NEWSLINE Action Plan for Emerging Molecular Imaging Technologies s a major element of its ongoing molecular imaging marker to characterize disease status and to demonstrate the campaign, SNM convened a retreat on June 23 and 24, effectiveness of a given therapeutic intervention. A2007, in Reston, VA, to address issues related to the It is clear that molecular imaging represents a poten- utilization of current PET probes, to the development of the tially powerful addition to the diagnostics armamentarium. next generation of molecular imaging probes and technol- Several sophisticated molecular imaging agents and ogies, and to their regulatory approval, clinical introduction, technologies are currently available for clinical use. Their acceptance, and reimbursement. ‘‘Development Strategies utility and promise are evident in the substantial number for Imminently Emerging Technologies: An Action Plan- that have been studied in clinical trials. None of these ning Retreat’’ brought together SNM members and invited agents, however, is officially approved and reimbursed. In experts from government, academia, and industry to de- fact, only 2 new imaging agents have been approved by the velop a strategic action plan through which SNM can play FDA in more than 10 years. This is a reality and a challenge an active role in moving emerging molecular imaging tech- that the molecular imaging community must face as it nologies from bench to bedside. The group discussed the prepares to introduce the next generation of imaging agents. current status of PET and molecular imaging, focusing on Many barriers contribute to the paucity of molecular barriers to product development, approval, reimbursement, imaging agents in clinical practice, and overcoming these and clinical acceptance and use by oncologists and other barriers will require a coordinated effort by academic re- clinicians. searchers, industry, patient advocacy groups, and regulators. Among the critical issues identified by the group was These issues fall in 3 broad categories: clinical develop- the effect that the Deficit Reduction Act has had on current ment, regulatory approval and reimbursement, and clinical utilization patterns of FDG, as well as difficulties asso- acceptance. ciated with expanding rates of utilization for current indi- To successfully bring molecular imaging as a biomarker cations. into clinical practice, we will need to ensure that the im- In order to identify actions required to ensure appropriate aging biomarkers are appropriately validated, are incorpo- and timely approval, reimbursement, and acceptance of the rated in the earliest stages of clinical trial design, and have next generation of PET tracers, the retreat focused on 3 areas a significant impact on patient management. Imaging of functional imaging in which the panelists felt the greatest methodologies and biomarkers must be discussed with clinical yield was most likely: cell proliferation imaging, regulators early in the development process and then ap- hypoxia imaging, and amyloid imaging. Activities focusing propriately validated for regulatory approval. Clinicians on these 3 areas will serve as models for addressing issues and scientists need to be trained in clinical study design, related to U.S. Food and Drug Administration (FDA) policy, especially for biomarker-type studies. Collaboration and standardization of procedures, reimbursement, engagement data sharing are essential among industry, academia, pro- of health care communities of practice, and intellectual prop- fessional societies, patient advocacy groups, and govern- erty concerns. ment representatives. Background: The Need for Accelerated Opportunities for Product Development in the Development of Emerging Molecular Imaging Next 5 Years Technologies Three groups of radiotracers typify the promise and Molecular imaging targets processes at a cellular level, potential of molecular imaging, are in fairly developed stages enabling a more comprehensive interrogation of physiology of clinical development, identify unique biologic processes and pathology. Advances in molecular imaging have the po- of importance as biomarkers, and exemplify the issues tential to improve risk assessment, prevention, early detection, related to imaging biomarker development: imaging agents diagnosis, prognosis, and treatment of a variety of diseases. that identify proliferation, hypoxia, and amyloid. The bio- Molecular imaging can help select and guide patients for markers are of critical importance in cancer (proliferation, individualized therapy in drug development, clinical trials, and hypoxia); cancer, infection, and cardiovascular events (hyp- clinical practice. oxia); and neurodegenerative disease (amyloid). An under- Molecular imaging can contribute to both translational standing of the development of these radiotracers will provide research and clinical care by increasing biological un- insight into imaging biomarker development. derstanding from molecules to organisms, assessing disease Cell proliferation imaging is emerging as an important changes, and providing information for the development and tool for the characterization of solid tumors and tracking assessment of therapies. Molecular imaging is thus a bio- responses to therapy. Measuring proliferation is based on Newsline 37N Key Issues in Emerging Molecular Imaging Technologies 1. Development and Clinical Introduction Issues in terms of efficacy and safety that may exceed Research funding what is reasonable or, at times, what is possible. NEWSLINE Intellectual property and university/industry interface Clinical validation 3. Issues Related to CMS Funding, Clinical Market size Costs of development are high and still growing, Acceptance, and Expansion of Indications but the return on investment for new Many imaging studies have been inappropriately molecular imaging agents is uncertain. designed or powered. The research and development infrastructure, Endpoints derived from conventional imaging in general, for imaging agents is a fraction experience may appear to have limited validity of that available for development of and utility for future molecular imaging therapeutic agents. applications. The shortage of patients for some clinical trials No outcomes parameters are available for leads to extended development time frames. molecular imaging that are comparable to the Response Evaluation Criteria in Solid Tumors 2. Regulatory Issues criteria for response to therapy in solid tumors. Cost and complexity Technical issues/obstacles are abundant, Biochemical versus disease indication particularly use of different platforms and less Indication fragmentation than comprehensive standardization of Clinical trial issues of radiopharmaceutical manufacturing, image acquisition, and image development analysis. Role of molecular imaging in clinical trials Clinicians are fixed on the idea of using imaging Imaging/surrogate biomarker issues to detect a disease and reluctant to expand Lack of definition by regulatory authorities on their vision to use imaging to characterize what is required to qualify or validate an imaging disease, including changes over the course biomarker of treatment. Regulators treat imaging agents as therapeutic Many physicians are skeptical about the drugs, applying therapeutic drug expectations usefulness of molecular imaging data. the incorporation of labeled thymidine into DNA. 18F-labeled Action Steps for SNM and Others thymidine analogs, fluorothymidine (FLT and FMAU), have The 3 biomarker groups share the same approval, reim- been evaluated as markers of proliferation. Initial studies in bursement, and acceptance challenges. Although each group humans have shown the promise of these probes; however, is biologically unique, there was consensus that SNM could a concerted effort is still needed to demonstrate their utility drive a new set of processes applicable to all 3 and gen- as biomarkers of cell growth and proliferation. eralizable for approval of molecular imaging agents. The Hypoxia is a process that is relevant to evaluation of following specific objectives were discussed. solid tumors and myocardial ischemia/infarction. In cancer, Demonstrating Clinical Effectiveness of Molecular for example, imaging biomarkers of hypoxia may help deal Imaging: SNM should conduct a health technology assess- with therapeutic challenges related to resistance or enhanced ment (HTA) of imaging agents to serve as a model for tumor progression. Labeled nitroimidazoles (18F-AZA, 18F- evaluating their effectiveness. For example, detection of b- MISO) have been validated as biomarkers of hypoxic tis- amyloid plaques with PET agents could be selected as a test sue, and further human studies are warranted to identify case to conduct an HTA to establish the process. An HTA areas of clinical utility. Hypoxia agents may be valuable involves assessment of the clinical utility of medical inter- tools for identification and monitoring of patients who may ventions through systematic review of the literature and use respond to antihypoxia treatment. of appropriate qualitative and quantitative methods of syn- b-amyloid plaques are considered to be hallmarks of thesizing data from multiple studies. Economic models for Alzheimer’s disease and possibly other forms of dementia. cost-effectiveness analysis incorporate, process, and analyze A number of plaque-avid tracers have emerged as potential multiple datasets, allowing for a better understanding of the agents for the detection of early disease, differential di- efficacy