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Preface The cost containment crisis and the AIDS crisis have worked in tandem to acutely reawaken interest in medical innovation -- how it occurs, what can be expected of it, and how it might be improved. Technological innovation in medicine covers the wide range of events by which a new medical technology is discovered or invented, developed, and disseminated into health care. In the present-day health care environment one of the most vulnerable links in this innovation chain is the sequence by which research findings are translated into clinical practice; that is, the "d~eve~opment" of drugs, devices and clinical procedures. Medical technology development (the 'D' of 'R&D') can be defined as a multi-stage process through which a new biological or chemical agent, prototype medical device? or clinical procedure is technically modified and clinically evaluated until it is considered ready for general use in health care. Although this definition may give the impression of the process being organized and systematic, one should realize that much developmental activity occurs in a non-orderly fashion in everyday clinical practice. This is illustrated, for instance, by changing practice styles with regard to surgery. The Institute of Medicine (IOM) Committee on Technological Innovation in Medicine was established to seek a more fundamental understanding of the critical process of technology development in medicine, and to address opportunities for improving its effectiveness and efficiency. The committee observed that among the many factors influencing development, the criteria and methods of clinical evaluation have become increasingly important determinants of how and indeed whether new medical technologies are developed. The committee decided to focus their initial efforts on the interplay between present-day strategies for clinical evaluation and the development of new drugs, devices and clinical procedures. Two major considerations influenced that decision. The first is the emergence of widespread concerns over the ways in which new medical technologies are clinically evaluated throughout the development process2. For example, the development of drugs for life-threatening diseases has become the ~ Effectiveness here refers to producing a desired effect, while efficiency refers to accomplishing this effect with minimum expenditures of time and effort. 2 These concerns have also emerged regarding the economic evaluations of new technologies during their development. The nature of these analyses (such as cost-effectiveness analyses or cost-utility analyses), their role in coverage decision making, and the potential influence of reimbursement policies on medical technology development wild be the subject of a subsequent workshop of the committee and wall not be further discussed in this paper. i
subject of extensive reporting in the professional literature and the daily press, as well as an issue of serious policy debate (cf. the establishment of a President's Committee) (59~. The issue is whether the pre-marketing evaluative requirements governing drug development are sufficiently flexible or are interpreted flexibly enough in the case of drugs for fatal diseases such as cancer or AIDS. In addition to increasing development times, these requirements have raised the costs of drug development for the industry and their implementation has placed a heavy burden on the already severely constrained budget of the Food and Drug Administration (FDA). Furthermore, one should keep in mind that, in spite of the elaborate and sophisticated system of pre-marketing evaluation, valuable therapeutic information on the risks and benefits of a new drug may emerge only after its diffusion into the often "messy" circumstances of general uses. For example, in the period] 1982-1986, six newly approved drugs had to be withdrawn shortly after introduction and five others required substantial relabelling (149~. A classic example of side effects that may be- hard to discern in the carefully controlled setting of pre-approval trials is the acute hypertension induced by the antidepressant trany~cypromine if the patient happens to eat a particular kind of cheese. The traditional response to the realization that taking drugs may be a risky business has generally been to increase pre-marketing requirements for clinical evaluation. Over time these requirements have resulted in important benefits4. However, it is appropriate to ask whether the traditional response wall remain appropriate, or whether a point of diminishing returns (both socially and economically) has perhaps been reached in this respect. With regard to clinical procedures, concerns have been raised about the adequacy of the clinical evidence on the basis of which many clinical procedures have been developed and disseminated into health care (36~. For example, the first application of extracranial-intracranial bypass surgery to humans occurred in 1967; the procedure underwent rapid diffusion during the 1970s, but was only recently found to be ineffective in preventing cerebral ischemia in patients with atherosclerotic disease of the carotid and middle cerebral arteries (34~. At a national level, the considerable geographic variations in the use of certain clinical procedures may largely be explained by insufficient evidence about their health effects (144~. The consequences of such variations for the quality of medical care and the cost-effective use of resources hardly need further explanation, and an argument for more systematic evaluation of clinical procedures has often been 3 "messy," or uncontrolled -- or even uncontrollable -- that is, when contrasted with the mostly highly structured controlled laboratory-settings under which 'development' evaluation generally occurs; genera] use cannot of course but reflect the endless diversity of ever-changing human life-style patterns worldwide. 4 For example, the prevention of undue long-term health risks to the population at large (cf. the thalidomide affair). · ~ 11
made. Important questions, however, remain as to what evidence -- long-term or short-term -- should be collected and by which methods, during the different stages of the development process. For example, when in the development process of a new surgical procedure should a randomized controlled clinical trial be initiated? What are. the strengths and weaknesses of modern epidemiologi.c'al methods during; the development of clinical procedures? G~ven~the increasing importance of quality of life as an endpoint in medical care, how do we obtain a more systematic understanding~of patient preferences about different types of health outcomes? Which policy and institutional mechamsm's can. assure that adequate clinical studies are the basis for decision-makir~g during. the development process of new clinical procedures? These issues, which concern the scientific basis on which decisions are made during development, need to be addressed. i The second consideration in the committee's decision to focus on the interplay between clinica.] evaluation and technology development concerns the rapid advance in the evaluative clinical sciences today.. In.the early .195Qs, the randomized controlled clinical triad (RCT) emerged as a preferred technique to assess the efficacy of new drugs and biologicals. Over time, RCrs have been accepted as extremely powerful tools to assess the efficacy of new therapies. However, it has also become clear.. that RCTs are not practical nor feasible.for answering all clinical questions (see Chapter S).: Therefore, the translation. of research findings into clinical practice often relies on a variety of nop-experimenta-~.methods -- such as nonrandomized trials or obse~vationta] methods -- to provid~e-complementary information. In comparison with RCTs,- these non-experimental methods were traditionally depicted as constituting the weaker methods of clinical evaluation. Recent methodological advances, such as those in non-cIassica] statistics, have strengthened these methods. ~ Furthermore, the-.increased availability of large-scale automated data bases (those of, e.g., HMO.s) and the..possibility of linking different data systems (e.g., those of health insuranc.e~networks) open exciting possibilities for the inexpensive monitoring of health outcomes in "re.a] world" clinical practice. Such outcomes research differs conceptually from traditional approaches to clinical evaluation in a number of ways. Its point of departure is. the actual use of a new technology in clinical practice, therefore this research should allow one to assess the effectiveness and long-term safety of a new technology in everyday use. Furthermore, the focus in outcomes research tends to shift toward clinical conditions and the comparative assessment of alternative;options,.instead of focusing on individual technologies. Finally, this research tries to systematically incorporate patient preferences for various health outcomes. Such outcomes are determined not only in terms of traditional measures such as mortality or biochemical, physiological, or anatomical parameters, but increasingly in terms of symptom responses, functional status and quality of life. Although these methods · · ~
are conceptually appealing, important questions exist as to their strengths and weaknesses and the quality of the evidence they are able to provide. The committee observed that these methods may provide an important opportunity to address some of the evaluative problems encountered in the development of new medical technologies. At first sight this observation may seem somewhat farfetched, because in the traditional image of what constitutes technological development, outcomes research would take place post development. However, one important practical observation is that the clean distinction often made in the literature between R&D and diffusion does not hold in reality (108~. To a certain extent development and diffusion overlap and many developmental activities continue after the initial innovation diffuses into clinical practice. For example, the development of devices and clinical procedures is often incremental; that is, concerned with modifying the initial device prototype or the way a procedure is performed. Even for drugs, where development is less likely to involve incremental improvements, information on the effects of a drug in general use may stimulate the search for similar but improved agents. At least in theory, information on the health outcomes of a technology in general use is an important impetus for further developmental activities. For drugs and devices, there is a potentially important trade-off between pre-marketing and post-marketing evaluations; if the methods for undertaking and conducting post-marketing research could be improved (as well as the confidence in their results), perhaps some of the time spent in pre-marketing evaluations could be diminished. In view of these considerations, the committee has planned a workshop to address the role of various non-experimental methods -- and how they should relate to randomized controlled clinical trials -- for measuring health outcomes. It will do this explicitly within the broader framework of technological innovation in medicine; i.e. it wall explore whether their systematic application (next to RCrs) would improve the development for new medical technologies and, if so, what the policy and institutional implications would be for assuring such appropriate application. This paper is intended to serve as a background document to this workshop. Its objective is to provide a comparative analysis of present-~ay evaluative strategies employed in the development of new drugs (Chapter 2), medical devices (Chapter 3), and clinical procedures (Chapter 4~. Chapter 5 considers the implications of these strategies for the development process and concludes with some opportunities for improving both the effective and efficient translation of biomedical research findings into clinical practice. 1V
