6

Suggesting an Agenda for Transforming Elements of the Clinical Trials Enterprise

A wrap-up session concluded the workshop and included interpretive summary reports by the chairs of each of the four previous sessions, a panel discussion in which panelists considered elements of an agenda for a transformed CTE, and an open discussion among panelists and audience participants oriented around key questions identified by the workshop planning committee. CTE transformation could substantially benefit several types of stakeholders, for whom such transformation is a shared responsibility:

•      patients and families;

•      health professionals, including community practitioners;

•      hospitals and integrated health delivery systems;

•      public and private payers;

•      pharmaceutical and medical device manufacturers; and

•      the community of investigators, funding organizations, and regulatory agencies engaged in, supporting, or evaluating clinical research.

The chairs of the workshop sessions delivered summaries of their respective discussions. The summaries and workshop discussions generated several key themes on the need for, and possible avenues for transforming, the CTE. Box 6-1 displays these themes. The information in Box 6-1 provides an integrated summary of their remarks and discussions during the panel and should not be construed as reflecting consensus or



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6 Suggesting an Agenda for Transforming Elements of the Clinical Trials Enterprise A wrap-up session concluded the workshop and included interpre- tive summary reports by the chairs of each of the four previous sessions, a panel discussion in which panelists considered elements of an agenda for a transformed CTE, and an open discussion among panelists and audience participants oriented around key questions identified by the workshop planning committee. CTE transformation could substantially benefit several types of stakeholders, for whom such transformation is a shared responsibility: • patients and families; • health professionals, including community practitioners; • hospitals and integrated health delivery systems; • public and private payers; • pharmaceutical and medical device manufacturers; and • the community of investigators, funding organizations, and reg- ulatory agencies engaged in, supporting, or evaluating clinical research. The chairs of the workshop sessions delivered summaries of their respective discussions. The summaries and workshop discussions gen - erated several key themes on the need for, and possible avenues for transforming, the CTE. Box 6-1 displays these themes. The information in Box 6-1 provides an integrated summary of their remarks and discussions during the panel and should not be construed as reflecting consensus or 63

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64 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE BOX 6-1 Key Themes of Clinical Trials Enterprise Transformation Suggested at the Workshop This box provides an integrated summary of presentations by Alastair Wood, Professor of Medicine and Pharmacology, Weill Cornell Medical College, and Symphony Capital LLC; Sherine Gabriel, William J. and Charles H. Mayo Professor of Medicine and Epidemiology, Mayo Medical School; Arthur Rubenstein, Profes- sor of Medicine, Division of Endocrinology, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; and Clyde Yancy, Chief of Cardiology, Northwestern University Feinberg School of Medicine, and Associate Director, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital. These speakers were asked to summarize and discuss key themes arising from their respective sessions of the workshop. Convergence of Clinical Research and Clinical Practice • ncorporate clinical research and clinical trials into continuous quality improve- I ment activities of the health care system. Most clinical decisions apparently are not yet based on scientific evidence; broad engagement of, and partnership with, community health care providers and patients could provide excellent opportunities to generate valid, reliable, and relevant evidence and incorporate it into medical practice. • ocus clinical trials on answering important health questions likely to draw F greater interest and support from patients, the public, practitioners, and payers. • esign less bureaucratic platforms for studies, using EHRs maintained in rou- D tine care and novel ways of randomizing patients. Different treatments and populations will give rise to the need for different approaches. • xpand research networks and collaborate with professional societies in order E to centralize processes and induce more physicians to participate in research. Strive to reduce the large footprint on clinical practice that research imposes; research will become part of routine practice only if it is not overly cumbersome. Workforce and Career Development • nsure that those who develop clinical trials examine trial proposals from the E perspective of a scientist, as well as from the patient perspective in order to understand what an appropriate and meaningful clinical trial would look like for patients and society. • reater diversity in the research workforce would help respond to changing G U.S. demographics. • econdary education may be an effective venue for educating the public about S scientific evidence and beginning to attract young people to careers in science. • ore attention to research in medical schools could improve practitioners’ M attitudes toward research and attract young physicians to research careers. Innovations in education and training to prepare researchers to collaborate with clinicians could lead to better trials. • uild education programs—prelicensure, graduate, and lifelong learning—on B needs assessments that take into account knowledge gaps, research meth- odology, interpretation of results, implementation of findings, design thinking, team leadership skills, and business skills. • lace a higher value on clinical trials research in tenure decisions could nhance P e CTE career ladders.

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65 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE Public Engagement and Partnership • ecognize patients as partners in transforming clinical trials. Consider virtual R clinical trial models that use mobile and web-based technologies to conduct clinical trials so that participation in a clinical trial is not dictated by geographic proximity to a trial site. • ngage the public in order to obtain sufficient and sustained support of the E CTE, through both participation in trials and general recognition of the value of clinical research. • he public and policy makers often do not see how research leads to better out- T comes and savings. Creating national awareness of the linkages between clini- cal research, medical breakthroughs, and ultimately improvements in atient p care will require effective communication strategies developed in partnership with the clinical research community and the public. • onsider implementation of a default consent or “opt-out” process for participa- C tion in some types of clinical research. Default consent would create a legal presumption that the patient agrees to allow use of his or her deidentified record for research purposes. • ndertake communication efforts to the public by the research community to U pave the way for direct-to-patient research and the use of social media to recruit individuals into community-based models of research, perhaps eventually sup- planting the traditional academic model of Phase III clinical trials. • nvolve patients, the public, practitioners, and payers (including, for example, I pharmacy benefit managers) more heavily in conversations about CTE trans- formation. A new lexicon may be needed to facilitate communication between researchers and the public. Regulatory Environment • mprove understanding and communication between government regulators I and research organizations. • ase the regulatory environment when appropriate, in order to reduce the E dura ion and cost of trials and make them more feasible, especially in domestic t settings. • pdate the Common Rule to facilitate fit-for-purpose, patient-friendly reposi- U tories of patient data and randomized research projects, especially involving biomarkers and the development of personalized medicine. Cultural and Financial Incentives • ndertake the “creative destruction” of old clinical trial business models in favor U of newer business models that complement advances in technology. • ncourage academic health and science centers and research organizations E to move beyond provincial systems in favor of greater efficiency for the CTE (e.g., legacy systems, such as site-specific IRBs in favor of using a centralized IRB model). • reate template contracts to streamline collaborations and subcontracts. C • onsider the role of CMS in CTE transformation. Should tasks associated with C bridging the divide between clinical research and clinical practice become a component of Accountable Care Organizations (ACOs)? Should new incentives be created to spur the sustained and collaborative participation of ACOs in research? • orrect disincentives for research, by using more coverage under evidence C devel pment (by private payers as well as Medicare) and reimbursing the o routine care costs of research participants.

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66 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE endorsement by the workshop participants, the planning committee, the Forum, or the National Academies. Several participants expressed the view that, to spur transformation by 2020, it would be advantageous to move from discussion to action quickly. Patience is needed, however, as each major step along the way is likely to be measured in terms of years. Clyde Yancy, Northwestern University, noted a few issues raised during the discussion on the clinical trials infrastructure: • Who pays, and how much? The ideas suggested at the workshop will generate substantial costs. • How can poorly designed trials be avoided? • Which regulatory objectives should be relaxed in order to reduce the regulatory burden on clinical research? • Who is liable for adverse events in globalized research? • Who owns aggregated patient care data, and what rights or privi- leges does ownership entail? REFLECTING ON POTENTIAL PATHS FORWARD It is a huge opportunity to . . . harness a new level of interest in a lot of organizations that would have never thought collectively about participating in research. —Douglas Cropper, Genesis Health Systems Perspectives on developing an agenda for CTE transformation were offered by Douglas Cropper, President and CEO, Genesis Health Systems; Lynn Etheredge, Independent Consultant on health care and social policy issues, and Head, Rapid Learning Project, The George Washington Uni- versity; Ronald Krall, Associate Fellow, University of Pennsylvania Center for Bioethics; James Doroshow, Director, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH; and Jean Rouleau, Sci - entific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health and Research. A Health Delivery Systems Perspective1 Collaboration across community-based systems of care could sub- stantially enhance the CTE infrastructure. Although such collaboration would represent something of a departure from existing practice, because 1 This section is based on the presentation by Douglas Cropper, President and CEO, Genesis Health Systems. Genesis is a six-hospital system in the Quad Cities area of Iowa and Illinois.

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67 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE the health care system is currently undergoing a great deal of change, many current practices are able to be reconsidered. Much of the change is caused by new incentives. Payers are starting to gear payment levels to value rather than volume and are prodding providers to assume risk for the health of the populations they serve. These payment changes make use of best practices that undergird the provision of adequately reimbursed care. Other actions by payers also could facilitate further development of a learning health system. Just as federal “meaningful use” incentives are driving health systems nationwide to adopt EHRs more rapidly, so could Medicare be used to create incentives for providers to use EHRs for research (not just to make care more efficient and easily monitored) and to help determine ways to connect data repositories. CEOs of health systems have been a largely untapped resource in pro- moting clinical research. Box 6-2 suggests ways health system leadership can serve transformation of the CTE. Engaging this group of leaders can be accomplished by appealing to their business and clinical interests. BOX 6-2a CEOs of Integrated Health Systems Could Promote Clinical Research Health system CEOs could play a crucial role in transformation of the CTE. This role might include • cting assertively to embed research in the mission and culture of the health a system, creating opportunities for the pursuit of scientific evidence within clini- cal care in order to improve quality, and moving their organizations in the direc- tion of becoming learning health systems (as discussed in Chapter 2); • romoting clinician training in research (as discussed in Chapter 3); p • acilitating research projects, partly by creating incentives for clinicians to f e ngage in research (as discussed in Chapter 4) and by providing seed grants for health professionals to pursue their research interests; and • oining research collaboratives or networks on behalf of their organizations (as j discussed in Chapter 5). a This box is based on the presentation by Douglas Cropper, President and CEO, Genesis Health Systems.

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68 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE A Health Sciences Policy Perspective2 A high-performance clinical research system would produce and dis- seminate research results on a timely basis. Such a system would encompass more than clinical trials, which—although growing in importance and per- haps volume—will occupy only a portion of the clinical research universe. Box 6-3 lists some of the changes that could take place as the new high- performance clinical research system emerges. Today’s data-poor environ- ment would yield to one that is rich with data about virtually all patients and all health conditions, collected through repositories, registries, and net- works. The availability of these data would enable a continuous cycle of quality improvement. Participation would be a matter of course, instead of a matter of exception, and clinicians, too, would routinely engage in research. Data silos would disappear. The change could be global in scope. As part of this change, the CTE would begin to look like other twenty- first century areas of science, such as physics, where there is a European Organization for Nuclear Research, or CERN, which is now leading the search for the Standard Model Higgs boson (CERN, 2011; Vastag and Achenbach, 2011). This means the CTE would rely more on observational studies and predictive models and less on experiments that compare lim - ited, or even ineffective, uses of specific molecules. Such experimentation, after all, is more suited to a slow learning system than a rapid one. Although public and private payers are attempting to promote the use of research results and scientific evidence in clinical practice, today’s clinical effectiveness evidence base is too small, according to Etheredge. Large payers—Medicare especially—have the capacity to collect data on very large populations and use the data to steer clinical practice in more effective directions. To this end, Medicare has established the Partnership for Patients (a public–private venture to prevent unnecessary complica - tions of care, such as hospital-acquired infections), with an eye toward creating more demand by patients and providers for better evidence. This represents a strategy shift from “push” to “pull” in promoting change. To generate and use data on a far larger scale, and consistently, will require a new technology learning system, in which payers support a research plan for each clinical issue that arises, such as how and when to use a new drug or device. It also will require a new payment system, which bases reimbursement on adherence to evidence-based guidelines that result from research. Then, payers will be able to pay for care that has been shown to be safe and effective. Providers would compete on the basis of quality, determined through proven measures. 2 This subsection is based on a presentation by Lynn Etheredge, Independent Consultant on health care and social policy issues, and Head, Rapid Learning Project, The George Washington University.

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69 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE BOX 6-3a Aspects of a High-Performance Clinical Research System A clinical research system that generates, disseminates, and supports the use of scientific findings on a timely basis could have several distinguishing features or characteristics: • utcomes data would exist on the great bulk of patients and health conditions O and would be shared through data repositories, registries, and networks. • hese data would drive continuous quality improvement for health care pro- T viders generally. • eople and health professionals would routinely engage in the research process. P • he transformed clinical research system would even collect data from other T countries and could inform health care globally. • he clinical research system would be more predictive and observational and T less experimentally based. In this respect it would move closer to other fields of science. • ublic and private payers, especially Medicare, would use their patient care P databases to construct useful evidence about the effectiveness of treatments and other health care interventions. • new technology system would link a specific research plan to the rise of each A new health care product and modality, to ensure the development of timely findings to inform how and when the product or modality will be used. • new payment system would reward quality, based on adherence to A e vidence-based care. Providers would compete on quality. a This box is based on the presentation by Lynn Etheredge, Independent Consultant on health care and social policy issues, and Head, Rapid Learning Project, The George W ashington University. A Research Organization Perspective3 The capacity of the CTE, in terms of time, money, and patient partici- pation, is inadequate to efficiently conduct the number of trials that are currently initiated. By one analysis using ClinicalTrials.gov data, clinical trials today call for the enrollment of 1 in every 200 Americans as study participants (IOM, 2010a). In addition, it has been suggested many of the trials being conducted today are of low quality or provide a question - able contribution to advancing knowledge of medicine or health care. A number of workshop participants indicated an interest in systematically 3 This section is based on the presentation by Ronald Krall, Associate Fellow, University of Pennsylvania Center for Bioethics.

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70 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE studying the quality of clinical trials submitted to the ClinicalTrials.gov registry to validate or refute the impression of generally low quality clini- cal trials. Given the concerns with the capacity and quality of the CTE, the question was posed: Should the nation’s research portfolio be managed, or should it continue to evolve naturally? A managed approach would help ensure that clinical research, a scarce resource, is used efficiently, with the highest priority being assigned to the most important clinical questions. Under a managed approach, central managers or key decision makers could help ensure that trials meet high scientific standards, if this central authority had authority to deny funding for proposed studies of inferior quality. Management also could help ensure that research results are used systematically to improve care. How would management occur? Box 6-4 displays some alternative ways in which decisions in managing the CTE could be made. An NIH Perspective4 Involving a full range of stakeholders—patient advocacy organiza- tions, participants in trials, professional associations, regulatory agencies, and others—in strategic decision making, while time-consuming, is valu - able and appropriate. Box 6-5 contains reflections offered by Doroshow on the need for NIH to relate effectively to patient advocates. In pursuing change, NIH has achieved some key small successes, and small successes can create momentum for a deeper transformation. The NIH successes have included some achievements by the NCI, which, taken together, have had the effect of reorganizing the NCI clinical trial system.5 These achievements include • reducing the length of time for initiating clinical trials; • centralizing IRB review; • streamlining the process for gaining access to INDs and obtaining investigational device exemptions; 4 This section is based on the presentation by James Doroshow, Director, Division of Can - cer Treatment and Diagnosis, NCI, NIH. 5 Also of note is NCI’s Provocative Questions initiative, which provides an opportunity for investigators to propose intriguing questions in cancer research that need attention but would usually find it difficult to get. The initiative has drawn participation from investiga - tors from a wide range of scientific disciplines and career stages to develop well-conceived, yet provocative, scientific questions in cancer research. NCI has set aside $15 million from the 2012 budget to support new grants for the best ideas to answer the provocative questions that have been developed (Varmus and Harlow, 2012). For more information visit http:// provocativequestions.nci.nih.gov/ (accessed March 28, 2012).

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71 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE BOX 6-4a Possible Ways to Manage the Research Portfolio in the United States • y a formally convened panel of stakeholders that applies explicit standards, B based on a utilitarian criterion of the greatest benefit to the greatest number of people and (to a lesser extent) a cost criterion of the greatest potential savings; • hrough a market model, as health plans, IHSs, or people themselves decide T which studies to participate in, and only studies drawing enough support are conducted; or • n “shining the light” on individual decisions, by using social media to let people I vote their preferences among possible studies. These approaches are not mutually exclusive and could be combined as appro riate. For example, a narrow set of research questions of great importance p to population health could be determined by an expert committee, a market a pproach could be applied to remaining research questions, and a “shine the light” approach could overlay the entire research portfolio. a This box is based on the presentation by Ronald Krall, Associate Fellow, University of Pennsylvania Center for Bioethics. BOX 6-5a One NIH Official’s Reflections on Collaborating with Patient Advocates I have learned a great deal about advocacy and the role of advocates. And while it sometimes can be difficult to satisfy the needs of all of the advocates across all of the disease entities that are represented in the diseases that the NCI provides support for its clinical trials, it has really been remarkably important. Because advocates represent patients, and patients are not satisfied with the status quo. And they really have pushed, and they have pushed very hard, for us to do things differently, to do things more effectively, to do things much, much faster. And [they] have not allowed us to settle in. a This quote is from James Doroshow, Director, Division of Cancer Treatment and iagnosis, D NCI, NIH.

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72 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE • decentralizing the process for prioritizing research areas; • implementing a new trials data management system, with specifi- cations designed primarily by investigators; • certifying imaging sites and radiation therapy programs for quality control, so that results of studies conducted at different sites can be reliably compared; • enhancing core clinical laboratories, so that laboratory tests in dif- ferent trials will have the same platforms; • creating the NCI Clinical Investigator Team Leadership Award, to promote genomic research by providing small grants to younger researchers; and • reforming the NCI network, to support an increased level of grant support. An International Perspective6 Canada, like the United States, faces the twin problems of develop- ing a scientific evidence base for clinical care and constraining health care costs. Health expenditures account for 11 percent of Canada’s gross domestic product (compared with 18 percent in the United States) and the rate of increase in expenditures is considered unsustainable. In response, the Canadian Institutes of Health and Research has spearheaded an effort to promote the development, translation, and use of “patient-oriented research.” Box 6-6 shows components of the strategy underlying this effort. Key features of the strategy include citizen engagement and part- nerships with stakeholders (such as academic institutions and life science industries), comprehensiveness in addressing all types of obstacles to clinical research (such as biostatistics and infrastructure), and a focus on improving quality and containing costs. A national task force might be an effective vehicle for creating the organizational underpinning of CTE transformation in the United States, suggested Rouleau. Other suggestions included streamlining regulations, involving young scientists and clinicians in designing education and training initiatives, helping academic health and science centers develop research networks, integrating research data and EHRs through a new business model, promoting adaptive research designs such as cluster trials, sponsoring “research on research,” and participating in interna- tional collaborations. 6 This section is based on the presentation by Jean Rouleau, Scientific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health and Research.

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73 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE BOX 6-6a Components of the Canadian Strategy for Patient-Oriented Research • mprove the research environment and infrastructure, through research net- I works, beginning with primary care and mental health, and through provincially based support units on data management, project management, and other aspects of studies. • et up mechanisms to better train and mentor health professionals and non- S clinicians in health research, through career paths established by partnerships with organizations that fund relevant education and training programs. • trengthen organizational, regulatory, and financial support for multisite studies, S through provincial ethics review panels, a national template for contracts, national cost and operations standards, a simplified procedure for reporting adverse events, common databases, and common EHRs. • upport best practices in health care, through knowledge transfer to patients. S a This box is based on the presentation by Jean Rouleau, Scientific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health and Research. BUILDING A FRAMEWORK AND SUGGESTING AN AGENDA We need to pay for things that are safe and effective. We need to stop paying for things that are not safe and effective. —Lynn Etheredge, The George Washington University The workshop’s concluding discussion was oriented around six ques- tions presented to workshop participants: 1. Long-term goals: What are the long-term strategic goals that we need to identify and meet? 2. Priorities: What are the top three priorities for reform, based on their urgency, scope, and/or importance to the transformation effort? 3. Short-term goals: What are the top three to five opportunities that represent “low-hanging fruit” or are realistic short-term goals for improving the productivity and effectiveness of our CTE? 4. Workforce: What are key opportunities and strategies for develop- ing and leveraging a workforce to support the CTE? 5. Infrastructure: How can disease and patient advocacy networks, voluntary health associations, and other nongovernmental and

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74 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE nonprofit organizations contribute to or coordinate efforts to build an infrastructure for clinical trials? 6. Stakeholder engagement: How do we build an agenda through the following stakeholder groups: (a) health care delivery systems; (b) the pharmaceutical and biotech industries; (c) payers; (d) disease and patient advocacy networks, voluntary health associations, and other nongovernmental and nonprofit organizations; (e) the educa- tion and training enterprise, including academic health and science centers; and (f) regulators and federal agencies that fund or support research? Workshop chair Jeffrey Drazen, New England Journal of Medicine, led the discussion. The next subsection summarizes individual participants’ sugges- tions responding to questions 1-4. The subsection after that summarizes individual participants’ suggestions responding to questions 5 and 6. It should not be construed as reflecting consensus or endorsement by the workshop participants, the planning committee, the Forum, or the National Academies. Building an Agenda, Establishing a Framework What are the long-term strategic goals that we need to identify and meet? Among possible long-term goals mentioned by individual partici - pants were • moving research “into the community” by enlisting greater participa- tion by community practitioners, partly through leverage exerted by leaders of IHSs. Together with making research “business-critical” or “mission-critical”—making research an essential component of the work of IHSs and other large providers of care—a community focus could greatly help align the CTE and the health system; • greater regulatory harmonization and simplification, especially with regard to IRBs; and • routinely enrolling people newly diagnosed with key chronic diseases, such as diabetes, into clinical trials. The clinician plays a pivotal role in recruitment at the point of care and can partner with the patient to determine if participation in a clinical trial is in her or his best interest. Moving the CTE “into the community” and routinely enrolling newly diagnosed people into trials could improve the utility of research, increase

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75 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE BOX 6-7a Public Engagement in Clinical Trials Public engagement in clinical trials may include obtaining more public input into decisions about which topics to study and about the actual designs of tudies, s including clinical end points (that is, the measurable outcome that denotes a suc- cessful treatment). This could happen through several means, including a type of online voting or discussion, structured involvement by patient-oriented advocacy groups, and training of community health leaders. Public engagement also could be linked to formal public education. Patients and citizens may be most likely to engage in trials if they become aware that a great deal of new research is needed to ensure that people receive care that will help them. And, public education could have the best chance of creating an impact if it is undertaken through a formal strategy, rather than by relying on the news media and social media. a This box is based on remarks by John Gallin, Director, NIH Clinical Center; Janet Tobias, CEO, Ikana Health; Annetine Gelijns, Co-Chair, Department of Health Evidence and Policy, Mount Sinai School of Medicine; and Heather Snyder, Senior Associate Director for Scien- tific Grants, Alzheimer’s Association International Research Grant Program, and workshop discussions. participation rates, and enhance public support for clinical research in general.7 Box 6-7 describes some possible features of such public engage- ment. The specific suggestion of allowing the public to “vote with their feet” to choose which areas to study (see the description of the market model in Box 6-3) received support from some workshop participants as a way to root the research enterprise in communities, but it also was criticized as unrealistic, partly because most patients typically are not educated to evaluate trial designs and methods. What are the top three priorities for reform, based on their urgency, scope, and/or importance to the transformation effort? In pursuit of these goals, possible priorities mentioned by individual participants were 7 The NIH launched a new website, “NIH Clinical Research Trials and You,” with user- friendly information on what clinical trials are, why they matter, and how an individual can get involved (http://www.nih.gov/health/clinicaltrials/index.htm [accessed March 28, 2012]). The website also includes resources for health care providers, drawn from successful approaches used in pediatric oncology, to help them discuss with patients the possibility of enrolling in a clinical trial.

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76 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE • education of patients, health professionals (including the use of continuing education), and payers; • incentives for research, perhaps informed by research into how other industries have developed thriving and sustainable systems of research and development; and • adoption of the proposed revisions to the Common Rule.8 Education could include educating practitioners about clinical research and defining the attributes of a good, or at least internally valid, study. But education alone is not likely to suffice in bringing about reform. A theme mentioned several times during the workshop is that transforma- tion of the CTE requires a shifting of the incentives that payers impose on providers of care—namely, a shift away from procedures and volume and toward value, population health, and quality of care, as determined through scientific evidence. What are the top three to five opportunities that represent “low-hanging fruit” or are realistic short-term goals for improving the productivity and effectiveness of our CTE? Realistic short-term goals for CTE improvement identified by indi- vidual participants include • making the health IT systems of most providers of care interoperable; • simplifying the IRB process, through ways suggested in Box 6-8; • exempting low-risk research (e.g., quality improvement initiatives, research conducted by surveys) from the traditional regulatory and administrative burdens on research, such as the IRB process; • HHS development of “work plans” on specific research ques- tions, with time-limited, open competition for other researchers to develop better, cheaper, or faster ways to answer the same question; • standardizing the clinical trials nomenclature (harmonization of the concepts that are universal across clinical trials but have differ- ent names currently in use); • improvements in the ClinicalTrials.gov process, such as entering of more and better data by trial registrants9 or making website contents subject to editing or oversight; 8See Chapter 5, footnote 4, and surrounding text. 9Timely reporting of trial results on ClinicalTrials.gov has been found inadequate by one study. According to a study of 40,000 trials registered on the site between 1999 and 2010, only 12 percent reported results within the required 1 year of completion of the trial. Late reporting, say the study authors, “is troublesome and may affect the overall usefulness of the registry in expanding clinical knowledge in a timely manner.” The study further found

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77 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE BOX 6-8 Individual Workshop Participants’ Suggestions for Simplifying the IRB Process • entralizing IRB functions within IHSs and other large research organizations, C perhaps by creating “super IRBs”; • voiding overly long informed consent forms that discourage would-be A participants; • mproving consistency in how different IRBs interpret the standard questions I in the basic IRB application form; and • educing regulatory requirements for non-research-related uses of data, such R as quality improvement or reporting of medical errors. • engaging more health care system CEOs in clinical research, per- haps incorporating “clinical research” within the framework of “quality improvement” or “best practices” in order to demystify it; and • creating a national, publicly accessible roster of clinical researchers (similar to what has been done at NCI recently). These achievements were seen as “small wins” that could create momen- tum for change. What are key opportunities and strategies for developing and leveraging a workforce to support the CTE? According to several workshop participants, a key workforce-related strategy is the creation and maintenance of vibrant and continually ener- gized research networks. These networks could be organized around spe- cific diseases, other discrete health issues, or alliances of IHSs. Networks could provide ongoing credentialing or engagement of researchers, so that a new team—sometimes with less-skilled members—does not have to be recruited, trained, and approved for each new study. that the number of registered trials declined steadily after 2008 and, by January 2010, had fallen to the same level in place before the federal mandate to register all clinical trials took effect. Yet, no penalties for noncompliance with the mandate were issued as of February 2010 (Law et al., 2011). (The mandate was part of the 2007 FDA Amendments Act and applies to all Phase II and higher trials conducted in the United States or as part of the FDA’s IND application process.)

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78 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE Building an Agenda, by Stakeholder How can disease and patient advocacy networks, voluntary health associations, and other nongovernmental and nonprofit organizations contribute to or coordinate efforts to build an infrastructure for clinical trials? Ways to enhance the roles of advocacy groups, in the views of various individual participants, include • expanding public education about clinical research, so patients and families are better prepared to support research efforts; • promoting the Health Research Alliance, a consortium of organiza- tions supporting clinical research, as a site for “one-stop shopping” for research organizations seeking to collaborate with voluntary and advocacy associations; and • encouraging groups representing patients and families to use the CF community, the multiple myeloma community, and people with HIV/AIDS as some of the models for promoting a vigorous research agenda and obtaining a high level of participation in trials. Advocacy groups, an individual participant noted, are moving toward direct sponsorship of studies, forsaking their previous “hands- off” approach to research. Advocates tend to be supportive of the role of pharmaceutical, biotech, and medical device research and manufacturing firms, while occasionally criticizing academic health and science centers, private third-party payers, and authors of regulations, and so the latter entities could benefit from working to improve these relationships. How do we build an agenda through the following stakeholder groups: (a) health care delivery systems; (b) the pharmaceutical and biotech industries; (c) payers; (d) disease and patient advocacy networks, voluntary health associations, and other nongovernmental and nonprofit organizations; (e) the education and training enterprise, including academic health and science centers; and (f) regulators and federal agencies that fund or support research? Table 6-1 lists ideas presented by the panelists and workshop partici - pants. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the Forum or the National Academies, and they should not be construed as reflecting any group consensus.

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79 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CTE TABLE 6-1 Illustrative Strategies for Action by Stakeholder Groups Suggested by Individual Workshop Participants Stakeholder Possible Strategies to Advance CTE Transformation Suggested by Group Individual Workshop Participants Health care • uild research into quality improvement programs and strive B delivery for cultural change as a business opportunity; systems • nlist CEOs to lead local public education efforts; E • evelop research business plans, and adapt to a new business D model; and • se EHRs for research. U Pharmaceutical • educe outsourcing of studies (to ensure their applicability to R and biotech the U.S. population); firms • reate a standing research capacity with an IHS partner as a C demonstration project; and • se new research approaches, e.g., cluster randomization, U pragmatic trials, adaptive designs, and virtual trials. Public and • mplementation by CMS of research conclusions, especially in I private third- coverage with evidence development (CED); party payers • over study participants’ medical costs and community C practitioners’ research work; • se more value-based insurance design, incorporating scientific U evidence; and • ncrease involvement in research, such as by suggesting studies. I Advocacy • dvance public education of clinical research to engage the A networks and public as part of the CTE workforce; voluntary • evelop new and stronger consortia and research alliances; and D associations • ncrease involvement in research, such as by contributing to I study designs. Academic • atch new graduate researchers with projects that will generate M health and results, and assign them to mentors; science centers • oster research as part of health professions curricula; F and educators • uild five-tier system of workforce development (public, B community practitioners, implementers, investigators, methodologists), with demographic diversity; • romote elementary and secondary school education on P research; • nclude research questions on professional licensing and board I exams; and • se online training for research project staff. U continued

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80 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE TABLE 6-1 Continued Stakeholder Possible Strategies to Advance CTE Transformation Suggested by Group Individual Workshop Participants Regulators and • nhance collaboration in developing the learning health E federal agencies system among NIH, FDA, and other HHS components, with that support overarching attention by the HHS Secretary to clinical research; research • ake large databases accessible to researchers, with registries M online; • lace the organization of CER efforts under the purview of the P HHS Secretary; • evelop more public–private research partnerships; and D • elax principal investigator requirement, harmonize R regulations, show greater flexibility, and promulgate regulatory “safe harbors.” Illustrative actions that could be taken by all stakeholder groups include the following suggestions made during the course of the workshop: • strengthening the “four labs” of innovation, traditional, health care delivery, and community engagement; • agreeing on national leadership of the CTE; • establishing a national research agenda, to be reviewed and modi- fied every several years; • creating a central data repository, to merge treatment results from all providers; • merging research organizations’ information systems on compli- ance and preparing standard contracts, to reduce study costs; and • creating a standard international nomenclature, to make study results from different countries compatible. Moving, within one decade, from relatively few decisions being evidence-based to nearly all decisions being evidence-based—and being entered into a researchable database—will require traversing a great distance. Individual workshop participants variously mentioned at least five discrete steps that could be applied to each medical treatment or interven- tion: (1) Results of previous experience with the treatment or intervention could be obtained (through clinical trials or observational data) for suffi- cient numbers of patients in order to permit valid statistical analyses of the treatment’s efficacy or effectiveness; (2) demographic, disease, and biologic factors affecting the success of the treatment could be identified; (3) a pro- tocol could be developed for applying these research results to the care of individual patients; (4) the bulk of clinicians could use the protocol when appropriate; and (5) patients and families would understand the advantages of evidence-based care, participate in the studies necessary for medical advances, and join with clinicians in demanding clinical care that is based on medical evidence. The foundation of all these steps is the CTE.