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5. Improving the Translation of Research Findings into Clinical Practice: Some Opportunities for Change The increase in knowledge concerning human health and the mechanisms of disease has been so rapid during the second half of this century that the present era has been described as that of the biological revolution. This biological revolution may prove as decisive for the future of medicine as the industrial revolution was for economic development in the past (77~. The extent to which this occurs, however, depends in part on the effectiveness and efficiency of the process by which advances in biomedical research are translated into clinical practice. As indicated earlier, in medicine this translation or the development process includes three components: the development of new drugs, of medical dewces, and of clinical procedures. This paper has described the similarities and differences that exist among the development processes for drugs, medical devices and clinical procedures. A primary difference concerns the asymmetry of the evaluative strategies employed: drugs have over the last quarter century come to undergo rigorous clinical testing before their introduction into general use, while clinical procedures are still being assessed only in a more ad hoc fashion, and new medical device evaluations are to be found somewhere in between. It might be expected that this asymmetry reflects important differences in the effectiveness and efficiency of the three different processes by which research findings are translated into clinical practice. Following are some major observations with regard to these differences, and some inferences as to opportunities for improvement. He Develop~,tent of Drugs In comparison to the medical device industry, the multinational pharmaceutical industry is older, highly regulated and very research- intensive. The pharmaceutical industry annually invests approximately $6.5 billion in R&D in the U.S. (about 17 percent of sales52), roughly $1.5 billion of which goes to pre-marketing clinical testing. The investments in research, but especially those in development, are consistently increasing (since 1980, an increase of roughly 30%~. According to the Wiggins analysis, the R&D process is estimated to now cost $125 million per marketed new chemical entity (NCE)~151~. On the input side, the resource commitments to drug R&D, the relevant scientific knowledge and the technical capabilities have al] grown impressively since the 1950s, 52 The OECD in general defines industrial companies with If% of their turnover in R&D already as "research intensive." 40

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but this growth has not been reflected on the output side, at least not quantitatively (85). The number of NCEs entering human testing fell from a mean of 89 a year in the period 1950-1962, to 35 a year in 1963-1972, to 17 a year in the period 1975- 1979 (an overall reduction of 81 percent) (95,97,76). In recent years, IND filings in the U.S. are increasing again especially those for biological drugsS3 (116). But these INDs are increasingly acquired from non-U.S. sources. Especially noteworthy is the fact that Japan has been increasing as a source since the early 1970s, by the end of the 1970s surpassing Europe, traditionally a stronghold for producing new chemical compounds (see Figure 3). A similar trend occurs with regard to the number of new drug approvalsS4. Figure 3: Origin of NCEs on which INDs have been filed by US-owned firms. tar 14t 13 12 ~ ~0 U At o MU 3 it 6 _ 4 _ 2 1 o Source: (95) - ~ , ~ ye \ ~ ~ JAPAN , ^% / Jan ,^ EUROPE -. ... , /e ,*- -U.S. ~ ~-"'1"-.''''",,, - lt64 lg64 1968 1970 1972 1974 1976 1978 19" 1982 YEAR OF IND flLING 53 One furthermore should keep in mind that, whereas the success rates of NCEs are higher for 1970 cohorts than for earlier cohorts, at present 73 percent of NCEs initiating human testing are still discontinued before an NDA is submitted (135~. 54 The number of drugs approved for the U.S. market averaged 36 NCEs per year between 1950 and 1960. A decline of 54 percent occurred in the early 1960s, after which the numbers fluctuated, averaging 14 NCEs per year, through the end of the 1970s. Since the end of the 1970s, approval rates recovered somewhat (26 in 1985, 20 in 1986), though this recovery did not specifically take place in US- originated but in foreign-owned approvals (95,97,76~. 41

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Over the years these output measures of the development process have been extensively reviewed in the literature and the halls of Congress (see Appendix I). The dates given above indicate that the beginning of the decline in the number of new U.S. drug introductions occurred at roughly the same time as the introduction of the 1962 amendments to the Food, Drug and Cosmetic Act. A substantial body of policy analysis was undertaken to consider the causal effect of these regulatory changes on the declining number of new drug approvals. Originally it was concluded that the decline in drug introductions could be attributed fully to changes in regulatory requirements for evaluative practice during development. Currently, however, in view of the increasing recognition of social, economic, managerial and political factors as determinants of the decline, it is apparent that no such straightforward link can be established (133~. Nonetheless regulatory requirements -- and their interpretation by the regulatory agencies concerned -- remain an important factor in the potential rise and fall of new drugs; not to mention the scientific, commercial and public perceptions of such regulations as determinants of whether and how a drug is developed. Generally speaking, these regulatory configurations and the resulting clinical P.~l~tinnc have lerl to important henPfit~Ss TInt1er ~or.i~1 and political pressures, time. As a result the t~me-span ot pre-mar~et~ng development has Increased trom about 4.5 years in 1964 to 9 years in 1984 (95). This interval has reached a point where access to useful new drugs may be delayed. The tension between increasingly thorough pre- marketing evaluations and early availability becomes urgent in the case of life- threatening disease. ^~ ~ 4~~ ~~ berm ~ . --em . ~~ . he ^ these requirements have become increasingly detailed over .. ~ ~ .. . . . ~ . . ~ For example, the prominence of AIDS has raised two fundamental issues as to the clinical basis on which decisions are being made. The first concerns the endpoint issue mentioned earlier, i.e. considerable uncertainty exists as to what endpoints should be evaluated during which stage of the development process. For instance, to expand on the AIDS example, the questions concerns whether and in which cases intermediate endpoints (instead of survival) should be evaluated in pre-marketing trials. Equally, the question concerns whether and when quality of life endpoints should be built into the developmental evaluation process. sS Notably the structural prevention of potentially unsafe and/or ineffective drugs; these basic premises on which the regulatory system is based are generally considered valuable. However, it is interesting that -- in contrast to the medical device amendments -- there is no legal mandate to encourage development and innovation, but only to assure the marketing of "safe and effective" drugs (85~. 42

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The second issue concerns the balance between pre- and post-marketing evaluation, regarding which some new initiatives have recently materialized. The FDA, for example, has proposed to streamline the drug approval process for life-threatening diseases by shortening the pre-marketing evaluation stage (Phase IT and Phase ITI clinical trials wall be merged into more definitive Phase IT trials), and by emphasizing more strongly the post-marketing evaluation stage (Phase {V) for providing safety and effectiveness information on a new drug. Even apart from life-threatening diseases, there is a general need for such Phase IV information, because the full range of a drug's risks and benefits wall emerge only when it is used in actual circumstances of clinical practice. Drugs, once marketed, are subject to empirical innovation -- just like devices or clinical procedures. That is, in the hands of physicians trying to solve problems, new theories are spun out and drugs are used as if those theories were true (e.g., cimetidine). It is only through Phase IV monitoring and surveillance broadly construed (i.e., regarding general use) that the identification of these theories can be accelerated and steps taken to assure their timely testing. AS argued in Chapter 2, the Phase {V studies that would provide this information wait depend heavily on observational methods. In recent years, methodological advances (see below) have opened up new opportunities for inexpensively monitoring the use and long-term risks of drugs. These methods may well be useful, not only in providing risk information, but also in providing effectiveness information. So far, however, uncertain prevails as to the scientific value of the practical application of these methods to medicine in general and drugs in particular. In view of the potential effects of these methods on shifts between "development" phases and the subsequent implications for medical innovation in general, any serious investment strategy for medical technology development must address the possible promise of such an application. A broader argument exists to carefully consider the potential and problems of post- marketing evaluationS6. The increasing time-span of development has not only made the process more costly but also has decreased the return on investments by lowering the effective patent life of new pharmaceuticals. The average patent life of NCEs, from date of approval to expiration of the patent, was 16.3 years in 1960 and roughly 9 years in the mid 1980s57. The need to consider patent life was recognized in the U.S. and the "Drug Price Competition and Patent Term Restoration Act" was s6 For example, getting a drug on the market one year earlier would reduce the average break-even point economically (i.e. R&D costs equal revenues) by 3 to 4 years (61~. s7 Grabowski (61) has analyzed that it would take 12 years of projected revenues at the present rate to achieve a read return on capital of ~ percent. A 10 percent real return would require 19 years of projected revenues at the present rate. 43

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enacted in 1984. The law however restores only some of the patent life lost during the regulatory process as it also allows generic drugs to receive more speedy marketing approval through a system of abbreviated NDAs (ANDAs)58. The overall result of this law is that the effective exclusive marketing time of innovative products has not increased because generic drugs can be marketed more rapidly. The impact of this law may be considerable since Sl of the most important 100 drugs used currently in the U.S. will go off patent by 1991 (and will thus become generic drugs)5 . Furthermore the economic climate is becoming much more price competitive e.g. most states have passer] pro-generic substitution laws (allowing pharmacists to dispense generic drugs for the brands specified on the prescription forms)60. Whereas industries other than the pharmaceutical such as electronics or optics but also the medical device industry can react to more competitive environments by decreasing the turn-arounc] time of their innovative cycles such a strategy will be much more difficult in a pharmaceutical industry subject to long and relatively fixed R&D cycles. Although the pharmaceutical industry has generally been very profitable and recent advances in biomedical research seem to present exciting opportunities for the development of new drugs the trends visualized in Figure 4 may constitute an impediment to drug development in the long run. Whereas the effective translation of research findings into clinical practice will require information on the health outcomes of a drug in general use the above underlines the necessity to provide this information as efficiently as possible. 58 Furthermore while the advantages for generic drugs can be reaped immediately the advantages inherent in the law for innovative products can only be reaped further in the future (i.e. at the point where the patent term would have expired without the law). s9 Although a drug may continue to earn positive profits after the patent expiration date under the pressure of generic competition sales of a patent-expired product currently fall by SO percent or more in the 2 or 3 years after patent expiry. 60 Furthermore hospital formularies favor the lowest cost products and the Maximum Allowable Cost Program reimburses Medicare patients only for the lowest cost product. In addition international competition from Japan and Europe has increased (recently the EEC introduced the protection of the exclusive rights of the company that submits a file for regulatory approval. Files of new products irrespective of the patent situation watt remain inaccessible to others for up to 10 years from the time the first EEC approval has been granted (148~. 44

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Figure 4: 1 Bus - ~~ As costs nse . patents are eroded . R & D expenditure by US companies Effective patent life of new in America sea ages ~'p~ 4 s ~ drugs in America Yws ,6 . ~ .. ..................................................................... ........................ ..... ...... ... ;/ 4 0 ~ ~ 14 ~ . ~`j; . ;~;~ ~ 12 .......................... 7~ 3 ~.0. ~ . ~ _ 2 5 . ~; . ;,~ ~ ~ . ~ .~ 2 0. .................................................... ~.8. ........................................................... 1.5 ... 6 ED F - a ~ .................................................................. - . , ~ _~ , _ , _ ~ _ , ~ 1981 83 85 87 89 1962 66 70 74 78 82 84 ;..and competition increases ~ .' ~ . Number of drugs under development worldwide 200 ..................................................................... 1980~100 ~ ~ 180 . j, 1 160 . ~ / 140 .................. ............................ ~ 120 ':......................................... , _ ~ ~ _.'.00. 1981 82 83 84 85 86 .................. N ~ ) ........................... 0 Source: Economist, February 1989 The Developmentof Medical Devices Moving from the pharmaceutical to the medical device industry, the latter is younger, more nationally oriented, and characterized by smaller firms; the image of the innovative engineer developing a device prototype in his basement, garage, or study still has some relevance, although it may become a metaphor in the 199Os. In recent years the market for medical devices has been growing rapidly. The overall U.S. medical device market is estimated at over $20 billion dollars in 1987, and parts of that market are expanding at annual rates ranging from 10 to 25 percent (135~. Investment in medical devices R&D is smaller than for pharmaceuticals. On average, medical device firms invested 7.5% of sales in R&D in 1988 (~17), and it appears that this percentage remains relatively stable. Differences in R&D investment can be observed to depend on the size of the firm, and the particular type of device under development. For example, small firms invest almost double the industry average (~19~. In comparison with drugs and biologicals, there is a much greater heterogeneity in medical devices in terms of design, purpose, and use; and variation in the kind of clinical evaluations undertaken (129~. In view of this heterogeneity, the medical device amendments to the FD&C Act divided devices into three classes and differentiate the level of regulatory control according to the likelihood of risks inherent in a particular device class. Whereas, ninety percent of all new medical devices are subject to "genera] controls" (including good manufacturing practices, pre-marketing notification and, potentially, technical performance standards), only 10 percent of new medical devices are subject to full pre-marketing review for safety and efficacy (55~. It is interesting to observe that (unlike the Drug Act) the device amendments explicitly incorporate in their mandate the need to encourage medical device developmental. consequently much more 6] "It is the purpose to encourage, to the extent consistent with the protection of 4s

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In contrast to pharmaceutical innovation, there is a steady growth in the number of medical devices entering clinical investigation (17~. In the past few years, IDEs62 include an increasingly broad range of investigational devices. But, since 1980, the proportion of TDE `devices that in first instance successfully completed their developmental evaluation has decreased to 30 percent (although eventually 80 percent are approved). This decrease reflects the more complicated safety and efficacy issues surrounding new investigational devices, a more stringent regulatory climate, and the relative inexperience of many device manufacturers (80 percent of the device developers have only submitted one IDE since 1980~. In terms of efficiency and effectiveness of development, those who submitted 7 or more IDEs since 1980 had an approval rate twice as high as those who submitted only one IDE (17~. The impression exists that the R&D cycle of incremental device innovations is only 2 to 3 years, whereas with radical device innovations (such as ultrasound or MRI) it is more like 10 years. Development times then can be estimated to range roughly from ~ year for incremental devices to 5 years for radical devices. Unlike drugs, a medical `device is generally not created "de nova" but arises in a development process typically representing continuous technical modification and incremental improvement. Clinicians provide significant input by evaluating the clinical efficacy and safety of a device as well as by suggesting technical improvements to enhance its clinical utility. For certain devices the users are also the innovators, designing and building the original prototype (68~. Although already fairly common, close interaction between device manufacturers and the clinical community is an even more crucial prerequisite for effective and efficient device innovation than is the case with pharmaceutical innovation. . , , The initial evaluation stage of a new device usually depends on careful clinical observations based on informal experimental methods. The main question at this stage concerns whether the device prototype has the postulated effect in humans and may be clinically useful. As indicated above, this pilot stage then normally leads to improvements in a device's design and materials. Chalmers (26) has argued for randomizing the first patient who receives a procedure involving a new medical device (or a new surgical technique). In view of the technically evolving nature of the device and the fact that investigators usually must be educated and trained in the public health and safety and with ethical standards, the discovery and development of useful devices intended for human use and to that end to maintain optimum freedom for scientific investigators in their pursuit of that purpose" (520, Aim 62 TDEs are devices under development which require FDA approval to initiate clinical evaluation in humans. 46

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how to operate certain equipment, randomization of the first patient is generally not considered feasible (this equally holds for surgical techniques). This then does raise the question of the timing of (a multicenter stage of) safety and efficacy evaluations, when exactly in the development process should these evaluations be initiated. If these studies are undertaken too early, the changing characteristics of the device may render the results obsolete. If they are undertaken too late, the results may be unimportant for decision making. Ideally, these studies would be based on randomized controlled trials. However, in many cases, the RCr as generally used in drug studies (involving double blinding and placebo controls) mI] be much- more difficult to undertake, especially with diagnostic devices. In such cases other well- controlled study designs wall have to be used to evaluate efficacy. Until recently, however, new device evaluations often are uncontrolled (129), and the use of adequate controls needs to be stimulated. Once the device has been approved and diffuses into more general practice, its long-term safety and effectiveness should remain parameters of the dev~ces's 'long-term' development evaluation. Because device development often involves incremental innovation (for a considerable part of its lifespan) and because RCrs are not ideally suited to provide information on a slightly different version of a device, these studies wild usually depend on observational methods. When comparing the effectiveness and efficiency of device development to drug development and considering the welI-known methodological weaknesses of traditional observational methods, it is timely to assess the strengths and weaknesses of new non-experimental methods for providing reliable information about the health effects of new medical devices. In the quest for improved and more reliable methods of clinical device evaluation, however, it is necessary to consider the importance of small device firms in medical device innovation. One will need to keep in mind the potentially differential impact such requirements could have on small versus large firms, in terms of viability, innovation potential, competitiveness, etc. As discussed in Chanter 4. the distinction The Development of Clinical Procedures between "developers" and "evaluators/users" is a thin line in the development of clinical procedures. In- comparison to drugs and devices, no governmental regulatory system governs their development. The evaluation of developing clinical procedures is based in principle on the trust relationship between physicians and patients. Initiation of development and its evaluation thus depends heavily on professional self- regulation. In this respect the difference between radical and incremental innovations is important. Radical innovations may frequently originate in academia- or academic-associated centers, and are generally subject to approval by Institutional Review Boards (IRBs). A larger part of developmental efforts, however, concern incremental improvements in existing procedures. In cases of incremental improvement, the line between experiment and individualized therapy generally is 47

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difficult to draw clearly, with the result that TRBs are not usually approached for approval. There is very little information available on investments in R&D for clinical procedures. It appears, however, that considerable changes may be taking place as to the source of funding in this area. For example, wheras traditionally the development of many procedures was cross-subsidized through patient care revenues, with the changes in hospital reimbursement these funds are decreasing. Very little information is also available on the aggregate number of new procedures being developed as we]] as an the average time needed for deveic~nment. During the development process new clinical procedures generally have not been systematically evaluated in terms of safety, efficacy and effectiveness. Traditionally, their evaluation during the development process often depended on non-formal evidence or the use of historical controls; this usually leads to more optimistic results as to the potential benefits of a new procedure than would have been the case from well-controlled studies (574. As a result, the scientific evidence normally assumed to support day-to-day clinical practice is not always provided in a systematic and timely fashion. For example, a number of procedures were discarded only following their widespread use, when they were found to be ineffective on the basis of well- controlled studies. For some of these procedures, the weak quality of their clinical evidence is illustrated by considerable geographic variations in their use, such as those for coronary artery surgery, hip replacements, or lower back surgery. To achieve an effective development process for procedures, more systematic and improved evaluative strategies are needed. Such an improvement wait need to take into account that the development of clinical procedures is a very different endeavor from that of drugs and devices. The development of especially incremental innovations often occurs in a decentralized manner, involving change and refinement of a particular procedure by numerous physicians. During the initial development of a new procedure, the skills and experience with a technique still evolve and the risk/benefit ratio may change considerably. Pilot or feasibility studies at this stage will have to include "systematic and comprehensive collection of clinical experience" to determine whether a procedure works and to differentiate patients according to prognostic factors (22~. However, many clinical procedures do not now receive the careful Phase ~ studies required for drugs (144~. If and when the feasibility of a new procedure has been established, randomized clinical trials or otherwise welI-controlled studies should be undertaken at selected institutions. The transition from the feasibility study by a few developers to multi-center investigation is more difficult to determine with clinical procedures than is the case with drugs and even devices. Systematic surveillance of early clinical evidence could facilitate the timely implementation of such well- controlled studies. After efficacy has been determined under such trials, evaluation en en ~ Ha _ _ e ~ ~ . a a ~ a ~ Ha 48

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of a procedure's effectiveness and safety should again remain parameters of clevelopment evaluation. Compar~rlg the Outcomes of Drugs, Devices and Clinical Procedures Ultimately clinicians and patients, of course, are concerned with choices among a spectrum of alternative diagnostic and treatment technologies and want to Mow, for a clinical condition, which treatment is best for which patient. The rational assessment of technology thus requires a holistic and balanced strategy for assessment that provides comparable information about its relevant outcomes for all relevant technological options. This paper has already noted the present imbalance in regulatory assessment strategies that provide extensive documentation of (at least some) outcomes for drugs compared to other drugs or to placebos, while little attention is given to understand the relative merits of drugs compared to devices or to clinical procedures. The treatment of angina, gallstones or prostatism are examples where all three types of technology have been developed. but have as vet not received comprehensive and ongoing evaluation. ~ , This paper does not intend to imply the need for a federal regulatory system governing the development of procedures. Alternatives to such a system have been proposed. Bunker et al have suggested the establishment of a central reviewing authority (under which the various TRBs could resort) to initiate and coordinate clinical procedure trials as appropriate (22~. The initiation and coordination of studies determining effectiveness and (Iong-term) safety of a procedure would also be part of such an authority's mandate. The Bunker mode] does not, however, call for the systematic comparison of technological options (including drugs and devices). A more recent mode] may be found in the assessment teams now being initiated by the National Center for Health Services Research to evaluate alternative technological options available in the management of clinical conditions. These teams are to undertake the equivalent of Phase ~ and Early Phase IT studies now undertaken for `drugs, make recommendations for clinical trials (Phase IlI), and conduct Phase IV studies for new as well as established clinical procedures. These teams wall focus on specific clinical conditions, such as benign hyperplasia of the prostate and stable angina. They wall assess all relevant treatments and thus provide information on the relative safety and effectiveness of drugs, devices and procedure. Drug and device manufacturers could be expected to have interest in helping to fund these teams. Whereas -- on the positive side -- this scenario would imply that the stronger financial sectors of our health care system would share the financial] burden of performing evaluations of clinical procedures, their involvement could result in possible conflicts of interest. This policy question will need to be addressed if the assessment team approach is to prove a realistic mechanism for the systematic evaluation of alternative medical technologies. 49

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~ - e , In conclusion, serious inconsistencies exist in the evaluation of drugs, devices and procedures during their development process. The above indicates that these Inconsistencies may have contributed to shortcomings in the effectiveness and efficiency by which biomedical research findings and clinical theories are translated into clinical science and useful clinical practice (see' Table 11. . Furthermore, these inconsistencies may also have contributed to unnecessary health care costs, if one takes into account that the least svstematical~v evaluated technologies. clinical ~ .' ~ , procedures, are also the most costly63. Although these inconsistencies are to a certain extent a result of inherent differences among the development processes of drugs, devices and procedures, these differences do not seem to preclude a more balanced approach to assessing an medical technologies. Such an approach would strengthen the clinical evidence on which development decisions are made, and probably would improve the cost-effective use of health care resources. Table I: Comparison of Effectiveness/Efficiency of Technology Development l Drugs Devices Clinical | Procedures R&D Investment +++ + ? Development Time ++ + ? Number of New Innovations entering Health Care + ++ ? Clinical Basis for Decision Making: - Pre diffusion +++ i ' + l - Post diffusion + + 63 Consider' eager the management of angina. The development of coronary artery bypass surgery and that of beta-blockers were initiated roughly the same time. The imbalance in assessment strategies, however, implies that the surgical option could undergo much more rapid diffusion than the pharmacological option, as beta- blockers were not as rapidly available to practicing physicians. 50

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The paper concludes that. to achieve a proper balance Three issues can be identified that might fruitfully be addressed. by the workshop. Theorist issue concerns the criteria or endpoints of development evaluation. With regard to determining a technology's safety and efficacy, the role of intermediate endpoints in comparison to mortality, functiona.] status or quality-of-life endpoints should be clarified. In addition to clinical and scientific.considerations, the endpoint issue raises economic concerns; i.e. these decisions may have large. consequences for the length and-costs of pre-. marketing development. Both these. consid.erations.would need to be taken into account. Furthermore, following the approval decision for new drugs and devices and the more widespread diffusion of-new procedures, it. wall be increasingly important to include health.. outcomes in "real world" clinical practice as important evaluative endpoints (n.b. for.diagnostic.technologies this. may be inappropriate3. In view of the increasing numbers of alternative or competing technologies being developed, it seems especially important to provide comparative evaluations of the relative safety and effectiveness of technological options available in the management of clinical conditions. Inherent in these evaluations would be the need to incorporate patient preferences for the health benefits and risks associated with alternative technological interventions. The second issue concerns the methods for providing such information. Evaluation of the risks and benefits of new technologies during their development wild have to rely not only on experimental methods (including, randomized controlled clinical trials), but also on improved observational methods of clinical evaluation. This applies for devices and especially clinical procedures, but also to drugs; for example, these kind of studies can provide needed information on the long-term health outcomes of drugs in everyday use. In comparison to RCTs, these observational methods are usually considered to be the weaker methods of clinical evaluation. However, recent methodological advances may have addressed some of these weaknesses. It has been observed that (144~: 3. 4. Advances in statistical methods, for instance those in Bayesian statistics, make it possible to assess outcomes for alternative treatment strategies. These methods are useful for assessing outcomes in non-experimental study designs. The increased availability of large-scale automated data systems and improved methods of data base linkage, make it possible to inexpensively monitor use and outcomes. Advances have occurred in measuring the effects of a new technology on functional status and the quality of life of patients. Advances in decision analysis provide means to assess the importance of patient preferences and of the uncertainties about the probability for specific health outcomes. 51

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In view of these advances, it seems especially timely to explore the strengths and weaknesses of modern evaluative methods within the under context of existing methodologies. Third, depending on their strengths and weaknesses, a policy and institutional framework will have to be established for assuring the application of non- experimental methods as appropriate. For example, the workshop might consider alternative models for assuring the systematic evaluation of clinical procedures. It is only by addressing these complicated issues that will we be able to improve the effective and efficient transfer of research findings into clinical practice, and thereby strengthen a crucial link in the medical innovation chain. 52