Tài liệu Regulatory Europeanization, National Autonomy and Regulatory Effectiveness: Marketing Authorization for Pharmaceuticals pptx

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Feick: Marketing Authorization for Pharmaceuticals 5
1 Introduction
This paper
1
is about product regulation in an intensely regulated policy field in
which the regulatory landscape in the European Community (EC) has reached a
high degree of institutional variation and sophistication. It is about marketing
authorizations for pharmaceutical products for human use, and will focus on two
major blocks of questions. The first one has to do with the tension between regu-
latory supranationalization – be it central or hierarchical – and national autonomy
(Scharpf 1994), the second one with the efficacy and efficiency of regulatory Eu-
ropeanization. Both questions are connected to the wider topic of governing in
the EC (Scharpf 1999) – here by means of regulatory policies – with the aim of
correcting market behavior while simultaneously enabling the creation of a larger
market and also furthering the policy goals of industrial innovation and competi-
tiveness. The paper focuses mainly on implementation. Policy-making in the
European multi-level system has received most of the attention in the last dec-
ades. But when inquiring into the governing capacity of the EC, the complicated
relationships between European and national institutions, and the impact of
regulatory decision-making, it is no less important to analyze what happens after
regulatory law has been passed. Or, as Martin Shapiro puts it: “the crucial prob-
lem for the Union is now … implementing the regulatory statutes it has enacted”
(Shapiro 2001: 95).
The policy problem of market entry regulation for pharmaceuticals has been on
the agenda of the EC, the Member States and other industrialized countries since
the early sixties, after the thalidomide catastrophe had surfaced with thousands
of fetal deformities and children born with phocomelia. The United States reacted
first, amending already existing, comparably strict market entry regulation. Dur-
ing these years intensive international regulatory discussions took place among
many national governments, parliaments and regulatory authorities as to the ap-
propriate policy solutions. A specific motive behind the EC’s early involvement
in these exchanges on regulatory design was to remove already existing regula-
tory trade barriers and to avoid new ones. After thirty years of trials and relative
successes in harmonizing national legislation – the first legislative guideline


1 I would like to thank S. Schmidt and P. Bouwen for their reviews of preceding ver-
sions and very helpful suggestions, F. Scharpf for early discussions about the per-
spective of this paper, P. Urfalino and B. Hauray for their comments on French
regulatory behavior, and G. Abels for useful questions and remarks especially con-
cerning the biotech sector. I would especially like to thank many interviewees in
public institutions at different levels, in industrial and professional associations and
in operational organizations of the health care sector for helping me to understand
the issues discussed in the paper. F. Pfeffer was also extremely helpful in preparing
the graphs and tables.
6 MPIfG Discussion Paper 02/6
coming out as early as 1965 – and of failures in attempting to achieve mutual rec-
ognition through legal harmonization and soft policies of communication re-
quirements and procedural coordination (1975, 1983, 1987), the EC finally intro-
duced two ostensibly European procedures for marketing authorization in 1995,
backed by new regulatory implementation structures. These two European pro-
cedures – a purely national alternative having been retained – obey different in-
stitutional logics, reflecting in their design and allowing in their application the
intrusion of specific national and industrial preferences and interests. It is the still
rather brief experience with these new procedures which provides the empirical
basis of this paper.
Empirical information stems from a variety of sources. Primary information in-
cludes official documents such as legal provisions, administrative guidelines and
the written positions of crucial actors, oral information provided by participating
actors in different agencies and administrations, stakeholders and interested par-
ties, and also process-produced data such as statistics on the procedures and their
outcomes. Secondary information contains statistical data provided by third par-
ties, quantitative and qualitative survey data as well as secondary literature. It
should be noted that in this regulatory area the European tradition is one of ex-
treme secrecy and, furthermore, shows a lack of consistent data collection. This
means that often even seemingly hard data have to be interpreted with great care.
In the literature certain data are often cited – such as national counts of author-
ized or marketed pharmaceuticals – which lack comparability due to differing,
changing or obscured definitions. Where it seems advisable the reader will find
notes of caution.
In the spectrum of EU research
2
this paper’s general interest is on the capacity of
the EU to cope with perceived policy problems, to institutionalize a viable regu-
latory implementation structure and to reconcile potential tensions between
European centralization and the autonomy of national authorities. From a policy-
process perspective we are dealing with the output of policy-making, the
throughput system of implementation, and the outcome-related effectiveness of
implementation.
3
Analytically the institutionalized regulatory procedures are the
primary focus, because it is the institutional context which prescribes the way de-
cisions have to be taken and provides options as well as restrictions for involved
actors to bring both their cognitive and their normative orientations to bear.
4
Furthermore, the different institutional procedures develop their own logic,
making the functionality of the decision-making procedures and any possible
outcomes more or less probable. Although market entry regulation for pharma-


2 For overviews see Wolf (1999), Giering (1997) and Jachtenfuchs/Kohler-Koch (1996).
3 See Scharpf (2001a, 1970, 1999).
4 See Mayntz/Scharpf (1995: 43).
Feick: Marketing Authorization for Pharmaceuticals 7
ceuticals is only a rather limited field and probably not even approximately rep-
resentative of EU policy-making and implementation in general, it is nevertheless
an interesting case for different reasons:
– its regulatory history has traversed practically all approaches to European in-
tegration;
– its current regulatory state offers two radically different European regimes, to-
gether with a purely national option, for basically the same regulatory task;
– it is one of the rare governmental intervention fields in which a genuine Euro-
pean implementation structure has been institutionalized for the most Europe-
anized procedural alternative.
J. Weiler’s remark on the EU’s “stunningly small bureaucracy … and … laugha-
bly small budget” (Weiler 2000: 235) reminds us of its resource scarcity, which is
one of the reasons why the EU has been confined mainly to regulatory instead of
distributive policies (Majone 1996a) – except in agricultural and, to a lesser de-
gree, structural policies – and has to rely on Member State administrations for
implementation in a “two-tiered system” leaving the Commission with the prob-
lem of “regulating the regulators” (McGowan/Wallace 1996). The European
Commission generally does not possess the necessary administrative infrastruc-
ture (Scharpf 1994: 91) and Member States have been reluctant to furnish the
Commission with it. Pharmaceuticals regulation for market entry is one of the
rare policy sectors where, finally and selectively, the EU has not only introduced
a positive regulatory policy regime but also a genuine European implementation
structure for parts of the market. Such a regulatory policy-making output was
unexpected, because the Treaty of the European Communities (TEC) explicitly
preserves national intervention autonomy in public health matters (Art. 30 – for-
merly 36 – TEC). Almost ironically, it is this explicit preservation of national in-
tervention rights in the health sector which required rather strong steps being
taken towards Europeanization if other goals were to be achieved, namely the
establishment of a Single Market and the provision of a competitive and innova-
tive regulatory environment for industrial development. Because of this initial
national autonomy in health matters and the complexity of assessing the medical
risks and benefits of pharmaceuticals, the so-called “new approach” to harmoni-
zation could not be applied to medicinal products (Kommission der Europä-
ischen Gemeinschaften 1985). Based on the European Court of Justice’s Cassis de
Dijon decision, this “new approach” of 1985 regarded a minimal degree of legal
harmonization as sufficient to oblige Member States to mutually recognize one
another’s regulatory controls whenever these could be regarded as equivalent
measures of protection. Initially, the European Commission had tried to apply
this strategy to the marketing authorization for pharmaceuticals, too, but very
8 MPIfG Discussion Paper 02/6
quickly it became clear that in this regulatory sector “the old approach” of “total
sectoral harmonization” (Dinan 1999: 356–358) was advised if mutual recognition
should have a chance at all in face of the mutual distrust of national authorities in
each other’s implementation. Eventually, it was the failure to translate even this
extensive legal harmonization into the practice of mutual recognition which fi-
nally brought about what Abraham and Lewis call a “strong European regulatory
state” (Abraham/Lewis 2000: 113) in this domain: the introduction of a central-
ized European procedure for at least parts of the market in order to facilitate the
uniform application of European legislation. Such a policy output becomes possi-
ble or advisable – even in the institutionally difficult setting of multi-level policy-
making – whenever there is consensus about the general policy goals. In this case,
this meant the guarantee of specific market-correcting product standards, the
creation of a larger, more easily accessible transnational market (Scharpf 1999:
106–107, 110), and the improvement of the international standing of the EC-based
pharmaceutical industry.
5
The regulation of market entry in the pharmaceuticals sector with its peculiar
procedural differentiation is the result of decades of negotiated policy-making.
The policy output in the form of three different institutionalized procedures in-
corporates problem or product-specific exigencies and takes into account actor-
related orientations, interests and resources. At the same time the procedures
provide the gates and channels through which actors may pursue their specific
interests in the implementation process. Thus, it depends in large measure on the
characteristics of these distinguishable institutional structures and procedures
whether they are likely to contribute to the Europeanization of regulatory deci-
sion-making or are protective of national regulatory autonomy, whether they
tend to support the development of market uniformity or market diversity, and
whether or not they make a difference as regulatory environments for firms with
respect to regulatory efficiency.


5 Majone makes the point that in certain situations centralization of regulatory deci-
sion-making can be a viable means to counter distrustful national implementing
authorities by forcing them into an integrated, uniform procedure: “Until regulators
can trust each other to avoid … selfish strategies, centralisation of regulatory author-
ity is the only practical way of correcting transboundary externalities, or preventing
the local regulation of a local market failure from becoming a trade barrier” (Majone
1998: 32). In the case of pharmaceuticals one may, indeed, argue that centralized im-
plementation does succeed in integrating otherwise non-cooperative national author-
ities into a collective decision making process as long as there are no veto positions or
exit opportunities (Majone 1996b: 279–280). But one should also note that even cen-
tralized transnational regulation requires a minimum of mutual understanding and
trustworthy cooperation as can be seen in pharmaceuticals regulation.
Feick: Marketing Authorization for Pharmaceuticals 9
2 Context and Goals of European Market Entry Regulation
for Pharmaceuticals
2.1 The Context
The EEC was still in its infancy when the thalidomide catastrophe hit several
countries in which the medicine had been marketed in Europe and around the
world.
6
By 1961 at the latest, it had become evident that taking this drug, which
was supposedly “one of the safest sedatives ever discovered,” (Silverman/Lee
1974: 94) could lead to fetal deformation in pregnant women. The country most
affected was Germany but, except for France and the USA,
7
there have been vic-
tims in almost all highly developed societies. The thalidomide affair, though not
the only one during these decades, was classified as “the single most important
event to influence our attitudes to the unwanted effects of medicines” (McEwen
1999: 269). These revelations had immediate impact on policy discussions. For
practically all European countries it had become evident that effective pharma-
ceuticals regulation, able to protect the public from health hazards, was by and
large lacking. And, where a potentially adequate legal framework existed, as in
France, implementation deficits prevented it from being much more than an in-
strument to protect the home market. These events and the public discussions
they initiated shed light on the following characteristics of the policy problem
and its context:
– Due to scientific progress in pharmaceuticals research, the industrialization of
production and increasing internationalization of trade, different countries
were facing increasingly great and widespread risks at the same time.
– Voluntary intra-industry schemes of medicines control had failed, while public
pre-marketing controls were mostly absent, ineffectively designed or insuffi-
ciently implemented.
– While the internationalization of information through worldwide media cov-
erage was able to arouse suspicion and even panic for fear of dramatic nega-
tive events, the lack in international regulatory communication and coopera-
tion became even more evident.


6 Descriptions of the events, their pharmacological background and the reaction of dif-
ferent actors in this policy domain are provided by Kirk (1999) for Germany and by
Silverman/Lee (1974) and Abraham (1995) mainly for the Anglo-Saxon world.
7 For quite different reasons the medicine had not been approved in both countries,
which were among the few that enjoyed a formal public approval procedure for
pharmaceuticals at that time. Nevertheless, some babies were affected in the USA be-
cause their mothers had taken thalidomide during pregnancy while travelling
abroad, through access to Canadian pharmacies or through doctors’ samples widely
distributed by the American company Merrell, which marketed the medicine in Can-
ada and was preparing market entrance in the USA (Silverman/Lee 1974: 96).
10 MPIfG Discussion Paper 02/6
At the same time, policies to cope with the perceived problems were available:
– Technologically the same scientific and technical knowledge and tools which
facilitated an increasingly systematized development of medicinal products
could also be used for regulatory controls of their quality, toxicity and efficacy.
– Successful national policy models existed which could inspire policy-making.
8
Problem pressure was high enough – and viable solutions obviously available –
to prevent the handling of the situation by way of non-decisions or purely sym-
bolic politics.
9
Risk-averse politicians had every incentive to create regulatory re-
gimes and systems which would not only increase the safety for patients but also
make it possible for governments to avoid blame if accidents should occur de-
spite regulatory precautions.
10
It was in this context that the EEC – or more precisely the Commission – started
discussions about developing a harmonization strategy for pharmaceuticals
regulation in the early 1960s, as an attempt to standardize regulatory assessments
and evaluations in order to assure that equivalent national regulatory procedures
and decisions were in place. The thalidomide scandal actually marked a regula-
tory starting point for both the EC and the Member States. Therefore, one might
have expected a more unified approach from the very beginning. However, the
lack of rigorous regulatory legislation or implementation in the single Member
States did not signify the absence of nationally diverging conditions – be they
economic, political, legal, administrative or medical – when it came to the design
of a regulatory framework which would control the behavior of the pharmaceuti-
cal industry, prescribe regulatory action to be taken by implementing admini-
strations and influence the availability of pharmaceuticals for medical therapies.
In fact, the Commission was well aware from the outset that differences in ad-
ministrative practice could always jeopardize the desired effects of legal har-
monization.
11

8 In the thirties the US had institutionalized quality- and safety-oriented marketing
authorization procedures entrusted to the Food and Drug Administration (FDA).
These controls were tightened and extended to efficacy standards by the Kefauver-
Harris Amendments of 1962 as a reaction to the thalidomide scandal (Silverman/Lee
1974: 96). In Scandinavia, some rather strict licensing regulations had long been in
force – in Norway, for example, since 1928 and in Sweden since 1934 (Abraham/
Lewis 2000: 55; Dukes 1985).
9 It took some years, though, until effective control systems were installed in the dif-
ferent countries. For differences in policy-making speed, see Mayntz/Feick (1982)
and Feick (2000).
10 For a systematic discussion on strategies to avoid or to shift blame, see
Hood (2002).
11 The European Commission expressed its skepticism about a purely legal harmoniza-
tion strategy only one year after the Council had adopted the General Programme on
Feick: Marketing Authorization for Pharmaceuticals 11
2.2 The Goals
The general goals of European pharmaceuticals regulation are straightforward. In
the words of the Pharmaceuticals Unit of the Enterprise Directorate-General, all
regulatory measures are supposed to ensure a high level of public health protec-
tion, to establish a single market and to provide a stable and predictable envi-
ronment for pharmaceutical innovation (DG Enterprise 2000b: 4). These goals are
mirrored in the different Council Directives and Regulations as well as in Com-
mission Communications, starting with the first harmonization directive of 1965
“on the approximation of provisions laid down by law, regulation or administra-
tive action relating to medicinal products.” This states: “… the primary purpose
… must be to safeguard public health,” adding that this objective has to be
achieved without hindering “the development of the pharmaceutical industry or
trade in medicinal products within the Community.” The abolition of national
regulatory disparities through the “… approximation of the relevant provisions”
was meant to lead to “the establishment and functioning of the common market”
(European Council 1965: preamble).
While patients’ safety, public health protection, and industrial policy goals have
been common concerns of European and national policy-making alike, the spe-
cific European goal is linked to the creation of a Common Market (Art. 2 of the
Treaty establishing the European Community of 1957, as amended). Guarantee-
ing free trade among Member States and thus enabling the efficiencies of a larger
market (Cecchini et al. 1988: 5, 27), as well as contributing to the rationalization of
regulatory practice and the reduction of regulatory costs to industry (Deboyser
1995: 33) through substantive harmonization, procedural coordination and even
centralization were meant to maintain or strengthen the EU region as a competi-
tive research, development and production site especially vis-à-vis an increas-
ingly dominant US-American industry and rising Japanese industrial competi-
tion.
12
The partly conflicting policy goals may be summed up as follows:
– Patient protection and public health contain two interrelated, in practice poten-
tially conflicting, goals. One goal is protective, namely to avoid or limit the risk
of distributing qualitatively inferior drugs, those with unacceptably severe
side effects and those with non-existing or unacceptably low therapeutic effi-
cacy. The complementary health goal is promotive and linked to the therapeu-


legal harmonization with the goal of automatic mutual recognition (May 28, 1969).
Acknowledging that the Programme was a historical turning point with respect to
technical trade barriers, it made clear that their complete abolition might necessitate
EC implementation measures (Kommission und Gemeinschaften 1970: 127).
12 See a recent speech by the EU Commissioner for Enterprise and the Information So-
ciety, Eric Liikanen (Liikanen 2002).
12 MPIfG Discussion Paper 02/6
tic efficacy objective, namely to allow market entry for promising medicinal
treatments as fast as possible.
– The creation of an internal market is targeted at two groups. From the point of
view of the pharmaceuticals industry this means potential access to all Mem-
ber State markets for a medicine authorized within the EC, and from the point
of view of potential patients it means access to all pharmaceuticals available
within the EC.
– The industrial policy aim of supporting an innovative and competitive European
pharmaceuticals industry is twofold. Market entry regulation is intended to
promote the development of a larger-scale internal market and, thus, econo-
mies of scale. And the rationalization of regulatory procedures aims at reduc-
ing direct and indirect regulatory costs to industry and thereby providing in-
centives for research, development and production in Europe.
3 The Regulatory Development and the Changes in 1993
European market authorization for pharmaceuticals has traversed practically all
market integration strategies employed in the EC and, today, there co-exists a
regulatory policy-mix of different procedural solutions for the same basic task
within a harmonized legal framework. Up to the late 1980s, all attempts to pro-
vide for uniform marketing authorizations in the EC had, by and large, failed – be
it through an increasingly extensive and detailed harmonization of national leg-
islations in the hope that mutual recognition of national regulatory decisions
would come about, or through the subsequent introduction of cooperative or
concerted measures. National regulatory decision-making behavior differed too
much, revealing “that differences of opinion [in assessing and evaluating medici-
nal products] do exist” (DG Employment 1989: 5–6) and demonstrating the limits
of legal harmonization (Glaeske et al. 1988: 13–20). Those who would have pre-
ferred to cut the Gordian knot by a radical approach, namely the centralization of
marketing authorization at the European level,
13
were convinced that the idea
was not realistic under the prevailing political conditions (Merkel 1988, in:
Glaeske et al.: 80). However, five years later the European Council opted for just
such a step, even though this was limited to the category of especially innovative
medicinal products.


13 This policy idea had been brought up often since the first harmonization discussions
in the early sixties but it had always been abandoned as politically unacceptable – to
most of the Member States – and administratively unfeasible due to the lack of ad-
ministrative capacity with the Commission.
Feick: Marketing Authorization for Pharmaceuticals 13
3.1 The New Procedures of 1995/1998
In 1993, after two years of discussions, the European Council adopted three
pieces of legislation which introduced two new European authorization proce-
dures for the marketing of medicinal products for human use
14
: the Centralized
(CP) and the Mutual Recognition Procedures (MRP). These legislative reforms
were further developments of already existing “European” procedures which in-
troduced some radical structural changes. The new CP replaced the Concertation
Procedure, which had come into effect in 1987 (Council Directive 87/22/EEC)
and required European-level pre-assessments and pre-evaluations for specific
categories of pharmaceuticals – the same categories still applicable in the CP – be-
fore the single national authories made their nationally valid regulatory deci-
sions. But the national regulators were not obliged to follow the European rec-
ommendations. The MRP
15
replaced the Multi-state Procedure introduced in 1975
and revised in 1983, which involved a regime of sequential or parallel reviews of
national applications by national regulatory authorities and called for some inter-
agency communication and cooperation but led to little convergence concerning
the final national marketing authorization decisions. Thus, both preceding
“European” procedures somehow accompanied national regulatory decision-
making but did not replace it.
16
The result of the reform legislation of 1995 is the
remarkable range of three alternative regulatory routes for pharmaceuticals’
marketing authorization in the EC:
1. the different national procedures (NP) for marketing in one country only (excep-
tion: medicinal products for which alternative 3 is obligatory);
2. a Decentralized or Mutual Recognition Procedure (MRP) whenever a pharmaceu-
tical product is to be marketed in more than one Member State (exception:
medicines for which alternative 3 is obligatory);
3. an integrated Centralized Procedure (CP) for specific categories of pharmaceuti-
cals – obligatory for category A pharmaceuticals (derived from biotechnologi-


14 The three texts are Council Regulation (EEC) No. 2309/93 of July 22, 1993, Council
Directive 93/39/EEC and Council Directive 93/41 EEC, adopted on June 14, 1993
and in force since January 1, 1995 and 1998 respectively.
15 This introduction of the MRP included a transition phase from January 1, 1995, to
December 31, 1997, during which multiple national procedures co-existed alongside
the MRP.
16 However, it seems fair to say that both preceding procedures contributed quite a lot
in terms of mutual inter-agency understanding and the Europeanization of a profes-
sional and regulatory dialog. Without these advances in discourse capability over
several decades, Europeanized regulatory procedures could not have been expected
to work at all.
14 MPIfG Discussion Paper 02/6
cal research and production), optional for category B pharmaceuticals (inno-
vative medicines – mainly new active substances – outside category A).
17
While surprising at first sight, this variety of regulatory options for the same task
does take into account the multitude of orientations and interests which have had
to be accommodated:
A variety of interests within the pharmaceutical industry are accounted for by the
different procedural options. Internationally oriented and research-intensive
pharmaceutical companies are prepared to face fairly strict control measures on
the basis of contemporary scientific evidence. They are best served by a uniform
centralized procedure that opens up the large Common Market in one regulatory
step, thus reducing regulatory costs and speeding up market access. Companies
producing more traditional medicines, targeting smaller, sometimes only na-
tional, markets and, to a certain extent, less prepared to fulfill strictly imple-
mented harmonized regulatory requirements are better served by the NP or
MRP, where the peculiarities of national regulatory environments – including
traditional therapeutic traditions and specialties – have a greater chance of being
respected.
A similar distinction of interests can be made with respect to health care profession-
als and patient groups, depending largely on their therapeutic convictions. The
available regulatory procedures allow for a variety of therapeutic options, in-
cluding what might be called traditional or alternative medicinal therapies, which
are often only of regional interest. The risks of these kinds of products failing a
centralized assessment and evaluation procedure are higher, since such a proce-
dure is biased towards stricter scientific evidence.
The regulatory orientations and preferences of national authorities vary also with
respect to pharmaceutical, medical or regulatory traditions. There is nevertheless
a common institutional interest in organizational influence and survival in the
face of potentially menacing institutional centralization. The NP and the MRP al-
low a high degree of national autonomy to be maintained in regulatory decision-
making. And even the uniform CP is designed in a way that integrates the na-
tional authorities as indispensable providers of assessments and evaluations.
Autonomy, on the one hand, and participatory inclusion, on the other, preserve
the existence and regulatory autonomy or influence of national authorities.
Less well served within this institutional structure are the “interests” of those
specialized patient or consumer protection groups or individual professionals


17 For the definition of the two categories, see ANNEX to Council Regulation (EEC) No.
2309/93 of July 22, 1993.