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TRANSCRIPT
The Dynamics of Regulatory Convergence
David VogelHaas School of Business
University of California, Berkeley CA94720E-mail: [email protected]
Prepared for presentation at a conference on “Regulation in Europe,” sponsored byLondon Business School and the Max Planck Institute, Bonn in association with the Anglo
German Research Foundation, November 4 – 5, 1999
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INTRODUCTION
This paper explores the dynamics of regulatory convergence within the European Union and
internationally. It primarily consists of two related case-studies of regulatory convergence, one focusing
on pharmaceutical regulation within the European Union and the second focusing on pharmaceutical
regulation at the global level. Both these cases illustrate the substantial progress that has been made in
coordinating national regulatory policies. The conclusion of the paper briefly discusses some other
cases of regulatory convergence and divergence and then assesses the factors that affect these
outcomes.
Drugs have long been among the most extensively regulated of all consumer products. Not
only do all governments closely supervise virtually every aspect of their development, testing,
production and marketing, but many also regulate their pricing and distribution. The pharmaceutical
industry is highly globalized, with over half the sales of the fifty largest drug companies made outside
their home country – (Tarabusi and Vivkery 1993). However, until recently, drug regulation was
virtually synonymous with national sovereignty. Firms were required to conduct separate tests, submit
separate applications, and meet distinctive criteria to enter each national market.
Because drugs are so extensively regulated and have such significant health and safety impacts,
drug policy coordination has proven extremely difficult. Nonetheless over the last decade, national
regulatory agencies have began to more closely cooperate with one another. The European Union has
established a centralized drug approval system, the United States Food and Drug Administration has
become more willing to cooperate with its foreign counterparts, and the United States, the EU and
Japan have made substantial progress in harmonizing drug approval requirements under the auspices of
the International Conference on Harmonization of Technical Requirements for the Registration of
Pharmaceutical Products (ICH).
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THE EUROPEAN UNION
The Scope of the Problem
Separate national drug approval policies and requirements long presented a critical obstacle to
European integration (Kingham, Bogart and Eddy 1994, 301). According to the 1988 Cecchini report
on the single market published by the European Commission, the European pharmaceutical industry
was significantly constrained by the “lengthy and differing drug registration procedures” of the Member
States. (Cecchini 1988, 67). Moreover, “all pharmaceutical companies . . . treat the Member States as
separate markets” (Oraz, Kaitin and Lasagna 1992, 849). Some multinational firms did not even bother
to apply for product approval in each Member State, and most smaller firms limited their product
marketing to their own country. The Financial Times observed in 1990 that:
If you suffer from stomach problems and live in France or Germany, do not ask yourdoctor to prescribe Zantac, the world's best-selling medicine. The product, made byBritain's Glaxo, is called Azantac in France; in Germany it is Zantic. The linguisticdistinctions are a symptom of the difficulties faced by western Europe's 30 billion-pounds-a-year pharmaceuticals industry in moving to a single market . . . Suchfragmentation has the effect of imposing trade barriers of the kind that 1992 issupposed to eliminate (Marsh 1990, A13).
Distinctive national registration requirements also imposed substantial costs on governments,
since each was required to maintain its own regulatory bureaucracy. In 1993, the EC's twelve Member
States employed 2,000-2,500 full-time drug evaluation staff, plus about 1,000 expert consultants. The
annual cost of twelve separate national drug authorities was approximately $300 million, a cost borne
by pharmaceutical manufacturers, since they pay for clinical trials as well as registration and licensing
fees, and indirectly by consumers. (Melloan 1994, A13). Since regulatory approval costs are linked to
clinical testing requirements rather than to market potential, many firms avoided smaller markets
altogether (Howells 1992, 36).
Not surprisingly, drug approval policies varied significantly throughout Europe, due to cultural
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factors, the degree of acceptance of folk remedies, religious beliefs and the differences in the
assessments of risks and benefits by regulatory authorities. Member States also differed in the speed
with which they approved new drugs, further complicating marketing in what was potentially the
world's largest pharmaceutical market. For example, approval in England and France could be received
in less than one year while Germany regularly required up to five years. (Green 1995a, 2).
However Member States were reluctant to surrender their control over drug approval. This
was due not only to their distinctive regulatory styles and traditions, but also to the close ties between
drug approval policies and national health care policies -- and thus to national budgets. Approximately
half of the industry's revenues in Europe come from national governments. In addition to controlling
new product registration, Member States controlled drug prices and subsidized development costs,
making this industry among Europe's most extensively and closely regulated (van de Gevel 1992, 5).
When the European Community was established, health care, like all other aspects of welfare policy,
was left exclusively to the Member States (Richards 1991, 1322).
As one student of EU drug policy noted in 1989:
The free movement of drugs in the European Community is not only hindered by thefact that the national competent authorities render different value judgments on themerits of therapeutic approaches and on issues of relative benefits and risks of drugs. On top of these drug-specific differences come health-policy-specific differences in thecontrol of the social-security system, and industry-specific differences in the control ofthe drug industry's prices and profits, and differences in the extent to which nationalgovernments assist their national drug industry (Kaufer 1989, 20).
Initial Efforts
Efforts to reduce national disparities in drug regulation began in 1963, when the European
Commission convened a conference of industry representatives, doctors, and consumers to discuss
standardizing pharmaceutical laws (Oraz, et. al. 1992, 853). However little was accomplished. In 1965,
the EU issued its first pharmaceutical directive. It established baseline “criteria for safety, quality and
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efficacy as preconditions for marketing authorization for new drugs. The directive also defined
medicinal products and required Member States to ensure that submissions of medicinal products to
national authorities were prepared and signed by experts with “the necessary technical or professional
qualifications” (Quoted in Oraz, et. al. 1992, 853-54). These qualifications, however, remained
undefined the efficacy test itself was restricted: Yet even this minimal standard was enacted by only
seven of the twelve Member States (Oraz, et. al 1992, 854). Through the mid-1970s, virtually no
progress had been made in creating a single market for pharmaceutical products.
A New Approach
In 1975, the EC established the Committee for Proprietary Medicinal Products (CPMP), with
members drawn from the regulatory authorities of the Member States (Oraz, et. al 1992, 855). The
CPMP was given the authority to review all drug applications within the EC. Applications would be
examined for conformity to European Union safety, quality, and efficacy standards, and the Committee
would then issue an opinion on marketing approval (Buono 1995, 145). However the CPMP's role was
only advisory. Member States maintained the right to deny approval of a pharmaceutical product even
if the Committee recommended that it be approved (Oraz, et. al. 1992, 855).
That same year, the EC also established a multi-state or “decentralized” procedure for drug
approval, which is subsequently revised in 1983 (Kanusky 1994, 677). Under this procedure, a
manufacturer would first submit its product to any national pharmaceutical regulatory agency. If that
body granted approval, the company could then submit “concurrent applications” to at least five other
Member States. The latter, in turn, were required to take the initial authorization into account in their
own review, thus presumably expediting their approval process. If any refused authorization, they
were required to submit a “reasoned objection” to the CPMP within three months. The CPMP would
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then have two months to issue an opinion on the objection.
But the establishment of multi-state procedure had little impact on national drug approval
policies, primarily because final approval still resided with the regulatory bodies of each Member State.
German firms boycotted the procedure “as a matter of principle” (van de Gevel 1992, 5). Although
Member States were only supposed to reject CPMP recommendations in “exceptional cases,” and after
making “reasoned objection,” such objections in fact became the norm. Only half of the licenses
originally granted by a Member State were accepted by the other Member States to which they were
submitted (van de Gevel 1992, 6).
The multi-state procedure was intended not only to generate confidence among Member States
about each other's scientific competence, but also to speed the approval of safe and effective drugs.
Results were mixed for this goal as well. Since the multi-state procedure had strict time limits (a state
had four months to evaluate a dossier that another state had already approved) Member States did give
priority to multi-state applications. However, because they still carefully investigated each application
rather than relying on the initial state's opinion, the multi-state time limits were frequently violated (van
de Gevel 1992, 6). Only in France were the time limits ever approached. In Germany and the United
Kingdom it took an average of two years to process applications, while in Italy, Spain, the Netherlands,
or Belgium it took three years or more (Howells 1992, 34).
Although all Member States agreed to accept test evidence obtained elsewhere in the
Community, there was no real progress towards mutual recognition of drug approval. As the
Committee's chair noted in 1988, “Each concerned state seemed to conduct its own assessment and
raised its own objections . . . In practice there have been objections with regard to each and every case
dealt with under the Multi-State procedure.” He concluded that “on the whole, the Member States do
not yet accept each other's assessments” (quoted in Oraz, et. al. 1992, 856). The resulting financial
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costs were substantial. The Cecchini Report on “The Benefits of the Single Market” estimated that the
lost revenues of companies forced to wait over the agreed 120 day limit ranged between 100 - 175
million Ecus, while multiple registration requirements required firms to employ extra staff at a cost of
between 40 and 55 million Ecus (Cecchini 1988, 67).
Toward Harmonization
In 1987, frustrated by the ineffectiveness of the multi-state procedure and committed to the
Community's newly established goal of creating a single European market by 1992, the European
Council chose a radical new approach. It approved a directive establishing a CPMP-administered
“Centralized Procedure.” This procedure was designed especially for biotech and high technology
products, since Brussels reasoned that it would be easier to harmonize standards that had not yet been
created than to force states to change their existing ones. The CPMP pooled scientific expertise in this
new area of medical research in order to create a Europe-wide consensus as to what constituted good
manufacturing practices, appropriate laboratory procedures and appropriate evaluation criteria (Sauer
1991, 455, 460).
Once a manufacturer submitted its application, the CPMP would have seven months to
complete its initial evaluation; firms were required to respond to both CPMP and Member States'
concerns within three months. The Member States then had up to one month to make their final
recommendations, following which the CPMP would send its report to all additional parties (Kanusky
1994, 681). While the CPMP's report was nonbinding, this new procedure was intended as the first
move towards genuine supra-national evaluation: “While fundamentally national, it [was] seen by the
Commission as a significant step in the direction of a single evaluation procedure applicable throughout
the Community” (quoted in Oraz, et. al. 1992, 856).
Following approval of the Maastricht Treaty on European Union (1992), which gave the
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EU binding authority on some health care issues, the European Commission undertook another
initiative to harmonize national drug approval policies (“How Should European Health . . .”
1994). It established a new regulatory institution, the European Medicines Evaluation Agency
(EMEA) and two new regulatory procedures (Kingham, et. al 1994, 303). The EMEA consists of
the CPMP, the corresponding body for veterinary medicine, “a secretariat, an executive director,
and a management board composed of representatives of the Member States, the Commission,
and the European Parliament.” The EU's goal was to transform the relationship between national
regulatory authorities and those of the Union, thus finally creating a common market for
pharmaceutical products.
An important objective of the creation of a single European drug approval procedure was to
promote more European-wide drug research and development, thus helping this industry “confidently
continue to hold its place on the world stage in the foreseeable future (“Pharmaceuticals…” 1995). A
1995 communication from European Commissioner Martin Bangermann noted that over the last two
decades the share of all new medicines developed in the EU had declined from half to one-third, while
in the critical biotechnology sector, 65 percent of all patents were American while only 15 per cent
were European. (“Pharmaceuticals …” 1995). Improving the efficiency of European drug approval
was regarded as a way of strengthening the effectiveness of this critical industry.
The centralized application procedure placed final regulatory approval at the Union level for
the first time. It permits manufacturers to submit applications directly to the European Agency, which
then refers them to the CPMP for evaluation. The latter is required to issue its opinion within 210 days.
If approval is denied, the drug's sponsor may file an appeal, which in turn must be reviewed within sixty
days. Final approval rests with the European Commission, which has ninety days to draft its own
opinion. If the Commission grants marketing authorization, it automatically becomes valid throughout
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the EU for renewable periods of five years. The EMEA centralized approval process was designed to
be relatively rapid, with application to final approval to take a maximum of ten months (Kingham, et.
al. 1994, 307). This is more than twice as fast as that of many Member State drug regulatory agencies.
To help the EMEA meet its own deadlines, applications can be accepted on CD-ROM, and the
agency's recommendations were to be distributed by e-mail (Green 1995b, 13).
The centralized procedure specifically targeted biotechnology drugs, which must be approved
by EMEA, as there is no national alternative (Green 1995a, 2). Biotechnology was targeted because of
its potential for economic growth and, because since it is such a new field, individual states had not yet
created their own testing infrastructures (Buono 1995, 134). As one European official explained,
“Global participation means we don't have to keep on reinventing the wheel. A new technique . . .
offers the chance to put together a unified international approach before separate guidelines are issued .
. . The most obvious candidate here is biotechnology” (“Global harmonization …” 1991). The
centralized procedure was intended to particularly benefit small firms with limited resources, which
were more likely to be found in the biotechnology sector. However, manufacturers of other
pharmaceutical products may also elect to use the centralized procedure (Kanusky 1994, 699).
The EU also established a decentralized procedure open to all pharmaceutical products, except
those produced through biotechnology (Kingham, et. al. 1994, 309-312). This procedure, based on
the principle of mutual recognition, was approved in 1993 and went into effect on January 1, 1995.
According to its terms, if a product has been approved for use in any Member State, its manufacturer
may submit an identical scientific and technical dossier to any or all other Member States. It also must
notify both the CPMP and the Member State to which its application was first submitted; the latter then
is required to furnish its assessment report to each country where recognition is sought. Each Member
State then has ninety days to decide whether to recognize the first nation's approval. It must do so
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unless “there are grounds for supposing that the authorization of the medicinal product concerned may
present a risk to public health” (quoted in Kingham, et. al. 1994, 311). In cases of disagreement,
Member States are encouraged to solicit the opinion of the CPMP. This was subsequently
strengthened. Beginning on January 1, 1998, any Member State which receives an application for a
product which has been approved by another member of the Union, must either recognize that
approval, or refer the application to the CPMP for binding arbitration. In addition, a firm can now only
apply for marketing approval in one country if its product will only be marketed in that country.
Unlike the FDA, the EMEA's role is a coordinating one; the actual processing of applications is
delegated to national regulatory agencies. This in turn means that the agency must rely on Member
State authorities not only to process applications in a timely fashion, but also to apply similar standards.
The harmonization of national requirements is even more critical for the viability of the EU's
decentralized procedure, since under this procedure a single national authority will be able to approve a
product for the entire EU. The inspection of manufacturing facilities and the certification of the
reviewers of applications will also depend on national authorities. Nonetheless, according to Fernand
Sauer, the agency's executive director, “after fifteen years of harmonization we now have everything in
place so that EMEA and all of the national authorities practice exactly the same requirements”
(Koberstein 1996, 46).
Both new procedures promise to provide important benefits to manufacturers. Streamlined
approval allows cash flow to start sooner. “Successful new drugs earn $1 million per day in global
sales revenues. The European Union accounts for about 40 percent of global sales” (Green 1995b, 13).
Also, more rapid drug approval will increase the effective life of drug patents, enhancing the expected
value of future research (Green 1995a. 2). Since companies can submit one application rather than
fifteen, large firms may save up to $5 million annually in national clinical staff and testing equipment
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(Green 1995a, 2). While the application fee for submitting a drug to the EMEA is high - a typical filing
costs approximately 200,000 ECUs - this is about half of what it would cost to pay all fifteen national
fees. Centralized approval also enables firms to use identical package inserts and make similar
promotional claims throughout the EU.
The EMEA in Operation
Although delayed for a few months by a last-minute debate over its fee structure, the European
Agency opened its doors to great fanfare on Canary Wharf in London on January 26, 1995 (Internal
Market Council 1994; Perry 1994). London was chosen both because of the preeminence of the British
pharmaceutical industry and the British government’s historic expertise in pharmaceutical regulation.
Its 1995 budget was 9.5 million ECUs, but through registration and annual fees, the Agency is
expected to be self-supporting and anticipates a budget of 50 million ECUs by 2000 (Hirschler 1994).
Its staff will remain relatively small because the EMEA will coordinate with teams of experts from EU
Member State drug approval boards, whose combined staff of over 1,600 will actually conduct the
drug evaluations (Hirschler 1994). Nonetheless, this represents a 50% reduction in the national
regulatory staffs from pre- to post-EMEA levels (“EMEA Doors Now Open …” 1995).
European industry has been generally supportive of the EMEA. European Federation of
Pharmaceutical Industries Association President Kurt Briner stated:
Our task is to produce high-quality medicines for patients. The agency's task is tobring into operation a high-quality, high-performance, efficient registration mechanismthat gives patients speedy access to those products . . . The credibility of Europe, itspharmaceutical evaluation bodies and of its pharmaceutical industry are at stake, andwe must all do our utmost together” (“EMEA Doors Now Open…” 1995).
Many companies have set up liaison offices on Canary Wharf and several others are expected to do so
shortly (Green 1995b, 13). One major firm, the German company Bayer, has relocated its European
regulatory headquarters to Canary Wharf.
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In October, 1995, the first pan-European drug was approved. The fertility treatment drug
Gonal-F, developed by an American firm, was given a single commercial license, permitting its sale in
all fifteen Member States (Green 1995a, 2). Through April 1, 1997, a total of thirty-three European-
wide marketing authorizations had been granted and eleven others were awaiting final approval by the
Commission (Green 1997). Equally importantly, two-thirds of the applications received by the EMEA
were not for biotechnology products, indicating industry confidence in the centralized system.
Moreover, there were fifty completed mutual recognitions of national authorizations for human
medicinal products, with only three arbitrations. (EMEA Status Report 1996). By the end of 1998,
approximately one hundred European-wide marketing authorizations had been granted and more than
four hundred drugs had been approved through the mutual recognition process.
Compared to most other consumer products, including those with important health and safety
dimensions such as food and automobiles, the EU has found it relatively difficult to create a single
market for medical products (Vogel 1995, ch. 2-3). Nonetheless it has now finally created a legal and
institutional framework for accomplishing this goal. The EU's considerable progress in coordinating
drug approval policies among its fifteen Member States has been paralleled by progress in coordinating
drug regulation policies among other developed nations, a topic to which we now turn.
INTERNATIONAL HARMONIZATION
Preliminary Efforts
While the EU represents the world's most ambitious effort to coordinate regional
pharmaceutical regulations, a number of important initiatives have been undertaken at the global level
as well. Informally, pharmacopoeias (official drug manuals), especially the Nordic, European and
International Pharmacopoeias, have historically played a role in creating uniform norms. These
manuals allowed scientists around the world to compare notes on drug descriptions, compounds, and
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expectations of efficacy. Often, though, they simply gave administrators from different countries the
opportunity to dig in their heels by officially publishing their preferred interpretations (Kanusky 1994,
689).
The first formal international harmonization took place in 1973, when the Benelux countries
initiated a supranational registration system. According to the survey The Effects of Drug Regulation,
“It was perhaps this venture, more than anything else, which caused the pharmaceutical industry to
argue for 'mutual recognition' of regulatory decisions, particularly in the European Community”
(quoted in Kanusky 1994, 688). The five members of the Nordic Council, only one of which then a
member of the EC, also adopted a common drug registration procedure. Although its results were non-
binding, a drug approved in one state could be licensed by another without a separate testing
procedure. At the international level, a 1979 conference in Rome led to a multilateral agreement to
work toward creating testing and evaluation guidelines that could be shared by Council for Mutual
Economic Assistance, European Free Trade Area, and Nordic Council of Medicines (Kanusky 1994,
687-688). No concrete results developed, however, until this working group's efforts began to overlap
with those of the EC and the United States in the mid-1980s.
United States
Prior to the mid 1980s, the cooperation of the American Food and Drug Administration with
its counter-parts in other nations was extremely limited. The FDA had entered into an agreement
defining good manufacturing practices with Switzerland, Sweden, Canada, and Japan and had signed
an agreement establishing good laboratory practices with Canada and seven European countries
(Kanusky 1994, 689). However the U.S. required that clinical testing for all drugs, whether domestic
or imported, be performed in the United States. This forced importers to duplicate costly tests and
restructure trials to conform to American laboratory standards. “This policy seems to have had a
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significant effect in delaying the introduction of foreign-discovered drugs into the United States -- even
those foreign drugs that represented significant advances.” (Jordan 1992, 490).
As a result of the 1962 Kefauver amendments to the Food, Drug and Cosmetic Act, the time it
took the FDA to approve a new drug application increased fourfold to an average of ten years. During
the 1970s, the FDA came under heated criticism for the emergence of a “drug lag” - the length of time
before a drug approved in a European country became available in the United States. According to one
of the agency’s Congressional critics, “the Food and Drug Administration is contributing to needless
suffering and death or thousands because it is denying them life-saving and life-enhancing drugs that
are available abroad for sooner than they are here.” (Scheurer 1980, 35). A study by the Government
Accounting Office reported that out of 14 significant new drugs, 13 were available in Europe years
before they were approved for use in the United States. (Proposals to Reform… 1979).
During the mid 1980s, these criticisms of the FDA’s slow rate of drug approval became
politically significant as AIDS activists blamed the agency for the unavailability of any drugs that might
be effective against the deadly virus (Vogel 1990, 458-461; Proposals to Reform). In 1989, the FDA
took a highly unconventional step to accommodate AIDS patients, granting a “personal use
exemption” for individuals to bring a drug into the United States for their own use if it has been
approved for use in another. (Lindermann 1994, 134, 140-142). Under increasing domestic political
pressure to expedite the drug approval process not only for AIDS drugs but for other medicines as
well, U.S. regulators became more willing to cooperate with foreign regulatory agencies. In 1990, the
U.S. and the European Commission completed a Memorandum of Understanding which standardized
good manufacturing practices and good laboratory practices between FDA and EC Member States.
The following year the United States, the EC, and Canada sponsored a conference to harmonize the
names of health care products. On November 14, 1991, as part of a more comprehensive reform
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package, HHS Secretary Sullivan announced the FDA's support for harmonizing American testing
standards with those of other industrialized nations in order to reduce duplication and speed the
development of drugs worldwide. (Jordan 1992, 492).
Four days later, the President's Council on Competitiveness sounded a variation on this theme,
calling for “reciprocity agreements,” or mutual recognition of drug approval which would be
“negotiated on a country-by-country basis.” (Relihan 1995, 256; Jordan 1992, 496). The FDA
subsequently issued a report which argued that harmonization offered a number of major public health
benefits, including decreasing the spread of disease within countries and across borders; increasing
patient access to safe and effective products; improving the quality, safety and efficacy of imported
drugs; and increasing information transfers between countries on public health issues (Contrera 1995,
930). Between 1992 and 1995 the FDA published four rules in the Federal Registrar which
progressively eliminated its barriers to sharing information with its foreign counterparts. (Horton 1997,
105). During this same period, the FDA established both an Office of International Policy and an
Office of International Affairs to facilitate international regulatory coordination.
The International Conference on Harmonization
The most important effort to promote the global standardization of drug approval policies and
procedures has taken place through the International Conference on Harmonization of Technical
Requirements for the Registration of Pharmaceutical for Human Use (ICH). ICH participants include
officials from the U.S. FDA, the EU's Committee for the Proprietary Medicinal Products (CPMP) and
the Japanese Ministry of Health and Welfare (MHW) as well as representatives from multinational
pharmaceutical companies.
The ICH grew out of meetings among regulatory officials from Europe, the United States and
Japan -- these three markets account for seventy-five percent of the world's production of medicines
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and ninety percent of global pharmaceutical research and development (Jordan 1992, 492) -- and the
International Federation of Pharmaceutical Manufacturers Association. Its first session took place
shortly after the EC Council began the process of drafting the Mastricht Treaty, since the commitment
of the EC/EU to establish regional regulatory standards made it possible for it to seek agreement on
global ones.
Over 1,000 participants attended the first ICH conference, which was held in the EC’s capital,
Brussels, in 1991. In addition to establishing a process of negotiated rulemaking to harmonize
regulatory guidelines, the conference approved a “minimum data blueprint” guideline, subsequently
incorporated into U.S., EU and Japanese law (Jordan 1992, 493). The blueprint defines data collection
conditions acceptable in all three regions, thus allowing a firm to file the same data package in each.
While the data submitted are still evaluated by national officials--who may still demand data beyond the
scope of the minimum data blueprint--this guideline eliminates the need for costly and repetitive tests.
For example, before the ICH, the EU, Japan and the United States had no common control conditions
for conducting laboratory tests. Now control conditions, such as the definition of “room temperature,”
are precisely defined.
The guideline also standardized long-term toxicity tests, limiting repeated dose toxicity
studies to six months. The previous standard, “Lethal Dose 50,” increased doses administered to
laboratory animals until 50% of the animals died. Ironically, this testing phase had lasted longest
for drugs that had the safest toxicity levels. This should “cut industry's costs by a total of $100
million annually -- and save the lives of 35,000 laboratory animals, itself an increasingly important
consideration” (“A Faster Track…” 1991, 20). According to one estimate, the elimination of
duplicate testing will save up to 100,000 Ecus for every new medicinal product, while reducing
long-term toxicity tests from one year to six months will save as much as 500,000 Ecus per new
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substance (“EC, USA and Japan …” 1991). Following the Brussels meeting, the FDA announced
that it would accept more of the animal and clinical studies conducted by foreign regulatory
agencies. (“Radical Change” 1991, 84, Relihan 1995, 251). Since then the FDA has approved five
new drug applications based on foreign data alone as well as nine based on both domestic and
foreign data (Kanusky 1994, 675).
Still, the most important outcome of the 1991 Conference was political. The Pharmaceutical
Business News noted that “to put all the emphasis on the conference as a scientific meeting would be to
distort its impact, representing as it did the first time regulators and industry have met on such a large
and public stage” (quoted in Jordan 1992, 494). Its primary accomplishment was to publicly commit all
three regulatory agencies to the principle of harmonization. This in turn reflected the regulators'
acknowledgment that “they were all wasting a lot of money by requiring duplicate testing without
contributing anything to improving health protection” (Jordan 1992, 495). The FDA's participation was
especially significant since, as recently as the mid-1980s, it had publicly regarded foreign clinical data as
“too precarious” for making marketing approval decisions (Jordan 1992, 495).
A second ICH conference was held in October 1993 in Orlando, Florida. In his keynote
address to the conference's 1,600 participants, FDA Commissioner David Kessler stated that, “Science
driven harmonization can curtail duplication, and thereby significantly reduce the cost of new drug
development -- not just in dollars spent by the industry but in the risk taken by patients, in the
experimentation with laboratory animals, and in the regulatory efforts of our governments.” He added,
“It has the potential for a major breakthrough in the drug approval process by making a common
registration package a realistic possibility” (Contrera 1995, 929). Participants of the Orlando
conference agreed on common procedures for animal-based experiments to detect toxicity in
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reproductive systems and established common definitions and standards for clinical safety data
management (Kidd 1997, 5).
A third session, attended by 2400 delegates from pharmaceutical firms and forty governments,
took place in Japan in November, 1995. Its primary accomplishments were agreements on uniform
guidelines for the clinical testing of new drugs and good clinical practice. These agreements are
intended to facilitate the mutual acceptance of data on clinical trials, thus significantly reducing the
costs of drug development. ICH3 also agreed on a working program to complete the development of
50 common guidelines on the steps necessary to demonstrate the safety, quality and efficacy of new
medicines. One ICH working group is working on harmonizing both the medical technology used by
regulatory agencies as well as electronic data transmission standards. Agreement on the latter could
eventually make it possible for a company to electronically submit the same dossier or application to
the FDA the EMEA and the MHW. As the closing plenary session of the Japan conference, Roger
Williams, associate director of the Science and Medical Affairs Center for Drug Evaluation and
Research of the FDA stated: “We've just stepped up close to the realization of a dream. We can say it's
a global dossier, [the FDA has since relabeled this a common technical data set] which is available
though any country in the world, or is acceptable to any regulatory authority in the world” (“ICH…”
1995).
By 1996, nineteen guidelines had been formally approved by conference participants, four of
which had been enacted into law in Europe, the United States and Japan (Bermann 1996, 964). They
covered reproductive toxicity in animals, clinical studies among the elderly, stability testing of new
active substances, and dose/response information to support drug registration. An additional thirty-
eight guidelines are under development. A large number of firms in the United States, Japan and
Europe have already adopted the first eleven guidelines agreed to by the ICH (“Impact of First ICH
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Guidelines” 1995). According to a survey conducted by Japan's MHW, more than 90 percent of the
quality guidelines developed through the ICH process are being used by companies (“FDA
Challenged…” 1996). The world's twenty-five largest firms have adopted nearly all of them (“Euro
Commission…” 1996). A survey of companies conducted prior to ICH4 reported that 75% had used
ICH guidelines in their drug development. (ICH is Dead, 1997)
ICH meetings have also helped improve communication and trust among regulators in different
regions and fostered the establishment of more sophisticated and comprehensive mechanisms for data
exchange, including an experimental effort to exchange data regarding the side-effects of previously
approved drugs though floppy disks and across the Internet (“Better Medicine…” 1996). They have
also developed a common glossary of medical terminology.
While ICH was originally envisioned as a six-year process, the Steering Committee decided to
schedule a fourth meeting, which took place in Brussels in 1997. ICH made considerable progress in
adopting guidelines for internationally accepted principles and practices for conducting and evaluating
clinical trials – which constitute one third of the cost of developing a new chemical entity- as well as on
developing a core dossier acceptable to regulatory bodies in the United States, Europe and Japan.
Originally comprised of only government and business delegations from Japan, the EU and the
U.S., each successive meeting of the ICH has been attended by delegates from additional countries.
However in light of the fact that virtually all nations have pharmaceutical industries dominated by
American, European or Japanese firms, ICH guidelines are likely to become de facto international
standards. In fact, the World Health Organization has begun to encourage developing countries to
adopt them. In brief, “ICH has been far more successful than anyone anticipated” (Wechsler 1996, 16).
National Responses
Not surprisingly, the region which has found it the easiest to adjust to the ICH's guidelines and
20
standards has been Europe. Most guidelines “largely overlap with current EC legislation, so the ICH
guidelines do not imply any major changes in the EEC acceptance policy for pharmaceutical products”
(“EEC/US/Japan . . . ” 1991, III-1). This is particularly true of the Good Clinical Practice guidelines.
As in the case of a number of other global standards, most notably ISO 9000, the experience the
Europeans gained in harmonizing regulations among the EU's Member States has both enabled and
encouraged them to play a leadership role in promoting international regulatory cooperation. At the
same time, the work of the ICH in defining “state of the art” standards has itself contributed to the
harmonization of drug approval standards and procedures within the Union: the first three meetings of
the ICH paralleled the EU’s progress in creating a single market for drugs in Europe. It was the
impetus provided by the progress toward regulatory integration in Europe that inspired the ICH to
convene a fourth meeting – held significantly in Brussels – while the EU adopted a draft directive on
the legal protection of biotechnological inventions to coincide with the opening of ICH 4. (Talbert,
1997, Walser, 1998).
Japan has experienced the most difficulty adjusting to the ICH. Of particular concern to the
Japanese are racial differences that can lead to different reactions to the same dose of the same drug
across populations. Japan, like other states, has been reluctant to accept foreign data as the basis for
drug evaluation. This began to change in 1986 following bi-lateral negotiations with the United States.
But while Japan is “increasingly willing to accept toxicity tests and preclinical data from other countries
. . . it still insists on Japanese clinical data” (“Prescription for Success…” 1990, 7). In addition, Japan's
distinctive evaluation standards and criteria require considerable additional testing (Currie 1989, 100ff;
Kanusky 1994, 683-686). Nobuto Nakamura, general manager of the Pharmaceutical Development
Division of Takeda Chemical Industries, has expressed concern that “when it becomes possible to use
Western Clinical Data in Japan based on the results of the International Conference of Harmonization,
21
there is a risk that clinical trials [in Japan] will be reduced to a mere formality since sponsors will
minimize the number of studies performed locally and transfer them overseas” (“Japan Urgently . . .”
1995).
However, in preparation for ICH2, the Japanese Ministry of Health and Welfare created
“Pharma Dream 21,” a $10 million scheme “for the promotion of harmonization of drug regulation . . .
particularly in the area of racial differences from the point of view of clinical science (“Funding . . . ”
1992). Japan has also responded to the need for harmonizing good clinical practices by increasing its
number of inspectors, as Japanese monitoring of drug testing has been a continuing source of
complaints by US and European regulators (“Japan: Mr. Fujii..” 1992, 1). At the closing session of
ICH3, a senior Japanese MHW stated that he was pleased that so “many guidelines in which
international standards are provided for were agreed upon in order to avoid duplicating tests and
wasting time and costs,” and pledged to make sure that these guidelines are put into practice”
(“ICH…” 1995). The ICH will thus make it easier for drugs developed in Europe and the U.S. to be
marketed in Japan. Recently, Pfizer won approval for Viagra to be marketed in Japan using clinical
data collected entirely in the west (Pilling 1999)
For the FDA, its participation in the ICH has both complimented and assisted its efforts to
speed up the drug approval process. Since the passage of legislation in 1992 giving the agency more
resources by permitting it to charge the drug companies “user fees,” the approval times for new drug
applications has declined significantly. In 1995, the average approval time for a new drug was 19
months, as contrasted to 33 months in 1987 (Mintz 1996, 21). The approval time for the 15 drugs
given priority because they were deemed “major therapeutic advances” was only six months in 1995
(Mintz 1996, 21). Indeed, as a result of these changes, the “drug lag” has virtually disappeared.
According to an FDA study which compared the approval and availability of new drugs in the United
22
to other drug-producing nations between 1990 and 1994, the U.S. was slightly ahead of the United
Kingdom and substantially ahead of both Germany and Japan. An analysis of those drugs approved in
more than one country found that the U.S. lagged slightly behind the U.K. but was substantially ahead
of both Germany and Japan (Wechsler 1996, 16). Forty per cent of the world’s new drugs are now
approved first in the U.S. (Green 1995). According to FDA Commission Kessler, “Americans have
access to essentially all clinically important drugs that are available anywhere else in the world.” He
added, that although “the United States does not stock every product that has been approved
worldwide, neither does anyone else” (Wechsler 1996, 16).
Still, the FDA remains under continued domestic political pressure to approve drugs more
rapidly - pressures which have been exacerbated by the EMEA’s success in expediting the drug
approval process in the EU. While mutual recognition of drug approval between the FDA and the
EMEA is unlikely in the foreseeable future, a number of the EMEA's criteria for both efficacy and
effectiveness, as well as its requirements of clinical review and scientific vigor, are sufficiently similar to
those of the FDA so as to permit both agencies to rely more on data prepared for their counterparts
(Katz 1993, 585-586). Indeed, in the not too distant future, there is likely to be a common drug
approval application for both the US and the EU and there is even discussion of adopting a system of
the mutual recognition for drug approvals. The FDA has formed internal working groups that mirror
those established by the ICH's steering committee and their recommendations have reduced the number
of overlapping requirements imposed on firms seeking marketing approval for their products in the
United States (“FDA Challenged…” 1996). A number of FDA regulations have been rewritten to
adopt to ICH requirements and while ICH guidelines are not formally binding in the US, the FDA has
indicated that its reviewers will not normally ask for more information than required by ICH.
23
Implications
These developments represent part of a much broader effort on the part of governments to
improve international regulatory cooperation (Sykes 1995; Regulatory Co-operation . . . 1994). It is
therefore worth reflecting on the circumstances which affect the dynamics of such cooperation. In the
case of pharmaceutical regulation, the substantial progress in international regulatory cooperation was
made possible by three factors: uniform preferences on the part of industry, the lack of consumer
opposition, and the complimentary relationship between harmonization within the EU one hand and
between the EU and the US on the other.
In contrast to many trade negotiations which have pitted the interests of internationally-
oriented producers against domestic ones, the firms in this sector have similar interests. Neither the
large multinational firms nor the smaller biotechnology start-ups want distinctive national regulatory
requirements. All firms in this sector have a common interest in reducing the costs associated with
marketing their products in as many countries as rapidly as possible. Indeed in recent years, the large
multinational firms which dominate this industry have become even more supportive of regulatory
harmonization due to both the increasing costs of research and development and the decline in the
effective patent life of drugs. “Research-based firms realized that, for innovation to be profitable, new
drugs must reach markets all over the world in as short as time as possible” (Tarabusi and Vickery
1993). Moreover, “the costs of duplicative inefficiencies of [distinctive national] specification standards
. . . are enormous. (Braithwaite 1994, 210) In 1990, it cost firms an average of $231 million to
develop and test a new drug. “A one and one-half year reduction in drug approval time can reduce the
time necessary to recoup research and development expenditures by five years” (Dillman 1991, 936).
In this context it is important to note that distinctive national regulatory requirements for drug
approval have not functioned as trade barriers. (Vogel 1995) The relative structures of American
24
regulatory requirements have not conferred a competitive advantage on drugs developed by American
firms any more than fifteen separate EU drug approval procedures protected the market share of
European firms. Only one developed country, Japan, has been accused of using its drug approval
requirements to discriminate against foreign firms. No one has claimed that the onerous post-1962
American drug approval requirements are non-tariff trade barriers; they have made it just as time-
consuming and expensive for American firms to secure marketing approval in the United States as for
foreign ones.
Secondly, there was no public opposition to increased regulatory cooperation. This was in part
due to the fact that at the international level, the efforts of ICH have to date focused on the
development of common regulatory procedures rather than on the approval of specific products. The
same is true within the EU. More generally, there has been a notable lack of public interest or even
awareness of the work of ICH or the EMEA. Negotiations have primarily involved government
officials and industry representatives; NGOs have been noticeably absent. In part for both these
reasons, regional regulatory cooperation reinforced regulatory cooperation at the global level.
A similar dynamic has informed regulatory cooperation for the testing of new chemicals.
During the mid-1970s the European Community, responding to increased public concern about the
environmental impact of chemicals, attempted to strengthen its standards for chemical safety. However
agreement proved impossible because of differences between Europe’s two main chemical producers,
Great Britain and Germany. Neither was willing to surrender its national authority over the regulation
of this important and politically powerful industry.
This deadlock was broken in 1976 by the passage of the Toxic Substances Control Act
(TSCA) by the United States. This legislation, which established new requirements for the
manufacture of all new and existing chemicals in the United States, created considerable anxiety on the
25
part of European chemical producers: they feared it would undermine their ability to export their
products to the United States. European officials recognized that their bargaining power would be
significantly strengthened if they were able to reach agreement among themselves. In the spring of
1978 the European Commission asked the European Council for a formal mandate to negotiate with
the United States and to develop parallel legislation. A year later, with the United States about to
implement TSCA, the council approved the sixth amendment to the 1967 Framework Directive on
Dangerous Substances. This established a European standard for the premarket notification of new
chemicals based on a modified system of mutual recognition.
Following the approval of this amendment, the EU entered into negotiations with the United
States under the auspices of the OECD. Although the OECD had been involved in coordinating
chemical regulations since the early 1970s, the enactment of new, comprehensive, and divergent
approaches to the screening of new chemical substances on both sides of the Atlantic lent considerable
urgency to its efforts. European and American firms were responsible for the majority of international
trade in chemicals. “Agreement on the basic contours of premarket notification packages would go far
to ensure that the previously unfettered commerce in new industrial chemicals would not be impaired
by conflicting or discriminatory regulatory controls.” (Brickman, 1985, 282).
After extensive negotiations, in 1981 the OECD countries adopted the Decision of the Council
Concerning the Mutual Acceptance of Data in the Assessment of Chemicals. This agreement, which is
binding on all OECD member countries, requires that the data generated in the testing of chemicals in
any OECD member state be accepted in all other OECD countries for health, safety, and environmental
assessment. To implement the agreement, the OECD’s Environment Policy Committee has issued
Test Guidelines, a common set of test methods for chemicals. The guidelines were developed by a
network of national coordinators, one in each OECD country, who worked with teams of regulatory,
26
academic, and industrial experts. Since 1981, eighty-four test guidelines have been adopted: they
specify methodologies by which chemicals are to be tested for characteristics such as genetic toxicity,
biodegradability, toxicity to fish, and so forth.
The adoption of these test guidelines remains optional, but any OECD country requiring that
chemicals be tested for any of the characteristics addressed by the guidelines must accept the test
results from other OECD countries, provided that the data were produced using the Test Guidelines
methodologies. This means that any of the tests must only be conducted once. This agreement has not
only facilitated trade in chemicals but has increased the generation of scientifically valid and high-
quality test data and reduced the costs of chemical testing for both governments and the private sector.
Equally important, it has established a mechanism for the creation of new international guidelines and
the revision of existing ones. And, as in the case of drug approval procedures, regulatory cooperation
in this sector has attracted virtually no public attention.
Both these cases stand in marked contrast to the regulation of beef hormones and food-related
biotechnology products. Five kinds of beef hormones are permitted for use in the USA; none in
Europe. The use of BST to increase the milk production of cows has been permitted in the USA but
banned in the EU. Most importantly, while American regulatory officials have adopted a relatively
supportive policy toward both the release of genetically-modified organisms into the environment as
well as the marketing of food products which are produced from genetically-engineered seeds, the
European Union has been much more restrictive in both areas. While the USFDA has approved the use
of fifty genetically modified crops, the EU has approved only nine – and none since April, 1998.
(Vogel, 1997)
Thus in this area of regulatory policy, not only is there no move toward regulatory
convergence but American and European regulatory policies have become more divergent. While in
27
the case of chemicals and ethical drugs, the creation of a single European market has contributed to
trans-Atlantic regulatory cooperation, in the case of biotechnology, it has impeded it: in general, the
more active role the EU has played in shaping biotechnology regulation, the greater the divergences in
regulatory policies between the US and the EU. The difference is due to two factors: the role of
industry and public preferences. Agriculture remains a domestic industry in both Europe and the United
States. Not only are there no trans-national firms in this sector but European and American firms are
structured very different.
European agricultural production is dominated by small-scale relatively inefficient farmers who
produce primarily for domestic consumption. Equally importantly, the EU, which heavily subsidizes
these farmers, has an interest in minimizing their output since the more they produce the more
resources it has to allocate to purchasing their “surplus” production in order to maintain high prices.
Thus neither European farmers nor the EU stand to benefit from innovations in agricultural technology.
By contrast, American agriculture is both highly commercialized and much of its production is
exported. The thrust of American agriculture policy has generally been is to reduce the level of
government support by making American farmers as efficient and productive as possible – not as, in
Europe, by protecting them from international competition. Thus both American farmers and the
American government have been generally supportive of new technologies for food production. These
differences are both reflected and reinforced by the divergence in developments in the
commercialization of biotechnology in Europe and the United States; it is much more advanced in the
latter than the former. There is no European counter-part to Monsanto - an American-based chemical
firm which has invested considerable resources in developing and marketing agricultural biotechnology.
At the same time, public attitudes in America and Europe differ substantially. With the
exception of BST, there has been relatively little public opposition to food produced through
28
biotechnology in the U.S. In Europe however, there has been a major public outcry against so-called
“Frankenstein foods,” resulting in the refusal of a number of European supermarket chains to carry
such products and in considerable public pressure on the EU to either keep out “new foods” or require
that they be labeled.
In short, regulatory cooperation requires both that firms in different political jurisdictions
have interests in a common regulatory standards and that consumers are not opposed to such
standards. This is the case for pharmaceuticals and chemicals; it is not the case for food production.
Hence there is cooperation with respect to the former and not the latter.
29
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