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1 From the Department of Radiology, University of Virginia, PO Box 800170, Charlottesville, VA 22908 (B.J.H.) and the Department of Radiology, Western Pennsylvania Health System, Pittsburgh (H.L.N.). Participants in the colloquium are listed at the end of this article. Received September 19, 2001; accepted September 20.
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Index terms: Education • Molecular analysis • Radiology and radiologists, research • Radiology and radiologists, socioeconomic issues • Special Reports
| INTRODUCTION |
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Radiologists have been involved in molecular imaging for some time—most notably in their use of such nuclear medicine techniques as the application of iodine 131 to search for recurrent thyroid cancer. However, with the maturation of the field of genomics, including the initial sequencing of the human genome, it is evident that medicine is entering a new era of molecular medicine for which molecular imaging will play a critical role. As researchers develop new chemicals and biologic agents that will act at the molecular level, molecular imaging will (a) be the noninvasive biopsy used to screen for or detect disease at preclinical stages, (b) help stage disease to assess what might be the most appropriate therapy, (c) help guide treatment, and (d) help assess its efficacy. Over time, the expectation is that much of what is today’s imaging will shift toward new imaging techniques that have their foundations in molecular medicine.
Radiologists and other physicians may be only broadly aware of this coming revolution in imaging diagnosis and treatment. Although there have been numerous review articles in the recent radiology literature (1–4) in which molecular imaging has been addressed, many radiologists have found these difficult to approach, given their emphasis on biochemistry and molecular pathways, and may have failed to grasp their relevance to clinical practices. Indeed, much of the information on which molecular imaging is based is recent enough that it was not available to the majority of radiologists during their formal medical education. As such, many radiologists may view learning the principles of molecular imaging as a formidable enough obstacle that it will hinder adoption of molecular imaging into their practices.
Recognizing that there are elements of molecular imaging that differ from what radiologists have encountered in the past and realizing the importance of molecular imaging to radiologic practice in the future, the American College of Radiology (ACR) invited a group of radiologists to attend a 2-day colloquium on this topic in April 2001. The group constituted acknowledged experts on molecular imaging, the economics and politics of medical practice, and the diffusion of technology, as well as organizational leaders responsible for training and reimbursement in the specialty. Prior to the group’s meeting, the ACR commissioned summary papers on the following topics: (a) the science of molecular imaging, (b) factors influencing the diffusion of new imaging technologies into practice, (c) the impact of turf and competition, (d) training requirements and board certification, and (e) centers involved in molecular imaging training and research. These articles, which would be the basis for individual sessions, were sent to all participants 3 weeks prior to the colloquium. Participants also received a series of questions based on each article that would guide initial discussion at the colloquium.
Each of the five sessions began with a presentation by an author of one of the summary papers. After the presentation, the moderators initially encouraged broad-ranging discussion of the topic based on the previously prepared questions; however, they then encouraged deviation from the "script" to ensure the broadest range of discussion possible. Finally, the group focused their colloquy on specific critical issues and made recommendations to the ACR about what it could do to facilitate the translation of molecular imaging from its current stage of animal research and nascent human investigation into clinical practice.
The purpose of this white paper is to express the richness of the colloquium while organizing the proceedings in a manner that will be approachable to individuals involved in radiologic practice, molecular imaging research, health policy and economics, and regulation and reimbursement, as well as to the general public. By so doing, the authors hope to engage a broad array of interested individuals in the development of this field, to the greater societal benefit.
The remainder of this report is ordered into five sections, four of which represent the topics undertaken by the colloquium. For each of these sections, we will provide a brief overview to orient the reader followed by a set of issues detailing the current situation as it affects molecular imaging. The last section presents the recommendations of the colloquium to the ACR.
| THE SCIENCE OF MOLECULAR IMAGING |
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Unlike much of the rest of medical imaging research, research in molecular imaging is primarily driven by biologic questions rather than questions related to technology. The image-capture technologies most frequently used in molecular imaging include PET, MR imaging, and optical imaging, although techniques are currently under development for ultrasonography (US) and x-ray computed tomography (CT). There are trade-offs among the technologies with regard to the specificity of the molecules that can potentially be addressed by the modalities and how sensitive the modalities are to the concentrations of molecules that might be available in living systems. System resolution and depth of visualization are two other important characteristics that vary among the technologies. As a result, depending on the biologic question and organ of interest, any one of these technologies or a combination of technologies may be used.
As critical to the effort as image-capture technology is the development of molecular probes that can be used to interrogate the molecular and physiologic processes of interest. There now exist numerous exemplary systems that represent scenarios on which future developments can be based. Inevitably, however, new paradigms will be developed that will permit a broadened scope for the field.
The development of such systems is the purview of chemists and molecular biologists. It is evident from the foregoing that imaging physicists also are essential to the effort as they work to improve the spatial, temporal, and contrast resolutions of imaging systems. The data generated from molecular imaging are copious, requiring the participation of information scientists to generate new means of viewing the data in a coherent fashion. Thus, more than ever before, radiologists wishing to enter this field of research must be trained and able to work with a host of basic scientists and clinicians.
To date, the majority of the research in molecular imaging has focused on oncologic applications, largely because the National Cancer Institute has been the most active in funding molecular imaging studies. However, there is clearly interest in applying the techniques developed for cancer to elucidating the mechanisms behind neural and cardiac diseases, as well as to myriad diseases of other organ systems. Image-capture research is focusing on the development of small-animal technologies that will advance imaging in rodents as a prelude to the movement to human disease analogs.
Critical Issues for Radiology
1. The influences driving molecular imaging come from the much broader field of molecular medicine.
2. Playing an important role in molecular imaging research is essential to radiologists eventually participating in molecular imaging clinical practice.
3. The role of the radiologist in molecular imaging remains to be defined but likely will evolve over time. In the early stages, radiologists will need to work with other medical specialists and basic scientists to generate hypotheses and integrate people and technologies.
4. Few academic radiology departments are set up to seriously address molecular imaging research. Departments wishing to invest in molecular imaging must hire experts (eg, biochemists and molecular biologists) in areas with which they have generally been unfamiliar in the past and take a more interdisciplinary approach than previously.
5. Success in establishing a molecular imaging research program will require a major initial investment and substantial continuing costs into the indefinite future. To some extent, departments wishing early involvement in molecular imaging can gain entrance at lower cost by focusing on rodent imaging.
6. Institutions most likely to be successful in establishing research programs are ones with a successful history in research and a diverse array of research resources at their institution outside of radiology.
7. Radiologists traditionally have defined themselves by their technology. Molecular imaging requires that they define themselves by biology—and become much more knowledgeable about chemistry and physiology—while still proffering their expertise in imaging as the major attractor they have for their participation.
8. There currently are few radiologists involved in molecular imaging, nor is there currently a defined pipeline for increasing involvement.
9. Molecular medicine and molecular imaging use a language of molecular biology and biochemistry that is unfamiliar to most radiologists.
10. Unlike previous imaging innovations, molecular imaging is not a single technology; rather, it is a combination of diverse technologies.
11. The lengthy term of development and diffusion of molecular imaging requires that radiology take a longer term view than it has with new technology in the past and plan its research investment strategically.
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Whether training in research is offered as part of residency or fellowship training is the decision of individual radiology training programs. There is enormous variability in this regard across the 193 residency training programs in the United States. The vast majority of programs appear to offer no formal training, nor do they have requirements that trainees participate in research projects during their tenure. Most programs appear to sanction informal arrangements between trainees and staff to facilitate trainees’ participation in mostly clinical research projects. There are sporadic programs that require 1 month or more of resident involvement in planned research projects. A few radiology training programs provide extensive formal research training for as much as 1 year, usually with the trainee returning to clinical training at its conclusion. This is permitted by the American Board of Radiology either as a preapproved clinical and research training regimen known as the Holman Pathway or under American Board of Radiology rules that training eligible for board certification may include as many as 12 months in any area of study (interpreted to include research). Both mechanisms are known to be used in programs nationally.
Formal training programs in molecular imaging are scarce in radiology. The National Cancer Institute has recently funded several centers of excellence in molecular imaging that have a training component. The National Cancer Institute has also funded a larger number of institutions to develop sufficient infrastructure so that they can later compete for molecular imaging requests for applications. A survey of the centers of excellence showed no consistent features among the programs with regard to the sorts of individuals they train or the training regimen.
Critical Issues for Radiology
| TECHNOLOGY REGULATION AND DIFFUSION |
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To some extent, the image-capture technologies to be used in molecular imaging, such as MR imaging, PET, and US, are likely to be variations on the technologies that exist today. Thus, these technologies most likely will not be subjected to the intense scrutiny of class designation—as was MR imaging in the 1980s—that would require device manufacturers to file for FDA Pre-Market Approval. Still, even the 510K process for class II devices may require rigorous testing and data submission, depending on the extent of innovation and the prospective risk to patients involved.
New drug applications follow a different path through the FDA, a path that tends to be more complex and elongated. Manufacturers must file a New Drug Application. Preliminary studies are performed on animals to study metabolism and toxicity. If the results of these tests are acceptable, the company files for an Investigational New Drug Approval from the FDA for permission to conduct human clinical trials. Classically, new drug testing proceeds in three phases. Phase I tests are studies to determine side effects and toxicity, usually in a small group of healthy volunteers. Phase II tests are, in essence, pilot studies to determine whether the drug has an effect in the population of patients for which it is intended. Given a positive result here, the investigators go on to a phase III trial in a larger population of patients to test broadly for efficacy and morbidity. The entire process can take many years and cost tens or even hundreds of millions of dollars. With biologic agents such as the kind that might be developed as probes for molecular imaging, there is additional emphasis on validating the process by which the substances are derived from living organisms. Recognizing that the time and money required to bring new drugs to market is daunting, particularly if the size of the market is uncertain, the National Cancer Institute recently initiated the Development of Clinical Imaging Drugs and Enhancers, or DCIDE, program. Both independent investigators and corporations can apply to the DCIDE program. Successful applicants can have the National Cancer Institute commission prequalified contractors to perform the research needed to apply for an Investigational New Drug Approval.
In addition, there are specific details related to the regulation of medical imaging agents. Specifically, the FDA Web site (www.fda.gov) notes that "the effectiveness of a medical imaging agent will be assessed by evaluating the agent’s ability to provide useful clinical information related to its proposed indication." Since PET imaging agents to be used in molecular imaging will be radioactive, the radiation dose also must conform to the ALARA (as low as reasonably achievable) principle.
The other major regulatory element that may affect molecular imaging is a state certificate-of-need statute. Although funding was eliminated for the enabling federal legislation for the state certificate of need during the Reagan administration, many states retained this requirement as a means of regulating the deployment of expensive medical technologies. The certificate of need varies enormously among the states, with many states having "sunset" the statutes, while others still maintain rigorous enforcement.
Prospective View on the Diffusion of Molecular Imaging
In the classical literature on the diffusion of medical technology, it is said that major innovations progressively diffuse from major academic medical centers to university-affiliated hospitals to community hospitals to outpatient centers and office practices and from urban to rural. However, studies of MR imaging showed a very different pattern of diffusion based on the medical economic environment of the times (5–7). Specifically, along with regulation, competition among providers played a major role in promoting the acquisition of MR imagers among atypical providers who either would ordinarily be expected to acquire technology later in the diffusion process or who had not previously been involved in medical imaging. Early acquirers ignored even the fact that there was no third-party reimbursement in their desire to use MR imaging as a competitive tool, choosing to wait out what they correctly believed would be inevitable decisions to reimburse for the technology.
Although the competitive climate in health care and imaging has progressed since the introduction of MR into the United States in the mid-1980s, there are elements of molecular imaging technology that suggest a more traditional diffusion process will occur. Specifically, the complexity of the technology, the fact that its current applications require so much interdisciplinary collaboration, and the expense of establishing a working molecular imaging center all suggest that molecular imaging will largely remain the purview of major academic institutions for some time. It is likely that at some point in the future, however, there will be commercialization of the technologies and processes. This transition will presumably shift the currently essential "back room" biochemistry operations to companies specializing in these services to allow broader distribution to other potential providers. Clearly, once commercialized, new probes with broad screening, diagnostic, or therapeutic applications might enjoy considerable success in general practice.
Critical Issues for Radiology
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It is already evident, however, that molecular imaging will be the focus of competition among multiple specialties that have evinced an interest in this technology. Most notably, psychiatrists, neurologists, oncologists, and cardiologists have immersed themselves in molecular imaging research, and the topic has been the subject of colloquia by other medical specialty organizations. Experience with previous imaging innovations has shown that the specialists most involved in the research and development of a new technology are the ones most likely to dominate eventual clinical applications.
Self-referral for medical imaging by nonradiologists is a common practice in the United States despite the well-proved axiom that self-referral by physicians of their own patients for imaging technologies in which they have a financial interest results in greater frequency of imaging and higher cost (8,9). There are numerous rationales for why physicians whose principal practice is not imaging (ie, nonradiologists) acquire imaging modalities for their practices. The most obvious of these—and the one that has been the greatest focus of attention—has been the financial incentive. Imaging procedures have been well reimbursed relative to the procedures of many other medical practices; it has generally been presumed that the higher rate of utilization associated with self-referral has been financially motivated.
Clearly, however, other incentives to self-referral are also important: competition with peers in their own specialty, intellectual satisfaction of being on the "cutting edge," recognition and status among colleagues, and patient convenience. It is likely that all of these play a role to greater or lesser degrees, depending on the circumstances. Given the current intellectual excitement surrounding molecular imaging and the ultimate transition over time to molecular medicine, it is likely that similar competition among specialties will eventually develop over molecular imaging.
Critical Issues for Radiology
| SUMMARY AND RECOMMENDATIONS OF THE COLLOQUIUM TO THE ACR |
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Recommendations Related to Training and Certification
Recommendations Related to Regulation and Diffusion
Recommendations Regarding Turf and Competition
| ACKNOWLEDGMENTS |
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