Saving Women's Lives Strategies for Improving Breast Cancer Detection and Diagnosis (2005) / Chapter Skim
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6 The Necessary Environment for Research and Development
6 The Necessary Environment for Research and Development
Pages 188-248
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From page 188... ...
The value of any new technology must be demonstrated through a series of increasingly stringent steps, each of which can take years.a Figure 6-1 illustrates the pathway of medical technology development from discovery to adoption in clinical practice. Once a technology reaches the prototype, or investigational, stage, it is typically tested in small clinical studies, usually involving fewer than 50 subjects.
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From page 189... ...
listed by NCI is only 276 projects and 8 clinical trials. In addition to
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From page 190... ...
The panel's recommendations included research to identify biomarkers, molecular analysis of the transition from pre-invasive to invasive disease, the importance of tissue banks as a critical research resource, the need for biologically based imaging, and the need to develop databases and bioinformatics so that the wealth of data can be National Cancer Institute 60% Department of Defense 22% Avon Foundation 10% Susan G Komen Foundation Breast Cancer Research 3% Foundation California Breast Cancer American Cancer 1% Research Program Society 2% 2% FIGURE 6-2 Distribution of public and charitable funding of breast cancer.
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From page 191... ...
Three years later, these same areas were recommended for support in the 2001 Mammography and Beyond report.33 The NCI and DoD breast cancer research portfolios reflect these priorities, as do the research portfolios of key private funders. Further, these same themes have been equally emphasized for all types of cancer.
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From page 192... ...
disease, by advancing research, education, screening and treatment; 90 percent of money raised goes to research California Breast Seeks to reduce the impact 64 grants State Cancer Research of breast cancer in ($18 million) government Program California by supporting research on breast cancer and facilitating the dissemination of research findings and their translation into public health practice American Cancer Dedicated to eliminating Overall: Nonprofit Society cancer as a major health 84 grants problem by preventing ($46.4 million)
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From page 193... ...
2 This definition includes clinical studies of efficacy, effectiveness, diagnostic accuracy, the impact of a technology on quality of life, FDA review, and assessment for health insurance coverage, and post-market.
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More than 120 NIH Consensus Statements and State-of-the-Science Statements have been issued since the program's inception. PRIVATE ORGANIZATIONS Blue Cross Blue Shield Evaluates the clinical effectiveness and Association Technology appropriateness of medical procedures, devices, Evaluation Center and drugs.
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The NIH budget is more than 100 times greater than AHRQ's, but its mandate for technology assessment is limited to clinical trials and NIH has historically resisted further expansion in that direction. In coming years, the gap between technology innovation and assessment might begin to narrow.
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From page 196... ...
Clinical trials were launched in 1999. 2001 National Institute of Biomedical Imaging and Bioengineering (NIBIB)
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From page 197... ...
. Cost-effective analysis also can be used to choose between alternative strategies to achieve some overall societal or population goal; for example, in choosing whether to implement a screening program for breast cancer versus a screening program for ovarian cancer to reduce the burden of cancer in women.
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From page 198... ...
The developer of a new technology has typically invested millions of dollars in a clinical study -- not to mention the time and effort of participating physicians, nurses, and patients. The ability to fund a clinical study is often a limiting factor for a small company hoping to develop a promising medical technology.
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From page 199... ...
Problems with the meta-analysis included a lack of standardization of risk factor reporting, lack of standard reporting formats, and failure to link risk factors to an eventual diagnosis of breast cancer.6 Because improving the early detection of breast cancer requires the development of better models to assess risk, critical attention must be given to improving the quality of clinical trials. Population Measure of Cancer Status There are three major measures of cancer status in a population: incidence, survival, and mortality.
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From page 200... ...
(Primary prevention is the control of cancer through reduction in the incidence of the disease.) Screening tests are not intended or expected to affect the underlying cancer incidence rates, but rather to save lives by detecting cancer earlier than in the absence of screening.
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From page 201... ...
Definitive Evaluation of a Cancer Screening Modality The evaluation of any screening test can be affected by two profound sampling biases, length-biased sampling and lead-time bias, and these can only be circumvented by a randomized trial of women at risk of breast cancer, with breast cancer mortality as the endpoint.37 Length-biased sampling occurs when the survival experience of a group of screen-detected cases is compared with a complete sample of incidence cases or with symptomatically detected cases. Because the growth rates of tumors are generally heterogeneous, patients with slow-growing tumors will enjoy a longer period during which the cancer is potentially screen-detectable but not yet symptomatic than patients with fast-growing tumors.
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Studies to Improve Screening and Diagnostic Accuracy Many techniques designed to enhance the accuracy of or complement mammography screening are under active development. These include digital mammography, computer-assisted detection (CAD)
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This issue is exemplified by the design of the American College of Radiology Imaging Network (ACRIN) Digital Mammography Imaging Screening Trial (DMIST)
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From page 204... ...
Efforts to identify individual overexpressed proteins, such as riboflavin carrier protein,59 or patterns of proteomic over- or underexpression, such as in the study of ovarian cancer by Petricoin and colleagues,56 are likely to expand in the foreseeable future. The preliminary evaluation of a serum marker is simpler than for a radiologic test, because the serum marker study can be applied retrospectively to stored blood samples.
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, as in the analysis by Petricoin and his colleagues. LARGE-SCALE, HIGHER QUALITY CLINICAL TRIALS ARE NEEDED Inevitably, more exciting new technologies are announced than are proven useful in clinical practice.
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From page 206... ...
There are few large clinical trials that directly compare the effects of different treatments and even fewer that are comparisons among active, standard interventions. The ALLHAT was a watershed trial, because it was a large-scale trial that directly compared different FDA-approved drugs already in widespread use -- in this case, treatments for hypertension and high cholesterol.
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From page 207... ...
Engaging the Public in Clinical Studies Large-scale, well-designed clinical trials are the linchpins for converting the raw potential of new technologies into interventions that improve health and prolong lives. High-quality trials generate high-quality information, but that information accumulates slowly, one person at a time.
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From page 208... ...
However, there are different classes of clinical trials and they pose very different challenges for accrual. Trials that evaluate cancer risk or screening strategies in healthy, symptom-free people are fundamentally different from those that evaluate treatment interventions for cancer patients.
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From page 209... ...
Even with a major, well-orchestrated effort such as this one, it is difficult to persuade the majority of candidates to donate DNA samples and fill out questionnaires. Many people decline to participate in genetic testing or research because they fear the results of tests could be used by health and life insurance companies and employers to discriminate against them.16 One study investigated the reasons that relatives of people with hereditary colon cancer would decline an offer of genetic testing, and found nearly 40 percent rated the potential negative effect on their health insurance as the most important reason to not undergo testing.28 Without protections in place, individuals who do agree to participate will represent a self-selected group that could skew research results and interfere with efforts to find better ways of improving breast cancer screening.17 Various strategies for improving enrollment in clinical trials have been tested.18,36,39,54 Passively distributed information, such as brochures, has little effect, whereas personal discussions are more successful.
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From page 210... ...
When well-designed trials were eventually completed, the treatment was shown to be largely ineffective. Over time, breast cancer advocacy groups rallied to support these trials, and they are clearly an important ally in the success of clinical trials in breast cancer (Table 6-3)
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Breast cancer advocates are expert in mobilizing support for breast cancer research. They are also attuned to how potential study participants might react to enrollment requirements and could provide time-saving advice on ways that the design of clinical studies might be refined to promote more efficient enrollment, or to identify aspects of a study design that might needlessly deter enrollment.
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clinical trials via links to clinical trial listings and informational articles. NBCC partners with industry to help recruit
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The HIPAA Privacy Rule went into effect on April 14, 2003. Although the Privacy Rule applies only to "covered entities" (health plans, health care providers, and health care clearinghousesb)
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How Researchers Can Obtain Protected Health Information Central to understanding the Privacy Rule is an understanding of what it defines as "protected health information" (PHI)
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or Privacy Board. Impact of HIPAA on Medical Research The potential effects of the HIPAA Privacy Rule on research are farreaching.13 Researchers in medical and health-related disciplines rely on access to many sources of health information, from medical records and epidemiological databases to disease registries, hospital discharge records, and government documents reporting vital and health statistics.
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To qualify as needs to link records, deidentified health information, all including many longitudinal 18 identifying elements enumerated or epidemiologic studies. in the Privacy Rule must be Can result in duplication of removed.
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This requires a formal declaration that the use is solely to prepare a research protocol, no PHI will be physically removed from the covered entity during the course of review; and the PHI is necessary for research purposes. Variations in interpreting the HIPAA Privacy Rule are contributing to high levels of uncertainty and confusion that have already resulted in delays in research.
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From page 218... ...
has been deeply concerned about the effect of HIPAA on biomedical and health research and lobbied vigorously for modifications to earlier versions of the Privacy Rule. After intense lobbying by the AAMC and numerous other groups, the AAMC decided the most effective approach to further mitigation, either by regulatory change or legislation, will depend on credible evidence of adverse effects of the HIPAA Privacy Rule on ongoing or future research.
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From page 219... ...
For example, the T-ScanTM device that measures electrical impedance in breast tissue was approved as an adjunct to mammography by the FDA in 1999, but 4 years later the manufacturer had not sold a single machine in the United States. The following section provides an overview of the FDA approval process for medical devices, how medical devices can be utilized without FDA approval, FDA efforts at collaborating and fostering communication with industry, and the unique regulatory problems posed by novel in vitro diagnostics, such as genetic tests that might be used in breast cancer diagnosis or risk prediction.
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* For all Class III devices a premarket approval application is required unless the device was on the market prior to the passage of the medical device amendments in 1976, or substantially equivalent to such a device.
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But if a device is likely to be used for a specific clinical purpose as opposed to a general indication covering a variety of purposes, then the FDA is likely to require clinical studies to prove the safety and effectiveness of the medical indication for the device. When digital mammography came under FDA scrutiny, "We were not willing, and we have not been willing with breast cancer detection to say, these are just tools [that provide images]
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From page 222... ...
Checker TM 2000D TM TM HDI FFDM Technology, ® 9 System BR Imager ® Look Image Catheter Approvals Name Digital Hill 2000 Breast FFDM Aspirator Technologies, Device Lorad SensoScan Senographe Second MammoReader M1000 ProDuct Windy BreastScanIR BioScanIR T-Scan Ultramark Ultrasound Truquant Device FDA Breast system 6-6 test impedance TM imaging Type lavage doppler system TABLE Device Digital mammography system CAD Ductal DucPrep Infrared Electrical scanner Pulsed ultrasound Diagnostic (radioimmunoassay)
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From page 223... ...
223 (99 of drug the a friction of as diagnosis ion self- skin and reducing and cancer detect breast by in fingers Screening breast cancer aid to breast Pad examination between breast for approved FDA is 11/26/2002 7/20/1999 12/22/1995 07/11/2001 07/11/2001 02/05/1999 02/05/1999 07/17/1998 05/08/1997 01/10/1997 02/26/1996 03/31/1995 03/31/1995 it Inc Inc.
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From page 224... ...
Finally, on its website, the FDA offers numerous guidance documents, device advice, and other information to clarify what manufacturers need to do to legally put their devices on the market. Some Medical Devices Do Not Require FDA Approval There are a surprisingly large number of ways that medical devices used for cancer screening purposes can enter the market without FDA approval for those indications.
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From page 225... ...
One of the first-ever proteomics diagnostic tests, OvaCheck, which tests for ovarian cancer in blood samples, is scheduled to be released early in 2004. As required, the tests will be CLIA-certified but will not require FDA approval under existing regulations.
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Accelerating Medical Technology Development at the FDA Medical technology developers have long expressed frustration at the rising costs of product development and the uncertainty of the FDA review process. In January 2003, the FDA launched an initiative designed to accelerate the development of new technologies.
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From page 227... ...
Many, however, do utilize the FDA's Device Advice group, which answers 45,000 telephone inquiries a year and posts information on the agency's website.22 FDA's detailed guidance documents on what is needed for FDA approval of various types of devices expedite the approval process. When a guidance document exists for a Class II product, the manufacturer of such a device has about an 85 percent chance of getting it approved after the first cycle of FDA's review of the company's submission (as opposed to having to gather more data and undergo additional FDA review cycles before approval)
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From page 228... ...
Medicare is particularly interested in knowing whether the new technique will be useful to its older beneficiaries. Because most clinical trials exclude participants older than 65 years, most trials do not have adequate numbers of elderly patients.
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· Improved health outcome verified using evidence-based medicine framework · Equivalent to or better than current intervention · Outcomes can be generalized to Medicare population · Coding · Payment · MCAC Guidelines for Diagnostic Tests · Adequate evidence to determine whether test provides more accurate diagnos tic information · Evidence to determine how accuracy affects health outcomes mammography detects breast cancer better or even with the same accuracy as film mammography, Congress has mandated higher reimbursements for digital mammography.11 The higher reimbursement levels have encouraged increased adoption of the technology before the results of the definitive digital mammography trial, DMIST, are released. Various states have passed laws that require private insurers such as WellPoint to cover specific procedures or treatments.35
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From page 230... ...
Research on preventive services often is unable to determine outcomes within the desired timeline of a technology producer's desire to bring a product to market. As Sean Tunis from CMS noted, there is a clinical research "Catch-22" in that insurance coverage of the new technology would increase its use, providing both some of the resources needed for its developers to study its clinical value and more clinical experience with the new technology.
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From page 231... ...
Almost no confirmatory clinical studies have been completed on these drugs.49 But for accelerated approval, the FDA does not specifically require that confirmatory studies be under way at the time of approval. Such a specification might give the agency the added muscle it needs to make accelerated approval work the way it was designed.22 An important prerequisite for conditional coverage is that the decision to cover a new entity must be linked to high-quality studies whose funding is assured.
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From page 232... ...
Rosenberg noted that a WellPoint committee meets annually to evaluate new medical technology. The committee relies on a number of inputs to determine which medical products should be evaluated, such as reviews of recent FDA-approved medical products, requests from WellPoint's claims and medical review units, and information supplied by device manufacturers.
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From page 233... ...
The assigning of Medicare payment codes is under the control of the AMA and various partner organizations, such as the American College of Radiology and the American Society of Clinical Oncology. Delays in assigning CPT codes to new medical technologies have long been a source of frustration to technology developers.
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From page 234... ...
They are not a comprehensive summary of all such initiatives, but rather a set of examples that are particularly relevant to breast cancer detection. AHRQ Initiative for Research Networks Since 1999, the AHRQ has issued a series of research funding announcements that support projects on the translation of research findings into "sustainable improvement in clinical practice and patient outcomes." In 2002, the NCI articulated that a key part of its mission was the rapid movement of research discoveries through program development into service delivery, which included projects designed to "identify and overcome infrastructure barriers to the adoption of evidence-based interventions in clinical and public health systems that serve the American public, with a particular emphasis on reaching those who bear the greatest burden of cancer." In 2003, AHRQ and NCI issued a joint request for applications, for research projects that assess the use of intervention to translate research into practice in the primary care setting and measure the impact of those interventions.
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From page 235... ...
If successful, this project may have a significant positive impact on translating basic research into better patient outcomes. ACRIN: Network for Cooperative Development of Imaging Technology ACRIN is an organization of institutions, funded by the NCI, which manages clinical trials of cancer-related imaging technologies.
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From page 236... ...
It was followed by ACRIN, which has been in operation since March 1999 and is funded by NCI, at least through 2007. ACRIN offers a unique opportunity to assess emerging technologies and determine their optimal use by providing both funds and an infrastructure for multi-institutional clinical trials.
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From page 237... ...
They factor into each of three major initiatives listed above. The theme of reengineering the clinical research enterprise is particularly relevant to what the Committee believes is especially needed to promote the development of more effective approaches to the early detection of breast cancer, and is described on the NIH website as "undoubtedly the most difficult but most important challenge identified by the NIH Roadmap process."53 This theme is further subdivided into three initiatives -- translational research, clinical workforce training, and enhancement of clinical research networks -- all of which address the Committee's conclusion that basic research should be integrated with technology development and assessment (see Box 6-9)
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From page 238... ...
The NIH Roadmap will promote the creation of better integrated networks of academic centers that work jointly on clinical trials and that include community based physicians who care for sufficiently large groups of well-characterized pa tients. Implementing this vision will require new ways to organize the way clinical research information is recorded, new standards for clinical research protocols, modern information technology, new models of cooperation between NIH and pa tient advocacy alliances, and new strategies to reenergize the clinical research workforce.
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From page 239... ...
Because of the vast number of procedures and technologies that must be evaluated through clinical trials, many clinical research networks operate simulta neously, but independently of each other. As a result, researchers must some times duplicate already existing data because they are unaware the data exist or they cannot access them.
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From page 240... ...
Developers of early stage medical technology have long commented that the process of FDA and CMS review are so unpredictable and burdensome that they unduly impede the development of innovation technologies.33 ICBIO is one example of the series of proactive strategies that federal agencies have taken in recent years to address these problems. National Digital Mammography Archive As digital imaging technology becomes increasingly cost-effective, mammography is expected to move away from a film-based format.
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From page 241... ...
During the first 3 years of the project, researchers enrolled about 10 patients per day, uploading their mammography data to the NDMA.68 Archived images are primarily derived from digital mammograms; films also have been digitally scanned for inclusion in the archive, but produced Digital Acquisition Device NDMA Portal Internet2/ VPN Tunnel NGI Hospital Network Viewing Station Report Creator User Hospital FIGURE 6-4 Architecture of the National Digital Mammography Archive (NDMA)
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From page 242... ...
Unlike the standard Internet, the bandwidth and technology of Internet2 can accommodate the storage of very large digital image files -- which are predicted to exceed capacity for management and storage by breast center sites -- and enable their instant transfer across the network.1 The use of grid-computing addresses is "the trick of making use of digital images, indexing them, and delivering them to hospital locations on demand," says Robert Hollebeek, chief architect of the NDMA. The Internet2 "grid" framework is also key to ensuring patient privacy and confidentiality, as required by the HIPAA Privacy Rule.
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From page 243... ...
Currently, very few clinical trials are funded annually to determine whether new technologies might improve the detection and/or diagnosis of breast cancer. Such trials require access to patient populations willing to undergo extra experimental tests, as well as a cadre of investigators who are skilled in trial design and execution.
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REFERENCES 1. National Digital Mammography Archive.
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From page 245... ...
2003. Why patients don't take part in cancer clinical trials: an overview of the literature.
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2003. American College of Radiology Imaging Network: future clinical trials.
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1997. Barriers to black women's participation in cancer clinical trials.
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2003. Private Payers' Perspectives on Adoption of New Breast Cancer Detection Technologies.
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