cells tissues ATMPs

Section 3 - GMOs

Section 4 - Conclusion

Table of contents




Protection


Definition of “medicinal product”:“Any substance or combination of substances presented as having properties for treating or

preventing disease in human beings; or

Any substance or combination of substances which may be used in or administered to human

beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic

action, or to making a medical diagnosis.”

(Directive 2001/83/EC)


Brief introduction on medicinal productsWhat is a medicinal product ?

Broad, twofold definition● presentation criterion

● application criterion

Case law● Medicinal product / Food

• Vitamin preparations can be medicinal products

• Herbal tea can be a medicinal product

● Medicinal product / Cosmetics

• A hair growth product is a cosmetic, but can be presented as a medicinal product

• Eye lotions can be medicinal products


Brief introduction on medicinal productsThe legal framework

EU law

● Community Code on medicinal products = Directive 2001/83/EC• Supplemented by other sources

- Regulations (a.o., Regulation 726/2004)

- Guidelines (EMEA)

- Court of Justice/General Court case law

Belgian law

● Implementation of Directive 2001/83/EC• Act of 25 March 1964

• Royal Decreee of 14 December 2006

● Key role of the competent authority : Federal Agency for Medicinesand Health Products (FAHMP)


Brief introduction on medicinal productsThe Marketing Authorisation (MA)

Basic rule : all medicinal products are subject to a MA

MA dossier intended for the assessment of :● Quality● Safety● Efficacy

MA procedures for medicinal products● Centralised● Decentralised procedure (DCP)

and mutual recognition procedures (MRP)● National procedure


Key role of the ReferenceMember State

Application in one MemberState (e.g. Belgium)

Dossier filed at the FAHMP (Federal Agency for Healthand Medicinal Products)Competent authority : Ministry of Public Health

MA only valid in Belgium MA valid throughout the EUNational MAs

Dossier filed at the EMEA (London)Competent authority : European Commission

Dossier filed in one or several Member States (simultaneously or not) -MA may be extended to other Member States

Centralised procedureMutual recognition

procedureDecentralised procedure

Overview of MA procedures under EU law


Timeline of a medicinal product

10 25201550

Life cycle IP

SPC

2 1RDP 8

Patent Application

Pharmacology

Chronical toxicity

Acute toxicity

Clinical Trials IPhase II

Phase III

Marketing authorization

Price

Reimbursement

Pharmacovigilance

SPC

Basic Patent SPC

R&D Clinical trials Placing on the market


Information to provideThe full dossier

Bio-pharmaceutical StudiesStudies Pertinent to Pharmaco-kinetics Using Human Bio-materialsHuman Pharmaco-kineticHuman Pharmaco-dynamicEfficacy and Safety StudiesPost-marketing Experience

Clinical study reports

PharmacologyPharmaco-kineticsToxicologyOther Toxicity Studies

Non-clinical reports

Summary of product characteristics, labelling and package leaflet, etc.

Administrative information

See Annex I of Directive 2001/83 and Notice to Applicants


Types of abridged procedures

« without prejudice to IP rights », the applicant will not have to provide the results of pre-clinical tests and clinical trials under:

● Bibliographic procedure

● Two abridged procedures

● Hybrid abridged procedure


Generics : abridged procedure

Medicine

Compared to the reference product :

● Same qualitative and quantitative composition in active substances

● Same pharmaceutical form

● Bioequivalence (demonstrated by bioavailability studies)

Article 10.1 Directive 2001/83● the applicant is not required to provide the results of pre-clinical

tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorized under Article 6 for not less than eight years in a Member Stateor in the Community

● Right of reference


Regulatory Data Protection / Exclusivity

For pioneer applicant (innovator):● Right to prevent during a certain period of time the regulatory authorities

from relying on the preclinical and clinical trials results of the princeps(reference medicinal product) when considering the approval of a second application (for a generic)

For second applicant (usually a generic):● Right to apply for MA according to an abridged MA procedure and thus to

rely on the original data submitted by the pioneer applicant when the data exclusivity period has expired

Means a generic has to provide his own clinical data while RDP is in force● But that a generic can rely on data filed by innovator after expiry of RDP

RDP rules have evolved over time● Mainly to encourage generic competition and reduce drug prices


Duration of RDP: the “8+2+1” rule

Data exclusivity period for all reference medicinal products (MRP, CP, DP)No reference can be made to the results of the tests/trials conducted for the reference product

Marketing exclusivity for all reference medicinal products Generic cannot be put on the market but generic applicant can seek a MAby referring to the data of the reference product (abridged procedure)

Extension (see hereafter)

8 years

2 years

1 year

+

+


8+2+1 RDP for new indications: new NCE’s

Directive 2001/83, article 10.1, al 4

New therapeutic indications have to bring a significant clinical benefit in comparison with existing therapies

Application for a new indication for a well-established substance

Non-cumulative period of 1 year of data exclusivity

Data exclusivity period refers exclusively to the data concerning the new indications

Once the well-established character is demonstrated, the additional 1 year exclusivity can be obtained without time limit


Active Substance

What is meant by active substance?• The different salts, esters, ethers, isomers, mixtures of isomers, complexes

or derivatives of an active substance = same active substance - art. 10.2 (a) Directive 2001/83 and SmithKline Beecham decision

• Unless they differ significantly in properties with regard to safety and/or efficacy - in such cases, additional information providing proof of the safety

and/or efficacy of the various salts, esters or derivatives of an authorized active substance must be supplied by the applicant

What is meant by pharmaceutical form?• The various immediate-release oral pharmaceutical forms = one and same

pharmaceutical form

Only a medicinal product authorized on the basis of a complete dossier (quality, safety, efficacy, with non-clinical tests and clinical trials) can be used as reference


Is there any additionnal period for RDP for new strenghths, pharmaceutical forms,…

“Global MA” concept

● No further period of RDP

● “When a medicinal product has been granted an initial marketing authorization in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorization in accordance with the first subparagraph or be included in the initial marketing authorization. All these marketing authorizations shall be considered as belonging to the same global marketing authorization, in particular for the purpose of the application of Article 10(1)”, see Art. 6 (1), al. 2 of Directive 2001/83

● Meaning no additional RDP for line extensions (other than new indications)


Global MA - issues

Meaning of the « same MA holder »?● = applicants belonging to the same mother company or group of companies,

as well as applicants which have concluded agreements (e.g. licensees) or which exercises concerted practices concerning the placing on the market of the relevant medicinal product

● see NTA, Chap. 2, para 3.2.1. & Commission Communication on the Community MA procedures for medicinal products, OJ C 229

What if a subsequent MA (i.e. for a new pharmacological form) isgranted centrally?● « Where a product is initially authorized nationally and subsequently, an

additional strength, pharmaceutical form, administration route or presentation is authorized through the centralized procedure, this shall also be part of the global marketing authorization » (see NTA, Chap. 1 , para.2.3)

What about « multiple applications »?● covered by the “Global MA” concept (see NTA, Chap. 1, para 2.3)


Main Changes in EU RDP Regulation (1)

Previous rules

Line Extension

Duration

Current rules (nov. 2005)Directive 2001/83 as modified

by Directive 2004/27

• MRP: 6 – 10 yearsCP: 10 yearsEx-concertation: 10 years in all MS

• Limitation to patent expiry

• MRP: 6 – 10 yearsCP: 10 yearsEx-concertation: 10 years in all MS

• Limitation to patent expiry

No supplementary RDP (art. 6), except +1 year when:- new therapeutic indication- new indication for well-established substance

No supplementary RDP (art. 6), except +1 year when:- new therapeutic indication- new indication for well-established substance

No supplementary RDPNo supplementary RDP

Change ofclassification +1 year RDP+1 year RDPNo supplementary RDPNo supplementary RDP

• 8 years

+ 2 (marketing exclusivity)

+ 1 (see hereunder)

• No limitation to patent expiry

• 8 years

+ 2 (marketing exclusivity)

+ 1 (see hereunder)

• No limitation to patent expiry


Main Changes in RDP Regulation (2)

Characteristic of considered

product

« Generic » medicine(SmithKline Beecham, Novartis)

« Generic » medicine(SmithKline Beecham, Novartis)

• Medicine « essentially similar » to the reference product

• Concept not defined in legislation• Conditions: Notice to Applicants + case law

• Medicine « essentially similar » to the reference product

• Concept not defined in legislation• Conditions: Notice to Applicants + case law

Bioequivalence Unclear situation : see Generics, NovartisUnclear situation : see Generics, Novartis Must be demonstrated by appropriate bioavailability studies

Must be demonstrated by appropriate bioavailability studies

Previous rulesCurrent rules

Directive 2001/83 as modified by Directive 2004/27

ReferenceProduct

• « is or has been authorized »• European reference product,

must not be authorized in the MS where the protection is sought

• Global MA: one and unique application for a product line

• « is or has been authorized »• European reference product,

must not be authorized in the MS where the protection is sought

• Global MA: one and unique application for a product line

• Must be « marketed », = authorized• In the country where generic

authorization is sought• Authorization of generic even if

MA of reference product is withdrawn (AstraZeneca)

• Must be « marketed », = authorized• In the country where generic

authorization is sought• Authorization of generic even if

MA of reference product is withdrawn (AstraZeneca)


Sub-Section 2 – Biological medicinalproductsbiosimilars


Definition of “Biological medicinal product”

Means that the active ingredient is a biological substance derived from living cells

“Biological substance”● Substance produced or extracted from a biological source● Combination of physico-chemical-biological testing, production process and its

control are needed for its characterization and determination of quality

Examples of biological medicines:● Immunological medicinal products and medicinal products derived from blood

and human plasma (article 1.4 et 1.10 of Directive 2001/83)● Medicinal products developed by recombinant DNA technology, controlled

expression of genes coding for biologically active proteins from a cell culture, hybridoma and monoclonal antibody methods

● ATMP

Biologicals are among best-selling/fastest growing drugs in the world● Epogen/Procrit®, Enbrel®, Humira®, Remicade®, Herceptin®, Avastin®

See Annex 1 of Directive 2001/83, Part I; point 3.2.1.1 (b))


Centralised procedure

Annex to Regulation 726/2004 (centralised procedure for MA) considerstwo types of ‘biotechnological’ medicinal products :

● Medicinal products developed by means of certain biotechnological processes:

• recombinant DNA technology,• controlled expression of genes coding for biologically active proteins in

prokaryotes and eukaryotes including transformed mammalian cells,• hybridoma and monoclonal antibody methods

● Advanced Therapies (Advanced Therapy Medicinal Products) –a more recent addition, through Regulation 1394/2007

Those products have to be authorized through the centralisedprocedure


Centralised procedure

Characteristics

● Single application

● Single evaluation

● Single decision for the whole EU territory (+ Iceland, Liechtenstein and Norway)

Application procedure can take up to 2-3 years

The dossier requirements are extensive, expensive and take a lot of time to prepare

www.ema.europa.eu

www.ema.europa.eu


Adoption of CHMP Opinion + CHMP Assessment Report. Adoption of a timetable for the provision of product information translations

Final draft of English SPC, labelling and package leaflet sent by applicant to theRapporteur and Co-Rapporteur, EMEA and other CHMP members.

Restart of the clock and oral explanation (if needed).

CHMP discussion and decision on the need for adoption of a list of “outstanding issues” and/or an oral explanation by the applicant. If an oral explanation is needed, the clock is stopped to allow the Applicant to prepare the oral explanation. Submission of final inspection report to the EMEA, Rapporteur and Co-Rapporteur by the inspection team (at the latest by day 180).

Deadline for comments from CHMP Members to Rapporteur and Co-Rapporteur, EMEA and other CHMP members

Joint Response Assessment Report from Rapporteur and Co-Rapporteur received by CHMP members and the EMEA. EMEA sends this joint Assessment Report to the applicant making clear that it is sent for information only and does not yet represent the position of the CHMP. Where applicable inspection to be carried out. EMEA/QRD sub-group meeting for the review of English product Information with participation of the applicant (optional) around day 165.

Submission of the responses, including revised SPC, labelling and package leaflet texts in English.Restart of the clock

CHMP adopts the LoQ as well as the overall conclusions and review of the scientific data to be sent to the Applicant by the EMEA.Clock stop. At the latest by Day 120, adoption by CHMP of request for GMP/GLP/GCP inspection, if necessary (Inspection procedure starts).

Receipt of draft list of questions (including the CHMP recommendation and scientific discussions), from Rapporteur and Co-Rapporteur, as discussed with the peer reviewers, by CHMP members and EMEA

Rapporteur, Co-Rapporteur, other CHMP members and EMEA receive comments from Members of the CHMP (including peer reviewers).

Receipt of the Assessment Report(s) or critique from Rapporteur and Co- Rapporteur(s) by CHMP members (which includes the peer reviewers) and EMEA. EMEA sends Rapporteur and Co-Rapporteur Assessment Report/critique to the applicant making it clear that it only sets out their preliminary conclusions and that it is sent for information only and does not yet represent the position of the CHMP.

Start of the procedure

ACTION

* Target dates for the submission of the responses are published on the EMEA Website

Source : EMEA, EMEA Pre-submission procedural advice for users of the centralised procedure, May 2008

Timetable for the evaluation of the MA Application

150

By 210

181 > 210

181

180

170

121*

120

115

100

80

1*

DAY


Follow-up of the CHMP Opinion

Dossier to EMEA

CHMP Opinion

210 days(clock stop possible)

unfavourable favourable

Applicantannounces

appeal

Applicant doesnot appeal

15 days

60 daysto submit

CHMP reconsiders

or not60 days

CHMP Opinion

30 days

15 days

Transmission of Opinion (+annexes) to Commission, Member States, Applicant

Draft Commission decision

ApplicantMember States

Commission decision

Appeal(CFI)

ECJ


Timeline of a medicinal product

10 25201550

Life cycle IP

SPC

2 1RDP 8

Patent Application

Pharmacology

Chronical toxicity

Acute toxicity

Clinical Trials IPhase II

Phase III

Marketing authorization

Price

Reimbursement

Pharmacovigilance

SPC

Basic Patent SPC

R&D Clinical trials Placing on the market


What is a biosimilar?

According to article 10.4 of Directive 2001/83

● Where a biological medicinal product which is similar to a reference biological product does not meet the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or manufacturing processes, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.

● Type and quantity of supplementary data provided must comply with • relevant criteria stated in the Annex; and • related detailed guidelines.

● The results of other tests and trials from the reference medicinal product's dossier shall not be provided.

Consequence: a biosimilar is defined by what is accepted or not by the EMEA (or other competent authorities)● No a priori definition of the acceptable differences between a biosimilar

and the reference product


Active substance for biological medicinalproducts

“Biosimilar”

● “similar” product made according to a different process

• For example different construct, host, cell line, protocol or purification steps

• In practice: impossible to know without access to original process

• But developers of biosimilars have normally no direct access to originator’s data

- Have to reverse engineer

● (i.e. made using different process): additional pre-clinical tests or clinical trials required to show similarity


Same active substance (NTA for biological medicinal products) =

• Same molecular structure

• Same nature of source material

• Manufacturing process

“Biogeneric” and biosimilar● same product made according to the same process

• In practice: impossible to do without access to original process

● no additional tests or trials required

• But requires the same process to be used (usually not accessible to generic)

Active substance for biological medicinalproducts


Which approval route for biosimilars?

Centralized procedure for MA is compulsory for the following biotechnological processes (EU Regulation 729/2004)

● recombinant DNA technology

● controlled expression of genes coding for biologically active proteins from a cell culture

● hybridoma and monoclonal antibody methods

Biosimilars: mainly follow the central route

But could fall outside

● if developed according to other biotechnological processes

● non-biotech


Biosimilars’s specific route for approval: EU Legislative Framework

+

Article 10.4

Biosimilars ≠ Generics

Supplementary data to be provided

Refers to Annex I and Guidelines

re. the type and quantityof data

Annex 1 +Directive 2001/83 Also

General Principles Practical Requirements

Part II, Section 4

Type and quantity of supplementary data

is determined on a case-by-case basis

→ Specific Guidelines

Applicable general principles in a guideline

→ Overarching Guideline

Other relevant Guidelines

GMP’s: Directive 2003/94

+ Guide

Regulation 726/2004


Overarching GuidelineDefines basic principles, philosophy + « User guide »

General Guidelines

General principles for assessing quality,

non-clinical, clinical aspects

Product Specific Guidelines

Annexes to General Guideline on (non-) clinical issues

Address specific pre-clinical andclinical issues re. specific products

Guidelines on biosimilars

Somatropin

Insulin

Granulocyte-colony Erythropoietins

IFN-alpha

LMW heparin, etc.

Quality issues

(Non-) Clinicalissues

Apply to all

biosimilars


Specific nature of biosimilars and consequences

Generics Biosimilars

Simple SmallStable

ComplexLarge

Less stable

Easy to characterize

Chemical process

Easy to reproduce

Identical copies

Biological substancesExtremely complex biological process :

not easy to reproduceSimilar copies

Difficult to characterize

Characteristics

Characterization

ManufacturingProcess

Bioequivalence Comparability studiesto demonstrate

similarity

Abridged Procedure for MA


Source : Cecil Nich, BSC, Future opportunities for biosimilar mAB, 2010


Information required for a biosimilar’s MA

Quality dataComplete self-standing quality dossier

+ Comparability exercise

Non-clinical data

Clinical data

Pharmacovigilance

Case-by-case basisAbridged programs (in vitro/in vivo)+ Comparability exercise

Abridged programs but most of the time: extensive trials are requiredAll results must be submitted ( + and -)

+ Comparability exercise

Monitoring = necessary, as for all other medicinesPharmacovigilance SystemsRMP


Comparability of different processes?

“The product is the process”: marketing authorisation is granted for the product (defined by INN name) made according to a specific process

● The development of a biosimilar requires a complete independent product and process development

● Plus comparative testing at all stages in order to obtain approval

● Biological product is defined by the way it is manufactured● Process determines structure of product (e.g. glycosylation) and of impurities (e.g. isomers)

which may influence either affinity or potency

● Any change in the process inevitably affects the final product

Reference product

Target Qualityby Design

Quality Module 3

Physico-Chemical and

BiologicalComparability

Comparative Preclinical

Studies

Comparative clinical studies

RiskManagement

Plan

Comparative Comparative


Experience so far:Overview of EU authorized biosimilars

Somatropin

INN Biosimilar

Epoetin alfa

Epoetin zeta

Filgastrim

Omnitrope® (Sandoz)

Valtropin® (BioPartners)

Binocrit® (Sandoz)

Epoetin alfa Hexal®

Abseamed® (MAP)

Silapo® (Stade Arzneimittel)

Retacrit® (Hospira)

Biogastim® (CT Arzneimittel)Filgastrim Ratiopharm®, Ratiogastrim®, Tevagrastim®

Reference Product

Genotropin® (Pfizer)

Humatrope® (Eli Lilly)

Eprex®/ Erypo® (J&J)

Neupogen® (Amgen)

Filgastrim Hexal®, Zarzio® (Sandoz)


Experience so far:Refusal/Withdrawals of biosimilars

Interferon alfa

INN Biosimilar

Human insulin

Alpheon (Biopartners)

Insulin Marvel short

Insulin Marvel Intermediate

Insulin Marvel long

Status

Refused in June 2006

Withdrawn

Not all biosimilar applications have been successful


Acceptable differences between biosimilarsand reference product

Different host cells

Quality differences between biosimilars and reference drug products

Different levels of impurities

Different formulation

Different glycosylation

ValtropinAbseamed, Binocrit,Epoetin alfa Hexal

Retacrit and Silap

Source: H. Schellekens & E. Moors, « Clinical comparability and European biosimilar regulations », in Nature Biotechnology January 2010, nr. 1, vol. 28, p. 29

Zarzio and Filgastrim Hexal

Biograstim, Filgrastim,

Ratiopharm, Ratiograstim

and Tevagrastim

Abseamed, Binocrit,Epoetin alfa Hexal

Retacrit and Silap

Zarzio and Filgastrim Hexal


Acceptable differences between biosimilarsand reference product

These variations can have a potential major effect on a productsafety and efficacy

So far: clinical studies show no negative effect

● The differences have not compromise the efficacy or increasedthe level of adverse effects

• compared with the reference product

● Raise the question of the relevance of the comparison exercice• Comparison of quality characteristics between biosimilar and

reference product will always show differences (« product is the process »)

• Clinical data are mandatory


Strategic Issues (1)

Merits / added value of comparability exercises are put into question● Often lack in the dossier or are incomplete, sometimes

even show that biosimilar lacks (clinical) comparability● May be a barrier for development of biosimilars of

complex biologics● Drop it?

Which degree of discretion for the competent authority?

General wording of the Guidelines● « appropriate comparability exercise », « deviation has

to be justified or, if necessary, demonstrated »« normally comparative clinical trials are required »…

● Large margin of appreciationRole of the industry in the development of guidelines


Strategic Issues (2)

Do biosimilars get all indications ?

INN

Clear labelling

No substitution


Sub-Section 3 – The use of human cells tissues ATMPs


Introduction on cells and tissues


Cells and tissuesIntroduction

Example : uses of Mesenchymal Adult Stem Cells© stemcell-bridge.com

There are many types of cells and tissues, from embryonic stem cells to adult organs

The source of cells and tissues can behuman or animal

Cells and tissues can be used for various applications, e.g.

Scientific research

Autologous or allogeneicgrafts

Medicinal products

In vitro Diagnostics

…


Cells and tissuesInternational Framework (examples)

•Universal texts● International

• Universal Declaration of human rights of 10 December 1948• International Covenant on Economic, Social and Cultural Rights (1966)• Universal Declaration on Bioethics and Human Rights of 19 October 2005• UN Declaration on the Rights of Indigenous Peoples in 2007• (…)

● General EU texts• Convention for the Protection of Human Rights and Fundamental Freedoms of 4 November 1950• Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of

Biology and Medicine: Convention on Human Rights and Biomedicine, Oviedo, 4 April 1997, (not ratified by Belgium)• Charter of Fundamental Rights of the European Union of 12 December 2007

•Specific texts● Patient rights

• Declaration of Lisbon on the rights of the patient (2005)• UN Political Declaration on HIV/AIDS• Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals

with regard to the processing of personal data and on the free movement of such data• Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code

relating to medicinal products for human use● Experiments

• Nuremberg Code (1947) • WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects (1964)• Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws,

regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use

• Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research(2005)


Cells and tissuesEuropean Directives

Directive 2004/23 of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

Directive 2001/83 Community code relating to medicinal products for human use

● Directive 2002/98 of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC

● Directive 2004/33 of 22 March 2004 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components

● Regulation 1394/2007 on Advanced Therapy Medicinal Products

Directive 98/79/EC : in vitro diagnostics (IVD)

● Genetic testing with medical purpose


Transversal principles of healthcare law

● Respect for human dignity

● Right to respect of privacy

● Right to body integrity

● Unavailability of the human body

● Non-commerciality of the body and the biological material


Directive 2004/23/ECScope, objective and main principles

● Scope• Human tissues and cells intended for human application

● Objective• Standards of quality and safety on EU scale

● Main principles• Donation : voluntary and unpaid

- compensation for the donors strictly limited to the expenses and inconveniences related to the donation

- Informed consent• Procurement :

- carried out on a non-profit basis, - by persons who have successfully completed a training programme,- in a tissue establishment authorised for procurement or in a procurement

organisation• Traceability of the tissues and cells• Basic requirements for import and export

- Imports from third countries must comply with standards equivalent to those laid down in the Directive

- Exports to third countries must comply with the requirements of the Directive


Use of human cells and tissuesDifferent finalities

● Grafts (no substantial manipulation before graft)• Autologous (donor = receiver)• Allogeneic (donor is not the receiver)

● Scientific research• With human application• Without human application

● Substantial manipulation(s)• Tissues and cells can become a medicinal product


Advanced Therapies


Advanced therapy medicinal products

Medicaldevices

Legislation

Science

Medicaldevices

Tissueengineering

Celltherapy

Gene therapy

Biotechex : insulin

Medicinalproducts

ex: aspirin

« Advanced therapies »

Source : P. Selis, 1st EMEA Workshop on ATMP, 3/4/2009

CHMP expertise

CAT (new)Committee for Advanced

Therapies – Scientificexpertise

ATMP Medicinal products


Regulation 1394/2007 : objectives & scopeLex specialis which introduces additional provisions to those laid down in Directive 2001/83/EC● Lays down specific rules for ATMPs

Principles of existing legislation on medicines apply to advancedtherapies● Centralised procedure for MA

● Demonstration of Quality, Safety & Efficacy

● Post-authorisation vigilance

ATMPs may contain human or animal cells

Regulation is directly applicable (but a transitional period is provided for)

Directive 2001/83 Regulation1394/2007


Ruled by Directive 2004/23 except in the case of manufactured products covered by other Community legislation (e.g. Regulation 1394/2007)

Always ruled by Directive 2004/23 insofar as the human tissues and cellsare intended for human applications

● Donation

● Procurement

● Testing

● Processing

● Preservation

● Storage

● Distribution

Interaction Directive 2004/23 and Regulation 1394/2007


The Belgian legislation on the procurement and use of human biological material


Several drafts have been discussed in Parliament

Long debates in Senate Commission

Purpose● Initially : confusion around the umbilical cord blood storage (ethical)

issues● Implementation of Directives 2004/23, 2006/17 and 2006/86● Creation of a legal framework for the activities implying the use of human

biological material

Now : Act of 19 December 2008 on the procurement and use of human biological material for human medical applications and scientific research● Entered into force since 1 December 2009● Exception : biobanks regime (art. 22)

Law on human biological materialNew Belgian legal framework (1)


Law on human biological materialScope

Human applications

- Transplantation

- Manufactured products

Scientific research

Implying a human application or not

Human cells and tissues, including- Gametes- Embryos- Foetuses- Substances extracted thereof

Blood, organs, hair (exceptfollicles), nails, urine, breastmilk, faeces, tears and sweat.

In scope

Not in scope

Product finalityProduct

Donation and operationscarried out for exclusivelydiagnostical purpose, collection and operations in the framework of a single intervention


Law on human biological materialBasic principles

● Donation and collection : informed consent

● Data protection, privacy and patients’ rights

● Unpaid donation

● No advertising

● Informed consent • Written

• Subject and purpose defined

• Always revocable (until first use after procurement)

• Donor must be informed of possibility of second use / opposition to it

● Collection on deceased persons : articles 10 to 14 of the Law of 13 June 1986 on transplantation apply


Law on human biological materialNew Belgian legal framework (2)Numerous provisions of the Law required implementing measures, laid down in Royal Decrees

5 Royals Decrees of 28 September 2009

2 Ministerial decrees : price of human biological material + appointmentof Minister’s delegate

No RD yet (maybeamendments to Law

Biobanks

Regime applicable to gametes, gonades, fragments of gonades, embryosand fœtal human corporal material

Notification of serious adverse reactions and events

Standards for hospitals

Quality and safety standards for the operations performed on humancorporal material 1 December 2009

(Publication 23 October 2009)

General requirements for banks for human corporal material, intermediary structures and production establishments

entry into force

01.12.2012 (withretroactive effect on samples collected as

from 01.02.2012

Cord blood storageNEWNEW


Scope of the Law vs. Scope of Directive 2004/23

In scope as far as the cells and/or tissues are meant for humanapplication

Always in scope

• Tissue establishments• Procurement organisation

• Banks for human biologicalmaterial• Intermediary structures• Production establishments • Biobanks

Only applies to the donation, procurement and testing of the cells and tissues intended for the manufacturing of products ruled by other Community legislations.

Autologous : standards of qualityand safety only related to (7, §4, 2) donation, procurement and testing.

Human cells and tissuesHuman biological material

Scientific research

Accreditedstructure(s)

Manufacturedproducts

Concerned material

Directive 2004/23Law

Allogeneic : standards of qualityand safety related to all phases/operations


Four types of structures under Belgian law


Law on human biological materialFour different structures

Bank for human biological material (BHM)

Intermediary structure (IS)

Production establishment (PE)

Biobanks (BB)

All structures must be accredited

BHM, IS and PE are subject to common requirements

BB are subject to a specific regime

Humanapplications

Scientificresearch


StructuresOperations subject to accreditation

**

Imp

ortation

and

exporation

collection

**

*

distribu

tion

***Intermediary structures

Human corporal banks

***Biobanks

********Production establishments

Hu

man

app

lication

storage

preservation

processin

g

testing

procu

remen

t

Human corporal material

Ruled by the provisions of the lawand/or its implementing provisions

Must be performed in a hospital

* : in cooperation with a bank** : only for the production of autologous ATMPs*** : also makes the material available. Only for

scientific research without human application


Law on human biological materialBank for human biological material (BHM)May be accredited to perform any operation

Managed by accredited hospital (Act of 7 August 1987)or National Defence Hospitalor Medical Science Faculty with Academic Hospital

Distinct legal entity

Not for profit organisation

Open issue : type of control on the structure : managed by hospitalonly? Public/private partnership possible ?

Depots Article 20 RD « standards »

● subdivision of a BHM that stores human biological material intended for human applications on the hospital site

● The BHM remains responsible for the compliance of the stored material


Law on human biological materialIntermediary structures (IS)

Public/private entity

May be accredited to perform the processing, preservation, storage and distribution

Compulsory cooperation with a bank (agreement required)

Structure can be used to produce allogeneic ATMPs


Law on human biological materialProduction establishment (PE)

Public/private entity

May be accredited to perform any operation (except testing) in the framework of the industrial manufacturing of autologousATMP

Not allogeneic ATMPs

Biological material can be transmitted directly to the PE aftercollection, without intervention of a BHM


Law on human biological materialRequirements common to BHM, IS and PE

Accreditation

● Prior inspection by the Agency

● Validity : maximum 4 years (+ inspection every 2 years)

● Procedure

● Dossier requirements

● EC opinion (EC as defined in the Law on experiments on humans)

Accreditation specifies type of material, type of operation(s) and for the PE : type(s) of ATMP

Manager needs to be a doctor with a special training

The same legal entity can be accredited as IS and PE

● Activites and management of both structures must however be distinct

Register


Law on human biological materialSecond use

Principle : donor must consent to any second use

● Explicit written consent to the person responsible in the establishment (not the doctor who made the collection)

Any kind of second use : advice Ethical Committee

Exceptions

● Scientific research : informed consent considered as given if no prior explicit opposition to second use (implied IC)

● Biobanks : EC opinion not required• EC opinion given in the framework of BB accreditation is sufficient

• Limit : second use must form part of the activities and finalities for which BB has been accredited


Law on human biological materialQuality standards for the operations performedon human biological material and traceability

QualityQuality system based on good practices and kept up-to-date, including atleast standard operating procedures, guidelines, handbooks, reportingforms, donor records and information on the final destination of the biological material

Quality standards in principle applicable to all operations

Specific to PE : human biological material intended for the preparation of medicinalproducts (vaccines, medical devices, ATMP,…) : standards are onlyapplicable to donation, collection, procurement and testing

TraceabilityUnivocal donor identification system (unique code allocatedto every donation)

Traceability must remain possible during 30 years (and maximum 50 years)

See also upcoming RD implementing Directive 2009/120


Law on human biological materialQuality and safety standards for the operationsperformed on human biological material

Collection of the human biological material

Performed by doctors, pharmacists, dental surgeons, nurses, midwives, labtechnicians, graduates in biological, chemical or biomedical sciences who have attended a specific training

Procedures and criteria are laid down for :Donor selection

Biological testing of the material

Procedure for the collection, procurement and reception of the material

Quality standards forManagement, equipment, buildings, documentation of the establishments

Processing of the material

Storage

The establishments are responsible for the quality of the material during the distribution of it


Biobanks and scientific research



● Public/private entity

● May be accredited to store human biological material and to make it available exclusively for scientific research withouthuman application

● Subject to a specific regime still to be defined• Initially a Royal Decree would define it

• It seems the specific regime will be included in the Law itself (by end 2012 or mid 2013)



● Any research activity (with or without human application) implying human biological material is subject to the provisions of the Law

● Legal restrictions applicable to scientific research:• Prohibition of any use of the material without a prior favourable

opinion of an EC unless the intended use is part of the activitieswherefore the biobank had been approved by an EC (part of the « notification/accreditation » process

• Import and export of human biological material by a biobank : prohibited if biobank has not been notified on beforehand, and approved for such activities


Hot topics

Different regime for allogeneic and autologous ATMP● PE are independent from BHM whereas IS are not● Manufacturing autologous ATMP can take place without intervention of a

BHM : direct transfer of biological material to the PE after collection● Manufacturing allogeneic ATMP subject to a heavier burden, a.o. prior

agreement with BHM● Ethical issues and interest of public research

Article 7, § 4 of the Law provides that the quality standards withwhich PE must comply only concern the donation, collection, testingand procurement of the human biological material● The same rule does not apply to IS● This means IS are subject to the quality standards laid down by application

of the Law for every operation


Extent and scope of the informed consent when material collectedfor diagnostical/treatment purposes is further used for scientificresearch

● There is an « implicit consent » provided for the second use of residual material collected in compliance with the law

• Residual material is the part of the human biological material that has been collected for diagnostical or treatment purposes for the donor and that, after a sufficient and relevant part has been preservedfor the diagnostic itself or the treatment as such on grounds of new scientific data, is redundant as to these objectives, and couldtherefore be destroyed.

Hot topics


Section 3 – GMOs


GMOs

Genetic modification is also known as "genetic engineering” or “recombinant-DNA technology”

● Purpose : introduce novel traits to micro-organisms, plants and animals

GMOs = organisms in which the genetic material (DNA) has been altered in a way that does not occur naturally by mating or natural recombination.

● Most common types of GMOs that have been developed and commercialised= genetically modified crop plant species

Highly regulated : a GMO or a GM food or feed product can only be put on the market in the EU after it has been authorised on the basis of a detailed procedure, based on a scientific assessment of the risks to health and the environment


Use of GMOs

GMOs can serve various purposes● Feed, Food, Textile industry, …

Some areas subject to Health, Environmental as well as Ethicalconcerns

Where GMOs are used for food or feed, specific rules apply thataim at ensuring● high level of protection of human life and health

• safety assessment

● promoting the right of consumers to information • specific labelling requirements


Examples

Examples of genetically modified crop plant species

● Genetically modified maize, soybean, oil-seed rape and cotton varieties

Examples of purpose of genetic modification

● Resistance to certain insect pests

● Tolerance to herbicides

● Modifications of taste, shape or color

● Better yield


Deliberate release(experimental)

The timeline of a GM crop species : an overview

Containeduse

R&D

Directive 2009/41/EC Directive 2001/18/EC Regulations 1829/2003

and 1830/2003Directive 2001/18/EC

Authorization atnational level +information to

EU Commission and other MS

Authorization atnational level +

reinforcedinformation to


Application with national authorities,

then EFSA (assessment) + EU

Commission (authorisation + risk

management




Phase

Decisionlevel

Relevant EU legislation

1 2 3 4Deliberate release Marketing

Exposure/ risk level

LowHigher

Higher

Highest


First phase : « Contained use » (1)

Contained use = any activity in which micro-organisms are genetically modified or in which such GMMs are cultured, stored, transported, destroyed, disposed of or used in any other way, and for which specific containment measures are used to limit their contact with, and to provide a high level of safety for, the general population and the environment (Directive 2009/41/EC).

Also applies to GMOs in general, although Directive 2009/41/EC only refers to GMMs explicitly


First phase : « Contained use » (2)

First step of the R&D process (research phase, in laboratories)

Risk of contamination is low, except in case of « accident » (as defined in Directive 2009/41/EC)

Regulatory requirements relatively flexible but some obligations must be complied with:

● User of GMO evaluates the contained use as to the risksinvolved > classes 1 to 4 : level of containment

● Evaluation dossier is submitted to (national) competentauthority

● An emergency plan must be put in place by the user


Second and third phases : « Deliberate release » (1)

« any intentional introduction into the environment of a GMO or a combination of GMOs for which no specific containment measures are used to limit their contact with and to provide a high level of safety for the general population and the environment »

● For any other purpose than for placing on the market

● Experimental or not

Subject to an authorization procedure

● Standard procedure (directive 2001/18/EC, article 6)

● Differentiated procedures (directive 2001/18/EC, article 7)

● Simplified procedures (commission decision 94/730/EC)



Standard procedure : notification including: ● Technical dossier (contents : Annex III of Directive 2001/18/EC)

providing notably:• general information including information on personnel and training,• information relating to the GMO(s),• information relating to the conditions of release and the potential receiving

environment,• information on the interactions between the GMO(s) and the environment,• a plan for monitoring in accordance with the relevant parts of Annex III in order to

identify effects of the GMO(s) on human health or the environment,• information on control, remediation methods, waste treatment and emergency

response plans,• a summary of the dossier;

● Environmental risk assessment and the conclusions required in Annex II, section D + any bibliographic reference and indications of the methods used


Second and third phases : « Deliberate release » (3)Follow-up of standard procedure

● Decision within 90 days –can be suspended:• if missing info (suspension until provision of missing info –no

deadline)

• if public inquiry or consultation (maximum extension: 30 days)

● Exchange of info between competent authorities, through the Commission – observations from other MS

● Written decision allowing or rejecting the release, possiblysetting specific conditions

● Continued update of info by notifier, during and/or afterdecision

● After completion of release : reporting by notifier



Differentiated procedures

● Two conditions :• sufficient experience has been obtained of releases of certain

GMOs in certain ecosystems

• concerned GMOs meet the criteria set out in Annex V of Directive 2001/18/EC

● If both conditions are met : reasoned proposal for the application of differentiated procedures from the competentnational authority to the Commission


Second and third phases : « Deliberate release » (5)Follow-up of differentiated procedures

● 30 days after receipt of proposal, Commission :• Transmits proposal to other competent authorities > observations

• Make the proposal available to the public > comments

• Consults Scientific committee > opinion

● Decision on the proposal within 90 days (same possibilities of suspension

as in standard procedure) (in accordance with article 30, § 2 of Directive 2001/18/EC)

• establishes the minimum amount of technical information from Annex III necessary for evaluating any foreseeable risks from the release, in particular:

- information relating to the GMO(s);

- information relating to the conditions of release and the potential receiving environment;

- information on the interactions between the GMO(s) and the environment;

- the environmental risk assessment.

● Written decision allowing or rejecting the release, possibly setting specificconditions

● Continued update of info by notifier, during and/or after decision

● After completion of release : reporting by notifier

Reaction (if any) within 60 days



Simplified procedures (Commission Decision of 4 November 1994 establishing simplified procedures concerning the deliberate release into the environment of genetically modified plants pursuant to Article 6.5 of Council Directive 90/220/EEC)

● Simplified procedure = single notification dossier to be submitted for more than one release of GM plants which have resulted from the same recipient crop plant species but which may differ in any of the inserted/deleted sequences or have the same inserted/deleted sequence but differ in phenotypes.

● Notifier can submit in a single notification information on several releases of GM crop plants, to be released on several different sites, on conditions described in Annex to Decision 94/730


Fourth phase:« Placing on the market » (1)“placing on the market" = holding of food or feed for the purpose of sale, including offering for sale, or any other form of transfer, whether free of charge or not, and the sale, distribution and other forms of transfer themselves.

Regulation 1829/2003 provides for a single authorisation procedure for food products containing GMOs:

- application in accordance with the Regulation for all food products containing GMOs that comply with the provisions provided for by Directive 2001/18

- single application for food and feed uses and for cultivation : a GMO which is authorised can be used not only in food and animal feed but also for cultivation or deliberate release into the environment.

MA is renewable for 10-year periods

The granting of authorisation does not lessen the general civil and criminal liability of any food operator in respect of the food concerned

Authorisation procedure in a nutshell : Application

with national authorities

EFSAassessment

6 monthsEU Commission draft decision

Standing Committeeon the Food Chain and Animal Health

Approval draft decision

Rejection draft decision Council of Ministers3 months

decision

no decision

3 months

Final decision by Commission

Final decision by Commission


Deliberate release(experimental)

The timeline of a GM food product : an overview

Containeduse

R&D

Directive 2009/41/EC Directive 2001/18/EC Directive 2001/18/EC

+ Regulations 1829/2003and 1830/2003

Directive 2001/18/EC + Regulations 1829/2003

and 1830/2003

Authorization atnational level +information to





Authorization atEU level (EFSA)

Authorization atEU level (EFSA)

Phase

Decisionlevel

Relevant EU legislation

1 2 3 4Deliberate release Marketing

Exposure/ risk level

LowHigher

Higher

Highest


Specificities of the framework applicableto GM food (1)GM foods can only be authorised in the EU if they have passed a rigorous safety assessment.

Procedures for evaluation and authorisation of GM foods

● Regulation 1829/2003 on GM food and feed

● Directive 2001/18/EC on the release of GMOs into the environment

Authorisation is applied for in the MS, and granted by the European Commission, with the support of the EFSA

GMO Panel of the EFSA carries out assessments

● Panel composed of independent scientific experts supported by a number of specialised Working Groups drawing on a pool of more than 40 external experts in fields such as allergenicity, ecology, microbiology, toxicology, plant physiology and molecular genetics

● Independence of the experts guaranteed through policy on declaration of interests (experts have to declare any potential conflicting interests in advance of each meeting)


Specificities of the framework applicableto GM food (2)

EFSA GMO Panel assessment

● are based on scientific dossiers presented by applicants and any other relevant scientific information;

● aims to ensure its evaluations meet the highest scientific standards, which is reflected in the GMO Panel guidance, which describes the data applicants must include in their application dossiers, including all the necessary studies on human and animal safety and on environmental impact (http://www.efsa.europa.eu/en/gmo/gmoguidance.htm)

www.efsa.europa.eu/en/gmo/gmoguidance.htm

http://www.efsa.europa.eu/en/gmo/gmoguidance.htm


Specificities of the framework applicableto GM food (4) - Labelling requirements (articles 12 to 14 of Regulation 1829/2003)Specific labelling requirements (in addition to the other requirements of Community law concerning the labelling of foodstuffs):● if list of ingredients:

• more than one ingredient : words ‘genetically modified’ or ‘produced from genetically modified (name of the ingredient)’ in parentheses immediately following the ingredient concerned;

• ingredient designated by the name of a category: words ‘contains genetically modified (name of organism)’ or ‘contains (name of ingredient) produced from genetically modified (name of organism)’;

• the indications may appear in a footnote to the list of ingredients, if printed in a font of at least the same size as the list of ingredients.;

● if no list of ingredients : words ‘genetically modified’ or ‘produced from genetically modified (name of organism)’ on the labelling;

● Special rule : food offered for sale to the final consumer as non-pre-packaged food, or as pre-packaged food in small containers of which the largest surface has an area of less than 10 cm2: the information required must be displayed either on the food display or immediately next to it, or on the packaging material, in a font sufficiently large for it to be easily identified and read.


Specificities of the framework applicableto GM food (4) - Labelling requirements (articles 12 to 14 of Regulation 1829/2003)

In specific cases, labelling must also mention any characteristic or property, as specified in the authorisation :● where a food is different from its conventional counterpart as regards

composition, nutritional value or nutritional effects, intended use of the food and/or implications for the health of certain sections of the population;

● where a food may give rise to ethical or religious concerns.

Labelling of foods which do not have a conventional counterpartmust contain appropriate information about the nature and the characteristics of the foods concerned.


Currently authorised GMOs

EU Register of GM food and feed : http://ec.europa.eu/food/dyna/gm_register/index_en.cfm

Currently around 50 authorised GM food and/or feed :

● 26 types of GM maize,

● 8 types of GM cotton,

● 7 types of GM soybeans,

● 2 types of GM oilseed rape,

● 1 type of GM starch potato,

● 1 type of GM sugar beet.

● 1 type of Swede-rape (koolzaad)

● 2 microorganisms (bacterial proteins and yeast)

http://ec.europa.eu/food/dyna/gm_register/index_en.cfm


Controversy and scientific criticism towardsGMO: the recent case of Biologist Seralini● Pictures of rats with impressive

tumors have gone around the world in no time

● Study published in "Food and Chemical Toxicology“, August 2012

● Publication of a study denouncing long term toxicity of Roundup (herbicide) and a GM type of maize (Roundup tolerant)


Controversy and scientific criticism towardsGMO: the recent case of Biologist Seralini

● Controversy grew as no scientific consensus can be found around the methodology of the Biologist

• choice of the rats species

• attitude towards press : sensationalism, search for immediate release of the (shocking) information, study immediately communicated to mass media, etc.

● Difficulty to evaluate the ethics and independence of the Biologist(well-known for anti GMo positions) vs. powerful lobby from GM producers

• Industry also carries out tests and uses them to support inocuity of GMO

• precautionary principle vs. profit?

Thank youMarc Martens

Avenue Louise 235 /1 Louizalaan

1050 Brussels

[email protected]

Bird & Bird is an international legal practice comprising Bird & Bird LLP and its affiliated businesses. www.twobirds.com

www.twobirds.com

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