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Building Research Programs in Diagnostic Radiology

Part III. Clinical and Translational Research¹

¹ From the Department of Radiology, Massachusetts General Hospital, MZ-FND 216, Box 9657, 14 Fruit St, Boston, MA 02114. Received December 18, 2006; final version accepted January 1, 2007. Address correspondence to the author (e-mail: thrall.james{at}mgh.harvard.edu).

The ultimate goal of medical research is the discovery and implementation of new and better ways of delivering care to patients. The realization of this goal begins with a discovery or an invention at the laboratory bench or with the formulation of a new clinical application. The new method—drug, device, or treatment protocol—must be tested through clinical research—clinical trials in human subjects to establish safety and efficacy. Knowledge derived through clinical research then serves as the evidence base for the development of new "best practices." Finally, the new methods must be integrated into the clinical care delivery system, including the education of providers.

	WHY CLINICAL RESEARCH IS IMPORTANT TO RADIOLOGY

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
During the past 3 decades, remarkable breakthroughs in basic imaging technology and associated clinical applications have found their way into clinical practice and have propelled radiology forward. These new methods have collectively transformed radiology from a medical ancillary into a key player occupying a central position astride the critical pathway for diagnosis and management of innumerable diseases and conditions—the efficiency and quality of contemporary acute care hospitals are determined in substantial part on how well imaging services are provided.

While the blistering pace of development in medical imaging has elevated the specialty of radiology and has had many very positive effects on improving patient care, the potential to clinically implement new imaging methods in the future will hinge increasingly on successful accomplishment of clinical research on a scale and with a level of rigor not seen in the past; payers are requiring more evidence of cost-effectiveness before agreeing to reimburse for new imaging applications. A major part of the reason for the increased scrutiny is the simple observation that the number and diversity of new imaging methods are outstripping the ability of the health care system to readily assimilate their costs, which have been increasing more rapidly than overall health care costs during the past 20 years. Between 1999 and 2002 alone, Medicare payments (1) for imaging services grew 45% compared with an average of 22% for all other services.

Reimbursement for new clinical applications of imaging depends on the quality of evidence gathered in clinical trials. Computed tomographic (CT) angiography of the coronary arteries and colon cancer screening with CT colonography are examples of new applications that are extraordinarily promising, but the lack of solid data from large prospective multicenter clinical trials has resulted in deferred reimbursement decisions from many payers. Both of these applications have the potential to substantially change the care process in a positive way for millions of patients but only if clinical trial data support the efficacy of the applications and if reimbursement is forthcoming.

Reimbursement decisions for a number of other imaging procedures such as magnetic resonance (MR) spectroscopy of brain tumors and MR imaging of the breast have suffered reversal from payers, including the Centers for Medicare and Medicaid Services (CMS), on the basis that there is insufficient evidence to warrant payment. The CMS transmittal (2) affirming noncoverage for MR spectroscopy simply states: "Upon reconsideration of existing noncoverage policy, CMS determines that magnetic resonance spectroscopy used as a diagnostic tool for distinguishing indeterminate brain lesions and/or as an aid in conducting brain biopsies is not reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act." In other words, there is not enough evidence of value to support coverage. Reimbursement for positron emission tomographic procedures was held up for many years by CMS because of generally spotty clinical trial data, and there is still a highly variable payment policy among other payers, probably for the same reason.

The largest single blow ever experienced to reimbursement for imaging procedures is contained in the Deficit Reduction Act (DRA) (3) passed by the Congress of the United States in 2005. The act seeks a 5-year reduction of $2.8 billion in payments for imaging services beginning in 2007. While this act is not directly related to the cost-effectiveness of any single imaging procedure, the rapid growth in the overall expense of imaging services has obviously come to the attention of policymakers and lawmakers whose solution in the DRA is to simply cut reimbursement per unit of service rather than critically looking at appropriateness of utilization or the efficacy and cost-effectiveness of specific imaging applications.

Given the financial burdens facing the health care system in the United States, there is no guarantee that better clinical research data demonstrating the efficacy and cost-effectiveness of new imaging methods will garner approval for reimbursement, but the opposite is undoubtedly true—incomplete or poorly performed clinical research will doom even the most promising new applications. Simply stated, the constrained economics of the health care system have resulted in a raising of the bar for the quality and quantity of evidence required to justify expenses associated with any new service, including imaging.

	TRANSLATIONAL RESEARCH

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
The term translational research is widely used (4,5) to reference the sequence of clinical research events necessary to move new knowledge in the basic sciences into beneficial clinical use. Sung et al (4) capture this paradigm in their statement: "Translating the information gained through these basic discoveries into knowledge that will affect clinical practice and, ultimately, human health requires clinical research involving human subjects and human populations, as well as development of improved health services based on that research." In this construct, the first translational step is from basic science discoveries to human studies—"first-in-man" or "bench-to-bedside" translation and associated clinical trials—and the second major translational step is to move accumulated clinical knowledge into widespread clinical practice and health decision making, which results in improved health of the population. These two major translational steps each present numerous challenges that can block the orderly passage of a new method from discovery to beneficial clinical use. Sung et al and others (4,5) use the terms first translational block and second translational block as shorthand to collectively reference the hurdles and challenges posed by these major steps.

Apart from the special issues related to the first and second translational blocks, Sung et al identify four overarching challenges to translational and clinical research: (a) the need for more public participation in clinical research—including volunteers for clinical trials, (b) the need for better information systems, (c) the need for an adequately trained workforce to perform clinical research, and (d) the need for better funding from both the federal government and private industry. All of these apply to clinical and translational research involving imaging methods.

	FIRST TRANSLATIONAL BLOCK: SPECIAL ISSUES FOR RADIOLOGY

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
Although all new methods go through the same series of translational steps at an abstract level, the details are highly different between categories of technology, including the nature of the hurdles to be overcome and the sources of funding to support clinical research. For pharmaceutical products, a commercial company typically undertakes financial and management responsibility for the entire process from start to finish: from discovery activities at the laboratory bench through the multiple phases of clinical trials to obtain approval from the Food and Drug Administration (FDA) to sell the drug for certain indications and then also funding the promotion of the drug to achieve its maximum clinical use. The pharmaceutical company chooses the clinical indications for which it intends to seek approval from the FDA and designs the associated clinical trials. The company undertakes the promotion of new best practices related to the use of its drug and typically funds educational programs for providers on the correct use of the drug.

The sequence for imaging methods is quite different because the approval for companies to sell equipment is typically not linked to specific clinical applications except in special situations. For CT, conventional and digital radiography, MR imaging, ultrasonography, and angiography, the equipment is typically used for dozens or even hundreds of different purposes. The goal of imaging device companies is to obtain generic approval to sell their equipment and not to undertake clinical trials to obtain specific indications for use.

Once the overall safety of a modality has been accepted, and assuming new generations of the equipment can be used for existing approved applications, there are no major barriers to FDA approval to sell the new equipment. Companies can use a principle of "substantial equivalency" (6) under which they claim that their new device is generally the same as others on the market, including previous generations of the same modality, and thereby avoid clinical trials altogether.

Compared with obtaining approval for a new drug, the approval process for imaging devices is far simpler, less expensive, and less time-consuming. While the simpler approval process when compared with that of drugs has helped move new imaging technologies such as multidetector CT scanners rapidly into clinical practice, it has also left an important gap because third-party payers are now demanding rigorous scientific evidence that specific applications, such as CT angiography of the coronary arteries or CT colonography, are efficacious and deserve reimbursement.

Commercial imaging device companies have not faced the need to support large-scale clinical trials in the past and, unlike the pharmaceutical industry, there is no proprietary advantage for any one company to obtain the data to support claims for specific advanced clinical applications. This is because the technical distinctions in the devices offered by one company versus the next are generally not substantive at an applications level. There is nothing available to protect investments in trials of clinical applications of imaging methods equivalent to the patent protection associated with new drugs that protect a given company's investment in its clinical research. Any company selling similar equipment to that used in the trial of an imaging application stands to benefit without investment; so, no one invests.

The implications of the unique dynamics faced by the imaging community in the first translational block have not been widely recognized or articulated but need to be addressed if new clinical applications are going to be studied sufficiently to gain support for reimbursement. The imaging community needs to collectively awaken to the increased expectations for better, more complete clinical research data and needs to further understand the nature and magnitude of the funding gap for clinical trials of new imaging applications. The affected stakeholders include industry and imaging providers but also include the public because the potential value offered by the use of new imaging applications for many diseases and conditions will not be available to patients without reimbursement.

The imaging program of the National Cancer Institute (NCI) (7) has been a bright spot in this story. Through its activities, including support of the American College of Radiology Imaging Network (ACRIN), substantial funding has been made available for clinical trials related to cancer-directed imaging applications. The protocol summary (8) on the ACRIN Web site lists 24 current trials, including major efforts aimed at CT colonography for colon cancer screening and image-based screening for lung cancer. The recently completed ACRIN trial supported by the NCI, entitled "Digital Mammographic Imaging Screening Trial" (DMIST), (9) that compared conventional with digital mammography for breast cancer screening was a landmark trial with enrollment of 49 500 women. Results of the DMIST demonstrated the superiority of digital imaging over analog imaging in some categories of patients.

Results of the DMIST illustrate the conundrum of clinical trial results benefiting any corporation selling the kind of equipment used in the trial. If the DMIST had been supported by a single corporation, all other companies selling FDA-approved digital breast imaging systems would still have benefited through the principle of substantial equivalence, thereby taking away any proprietary advantage. It seems apparent that without proprietary advantage individual commercial companies will not invest in large clinical trials unilaterally, which leaves the question of how stakeholders can work and invest together to everyone's benefit.

At present, ACRIN is the only permanent, large-scale organization devoted to prospective, randomized, multicenter clinical trials in diagnostic imaging. Because the establishment of ACRIN through a grant from the NCI was specifically aimed at cancer-related trials, there has not been an opportunity to address other areas, such as cardiovascular disease or musculoskeletal disease, through ACRIN. The leadership of ACRIN is addressing this shortcoming through new initiatives with industry and through new sources of financial support.

	RADIOLOGY AND THE SECOND TRANSLATIONAL BLOCK

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
The second translational block occurs when clinical evidence is in hand but not in a form that is useful to the practicing community. Results of individual clinical trials per se do not provide information about the practical use of new methods or their formulation into practice guidelines. These steps often require a meta-analysis of multiple research efforts, the formulation of new clinical protocols that incorporate the new methods, and the education of the provider community about new best practices so that they can incorporate them into their own systems of care. Applications to third-party payers for reimbursement require these same kinds of analyses and the organization of the clinical research evidence base into information sets suitable for evaluation—conversion of data into knowledge.

By using the drug industry again as a counterpoint to imaging, when the second translational block is reached with a new therapeutic pharmaceutical product, the company with ownership interest in the drug also undertakes the work necessary to address the translational issues. Clinical investigators are supported financially to continue doing research and to publish data about the new drug. Companies organize these data and press their case with the payer community. So-called phase IV studies are sponsored to extend indications and garner more publicity for the drug. Companies hire sales people and detail people to call on physicians to encourage them to use the new drug, and companies sponsor continuing education events to teach physicians about the new drug. Detailing has been done on a massive scale by the pharmaceutical industry, including direct-to-consumer advertising.

Activities aimed at addressing the issues associated with the second translational block are done with much less corporate involvement in the imaging arena, which leaves more of the effort to the academic community and to professional societies. Some imaging device companies run "halo" advertisements that tout their imaging equipment in a general way, but no company in the imaging industry undertakes the activities necessary to get through the second translational block for specific clinical applications that are routinely undertaken by pharmaceutical companies. It is also left largely to professional societies in imaging to do battle with the payer community about reimbursement for new clinical applications of imaging methods. The same is true for physician education because the imaging device industry tends not to approach referring physicians in any major way to encourage the adoption of new clinical applications. While this relative lack of engagement by industry has left more of the burden to others, it can also be argued that the imaging device industry has not been beset with the issues of impropriety seen in the promotional activities of the drug industry.

	DEPARTMENTAL STRATEGIES

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
The active participation of departments of radiology in clinical research is vital to the gathering of the evidence base needed to test the safety of new methods and establish their efficacy and cost-effectiveness. There is no other pathway. To this end, there are a number of initiatives that departments can undertake to strengthen and expand their capabilities. Departmental leaders can start the process by helping foster a culture that supports and values research participation by their faculty members and by working within their institutions to build the infrastructure necessary to facilitate the execution of clinical trials. Important support elements for investigators include access to personnel with training in clinical trials management, help with biostatistics and trial design experts, access to computer databases, help with budgeting and accounting, and establishment of an organized system to access departmental equipment for use in clinical trials on a per-use charge-back basis. Done properly, clinical trials should pay for themselves and the infrastructure supporting them. Departments of radiology need to accurately determine their costs and work with trial sponsors to recover them.

Departmental and hospital information systems are vital to clinical trial activities as the source of patient data and a repository for trial generated information. However, most radiology information systems (RIS) and picture archiving and communication systems (PACS) were not designed with clinical trials in mind, and departments of radiology should consider adding features such as data mining tools or search engines to them. At Massachusetts General Hospital (MGH), we have had a search engine available for the RIS database for many years that allows investigators to perform free text Boolean queries of our online archive of radiology reports—now 19 years worth. Although most helpful for retrospective investigations, this program allows investigators to gain a sense of how commonly certain diagnoses have been encountered over time as a measure of prospective trial feasibility. This capability has recently been augmented by using a novel data mining program, LEXIMER (Lexicon Mediated Entropy Reduction) (10), that uses a rules-based natural language processing system to determine the yield from an examination as expressed in unstructured radiology reports. Another useful adjunct for clinical research is a system that tracks every case downloaded from the MGH PACS into a teaching file or other database, such as working files prepared for teaching or clinical conferences. By keeping track of downloaded cases systematically since the inception of the PACS, we now have a unique, highly distilled set of interesting cases that can be searched rapidly for research or teaching purposes.

One of the most important initiatives a department can undertake is the training of its faculty in clinical trials methodology. The Radiological Society of North America (RSNA) has multiple programs (11) designed to help new investigators, including its grantsmanship workshops and a newly established course for training people specifically in how to design and perform clinical trials. ACRIN offers fellowships aimed at providing in depth exposure to clinical trials. The American Roentgen Ray Society, the Association of University Radiologists, and the RSNA all offer grants or fellowships designed to support young investigators, and a number of subspecialty societies offer grant support for clinical research activities. Department leaders should become familiar with these sources of mentoring, training, and start-up funding and recruit their interested faculty members to apply. Senior mentors within the department can help with ideas and in the development of proposals. Many institutions offer training in clinical research methods, and radiology faculty should avail themselves of this avenue for learning.

The ACRIN program offers new investigators the chance to take part in clinical trials and gain insight before taking on the primary responsibility as principal investigator themselves. This is a valuable experience, and participation in ACRIN trials should be encouraged. Individual investigators can propose protocols to ACRIN and have the opportunity to serve as the principal investigator. Departments should consider having an "ACRIN strategy."

Radiology department leaders should assess the overall clinical trial landscape in their respective institutions. For example, many trials of therapeutic drugs now involve imaging biomarkers or image-based surrogate endpoints as the arbiters of drug performance. Too often radiologists are left out of the design phase for these trials and are then confronted with suboptimal use of imaging—wrong examination, wrong protocol, inappropriate timing. Radiologists should work institutionally to engage their colleagues to take part in these trials from their beginnings in order to optimize them and to receive academic recognition as coauthors of resulting publications.

	CONCLUSIONS

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 
Clinical research is a sine qua non for medical progress. New methods must undergo clinical testing to establish their safety and to establish whether they merit incorporation into the care process. This fundamental translational paradigm encompasses all medical specialties and all new methods.

Translational research is especially challenging in imaging because of the wealth of new methods that must be tested and the relative lack of industry funding for clinical imaging trials compared with other new technologies. The clinical imaging community must recognize this and work with industry, granting and funding agencies, and organizations like ACRIN to develop the capabilities needed to turn new knowledge into new ways of delivering better care to patients.

Academic departments of radiology are the heart of translational and clinical research activities. If they perform at a high level, the specialty will continue to flourish. If their efforts are weak, new clinical applications will languish with promises for better care unmet.

High-quality clinical research is vital to the future of radiology, and it is worth the participation of all radiologists, including those in both academic and private practice, to support clinical research and the organizations and individuals engaged in its performance.

	FOOTNOTES

 
Author stated no financial relationship to disclose.

	References

TOP INTRODUCTION WHY CLINICAL RESEARCH IS... TRANSLATIONAL RESEARCH FIRST TRANSLATIONAL BLOCK:... RADIOLOGY AND THE SECOND... DEPARTMENTAL STRATEGIES CONCLUSIONS References

 

1. MedPAC recommendations on imaging services. MedPAC Web site. http://www.medpac.gov/publications/index.cfm?section=publications. Accessed December 9, 2006.
2. Centers for Medicare and Medicaid Services 2004 Transmittals. Magnetic resonance for diagnosing brain tumors transmittal 3425. U.S. Department of Health and Human Services Web site. http://www.cms.hhs.gov/Transmittals/2004Trans/list.asp?sortRyDID=4&filterType=none&filter. Accessed December 12, 2006.
3. S. 1932, deficit reduction act of 2005. Congressional Budget Office Web site. http://www.cbo.gov/showdoc.cfm?index=7028&sequence=0. Accessed December 17, 2006.
4. Sung NS, Crowley WF, Genel M, et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278–1287.[Abstract/Free Full Text]
5. Crowley WF, Sherwood L, Salber P, et al. Clinical research in the United States at a crossroads: proposal for a novel public-private partnership to establish a national clinical research enterprise. JAMA 2004;291:1120–1126.[Abstract/Free Full Text]
6. Use of standards in substantial equivalence determinations. U.S. Food and Drug Administration Web site. http://www.fda.gov/cdrh/guidance/1131.html. Accessed December 17, 2006.
7. American College of Radiology Imaging Network. National Cancer Institute Web site. http://www.imaging.cancer.gov/clinicaltrials/acrin/. Accessed August 6, 2006.
8. Current protocols. American College of Radiology Imaging Network Web site. http://www.acrin.org/current-protocols.html. Accessed December 17, 2006.
9. Digital mammographic imaging screening trial. National Cancer Institute Web site. http://www.cancer.gov/dmist. Accessed December 17, 2006.
10. Dreyer KJ, Kalra MK, Maher MM, et al. Application of recently developed computer algorithm for automatic classification of unstructured radiology reports: validation study. Radiology 2005;234:323–329.[Abstract/Free Full Text]
11. RSNA department of research: educational courses. RSNA Web site. http://www.rsna.org/Research/educational_courses.cfm. Accessed May 29, 2006.

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