8

The Health System’s Structure and Culture

BUILDING A SUPPORTIVE CLINICAL TRIALS ENVIRONMENT IN ACADEMIA1

Clinical trial organization is typically one-off. There is no guiding structure or organizational infrastructure. Everyone involved in a trial is brought together around the conduct of that single trial, then the group disbands. Little learning about “best trial practices” is carried forward, particularly in light of the high dropout rate among investigators.

Fundamental obstacles hindering the academic clinical trials enterprise in the United States, as cited by Eric Rose, Chair of the Department of Health Evidence and Policy, Mount Sinai School of Medicine, are cultural, economic, and ethical. These obstacles are responsible for

•   the slow pace of designing and implementing trials;

•   declining patient enrollment at trial sites;

•   loss of clinical investigators to other work; and

•   the failure to produce evidence for optimal clinical practice.

Evidence of our current difficulties is apparent in a range of data on trial experience. An estimated 20 percent of principal investigators fail to enroll a single patient, and another 30 percent under-enroll in a given trial. Moreover, the proportion of people randomized into a trial who complete

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1 This section is based on the presentation by Eric Rose, Chair of the Department of Health Evidence and Policy, Mount Sinai School of Medicine, and workshop discussions.



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8 The Health System’s Structure and Culture BUILDING A SUPPORTIVE CLINICAL TRIALS ENVIRONMENT IN ACADEMIA1 Clinical trial organization is typically one-off. There is no guiding structure or organizational infrastructure. Everyone involved in a trial is brought together around the conduct of that single trial, then the group disbands. Little learning about “best trial practices” is carried forward, particularly in light of the high dropout rate among investigators. Fundamental obstacles hindering the academic clinical trials enter- prise in the United States, as cited by Eric Rose, Chair of the Department of Health Evidence and Policy, Mount Sinai School of Medicine, are cul- tural, economic, and ethical. These obstacles are responsible for • t he slow pace of designing and implementing trials; • d eclining patient enrollment at trial sites; • l oss of clinical investigators to other work; and • t he failure to produce evidence for optimal clinical practice. Evidence of our current difficulties is apparent in a range of data on trial experience. An estimated 20 percent of principal investigators fail to enroll a single patient, and another 30 percent under-enroll in a given trial. Moreover, the proportion of people randomized into a trial who complete 1 This section is based on the presentation by Eric Rose, Chair of the Department of Health Evidence and Policy, Mount Sinai School of Medicine, and workshop discussions. 65

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66 PUBLIC ENGAGEMENT AND CLINICAL TRIALS it is declining—less than half, in 2003-2006. Finally, 38 percent of principal investigators who participated in clinical trials between 2000 and 2005 did not return to conduct another clinical trial within the next 3 years. Cultural Obstacles More than 90 percent of trial delays are caused by overambitious timelines and difficulties with patient enrollment. Timelines turn out to be too optimistic in large part because investigators encounter adminis - trative and institutional hurdles, such as protracted budget negotiations, slow IRB review and approval, and, as noted, poor patient recruitment. At BOX 8-1a Building Connections Between Community Physicians and Clinical Trials: Challenges and Potential Solutions Community physicians play a key role in the clinical trials enterprise. In discuss- ing the need to bring clinical trials to where the patients are, workshop participants noted that community physicians are important stakeholders and partners in con- ducting clinical trials. Community physicians can engage in a number of points across the lifecycle of a clinical trial—from the generation of research questions, service as the principal investigator, facilitating the recruitment and retention of patients, and community-focused dissemination of trial results. Panelists and work- shop participants discussed a number of challenges and potential solutions to facilitate the development of effective connections between community physicians and researchers conducting clinical trials in academic medicine. Challenges discussed at the workshop for community physician engage- ment in clinical trials: • Significant time constraints due to busy clinical practice and the concern that it will take the physician extra time to locate an appropriate clinical trial for a patient and explain the value of the trial to the patient. • Information overload (e.g., a physician receiving “100 emails per day” con- cerning clinical trials, but none of those coming from an entity or individual the physician knows or trusts). • Failure of communication with researchers throughout the lifecycle of the trial— including concern that physicians will be caught by surprise or will be unaware of treatments and side effects their patients experience as part of the trial. • General lack of physician knowledge as to the array of clinical trials available and how the trial might help their patients. • Heterogeneous patient mix and a diversity of patient medical needs that may or may not be solved or improved through care received in a clinical trial.

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67 THE HEALTH SYSTEM’S STRUCTURE AND CULTURE least some of these problems might be remediated with a stronger insti- tutional infrastructure that could support investigators as they navigate the approval process. Nor are there strong incentives for investigators to participate in research. Trial involvement earns little currency within the culture of academia when decisions about appointments and promotions are made. Finally, Rose noted that a minority of the physician population is actively engaged in recruiting and enrolling patients in clinical trials (see Box 8-1 for additional discussion of physician engagement in clinical tri - als). Encouraging participation is not part of their routine practice or their hospital departments’ priorities, quality plan, or metrics. The opportunity • Need for consideration of patients’ insurance coverage, or lack thereof, which could determine whether a clinical trial would make financial sense. Methods and potential solutions discussed at the workshop to improve com- munity physician engagement in clinical trials: • Prioritize timely, two-way communication among community physicians and researchers throughout the course of the trial. • Educate and assist the community physician in distilling information on cur- rently available clinical trials and the importance of particular trials for the physician’s patients. • Simplify and improve the clinical trials infrastructure so that patients can participate in a trial in their community (e.g., a cancer patient in Cincinnati can receive a novel agent as part of a clinical trial at his/her oncologist’s office, instead of driving to Indianapolis three weeks each month). • Partner with community physicians early in the development of a clinical trial to develop research questions that are of value to them and clinical trial protocols that can be implemented in the clinical practice setting without major difficulties. a Based on the panel discussion with Rafat Abonour, Chairman, Hoosier Oncology Group, Associate Dean for Clinical Research, Professor of Medicine, Professor of Pathology and Labo- ratory Medicine, Indiana University; Sanford Friedman, Associate Clinical Professor of Medicine of Cardiology, The Mount Sinai Hospital; Carol Horowitz, Associate Professor, Department of Health Evidence and Policy, Mount Sinai School of Medicine; Ramon Murphy, Clinical Professor of Pediatrics and Preventive Medicine, Vice-Chair of Department of Pediatrics, Voluntary Affairs, Associate Director, Mount Sinai Global Health Center, and Director, Off-Site Pediatric Residency Program at the Mount Sinai School of Medicine; and Hugh Sampson, Professor of Pediatrics and Immunology, Mount Sinai School of Medicine, Director of the Jaffe Food Allergy Institute, Dean for Translational Biomedical Research, and Principal Investigator and Director, Conduits, Institutes for Translational Sciences, Mount Sinai Medical Center. This box provides an integrated summary of each of their remarks and discussions with workshop participants during the panel, and should not be construed as reflecting consensus or endorsement by the planning committee, the Forum, or the National Academies.

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68 PUBLIC ENGAGEMENT AND CLINICAL TRIALS to enroll patients is neglected despite the apparent willingness of many Americans to participate in trials, if asked. Kenneth Davis, Mount Sinai School of Medicine, noted that metrics and criteria are needed for evalu - ating the performance of clinicians who engage in clinical trials during promotion and tenure discussions. People who design and conduct clini - cal trials should not be regarded as all the same; they may be on different tracks. They may be coming up with the new ideas and, therefore, are on a research track; or, they may be skilled at developing creative ways to implement trials and, therefore, are on a clinical educator track. However, a third group includes people doing clinical trials who are not developing the ideas, nor are they innovators with respect to developing new meth- ods, measures, biomarkers, and the like. In that case, they may not be on a tenure track in academic medicine, said Davis. Economic Obstacles Economic disincentives appear at every stage of trial design and implementation. Clinical departments, hospitals, medical schools, and academic medical centers have little or no budget to support trial infrastructures. However, the CTSAs are one unique example of a clinical research mechanism that supports and funds the development of trial infrastructures. Enrollment payments are typically given to physicians after patient enrollment. But the capital to support trial infrastructure needs to be in place prior to enrollment. Patients randomized to control groups that do not receive a billable procedure generate less clinical revenue for physi - cians and hospitals than if those patients were not in the trial and received the procedure, thus creating enormous resistance to using control groups. Finally, Rose said, specialists frequently perceive randomization of patients referred to them by physicians for a treatment as a threat to their referral relationships and their standing in that community. Ethical Obstacles Among the ethical obstacles a researcher must overcome are those involving perception and misperception; for example, the perception that trial participants are being treated as guinea pigs or that randomization is a threat to the physician’s unfettered exercise of clinical judgment. A more tangible worry may be a concern or perception that the investigators or clinical community lack equipoise with regard to the trial hypothesis. An underlying dilemma is that most trials are designed to help bring a product to market, Rose said, not to identify the best options for patients. The latter issue reemerged in the panel discussion, led by the state -

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69 THE HEALTH SYSTEM’S STRUCTURE AND CULTURE ment that not all clinical studies are equal. “Do we really need another study of the tenth variation on the same theme, or another lookalike drug?” a panelist asked. Potential Solutions The key cultural change, Rose believes, has to be to reenvision qual- ity measurement. Current metrics for determining quality in medical care are substantially poorer than those in other high-risk industries where quality is measured, monitored, and improved more rigorously. Quality metrics that would make sense in health care involve patient character- ization, phenotype definition, process definition and monitoring, and outcomes. Processes and outcomes should be benchmarked against peers and against past performance, and they should be iterative, not static. The competencies required to assess patient care quality in this way go well behind those that have traditionally defined the “good doctor.” Some such competencies identified by the Accreditation Council for Graduate Medical Education are system-based practice, practice-based learning, communications skills, and professionalism (ACGME, 2007). Reinforcing the “learning organization” goal articulated in an earlier ses - sion, Rose said that “medical quality measurement is essentially a broad array of ongoing observational clinical trials,” and he further argued that an academic medical center that is not managing quality, using the tools and skills integral to observational trials is, by definition, not a high- quality institution. Enrolling patients in clinical trials is typically not used to measure individual academicians’ divisional, departmental, or institutional perfor- mance. In the past 5 years, the percentage of patients enrolled in clinical trials was made a performance metric for clinicians in Columbia Univer- sity Medical Center’s department of surgery. Chiefs of divisions that were not enrolling at least 10 percent of their patients in clinical trials were considered to be underperforming. Performance metrics like this will create a culture vastly more supportive of clinical trials. PUBLIC-PRIVATE PARTNERSHIPS IN CANCER TRIALS2 Cancer is not a monolith but has been revealed as thousands of different genetically distinct and molecularly driven diseases. New technology that over the past few years has permitted researchers and 2 This section is based on the presentation by George D. Demetri, Senior Vice President for Experimental Therapeutics, Dana-Farber Cancer Institute and Director, Ludwig Center at Dana-Farber/Harvard Cancer Center, and workshop discussions.

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70 PUBLIC ENGAGEMENT AND CLINICAL TRIALS pathologists to examine tissue at the chromosomal level has revealed significant differences among cancers once thought to be single entities. Without the ability to differentiate cancer types and treat them with spe - cific therapies, treatment has taken place in one of those “evidence-free zones,” said George D. Demetri, Senior Vice President for Experimental Therapeutics, Dana-Farber Cancer Institute and Director, Ludwig Center at Dana-Farber/Harvard Cancer Center. Understanding the differences among cancer types leads to the ques - tion: How do we personalize therapy and guide patients into the right trial at the right time for the specific cancer they have? According to Demetri, patients’ interest in personalized approaches is rekindling their interest in clinical studies. However, referrals are slowed because many clinicians have come to believe that their patients will not be eligible for a trial until none of the existing treatments work for them. The result is that patients referred to trials can be among the most difficult to treat, making it increasingly difficult to achieve the next advance. Demetri described several research projects that have taken advantage of new insights about the unique genetic characteristics of specific can- cers involving sarcomas. Two similar but rare sarcomas (gastrointestinal stromal tumors [GISTs] and leiomyosarcoma) are cancers of the smooth muscle cells that had previously been undistinguishable but are now rec- ognized as separate diseases. Laboratory scientists studying mutant cells in the gut found a causative target for GISTs, and further research showed that, if an abnormal enzyme is shut down, the GIST cells die. Previously, there was little to offer these patients, but the treatment developed from these observations works perfectly, according to Demetri. To recruit patients for an early study of this drug, the researchers designed a website that would appear in response to Google searches for either GIST or leiomyosarcoma, since the chance for conflating the two was so high. This helped the team educate both patients and clinicians to reexamine previous diagnoses of these cancers. The study of rare cancers poses several patient recruitment problems. Because the number of cases is so small, one strategy is to recruit patients across multiple centers, either in the United States or through collabo - ration with researchers in other countries. Recruitment (and operation of an international study) is costly, and, he said, the National Cancer Institute has requirements for regulatory review of multicenter interna - tional trials that preclude application by a single U.S. cancer investigator. Demetri reported that in multiple instances, drug sponsors have helped to overcome obstacles related to managing and implementing a trial. For example:

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71 THE HEALTH SYSTEM’S STRUCTURE AND CULTURE • trial originally being conducted in two centers was able to A expand to 365 centers across the world once the drug sponsor, Pfizer, contributed to its management. • or another trial, Demetri wrote the phase III application and is the F principal investigator, but Bayer Oncology is handling implemen- tation in several hundred sites around the world. In the latter case, Bayer Oncology had supported earlier phases and was willing to participate in the phase III trial because it believed that if the company did the work on its own it would require “an extra seven years and $50 million,” Demetri said. Although sarcomas collectively account for only 1 percent of human cancer cases, the knowledge gained through identification of successful molecularly targeted therapies appears applicable to other kinds of can - cers and has shown the real value of public-private collaboration. Underscoring this point, Gail Cassell, Department of Social and Global Medicine, Harvard Medical School, noted that other countries “have figured out why the United States has been so successful in bio - medical research, and it is the collaboration between the public and pri- vate sectors.” Moreover, Cassell pointed to a survey that indicates that Americans strongly support cross-sector and cross-institutional collabora- tion (Research!America, 2010). ENGAGING COMMUNITY PHYSICIANS IN RHEUMATOID ARTHRITIS RESEARCH3 The Rheumatoid Arthritis Investigational Network (RAIN) began in 1989, in part due to perceived problems with rheumatoid arthritis drug trials sponsored by industry, specifically: • atient groups studied were not representative of or generalizable P to the whole population • ctive therapies were not compared to each other A • lacebos were used liberally P • atients and their clinicians often did not know which arm patients P were assigned to, even long after trial completion • nvestigators were believed to have severe conflicts of interest I • here was a bias toward publication of only those trials that have T a positive (statistically significant) result 3 This section is based on the presentation by James O’Dell, Rheumatoid Arthritis Inves - tigational Network (RAIN), Larsen Professor, Vice Chair Internal Medicine, Chief of Rheu - matology, University of Nebraska.

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72 PUBLIC ENGAGEMENT AND CLINICAL TRIALS • he trials had an underlying objective of maximizing the effects of T the sponsor’s product, not producing maximum benefit to patients RAIN is housed at the University of Nebraska and involves some 40 practicing rheumatologists from six states—mostly in the Midwest. It specializes in investigator-initiated trials that are conducted in the offices of physicians in private practice. The university provides both infrastruc - ture and trial experience so that the private clinicians are not burdened with responsibilities for trial startup. For example, about half of them do not have their own IRBs, in which case they become offsite investigators of the university; for the remainder, the university IRB coordinates with the physician’s IRB. As a trial proceeds, communication and interaction with physicians, trial study coordinators in different sites, and the nurses involved are scrupulously maintained, said James O’Dell, RAIN, Larsen Professor, Vice Chair Internal Medicine, Chief of Rheumatology, Univer- sity of Nebraska. The first RAIN trial, results of which were published in the New Eng- land Journal of Medicine, took 7 years to reach publication (O’Dell et al., 1996) but has been credited with popularizing combination therapies for rheumatoid arthritis. (RAIN also was the first to publish information on genetic associations with treatment responses.) From the beginning, RAIN projects have been designed to relate to how clinicians actually take care of patients. To accomplish this, the organizers meet with RAIN clinicians (and patients) and together decide the questions the trial will attempt to answer and details of the research protocol. Examples of questions of direct relevance to practicing clinicians that O’Dell cited are: • ow much improvement has the patient experienced, regardless H of starting point? • an we predict, based on studies of first-degree relatives of C patients, who will develop rheumatoid arthritis in the next 2 to 5 years? In RAIN’s first trial, the protocol design responded to clinicians’ con - cerns that their patients not be kept on a therapy that did not work for them. As a consequence, the protocol specified that if patients were not having good results, the team would increase medication dosages, and if they still did not experience at least a 50 percent improvement, they would come out of the trial after a year. RAIN also participated in a collaborative trial called TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) out of recognition that, even with approximately 40 physicians in its network, running a clinical trial

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73 THE HEALTH SYSTEM’S STRUCTURE AND CULTURE is so complicated that it must work with other teams. As a result, O’Dell said, RAIN has engaged in a number of research consortia and collabora- tions with academic institutions and VA. In several of these trials, RAIN was the primary enroller of patients, indicating the participating physi - cians’ ongoing commitment to the network. When RAIN physicians enroll a certain number of patients they are named as authors in trial-related publications. During the workshop discussion period, a participant suggested that, as the United States moves toward accountable care organizations, all of the incentives will be against physicians taking the time necessary to adequately inform patients about research projects. That difficulty may be counterbalanced in the future if it becomes feasible to collect study data directly from EHRs. O’Dell attributes RAIN’s success to having recruited the right inves- tigators. By involving these clinicians from the start of its studies, they have shared ownership of protocols, trial implementation, and results. Because they understand why the trial was designed as it was, they are more effective at keeping their patients involved. Finally, they are much more likely to have confidence in and adopt the therapeutic approaches the trials show to be more effective, because, in many cases, this greater effectiveness has been demonstrated in their own patients.

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