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INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY
Comparing National Innovation Systems at the Sectoral Level
INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY

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INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY
What are the specific characteristics of innovation in pharmaceutical biotechnology? How
do biopharmaceutical innovation systems in OECD countries perform and which policies are
suitable to foster performance?
This publication examines the innovation system in pharmaceutical biotechnology in eight
OECD countries – Belgium, Finland, France, Germany, Japan, the Netherlands, Norway and
Spain. The report summarises the results of in-depth studies, providing a comparative analysis
of participating countries’ performance in science and innovation in biopharmaceuticals.
It highlights specific characteristics of the national biopharmaceutical innovation systems
in terms of their international openness and the specific role of demand-side factors
in the innovation process. Major systemic failures affecting the functioning of the
biopharmaceutical innovation systems are identified. Based on rich evidence, the report draws
policy recommendations to foster innovation in biopharmaceuticals advocating an integrated
policy approach.
This study forms part of a larger effort to compare innovation processes in different industry
sectors and technological fields to provide policy guidance and to more fully elaborate the
national innovation systems (NIS) approach to policy making.
Further reading:


Innovation in Energy Technology: Comparing National Innovation Systems at the Sectoral
Level,
OECD (2006)


Governance of Innovation Systems, Volume 1: Synthesis Report
, OECD (2005)


Innovation Policy and Performance: A Cross-Country Comparison
, OECD
(2005)
Innovation in Pharmaceutical Biotechnology
COMPARING NATIONAL INNOVATION SYSTEMS
AT THE SECTORAL LEVEL
www.oecd.org
ISBN 92-64-01403-9
93 2006 01 1 P
-:HSTCQE=UVYUX^:
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Innovation
in Pharmaceutical
Biotechnology
COMPARING NATIONAL
INNOVATION SYSTEMS
AT THE SECTORAL LEVEL
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INNOVATION BIOTECHNOLOGY
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OECD
PUBLISHING
OECD
PUBLISHING
ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT
Innovation
in Pharmaceutical
Biotechnology
COMPARING NATIONAL INNOVATION SYSTEMS
AT THE SECTORAL LEVEL
ORGANISATION FOR ECONOMIC CO-OPERATION
AND DEVELOPMENT
The OECD is a unique forum where the governments of 30 democracies work together to
address the economic, social and environmental challenges of globalisation. The OECD is also at
the forefront of efforts to understand and to help governments respond to new developments and
concerns, such as corporate governance, the information economy and the challenges of an
ageing population. The Organisation provides a setting where governments can compare policy
experiences, seek answers to common problems, identify good practice and work to co-ordinate
domestic and international policies.
The OECD member countries are: Australia, Austria, Belgium, Canada, the Czech Republic,
Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Japan, Korea,
Luxembourg, Mexico, the Netherlands, New Zealand, Norway, Poland, Portugal, the Slovak Republic,
Spain, Sweden, Switzerland, Turkey, the United Kingdom and the United States. The Commission of
the European Communities takes part in the work of the OECD.
OECD Publishing disseminates widely the results of the Organisation’s statistics gathering and
research on economic, social and environmental issues, as well as the conventions, guidelines and
standards agreed by its members.
Also available in French under the title:
Titre de l’ouvrage
Sous-titre
© OECD 2006
No reproduction, copy, transmission or translation of this publication may be made without written permission. Applications should be sent to
OECD Publishing: rights@oecd.org or by fax (33 1) 45 24 13 91. Permission to photocopy a portion of this work should be addressed to the Centre
français d'exploitation du droit de copie, 20, rue des Grands-Augustins, 75006 Paris, France (contact@cfcopies.com).
This work is published on the responsibility of the Secretary-General of the OECD. The
opinions expressed and arguments employed herein do not necessarily reflect the official
views of the Organisation or of the governments of its member countries.
FOREWORD –
3



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
Foreword
The OECD Working Party on Innovation and Technology Policy (TIP) launched
three case studies in 2002 with the goal of developing analytical work aimed at:
• Improving the understanding of innovation processes in specific technology fields
or sectors within the overall National Innovation Systems (NIS) framework.
• Drawing policy conclusions concerning the balance between horizontal
innovation policies and more customised measures that take into account the
specific characteristics in selected technology fields or sectors.
The three case studies included pharmaceutical biotechnology, energy technology as
well as knowledge-intensive service activities (KISA). This report presents a synthesis of
the case study on innovation in pharmaceutical biotechnology.
The purpose of the pharmaceutical biotechnology case study was to:
• Investigate the specific characteristics of national innovation systems for
pharmaceutical biotechnology.
• Examine the structure and dynamics of the innovation networks generating
knowledge, technologies and products
• Analyse the role of demand-side factors in the innovation process.
• Identify the systemic imperfections related to interactions between actors and the
absence or inappropriate functioning of specific elements in the innovation system
with special emphasis on R&D funding, public-private partnerships, IPRs,
product-related regulation and the configuration of lead markets.
• Perform cross-country analysis to develop recommendations that enhance the
effectiveness of policies to encourage the performance of the national systems for
pharmaceutical biotechnology.
The pharmaceutical biotechnology case study comprised eight participating countries:
Belgium, Finland, France, Germany, Japan, the Netherlands, Norway and Spain. The
Netherlands, Germany and Norway chaired the focus group. National experts from
participating countries prepared national reports based on a common framework (for a list
of country studies and their authors, see below). The case study greatly benefited from
focus group workshops and discussions of the OECD Committee for Scientific and
Technological Policy (CSTP) and its Working Party on Innovation and Technology
Policy (TIP). This report was prepared by focus group co-ordinators Christien Enzing
(Netherlands), Thomas Reiss (Germany) and Terje Gronning (Norway), in co-operation
with the OECD Secretariat. The chapters were prepared by the following authors:
4
– FOREWORD


INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
• Chapter 1: Christien Enzing (TNO-STB, Netherlands) and Thomas Reiss
(Fraunhofer ISI, Germany)
• Chapter 2: summaries prepared by the authors of the national reports
(see list of national project teams below)
• Chapter 3: Thomas Reiss (Fraunhofer ISI, Germany)
• Chapter 4: Mark Knell (University of Oslo, Norway)
• Chapter 5: Terje Gronning (University of Oslo, Norway)
• Chapter 6: Christien Enzing and Sander Kern (TNO-STB, Netherlands)
• Chapter 7: Christien Enzing and Sander Kern (TNO-STB, Netherlands)
• Chapter 8: Christien Enzing (TNO-STB, Netherlands).

The eight national reports and their summaries in Chapter 2 were prepared by the
following country project teams:
1

• Belgium
2

Eric Cantarella
Politique Scientifique Fédérale, Brussels

• Finland
Malin Brännback
Abo Akademi University

Gabriela von Blankenfeld-Enkvist, Riitta Söderlund and Marin Petrov
Turku School of Economics and Business Administration/Innomarket, Turku
• France
Alain Rochepeau
French Ministry of Research and New Technologies, Technology Directorate,
Bio-engineering Department, Paris
• Germany
Thomas Reiss and Sybille Hinze
Fraunhofer Institute for Systems and Innovation Research, Karlsruhe
• Japan
Kazuyuki Motohashi
Research Centre for Advanced Science and Technology, University of Tokyo
• Netherlands
3

Christien Enzing, Sander Kern and Annelieke van der Giessen
TNO Strategy, Technology and Policy, Delft


1. The full-length country studies are available on line at www.oecd.org/sti/innovation under the heading
“Case Studies in Innovation”.
2. Belgium did not contribute a full-length national report.
3. The full Netherlands country study also includes the food sector; the summary only addresses the
biopharmaceutical sector.
FOREWORD –
5



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
• Norway
4

Eva Dobos, Terje Grønning (project manager), Mark Knell
Dorothy Sutherland Olsen and Bjørg Kristin Veistein,
Centre for Technology, Innovation and Culture, University of Oslo
• Spain
Author: Emma Gutiérrez Mesa
Departamento de Empresa, Faculdad de Economía, Derecho y Empresariales,
Universidad Europea de Madrid
Co-ordinator: Dr. Emilio Muñoz
Consejo Superior de Investigaciones Científicas CSIC, Madrid

The data collection and calculations of the bibliometric and patent analysis presented
in the national reports and in Chapter 3 of this report are by Sybille Hinze of Fraunhofer
ISI. Françoise Laville (Observatoire des sciences et des techniques – OST, Paris)
contributed statistical information. From the OECD Secretariat, Emmanuel Hasan and
Sandrine Kergroach provided statistical support and analysis. Gernot Hutschenreiter,
following Jean Guinet, supported the work of the focus group and co-ordinated the
preparation of this publication.



4. A complementary national case study on innovation in marine biotechnology was prepared by Terje
Gronning with Eva Dobos, Ingeborg Frogner Dahl-Hilstad, Mark Knell, Ovar Andreas Johansson, Mark
Knell and Dorothy Sunderland Olsen of the Centre for Technology, Innovation and Culture, University
of Oslo.
TABLE OF CONTENTS –
7



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
Table of Contents

Foreword........................................................................................................................................3
Executive Summary.......................................................................................................................9
Note de synthèse..........................................................................................................................15
Chapter 1. Introduction................................................................................................................21
Chapter 2. Summary of Country Studies.....................................................................................33
Belgium..................................................................................................................................34
Finland....................................................................................................................................41
France.....................................................................................................................................50
Germany.................................................................................................................................62
Japan.......................................................................................................................................70
The Netherlands.....................................................................................................................75
Norway...................................................................................................................................86
Spain.......................................................................................................................................95
Chapter 3. Comparison of Performance in National Biopharmaceutical
Innovation Systems..................................................................................................105
Chapter 4 .Openness of the Biopharmaceutical Innovation System.........................................121
Chapter 5. Comparison of Selected Demand-side Factors........................................................131
Chapter 6. Structure, Dynamics and Performance in National
Biopharmaceutical Innovation Systems..................................................................147
Chapter 7. Systemic Imperfections in Biopharmaceutical Innovation Systems........................165
Chapter 8. Policy Implications..................................................................................................179
EXECUTIVE SUMMARY –
9



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
Executive Summary
Innovation policies and sectoral innovation
systems
Biotechnology has become the driving force of radical changes in innovation
processes in various sectors. This is best illustrated by the pharmaceutical industry where
the traditional chemical paradigm of drug discovery and development is being replaced
by a new biotechnological paradigm. This has important consequences for the structure
and functioning of the biopharmaceutical innovation system: biotechnology firms and
public sector research organisations are becoming key actors generating new knowledge,
tools and substances for the pharmaceutical industry. Regulations, standards and
intellectual property rights (IPR) schemes have to deal with new types of components,
and, on the demand side, new solutions are emerging for as yet unmet needs.
For this reason the biopharmaceutical sectoral innovation system was chosen as one
of the pilot sectors of the OECD Case Studies in Innovation.
1
Building on previous work
on national innovation systems (NIS), the OECD Case Studies in Innovation are aimed at
improving the understanding of the idiosyncratic properties of particular areas of
technology and sectoral innovation systems, so that a consistent and transparent policy
mix can be designed that combines generic innovation policies with customised policies
adapted to the characteristics of a specific area of technology or of a sectoral innovation
system.
Aims of the case study
The general aim of the case study on pharmaceutical biotechnology was to provide a
systematic comparison of biopharmaceutical innovation systems in a number of OECD
countries. In particular, the characteristics of the national biopharmaceutical innovation
systems that relate to the structure and dynamics of the systems, the role of demand
factors and markets, and the openness of the systems were investigated, including an
assessment of the performance in science as well as in innovation and industrial
development and an assessment of the influence of incentives and other framework
conditions shaped by government policies. In addition, systemic imperfections hampering
the functioning of innovation systems were identified.
Based on this analysis, the study aimed at developing recommendations that enhance
the effectiveness of policies to foster the economic competitiveness of national
biopharmaceutical innovation systems. On the basis of a cross-country analysis and an
identification of systemic imperfections which vary across countries, policy conclusions
were drawn as to how to achieve a balance between horizontal innovation policies


1. The other two pilot sectors are energy technology and knowledge-intensive service activities (KISA).
10
– EXECUTIVE SUMMARY


INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
applying across industries and fields of technology and measures that take into account
the sectoral or technological characteristics of biopharmaceutical innovation systems.
A case study approach, combining
quantitative and qualitative methods
Advancing the understanding of innovation systems requires a methodology which
makes it possible to study these systems in depth as well as to make comparisons across
innovation systems. The explorative and comparative nature of the study renders a case
study approach most appropriate. A case study requires the description of the working,
structure and dynamics of a sectoral innovation system in developing, producing and
delivering products and services to satisfy demands of users and consumers, and of the
way a sectoral system changes over time. However, a methodology which makes it
possible to systematically compare innovation systems also requires quantitative
information. In order to facilitate comparability across countries, a common methodology
was developed for the national case studies combining both qualitative and quantitative
methods. National reports – following a common structure – were prepared for Belgium,
Finland, France, Germany, the Netherlands, Norway, Japan and Spain.
National performance in science and in
innovation and industrial development
The analysis of the eight countries shows that in terms of overall performance in
science as measured by a set of five indicators related to publications and citations,
Belgium, Finland, the Netherlands – all smaller countries – take a leading position. Japan
and Spain are ranked at the lower end of this scale, both with performance below the
European average. For performance in innovation and industry development as measured
by patent applications, the number of drugs in the pipeline, venture capital invested in
biotechnology and the number of new biopharmaceutical firms (all per million
population), Belgium and the Netherlands are among the leading countries. Spain, Japan
and Norway, on the other hand, do not seem to perform very well.
Combining the rankings of each country for performance in “science” on the one
hand and “innovation and industrial development” on the other reveals different clusters
of countries. It turns out that Belgium scores highest in terms of “innovation and
industrial development” and second in “science”. Finland and the Netherlands are rather
strong in “science” but have medium performance in “innovation and industrial
development”. Germany performs relatively well in “innovation and industrial
development” but less so in “science”. France and Norway do not excel in either
“science” or “innovation and industrial development” but France still performs better in
“innovation and industrial development” and Norway better in “science”. Japan and
Spain are performing poorly in both “science” and “innovation and industrial
development”.
Structure and dynamics of national
biopharmaceurical innovation systems:
openness
The openness of national biopharmaceutical innovation systems can be studied from
different perspectives. International trade data seem to indicate that Finland, Japan and
Norway tend to be more import-oriented while France, Germany and the Netherlands
EXECUTIVE SUMMARY –
11



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
tend to be more export-oriented. Activities of large multinational pharmaceutical companies
help explain these patterns. It can be shown that the value added of pharmaceutical
production was predominantly realised by foreign-owned firms in France, Norway and
Spain, while domestic enterprises were more prominent in Finland and the Netherlands.
However, very few of the small dedicated biotechnology firms were foreign-owned,
reflecting the domestic origin of these firms as spin-offs from universities, public research
organisations and other firms. The third and fourth indicators for openness focus on the
international dimension of collaboration. The pharmaceutical industry is one of the most
global industries in terms of alliances and collaborative activities. The surveys of
dedicated biotechnology firms found that a majority of these firms that were involved in
collaborative arrangements with other firms had foreign partners. The percentage of
patent applications in biopharmaceuticals that involved international co-operation was
high in Europe when compared to the United States and Japan. During the late 1990s
there was a noticeable shift towards greater reliance on domestic knowledge sources. This
could have been caused by the entry of many new dedicated biotechnology firms that
were spun off from universities, firms, etc. Biotech firms that are active in the
biopharmaceutical sector and which do not have alliances with large pharmaceutical firms
tend to rely more heavily on domestic sources in their innovative activities, including
universities and public research organisations.
Structure and dynamics of national
biopharmaceutical innovation systems:
demand-side factors
The analysis of the role of the demand side in national biopharmaceutical innovation
systems, interpreting demand as “market pull” in a broad sense, shows that while market
size may function as an attraction to industry, it is not necessarily conducive to
innovation. This is because less innovative products may be sold in suitable volumes. In a
more narrow sense corresponding to the “lead market” concept, a market may exert a pull
effect if it is “demanding”, i.e. if it requires sophisticated products. Such requirements
may be articulated by customers themselves, or by their representatives, i.e. physicians, or
they may be set by regulatory authorities. The necessity of cost containment measures,
however, dictates a different strategy, leaving hardly any incentives to develop innovative
products. Rather, incentives predominantly work towards the use of generic products.
This may in turn have an adverse impact on industrial strategies. Another main finding is
that the influence of “users” is extremely limited in all countries studied. This is perhaps
not surprising given the complex nature of the products in question. In order to stimulate
diversification and the diffusion of innovative products, decisions to reward product
differentiation and products developed for specific niches may be warranted in the future.


Structural and dynamic characteristics and
the performance of the systems
There is no single “optimal” configuration of the national innovation system leading
to superior performance measured by indicators based on either science or innovation and
industrial development. For this reason, the structural and dynamic characteristics of the
biopharmaceutical innovation system of countries with similar performance in science as
well as in innovation and industrial development may vary widely. Some features,
however, appear to be conducive to performance in innovation and industrial
development in a rather robust manner. With respect to framework conditions,
12
– EXECUTIVE SUMMARY


INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
institutional set-up and policy, such factors appear to be, for example, the maturity of the
national private equity markets, the existence of policies and instruments for the
commercialisation of technology and the biotechnology-specific character of these
commercialisation policies. Policies creating and sustaining an advanced knowledge base
tend also to be crucial for commercialisation, but the reverse is not true. Countries
adopting a comprehensive policy approach using a broad set of policies to promote
biotechnology that address all functions of the innovation system tend to perform better
than countries with patchy and fragmented policies.
Systemic imperfections
Systemic failures can raise barriers or lead to severe disadvantages in the innovation
process. Systemic imperfections include the absence or inappropriate functioning of
actors in the production, diffusion and application of new knowledge, the absence of
linkages and interactions between parts of the system, etc. The national case studies have
identified a large number and variety of systemic imperfections in all parts of the
innovation system, but most are related to the exploitation and commercialisation of
knowledge and to framework conditions. Examples are the lack of biotechnology expertise
in technology transfer offices, inappropriate models for attributing the ownership of and
returns from intellectual property between the researcher and the research organisation,
insufficient valorisation and exploitation policies of public research organisations,
inadequate public-private linkages, the shortage of risk capital, the availability of specific
expertise in human resources. Most of the systemic imperfections do not seem to be
caused by a single category (actors, functions, institutions and interaction) but rather are
rooted in a combination of factors.
Policy recommendations
The role of governments in innovation policy making has changed considerably over
the last decades. Based on the linear model of innovation, first generation innovation
policies in the post-war period were focused on funding R&D, especially basic – i.e.
generally applicable – research as its major policy instrument. This funding – “at a certain
distance from the market” – was designed to compensate for market failures leading
companies to underinvest in R&D. Since the mid-1990s the complexity of the innovation
system requires governments to address “systemic failures”. Recognition was given to the
diffusion of innovation, the interactive character of the innovation process (with many
feedback loops between the different stages of the process) and the regional and/or
sectoral specificity of innovation processes. Policies are designed to address systemic
failures which block the functioning of the innovation process. These failures provide a
rationale for government involvement not only through the funding of basic research, but
also – and here the second generation of innovation policies comes in – more widely in
ensuring that the innovation system performs well as an entity.
A new role of government involvement in the coming years is to recognise the
importance of innovation in the innovation policy governance system itself. The focus of
first and second generation policies was on the research and education system, the
business system, framework conditions, infrastructure and intermediaries. The focus of
third generation policies will be on government itself. An important function is to close
the “co-ordination gap” within the government between the separate departments that
EXECUTIVE SUMMARY –
13



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
each deal with specific aspects of the innovation chain, but also between national,
international and regional governments.
Given the systemic failures that have been identified in the national
biopharmaceutical innovation systems in the national case studies and the need for an
integrated innovation policy approach that includes first, second and third generation
policies, recommendations have been formulated that address:
• Coherent and consistent innovation policies: combine objectives such as improving
international competitiveness through innovation policies towards pharmaceutical
biotechnology on the one hand, and a high-quality and affordable public health care
system on the other hand.
• Public governance: facilitate a more active role of patients and/or their organisations
in innovation processes, clinical trials and market access; potentially important
sources of innovation remain untapped.
• Promote co-operation and networking: create network linkages throughout the
biopharmaceutical innovation system, especially between actors in science and the
business system.
• Support for an innovative industry: develop instruments that provide incentives for
private financers to invest in biopharmaceutical firms.
• Regulatory framework: develop transparent and stable regulations with short
application procedures and good information on procedures and the development of
an adequate system for protecting biopharmaceutical innovations.
• Technology transfer: stimulate the exploitation of public sector biopharmaceutical
research, include IPR indicators in review and evaluation procedures, establish
qualified supportive infrastructure for start-ups (legal, business, marketing expertise,
incubator and technical facilities).
• Stimulate sound science systems: the persistence of market imperfections associated
with basic research requires a role for government research policies and research
funding.


NOTE DE SYNTHESE –
15



INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
Note de synthèse
Politiques de l’innovation et systèmes
sectoriels d’innovation
Les biotechnologies sont désormais le moteur de changements radicaux dans les
processus d’innovation de divers secteurs. La meilleure preuve en est que, dans l’industrie
pharmaceutique, le paradigme traditionnel de la découverte et du développement d’un
médicament fondé sur la chimie a été remplacé par un nouveau paradigme fondé sur ces
nouvelles technologies. Ce phénomène s’accompagne de conséquences importantes pour
la structure et le fonctionnement du système d’innovation biopharmaceutique : les
entreprises de biotechnologie et les organismes de recherche du secteur public sont en
passe de devenir des acteurs essentiels produisant du savoir, des substances et des outils
nouveaux pour l’industrie pharmaceutique. La réglementation, les normes et les régimes
de droits de propriété intellectuelle (DPI) doivent porter sur de nouveaux éléments et, sur
le plan de la demande, de nouvelles solutions se dessinent pour répondre à des besoins
non satisfaits jusqu’à présent.
C’est pour cette raison que le système sectoriel d’innovation biopharmaceutique a été
choisi comme l’un des secteurs pilotes des Études de cas de l’OCDE sur l’innovation [les
autres étant les technologies de l’énergie et les activités de services à forte intensité de
savoir (KISA)]. S’inspirant des travaux antérieurs consacrés aux systèmes nationaux
d’innovation (NIS), les Études de cas de l’OCDE sur l’innovation visent à mieux
comprendre les propriétés idiosyncrasiques de domaines technologiques particuliers et de
systèmes sectoriels d’innovation. A partir de là, on doit pouvoir élaborer une panoplie de
mesures cohérentes et transparentes conjuguant des politiques génériques d’innovation et
des politiques « sur mesure », adaptées aux caractéristiques de tel ou tel domaine
technologique ou système sectoriel d’innovation.
Objectifs de l’étude de cas
Globalement, l’objectif de l’étude de cas sur les biotechnologies pharmaceutiques
était d’effectuer une comparaison systématique entre les systèmes d’innovation
biopharmaceutique dans un certain nombre de pays de l’OCDE. Nous nous sommes
penchés sur les caractéristiques des systèmes nationaux d’innovation biopharmaceutique
du point de vue de la structure et de la dynamique de ce type de système, sur le rôle des
facteurs relatifs à la demande et des marchés, ainsi que sur l’ouverture des systèmes.
Nous avons notamment procédé à une évaluation des résultats affichés par ces systèmes
en matière de sciences mais aussi d’innovation et de développement industriel, ainsi que
de l’influence des incitations et autres conditions-cadres déterminées par les politiques
publiques. En outre, nous avons recensé les imperfections entravant le bon
fonctionnement des systèmes d’innovation.
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S’appuyant sur cette analyse, l’étude visait à formuler des recommandations sur la
manière de renforcer l’efficacité des politiques destinées à favoriser la compétitivité
économique des systèmes nationaux d’innovation biopharmaceutique. D’une analyse
transnationale et du recensement des imperfections systémiques – qui varient d’un pays à
l’autre – nous avons tiré des conclusions à l’intention des pouvoirs publics sur les moyens
d’équilibrer les politiques transversales d’innovation qui s’appliquent à tous les secteurs
d’activité et domaines technologiques, d’une part, et les mesures tenant compte des
caractéristiques sectorielles ou technologiques des systèmes d’innovation
biopharmaceutique, d’autre part.
Approche par études de cas combinant des
méthodes quantitatives et qualitatives
Pour progresser dans la compréhension des systèmes d’innovation, il faut une
méthodologie permettant d’étudier ces systèmes de manière approfondie et d’effectuer
des comparaisons entre différents systèmes. Le fait que l’étude revête un caractère à la
fois exploratoire et comparatif rend l’approche par études de cas particulièrement
appropriée. Une étude de cas exige la description du fonctionnement, de la structure et de
la dynamique d’un système sectoriel d’innovation en matière de mise au point, de
production et de distribution de produits et de services pour satisfaire la demande des
usagers et consommateurs, ainsi que de la manière dont un système sectoriel évolue au fil
du temps. Toutefois, une méthodologie permettant de comparer les systèmes d’innovation
de manière systématique nécessite aussi des informations d’ordre quantitatif. Pour
faciliter la comparabilité internationale, une méthodologie commune a été mise au point
pour les études de cas par pays, combinant méthode qualitative et méthode quantitative.
Des rapports par pays – tous structurés de la même manière – ont été établis pour
l’Allemagne, la Belgique, l’Espagne, la Finlande, la France, le Japon, la Norvège et les
Pays-Bas.
Performances nationales en matière de
sciences, et d’innovation et développement
industriel
L’analyse des huit pays révèle que sur le plan des performances scientifiques
globales, mesurées au moyen d’un ensemble de cinq indicateurs fondés sur les
publications et les citations, ce sont la Belgique, la Finlande et les Pays-Bas (tous des
petits pays) qui se classent en tête. Par contre, l’Espagne et le Japon se classent en bas de
l’échelle, tout deux affichant des résultats inférieurs à la moyenne européenne. S’agissant
des performances en matière d’innovation et de développement industriel mesurés
d’après les demandes de brevets, le nombre de médicaments en préparation, le montant
du capital-risque investi dans les biotechnologies et le nombre de jeunes entreprises
biopharmaceutiques (toutes les valeurs étant exprimées par million d’habitants), la
Belgique et les Pays-Bas figurent parmi les pays de tête. En revanche, l’Espagne, le Japon
et la Norvège ne semblent pas enregistrer des résultats très probants.
Si l’on combine les classements de chaque pays au regard de leurs performances en
« science », d’une part, et en « innovation et développement industriel », d’autre part, les
groupes de pays que l’on observe se présentent différemment. Il s’avère que c’est la
Belgique qui se classe au premier rang pour « l’innovation et le développement
industriel » et au second pour la « science ». La Finlande et les Pays-Bas sont assez bien
placés en « science » mais n’obtiennent que des résultats moyens en « innovation et
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développement industriel ». L’Allemagne affiche d’assez bons résultats en « innovation
et développement industriel » mais se classe moins bien en « science ». La France et la
Norvège n’excellent ni en « science », ni en « innovation et développement industriel »
mais la première obtient de meilleurs résultats en « innovation et développement
industriel » tandis que la seconde est mieux placée en « science ». L’Espagne et le Japon
enregistrent tout deux des performances médiocres à la fois en « science » et en
« innovation et développement industriel ».
Structure et dynamique des systèmes
nationaux d’innovation biopharmaceutique :
ouverture
On peut étudier le degré « d’ouverture » des systèmes nationaux d’innovation
biopharmaceutique sous différents angles. Les chiffres du commerce international
semblent indiquer que la Finlande, le Japon et la Norvège privilégient plutôt les
importations alors que l’Allemagne, la France et les Pays-Bas sont plutôt axés sur
l’exportation. Observer les activités des grands groupes pharmaceutiques multinationaux
nous aide à expliquer ces schémas. On peut ainsi montrer que la valeur ajoutée de la
production pharmaceutique a été réalisée principalement par des entreprises sous contrôle
étranger en France, en Espagne et en Norvège alors que les entreprises nationales
occupent une place prépondérante en Finlande et aux Pays-Bas. Toutefois, très peu des
petites entreprises dédiées aux biotechnologies sont des sociétés sous contrôle étranger,
ce qui témoigne de l’origine nationale de ces entreprises qui ont en fait « essaimé » des
universités, des organismes publics de recherche ou d’autres entreprises. Les troisième et
quatrième indicateurs du degré d’ouverture se rapportent à la dimension internationale de
la collaboration. L’industrie pharmaceutique est l’une des industries les plus
« mondialisées » en termes d’alliances et d’activités en collaboration. Les enquêtes auprès
d’entreprises à vocation biotechnologique révèlent qu’une majorité de celles qui sont
parties prenantes à des arrangements de collaboration avec d’autres entreprises ont des
partenaires étrangers. Le pourcentage de demandes de brevets sur des produits
biopharmaceutiques impliquant une coopération internationale est élevé en Europe,
comparé aux États-Unis et au Japon. A la fin des années 90, on a pu observer un net
revirement en faveur du recours plus fréquent à des sources de savoir nationales. Ce
phénomène s’explique peut-être par l’arrivée sur le marché de nombreuses jeunes
entreprises à vocation biotechnologique ayant essaimé des universités, d’autres
entreprises, etc. Les sociétés biotechnologiques dont l’activité se situe dans le secteur
biopharmaceutique et qui n’ont pas conclu d’alliances avec de grands groupes
pharmaceutiques s’en remettent généralement davantage aux sources de savoir nationales
quand elles innovent, y compris les universités et les organismes publics de recherche.
Structure et dynamique des systèmes
nationaux d’innovation biopharmaceutique :
facteurs liés à la demande
L’analyse du rôle du volet « demande » des systèmes nationaux d’innovation
biopharmaceutique (la demande s’entendant comme le facteur tendant à tirer le marché au
sens large) montre que si la taille des marchés exerce probablement un effet d’attraction
pour l’industrie, elle n’est pas nécessairement propice à l’innovation. En effet, certains
produits même moins novateurs peuvent se vendre en quantités appropriées. Dans un sens
plus strict correspondant à la notion de « marché porteur », un marché peut exercer un
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effet d’attraction s’il est « en demande », autrement dit s’il exige des produits élaborés.
Ces exigences peuvent être exprimées par les clients eux-mêmes, ou par leurs
représentants, c’est-à-dire les médecins, ou bien être fixées par des autorités de
régulation. La nécessité d’éviter la dérive des coûts impose une stratégie différente. C’est
alors à peine s’il subsiste quelque incitation pour stimuler la mise au point de produits
innovants. Les incitations ont plutôt pour effet d’orienter le choix vers les produits
génériques, ce qui peut avoir un impact défavorable sur les stratégies industrielles. Parmi
les principales observations, il ressort aussi que l’influence des « consommateurs » est
extrêmement limitée dans tous les pays étudiés. Il ne faut peut-être pas s’en étonner étant
donné la complexité des produits considérés. A l’avenir, pour stimuler la diversification
et la multiplication des produits innovants, il pourrait se révéler nécessaire d’opérer une
différenciation en fonction de principes plus explicites, fondés sur la notion de « niche »,
récompensant l’innovation.
Caractéristiques structurelles et dynamiques
et performances des systèmes
Il n’existe pas de configuration « optimale » unique de système national d’innovation
permettant d’obtenir de plus hautes performances mesurées par des indicateurs fondés
soit sur la science, soit sur l’innovation et le développement industriel. C’est pourquoi on
peut observer des écarts considérables entre les caractéristiques structurelles et
dynamiques des systèmes d’innovation biopharmaceutique de pays affichant des résultats
analogues en matière de science, et d’innovation et développement industriel. Il semble
toutefois que certains facteurs soient extrêmement propices aux performances en matière
d’innovation et de développement industriel. S’agissant des conditions-cadres, du
contexte institutionnel et de la politique publique, ces facteurs pourraient être, par
exemple, la maturité des marchés nationaux des actions, l’existence de politiques et
d’instruments de commercialisation de la technologie et l’orientation proprement
biotechnologique de ces politiques de commercialisation. En outre, les mesures visant à
créer et à entretenir une base de connaissances de pointe sont généralement primordiales
pour la commercialisation mais l’inverse n’est pas vrai. Les pays qui adoptent une
stratégie d’action globale en recourant à une large panoplie de mesures pour promouvoir
les biotechnologies correspondant à la totalité des fonctions du système d’innovation
affichent généralement de meilleurs résultats que ceux qui appliquent des politiques
fragmentaires, au coup par coup.
Imperfections des systèmes
Les défaillances systémiques peuvent créer des obstacles au processus d’innovation
ou le fragiliser gravement. Parmi les imperfections des systèmes, on citera l’absence ou
l’intervention inappropriée des acteurs de la production, de la diffusion et de l’application
du nouveau savoir, l’absence de liens et d’interactions entre les différentes parties du
système, etc. Les études de cas par pays ont répertorié des imperfections systémiques
aussi nombreuses que diverses dans toutes les parties des systèmes d’innovation.
Toutefois, la majorité d’entre elles sont liées à l’exploitation et à la commercialisation du
savoir, ainsi qu’aux conditions-cadres. En voici quelques exemples : absence de maîtrise
des biotechnologies par les organismes de transfert technologique, inadéquation des
modèles d’attribution des droits de propriété et de répartition des avantages économiques
de la propriété intellectuelle entre le chercheur et l’organisme de recherche, carences des
politiques de valorisation et d’exploitation des organismes publics de recherche, mauvaise
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articulation entre les secteurs privé et public, insuffisance du capital-risque, manque de
compétences spécialisées en ressources humaines. Il semble que la plupart des
imperfections systémiques ne puissent être imputées à une seule catégorie de causes
(acteurs, fonctions, institutions et interactions) mais qu’elles relèvent de la combinaison de
plusieurs facteurs.
Recommandations à l’intention des pouvoirs
publics
Au cours des dernières décennies, le rôle des pouvoirs publics en matière de politique
de l’innovation a considérablement changé. En prenant un modèle d’innovation linéaire,
on voit que la politique d’innovation de la première génération (dans la période d’après-
guerre) a privilégié le financement de la R-D, en particulier la recherche fondamentale,
c’est-à-dire la recherche d’application générale. Ce financement « prenant une certaine
distance avec le marché » était destiné à compenser les défaillances du marché, ce qui a
conduit les entreprises de pointe à investir insuffisamment dans la R-D. Depuis le milieu
des années 90, les systèmes d’innovation sont devenus si complexes que les pouvoirs
publics doivent s’attaquer aux « défaillances systémiques ». La diffusion de l’innovation,
le caractère interactif du processus d’innovation (et les multiples phases de rétroaction
entre les différents stades du processus) ainsi que la spécificité régionale et/ou sectorielle
des processus d’innovation sont désormais reconnus. Les politiques sont conçues pour
remédier aux défaillances systémiques entravant le fonctionnement du processus
d’innovation. Ce sont précisément ces défaillances qui justifient l’intervention des
pouvoirs publics, non seulement par le biais du financement de la recherche fondamentale
mais aussi (et c’est là qu’interviennent les politiques d’innovation de deuxième
génération) de manière plus large afin de s’assurer que le système d’innovation, considéré
comme un tout, obtienne de bons résultats.
Dans les années à venir, un nouveau rôle échoira aux pouvoirs publics, à savoir
d’admettre l’importance de l’innovation dans le système de gouvernance des politiques
d’innovation lui-même. Les politiques de première et de deuxième générations visaient le
système d’enseignement et de recherche, le monde des entreprises, les conditions-cadres,
l’infrastructure et les intermédiaires. Les politiques de troisième génération seront axées
sur les pouvoirs publics en tant que tels. Il s’agit tout particulièrement de combler, au sein
des gouvernements, le « déficit de coordination » entre les différents ministères qui,
chacun, s’occupent d’aspects particuliers de la chaîne de l’innovation, mais aussi entre les
administrations nationales, internationales et régionales.
Compte tenu des défaillances systémiques recensées dans les systèmes nationaux
d’innovation biopharmaceutique à l’occasion des études de cas par pays, et de la nécessité
d’adopter une approche intégrée englobant les politiques d’innovation des première,
deuxième et troisième générations, un certain nombre de recommandations ont été
formulées qui portent respectivement sur les aspects suivants :
• Cohérence et homogénéité des politiques de l’innovation : conjuguer des objectifs
tels que l’amélioration de la compétitivité internationale par le biais de politiques de
l’innovation axées d’une part, sur les biotechnologies et, d’autre part, sur l’existence
d’un système de soins de santé de grande qualité et d’un coût abordable.
• Bonne gestion des affaires publiques : faire en sorte que les patients et/ou leurs
représentants jouent un rôle plus actif dans les processus d’innovation, les essais
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cliniques et l’accès au marché. (D’importantes sources potentielles d’innovation
demeurent inexploitées à ce jour).
• Promotion de la coopération et du travail en réseau : tisser des liens pour bâtir un
réseau au sein du système d’innovation biopharmaceutique, en particulier entre les
acteurs du monde scientifique et de la communauté des entreprises.
• Soutien à un secteur innovant : élaborer les instruments qui inciteront le secteur
privé à investir dans les entreprises biopharmaceutiques.
• Cadre de réglementation : élaborer des réglementations transparentes et stables
n’exigeant pas de lourdes formalités et offrant un bon système d’information sur les
procédures et la mise au point d’un régime adéquat pour protéger les innovations
biopharmaceutiques.
• Transfert de technologie : stimuler l’exploitation des fruits de la recherche
biopharmaceutique du secteur public, inclure les indicateurs de DPI à l’examen ainsi
que les procédures d’évaluation, et mettre en place une infrastructure idoine pour
épauler les « jeunes pousses » (connaissances spécialisées sur le plan juridique, des
entreprises et de la commercialisation, pépinières d’entreprises et autres
infrastructures techniques).
• Stimulation de systèmes scientifiques solides : la persistance des imperfections du
marché liées à la recherche fondamentale indique aux pouvoirs publics qu’ils ont un
rôle à jouer en matière de politiques et de financement de la recherche.

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Chapter 1

Introduction
This chapter sets the stage for the subsequent examination of eight cases studies on
biotechnology and the pharmaceutical sector in the context of the national innovation
systems in OECD countries. It presents the methodology used and points out the main
areas in which biotechnology plays an active role in the pharmaceutical sector.
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Background
Building on previous work on national innovation systems, the OECD Case Studies in
Innovation are designed to study specific sectors or fields of technology in order to
understand the idiosyncracies of specific areas of technology and sectoral innovation
systems. On this basis, policies can be developed that complement generic innovation
policies, which may have limited effects in the context of specific areas of technology or
sectoral innovation systems (OECD, 2002). The development of new policy initiatives
that stimulate and support the rapid development of national innovation systems calls for
an understanding of these specific properties. Hence, the challenge for innovation policy
is to develop a consistent and transparent policy mix which takes due account of these
specificities.
In accordance with these considerations, the OECD Case Studies in Innovation are
designed to contribute to the analysis and development of concrete policy initiatives in
specific areas. As the development of new policy initiatives requires an understanding of
the sector and the specific properties of innovation systems, a methodology is needed that
enables in-depth study and systemic comparisons of various innovation systems. Such a
methodology requires a combination of both quantitative and qualitative information.
This conforms to the view that deeper insight into the practical functioning of individual
innovation systems is needed and can be gained through case studies. The functioning of
an innovation system and its performance can to a certain extent be identified by
quantitative analyses but qualitative information is also needed to arrive at a deeper
understanding. This requires a description of the working, structure and dynamics of a
sectoral innovation system in developing, producing and delivering products and services
to meet demand from users and consumers, and the way a sectoral system changes over
time.
Biotechnology has become the driving force of dramatic changes in the innovation
process in various sectors. This is best illustrated by the pharmaceutical industry, where
the traditional chemical paradigm of drug discovery and development is replaced by a
new biotechnological paradigm. This has important consequences for the structure and
functioning of the biopharmaceutical innovation system: biotechnology firms and public
sector research organisations are becoming key actors generating new knowledge, tools
and substances for the pharmaceutical industry. Regulations, standards and IPR schemes
have to deal with new types of components, and on the demand side, new solutions are
emerging for hitherto unmet needs. For that reason, the biopharmaceutical innovation
system was chosen as one of the pilot sectors for the Case Studies in Innovation. The
other two pilot sectors are energy technology and knowledge-intensive service activities
(KISA).
The current state of biotechnology differs considerably between countries. A number
of factors are responsible for these differences. In the case of pharmaceutical
biotechnology, diverse health-care systems, product approval regulations and procedures,
or demand configurations can generate different feedbacks into the R&D process. The
growing internationalisation of the pharmaceutical industry may have profound impacts
on national biopharmaceutical innovation systems. Public support for R&D might
compensate unfavourable demand conditions. Education systems are adapted differently
to the changing requirements of the national life sciences industry, and public perceptions
of biotechnology have developed along different paths. In order to understand the role of
these and other forces in shaping the configuration, dynamics and performance of the
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various national biopharmaceutical innovation systems, international comparisons are
required.
The general aim of the study was to provide a systematic comparison of
biopharmaceutical sectoral innovation systems in OECD countries. On the basis of cross-
country analysis and an explanation of national differences, policy conclusions can be
drawn as regards the balance between horizontal innovation policies and measures that
take into account the more specifically sectoral or technological characteristics of the
biopharmaceutical innovation processes.
In order to achieve this goal, the following specific aims of this case study on
biopharmaceutical innovations systems were set:
• To investigate the specific characteristics of the national biopharmaceutical
innovation systems, especially the structure and dynamics of innovation networks and
the role of demand factors and the market. This includes the influence of government
incentives and governmental/public framework conditions that affect innovation
performance of the national biopharmaceutical innovation systems and to assess the
performance of the system.
• To develop recommendations enhancing the effectiveness of policies to encourage the
economic performance of national biopharmaceutical innovation systems. Systemic
imperfections are addressed in the investigation and in the policy recommendations.
National system, systems imperfections and the role of public policies: key questions
Given the specific characteristics of national biopharmaceutical innovation systems
and the role public policies can play in the management of innovation processes in order
to correct systems imperfections, two key questions were formulated:
• Can one identify important differences and similarities in the structure and dynamics
of national biopharmaceutical innovation systems which explain the performances?
• What are the main systemic failures in the national biopharmaceutical innovation
systems and how can they be addressed in policy recommendations?
Systemic failures can be seen as symptoms of sub-optimal innovation systems and are
judged as being a rationale for innovation policy actions, next to other rationales. Systemic
failures can be defined as mismatches between elements in an innovation system; they
hinder the functioning of an innovation system and the flow of knowledge and therefore
reduce the system’s overall efficiency (OECD, 1999). Examples of systemic failures are
overly stringent or loose appropriability regimes, lock-in effects, inefficient learning
processes, malfunctioning interfaces, etc. In general, the causes of systemic failures can
be classified in four broad categories:
• Absent/inappropriate innovation functions (e.g. production, diffusion and application
of knowledge).
• Absent/inappropriate actors.
• Absent/inappropriate institutions.
• Too much/too little interaction.
However, an in-depth investigation of these systemic failures and their implications
for policy has been lacking for biotechnology. The investigation of these systemic
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characteristics is one of the main goals of the OECD Case Studies in Innovation and
therefore a main issue in this study. A specific objective of this case study is to draw
policy conclusions with regard to the balance between horizontal innovation policies and
more customised measures that take into account the specific characteristics of innovation
processes in the biopharmaceutical innovation system. Considering the identification of
systemic failures as key to fostering innovation, recommendations will be presented on
how innovation policies can be customised to meet the particular needs and features of
the biopharmaceutical innovation system.
The concept of national innovation systems implies a definition based on a country’s
boundaries. However, developments in high-technology sectors, including biotechnology,
are to an increasing extent realised by international research and business networks; these
are found in international R&D co-operation agreements and the presence of foreign
companies such as major pharmaceutical multinationals in a given country. This national/
international dimension of system openness is especially relevant to national policy
making when developing and implementing national biotechnology policies and is also
addressed in this study. However, in addition to this national/international dimension,
openness is also understood in terms of the extent to which new actors (can) enter or must
leave the biotechnology innovation system and entry and exit barriers (e.g. lock-in
effects).
Demand-side factors play a major role in the successful development of new
technologies, with biotechnology as the most prominent example. However, in the
literature and research on (national) innovation systems, demand-side factors have gone
relatively unaddressed. Which specific actors and institutions constitute the demand side
of the innovation system (e.g. consumer and patient organisations, national health-care
systems, including insurance companies, organisations responsible for regulations on
market introduction of [bio]pharmaceutical products), and what is their specific
function/role in the innovation process? What is the influence of framework conditions
such as market access, regulation and the structure of national health care systems?
Demand-side factors and their influence on the performance of national
biopharmaceutical innovation systems are also investigated in the study.
Methodology
The explorative and comparative nature of this study makes a method based on case
studies the most appropriate. The ambition of this study is to compensate for some
drawbacks of case studies (OECD, 1999, p. 15) by linking quantitative indicators to the
basically qualitative case studies to the greatest possible extent. In order to facilitate
comparability across countries, a common methodology was developed for the national
case studies that could be used as a framework for the collection and presentation of data:
the Guidebook. The Guidebook presented definitions of biotechnology, the
biopharmaceutical and pharmaceutical sectors and structure, and dynamics of innovation
systems. Moreover, it provided an overview of the methods by which all necessary data
had to be gathered in order to answer the key research questions of this project (Enzing et
al., 2002).
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The main methods used in the study were:
• A descriptive analysis of the national biopharmaceutical innovation system, including
the biopharmaceutical innovation chain and the types of actors and organisations
involved. Moreover, this serves to describe the main framework conditions that affect
the outcomes of the biopharmaceutical innovation process. This step draws on an
extensive literature survey and desk research.
• Bibliometric and patent analysis for measuring national performance. This also
serves to identify the main types of actors and their actual relevance in the
biopharmaceutical innovation process. For the bibliometric and patent analysis, data
on publications and citations were taken from the Science Citation Index databases in
February 2003 and those for patent applications from the European Patent Office.
• Industry survey for data collection of R&D co-operation patterns of national firms.
The Guidebook contained a template for a questionnaire. The survey included both
dedicated biotechnology firms (high-tech companies specialised in biotech and active
in R&D and its application in processes/products and services) and diversified firms
(established firms that have integrated biotechnologies in their existing R&D and
production activities).
• Interviews with representatives of companies and publicly funded research
organisations on driving forces, the specific character of regional innovation
dynamics, collaboration patterns, barriers such as human resources, venture capital,
intellectual property rights, etc., role of users in the innovation process and role of
national innovation policies. Also, interviews with representatives of organisations
that play an important role on the demand side of the innovation process: patient
organisations, consumer organisations, the national health system, insurance
companies, authorities involved in product regulation, and approval of their role in
the innovation process.
National reports were prepared for Belgium, Finland, France, Germany, the
Netherlands, Norway, Japan and Spain. On the basis of these reports, a cross-country
analysis was carried out. The results of the analysis are presented in this report.
Biotechnology in the pharmaceutical sector: products and processes
Biotechnology mainly plays two roles in the pharmaceutical innovation process. First,
it has emerged as one of the key methods for biopharmaceutical and biomedical research,
because biotechnology approaches contribute significantly to the elucidation of the
regulatory and physiological mechanisms of disease. An important contribution to this
line of research is expected from the results of human genome research. Second,
biotechnology is central for research, development and production of new pharmaceutical
products, namely diagnostics, biopharmaceuticals and vaccines.
Human genome research
In 1990 the Human Genome Project was initiated in the United States under the
leadership of the US Department of Energy and the National Institutes of Health. Several
other countries joined in, resulting in a worldwide public sequencing project. In 1998, a
private sequencing project started to compete with public efforts and greatly accelerated
progress. In February 2001 the draft human genome sequence was published in two
papers by the public and private consortia (Human Genome Consortium, 2001; Venter
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et al., 2001). The draft sequence covered about 90% of the gene-rich (euchromatic)
portion of the genome; each base pair of the 90% was sequenced four times on average.
In total, the human genome contains 3.2x10
9
building blocks. A surprising result of the
human genome sequencing exercise was the low number of genes, which is estimated to
total 30 000-40 000. This result implies that the complexity of the human body is not
solely determined by the number of different genes but rather on more complex processes
of downstream gene expression. After the elucidation of the human genome, the next
challenge is to identify genes and their function, which is also an important prerequisite
for making use of genome information in the biopharmaceutical innovation process. The
implications of human genome research for the biopharmaceutical industry concentrate
on diagnostics and screening and the identification of new targets for drug development.
Diagnostics
There are two main strategies for diagnostics based on biotechnology:
immunodiagnostics and DNA diagnostics;
• Immunodiagnostics are based on the very specific interaction between antibodies and
antigenes. Using radioactive, enzyme, luminescent or fluorescent markers for either
component allows very sensitive detection of the immunoreaction. Novel approaches
for increasing sensitivity combine immunoreactions with DNA amplification: DNA
tags are used as markers and are amplified by specific DNA polymerising reactions.
In human diagnostics immunoassays can be used for identifying specific antibodies or
antigenes which indicate certain disease conditions, such as viral or bacterial
infections or cancer.
• DNA diagnostics rely on the specific structural features of the DNA molecule which
is made up of two strands which bind to each other. This implies that single strands of
DNA which code for specific genes can be detected – for example, in preparations of
human cells by using the other, complementary strand of DNA. If one of the strands
is labelled with a radioactive, chemical or biological marker, the binding reaction
produces a measurable signal. This basic principle of DNA diagnostics is also used in
DNA chips. However, in this case the binding reaction does not take place in solution
but on a solid state surface. Biochips allow the simultaneous detection of thousands of
genes.
Genome research has a strong impact on DNA diagnostics because an increasing
number of disease-related genes and their modifications is becoming available and can be
used for designing specific DNA diagnostic kits. Examples include genes for certain
cancers. DNA chips for diagnostic purposes have already been developed for HIV
diagnosis, for the detection of cancer-related genes and for the analysis of variations in
liver enzymes that are relevant for certain disease conditions.
Therapeutics
Using genetic engineering it is possible to produce foreign proteins in micro-
organisms or cell cultures from higher organisms. This basic principle is used for the
production of protein therapeutics. An important example of this approach is the
production of human insulin. The genes for this protein have been extracted from the
human genome and transferred into either bacteria or yeast cells. Both systems allow the
expression of the human insulin product which, after purification and modification, can
be used as a pharmaceutical. Other important biopharmaceuticals on the market include
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erythropoietin, growth factors, interferons and tissue plasminogene activators (TPA).
New product groups include biopharmaceuticals based on monoclonal antibodies. In 2003
about 370 biopharmaceuticals were in the clinical development and approval process in
the United States, and about 280 in Europe (BPI, 2003). Even though the use of
biotechnology for producing biopharmaceuticals has been quite successful, the potential
of this approach is probably limited. According to expert estimates it is unlikely that
biopharmaceuticals will gain more than 10% of the total market for pharmaceuticals.
More important than the use of biotechnology as a production method is its
application as an R&D tool in drug discovery. Biotechnology as an R&D tool is
considered to be one of the main driving forces of innovation in the pharmaceutical
industry, leading to a shift in the paradigm of drug discovery and development. An
overview of the new, biotechnology-driven mode of drug discovery is given in
Figure 1.1. An increasing number of new drug targets will be detected from the human
genome sequence information. Of the 30 000 to 40 000 presumed human genes only a
minority may turn out to be interesting drug targets. However, this may still account for
3 000 to 10 000 new targets. Compared with the existing number of drug targets this
would still correspond to an increase of about one order of magnitude (Reiss, 2001).
Figure 1.1. Biotechnology-driven drug discovery


Source: Jungmittag et al. (2000).

The increasing number of potential new drug targets eliminates an important
bottleneck in the drug discovery process. At the same time, the assessment of the
Synthetic

collections

Natural

products

Large combinational

libraries

hit

Focused

combinational

library

HTS

lead

Drug candidate

Preclinical/clinical

development


Target

Functional

disease models

Genome

sequencing

Pharmacogenetics

Patent

Chemistry

Biochemistry

Combinational

chemistry

Biotechnology

Molecular

biology

Bioinformatics

Robotics

Automation

Medicinal

chemistry

Pharmacology

New drug


Chemicals

Profiling

selection

EST

Comparative

genomics


Screening


HTS/UHTS

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usefulness of new targets introduces a new barrier. The key words are target validation. A
validated target is achieved when treatment with the therapeutic compound leads to
desirable clinical outcomes. The validation of new targets requires biological information
on the physiological role of the putative targets. A number of new approaches, such as
analysing the expression of genes, comparing genome information between different
organisms and between healthy and disease conditions, or even the use of three-
dimensional information on the structure of potential drug targets are used in this context.
Screening for the usefulness of putative new drug targets is currently performed in a
high-throughput manner, an approach that has made impressive progress over the last
decade. Today it is possible to perform 100 000 and more screening tests within one week
fully automatically. The increased screening capacity requires the availability of a
sufficient number of chemicals to be tested for potential pharmaceutical use. For that
purpose, combinatorial chemistry approaches, for example, are used in the drug discovery
process.
Pharmacogenetics
Pharmacogenetics denotes the study of polymorphisms in genes that affect the
response of an individual to drugs. More efficient clinical trials could be achieved by
using this information to select for clinical trials patient groups for which a good response
and low side effects from the new treatment can be expected. The long-term goal of
pharmacogenetic approaches is the development of customised and personalised
medicines. By identifying the genetic uniqueness of an individual, the therapeutic
strategies for treating a particular disease state can be refined. It should be pointed out
that such pharmacogenetic approaches rely on the availability and utilisation of individual
genetic information. This implies that procedures and structures need to be established
which assure confidentiality and responsible handling of such individual information.
Vaccines and antibiotics
Vaccines are considered to be among the most powerful health care tools of the 20th
century. They contribute both to preventing disease, disability and death and to
controlling health care costs. Even though impressive success has been achieved by
vaccination, including the global eradication of smallpox, tremendous problems remain
with respect to infectious diseases, the leading cause of death world-wide. No effective
vaccination is yet available for some traditional diseases such as tuberculosis and malaria,
but new and re-emerging diseases pose a continuing threat to health. Moreover,
antimicrobial resistance is developing widely. These examples indicate the increasing
need for new and improved vaccines.
Biotechnology provides new approaches to solve the scientific problems previously
associated with vaccine development. This includes a new generation of vaccines based
on specific parts of the protein of the infectious agents, which are produced by genetic
engineering. Other new strategies include the development of DNA vaccination or the
genetic engineering of plants to produce edible vaccines which may facilitate simple and
effective vaccination administration.
The increased resistance of pathogenic micro-organisms to commonly used
antibiotics, the growing frequency of infections, and the emergence of new pathogens
poses major challenges to health. The availability of genome sequences for an increasing
number of micro-organisms provides opportunities for the development of new
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antibiotics. Sequence information enables the identification of the bacterial gene products
that are most appropriate for targeting by antibiotics.
The pharmaceutical product development process
1

Once a new biopharmaceutical drug compound has been developed in the laboratory,
there is an extensive period of testing before it can be approved and be actually put on the
market (Table 1.1). The first step in this process is preclinical testing, in which the
pharmaceutical company conducts laboratory and animal studies to show the biological
activity of the compound against the targeted disease, and the compound is evaluated for
safety. These tests take approximately three and a half years on average (Alliance
Pharmaceutical Corp., 2003).
Table 1.1. Phases of product development in the pharmaceutical sector

Preclinical testing
Phase I
Phase II
Phase III
Competent
authority
Phase IV
Years 3.5 1 2 3 2.5
Test
population
Laboratory and
animal studies
20 to 80 healthy
volunteers
100 to 300 patient

volunteers
1 000 to 3 000
patient
volunteers
Purpose
Assess safety and
biological activity
Determine safety
and dosage
Evaluate
effectiveness,
look for side
effects
Verify
effectiveness,
monitor adverse

reactions from
long-term use
R
eview proces
s/
approval
Success rate
5 000 compounds
evaluated
F
ile IN
D
at c.a.*

5 compounds enter trials
File
NDA at
c.a.*
1 compound
approved
Additional
post-
marketing
testing
required by
competent
authority
*c.a.: competent authority, e.g. EMEA or FDA.
Source: Adapted from Alliance Pharmaceutical Corp. (2003).
After completing preclinical testing, the company files an Investigational New Drug
Application (IND) with its respective competent authority to begin to test the drug in
people. The IND shows results of previous experiments, how, where and by whom the
new studies will be conducted, the chemical structure of the compound, how it is thought
to work in the body, any toxic effects found in the animal studies, and how the compound
is manufactured.
Clinical trials, i.e. tests of the active compound in human subjects, are conducted in
three different phases plus a fourth after approval. Phase I tests take about a year and
involve about 20 to 80 healthy volunteers. The tests study a drug’s safety profile,
including the safe dosage range. The studies also determine pharmacokinetics and
pharmacodynamics (i.e. how a drug is absorbed, distributed, metabolised and excreted,
the duration of its action), and possible and optimal methods of drug administration. In
phase II, controlled studies of approximately 100 to 300 volunteer patients (people with
the disease) assess the drug’s effectiveness, which takes on average about two years.
More safety data are gained as well as information concerning the effectiveness of the
drug at treating the symptoms or conditions it is proposed for. It is focused at determining


1. This section is based on Fraunhofer ISI (2004).
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the therapeutic effectiveness in subjects, with further attention to safety. The results of
phase II are used to establish the parameters of phase III. This final phase of clinical trials
involves several hundred to thousands of individual subjects who suffer from the specific
condition or conditions that the drug is intended to treat. This phase is to determine if the
benefits of a treatment with the tested compound are significant enough to outweigh the
risks. The tests used in this phase must be extremely thorough and meet rigorous
standards, as they are the basis for approval of the drug.
Following the completion of all three phases of clinical trials, the company analyses
all of the data and files a new drug application (NDA) with its competent authority if the
data successfully demonstrate safety and effectiveness. The NDA must contain all of the
scientific information that the company has gathered. The review times differ from
country to country and have been subject to various attempts at regulation. Once the NDA
has been approved, the new medicine becomes available for physicians to prescribe. The
company must continue to submit periodic reports to the authority, including any cases of
adverse reactions and appropriate quality-control records. The product approval process
follows the same basic steps in the European Union, the United States and Canada. In
general, there are only slight differences concerning some details between regions.
The pharmaceutical industry
The pharmaceutical industry is the fifth largest industrial sector in the EU (EFPIA,
2002), accounting for about 3.5% of the total manufacturing production (Gambardella
et al., 2000). With an estimated share of 35% of the world pharmaceutical output, Europe
is the main manufacturing location, ahead of the United States and Japan (EFPIA, 2002).
In 2000, in the EU15, 479 100 persons were employed in the pharmaceutical sector and
the average employment growth rate was more than 2% between 1985 and 2000 (Eurostat
data; Lienhardt et al., 2003) with 88 200 employees in charge of R&D matters (EFPIA,
2002). Throughout the EU, nearly 80% of the employees work for large enterprises
(Lienhardt et al., 2003). Besides the research-based industry, the generics industry is very
relevant in the EU. In 1999, the generic market in western Europe, i.e. the EU member
states plus Switzerland, Iceland and Norway, was worth around EUR 10 billion
(European Generic Medicines Association, 2003). According to the US Bureau of the
Census (2001), in the year 1997, 203 337 employees (only those on payroll counted)
worked in pharmaceutical medicine manufacturing in 1 761 establishments of
1 428 companies. Nearly 70 000 employees worked in the field of R&D (PhRMA, 2003).
Over the past ten years, Europe’s R&D base has gradually eroded (Figure 1.2). Most
particularly, some new leading-edge technology research units have been transferred out
of Europe, mainly to the United States, but central R&D labs of some European
pharmaceutical companies have also been moved there (such as Novartis in 2002). R&D
expenditures in Europe doubled over the 1990s to reach EUR 17 billion in 2000. In 1997,
the US industry was able to overtake Europe in terms of total amount of R&D
expenditure. Between 1990 and 2001, R&D investment in the United States rose fivefold,
while in Europe it only grew 2.4 times, reaching EUR 24 billion in 2000. R&D
expenditure in Europe represented 1.90% of GDP in 2000, the same figure as in 1990,
whereas in 1999, the United States spent 2.64% of its GDP on R&D and Japan spent
3.04% (EFPIA, 2001, 2002).
In 1990, major European research-based companies spent 73% of their worldwide
R&D expenditures on EU territory. In 1999, they spent only 59% on EU territory. The
United States was the main beneficiary of this transfer of R&D location (EFPIA, 2001).
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INNOVATION IN PHARMACEUTICAL BIOTECHNOLOGY: COMPARING NATIONAL INNOVATION SYSTEMS AT THE SECTORAL LEVEL – ISBN-92-64-01403-9 ©OECD 2006
Figure 1.2. Pharmaceutical R&D expenditure in Europe, the United States and Japan, 1990-2000
EUR million
n.a.
0
5 000
10 000
15 000
20 000
25 000
30 000
1990 1995 1999 2000 (e)
Europe
United States
Japan

(e): estimate
Source: EPPA, PhRMA, JPMA; cited in EFPIA (2001).
This report
This synthesis report builds on the results of the eight national country studies and
addresses the key questions of the case study. Chapter 2 presents the summaries of these
national reports. In Chapter 3 a performance analysis of the eight national
biopharmaceutical innovation systems based on quantitative indicators is presented.
Chapter 4 addresses the openness of the national biopharmaceutical innovation systems.
Chapter 5 provides a comparison of the demand-side factors in the eight countries and
market attractiveness based on market-related factors in a narrow sense and on social and
regulative factors. Chapter 6 presents the structure and dynamics of the eight national
biopharmaceutical innovation systems and draws conclusions about which characteristics
of these systems might be responsible for their scientific and commercial performance.
Chapter 7 draws together the overall results of the analyses concerning systemic
imperfections. It also discusses the sectoral or generic character of these imperfections.
The report concludes by presenting how the role of governments in innovation policy has
evolved and presents the recommendations that can be used by national policy makers in
order to overcome the systemic imperfections and reach more consistent and coherent
innovation policies.
The chapters of this report build on input by the project participants from the eight
countries that have collaborated in this case study. A list of authors and national project
teams can be found in the foreword.
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