Modern Methods of Clinical Investigation (1990) / Chapter Skim
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Appendix A: Comparing the Development of Drugs, Devices, and Clinical Procedures
Appendix A: Comparing the Development of Drugs, Devices, and Clinical Procedures
Pages 147-201
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From page 147... ...
It provides an initial conceptualization of the medical technology development process within the broader innovation spectrum. It subsequently compares the evaluative strategies currently used in the development of new drugs, medical devices, and clinical procedures.
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This change in the science-technology relationship gave rise to the so-called linear model of technological innovation (see Figure A.1) , i.e., results were perceived to flow from basic research to applied research, targeted development, .
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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. In other sectors of the economy, this linear-sequential representation has been found to impose a number of important conceptual limitations for the purpose of analyzing the development process.
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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.
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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?
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. Over time, the drug discovery and research process has become increasingly complex and sophisticated.
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Yet, uncertainty remains a crucial element in drug discovery and preclinical research: the attrition rate traditionally has been such that, of roughly each 10,000 compounds synthesized, 1,000 will go into animal research and only 10 will initiate human testing (32~. Drug Development In the United States, the decision to proceed with the development of a compound, including its clinical evaluation, initially involves a drug company and the FDA.
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on the nature of the new compound, formulation and identification methodologies, stability information, manufacturing methods, the methods and results of preclinical animal studies, the proposed clinical development plan for trials, and the identity and qualifications of clinical investigators.13 The FDA classifies IND applications according to a compound's chemical We and its potential benefit, to determine priority for review. In principle, clinical trials can start 30 days after the FDA receives an IND application, unless the agency orders a "clinical hold." After an IND application has been approved, a multi-stage process of clinical investigation starts; the demarcation lines between the various phases are somewhat fluid.
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Traditionally, a number of intermediate endpoints, such as lowering blood sugar in diabetes or lowering blood pressure in severe hypertension, have been accepted as valid by the various parties involved in drug development. In other, more recent cases involving intermediate endpoints, such as clot lysis in myocardial re-infarction or the increase of hematocrit levels in anemic dialysis patients, there has been considerable disagreement about their value.
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The safety concerns in Phase II and in Phase III studies include cumulative organ toxicity, hypersensitivity reactions, metabolic abnormalities, endocrine disturbances, and if women of childbearing age are involved, teratogenicity (29~. The Food, Drug, and Cosmetics Act requires "substantial evidence .
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diseases, a sponsor may request a treatment IND in the course of Phase III studies. During Phase II and Phase III clinical studies much industrial effort is directed, usually by chemists and engineers, toward process optimalization and 'scaling up' for production.20 The scaling-up for an efficient production process, involving pilot plant operations and various other process and quality control measures, is a crucial part of the development process.
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While the full picture of the risks involved may become apparent only with the widespread diffusion of a drug, an equal argument can be made about benefits. The full range of information on effectiveness of a drug cannot be expected to emerge in Phase III clinical trials that are designed to test the null hypothesis of efficacy.
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One consequence is that cost analyses and cost effectiveness studies are becoming a much more prominent part of a drug's evaluation. However, these analyses and their influence on decision making are outside the scope of this paper.26 Following the marketing approval decision, a new drug generally diffuses into clinical practice (with the active help of marketing professionals)
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include experimental and observational methods. While experimental methods have especially been applied to further examine efficacy postapproval, risk measurements in specific patient populations are sometimes also undertaken.
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In view of the reciprocal relationship between research and development, we will briefly consider the interactions between the research and invention phase of medical devices and the development phase. The Invention of Medical Devices In addition to basic biomedical and clinical research, bioengineering research, which builds on advances in the physical sciences, mathematics, and engineering in other sectors, provides an important contribution to the knowledge base underlying medical device development.31 Basic bioengineering research predominantly takes place in university and government laboratories.
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Furthermore, with devices that require large capital costs, the need for large-scale investments may prevent competitors from entering the market, and small firms may depend more on trade secrets. Whereas the potential users of new medical devices, i.e., the physicianresearchers, may play an important role during the development process, they also may be crucial to the invention of medical device prototypes.
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If the user-dominance paradigm of Van Hippel plays an important role in some parts of the medical device industry, manufacturers' decisions will be made later in the R&D continuum. The decision whether to pursue development of a prototype involves both technical and market factors.35 Medical Device Development In most industrialized countries, the development of new medical devices is governed by regulatory schemes, either in the form of standards or extended pharmaceutical laws, which focus mainly on safety.
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, or were conducted with patients who signed consent forms. Because medical devices are a much more heterogeneous group of products than are drugs, it is understandable that some variation in clinical evaluation exists.
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Indeed, a recent GAO report found that roughly 90 percent of medical devices reviewed by FDA were marketed through 510(k) review, while 10 percent underwent the full pre-marketing approval process (82~.
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.39 In clinical practice, however, the question of interest is, if the patient has a positive test how likely is he or she to have a specific disease?
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On the basis of the results of clinical investigations, a device may be approved for marketing.42 In contrast to drug regulation, the device amendments require that advisory committees participate in the pre-marketing approval (PMA) decision for Class III devices (90~.
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There is little incentive for hospitals to use technologies which have long-term benefits, even though they may ultimately have a greater impact on the efficiency of the system as a whole. As the existing reimbursement system affects the market for new medical products, changes in this system may exert strong feedback signals to the development process, e.g., it has been observed that medical device manufacturers react to the demand for products that are cost-effective over the short term and neglect R&D projects dealing with products that are cost-effective over the longer run.43 With these changes in reimbursement, the coverage decision by the Health Care Financing Administration has become a more important factor in the development process.44 Traditionally, the coverage decision making process
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Uncertainty, however, remains as to the strengths and weaknesses of these methods in providing reliable evidence (97~. THE DEVELOPMENT OF CLINICAL PROCEDURES The last 25 to 30 years have seen rapid advances in basic biomedical research,46 strengthening the scientific underpinnings for the development of new clinical procedures in the years to come.
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Fox and Swazey, in their book The Courage to Fail, have described the scientific 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 (101~.
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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 (1021. In contrast to drugs or devices, no formal governmental regulatory system exists for the development and evaluation of clinical procedures.
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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 (108~. The Use of Controlled Clinical Studies According to Wennberg, many procedures have not received careful feasibility studies during their initial application in humans (109)
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With regard to RCTs, 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 (117,118~. Double blinding, for instance, is more difficult to achieve.
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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 devices, and of clinical procedures.
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New drug development in the United States, 1963 through 1984.ClinicalPharmacology and Therapeutics1988;43:290-301. roughly 30 percent)
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The FDA, for example, has proposed to streamline the drug approval process for life-threatening diseases by shortening the pre-marketing evaluation stage (Phase II and Phase III clinical trials will be merged into more definitive Phase II trials) , and by emphasizing more strongly the post-marketing evaluation stage (Phase IV)
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The impact of this law may be considerable since 81 of the most important 100 drugs used currently in the United States will go off patent by 1991, and will thus become generic drugs.59 Furthermore, the economic climate is becoming much more price competitive, e.g., most states have passed 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-around 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 A.4 may constitute an impediment to drug development in the long run.
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In comparison with drugs and biologicals, there is a much greater heterogeneity in medical devices in terms of design, purpose, and use, and consequently much more variation in the kind of clinical evaluations undertaken (67~. In view of this heterogeneity, the medical device amendments to the Food, Drug, and Cosmetics 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.
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Because device development often involves incremental innovation for a considerable part of its lifespan, and because RCTs are not ideally suited to provide information on a slightly different version of a device, these studies will usually depend on observational methods. When comparing the rationality and efficiency of device development to drug development and considering the well-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.
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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 (1101.
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If and when the feasibility of a new procedure has been established, randomized clinical trials or otherwise well-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.
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Furthermore, these inconsistencies may also have contributed to unnecessary health care costs, if one takes into account that the least systematically evaluated technologies, clinical procedures, are also the most costly.63 Although these inconsistencies are to a certain extent the 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 all 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.
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This applies for devices and especially clinical procedures, but also to drugs; for example, these kinds 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.
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It is only by addressing these complicated issues that we will 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. ADDENDUM The major decline in the number of new U.S.
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In the development process of drugs and biologics these initial studies in humans have been designated Phase I studies, which are generally followed by Phase II and Phase m 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
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In this paper we will also apply the terms Phase I to Phase IV clinical studies to the development of devices and clinical procedures.
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The law uses the term effectiveness to make explicit that drugs are approved and labeled for use under the general conditions of medical practice, not the more idealized conditions often found in an investigational sewing (371. Extending this argument, it is for this very reason that we will use the term efficacy in the context of pre-marketing clinical investigations.
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In view of rising health care costs, third-party payers are sometimes refusing to reimburse even the routine costs of medical care associated with clinical trials of experimental drugs.
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32. In view of the heterogeneity of medical devices, the type of device determines if animal research will be undertaken before a device prototype is evaluated in humans.
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51. 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 (119~.
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62. IDEs are devices under development which require FDA approval to initiate clinical evaluation in humans.
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Government health policy and the diffusion of new medical devices. Health Services Research 1986;21:681-711.
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Innovation and Acceleration in Clinical Drug Development. Roundtable 2: Early clinical trials Phase I-IIA: Optimal designs for maximum information.
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Randomized Clinical Trials. In Assessing Medical Technologies.
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Planning studies to evaluate medical devices. In Guide to Planning and Managing Multiple Clinical Studies.
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Clinical investigations with medical devices: New rules. Journal of the American Medical Association 1981;245:2053-2054.
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Therapeutic innovation: Ethical boundaries in the initial clinical trials of new drugs and surgical procedures. Daedalus 1969;Spring:502-522.
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New drug development during and after a period of regulatory change: Clinical research activity of major United States pharmaceutical firms, 1958 to 1979. Clinical Pharmacology and Therapeutics 1983;33:691-700.
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New Drug Introductions, Discontinuations and Safety Issues in the United States and the United Kingdom: 1960-1982.
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