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4. The Development of Clinical Procedures The last 25 to 30 years have seen rapid advances in basic biomedical researched, strengthening the scientific underpinnings for the development of new clinical procedures in the years to come. A clinical procedure can be defined as any practice of a health practitioner that involves a combination of special skills or abilities and may require drugs. devices. or both. As clinical ~ ~ ~ ~ - I- - - 7 - proceoures involving new Drugs or Devices, such as laser ang~oplasty, have been considered in Chapters 2 and 3, this Chapter will especially focus on those clinical procedures which are not to a large extent dependent on new health care products but on the technique of the provider performing the procedure. For example, the development of certain surgical procedures (although they may involve the use of scalpels, clamps and drugs) or psychotherapy. The development process of clinical procedures is very different from that of drugs and medical devices. Analytically, the distinction between the development of radical or breakthrough innovations and incremental innovations is useful. Radical innovations frequently arise in academic or academic-associated centers, where physical and professional resources are available and clinical development is stimulated. The development of incremental innovations usually occurs in a much more decentralized fashion, involving numerous physicians refining and motiving an existing procedure in everyday clinical practice. In contrast to medical device innovation, which requires -- as C.P. Snow would say -- the bridging of "two cultures" (that of engineers and clinical researchers), the distinction between "developers" and "evaluators/users" may be very fine or even non-ex~stent in the development of clinical procedures. Within the hospital those involved in experimental medicine may be physically down the hall from their clinical colleagues, but often they are embodied in the same person. Physicians who treat patients may at the same time be engaged in the development of clinical procedures. This sometimes-may lead to difficult conflicts of interest between the therapeutic and investigational role of a physician. As Swazey and Fox (132) observe "... their double-edged role causes 46 In absolute terms, the United States invest heavily in biomedical research and development. Shepard and Durch (127), for example, indicate that the U.S. account for 45% of funds spent in the OECD countries and the top five countries -- US. Japan' The FRG, France' The United Kingdom , . , , , account for 84% of all biomedical R&D expenditures. If considering per caput spending, however, Switzerland and Sweden head the list. 34

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stress for most physician-investigators. The strains that they experience are intensified by their typically close and continuous relations with the patients who are also their subjects; by colleagues' scientific and ethical judgments of their work; and by a certain vested interest not only in protecting their professional reputations, but also, in advancing them through recognition for being eminently successful with breakthroughs in knowledge or technique". In spite of the enthusiasm and fascination generated by potentially radical procedures, the initiation of first human application often remains inherently premature (particularly in the absence of a satisfactory animal model) (132~. Therefore this transition often is controversial, as recently illustrated by transplants of dopamine producing cells into the brain region (in need of that specific transmitter) of very severe Parkinson's disease patients. SIadek and Shouison in a review of the initial clinical application of this procedure in Science argue strongly that although "... the scientific rationale continues to build for neural grafting as a therapy for neurological disease ... we could benefit from more patience than pai'ents" (128~. Fox and Swazov. in their book at_ ~~ a_ I_ ~ ~ a ~ .~ .~. one Courage to rail-, nave aescr~oea tne scenic and emotional controversies that may arise during the development of clinical procedures such as kidney dialysis and transplantation. Their work indicates that radical innovations usually are first applied to life-threatening or very serious diseases, which often have no alternative treatment (501. In these cases the considerable uncertainty, and potential risks, associated with the clinical application of the innovative procedure may be considered more acceptable. Their analysis also indicates that during their development, procedures may often be subject to a partial or complete "clinical moratorium", i.e. human use of a still experimental procedure on patients is suspended (132~. For example, mitral valve operations were performed on animals since the turn of this century. The first application to humans occurred in 1923, but a clinical moratorium was invoked in 192S, in part due to the high mortality associated with the procedure. Following a series of drug, device, and surgical advances such as those in cardiac catherization, anesthetic techniques for intrathoracic surgery, ligation of the patent f]UCtUS, and antibiotic drugs, the clinical development of mitral valve surgery was resumed in 1945 (despite initially high mortality rates). Over time, as surgical experience increased and different patient groups were accepted, mortality declined and the technique became established. Comroe and Dripps have equally underlined how the development process of procedures for cardiovascular-pulmonary medicine depended on numerous advances in different areas of science and technology (30~. In contrast to drugs or devices, no forma] governmental regulatory system exists for the development and evaluation of clinical procedures. Their development 35

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has traditionally been placed in the context of the physician's clinical autonomy and the trust relationship between patients and physicians. Evaluation of these procedures cluring development therefore depends heavily on professional self- regulation (for instance, through peer review and Institutional Review Boards)47. In this respect, the difference between radical and incremental innovations may also be of importance. In the case of incremental innovations, the line between experiment and individualized therapy often is difficult to draw clearly (101), and as such Institutional Review Boards (IRBs) are usually not approached to give their approval for the evaluation of slight modifications of existing procedures. This is different regarding radical innovations, and their development and evaluation (at least those that are federally funded) is generally subject to the approval of TRBs. IRBs, however, do not usually conduct in-depth examinations of the research design (by. To date, the potential safety, efficacy, and effectiveness of many procedures has not been evaluated systematically during their development. Surgical techniques in the first half of this century were developed by pioneering surgeons on the basis of their intuition and insight, and were tested by trial and error. Many of these procedures attained acceptance in the medical community and resulted over time in useful treatments. A number were discarded, however, often after years of clinical application, such as surgery for constipation. According to Barnes, this pattern of development is due to a number of factors Air. Historically, there was often a poor understanding of disease processes and an uncritical acceptance of established dogma as dictated by leaders in the field. In addition, the analytical underpinnings of clinical investigations, in terms of sample bias, observer objectivity or standards for adequate follow-up, were often still rather weak. As Bunker et al conclude in their important work on the Costs, Risks and Benefits of SurgeIy: "In this respect, surgery shared with other branches of medicine at the time a process for groping for effective therapies, a process that did not have the help of extensive knowledge in the basic biological sciences or the understanding of sophisticated experimental designs to permit logical inductions from multivar~ate clinical circumstances" (21~. 47 it iS within this context, that medical societies are increasingly issuing guidelines regarding the use of a particular new procedure; however, usually these guidelines emerge after a new procedure has already diffused more widely into clinical practice. The NIH consensus development conferences may issue similar recommendations regarding the appropriate use and effectiveness of a new procedures in clinical use. 36

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In the second half of this century, rapid advances were made in the methodological underpinnings of clinical investigations. At the end of the 1970s, however, Bunker, Hinkley and McDermott describe that surgical development was still often based on inadequate evaluation (22~. Examples of procedures that diffused into health care and only later were to be found ineffective for treating certain conditions, include prefrontal lobotomies for schizophrenia, colectomies for epilepsy, and more recently, EC/IC bypass surgery to prevent stroke. In a recent article Eddy and Billings provide an extensive argument for the often weak evidence underlying a number of important present-day clinical procedures (36~. According to Wennberg, many procedures have not received careful feasibility studies during their initial application in humans (144), but have been introduced on the basis of investigations, involving historical controls or more anecdotal evidence. Generally, the results of such investigations tend to be more optimistic regarding the benefits of a new procedure (57~. On the basis of such optimism and a complex set of sociological, economic and scientific factors a procedure then may diffuse into more widespread use. Over time, uncertainty regarding the risks and benefits of a procedure, as used in specific patient groups and for various indications, may increase and clinical trials may then be undertaken (~10~. At this moment in time, however, the acceptance of the trial results has become inherently difficult as an advocate group for a procedure generally has been created48. Chalmers, therefore, has proposed to "randomize the first patient" receiving a new procedure(26~49. This proposal has not received wide acceptance, because during the initial stage the practitioner's skills and expertise with a procedure still evolve and the risks and benefits associated with the procedure may change considerably. In view of this "learning cuIve" phenomenon, the initial application of a new procedure will probably need to involve methodologically sound non-formal experimental stuffiest. Such early careful and comprehensive 48 The heated debate in the American Association of Neurological Surgeons and the New England Journal of Medicine illustrates the difficulties of a number of prominent physicians to accept the EC/IC bypass trial results (34,35), as well as the importance of ensuring "clear definition and relative homogeneity of the patients to be randomized." 49 Inherent in his proposal is a fluid protocol that allows incremental changes in techniques. so Alternatively, Buxton -- in a three-year evaluation of heart transplants in the UK -- uses cross-sectional analyses to estimate changes in benefit and cost parameters over a longer time period than the study period directly allows 37

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reporting of clinical experience may form the basis for the design of subsequent RCTs, if necessary, or of otherwise well-controlled trials to determine a procedure's efficacy and safety. The above does raise the question of the timing of these studies; when exactly in the development process should RCrs or otherwise well-controlled studies be undertaken? If a RCr is undertaken too early, the results may be obsolete before the trial is finished. For example, 15 years ago a randomized trial was initiated to compare the Vineberg procedure with medical treatment for coronary artery disease. Two years later the triad was abandoned because the tunnel implant had been replaced by coronary artery bypass grafting (44~. If a RCI is delayed, however, a constituency for the procedure may have formed. Bunker et al therefore suggested to initiate a reviewing authority to initiate and coordinate such trials as appropriate (22~. With regard to RCrs, one should bear in mind that some real conceptual, practical and ethical difficulties may exist regarding their use in the development of new clinical procedures (~S,19~. Double blinding, for instance, is more difficult to achieve. One possible solution may be to have one physician perform the procedure while another evaluates its effects. Controls may include standard accepted surgery or alternative treatments involving drugs or devices; it is generally accepted today that use of sham-operations is unethically. Surgical procedures will also depend much more strongly on the technical skills of the surgeon, who might be better at one Ape of surgery than another. Van der Linden (88) suggested that patients should be randomized to different surgeons who would perform the surgery they do best. Furthermore, if alternative treatment modalities are being developed with the aim to improve ~ . ~ ~ ~ ~ ~ . ~ ~ . rim . . . . ~ . ~ ~ ~ . ~ quality ot life, while the different interventions are associated with variable risks and benefits, randomization may be considered unethical. As Reiman noted: from the patient's point of view, surgical and medical therapy are not simply comparable arms of a clinical trial. They are vastly different treatments with very different persona] consequences (35~. In these cases, Wennberg has argued that assignment according to patient preferences may be the ethically necessary choice. This would require systematic analysis of how patients value different types of health outcomes (an understanding that today is not yet available) and an in-depth examination of how one wall be able to understand the "biases" associated with actual patient choice. (23~. 5] The few clinical trials using sham operations clearly demonstrated that a strong placebo effect can be associated with these surgical interventions, thus underlining the importance of controls (324. 38

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Finally, as argued in Chapters, the full range of information on the effectiveness and safety of a procedure may not emerge in randomized clinical trials, as these trials may exclude a spectrum of at risk patients. For example, Hlatly et al (70) compared the patient population in their cardiovascular disease databank with the patients enrolled in some large RCrs of coronary artery surgery. They found that only S% of their patients met the eligibility criteria for the European Cooperative Surgery Study, 13% met the criteria for the large Veterans Administration (VA) study, and 4% met those for the Coronary Artery Surgery Study (CASS) (70~. This indicates that the trial results may not always form a sufficient basis for clinical practice decision making. Therefore, following randomized or otherwise well-controlled efficacy and safety trials, long-term surveillance should be undertaken of the safety and effectiveness of new procedures as they are used in everyday clinical practice. These studies may involve experimental or observational methods. In view of some of the logistical problems involved, it may be especially useful to depend on modern observational methods that enable one to monitor clinical practice and changes in health outcomes. In recent years the use of such observational studies for assessing outcomes of clinical procedures has increased. For example, Wennberg (146) and Roos et al (122) have used claims data to evaluate health outcomes following prostatectomy, hysterectomy and cholecystectomy. Given the increased availability of computerized data banks, the possibilities of inexpensive monitoring are appealing. -A-more extensive examination of the advantages (such as low cost, ease of patient follow-up over long periods of time, and the absence of reporting bias) and the disadvantages (such as adequacy of the data to adjust for case-severity and lack of outcome information on quality of life and functional status) is needed. 39