1

Is the European medical products authorization regulation equipped to cope

with the challenges of nanomedicines?

BÄRBEL DORBECK-JUNG and NUPUR CHOWDHIRY

This article analyses the emerging European regulatory activities in relation to

nanopharmaceuticals. The central question is whether the regulatory responses

are appropriate to cope with the regulatory problems nanomedicinal development

is posing. The article explores whether the medical product regulations are robust

enough, whether there are certain regulatory gaps, and whether the competent

bodies have the expertise to evaluate nanomedicinal products when approval is

applied for. Based on a social-constructive approach the article identifies signifi-

cant regulatory actors, their ideas on regulatory problems and preliminary gov-

ernance responses to them. It finds that the current dynamic regulatory structure

seems robust enough to adapt to some of the technological challenges that are be-

ing posed by nanomedicines. It concludes that regulators have not yet responded

adequately to regulatory gaps related to definitions, classification and specific

safety, quality and efficacy standards nanopharmaceutical development seems to

require. As a consequence of these deficiencies legal certainty, a principle that

has a high priority in European medical regulation policy, cannot be provided

sufficiently.

INTRODUCTION

Nanomedicines1 have been on the market for more than 17 years. In the past,

nanodrugs have been treated as ordinary products in the marketing process. Since

some years awareness about particular regulatory questions and problems are

2

emerging. At present, many of the relevant stakeholders including the competent

authorities, pharmaceutical companies, pharmacists and other scientists, as well as

bodies like the International Standards Organisation (ISO), the European Scien-

tific Committee on Emerging and Newly Identified Health Risks (SCENIHR), and

the European Group on Ethics in Science and New Technologies (EPE) are ad-

dressing various kinds of regulatory issues. Some of them have questioned the ap-

propriateness of the existing regulations to provide for the safety, quality and effi-

cacy of nanodrugs because of new product properties, new modes of action and

unknown toxicity (Gaspar and Duncan 2009; Dorbeck-Jung 2009; Linkov et al.

2008; Sanhai et al. 2008; Gaspar 2007; Chan 2006; Wilson 2006; Kagan et al.

2005; Mehta 2004). Following are some of the recurrent questions that have

emerged within these regulatory debates: Are the medical product regulations ro-

bust enough to cope with the challenges of nanomedicines or do we need a new

regulatory regime? Are there certain regulatory gaps? Have regulatory bodies re-

spond adequately to address the regulatory problems? Do the competent bodies

have the expertise to evaluate nanomedicinal products when approval is applied

for?

This article aims to explore answers to these questions. It analyses the emerg-

ing European governance structure that is shaping the approval of nanomedicinal

products for human use. The main research question is whether the European me-

dicinal products authorisation regulation is equipped to cope with the regulatory

challenges of nanomedicines. The inquiry attempts to provide insights into how

existing regulation is applied, whether regulatory problems (including regulatory

gaps) are encountered in regulatory practice and how governance responses are

emerging. The analysis explores whether the current governance responses are

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appropriate in the face of the regulatory challenges and problems that were identi-

fied before. Since the European medicinal product regulations regime seems to

exert an influence on the other regulatory regimes of the medical technology ap-

plications (Kent et al. 2006; Altenstetter and Permanand 2006; Altenstetter 2003) 2

the regulatory responses to nanopharmaceuticals may indicate the general direc-

tion in which the nanomedical products regulation will develop. Considering the

increasing trend towards exploring international collaborative responses to drug

regulation (EMA 2010; Valverde 2007; Vogel 2001) this article can provide les-

sons for how to regulate promising, but potentially risky new technologies.

The exploration of the robustness of the European medical products authori-

zation regulation is based on an analysis of the regulatory problems nanomedici-

nes are posing and the governance responses that they have evoked so far. The ar-

ticle is organised into four sections. First, we give an overview of nanomedicinal

development, potential benefits and regulatory challenges. Second, we outline the

theoretical framework for the analysis of regulatory problems and governance re-

sponses. Third, we describe the relevant EU regulatory framework. In the fourth

section regulatory problems and emerging governance responses will be identified

and analysed. The analysis leads to tentative conclusions on whether the current

European pharmaceutical regime is equipped to address the development of

nanomedicines.

The description of regulatory structures, challenges, problems and responses is

based on literature, legal documents, policy documents and interviews with regu-

latory actors. All regulatory actors we interviewed are key representatives of a

company, regulatory bodies or scientific advisory bodies. In this context ‘key’

means that the respondent has been involved in the marketing of nanomedicines or

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in the consultation on nanomedicinal regulation. We interviewed 3 representatives

of pharmaceutical companies that have marketed nanomedicines. Interviews were

also held with two representatives of the European Medicines Agency (EMA),

representatives of three national medicines evaluation bodies, one representative

of the SCENIHR, one representative of the EPE, one representative of the ETP

platform on nanomedicine and one representative of the of N&ET Working

Group3. Below, we will refer to them as representatives of companies, the EMA,

national medicines evaluation bodies, the EGE, the SCENIHR and the N&ET.

NANOMEDICAL DEVELOPMENT, POTENTIAL BENEFITS AND REGU-

LATORY CHALLENGES

NANOMEDICAL DEVELOPMENT

Nanopharmaceuticals are part of the therapeutics area of nanomedicine which is

divided into “nanopharmaceuticals” and “nano-enabled devices”. 4 Other areas

include surgery, diagnostic (including imaging), implant technology, bionics, bio-

active surfaces, tissue engineering, textiles and actuators. Nanopharmaceuticals re-

fer to innovation in drug delivery and medicines based on the use of nanoparticles

of the active ingredient. Nanoparticles can also be used as a carrier material or po-

rous material from which the active ingredient is released in a controlled manner.

Cancer, Parkinson and Alzheimer are diseases in which products are being devel-

oped.5 Nanomedicines have been on the market for more than 17 years. A survey

stated in 2006 that there were 23 nanoscale drug-delivery systems which had al-

ready been launched in the market (Wagner et al. 2006: 1214-15). To date, 10

nanodrugs have come through the centralized authorization procedure overseen by

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the EMA.6 Since there are no statistics available on approvals of nanopharmaceu-

ticals that have come through the mutual recognition procedure the total number

of European authorizations is unclear. In the case of the United States, reports7

have suggested that the number of nanomedicines authorizations by the American

Food and Drugs Authority (FDA) stand between 12 to 18 and that there are sev-

eral new products in the pipeline that will be launched in the near future. The FDA

also identified drug delivery and in vivo imaging as the most active areas.8 In the

field of drug delivery dozens of products are in development. Estimates indicate

that by 2015 about half the drug delivery systems will be based on nanotechnol-

ogy (Zijverden et al. 2008:43). In the next decade breakthroughs are also expected

in the development of nanodrugs (e.g. activation of a nanomedicine using an ex-

ternal medical device) and the targeting of drugs to facilitate cell differentiation.9

Upcoming products are said to display distinct characteristics like complexity of

clinical use, multifunctionality, as well as integration of different areas of

nanomedicine and technology subsets from drugs to medical devices and human

material (‘combined products’).

POTENTIAL BENEFITS

Nanopharmaceuticals are currently regarded as the most promising field of

nanomedicine. According to influential commentators (Zijverden et al. 2008: 41)

the great strength of nanomedicines lies in the controlled release system. The ef-

fectiveness of the drug can be increased by the modification of the surface of

nanoparticles. Nanodrugs are expected to make a positive contribution to the pre-

vention, diagnosis and treatment of diseases such as cancer, infections, auto-

immune diseases and inflammations. They may also be suitable to treat diseases

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which at present can only be treated with drugs that have many adverse effects. It

is expected that nanomedicines have less adverse effects because the drug can be

more accurately targeted at its destination and because a reduced amount of the

drug will have to be administered.

REGULATORY CHALLENGES

Nanotechnologies question the appropriateness of the existing regulatory frame-

works and the space they leave to tailor rule implementation to new technological

and product development. These technologies put pressures on the capacity of

regulators to keep pace with developments of (nanomedical) science, new applica-

tions and risk assessment. They pose challenges to the expertise of regulators and

their ability to balance technological benefits against risks. Nanotechnologies re-

quire prudential regulators that are able to facilitate responsible development and

to gain trust of stakeholders (including the public).10 Regulatory challenges are in-

duced by a large range of technological, scientific, normative, conceptual and in-

stitutional uncertainties. There is insufficient knowledge about the paths of tech-

nological developments and the characteristics and behaviour of nanomaterials,

including data on exposure and hazards (NIOSH 2009; RCEP 2008; Zijverden et

al. 2008; SCENIHR 2007). Knowledge gaps about product formulations and

nanoparticles concentration raises questions about the applicability of European

regulations on the Registration, Evaluation, Authorization and Restriction of

Chemicals (REACH, see Hansen 2009: 22; Chaundhry et al. 2006). In this context

a conceptual question is whether nanoparticles are considered as ‘new substances’

to which the requirements of REACH apply. Uncertain and ambiguous risk prob-

lems of nanotechnologies (IRGC 2006) raise questions on whether regulators can

7

wait until there is more knowledge or whether they must respond promptly. Ac-

cording to the precautionary principle the European Commission adopted in 2000

(EC 2000) scientific uncertainty about technological risks is no reason for inaction

if there might be immense adverse effects. Particular regulatory challenges are

posed by conflicting norms and values that play a role in the perception and inter-

pretation of ‘immense adverse effects’, as well as in the decisions on risk-benefit

balances, on how to gain public trust and acceptance of regulation (Everson and

Vos 2009; Vos 2004). Institutional uncertainties refer to knowledge gaps on the

costs and the effectiveness of increasingly dynamic and fragmented multi-level

and multi-actor regulation (Rothstein 2009: 70; Hood et al. 2001).

Analyses of the scientific committees of the EU, its member states, the United

States and the OECD have concluded that there are still many knowledge gaps

about the risks of nanomaterials to humans and the environment. Knowledge gaps

in relation to the toxicological aspects of nanomaterials (particularly free, non-

degradable and insoluble nanoparticles) and their implications for health and envi-

ronment pose crucial challenges to safety regulation. To date, toxicological studies

have indicated that free nanoparticles might penetrate through blood and brain

barriers, or remain lodged in capillaries (Poland et al. 2008). These particles could

also have an impact on the immune system and be consumed by macrophages.

Another challenge is related to uncertainties about the biocompatibility of medical

products/materials in which nanoparticles have been used (Zijverden et al. 2008:

47). The toxicological risks of nanoparticles depend on material properties, expo-

sure route and dose (Geertsma et al. 2007). When nanoparticles are fixed in or on

a device health risks are indicated only if they are released due to, for example, a

chemical reaction. According to influential accounts the risks of the use of

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nanomedicines could, among other things, lie in a different distribution of the par-

ticles in the body compared to medicines not in a nano form (Zijverden et al.

2008: 46). Further toxicological risks of nanomedicines are as yet unknown (Jong

and Borm 2008).

ANALYTICAL FRAMEWORK: BASIC CONCEPTS OF SOCIAL CON-

STRUCTIVISM

Our analysis of regulatory problems and emerging regulatory responses refers to

basic concepts of social constructivism.11 This approach views regulation as a

‘project under construction’ which evolves on the basis of collectively meaningful

structures and processes. It offers a broad framework for the analysis of emerging

regulation. 12 Social-constructivist inquiry includes all actors at all regulatory lev-

els and all activities that exert influence in regulatory practice to achieve certain

policy goals. 13 It includes legal rules (‘hard law’) and rules that do no not have le-

gally binding force, but which nevertheless have effects in legal practice (‘soft

law’, see Senden 2004). It draws the attention not only to the regulatory activities

of standard-setting, implementation, oversight and enforcement (Scott 2002), but

also to preliminary activities of organised reflection on potential regulatory re-

sponses.

The version of social constructivism we are relying on refers to Giddens’ ac-

count of social structure functioning as both as a medium for, and an outcome of

the practices it repeatedly organises (Giddens 1984: 25; Berger 1991). By interact-

ing in daily practice actors are collaboratively creating, reproducing and modify-

ing rules, values and principles. Social structure is therefore seen as dynamic and

9

as both constraining and enabling in turns while co-evolving. Another basic as-

sumption of the socio-legal version of social constructivism is that rules are evolv-

ing in reflexive processes of learning based on intersubjective knowledge, ideas,

beliefs, and a ‘logic of appropriateness’ whereby actors try to figure out the ap-

propriate rule for a given situation (Trubek et al. 2006: 72). Rules are regarded as

being shaped by interactions among actors in the context of power relations where

influence and change build on certain pressures. Regulatory actors are recognised

as significant when they exert influence on regulatory activities. This means that

significant regulatory actors can involve legally mandated actors, but also other

actors that are influential in regulatory practice. This broad view is captured in the

language of governance which is used to explain a range of processes and prac-

tices that have a normative dimension but do not operate primarily through formal

hierarchic mechanisms of traditional command-and-control legal institutions (De

Búrca and Scott 2006:2).

According to the social constructivist approach basic concepts of our analysis

are: the regulatory structure (rules and significant regulatory actors) related to the

authorization of nanopharmaceuticals; the ideas and beliefs of regulatory actors in

relation to regulatory problems induced by nanomedicinal applications and their

interactions to ‘reproduce’ and to ‘produce’ new regulation (‘governance re-

sponses’). In this inquiry governance responses focus mainly on preliminary pol-

icy-making activities related to regulatory standard-setting and implementation

(amongst which research and discussion). By ‘significant regulatory actors’ we

refer to institutional players and stakeholder groups14 that exert influence on the

regulatory activities in relation to the authorization of nanomedicines. The signifi-

cance of these actors lies not only in their actual influence on the regulatory proc-

10

ess but also in their position and therefore their ability to influence debates and

discussions on this issue in the future. Given the explorative character of this in-

vestigation we attempt to find indications for the (potential) significance of certain

regulatory actors. Indicators are found in how these actors are participating in

regulation (highly active, moderately active, marginally active and dormant/at

present non-active), whether their regulatory activities are recognized and whether

regulatory advice is followed. Herein it is also important to note that some regula-

tory actors will play a direct role in terms of shaping regulation while the influ-

ence of others is indirect. This is the case, for example, with scientific bodies (‘in-

direct regulatory actors’) whose scientific inputs will provide the basis for regula-

tory decisions. However the nature, scope and coverage of any new regula-

tion/guidance will have to be negotiated between the regulatory agencies and

other stakeholders like manufacturers and patient groups that will play a more di-

rect role in negotiating regulatory policy decisions in the case of nanomedicines in

Europe.

EUROPEAN REGULATORY STRUCTURE ON THE APPROVAL OF

NANOMEDICINES: RULES AND SIGNIFICANT ACTORS

DEVELOPMENT OF THE REGULATORY STRUCTURE

The general EU pharmaceuticals regime under which nanomedicines may fall is a

well-established, dynamic and complex system of multi-level regulation (Dor-

beck-Jung and Oude Vrielink 2007; Feick; 2005; Broscheid and Feick 2005; Feick

2002; Abraham and Lewis 2000; Vogel 2001; Hart and Reich 1990). It is com-

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posed of European and national legislation which is accompanied by a large body

of soft law.15 Compared to the drugs regulation the European medical devices

regulation provides more room for private authorization bodies and private stan-

dards. Its implementation has been widely delegated to industry and national gov-

ernments (Hanson 2005; Altenstetter 2003; Altenstetter and Permanand 2006).

Drug disasters of the late 1950s like the thalidomide crisis gave rise to Euro-

pean regulations which have been launched in the 1960’s to ensure a high level of

public health protection in terms of safety, efficacy and quality. In 1993, funda-

mental institutional changes were initiated through two new authorization proce-

dures (‘centralised procedure’ and ‘mutual recognition procedure’) that replaced

the existing procedures.16 In the opinion of the Commission this was necessary to

create a centralised authorization that is compulsory for high-technology medici-

nal products, particularly those resulting from biotechnological processes, in order

to maintain the high level of scientific evaluation of these products in the EU. In

1993, a European agency for the evaluation of medicinal products was estab-

lished. Eleven years later new legislation was laid down and existing legislation

was amended.17 With regard to nanomedicines a relevant change is that Regula-

tion 726/2004 which enlarged the scope of the centralised procedure to new active

substances for four medical indications.18 Another important revision was the in-

clusion of manufactured cell therapy products with a pharmacological mode of ac-

tion into to the scope of the Medicinal Products Directive.19 According to Direc-

tive 2004/27/EC the applicant is required to provide an evaluation of the potential

environmental risks posed by the medicinal product and to limit them by specific

arrangements.20 Potential environmental impact, however, it is not a criterion for

the rejection of an approval application.21 Responding to developments of bio-

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medicine (such as gene therapy, somatic cell therapy, and tissue engineering)

Regulation 1394/2007/EC on advanced therapies medicinal products (ATMPs)

was launched in 2007. This Regulation established the Committee on Advanced

Therapies (usually referred to the acronym CAT) which is consulted in the au-

thorization process.22 Other specific regulatory carveouts include Medicinal Prod-

ucts for Paediatric Use23 and for Orphan Medicinal Products.24

RULES GOVERNING NANOMEDICINES

To date, in the EU no specific rules have been established with regard to

nanomedicines. Thus the current regime as it stands is applicable to the market au-

thorization of nanodrugs as well. The approval follows either the centralised or the

mutual recognition procedures laid down in the medicinal product regulation.

Nanopharmaceuticals that are qualified as advanced therapy medicinal products

can be approved only by the centralised procedure. To nanomedicinal products

that combine medical devices and medicinal products (‘borderline products’) pro-

visions of the EU medical devices Directives may apply. The application of the

regulatory regime depends whether the product falls within the definitions of me-

dicinal products25, ATMPs26 or medical devices27. The primary mode of action is

the criteria for determining the applicable regulatory regime. This means, for ex-

ample, that nanomedicines with a primary mechanical action and secondary

pharmacological action are brought under the medical devices regulation regime.

In this regime approval is granted by a notified body appointed by a member state

on the basis of conformity assessment and certification.28 With regard to

nanomedicinal applications that combine advanced therapies medicinal products

with devices, however, the centralised procedure is mandatory. 29 In this case the

13

EMA is required to take the notified body’s opinion as to the conformity to the

safety requirements for the device part of the product into account. Market au-

thorization depends on a positive outcome of the risk-benefit balance. 30 In this

context the applicant must demonstrate sufficiently the product’s safety, quality

and efficacy on the basis of a large set of objective scientific data. It is required

that the scientific evaluation of applications is based on the highest level of exper-

tise and the highest possible standards. Another set of general conditions refers to

the three benchmarking guidelines for good clinical practice in the conduct of

clinical trials for medicinal products,31 good manufacturing practice for both me-

dicinal products32 and investigational medical products and good clinical practice

regarding investigational medicinal products.33 Apart from these two sets of gen-

eral conditions that will horizontally apply to all medicinal products, there are two

sets of additional conditions that vertically crown the general conditions. The first

set of additional conditions is with reference to specific regulatory carveouts for

ATMPS, paediatric and orphan medicinal products. The second set of additional

conditions relates those medicinal products that use or include specific substances

like GMOs (genetically modified organisms), human blood and plasma and hu-

man tissues and cells. Thus if the medicinal product is either an ATMP, paediatric

or orphan or uses specific substances (viz. human blood and plasma, GMOs or

human tissues and cells) then it will have to conform to the applicable set of rules

in addition to those discussed under ‘general conditions’.

Figure I provides an overview of the applicable rules that regulate the marketing

approval of various types of nanomedicines (‘pure’ pharmaceuticals and combina-

tion products).

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Figure I: Overview of applicable rules governing the marketing approval of types of nanomedicines

COMBINATION PRODUCTS (Conflict Rules under Directive 90/385/EEC as amended by Directive 2007/47/EC)

- AIMD administering MPs (Each part separate evaluation- under Directive 2001/83/EC and Directive 90/385/EEC)

- MPs incorporated as integral part of device/AIMD (Directive 90/385/EEC)

MEDICAL DEVICES (MDs) - Active Implantable MDs (Directive 90/385/EEC) - MDs (Directive 93/42/EEC) - In Vitro MDs (Directive 98/79/EC)

MEDICINAL PRODUCTS (MPs) I GENERAL CONDITIONS (GC) Marketing Authorization Conditions:

1. 2001/83/EC (Mutual Recognition Directive - optional) 2. EC/726/2004 (Centralized Procedure Regulation –mandatory

and optional) Principles and Guidelines

1. Good Clinical Practice – clinical trials of MPs (Directive 2001/20/EC)

2. Good Manufacturing Practice for MPs (Directive 2003/94/EC) 3. Good Clinical Practice – investigational MPs (Directive

2005/28/EC)

II ADDITIONAL CONDITIONS (GC+) Specific Product Regulations (Implies Additional Conditions)

1. Advanced Therapy MPs ( Regulation EC/1394/2007) 2. MPs for Paediatric Use (Regulation EC/1901/2006) 3. Orphan MPs (Regulation EC/141/2000)

Specific Substances Directives (Implies Additional Conditions) 1. GMOs (Specific provisions under Dir. 2001/83EC) 2. Human Blood and Plasma (Directive 2002/98/EC) 3. Human Tissue and Cells (Directive 2004/23/EC)

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SIGINIFICANT REGULATORY ACTORS

To provide explorative indications of the influence regulatory actors are exerting

in the regulatory process of nanomedicines we distinguished between highly ac-

tive, moderately active, marginally active and dormant actors. These actors oper-

ate at multiple levels i.e. at the EU member state (national), the European level

(regional) and the international level. However, according to our empirical re-

search, the influence regulatory actors are exerting on the regulation of nanomedi-

cines does not depend on the regulatory level but rather on their functional rela-

tion with regulation. According to the functionalities we observed in the arena of

nanomedical product regulation the regulatory actors are divided into five groups,

viz. regulatory bodies, manufacturers of nanomedicines and their associations, us-

ers associations, advisory bodies and other regulatory bodies.34 The first three

groups are directly involved in the EU regulation on nanomedicines, while the last

two groups’ influence is rather indirect. Figure II identifies certain actors as criti-

cal in terms of the scale of their influence on emerging regulation.

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Figure II: Significant Actors in the context of Nanomedicine Regulation in the EU

Dormant

Marginally active

Moderately active

Highly active

Other Regulatory Bodies - ISO - OECD - ICH - WHO

EU Regulatory Bodies - EMEA - Competent Authorities

of Member states - Notified Bodies - European Commission

(Health & Consumers) - European Parliament

and Council - EDQM

Advisory Bodies - N&ET - SCENIHR - EGE

Manufacturers - Big Pharma - SMEs - ETP

Users Associations - Doctors Associa-

tions - Patient Associa-

tions

17

The group of regulatory bodies includes the European Medicines Agency, the

competent authorities of the member states, the notified bodies, the European

Commission (with DG Health and Consumers at the operative level), the Euro-

pean Parliament and Council, the European Directorate for the Quality of Medi-

cines and Health Care (EDQM35). In the past years the EMA has employed only a

few regulatory activities with regard to nanomedicines. Since this Agency cur-

rently is more actively organising and participating in regulatory workshops it is

characterised as a moderately active regulatory actor. According to our interviews

the competent authorities of the member states have taken minimal regulatory ac-

tion to respond to nanomedicinal development. A few of them have held internal

debates, have established a working group or informally contacted the EMA about

the topic. This is why we regard them as marginally active. Notified bodies on the

other hand have been dormant in these debates. However, given that the majority

of next generation nanomedicines will be combination products, notified bodies

are expected to play an important role not only in downstream regulatory imple-

mentation but also in shaping upstream debate on the scope and nature of regula-

tory guidance required for such combination products that include medical de-

vices. In contrast, DG Health and Consumers is characterised as moderately ac-

tive, because it has periodically organised workshops on nanotechnologies (in-

cluding nanomedicine). It is providing funding to various research activities re-

lated to the regulation of nanomedicine. Since the European Parliament36 and

Council, the EDQM have not yet been involved in any regulatory activities on

nanomedicine we characterise them as dormant.

18

The group of manufacturers includes large, medium and small (pharmaceuti-

cal) companies and their associations. According to our interviews large compa-

nies have been moderately active in contacting the national competent bodies and

the EMA on regulatory issues around nanomedicines. However regulatory activi-

ties by small and medium enterprises (SME’s) on this issue were limited. Pharma-

ceutical companies are exerting influence through the European Technology Plat-

form (ETP) on Nanomedicine, which is active with road mapping nanomedicinal

development and has taken up regulatory policy issues for discussion internally.

Regarding the high participation of companies within the ETP and the Platform’s

pro-active stance in coordination activities it can be expected that the ETP will

support a more active participation of the private sector on regulatory policy is-

sues in the future. At present, it is still marginally active.

The group of users is formed by the organisations of doctors and patients.

Doctors’ and patients’ associations have the potential to exert influence on regula-

tory activities. To date, however, these organisations have not yet participated in

the current debates surrounding the regulation of nanomedicines. Nevertheless,

like the notified bodies, this group is also expected to play a greater role in the fu-

ture.

The group of advisory bodies includes the Working Group on New and

Emerging Technologies in Medical Devices (N&ET37), the Scientific Committee

on Emerging and Newly Identified Health Risks (SCENIHR38), and the European

Group on Ethics in Science and New Technologies (EGE). Regarding its report on

nanotechnology and its current work on particular regulatory guidance the N&ET

Working Group is characterised as highly active. We regard the SCENIHR as well

as being highly active. This Committee has published opinions on health risks

19

nanotechnologies and on definitions relating to products of nanoscience and

nanotechnologies. It is actively involved in DG Health and Consumers debates on

regulatory issues (Delogu 2009). Although the EGE’s 2007 Opinion on the ethical

aspects of nanomedicine made several important points which could have a regu-

latory impact, its influence seems to be marginal. According to the interview with

a representative, the EGE as a body does not follow up on the impact and imple-

mentation of its own recommendations. It is an expert body constituted for the

purpose advising on a range of ethical issues which is not usually in a position to

become engaged with a specific issue over the long term.

The group of other regulatory bodies includes the ISO, the Organization for

Economic Co-operation and Development (OECD), the ICH39 and the World

Health Organisation (WHO). Both the OECD and the ISO have been highly active

in setting up standardisation processes and dedicating resources to nanotechnol-

ogy. Since all the other actors involved in nanomedical regulation rely on the

regulatory work of these two bodies their leadership seems to be accepted and

recognized. According the empirical research the ICH and the WHO40 have not

yet been involved on the issue of nanomedicine.

REGULATORY PROBLEMS AND GOVERNANCE RESPONSES

REGULATORY PROBLEMS

Regulatory problems identified by the interviewees include the lack of a definition

of nanomedicines, unnecessary regulatory hype, as well as the inappropriateness

of safety, quality and efficacy standards and methods to analyse the potential envi-

20

ronment impact. In the case of products that combine medical devices and drugs

other problems are the applicability of the regulatory regime and the lack of tai-

lored standards in the medical devices assessment. According to our interviews

most of the significant regulatory actors have encountered only a few regulatory

problems. The respondents affiliated to companies have not experienced specific

nano-related problems in the market authorization process of nanomedicines. To

date, evaluation bodies have treated nanopharmaceuticals as ordinary products.

For some years, awareness about particular questions and problems related to

nanodrugs is emerging. However, most of the interviewed evaluation bodies are

not sure whether there are many nano-product related regulatory problems and

what kind of problems this can be. Two representatives of such a body indicate

that they suspect that the hypothesis of regulatory problems that nanomedicine au-

thorization is facing within the current regime may contribute to a regulatory hype

in terms of creating a specific regulatory framework which, to their mind, is not

necessary.

Above we indicated that toxicity problems may induce particular regulatory

problems with nanomedicines. Another problem may be to mobilise the appropri-

ate expertise for the quality, safety, efficacy evaluation of nanomedicinal prod-

ucts. According to most interviewees, the European rules on the authorization of

medicinal products for human use, the methodology of the current regime of drugs

evaluation with its case-to-case risk-benefit balance approach is robust enough to

address nanomedicines. All respondents affiliated to authorization bodies judge

the current system of risk-benefit balance analysis to be sufficient. The in vitro41

and in vivo clinical testing processes are seen as robust in validating that the prod-

uct is safe. The representatives of the authorization bodies cannot see a reason

21

why specific evaluation criteria should be developed for nanomedicines. All the

nanomedicines that have been approved by now have not encountered particular

risk, quality and efficacy problems related to ‘nano properties’. One of these rep-

resentatives reports that two applications related to nanomedicines have been

withdrawn by the companies because there were concerns about the efficacy of

the product. In this context other respondents stress that the European evaluation

system does not take a ‘zero risk approach’. As long as the product meets its in-

tended purpose and the risk-benefit balance is positive the product will be li-

censed. Certain risks are accepted (also on the basis of a risk minimisation plan

the applicant has to handover) if there are certain benefits to be gained and if the

balance is positive. Representatives of competent bodies and companies experi-

ence that the measurement of the benefit depends on the kind of disease and on

whether the product seems to fulfil unmet health needs. As one of them put it:

“In cancer we accept a larger risk than in the case of headaches. In the case of headache we al-

ready have so many products. Therefore the new product will have to pass higher standards of

safety.”

This is also the experience of the companies that were interviewed. One of these

respondents mentions cancer drugs that contain nanoparticles. These products

were approved before all effects (including toxicity) were entirely investigated. In

this context, however, a representative of an authorization body stresses that bene-

fits that are mentioned in the application are not taken for granted. They are care-

fully assessed on the basis of mortality studies and data on the quality of life.

With regard to the characterisation of nanomedicines all respondents and com-

mentators conclude that adequate standards are lacking. An actual problem is the

characterisation of liposomal particles which needs differentiation. With regard to

22

the definition of nanomedicines the competent bodies refer to the work of the In-

ternational Standardisation Organisation (ISO) under the TC (Technical Commit-

tee) 229.

Considering the environmental impact analysis respondents of large and me-

dium sized companies indicate that are not yet prepared to identify the environ-

mental impact. A leading expert has identified this analysis as regulatory problem

of major importance, because it depends on reported physical characteristics and

available information from the biologic effects of specific nanomaterials which

are widely unknown (Gaspar 2007: 143). This expert has questioned the ad-

equateness of the general drug assessment standards to evaluate the safety, quality

and efficacy of coming nanopharmaceuticals. He stated,

“the fact that the new nanopharmaceuticals can be more complex in their structure, with major

differences in biofate and increased complexity of clinical use, integrating different technology

subsets from therapeutics to imaging and integrated non-invasive diagnostics will probably

force the creation of an new regulatory environment.”

In Gaspar’s view, new standards and new administration routes need to be consid-

ered to assess drugs inside nanosystems. An important issue of standardisation is

the characterisation of nanopharmaceuticals including availability of validated as-

says to detect and quality nanoparticles in tissues, medicinal products and process-

ing equipment. Among the most important quality aspects, there is the need to in-

corporate novel techniques for the characterization of different materials and tech-

nological options, looking at different structures, from colloidal systems to carbon

nanotubes.

Interestingly, the experiences and views of the interviewed evaluation bodies

are different. One of them mentioned that large pharmaceutical companies have

23

undertaken environmental risk assessment. These companies seem to be well

equipped to carry out the evaluation. In this context the competent bodies stress

that environmental risks are not a reason to reject an authorization application.

Applicants have only to demonstrate that they will take measures to limit potential

environmental impact.

According to all commentators nanomedicines that combine pharmacological,

immunological or metabolic action on the human body with mechanical action

(‘borderline products’) pose a ‘classification’ problem.42 Given the complex

multi-functionality nanopharmaceuticals are exhibiting the regulatory principle

that the regulation regime of the primary mode of action applies is regarded as be-

ing too simplistic.43 Respondents from companies report that there is much uncer-

tainty about the applicable regulatory regime in the case of combined products.

Companies tend to contact the competent bodies when borderline products raise

questions of regime applicability. They are seeking certainty, because, as an ETP

Nanomedicine representative argued,

“trying to get around the more stringent requirements can be detrimental to the sector’s reputa-

tion.”

In the context of combined products all commentators agree that standards vali-

dated specifically for nanoparticles are lacking in the current guidelines for the as-

sessment of medical devices. The voluntary standards of the medical devices as-

sessment system are less harmonised and less stringent compared to the drugs sys-

tem. As a consequence of its non binding character the scientific advice notified

bodies are required to request from the drugs evaluation bodies can be ignored

without sanctions. According to a representative of an evaluation body this has

happened on several occasions in the past.

24

GOVERNANCE RESPONSES

A literature review and our interviews show that EU governance responses in-

clude mainly the collection of data on characteristics and effects of nanomedici-

nes, the institutionalisation of particular forums, and the organisation of ad hoc re-

flection and the funding of particular initiatives.44 It seems that regulatory action

is still in the stage of reflection and preparation. A preliminary governance initia-

tive was the 2006 EMA Scientific Committee’s Reflection Paper on nanotechnol-

ogy-based medicinal products for human use. This Paper concludes that novel ap-

plications of nanotechnologies (amongst which combined products) challenge the

regulatory classification rules, regulatory expertise and the existing guidance of

drugs evaluation. To deal with these issues the EMA has created the Innovation

Task Force to ensure coordination of scientific and regulatory competence and to

provide a forum for early dialogue with applicants. The EMA’s Small and Me-

dium Size Enterprises Office provides regulatory support. An ad hoc Expert

Group of its Scientific Committee has been established which met in April 2009.

In September 2010 an international workshop on problems of borderline products

will be held with the EMA. In contrast, evaluation bodies of the member states

have been relatively slow in responding to these developments. While some are

confident that current methodologies and disciplines are adequate in dealing with

nanomedicines, others have been informally in touch with the EMA to coordinate

their approach. Since 2007 DG Health and Consumers has organised annual work-

shops on nanotechnology. In the interviews several informal forums for exchanges

of views on regulatory responses between the EMA and the FDA, and between

national level authorities were mentioned.

25

Both evaluation bodies and companies emphasise that they need to learn from

each other to answer regulatory questions. Representatives of companies report

that they seek to contact evaluation authorities in an early stage of product devel-

opment and to build a kind of a partnership. Interviews with evaluation bodies in-

dicate that briefing meetings that are offered free of charge to all companies and

all academic centers, which have developed innovative nanomedicinal products,

are very important for the bodies to ascertain the direction in which product de-

velopment is heading. In its proposed Road Map to 2015 the EMA emphasizes the

growing importance of the structural involvement patients and healthcare profes-

sionals in its activities, as well as the increasing transparency.45

With regard to the lack of definitions and standardisation the respondents af-

filiated to the EMA mentioned that they are participating in different initiatives of

the ISO as an observer or an invited expert. The EMA will look at the ISO’s

modification and improvement of the definition in the future. It is also closely fol-

lowing the sponsorship programs for manufactured Nanomaterials that have been

undertaken by OECD’s Working Party on Manufactured Nanomaterials. The in-

terviews indicated that there are no specific regulatory activities of the Interna-

tional Conference on Pharmaceuticals, the World Health Organization and the

European Directorate for the Quality of Medicines and Health Care.

To respond adequately to the problems of borderline products a respondent af-

filiated to a national evaluation body points to lobbying activities to put the har-

monisation of the medical devices regulation in the direction of stricter safety,

quality and efficacy requirements on the EU agenda. Harmonisation would dis-

suade manufacturers from going forum shopping in terms of identifying notified

bodies with the most lax operating standards. Another response to this problem

26

has been to apply the drugs regulation in authorisation practice. In this context a

representative of an evaluation body reports that some products with an initial ap-

parent physical main mechanism of action, like some contrast media, have been

considered as medicinal products. The evaluations of other borderline products

containing nanostructures with a systemic distribution through imaging media

have led to the same consideration. According to the respondent, the underlying

reasoning is that if there is a potential risk with respect to borderline products you

apply the most stringent regulatory regime.

ANALYSIS

The regulatory problems the interviewees addressed specify some of the regula-

tory challenges of nanomedicinal development we identified above in the litera-

ture. They indicate that there seem to be only a few regulatory gaps induced by the

lack of a definition of nanomedicines, inappropriate classification rules for com-

bined products and lacking tailored safety, quality and efficacy standards. Al-

though there has been a scientific consensus on the definition of nanomaterials to

be that between 1-100 nanometers, this still has to be translated into a legal defini-

tion. Such a legal definition would have to be different from and in this case more

specific than the scientific definition which is currently being used. The legal

definition would have to refer to a specific quantum that would trigger a specific

kind of regulatory obligations for all the stakeholders.46 Only once a threshold is

defined will it be possible to identify certain medical applications as nanomedici-

nes for purposes of regulation. Furthermore it is not clear whether the safety, qual-

ity and efficacy standards on which the risk-benefit balance evaluation rely are tai-

27

lored to nanomedicines. High level expertise on nanomedicines and their potential

effects seems to be lacking in authorisation procedures.

To date, the EU pharmaceuticals regulation regime has been adapted to new

technological development. The preliminary picture of the governance responses

to the challenges of nanomedicines indicates that regulatory action is still in the

stage of reflection. As has been charted out in figure II, bodies like the OECD,

ISO and SCENIHR are highly active to provide for regulatory standards and

measurements in relation to nanotechnologies. These are initial governance steps

to reduce technical and scientific uncertainties. Interestingly, the EU medical de-

vices advisory group, the N&ET, has been especially active in deliberating on this

issue and developing specific regulatory guidance47 for medical devices manufac-

tured using nanotechnology. In comparison the EMA has only been moderately

active in putting together an institutional set up to deliberate on operational issues

relating to authorization of nanopharmaceuticals last year. DG Health and Con-

sumers has been active in providing a larger European forum for experts, industry

representatives and policymakers across sectors to come and deliberate on a range

of safety issues vis-à-vis nanotechnology. However, since these forums cover all

sectors in which nanotechnology is being used, it is not expected that specific

regulatory issues relating to nanomedicines will be discussed in any great detail.

The dormant nature of the user associations is perhaps not unexpected given that

the technology is still under development and there is lack of information in the

public domain on the uses and effects of this technology in the medical sector.

However the dormancy of the ICH and the WHO is more difficult to explain. The

ICH has been the accepted forum for deliberations on medical regulation between

the US, Japan and the EU and this was also acknowledged by the interviewees.

28

The non involvement of the ICH and the WHO seem to suggest that although in-

ternational collaboration has been found to be necessary in the case of pooling re-

sources for scientific investigations and standardization activities in the ISO and

the OECD that may not be the case of developing regulatory guidance in the case

of specific sectors. This also perhaps explains the absence of any concrete coordi-

nation mechanisms (in addition to the existing institutional arrangements and the

information exchanged during public conferences on nanomedicines) between the

EMA and the FDA on the specific issue of regulation of nanomedicines. There

seems to be an understanding that regulatory debates would have to take place in-

ternally and some kind of consensus would need to be built before attempting

regulatory coordination at the international scale.

In comparison the EMA has only been moderately active in putting together

an institutional set up to deliberate on operational issues relating to authorization

of nanopharmaceuticals. Very recently, the Agency has taken the initiative to or-

ganize an international workshop on key features of nanomedicines and the

emerging scientific knowledge in the field.48 DG Health and Consumers has been

active in providing a larger European forum for experts, industry representatives

and policymakers across sectors to come and deliberate on a range of safety issues

vis-à-vis nanotechnology. However, since these forums cover all sectors in which

nanotechnology is being used, it is not expected that specific regulatory issues re-

lating to nanomedicines will be discussed in any great detail. The dormant nature

of the user associations (patients and doctors) is perhaps not unexpected given that

the technology is still under development and there is lack of information in the

public domain on the uses and effects of this technology in the medical sector.

However the dormancy of the EDQM, the ICH and the WHO is more difficult to

29

understand. It is likely that these bodies are waiting for the outcomes of the gen-

eral standardisation activities of the ISO and the OECD. This may also be an ex-

planation for the absence of any structural coordination between the EMA and the

FDA on nanopharmaceuticals governance.

The lack of concrete steps in addressing the regulatory issues surrounding

nanomedicines has attracted criticism from analysts (Bhogal 2009). The EMA’s

putting into place ad hoc structures is considered not to be enough to cope with

the regulatory problems. Currently, the EMA has recognized that there is an ur-

gent need that the European competent bodies act in concert with each other to

generate awareness and dialogue and to ensure a comprehensive and coherent re-

sponse.49 It is however unclear, whether the EU Regulatory System Network the

EMA is developing does include structural collaboration with the European Direc-

torate for the Quality of Medicines and Health Care and other regional and inter-

national bodies.

CONCLUSION

This article explores whether the European medicinal products authorisation regu-

lation for human use is equipped to cope with the regulatory challenges of

nanomedicines in terms of regime robustness and adequate governance responses

to regulatory gaps and problems on the basis of high level expertise.

First of all, the analysis indicates that the pharmaceuticals regulation regime

has proved to be robust in terms of well-established rules that have been kept up-

to-date and relevant by continuous and careful adaptation to new product devel-

opment and new insights into product safety, quality and efficacy. The principle of

30

risk-benefit balance that guides the authorization of drugs seems to be capable to

accommodate a certain amount of uncertainty. The successful marketing of

nanodrugs in the past indicates that EU pharmaceuticals approval regulation has

been capable to cope with nanomedicines. The emerging awareness of unknown

health and environmental risk as well as the increasing multi-functionality and

complexity of coming nanomedical products, however, question the appropriate-

ness of existing safety, quality and efficacy standards. Since new nanomedical

products go across the borders of the regimes of the EU medical technology regu-

latory systems the question arises whether a separate regulatory regime will be re-

quired in the future. One condition for singling out a specific regime (like the

ATMP regulation) is to isolate an integral thread running across all nanomedical

products. To date, such a thread has not yet emerged. Even if it can be isolated in

the future the threat of further fragmentation of the pharmaceutical framework

might dampen the support for establishing a new specific regime. Regarding the

robustness of the drugs regulatory regime another question is whether nanomedi-

cinal products should be approved only through the centralized procedure. This

procedure was mandated for high technology products in order to ensure consis-

tent, harmonized authorization and timely access to safe and innovative medicines

by pooling the best scientific expertise. Considering the innovative character of

nanomedicines and scientifically challenging evaluation we conclude that there is

a case for nanomedicines to be authorised through the centralized process. Nano-

pharmaceuticals should be included as a specific category within the mandatory

list of products that have to follow central authorization process (Chowdhury

2010:137). This would allow circumvention of the expertise deficit in the commu-

31

nity on these issues and also ensure effective harmonization of evaluation tech-

niques necessary to facilitate market access to these products.

Secondly, the analysis shows that appropriate governance responses to the

identified regulatory gaps and problems have not yet emerged. Regulatory gaps

mainly refer to implementation problems which require regulatory guidance tai-

lored to the approval of nanomedicines. With regard to standard-setting the lack of

a legal definition of nanomedicines and regulatory thresholds seem to be the most

urgent problems. As a consequence of these deficiencies legal certainty, a princi-

ple that has a high priority in European medical regulation policy50, currently can-

not be provided sufficiently. Whether the important regulatory gaps will be filled

depends on the Scientific Opinion of the SCENIHR on the scientific basis for the

definition of the term ‘nanomaterial’ that has been requested before the end of

May 2010.51 Regulatory responses seem to be in a preliminary stage. Very re-

cently, the European Medicines Agency has taken a proactive stance. The interna-

tional conference the Agency is convening in September 2010 seems to be an im-

portant step to reduce uncertainties on nanomedicinal product properties. Fur-

thermore, in its Road Map to 2015 the EMA has taken the initiative to develop a

regulatory science in coordination with the competent bodies of the member

states. It remains to be seen whether this development can contribute to the forma-

tion of high level expertise on nanomedicines that seems be lacking in the evalua-

tion procedures. The present EMA governance activities do not include concrete

regulatory steps with regard to combined products and specific safety, quality and

efficacy standards. The tendency to apply the ‘stricter’ drugs regime to cope with

the classification problems of combined products may not be the appropriate solu-

32

tion. Medical devices industries and their products, as Altenstetter points out in

this Issue, are too diverse for uniform requirements to be workable.

Since appropriate regulatory responses have not yet been developed further re-

search is needed. This article could only identify significant regulatory actors,

their ideas on regulatory problems and preliminary governance responses. These

are the very first steps to answer the question whether the European medicinal

products authorisation regulation for human use is equipped to cope with the regu-

latory challenges of nanomedicines. Further steps are to identify how much influ-

ence significant actors exert on the emerging governance structure and to explain

their regulatory behaviour. Moreover, insights are needed on the goals and princi-

ples that guide the emerging regulatory activities on nanomedicines. These in-

sights can be provided by further research that builds on an operationalization of

the social constructivist concept of the ‘logic of appropriateness’. With regard to

in-depth identification of the actors’ influence and the explanation of their regula-

tory behaviour the social constructivist approach falls short. These parts of the fur-

ther research agenda can draw on an institutional theory that provides a frame-

work for the analysis of power relations in regulatory networks.

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Notes

1 Nanomedicines are medicines made from new or existing substances which are applied on a nano-metre scale (Zijverden et al. 2008: 41). In this paper the terminology of nanomedicines, nanomedicinal products, nanopharmaceutical and nanodrugs are used synonymously. Nanomedicines are applications of nanotechnologies in view of treating or preventing diseases. Nanotechnologies mean the design, characterisation, production and application of structures, devices and systems by controlling shape and size at the nanometre scale where properties differ significantly from those at larger scale (see EMA 2006). These definitions are based on reports of the Royal Society and Royal Academy of Engineering (2004) and the European Science Foundation (2005), as well as on a paper of the European Technology Platform on Nanomedicine (2006).

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2 The regulatory regimes that constitute the medical product regulation system refer to medicinal prod-ucts, medical devices and human material. 3 European Working Group on New and Emerging Technologies in Medical Devices (established by the European Commission). 4 The description of the nanopharmaceuticals development is mainly based on reports of the Dutch In-stitute for Public Health and the Environment (RIVM) and the Roadmap of the European Technology Platform on Nanomedicine (Jong de et al. 2005; Zijverden et al. 2008; European Technology Platform on Nanomedicine 2009). These documents provide the most exhaustive overview of the current and the near term development of nanomedical products. 5 At the moment nanomedicinal research is being carried out on the use of nanoparticles, amongst which dendrimers, nanotubes, liposomes, nanocrystals, quantum dots, spheres or rods of substances such as gold, silica and albumin. 6 The 2006 EMA Reflection Paper on nanotechnology based medicinal products for human use (EMA 2006) specified that these authorized medicinal products containing nanoparticles are in the form of liposomes (Caelyx, Myocet), protein conjugates (PegIntron, Somavert), polymeric substances (Co-paxone) or suspensions (Rapamune, Emend) and nanoparticles (abraxane). 7 Market survey report on Medical Nanotechnology Markets: Trends, Industry Participants, Product Overview and Market Drivers, pegs the number of authorizations at 18 (Trimark Publications 2008). See also, presentation by Furgeson to the FDA (2008), who puts the number as 12. 8 FDA approved “nano-scale” therapeutics products include Gadolinium chelatefor MRI imaging (Gd-DTPA Dimeglumine), iron oxide particles for MRI imaging (Feridex), liposomes (Doxil, DaunoXome), microemulsions (Cyclosporine) and albumin-bound nanoparticles (Abraxane). Silver nanoparticles for anti-bacterial wound dressing; engineered calcium phoasphate (NanOssTM, dupli-cates microstructure, composition and performance of human bone) and nanoparticledental restorative (3M ESPE Filtek) are some of the nano-scale devices that have been approved by the FDA (see, Sa-drieh 2005). 9 These breakthroughs were mentioned at the ETP Nanomedicine roadmapping meetings in 2009. 10 Responsible development of nanotechnology can be characterized as the balancing of efforts to maximize the technology’s positive contributions and minimize its negative consequence (see, CRNNI 2006). A prudential approach to regulation is discussed by Dorbeck-Jung 2007. 11 Social constructivism is regarded as an ontological approach to social inquiry that serves to explore how social phenomena became what they are (Trubek, Cottrell and Nance 2006; Green Cowles 2003; Adler 2002; Finnemore and Toope 2001; Brunnée and Toope 2000; Finnemore 1996). Constructivist approaches have been developed in many disciplines, amongst which sociology, international relations, international law and technology assessment. Constructivism has also been closely interwoven with historical and sociological strands of institutionalism (Checkel 2001). Regarding the aim of this article we rely mainly on the socio-legal approach of Trubek, Cottrell and Nance (2006) which integrates no-tions of sociological and international relations theories. 12 This broad view has been promoted in international relations and international/European law ac-counts to overcome a legalistic view (Finnemore and Toope 2001; Koslowski 1999). 13 Regulation is commonly defined as intentional attempts to control or order people or states of affairs (albeit mindful of the unintended consequences of those intentions (Black 2002). 14 A stakeholder is to mean ‘a person or organization that has legitimate interest in a project or entity’ (Freeman 1983). Stakeholders are regarded as regulatory actors only if they (at least potentially) exert influence on regulatory activities. 15 Examples of soft law are the Committee for Advanced Therapies (CAT) 2009 Scientific guideline on the minimum quality and non-clinical data for certification of advanced therapy medicinal products (EMA/CAT/486831/2008), the EC 2006 guideline on the definition of a potential serious risk to public health (2006/C 133/05), the 2006 CHMP Guideline on the environment risk assessment of medicinal products for human use (EMA/CHMP/SWP/4447/00), the EMA guideline on scientific aspects and working definitions for the mandatory scope of the centralized procedure and the 2005 EC guideline on the packaging information of medicinal products for human use . 16 See, Regulation (EEC) No. 2309/93, OJ No L 214, 24. 8. 1993 p.133-169. 17 Regulation 2309/93 was replaced by Regulation 726/2004 of 31 March 2004 (OJ L 136/1). In 2001 the European Commission issued Directive 2001/83/EC on the Community Code relating to medicinal products for human use that was based on Article 95 of the Treaty establishing the European Union (OJ L-311/67). In 2004 the Commission adopted Directive 2004/27/EC (OJ L 136/34), which amended Directive 2001/83/EC. The amendments were formulated on the base of the findings of the evaluation of the marketing procedures that were published in 2001 (European Commission, DG Enterprise 2001).

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18 According to the Annex to Regulation 726/2004, certain biotechnological products, medicinal prod-ucts for human use for which the therapeutic indication is the treatment of certain diseases, as well as orphan medicinal products are to be authorised by the Community. Optional access to the centralised procedure is provided for medicinal products, although not belonging to the before mentioned catego-ries, are nevertheless therapeutically innovative. 19 See, EC 98C 229/03 and Annex 1 2001/83/EEC. 20 See Article 8.3(ca) Directive 2004/27EC amending Directive 2001/83/EC. See also, the 2006 CHMP Guideline on the environment risk assessment of medicinal products for human use (EMA/CHMP/SWP/4447/00). 21 Recital (18), Directive 2004/27/EC, OJ L 136, 30/4/2004 p. 34 - 57, 22 The final approval of pharmaceuticals by the European Commission is based on the EMA’s opinion. This opinion is based on the draft of its Committee for Medicinal Products for Human Use (CHMP). Due to the expertise of the members the recommendations of the EMA’s scientific committees are cru-cial for the EMA’s evaluation and the final decision of the European Commission. 23 Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, OJ. L. 378, 27.12.2006 p. 1-19. 24 Regulation (EC) No. 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, OJ L 18, 22/1/2000 p. 1-5. 25 A medicinal product for human use is defined as any substance having properties for treating or pre-venting diseases in human beings or that may be used in or administered to human beings with a view to restoring, correcting or modifying physiological functions by exerting principally a pharmacological, immunological or metabolic action (Article 1 (1b 2.) Directive 2004/27/EC. 26 Advanced therapies medicinal products mean any medicinal products for human use (see note 20) that include gene therapy medicinal products, somatic cell therapy products and tissue engineered products (Article. 2 Regulation 1394/2007/EC). 27 “Medical device” means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, together with any accessories, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for diagnostic or other purposes (Article 1.1 Directive 2007/47/EC). It achieves its principal intended action in or on the hu-man body by mechanical means. 28 More details on the authorization of medical devices, see Altenstetter in this Issue. 29 Article 2 (2) Regulation 1394/2007/EC. 30 According to Art.1 28, 28a Directive 2004/27/EC a risk benefit balance is defined as an evaluation of the positive therapeutic effects of the medicinal product in relation to the risks relating to the quality, safety or efficacy of the medicinal product as regards patient’s health or public health, as well as any risk of undesirable effects on the environment. 31 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the ap-proximation 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 hu-man use, OJ L 121, 1/5/2001 p. 34 – 44. 32Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational me-dicinal products for human use, OJ L 262, 14/10/2003 p. 22 – 26. 33 Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products, OJ L 91, 9/4/2005 p. 13 – 19. 34 As is evident from this listing, we also discuss the constituents of these groups. The name of the group, in that sense is an ascriptive term that best describes the functions the members of that group have with regard to nanomedicines and their regulation. 35 The European Directorate for the Quality of Medicines and Health Care is a key European Organisa-tion (Council of Europe) involved in the Harmonisation and co-ordination of standardisation, regula-tion and quality control of medicines, blood transfusion and organ transplantation, pharmaceuticals and pharmaceutical care. 36 It should be mentioned that the European Parliament has only witnessed the submission of a motion for a parliament resolution by Carl Schlyter, an MEP, on the regulatory aspects of nanomaterials.

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37 The N&ET Working Group has been established in 2005 on the proposal of the European Commis-sion. Participants are the competent authorities for medical devices of the member states. 38 The Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) is an experts committee of European Commission. It is part of the larger risk assessment structure of the European commission. The aim is to provide scientific advice to the commission on risk assessment. It is con-sulted by the Commission at its own initiative; however in some instances consultations are mandatory if it is provided for under EU legislations. See Delogu (2009). 39 International Conference on Harmonisation of Technical Requirements for the Registration of Phar-maceutical for Human use. The EDQM and the ICH are involved in pharmaceutical standardisation activities. In the ICH the European Pharmaceutical Association, the EMA, the FDA and the Japanese Competent Authority are participating 40 In any case not directly. Although the IFCS (Intergovernmental Forum on Chemical Safety) which is hosted by the WHO, did pass a resolution on the safety of nanomaterials in its Sixth Session, at Dakar in 2008. (IFCS/FORUM-VI/07W). 41 See Park (2009). The article explores the possibility for an enhanced role for in vitro toxicity studies in the risk assessment of nanomaterials. 42 With the terminology of ‘classification problem’ we refer to legal analysts like Miller (2007). 43 See presentation of M. Papaluca-Amati at the 2nd Annual Nanotechnoly Workshop, “Safety for Suc-cess”, Brussels 3 October 2008, retrieved at: http://ec.europa.eu/health/horiz_events_chrono_en.htm. 44 For example, the Nanomed Round Table with its Working Group on Regulation, see www.nano-medroundtable.org. 45 See European Medicines Agency, 26 January 2010 (EMA/299895/2009). 46 This was suggested in our interview with the member of SCENIHR 47 It is important to mention that although the MEDDEV guidelines are legally not binding, but it does create a presumption of conformity for manufacturers adopting these guidelines. This creates an incen-tive for the uptake of the guidelines. These guidelines therefore do have a de facto legal effect. 48 European Medicines Agency, 1st International Workshop on Nanomedicines, 26-27 April 2010, Lon-don (EMA/607891/2009). The Workshop has been shifted to 2-3 September 2010. 49 The EU Regulatory System Network is a partnership between all EU Regulatory Authorities (see EMA Roadmap, note 40). 50 See for example recital 7 of Directive 2004/27/EC and recital 28 of Regulation 726/2004/EC. 51 On March 1, 2010, the European Commission (EC) issued a request, via the accelerated procedure, for a scientific opinion on the scientific basis for the definition of the term “nanomaterial” from the Scientific Committee on Emerging and Newly Identified Health Risks. (see http://files.nanobio-raise.org/Downloads/scenihr.pdf). See also SCENIHR 2008.