Regulatory Regimes for the Safety and Efficacy of Biotechnological Health Products: Changing Pressures, Products and Processes

G. Bruce Doern

Professor, School of Public Policy and Administration
Carleton University, and
Politics Department, University of Exeter

A Paper Prepared for the Canadian Biotechnology Advisory Committee
July, 2003

Contents

1. Introduction

2. Emerging Pressures on the Regulatory Regime for Biotechnological Health Products

   • Increased Volume of Products
   • Greater Tailored Nature of Products
   • Re-balancing the Mix of Pre-market versus Post-market Regulation
   • Changing Nature and Meaning of Drugs, Medical Devices and Diagnostics
   • Need to Ensure that Canada's Bio-economy Firms Can Prosper in a Global Economy
   • New and Expanded Regulatory Capacity

   • Greater Need for Shared International Regulation

3. The Current Biotechnology Regulatory Regime

   • Rationale and key features
   • Canadian multi-agency focus
   • International Dimensions

   • Criticisms of Current Regime

4. Key Values and Criteria Regarding Possible Alternative Regulatory Regimes

   • Regulatory Effectiveness in Health, Safety, Ethics and Risk Assessment and Management
   • Regulatory Efficiency and Competitiveness in a Global Context
   • Democratic Accountability and Democratic Engagement
   • Sovereignty and the Limits of Sovereignty

   • Effective Regulatory Capacities Amidst Potential Scarce Expertise

5. Regulatory Regime Alternatives and the New Regulatory Governance of Biotechnology

   • Alternative Regime 1: The Status Quo With “add-on” Improvements
   • Alternative Regime 2: Greater Separation/Independence of Risk Assessment Aspects from Risk Management Aspects
   • Alternative Regime 3: The EU As a Multi-Country Regime Model
   • Possible Transference of EU model to a North American or NAFTA Context

   • Selective Unilateralism

6. Conclusions

7. References

Introduction

Biotechnology as an enabling technology for other sectors and as an industry in its own right continues to attract enormous attention and from a wide range of analytical perspectives, values, and points of view (Appleyard, 1999; Fukuyama, 2002; Sulston and Ferry, 2002; Bauer and Gaskell, 2002). It is a big subject in every sense of the word. This paper covers a smaller subset of biotechnology regulatory issues focussing ultimately on biotechnological health products but this too is a big and fast moving subject of growing interest to governments, industry, health and patient lobbies and civil society. The overall purpose of the paper is broadly to examine key pressures and factors which are likely to cause changes in the Canadian biotechnology health regulatory regime in the medium-term future.¹ Some aspects of biotechnology in environmental regulation are also included but this is not the main focus of the paper.

More specifically, there are four objectives to the analysis which follows:

1. to define the pressures on the existing biotechnology regulatory regime that will be a direct result of projected new biotechnology health products and processes;

2. to set out the key values and criteria for the design of the regulatory regime including concerns about sovereignty, risk assessment and risk management and cost-effective regulation;

3. to map and examine some broad alternatives for possible changed regulatory regimes; and

4. to offer conclusions on the likely most promising way forward in the medium term;

The exploratory nature of the paper must be stressed from the outset. For several reasons, it inevitably raises more questions than it can answer or evaluate in any detail. First, some of the projected forces, pressures and products are based on general projections by various experts and industrial expectations but exact data and more precise issues of scope and scale are often not fully available. Second, the total current system and the likely expanded notions of the biotechnology regulatory regime constitute a complex mix of agencies with different histories, cultures, and mandates and hence, in a brief paper, can only be captured through illustrative examples and at a fairly general level of analysis. This is true for both the Canadian and comparative parts of the regulatory story. Third, the sources for the paper are necessarily diverse and include reports and studies by, and about, the entities involved; general Canadian literature on biotechnology regulation and governance; as well as basic notions of regulation, accountability, and governance. The paper also draws on comparative biotechnology regulatory and institutional literature because clearly other countries and jurisdictions such as the European Union and the United States are also dealing with similar issues of regulatory change (Ames, 2001; Uchtmann and Nelson, 2000; The Economist, 1999; Kass, 2003; Patterson, 2000; Sheridan, 2001; Abraham and Lawton Smith, 2003). The paper also builds on and reflects some of the author's own recent research on biotechnology regulation and governance (Doern and Sheehy, 1999; Doern, 1999; 2000; 2000a; 2000b; 2002).

Several aspects of the broad changing architecture and analysis of the biotechnology regulatory regime need to be kept fully in mind from the outset. First, the biotechnology regulatory regime consists of an array of values, processes and regulatory bodies interacting with different firms, researchers, stakeholders and citizens. It is a regime which basically assesses and approves products before they are allowed on the market and which also engages in some forms of post-market review (Doern, 2002). It also has compliance and enforcement responsibilities. Second, until quite recently, the standard working definitions of the biotechnology regulatory regime were especially focussed on those bodies within it which regulated biotechnology food products, animals, seeds, feeds, and genetically modified organisms. The largest political controversies tended to be on food and these controversies were escalated at the global level by serious differences between the U.S. and the EU in part because the former had a biotechnology food industry and the latter basically did not. Hence, for these and other reasons, the EU opposed biotechnology food products (Ashford, 1996; Paarlberg, 2000; Ames, 2001; Patterson, 2000; Skogstad, 2003). In these conceptions of conflict and of biotechnology regulatory regimes on products, biotechnological health products stood, relatively speaking, in the background of political consciousness and controversy (Patterson, 2000; Vogel, 1998). (see further discussion below). As in North America, however, the larger dimensions of health and biotechnology on crucial ethical and health issues such as cloning, assisted reproduction, and stem cell research have been debated extensively in the EU (Abraham and Lewis, 2000; Bauer and Gaskell, 2002).

The situation inherent in the first two points noted above has changed to a considerable extent in the last five years and, as a result, a third and fourth point need emphasis about the basic definition and analysis of the biotechnology regulatory regime. The third point is that the breakthroughs in the human genome plus related scientific and technological developments have meant that new bio-health products in very large numbers are now in the regulatory pipeline (United Kingdom, 2003; Ratcliff, 2003; Morris, 2003). Thus, the health product sector, a relatively small part in the earlier phases of debate about regulatory development (though not about actual regulatory practice) has increasingly assumed a central place of importance and focus in public debate. The fourth point is that this fact alone has already changed the way the regulatory regime now needs to be defined and also how it is being perceived in global political-economic terms. On the definitional front, the biotechnological regime for bio-health (and for other products and processes) requires a need to deliberately include in this regime the rule making that occurs in realms such as intellectual property, human reproduction, research ethics, and federal and provincial bodies involved in doing technology assessments of these new technologies. The regime also includes the provincial gatekeeper functions which determine which products and services can be offered and paid for under Medicare, the pricing of pharmaceutical products by provincial government purchasers of drugs and federal bodies such as the Patented Medicines Prices Review Board. Day-to-day professional practitioners in government and industry have always realized these broader regime links but the overall national debate on biotechnology has not addressed all these issues and the agencies that deal with them. However, bio-health products compel their inclusion in thinking and practice about regime change.

Global perceptions about the raw politics of biotechnology also changes with the rise to prominence and consciousness of bio-health. The EU is completing a complex round of consultations and policy and regulatory development on biotechnology and the health and life sciences (Commission of the European Communities 2001; 2001a; 2002; 2003). But in this case the focus is much more than was ever the case for food products or GMOs on how the EU and European citizens can prosper from such an industry and benefit from health products and can learn to compete with the U.S. industry which has also been characterized by a significant shift to bio-health as well (Kass, 2003; Senker, 1998; Weintraub, 2003). (see more below). This does not mean that there are not serious concerns in the U.S.-EU global nexus about the safety of such products and about related ethical and social issues but it does mean that the global politics of biotechnology is much more complex, and, in a very real sense, more even-handed, precisely because bio-health has forced a broader discussion and engages a much more complex set of interests in the debate about regulatory regimes and biotechnology governance more generally.

The paper is organized into four sections. The first section examines the emerging pressures on the biotechnology regulatory regime, particularly those emerging from the larger bio-economy and health sector. The second section sketches out the key characteristics of the current Canadian biotechnology regulatory regime and some related aspects of the international regime. This is necessary to find out what kind of regulatory system exists now on to which, or into which, a reformed system might placed. This is followed by a section dealing with the key values and criteria involved in the architecture of any changed or alternative biotechnology regulatory regime. There are similarities in values to the current system but there are also some differences due to the imperatives of bio-health products and processes. The fourth section then explores at a very broad level three alternative regulatory regimes. Conclusions then follow.

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Emerging Pressures on the Regulatory Regime

Several pressures are emerging or already present on the biotechnology regulatory regime. Most arise because the biotechnology era has now shifted from an earlier food product focus (with related political controversies) to a bio-health and genome-centred focus (with its own mix of positive and negative concerns and controversies). The pressures are multiple and interacting and include:

• Significantly increased volume of products, processes, services and devices generated through genomic and related technologies, all needing regulation and monitoring;

• The greater tailored nature of such items aimed at smaller subsets and markets of persons/consumers/patients and hence, for firms, higher capital costs and shorter shelf-life of products;

• Pressures to re-balance the mix of pre-market versus post-market aspects of the regulatory regime

• Pressures to revisit the nature and meaning of drugs, diagnostics, and devices as separate versus combined “products” and “processes” needing regulation.

• The need to ensure that Canada's bio-economy firms can survive and prosper (and create jobs) in a global competitive context where innovation is the key imperative.

• Pressures for new and expanded needs in regulatory capacity (staff competences and S&T knowledge, information, and equipment).

• Pressures and need for greater international shared regulation of the “health, biotechnology, bio-economy” regulatory system.

Each of these pressures are elaborated on briefly in the paragraphs which follow.

The pressures regarding the higher volume of products comes largely from the health/genome side rather than from the agriculture and food side of the regulatory process. Estimates vary depending on what is being counted and what stage of regulation one is talking about. Statistics Canada data indicates that the number of products and processes in the pipeline at all stages of development grew from 1,752 in 1997 to 6597 in 1999 and then almost tripled to 18,020 in 2001 (Statistics Canada, 2001). In 2001, about 57 percent of this activity was in human health with agriculture at 37 percent. The same study indicated that over 2400 health products were under development, of which 346 were pre-clinical and 121 were in the regulatory system. Health Canada's Biologics and Genetic Technologies Directorate indicated that submissions for clinical trials grew from 150 in 2000 to 183 in 2002. The average time of eight years for completion of the full cycle of development and regulation means that there is a considerable backlog even before one takes into account the true impacts of greater volume and the changed technology and nature of the products. Industry spokespersons suggest that the knowledge base has doubled in the last five years and that there has been a significant shift to platform technologies where computer simulations are being used for new products and suites of new products. In some cases this has lead to some firms reducing the 8 to 12 year clinical trial process to 6 to 12 months.

In the United States, there are currently more than 370 biotechnology drug products and vaccines in clinical trials and the number of such approved products on the market has increased seven-fold in the last decade. In 1993 there were 7 products approved but in 2002, 35 products were approved (see Web reference).

The exact scale of the high volume issue thus involves a range of estimates. But there is no doubt that the volume is growing and that regulators have to be able to deal with this volume nationally and internationally.

The dynamics regarding the greater tailored nature of products are also complex. At its core, the notion of tailored refers to products (drugs and devices) derived from the genome mapping and DNA characteristics of small sub-populations. This raises the far higher probability of products aimed not at huge target markets (the typical current drug product) but rather at very small sub- markets and niche markets (United Kingdom, 2003). But this in turn depends on the availability of risk capital for firms, especially for the numerous small firms developing these products (see discussion below on small business risk capital issues).

Similar pressures, but on a lower volume scale, have already been encountered in the past concerning so-called orphan drugs. These were drugs which would not otherwise have reached the market because of market imperatives but which were crucially needed and useful to smaller sub markets of patients. The U.S. developed special incentives to enable some such products to get to market (Maeder, 2003). In principle, there will be many more such potential orphans in the new tailored market that many envisage is at hand. This also means that a much larger proportion of actual or potential drugs that may not be available in Canada as the local market may be too small to support the cost of regulatory review.

This characteristic is important in its own right but it is ultimately tied to other features of likely market and patient pressures. The Internet and the existence of patient lobby groups and self-informed patients means that individuals will learn about prospective new drugs/devices/products and will exert pressures on national regulators to approve them or to allow them to be imported. One impact of this is that health regulators may have to make greater use of their provisions regarding exceptional circumstances, regulatory provisions which allow faster approval or temporary use (such as has been used for some AIDS-related drugs/products). Health Canada operates a Special Access Program which “provides access of non-marketed drugs to practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, are unavailable, or offer limited options” (see Web reference). But the logic of the combined volume and complexity variable and the tailored product variable is that there may be more and more exceptions or “special access” needs. With these products approved and available in other countries, and likely flowing into Canada, increasing the amounts under special access programs, it can be anticipated that it will raise serious questions about what is value-added to the regulatory system and whether it is worth the cost.

The need to re-balance the mix of pre-market versus post-market aspects of regulation also needs to be taken into account as a pressure on the regulatory system. In the regulation of drugs the core logic of the current system is still strongly pre-market-oriented, largely a model of regulation dating back to the thalidomide crisis (Doern, 2000b; Vogel, 1998). There are aspects of post-market regulation as well but typically far fewer regulatory resources go into this kind of monitoring and reporting activity. One of the broad implications of the current drug regulatory system is that once they are approved/licenced then they are on the market for the long term.

There are also elements of the regulation of the research itself which are of increasing concern. This concern centres on the need to prevent the unintended release of experimental chemicals. Debates about xenotransplantation are raising concerns regarding the possible accidental introduction of human susceptibility to new diseases originating in the donor species. Numerous ethical and other issues are centred on the treatment of donor genetic material for scientific research (Foster, 2003).

The combined pressures of higher volume and complexity and more tailored products are likely to require a re-balancing of the regulation of research, and the pre-and post-market aspects of drug regulation. There will still be a great need for stringent pre-market processes on safety and efficacy but far greater post-market activity is likely to be needed. But this is also likely to increase the number of drugs that might have to be recalled or reviewed in the wake of adverse or unforseen effects discovered through post-market assessment of actual product use, efficacy and impacts.

The pressure to revisit the nature and meaning of drugs, medical devices and diagnostics receives very brief mention here but it logically follows from, and is linked to, the issues just profiled. First, it is likely that future products will include higher numbers of those which are combinations of drugs and medical devices inserted into the body. Typically drugs and medical devices have separate regulatory statutes and regulatory bodies or sub-agencies. Second, for medical devices in Canada the larger focus of regulation has been on post-market review rather than on pre-market approvals, in part because many are made/manufactured in the U.S. or abroad (Doern, 2000). This is the reverse logic to that described briefly in the previous section on drugs where the focus is on pre-market approval. So when drugs and devices are combined as products, there are also logical needs for the re-balancing or re-thinking of the pre-and post-market aspects of regulation.

The crucial need to ensure that Canada's bio-economy firms can survive and prosper is also a major imperative, all the more so when seen in the context of Canada's innovation agenda (Canada, 2002). Any discussion of this factor must be set in the context of the structure of the Canadian biotechnology industry and how rapidly its composition has changed in the last few years. The industry's national association, BioteCanada's, most recent state of the industry report, sets out the key features and its sense of key market factors:

• Canada had 391 biotech firms in 2001, up from 227 in 1997 and ranked 2^nd in the world after the U.S.;

• R&D activities have grown from $695 million in 1998 to $1.4 billion in 2001;

• Most Canadian biotech firms report growing losses with net losses for public firms increasing by 17 percent between 2000 ($667 million) and 2001 ($784 million)

• Regulatory barriers and lengthy approval times often prove to be insurmountable on the road from laboratory to commercialization;

• In 2001 over 50 percent of Canadian biotech companies were in the health care sector- up 42 percent from 1999. The agriculture sector, reflecting increased consolidation, has dropped in number of firms from 25 percent to 17 percent of total firms;

• The world market for biotechnology-based products will increase from $20 billion in 1995 to $50 billion in 2005.

• Domestic production will account for only 26.5 percent of drugs that Canadians consume. It is estimated that by 2005 Canada will import $10.7 billion worth of pharmaceutical drugs;

• The Canadian Intellectual Property Office (CIPO) currently has 20,900 biotech applications on file, with 8500 having a request for examination. CIPO anticipates growth at 4-5 percent per year. CIPO is also receiving more “jumbo applications”- the largest application so far is 70,000 pages long;

• In 2001, there were more than 20 approvals for new biotechnology-based medicines and vaccines

• From 1997 to 2001, Canadian biotech companies raised about $3.7 billion from the public capital markets; (BioteCanada, 2002, pp. 1-2.)

BioteCanada's profile of its “typical corporate member” is also of considerable interest:

• Is a public company
• Is in human therapeutics
• Has 1/3 of its work force working in R&D
• Is a likely to have a commercialized product as not
• Struggles with the cost and time required for regulatory approval
• With only 12 months of funding available, long term sustainable development is questionable, hence efforts to form alliances with international partners
• Access to market, human resources and intellectual property are on-going challenges
• Product development decisions are critical, while alliances/partnerships and financing are also major concerns
• Is looking outside Canada to form an alliance
• Out-sources some activities in the product development cycle

• Continues to be in the survival mode (BioteCanada, 2002 p. 2).

Within this core basic portrait, five related factors are especially germane to industry survival and growth. The first is that the industry is awash with fast changing re-structuring as new sub-sectors of the industry emerge including integrated bio-pharma companies, contract research companies, drug discovery companies, and diagnostic companies. In this restructuring context it must also be stressed that virually all of the 400 or so Canadian companies are new in the last decade.

The second factor is the shortage of risk capital because the industry is essentially dominated by small and medium-sized firms with, as indicated above, limited cash flow to survive the high front-end R&D development and regulatory costs; The second factor is that these shortages in risk capital are likely to be even greater as the above mentioned high volume and tailored niche products come into the pipeline, in essence producing more candidates for orphan drugs.

The third factor is the industry's more articulated view that the regulatory regime is much more than the drug approval process. Access to patients and to the managed medical market requires attention to all aspects of rule making and rules which effect products. This includes intellectual property regulatory processes and competences/capacities but it also extends to drug formulary processes largely controlled by provincial governments in Canada but also federally through the Patented Medicines Prices Review Board. The U.S. system of price setting is the only one that allows full actual costs of development to be included (albeit several current legislative initiatives may change this situation). All other key market countries use formulas based on the average of costs in several countries. Thus Canadian biotechnology firms want the U.S. to be one of the countries so listed for Canadian pricing or better still, a Canadian formula that better recognizes real costs. It must be stressed, however, that all medium-term scenarios envisage some form of managed prices, because of the growing costs of drugs in public and private health care systems. Even in the U.S., the proindustry Bush Administration is increasingly concerned about, and sympathetic towards the power of the ageing population “grey lobby” which is actively lobbying against drug companies and their high prices in the U.S. (compared to many other countries).

The fourth key factor for business, stated and unstated, is that market forces increasingly require nationally and internationally efficient and effective regulatory regimes. Global markets compel it. The high proportion of international alliances among smaller and larger firms also compel it. For these and related reasons, industry sources are concerned by what they see as the slower average approval time for new drugs. For Canada, this average is 608 days compared to Australia, 536, the U.S. 496, Sweden, 360 and the UK 344 days (figures cited in Bryant and King, 2003, p. 11).

It must also be emphasized that effective health and safety regulation, nationally and internationally, is also vital to corporate prosperity. Without regulation by governments, there is no product that is credible product (see more below) in the eyes of patients and consumers.

Pressures for new and expanded performance in regulatory capacity are already growing and will only increase in the coming decade. Regulatory capacity is not an easily defined concept because it can refer to many interlocked abilities, competences, budgets and systems of information bound up in agency staff (S&T and non-S&T) and equipment and ongoing training and capacities to recruit or to buy expertise. The current multi-departmental regulatory capacity for the current regulatory system is unlikely to do the job in several senses.

The S&T backgrounds of staff are likely to have to change to some considerable extent to be able to assess products centred on the newer biosciences and the genome. This is already happening in biotechnology regulatory agencies and in other regulatory bodies such as patent agencies. The sciences and technologies needed will put a premium on acquiring expertise that is scarce and hard to acquire not only because it is scarce but also because of lower public service salary scales.

A second manifestation of changed capacity needs is likely to be technical equipment. The best industry-standard equipment will be needed as a tool for assessments and monitoring but again, given many public sector and regulatory agency budget pressures, it is not at all clear that Canada's set of biotechnology regulators can afford such equipment. But it is equally true in a different sense that they cannot afford not to have it. Because this and other items of capacity are tied to budgets and funding, the question will naturally arise as to where the funds will come from, such as taxpayer and A-base funding, versus user fees and other forms of pooled or shared funding.

Third, and finally, one must consider under the capacity question the issue of pre- and post-market regulatory resources and balances. If Canada opts for a “full service” and made in Canada regulatory system, whatever reconfiguration of these tasks is decided upon in the next decade, will undoubtedly cost more in budgets, types of S&T staff and equipment and information systems.

Pressures regarding the need for greater international shared regulation is undoubtedly a crucial part of the political economy of biotechnology in health. This is discussed later in the paper where EU models are canvassed, but here we simply take note of the most central imperatives of this obvious kind of pressure. The first is simply that global markets are a crucial reality for biotechnology firms. It is the global regulatory system that concerns them and within which they must function and seek approvals. But they are also interwoven with global networks of patients and patient lobby groups and hospital purchasers of drugs and products for state run and private medicare systems. The health product market is not a fully free competitive market. It is a managed market with complex sets of national and international regulators.

A second internationalizing pressure comes in the form of the shared nature of risk assessment due to the likelihood of scarce front-line expertise on new products derived from the fast moving bio-health and life sciences. This kind of expertise is ever more likely to have to be shared and pooled ( see further discussion below on the EU's regulatory evolution). Moreover, as we see below, the EU does supply a workable model. It is not some form of “never been tried” institutional reform but rather one which has been experimented with across two decades. There are, of course, continuing concerns about sovereignty in any such globalizing and internationalizing regulatory set of pressures, a point to which we also return below.

The Current Biotechnology Regulatory Regime

If the above pressures and dynamics are emerging and require possible regulatory regime change then a logical question is what kind of current regulatory system will it be placed on? If reforms are needed what kind of system will future changes be assessed against, layered on to or imbedded in? The current Canadian biotechnology regulatory regime is sketched out very briefly in this section but crucially it is sketched out in relation to: its overall rationale and key features; its multi-agency and multi-statute nature; its links to international regulation and governance; and basic criticisms of the current regime.

Rationale and Key Characteristics

Biotechnology has gradually emerged on the national and international policy and economic agenda in the 1980s and 1990s in three main ways: in an evolving biotechnology regulatory system responding to the development of new products and processes by industry and university researchers; in overall federal biotechnology strategies in 1983, the early 1990s, and 1998; and in periodic controversies about products and scientific developments including royal commissions on blood products and on assisted human reproduction.

The main way in which biotechnology has emerged is in the gradual fashioning of a biotechnology regulatory system in response to the development of products. This led to the development of a Federal Regulatory Framework for Biotechnology (see more below). There is no single biotechnology regulator, though there are offices of biotechnology within both Health Canada and the Canadian Food Inspection Agency (CFIA). Instead, a framework of principles was developed to guide the several regulatory bodies and departments which were being called upon to assess biotechnology products (Canadian Food Inspection Agency and Health Canada, 2000; Canada, 1998; Prince, 2002; Doern and Sheehy, 1999).

A second way in which biotechnology emerged as a policy-regulatory issue was through a series of federal biotechnology strategies. An initial 1983 National Biotechnology Strategy was essentially an effort to promote R&D, investment, and market acceptance of this new technology. It was updated in the early 1990s and then was replaced by the 1998 Canadian Biotechnology Strategy (CBS), the focus of which was much broader. The CBS is intended to “support the responsible development, application, and export of biotechnology products and services” balanced within the context of “social and ethical considerations” (Canada, 1998, p. 1). The CBS set out a policy framework consisting of a vision, guiding principles and goals that reflect biotechnology's importance both to the economy and to Canada's quality of life. Ten themes “for concerted action” were identified and are being implemented on a partnership basis with stakeholders such as the provinces, industry, academia, citizens, environmental groups and other interests.

The centrepiece of the renewed CBS is the establishment of the Canadian Biotechnology Advisory Committee (CBAC), an expert panel which now advises ministers on the “ethical, social, economic, scientific, regulatory and environmental and health aspects of biotechnology” (Government of Canada, 1998, p.1). The CBAC has no role on specific regulatory decisions. But its policy advisory role includes its serving as a forum to give Canadians a voice in an “open and transparent dialogue on biotechnology issues” (Government of Canada, 1998, p. 1). This paper for CBAC fits into that overall role.

A third way in which biotechnology has gained a greater profile on the national and international scene is that it has become central to particular policy or regulatory controversies. These range from global scientific issues such as the cloning of Dolly, the sheep, gene prospecting and its links to biodiversity, and the huge human genome research project (Genome Canada, 1999; Grace, 1997; Appleyard, 1999; Rifkin, 1998; Shiva, 1997; Mironesco, 1998). But controversy can also includes specific products such as Canada's debate over the regulation of rbST (MacDonald, 2000; Mills, 2002).

A Multi-Agency and Multi-Statute Regulatory Regime

The 1993 Federal Regulatory Framework for Biotechnology provides the overarching principles for the functioning of the federal biotechnology regulatory system (Canada, 1998; Doern and Sheehy, 1999). Biotechnology is defined in Canadian legislation as “the application of science and engineering in the direct or indirect use of living organisms or parts or products of living organisms in their natural or modified forms”. Therefore, the federal framework was developed in the light of both interdepartmental and stakeholder consultation processes with diverse interests.

The framework is centred on a set of six principles with respect to the regulation of biotechnology. These include:

• maintaining Canada's high standards for protecting the human health of Canadians and the environment;

• using existing laws and regulatory departments to avoid duplication;

• develop clear guidelines for evaluating biotechnology products that are in harmony with national priorities and international standards;

• providing a sound, scientific knowledge base on which to assess risk and evaluate products;

• ensure that the development and enforcement of Canadian biotechnology regulations are open and include consultation;

• contributing to the prosperity and well-being of Canadians by fostering a favourable climate for investment, development, innovation and the adoption of sustainable Canadian biotechnology products and process (Canada, 1998, p. 12).

In various ways the six principles are intended to reflect a reasonable and balanced approach between ensuring health and environmental protection broadly speaking and fostering the development and practical benefits of biotechnology products/processes, including Canadian economic competitiveness in this sector. The principles also reflect Canada's international commitments under the United Nations Commission on Sustainable Development, the United Nations Convention on Biological Diversity and the World Trade Organization and NAFTA. (Buckingham, et.al. 1999; Phillips and Buckingham, 2000).

However, on a overall basis, it is also important to stress that these principles were based on a broad view that new products and processes covered by this policy were similar to those already being regulated but this becomes increasingly less true the more that issues such reproduction and stem cell research were added to the agenda (see further discussion below).

In addition to the above principles, the federal biotechnology product assessment process is also governed by generally accepted approaches which Canadian and international regulators have evolved regarding the regulation of novel foods. These include the view that safety assessment is on the final product and that it is based initially on a comparison of the modified organism to those of its traditional counterpart where such exists (the concept of substantial equivalence). But if such equivalence do not exist, then broader assessments will be necessary (Health Canada, 2000; Canadian Biotechnology Advisory Committee, 2002). Overall regulation is also governed by the general operation of phases of decision making which encompass risk assessment, risk management, and risk communication. Risk assessment involves scientific analysis as to: the likely severity of adverse health and environmental effects, the size of the population at risk, and other related factors. Health Canada engages in health risk assessment regarding novel foods, as well as biologics and genetic therapies, whereas the CFIA does environmental risk analysis regarding plants with novel traits and also risk regarding feeds, seeds, and animal health. Risk management involves analysis and positive actions to reduce or avoid risks or engage in actions to forbear. Such actions are determined by statutory responsibilities, commitments and partnerships, and by assessing public health or other benefits relative to risks. The ability to manage risks is also partly a function of available resources including staff, expertise, and money. Risk communication involves purposeful exchanges of information about health or environmental risks between regulators and Canadians.

As Table 1 indicates, the federal biotechnology regulatory system is also crucially governed by the statutes and mandates of the four main federal departments and agencies with direct regulatory roles: Health Canada; the Canadian Food Inspection Agency (CFIA); Environment Canada; and Fisheries and Oceans Canada. The CFIA is a key regulator because of its primacy in enforcement in areas related to plant, feeds, seeds and animal biotechnology. Health Canada regulates food biotechnology under its novel foods regulations whereas the CFIA does not regulate food biotechnology except in its enforcement capacity. The roles of Environment Canada and Fisheries and Oceans Canada are not examined in this paper but are certainly important for understanding the system as a whole.

Source: Adapted from Canada (1998a) Renewal of The Canadian Biotechnology Strategy: Related Resource Documents (Ottawa: Industry Canada), p. 13.

This section does not describe the details of each of the several statutes. Table 1 is simply intended to be an initial guidepost. What it initially conveys is that once we go “inside” the regulatory system, there are ultimately several pathways and erstwhile stages of product assessment depending upon the intended use of the biotechnology product. Thus the pathways are not just the product of laws and regulations per se, but also grow out of different inherent physical and technical realities to the nature of biohealth products, or to foods versus animal feeds, versus seeds versus aquatic products etc. There are also different institutional cultures in each of the main regulatory bodies (Prince, 2000; Doern and Reed, 2000; Mills, 2002).

The basic snap shot provided in Table 1 has not been significantly changed in any basic legal sense in the early 2000s. But there have already been developments at Health Canada which recognize the changed context and nature of health- related biotechnology products and processes evident in the early 2000s. This includes a strengthened focus on biologics such as blood, blood products and vaccines and genetics, influenced strongly by both new volumes and types of products but also by the legacy of the Krever Inquiry on Canada's blood system, the Royal Commission on Assisted Human Reproduction, the issues of stem cell research, and the reform of research ethics boards and processes. It has also had to deal more directly with bio-terrorism and emergency preparedness. Health Canada has also received additional funding to allow it to build greater biotechnology capacity in the department including an ability to increase its scientific capacity. In 2000 it also launched its Biotechnology Surveillance Project to strengthen its ability to perform post-market surveillance in two specific areas: genetically modified foods and bio-engineered pharmaceuticals and vaccines.

Links to International Norms, Regulation and Governance

Space does not allow any extensive account of the international aspects of biotechnology product assessment. But several basic features can be briefly noted. The system of product assessment for food for example is still very much a national system of assessment in that the same product will need national regulatory assessment in countries where the product is to be marketed. National regulatory sovereignty means that permission to market products does not always happen in all national jurisdictions, as the rbST case showed and as general disputes between the EU and North America make clear (Safrin, 2002; Paarlberg, 2000; Phillips and Buckingham, 2000; Doern, 2000). But in the food sector, greater international and multi-country food regulation will soon be in effect through the EU's new European Food Authority.

In the health products sector of biotechnology, there have been somewhat greater globalization and internationalization pressures and processes underway for some time. One is certainly the EU's system for the regulation of medicines which we discuss later in the paper. The other has centred on the work of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH processes have centred on the roles of the pharmaceutical regulatory bodies for the U.S., EU and Japan, the world's big three markets for drugs, and their pharmaceutical industry associations. As a recent analysis of the ICH concludes “ the ICH network....have, in effect become a transnational power in setting the regulatory standards on the safety, quality and efficacy of new prescription medicines” (Abraham and Reed, 2003, p. 82). The secretariat for the steering committee of the ICH has been the International Federation of Pharmaceutical Manufacturers' Associations (IFPMA, 1997). The ICH process has involved a series of expert working groups centred on key issues and harmonization needs.

With respect to actual product assessments in Health Canada and the CFIA, there are certainly international aspects of assessment present in three respects. First, the science of biotechnology is global science and hence the peer-reviewed literature is international and is drawn on in the product assessment process. Second, science assessors within Health Canada and the CFIA have their peers in other countries' regulatory bodies (especially in the U.S.) with whom they are in regular contact. This does not mean at all that they simply adopt the conclusions reached elsewhere. But it does mean, that they can make queries about particular technical and analytical problems and obtain advice (and of course tender advice to other regulatory staff abroad who are contacting the CFIA and Health Canada on a similar quest for shared knowledge).

The third way in which international aspects influence product assessment is of course through the influence of the previously mentioned “accepted approaches”. This is especially the case for the concept of substantial equivalence in food product regulation of novel foods. This concept was adopted through international experience and discussion largely in the 1990s. These discussions and enunciations of the substantial equivalence approach emerged in international arenas such the FAO and WHO and then in the OECD in 1993 (Organization for Economic Cooperation and Development, 1993). The approach was further endorsed and reinforced after a 1996 FAO and WHO expert consultation reviewed how several food product cases had been handled in various regulatory systems (Food and Agriculture Organization, 1996). It was also the focus of a joint FAO and WHO expert consultation in 2000 (World Health Organization, 2000).

The concept of substantial equivalence is very much a central concept in Canada's (and seven other countries') biotechnology product assessment process as a way of determining how extensive the search for novel traits is and hence what kinds of data and research can be reasonably relied upon by the teams of regulatory scientists. But substantial equivalence is not the assessment process itself. It is in effect the starting point but full assessment is centred on the substantive assessment of products by the science regulatory teams (Health Canada, 2000a; Doern, 2002). Thus, substantial equivalence cannot and will not be applied in the assessment of a novel food for which there is no adequate comparator as described in Health Canada's safety assessment guidelines and further detailed in the WHO study (World Health Organization, 2000). In these cases more detailed and more comprehensive data will have will have to be generated.

This concept, as a starting point, therefore has considerable support among professional regulators but it is a contested one, especially by those who see the next generation of biotechnology products being based on more complex and uncertain forms of genetic modification (Millstone, Brunner, and Mayer, 1999). Moreover, it must be stressed that substantial equivalence is not a concept that is central to the regulation of medicines and new bio-health products, in part because many of these products do not have close equivalents.

A further area of international actions are those centred on promoting the harmonization of regulatory systems and approaches. For example a series of meetings between Canada and the U.S. produced an agreement in 1998 as to how regulators in both countries would deal with the application of molecular criteria in plant biotechnology (Canadian Food Inspection Agency, 2000). Similarly Canada has been very conscious of, an engaged with, the larger ICH process referred to above.

Last but certainly not least in this selective inventory of international biotechnology regulatory aspects is the Biosafety Protocol agreed to in January 2000. The key features of the protocol are as follows (UNEP, 2000; Environment Canada, 2000; Doern 2000). First, as mentioned, the scope of the protocol is limited in that it applies to the transboundary movement, transit, handling and use of all living modified organisms that may have adverse effects on the conservation and sustainable use of biological diversity, taking also into account risks to human health. The human health reference is interpreted as health effects from environmental and occupational exposure and those resulting from an adverse impact on biodiversity. As mentioned food safety is not addressed. Pharmaceuticals for humans addressed by other relevant international agreements or organisations are exempted and only some of the provisions of the protocol apply to LMOs in transit or in “contained use”.

When one adds other particular agreements in sectors such as agriculture, food, and health as well as key provisions in trade agreements there are broadly over 25 different international agreements and processes which effect and are a part of biotechnology regulation in Canada writ large.

Basic Criticisms of the Current Biotechnology Regulatory Regime

By 2000 some 43 biotechnology novel food products had proceeded through the regulatory system, have been assessed by Canadian regulators and are on the market. But the overall system, in food regulation and in other realms as well has been criticized. Some commentators and interests see the current system as being flawed because it is not more centrally controlled by Environment Canada through CEPA legislation. Others would view it as profoundly illegitimate if it was so centralized and regard the present system as being more legitimate and effective precisely because it recognizes sectoral variety and scientific and technical complexity.

There have been various criticisms of the degree to which the system allows a consideration and scrutiny of ethical issues, allows real and genuine citizen engagement, and subjects in-house science to independent and transparent scrutiny and criticism (Canadian Biotechnology Advisory Committee, 2002; Mills, 2002). The core of these issues are especially germane and can only increase in scale and controversy as issues such as the use of human subjects in research, stem cell research and new bio-health products are debated and also as more medicare decision makers make choices as to which will be covered under health care an which will not. And, business interests, as we will see below, are concerned about relative regulatory efficiency and efficacy in the face of growing product development and in the context of very competitive global markets.

It must be said in summary that the current biotechnology regulatory regime is already complex, has no shortage of critics, and was designed in an era when the core concerns were mainly over food products and later genetically modified organisms. Drug regulation is of course a part of this regime, including biotechnology medicines, but the latter, relatively speaking, had yet to reach their now emerging prominence in public attention and debate. It is on to this regulatory tableau that the new pressures, products and processes from biohealth traced earlier are being placed.

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Key Values and Criteria Regarding Possible Alternative Regulatory Regimes

Any alternative regulatory regimes for biotechnological health products that might emerge in response to the set of pressures described earlier will have to meet key criteria and values that societies, political systems and markets will insist upon. How these criteria are defined, ranked and weighted can only be given real meaning through political processes. Most of these are already inherent in our description in the previous section of the current Canadian biotechnology regulatory regime and in our account of the new forces and pressures. Accordingly, in this brief section, we simply bring together a summary set of points about five key criteria and values:

Regulatory Effectiveness: Health, Safety, Ethics and Effective Risk Assessment and Management

Regulatory effectiveness refers to the processes used, centred on science-based regulation, to ensure that products produce the positive benefits claimed for them in terms of patient health effects and public health impacts and that they are safe for such use or the risks in use can be managed at an acceptable level. Canada's biotechnology industry, in concert with the global industry, needs such regulatory effectiveness which only or mainly the state can supply. Private or self-regulation will not provide this in a credible way. But what firms do before a product reaches the formal regulatory process is also crucial for ultimate regulatory effectiveness. Hence regulatory effectiveness is dependent upon a system of defacto shared regulatory governance between governmental regulators and private firms and other researchers.

Regulatory effectiveness is also a function of time, in short, the time needed to actually conduct careful science-based assessments of new products and processes. But time is also a function of the nature and competences of S&T and other regulatory staff. In principle, if there are more qualified staff, more products can be assessed as to their effectiveness as defined above. But if products are more complex than for the previous set of drugs or devices then the average time needed may be greater even with more regulatory staff in place.

Often treated as separate concern, ethics is included in the first value or criteria in this paper. Many Canadians and citizens of other countries are concerned about the ethical issues involved in biotechnology use and wish to see it built into current and any alternative regulatory regimes. The Canadian Biotechnology Advisory Committee (CBAC) report on the regulation of genetically modified foods and crops argued that ethical and social concerns “range from fundamental opposition to the artificial manipulation of plants and animals (playing God with nature) to the belief that global justice and beneficence (that is, doing or producing good) are not being served by the current applications of biotechnology” (Canadian Biotechnology Advisory Committee, 2002, p. 13-14). Other members of society see positive virtue in the use of biotechnology, perhaps especially in the broader context of bio-health. The EU's recent paper on biotechnology and the life sciences includes an explicit value that such developments should be “in harmony with ethical values and social goals” (Commission for the European Communities, 2002, p. 12).

Regulatory Efficiency and Competitiveness in a Global Context

Regulatory efficiency can refer to two different notions of efficiency. The first is a simple notion of administrative efficiency in which case one is seeking a regulatory regime which produces the desired level of regulatory effectiveness at the least cost to taxpayers and to firms seeking approval of their products. Some sense of this kind of regulatory efficiency might be assessed by comparing countries regulatory approval times but this is not an easy kind of comparison to make because the measures are always input costs or time but these only make sense if they are related to some definition of regulatory effectiveness.

The second notion of efficiency, linked to values about competitiveness in a global economy, is allocative efficiency. This is a much larger and dynamic notion of efficiency which refers to how a country thinks about dynamic wealth creation and economic growth (Thurow, 1999). In this context, biotechnologies are more overtly cast as enabling technologies for such transformations and growth. In this context regulatory efficiency can easily and necessarily refer to entire systems of regulation, ie. complex regimes of regulation and whether they are aligned with, and capable of, fostering such industries (while still protecting health and safety). It also means thinking more overtly and systematically about whether an entire regulatory regime is thought of and assessed in terms of its ability to be the best in the world at attracting both capital and firms and global products. In today's regulatory jargon, this approach could be cast as “smart regulation”.

Regulatory efficiency for biotechnological health products involves both of these notions of regulatory efficiency, but it is also further entwined in the need for enhanced global regulation of all biotechnologies. Judgements about these twin tests of regulatory efficiency are always complex and are always contested as to whether Canada is getting closer to the optimum achievement of this criteria.

Democratic Accountability and Democratic Engagement

Regulatory regimes for biotechnology have a third test to meet, namely the test of democratic accountability and democratic engagement. We comment on this question in two stages: core Cabinet ministerial and Parliamentary accountability; and complex accountabilities tied to other notions of democracy (Flinders, 2001; Aucoin and Heintzman, 2000)

In terms of basic Cabinet Parliamentary Government and democracy, accountability refers to systems of public information, reporting and answerability by public entities (Sutherland, 1991). Fundamentally, this encompasses accountability to elected ministers and Parliament, with Parliament's Auditor General of Canada (AOG) being a key agency in supporting Parliament's overall role. But other agencies and statutes are ultimately also a part of this basic accountability regime, including requirements for access to information, secrecy, privacy, and language laws. Accountability is tied ultimately to the concept of ministerial responsibility both for policy and for administrative actions carried out by a politically neutral civil service. It is also a democratic concept which implies that if something goes wrong, then elected political authorities will be able to take corrective action.

But biotechnology and related forms of health and safety regulation have also for some time had to deal with a world of much more complex accountabilities linked to other notions of democracy. In short, Canada and other countries function in accordance with more than one definition or theory of democracy. In biotechnology governance there have already been quite varied degrees of arms-length relations and of the need for independence from ministers, including the need for independent science and technology advice. In many other areas of regulatory governance such as energy and environment there are similar degrees of concern about just what accountability and modern arms-length governance mean (Hill, 1999; Flinders, 2001).

The general logic of these analyses in the last decade or so is that accountability is now a system of accountabilities in the plural, including accountability “up” to Cabinet and Parliament, “across” to other ministers and players inside the government as a whole, and “down” and “out” to clients, partners, and citizens in some broader overall sense (Hill, 1999). For those who wish emphasis to be placed on accountability to Cabinet and Parliament and to elected representative government, these latter forms and directions of accountability are secondary. But multiple accountabilities are increasingly the order of the day and in a very real sense they flow from other views of democracy such as interest group pluralism (stakeholder democracy) and direct democracy where civil society, and individual citizens are engaged on a regular and systematic basis (Palast et. al, 2003).

The overall changes in Canada's current and likely future biotechnology regime make basic political and democratic accountability more matrix-like. Accountability is more complex, multi-directional and difficult to negotiate and reform, and to evaluate.

Sovereignty and the Limits of Sovereignty

Sovereignty is an important concern about biotechnology regulatory regimes and indeed about most realms of regulation. But as the larger discussion of globalization and free trade already shows, sovereignty is an idea with many meanings and nuances (Camilleri and Falk, 1992; Held, et.al, 1999; Falk, 1999). Moreover, the larger debate also raises concerns about the limits of sovereignty or, to put it more positively, the need to share or pool sovereignty. As a functioning constitutional federation Canada already shares and pools sovereignty internally.

Legal sovereignty implies the right of nation states to pass laws and pass regulations. Most arrangements in global governance retain these ultimate notions of sovereignty in that states can withdraw from agreements and of course pass the initial laws and rules that enable them to enter into agreements in the first place. But concerns about sovereignty usually go well beyond these legal notions to extend to various notions of political sovereignty. One such dimension of political sovereignty is felt quite intensely by elected ministers, perhaps especially in health and safety regulatory matters. This centres on the fact that if something goes wrong with a product in Canada a minister is likely to be blamed whether he or she had “sovereign” jurisdiction over it or not. Hence, there arises an instinctive demand that ministers must have some final say over such issues which could affect Canadians as consumers, patients and citizens.

But sovereignty is also a term which various interests can employ to advance different notions of sovereignty and these views go well beyond the sovereignty of states. It easily extends into values expressed as consumer sovereignty....which could imply labelling and information about efficacy and safety but it could also, in health products in particular, extend to the claimed rights of citizens to get access to the best products in the world or simply to helpful products.. even when their governments have not approved them for market use.

Finally, there are powerful norms which stress the need for pooled or shared sovereignty, a norm which is usually linked to the actual capacity to solve real problems through regulatory or other policy action. Sovereignty, as a form of political independence, is not of much use on its own if nation states on their own cannot actually solve a policy and regulatory problem affecting their own citizens. Capacities for actually solving problems can be enhanced through shared regulation and shared regulatory capacity. Trade and market imperatives are inevitably a part of this practical world of shared workable sovereignty and pooled sovereignty. Products and processes are traded globally and the production cycle must be tracked and regulated globally because it crosses national borders in almost every conceivable way.

Effective Regulatory Capacities Amidst Potential Scarce Expertise

It is perhaps unusual to express the concept of “effective regulatory capacities” as a value itself or as criteria. But it logically is. As suggested in the previous section, regulatory capacity refers to many interlocked abilities, competences, budgets and systems of information bound up in agency staff (S&T and non-S&T) and equipment and on-going training and capacities to recruit or to buy expertise. If a jurisdiction has such capacities, then regulation can meet all or most of the previous criteria itemized above. But if it does not, then it fails or falls well short of the mark.

The notion of scarce expertise as an adjunct to this fifth criteria and value is an advisable one because, as we have seen, it is highly probable that not every country will be able to assemble the full range of regulatory capacities, especially for regulatory risk assessment where complex new mixes of S&T competence are needed.

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Regulatory Regime Alternatives and the New Regulatory Governance of Biotechnology

Given the pressures enunciated above and given the values and concerns that have to be a part of any changed regulatory regime for biotechnology, what alternative regulatory regimes can be visualized or suggested analytically and practically? This paper is not intended to provide detailed recommendations or designs regarding these alternatives. Rather it is intended to discuss possible options at quite a broad architectural level. In this context, we now look at three alternatives:

• Alternative Regime 1: The Status Quo With “add-on” Improvements
• Alternative Regime 2: Greater Separation/independence of Risk Assessment Aspects from Risk Management Aspects
• Alternative Regime 3: The EU as a Multi-country Regime Model
• Possible transference of Regime 3 to a North American or NAFTA model of multi-country biotechnology regulation

• Selective Unilateralism

Alternative Regime 1: The Status Quo With “add-on” Improvements

This alternative encompasses taking the current Canadian biotechnology regulatory regime and basically seek to improve it with new resources. New regulatory capacities would/could be created for key challenges such as assisted human reproduction, xenotransplantation, genetic testing, and privacy, depending on the circumstances. Some of this is already happening in the sense that Health Canada, as we have already noted, has been given additional resources and is seeking to build additional capacity both in terms of staff and equipment. There will undoubtedly be support for this incremental approach among existing departments and agencies with their own statutory mandates in biotechnology. Some of this support is based on a genuine belief by these regulatory practitioners that the current system has worked reasonably well. Some of this support is also simply the product of normal bureaucratic inertia and turf protection.

The major arguments against the viability of Alternative Regime I is that it will not handle the pressures and problems discussed above in that the new demands are not simply incremental add-ons but in fact are of a quantitatively and qualitatively different scale and scope. Of particular concern is whether a country like Canada can assemble the needed front-line expertise for initial science-based risk assessment (and related aspects of risk communication at the front end of regulatory process). Alternative Regime I tends to assume that such risk assessment capacities would be assembled, as at present, within each of the regulatory departments and agencies but a critic of the current regime would argue that this is unlikely to work, partly because of the complex nature of the new sciences and the transdisciplinary S&T involved, especially in bio-health.

Alternative Regime 2: Greater Separation/independence of Risk Assessment Aspects from Risk Management Aspects

Another possible way to think of a changed or alternative Canadian regulatory regime for biotechnology as a whole (or in combination with the new dynamics of bio-health traced in this paper) is to attempt to, as it were, separate out and consolidate the risk assessment aspects/phase of the regulatory process. Some have argued for this kind of model in the sense that they believe that government science needs to be to more transparent and arms-length from risk management processes (Leiss, 2000). The concentration of the government's regulatory expertise in a single place could also help to make the best use of scarce expertise. Given greater uncertainties in science and in the technologies employed, this argument for separation is also linked to the view that risk assessment must also involve greater opportunities for public scrutiny and citizen engagement. If extended to bio-health, then this argument of institutional separation and independence is potentially enhanced because of the larger socio-economic and ethical issues of tailored products, and high volume products, but also the role of platform technologies from which bundles of products emerge.

If this alternative was attempted in the form of literally one arms-length institutional location for all human health products or health and human food risk assessments, there are several natural counter-arguments that would be mounted against it. The first counterargument is that some key aspects of risk assessment are specific to sectors such as a food, biohealth, fish, plants, and animals and hence should be located and dispersed across the mandate areas, as they now are. The second counter-argument is that the nature of a “one stop” institution for all health or food risk assessment is such that it would simply be too radical and disruptive with large transitional costs and uncertainties. The third counterargument, is that even if something like this was adopted, it still may not have the economies of scale and scope to allow a small country such as Canada to assemble the proper kind of fast changing expertise for the new volume mix and the tailored nature of products. A final counterpoint is that the notion that one can separate out risk assessment from related tasks of risk management is a false one in that such activities are very closely interwoven and partly embedded in each other.

Alternative Regime 3: The EU as a Multi-country Regime Model

Earlier parts of the paper have already set the context for recent EU changes and for the larger climate for biotechnology in the EU, a climate forged in the politics of food biotechnology where political opposition was (and is) strong but which is now changing with the explosion in bio-health products and where the EU is keen to compete with the U.S. Our discussion here of the EU as a multi-country regime model ( an Alternative Regime 3) is confined to medical products and again to only a very basic sketch of how the EU system has evolved and what its basic elements consist of.

The European Union's approach to biotechnology regulation in health has evolved gradually since the mid-1970s (Vogel, 1998; Abraham and Lewis, 2003; 2000). It centres on the European Medicines Evaluation Agency (EMEA) now in its 9^th year of operation (European Medicines Evaluation Agency, 2003). The EMEA's mission statement states that the EMEA is

“To contribute to the protection and promotion of public and animal health by:

• Mobilizing scientific resources from throughout the European Union to provide high quality evaluation of medicinal products; to advise on research and development programmes and to provide useful and clear information to users and health professionals;

• Developing efficient and transparent procedures to allow timely access by users to innovative medicines through a single European marketing authorization;

• Controlling the safety of medicines for humans and animals in particular through a pharmacovigilance network and the establishment of safe limits for residues in food-producing animals” (European Medicines Evaluation Agency 2003, p. 2).

The EMEA manages two routes for authorization of medicinal products: the centralized procedure and the decentralized procedure.

• The centralized procedure is compulsory for medicinal products derived from biotechnology and available at the request of companies for other innovative new products. Applications are submitted directly to the EMEA. At the conclusion of the scientific evaluation, undertaken in 210 days within the Agency, the opinion of the scientific committee is transmitted to the European Commission to be transformed into a single market authorization applying to the whole European Union.

• The decentralized procedure (or mutual recognition procedure) applies to the majority of conventional medicinal products and is based upon the principle of mutual recognition of national authorizations. It provides for the extension of marketing authorizations granted by one Member State to one or more other Member States identified by the applicant. Where the original national authorization cannot be recognized, the points of dispute are submitted to the EMEA for arbitration. The opinion of the scientific committee is transmitted to the European Commission.

  The European Commission adopts its decision with the assistance of a standing committee composed of representatives of Member States (European Medicines Evaluation Agency, 2003, p. 2).

This EMEA-centred system involves the Committee for Proprietary Medical Products (CPMP) and the Committee for Orphan Medicinal Products (COMP). Also involved is the European Department for the Quality of Medicines (EDQM) an agency of the Council of Europe which coordinates the lot release quality control process once products are licensed. The core functional units within the structure of the EMEA include units for:

• The Pre-Authorization Evaluation of Medicines for Human Use;
• The Post-Authorization Evaluation of Medicines for Human Use; and

• Veterinary Medicines and Inspections

When the first biotechnology products emerged in the EU in the 1970s and early 1980s there were almost immediately pressures from firms to centralize the procedures for licensing medical products at the European level. But there was also resistance to a centralized system on the grounds of both national member state sovereignty and concerns about ensuring health and safety in national contexts.

The initial response came through the establishment of the CPMP linked to an EU-wide system of mutual recognition of medicines licensing by member states. The mutual recognition process was initially know as the CPMP procedure. But this system was not very successful because of the tendency of member states to seek arbitration. The CPMP was composed of scientific and technical delegates from each member state which would then issue advisory views. If these views were positive regarding the product in question, then the member state's regulatory body could agree or it could disagree but had to then indicate the reasons for a negative opinion.

Following the EU's major thrust in the 1986 to 1992 period to open up and make real its internal market, there were pressures on all member states to reduce commercial regulatory and policy barriers and to actively foster the single market. As a result, in 1987 a concertation procedure was made compulsory for biotechnological medicines and yielded the rapporteur system discussed further below. In 1995 bigger changes were made in that CPMP opinions in both procedural routes now became binding on member states. The EMEA was a part of this reform effort and it spearheaded an effort at much greater centralized processes for medical-health products. The essence of the problem, evident much earlier, was not just business pressure for single window approval processes but also a growing recognition that member government's had very uneven regulatory capacities, especially in core scientific regulatory capacity. The UK, France and the Netherlands had full-scope capacity but other member states such as Ireland, Spain and Portugal did not.

Under the system in place since the establishment of the EMEA decisions are now made through the two procedures noted above. Member states still have a process whereby they can opt-out of a decision, but these are rare and the standard for opt-out is extremely high. The decentralized procedure, as indicated above, is typically for traditional biologicals and traditional medicinal products and it involves the selection of one of the EU countries, such as France, as the rapporteur country or Reference Member State (RMS). That country then does the science-based risk assessment and sends it on to the EMEA. The RMS can recommend its licensing but at the CPMP committee there are opportunities for discussion and objections. There is also a provision for a company to have a hearing before the full CPMP.

Initially, the choice of the rapporteur or RMS country was made by the company applicant but gradually two criticisms emerged. First, a very few countries became the country of choice and this alone created some resentment among countries which were not selected. Secondly, there was some early concern that firms were possibly picking countries where the regulatory relationship with that country's regulatory body was perhaps too cozy or insufficiently rigorous. As a result, the EMEA now makes the choice of the rapporteur country. The EMEA is based in London but it's culture and legitimacy has evolved to the point where its member country staff analysts and assessors are not seen as a “nationals” but as experts making European choices. Indeed it has been referred to as a “virtual Euro-Agency” because it draws on every member state national agency which are thus a part of the EMEA and member states are also members through the CPMP (Abraham and Lewis, 2003).

The EU regulatory process for biotechnology products in medicine and health does not end with product licensing. There are also lot release controls for certain biologicals, vaccines and blood products. National systems provide the evaluation of each lot. Once again, concerns arose in Europe about this aspect of regulation as a further potential regulatory barrier to an internal market and thus member countries were urged to practice mutual recognition of other countries approvals and testing of lot releases. The previously mentioned European Department of Quality Medicines is the formal body for coordinating this aspect of the regulatory process.

The EU system for biotechnology health products has thus produced a multi-country system of regulation which has gradually become more centralized but in keeping with 15 to 20 years of evolving acceptance, legitimacy and practice. It has considerable centralization of risk assessment either at the EU level per se or by the rapporteur country system. Risk management is also centralized to some considerable extent although the role of national bodies is still important here. The product approval and licensing process is more efficient for firms compared to the earlier system where firms would literally have to obtain multiple approvals, one country at a time. The system also helps meet the obvious need to pool expertise among member countries, some of whom could not regulate on their own but who still have some concerns about national sovereignty which seem to be being met by this now evolved EU system. Our interest in this system has been at the level of its basic processes and evolution and thus we have not evaluated the process in any detailed way. As one would expect of any complex system, there have been criticisms of it, centred on whether it is striking the balances between science and non-science expertise, regulatory effectiveness versus commercial values, and balances among member states in the EU (Abraham and Lewis, 2003; 2000).

The Possible Transference of the EU Regime 3 Alternative to a North American or NAFTA Context

The discussion of the EU multi-country model logically suggests that if Canada wished to avail itself of, or become a part of, such as formal multi-country model then it is some version of a North American model which would immediately come to mind. Canada's health product regulators already have very close cooperative relationships with the U.S. Food and Drug Administration (FDA). Though a pure North American model would involve Mexico, there is no doubt that any consideration of this as a viable model in the medium term would turn on the realities and perceptions of Canada being tied more closely to the U.S. Unlike the EU model of several countries, many of roughly equal size and power, any North American model starts with the issues of dealing with one dominant power.

It is unlikely that a North American model of biotechnological health products regulation would emerge out of trade agreement processes in NAFTA. However, some key interests in both countries would see shared or pooled regulation as “trade enhancing”. Mexico as a North American partner may have quite different views although it faces even greater challenges than Canada in assembling the enhanced needed regulatory capacity discussed earlier. In some respects, therefore, Mexico is very much like Spain and Portugal when the early steps at EU medical product regulation reform began to change in the early 1990s.

But any shared or pooled regulatory system would be largely designed outside the trade agreement system. This is because the larger logic of such trade agreements is to foster trade by limiting or constraining the role of government. Trade agreements do contain provisions about health and safety standards and how they are set but any North American model for bio-health product regulation would require separate agreements. The advantages for such a system are clearly that the FDA is virtually the only regulator that would have some chance of assembling full scope regulatory capacity for risk assessment in the new bio-health economy. It also practices quite open and transparent regulatory processes and is aware at some important level that it is already a defacto global regulator.

For Canada, however, there would undoubtedly be serious concerns about real or perceived losses in sovereignty and also about exactly how the shared relations of regulatory trust would or could be developed. On the other hand, Canadian regulators in many realms, including health, already cooperate and de facto co-regulate on a daily basis with U.S. regulators. And so a North American model is well worth exploring and building.

Much of the future likelihood of this development is also dependent upon U.S. political attitudes more generally, including whether there is any momentum at all in making North America into a North American political community as opposed to just a North American free trade area. The status of the U.S. as the only global superpower and the tendency of the Bush Administration, in at least some policy realms, to prefer unilateralist approaches may mean that the U.S. is not at all interested in having its FDA become, the focal point for North American risk assessment work, comparable in some basic way to the EU system and organized through agreements with Canada and Mexico.

Selective Unilateralism

Last but not least in this broad architecture of regulatory change is the possible practice by Canada of selective unilateralism. Instead of waiting for broad scale international and multi-governmental regimes to slowly evolve, Canada might accept as valid the specific risk assessments done on products in other countries (such as Australia, the EU or the U.S.). A final decision on risk management and actual product approval could then still reside with Health Canada or other regulators but there would be some efficiency gains without any losses in regulatory effectiveness. In a sense, this would be a process whereby Canada would be accepting a form of “rapporteur” country or jurisdiction somewhat like the EU's system but without having to wait for a formal North American model to emerge. If this was adopted on a wider basis, it could potentially provide an opportunity for Canada to reorient its domestic regulation to concentrate or areas of special need and also to contribute to the larger global regulatory system.

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Conclusions

The purpose of the paper has been to examine key pressures and factors which are likely to cause changes in the Canadian biotechnology health products regulatory regime in the medium-term future. As a key part of this overall task, the analysis has set out the core values and criteria for the design of the regulatory regime, and mapped three alternative regimes for initial consideration. It must be stressed again that the discussion here has necessarily been broad and quite exploratory, given not only the pace of change in the bio-health economy, but also the fact that the author is not presenting any detailed analysis of the design of possible new regimes or a detailed account of the current regime. With this broad caveat in mind, several basic final conclusions and observations emerge on the likely most promising way forward in the medium term and on the key constraints facing Canada as it reforms its regulatory regimes for the safety and effectiveness of biotechnological health products.

The first conclusion is that the key changes and pressures discussed in this paper reflect the fact that the centre of gravity in the Canadian and global biotechnology regulatory regime has already shifted. Its previous focus on food and agriculture, though still important, has been supplanted by the surge in products and S&T development in bio-health products and processes. This is true in both the global U.S. versus EU context and in the context of biotechnology and bio-health as key parts of the innovation strategies of the U.S., EU and Canada. These combined changes also mean that a new sense of breadth of the biotechnology regulatory regime must be kept fully in mind and must inform any strategies for regulatory change. It is ultimately a regime of rules and values which encompass not only the various product approval processes but also closely tied realms such and intellectual property rules and the pricing of pharmaceuticals in health care systems which function, as most do, as a managed market.

A second overall conclusion is that the array of pressures discussed in this paper-- high volume, more tailored products, pre-and post-market assessment re-balancing, new combinations of drugs, devices and diagnostics, and industrial financing– combine to require a quantum and qualitative level of change in regulatory capacity. The odds are extremely high that “business as ususal” biotechnology regulation will not do. Significant new and changed capacities have to be constructed or tapped into.

On the other hand, when it comes to the values and criteria which will be brought to bear on the design of any reformed system of regulation, there is a sense of some continuity. The key values surveyed in the paper have not changed much across the entire biotechnology era. Canadians, and the citizens of other democracies, tend to seek a balance among the same set of core values for regulatory governance: regulatory effectiveness in ensuring health, safety, ethics and risk management; regulatory efficiency in global markets; demonstrable democratic accountability and engagement but with multiple views about what democracy entails; concerns about sovereignty but also the limits of sovereignty; and effective regulatory capacities. These values may be expressed somewhat differently across complex and diverse political and economic systems but in essence similar tests of regulatory regime change have to be met.

The third conclusion centres on the broad direction of possible regulatory regime change as posited in our discussion of three alternative regimes. Each of these alternatives: the status quo with “add-on” improvements; a regime with a greater explicit separation of risk assessment, and a multi-country regime such as the model provided by the EU, require more detailed analysis than was possible here. But the author's broad initial look at the basic architecture of these kinds of options does suggest that some form of enhanced multi-country model, drawing on the experience of the EU is the most plausible path for Canada to pursue in the medium term. It is difficult to imagine any scenario of regulation of biotechnological health products that does not imply greater shared international regulation. The issues of scarce expertise, actual capacities to examine health and safety and practice sound risk assessment; and actual capacities to have efficient regulation all point in this direction.

The fourth and final conclusion is that some form of North American multi-country model is likely needed. This model has not been assessed in any detail here. It could undoubtedly build on some of the EU's institutional experience but its potential for a workable regime in health biotechnology regulation will be different and controversial given the dominance of the U.S and of bodies such as the FDA in any North American context. Nonetheless, these facts and fears alone need not be a bar to real reform and institutional experimentation in that Canada (and Mexico) always have to deal with the U.S. in this hyper-power context. North America may well eventually develop into more of a North American community rather than just a free trade area and thus North American regulatory governance in biotechnology and other realms is bound to garner ever more serious consideration.

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¹ Thanks are owed to Richard Konchak, Marnie McCall, and Roy Atkinson at CBAC for their kind cooperation and advice including constructive comments on earlier drafts and outlines of this paper. The author also benefited from discussions at a CBAC workshop held on March 25-26, 2003 attended by experts from the Canadian biohealth sector, business, governmental and academic.