Redesigning the Clinical Effectiveness Research Paradigm Innovation and Practice-Based Approaches: Workshop Summary (2010) / Chapter Skim
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2 Cases in Point: Learning from Experience
2 Cases in Point: Learning from Experience
Pages 87-154
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From page 87... ...
By reviewing examples of high-profile studies and trials that evaluated the effectiveness of hormone replacement therapy, drug-eluting coronary stents, bariatric surgery, antipsychotic medications, and lung cancer screening, this chapter illustrates the range of issues facing current effectiveness research. Examples of these issues include capturing important health outcomes throughout the lifecycle of an intervention; contending with the biologic complexity of disease and disease progression and rapid evolution of devices or surgical procedures or rapid uptake and application in broader patient populations.
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JoAnn E Manson from Harvard Medical School reviews the divergent results of observational studies and RCTs, evaluating the effect of menopausal hormone replacement therapy (HRT)
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Harvard Medical School Observational studies and randomized clinical trials of menopausal hormone therapy (HT) and coronary heart disease have produced widely divergent results.
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Methodological Factors That Contribute to the Divergent Findings The potential role of methodologic factors must be considered in understanding the more favorable findings for HT in relation to CHD risk in observational studies than in clinical trials (Table 2-2)
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. In contrast to the greater weighting of long-term use in observational studies, clinical trial results tend to reflect shorter term use.
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Although large-scale randomized trials, the gold standard of clinical research, have the advantage of minimizing confounding by lifestyle practices, socioeconomic status, and other factors, they are often constrained by higher costs, shorter duration of follow-up, and, at times, limited applicability to populations of greatest clinical relevance. Furthermore, the findings of observational studies and clinical trials of HT are remarkably concordant TABLE 2-3 Hazard Ratios (HR)
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From page 93... ...
. Thus, women in HT clinical trials tend to have later stages of atherosclerosis than their counterparts in observational studies and a possibly greater vulnerability to the adverse vascular effects of HT (Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of the North American Menopause Society, 2007; Manson et al., 2006)
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The theory that the influence of estrogen on atherosclerosis and coronary events may vary according to the underlying health of the vasculature and the evidence that a woman's age and time since menopause onset may modulate CHD outcomes with HT, as well as implications for future research, are discussed below. Biological Factors That May Contribute to the Divergent Findings As noted above, randomized trials testing the effect of HT on clinical coronary outcomes have not confirmed the cardioprotective effect suggested by most observational studies.
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. A key difference between participants in observational studies and those in clinical trials of HT is the timing of initiation of treatment in relation to menopause onset, which occurs on average at age 51 in the United States.
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2006. Postmenopausal hormone therapy: New questions and the case bitmap image with vector elements for new clinical trials.
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However, given the striking discrepancies between findings from earlier observational studies and more recent randomized trials (including data from the large trials with hard clinical endpoints, smaller imaging studies, and experimental studies in animals) , WHI investigators pursued more detailed analyses of the data to examine whether the timing hypothesis might account for the seemingly contradictory evidence on coronary effects of HT.
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2007. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
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but an adverse impact in later years. Similar results according to age or time since menopause have been obtained in observational studies and small clinical trials (Brownley et al., 2004; Grodstein et al., 2006; Lobo, 2004)
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Most of the current guidelines recommend against the use of HT at any age to prevent CHD and other chronic diseases (Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of the North American Menopause Society, 2007; Executive summary. Hormone therapy, 2004; Hormone therapy for the prevention of chronic conditions in postmenopausal women: Recommendations from the U.S.
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2007. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
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Observational studies that utilize computerized health records and electronic pharmacy databases, however, may avoid these limitations due to their abil ity to capture prescription/medication data on a regular basis. Moreover, results of studies that use electronic health records tend to be largely convergent with results of clinical trials, supporting the advantages of this study design for medication-related research.
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Conclusions Observational studies, clinical trials, and basic research all have contributed critically important information to elucidate the health effects of HT and to inform decision making. Recent analyses have elucidated both methodological and biological explanations for the divergent findings and
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. Clinical trials must be adequately powered to assess clinically relevant subgroups and to address the possibility of a modulating effect of key clinical variables.
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a modest reduction in long-term restenosis rates by preventing negative remodeling. Implanted bare metal stents are foreign bodies and present an early thrombosis risk.
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DES were implanted in coronary arteries of animal models to evaluate device handling performance and histologic changes within arteries, myocardium, and other body organs. Both DES were evaluated in clinical trials that compared the DES to the identical bare metal (uncoated)
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Clinical Trials Utilizing Angiographic End-points The third DES to be FDA-approved was the Endeavor Zotarolimus Drug-Eluting Coronary Stent (Medtronic, Santa Clara, California)
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. Moreover, meta-analyses of available randomized trials of the CYPHER stent and the TAXUS stent showed a numerical increase in the rates of stent thrombosis for both DES compared to their respective bare metal stent controls after 1 year.
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the optimal duration of dual antiplatelet therapy in patients who receive DES. The Panel concluded that both the CYPHER and TAXUS DES are associated with a small increase in stent thrombosis compared to bare metal stents that emerges 1 year post stent implantation.
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As noted above, while stent thrombosis was known to occur with bare metal stents, simply extending the duration of antiplatelet therapy until a point beyond when drug elution is presumably complete (and theoretically, arterial healing would be complete with re-establishment of a functional endothelial covering on the stent) does not appear to have been sufficient to eliminate the risk of DES thrombosis.
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Issues Needing Resolution The issue of late stent thrombosis continues to be a critical issue for currently approved DES and the next generation of devices. Further study
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With clinical event rates in the single digits and multiple DES on the market, manufacturers and investigators will face challenges in developing clinical trials that do not require ever-increasing sample sizes and that can be completed in a reasonable time period. New technologies are also likely to pose additional issues for manufacturers and the FDA.
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As an example, an ideal safety end-point for a DES premarket trial would be a combination of cardiac death and MI; however, due to the low rates of these events, in a non-inferiority comparison to an approved DES that employs a clinically relevant non-inferiority margin, sample sizes would exceed 10,000. Therefore, the FDA recommends use of a composite that also contains an effectiveness measure (usually TLR)
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With this in mind, as part of its Critical Path initiative,3 the FDA is collaborating with device and drug manufacturers and academic physicians to develop a large study involving multiple DES in which clarity on this issue might finally be achieved. In summary, a number of challenges face the FDA, manufacturers, and the clinical community in designing clinical trials to support marketing approval of future DES, in assuring that critical safety issues are answered, and in achieving these goals without stifling innovation.
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Flum, M.D., M.P.H. University of Washington A Safer, Higher Quality, Learning Healthcare System in Surgery: The Role of Regional Collaboratives One characteristic of a learning healthcare system is its capacity to generate the evidence needed to judge the effectiveness and cost-effectiveness of delivered care and to employ this evidence to deliver optimal care.
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While pharmaceutical agents require rigorous pre- and sometimes postmarket testing to demonstrate safety and efficacy, the regulatory burden for approval of new devices is much less stringent. For devices/procedures, regulatory systems focus on proof of concept rather than comparative effectiveness or even safety once the technology is no longer exclusively "in the hands" of experts.
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Though this efficacy versus effectiveness conundrum is critical when evaluating intended treatment effects, it may be even more important when considering unintended effects such as safety problems. Most studies of devices and interventions are aimed at demonstrating therapeutic effect and so are relatively underpowered to identify important procedure-related harms (i.e., laparoscopic cholecystectomy and bile duct injury)
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, but equal reports from the media of high-profile adverse outcomes and deaths that stimulated some state agencies to close down bariatric programs and prompted radical responses from the academic and public health communities (Commonwealth of Massachusetts Betsy Lehman Center for Patient Safety and Medical Error Reduction Expert Panel on Weight Loss Surgery: Executive Report, 2005)
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. After years of being touted as life-saving treatment compared to selected or historic nonoperative cohorts, CMS restricted its payments of the procedures to patients enrolled in a randomized trial.
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In New England, vascular surgeons from over 10 institutions have recently partnered in a peer-to-peer network called The Vascular Study Group of Northern New England16 that is evaluating performance of certain novel vascular surgical procedures. In Washington State, surgeons from over 25 hospitals representing three-quarters of all the surgical care in the state have organized the Surgical Care and Outcomes Assessment Program (SCOAP)
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In this way, new procedures and techniques are simultaneously used and evaluated, and a learning healthcare system can be driven toward better performance. For example, using SCOAP data and the SCOAP quality improvement (QI)
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has been working for a decade to draw all hospitals in the state that deliver cardiac care together in programs that respond to variation found through the STS data such as reducing the use of transfusions to make surgical care safer. Barriers and Policy Opportunities for Creating a Learning Healthcare System Regional activities like SCOAP face tremendous obstacles because they are both hard to develop and sustain.
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There are several policy opportunities that would allow a regional collaborative to flourish and should be considered in the development of a more effective, learning healthcare system.
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Common approaches to evaluate interventions are ineffective • because they are not contemporaneous or sensitive enough (i.e., administrative database research) or because they are too costly and challenging to organize (large-scale randomized trials linked to coverage)
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Findings from the recently completed NIMH-sponsored comparative effectiveness trials of antipsychotic medications in patients with schizophrenia (the CATIE schizophrenia trial) and Alzheimer's dementia (the CATIE-AD trial)
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First, in the absence of information on the effectiveness of agents -- especially compared to available alternatives -- practice decisions are often made on the basis of efficacy and safety data that may not represent the outcomes achievable in typical patients or circumstances. For example, earlier randomized controlled clinical trials suggested that the newer second-generation atypical antipsychotics were less likely than the older conventional neuroleptics to cause side effects such as extrapyramidal symptoms and were possibly more efficacious for the negative symptoms of schizophrenia (Leucht et al., 1999)
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. In this analysis there appeared to be no consistent relationship between the application of prior authorization policies and overall spending on atypical antipsychotic medications, suggesting that Medicaid programs may not have sufficient data on their comparative effectiveness to know whether their use should be promoted or deterred.
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. Advances in Clinical Effectiveness Research How can investigators answer the many remaining questions concerning the clinical effectiveness of antipsychotic medications, enhance practice, and inform policy as well as purchasing decisions?
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. Examples of Clinical Effectiveness Research on Antipsychotic Medications The remainder of this article covers studies that illustrate how these developments in populations, databases, study designs, and analytic methods could be used to improve the clinical effectiveness of antipsychotic medications.
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. To shed light on the relative benefits and risks of such practices, NIMH also conducted a comparative effectiveness trial of atypical antipsychotic medications used in Alzheimer's dementia (CATIE-AD)
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, the risk of unmeasured or unadjusted confounding cannot be completely excluded in clinical epidemiologic studies. For this reason, a meta-analysis of randomized trials among elderly with dementia that found the conventional agent, haloperidol, increased short-term mortality versus placebo by 107 percent (a risk numerically greater than that seen for atypical agents)
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Clearly, clinical epidemiologic studies and quasi-experimental studies provide useful means for improving the effectiveness of antipsychotic medication practices and policies when comparative effectiveness trials may not be available, affordable, or feasible. However there also are many questions concerning the clinical effectiveness of antipsychotics that may not be answerable, even by clinical epidemiologic or quasi-experimental designs.
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Whether these potentially greater benefits as well as lower risks and costs for clozapine could justify its expanded use as a hypothetical first-line agent in treatment-sensitive patients remains a question for which empirical data are lacking. For that reason, we employed a simulation model to assess the effectiveness and costs of using clozapine as a potential first-line treatment for schizophrenia, relative to the current practice of restricting clozapine for only patients who have failed two trials of other antipsychotics (Wang et al., 2004)
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Bach, M.D., M.A.P.P. Memorial Sloan-Kettering Cancer Center New Cancer Screening Tests: Challenges for Evidence In the context of clinical medicine or typical practice, clinical disease usually "presents." That is, patients arrive with symptoms or signs -- fever and night sweats with a cough, or a fractured limb -- and thus the "afflicted population" is constituted of those individuals presenting with frank manifestations of their condition.
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. Value from Screening: Case Finding, Surrogate Markers, End-point Alteration To determine the value of screening tests is difficult, whether the test is a questionnaire or an expensive diagnostic test being used off-label for screening.
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Even though there is an established gold standard for the evaluation of screening tests, there is no guarantee that such comparative trials, be they randomized or historic, are done before screening tests are adopted. For instance, the PSA test for prostate cancer has yet to be evaluated in a
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The Princeton Longevity Center, for instance, advertises lung cancer screening. Its website includes some statements of fact about the lung cancer mortality rates in the United States.
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On the basis of solid evidence, screening would lead to false-positive results and unnecessary invasive diagnostic procedures and treatments. American Cancer Society Lung cancer screening is not a routine (Smith RA, Cokkinides V, Eyre HJ.
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The paper, which was the first comparative assessment of CT screening for lung cancer, used a computer simulation model to estimate what would have happened in the absence of screening among 3,000 individuals who were screened (Bach et al., 2007a)
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2007. Computed tomography screening and lung cancer outcomes.
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In general terms, randomized trials will not always be done, and so it is important to construct approaches to the evaluation of screening tests that are sufficiently valid in the absence of randomization. As we showed in our study, which took advantage of the relatively unique linkage between lung cancer risk and reportable risk factors, we were able to assess the impact of CT screening without randomization to some extent, and at
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Moreover, many unproven screening tests are affordable to some, even though the procedures and tests they trigger can add up to great expense. For instance, phone calls to the various I-ELCAP lung cancer screening sites demonstrated that most of the centers ask for $400 to $500 for a single screening test, so individuals with high net worth will obtain these tests without reimbursement.
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2004. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The women's health initiative randomized controlled trial.
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2004. Benchmarking lung cancer mortality rates in current and former smokers.
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2006. Validation of a model of lung cancer risk prediction among smokers.
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2005. Final results of the lung screening study, a randomized feasibility study of spiral CT versus chest x-ray screening for lung cancer.
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1997. Impact of postmenopausal hormone therapy on car diovascular events and cancer: Pooled data from clinical trials.
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1998. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
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2006. Postmenopausal hormone therapy: New questions and the case for new clinical trials.
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2006. Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease.
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2007. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
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2003. Lung cancer screening with CT: Mayo clinic experience.
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2002. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: A randomized controlled trial.
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