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1. Introduction: An Initial Conceptualization of the Development Process One of the essential and perhaps defining characteristics of Homo Sapiens has always been the development and use of tools, often in response to environmental demands and chaIlenges7. In this respect the development and use of instruments to catch, collect, transport and prepare food and make clothing can be traced back to the very origins of human societies. Whereas environmental conditions have influenced the development of specific technologies, it can equally be observed that technology has influenced the human environment, thereby changing its underlying conditions. For example, it has been argued that the efficiency of late Paleolithic hunting technology may have caused the disappearance of large animals; the resulting difficulties in finding food stimulated the development of the technologies of agriculture (13~. Throughout history, one can observe this complex interrelationship between the development of technology and the physical, social and economic environment. For example, making a quantum leap through time from Paleolithic tools to the emergence of modern technology during the Enlightenment, the development and large-scale introduction of John Kay's shuttles transformed the textile industry fundamentally and, together with James Watt's steam engine some decades later, was one of the major shaping forces in the industrial revolution (52~. Since then, technological change has had enormous economic consequences; in modern industrialized societies it has become the critical factor in long-term economic growth (123~. In addition, it has also contributed to the transformation of social relations, such as patterns of work and leisure, procreation and communication. But, as Landau and Rosenberg observe, technological change "functions successfully only within a larger social and economic environment that provides incentives and complementary inputs into the innovation process"~82~. Both cultural and economic forces (a society's intellectual baggage and tolerance for new ideas, ~ The characterization of a human being as a tool-making animal should be qualified. Animal species have been found to use a wide variety of tools, although as far as we know no animal species exists capable of handling fire -- in essence one of humans first technologies -- to its own benefit. A fine distinction between human beings and animals in this respect may be the ability of humans to use tools to make tools, and to communicate from one human to another the knowledge of how to develop them. 2 Kay's 'flying shuttle' in the textile industries was one of the early instances of a machine replacing human labor with technological labor and introduction of the economic concept of work-without-workers. 1

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investment in capital formation, savings quotas, etc.), and the government policies reflecting them, have greatly influenced technological development. In comparison to the cybernetica] relationship between technological change and environmental factors (going back al] the way to the origin of human societies3), the relationship between "science" and "the development of technology" is much younger. For many centuries the development of technology was largely based on empirical knowledge arrived at by trial and error and was essentially independent of scientific understanding. However, the nature of technology development has changed considerably over time. A crucial period in the relation between science and technology occurred in the 17th and 18th centuries, when through the work of such scientists as Renee Descartes, Francis Bacon, Isaac Newton, and in medicine, Claude Bernard, the concept of nature was changed and the basis of a mechanistic worI6view was laid. This new paradigm of the existence of mankind and its world -- based on the objectivation of nature and the establishment of the experimental investigational method -- fueled scientific advances and an increasing pace of technological chance. In the 19th and 20th century, science and technology became _ _ , _ . . . ~ ~ . .. . . . . .. .. . . . . . . . . . . truly interdependent; as 111UStrated by the growth in industrial technology related to scientific advances in such fields as mechanics, electrodynamics and chemistry (25), and more recently by the rapid expansion in professionally managed institutions for research and development (R&D). Figure I: A Linear Mode] of the Innovation Chain Basic W~|APP1ied Untargeted L-LManUfaCtUringL~IAdOPtiOnI Research Research Development I& Marketing ~ ~ ~ - ~ ~ ~ ~ ~ ~ use This change in the science-technology relationship gave rise to the so-called linear mode] of technological innovation (see Figure I), i.e. results were perceived to flow from basic research to applied research, targeted development, manufacturing and marketing, adoption, and use. With the rapid expansion in biomedical research since World War or, this mode! has also become the popular representation of the process by which biomedical research findings are translated into clinical practice. In medicine, this translation process can be categorized into three components: the development of new drugs and biologicals, that of medical devices, and that of clinical procedures. 3 Rosenberg: "In a fundamental sense, the history of technical progress is inseparable from the history of civilization itself, dealing as it does with human efforts to raise productivity under an extremely diverse range of environmental conditions"~123~. 2

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In other sectors of the economy, this linear-sequential representation has been fourth to pose a number of important conceptual limitations for the purpose of analyzing the development process. First, it implies technological innovation to be much more systematic than it really is. The stages of the innovative process are highly interactive with many feedback loops. For example, a strong reciprocal relationship exists between research and development: although both scientific and engineering research findings stimulate technology development, the availability of highly advanced technological products and processes stimulates and facilitates research. With regard to medical devices, for instance, the introduction of non- invasive imaging techniques made the central nervous system accessible to direct investigation ot anatomical correlates ot function, opening up new vistas tor research in neurophysiology. Furthermore. the linkage between research and development exists not only at the beginning of development, but also continues throughout the development process. In principle, the research and development stages are concurrent; for example, to solve problems encountered in the development of a new technology one may revert to the existing body of knowledge as accumulated in research or one may initiate new research (80~. The second limitation of the linear mode} is that not only research, but also the broader environment as expressed through market forces influences each stage of the development process. For years the literature on technological innovation could be divided into "technology or science-push" theories (emphasizing the importance of advances in research and technology as the main impetus to innovation) or "demand-pull'! theories (stressing the importance of- market demand as the main force in innovation). Mowery and Rosenberg, however, have demonstrated that technological development is an iterative process, in which both an underlying and evolving scientific an~ieng~neenng knowledge base and market demand interact to achieve a particular innovation (BOO. In a general sense, this observation holds also for innovations in medicine' and ~. ~ ~ ~ . ~ ~ ~ ~ . ~ ~ ~ ~ . Figure ~ visualizes one meccas ~ecnno~ogy Development process as influenced by both supply and demand factors. Health care technology development then can be defined as a multi-stage process through which a new biological or chemical agent, medical device prototype, or clinical procedure is modified and tested until it is ready for regular production and utilization in the health care market. This development process can be divided into two closely related series of activities: J

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technical modification and refinement (for pharmaceuticals and devices this includes 'scaling-up' for production) and clinical evaluation of a potential innovations (see Figure 2). Figure _: A Scheme of Research, Development and Diffusion Streams Flow I: Research, Di scovery and Invention , ~ ~ ~ ?~ ~ ~ ~ |F1OW II: AT I ' 1 Hi , . ~ ~ ~ ~ . f ~ Phase I I Phase II I Phase III Flow III: Health Care Market Diffus ion Whereas it is fairly obvious that current scientific and engineering knowledge (and its accessibility) determines the overall feasibility of specific technological developments, the influence of market demand factors is more difficult to determine. The notion of a "market" in health care is different from the market concept in other sectors of the economy, where in principle the consumer determines what product he or she wants and then subsequently purchases it. The following major differences can be discerned: 4 Within the development process, clinical investigation is essentially initiated with the first testing of a potential innovation in humans. In the development process of drugs and biologics these initial studies in humans have been designated so-called Phase ~ studies, which are generally followed by Phase IT and Phase TIT clinical studies before a `drug or biological can be marketed. Phase IV studies, conducted after an innovation diffuses into more widespread use, may reveal important information on the (cost-) effectiveness and (Iong-term) safety of an innovation, which subsequently may be an important impetus for further developmental activities. In this paper we will apply the terms Phase ~ to Phase {V clinical studies also to the development of devices and clinical procedures. 4

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The market demand concept implies autonomous choice and a knowledge of available alternatives by consumers and patients. However, both autonomous choice and a realistic knowledge of the alternatives are often severely limited, and therefore health care professionals usually decide the kind and volume of technological interventions needed (67~. In a sense, these professionals are the consumers in the health care market, although their demand is derived from that of patients. Furthermore, new medical technologies -- in addition to their benefits -- nearly always entail a certain element of risk. The beneficial or adverse effects of a medical technology are considered as being quintessentially different from those of many other technologies because, as Renee Fox observes, they affect 'basic and transcendent axes of the human condition: life, conception and birth, body and mind, ... and ultimately mortality and death"(SI). During development, the benefits and risks of a new technology are highly uncertain. To reduce this uncertainty, a new technology is subjected to continuous clinical evaluation. Finally, health care professionals usually are reimbursed for their services not by patients but by third party payers. As patients and professionals traditionally have been insulated from the financial consequences of their decisions, there have been no strong incentives to consider cost in their decision making. In the present-day environment of cost containment this situation is in the process of changing. ~ . . ~ . cat . These idiosyncrasies of the health care market have prompted government intervention in the development process. Over the years, for example, federal regulatory schemes have evolved to protect the public by allowing only those drugs and devices on the market that are found to be "safe and effective" on the basis of clinical studiesS. Because individual physicians cannot be expected to evaluate all emerging products. the Food and Drua Administration was established to implement _,, , _, ,. ~ , e ~ 1 the law. In comparison, the development and evaluation of clinical procedures IS not federally regulated, but depends heavily on professional self-regulation. Furthermore, because of its growing role as a purchaser of health care, government policies have s The Federal Food, Drug & Cosmetic (FD&C) Act of 193S, which provided for the premarket clearance of new drugs to ensure their safety, in its amended form still governs drug development today. In comparison, biologicals are governed by a separate law, the Public Health Service Act of 1944. Major changes to the FD&C law were provided by the 1962 Kefauver-Harris amendments, which increased the role of the Center for Drugs and Biologics of the Food and Drug Administration (FDA) in the development process. The medical device amendments were enacted in 1976, and are implemented by the Center for Devices and Radiological Health. s

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been established to control the adoption of new technologies. In the 19SOs the policy focus in this respect has shifted from allocative planning laws, such as the Certificate of Need program, to reimbursement and coverage decision making as important policy tools. These policies are providing strong incentives to evaluate the risks, costs, and benefits of a new technology during its development. A conceptual framework thus also should take into account another central characteristic of the development process: the extremely diverse and complex institutional structure within which development decision making takes placed. This structure differs to some extent in the case of devices, drugs, and procedures. Researchers in university, government and industry laboratories provide the knowledge for today's and tomorrow's development process. Development of drugs and devices is sponsored largely by the pharmaceutical, biotechnology and medical device industries, which have `distinctly different structural and behavioral characteristics. The development of devices and drugs takes place both in these industries as well as in clinical research settings in academia and government, where clinical investigators evaluate the likelihood of benefits and risks in patients. As mentioned, the FDA has an important decision making role during the drug and device development process. In comparison, procedures are both technically developed and clinically evaluated by physicians in clinical practice, most notably those in- academic medical centers and university affiliated hospitals. The broader medical community7, consisting both of individual (such as physicians) and organizational decision makers (e.g., hospitals), decide whether to adopt or acquire a particular medical technology. Patients traditionally have had less decision making power, although this seems to be changing somewhat. Finally, public and private third party payers, such as the U.S. Health Care Financing Administration (HCFA), are becoming increasingly important decision makers in the process. In short, the rate and the extent of transfer of a research finding into clinical practice is influenced by the inte~ela ted decisions of a large number of actors and institutions. A complex set of social, economic and organizational factors may affect decision making during development. An instance is the development and introduction of the anti-progesterone RU 486, or mifespristone, by Rousse} Uciaf in an ethically and culturally sensitive market (29~. In addition to these factors, information on the health outcomes of a new technology influences decision making. As mentioned in the preface, concerns have emerged as to the quality of the clinical evidence that 6 Nelson and Winter have developed a theoretical structure, incorporating both 'uncertainty' and 'institutional structure' as essential elements of technology development (108~. 7 The decision making processes are very different for individual or organizational adopters of technological innovations (63~. 6

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forms the basis for decision making. This paper will therefore address the following questions: I. What kinds of clinical evidence play a role in decision-making during the development of a potential innovation? What endpoints are assessed during the different stages of development?- 2. What are the methods by which these endpoints are assessed during the development of a potential innovation? 3. What are the implications of these evaluative strategies for the effectiveness and efficiency of the process by which research findings are translated into clinical practice? 7