NEWSLINE Action Plan for Emerging 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 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 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 , 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 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 and comparative costs of competing diagnostic and agnosis of dementias, monitoring of disease progression, therapeutic paradigms. Part of the HTA process is reaching and development of new antiamyloid therapeutic agents. consensus on the most appropriate economic model. The

38N THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 2 • February 2008 NEWSLINE basic idea is to articulate the value of detecting something (in determine the utility and impact of the diagnostic this case, amyloid plaques) from the standpoint of clinicians molecular imaging for directing patient treatment who are responsible for patient management decisions. HTAs and improving patient outcomes. The nature of the should be incorporated into plans for testing and dissemi- clinical trials would depend on whether the intended nating each new technology. use was to detect disease, provide prognostic or Ensuring Reimbursement for Use of Molecular Imag- predictive data, monitor response to therapy, or some ing Agents: SNM will collaborate with the Centers for combination of these goals. For example, a clinical Medicare & Medicaid Services (CMS) to create a trial of a novel molecular imaging agent might mea- for obtaining reimbursement for molecular imaging agents sure early response to cancer therapy, as compared when used to image biochemistry (i.e., as biomarkers). For with a gold standard, such as pathologic response, example, CMS should consider approval of FDG as a marker disease-free survival, or overall survival. for glucose metabolism, rather than for disease-specific Although the suggested approach is consistent with some indications. We will focus on demonstrating that detection aspects of the FDA’s current regulations for diagnostic im- of a disease process by molecular imaging contributes to aging agents, the current system is cumbersome and not well the economic and clinical aspects of patient care manage- suited to diagnostic molecular imaging agents. The current ment, the main criteria upon which CMS is likely to focus. Radioactive Drug Research Committee (RDRC) legislation SNM will need to identify what precedents exist and may allows early testing of some radiopharmaceuticals, including also have to help create new processes for this effort to be biodistribution and radiation dosimetry measurements; successful. however, it explicitly forbids clinical trials and tests of safety Obtaining FDA Approval Based on Validation Rather and efficacy of the radiopharmaceutical. Furthermore, only Than Clinical Results: Diagnostic agents for molecular radiopharmaceuticals in which the nonradioactive chemical imaging, especially radiopharmaceuticals, are fundamen- forms have been previously studied in humans can be used tally different from therapeutic drugs in that: (1) they are under RDRC authority. The RDRC mechanism cannot be not intended to have a physiologic or pharmacodynamic used when testing a new imaging agent in conjunction with effect; (2) they are given infrequently for any single patient a clinical trial of a new therapeutic agent. Finally, the RDRC and almost never more than a few doses; and (3) their legislation is quite old and has been subject to periodic changes efficacy as diagnostic agents is related to their ability to in interpretation. All of these considerations limit the ap- measure molecular processes, not to their ability to treat a plicability and utility of the RDRC mechanism for early particular disease. As such, the process for approval of molecular imaging testing, as envisioned in step 1 above. diagnostic molecular imaging agents should be substan- Exploratory Investigational New Drug (IND) approvals tially different from that for therapeutic drugs. SNM should have been proposed to facilitate early testing of low-risk develop a rationale and proposal for a new regulatory agents, such as diagnostic molecular agents. However, this process for new molecular imaging agents, with these mechanism does not appear to be intended to allow more points in mind. widespread use and large-scale clinical trials, nor is it tailored A 2-step process for testing and approval is envisioned: to molecular imaging agents. (1) The first level of approval would be related to the There is a particular need to enable greater standardiza- safety and efficacy of the molecular imaging agent tion and transparency in the legislation for testing and as a tool for detecting and measuring molecular approval of diagnostic molecular imaging agents so we may processes in patients. The safety criteria would more effectively and efficiently determine which imaging involve confirmation that the agent does not cause agents are valid and effective biomarkers. The proposed 2- toxicity and the estimation of radiation dose for step process is tailored to facilitate the appropriate testing and radiopharmaceuticals. In this step, molecular imag- approval of diagnostic molecular imaging agents and, at the ing agent efficacy would entail validation against same time, provide a mechanism that will lead to well- a reference or ‘‘gold standard.’’ For example, the use designed clinical trials prior to widespread clinical use. SNM of the PET imaging agent FLT to measure tumor can bring together the clinical perspective, standardization of proliferation could be validated against an estab- imaging, and manufacturing standards guidelines into lished assay of tumor proliferation, such as the Ki-67 a single package that will assist in these types of discussions immunohistochemical index, performed on tumor with the FDA. biopsy material. This level of approval would enable A new approval process for radiopharmaceuticals, ex- use of the molecular imaging agent for specific panding upon the exploratory IND process and mimicking molecular assay tasks and would facilitate clinical the oncologic orphan drug process, would make it possible trials to determine clinical efficacy. to test market drugs through combined phase III and phase (2) The second level of approval would require dem- IV trials. Legislative changes may be needed to make this onstration of clinical utility and efficacy, not simply possible. SNM can work with the FDA on the RDRC and accuracy in measuring specific molecular processes. exploratory IND guidances now to make them appropriate This would require phase II or III clinical trials to for step 1 of the proposed approval process and begin

Newsline 39N discussions on how to adapt the existing IND framework to Alexander J. McEwan, MB, FRCP(C) accomplish the goals of step 2 for new molecular imaging President, SNM agents. Cross Cancer Institute SNM is continuing its initiative to support the rein- Edmonton, Alberta stitution of the Medical Imaging Drug Advisory Committee Chair, Development Strategies for

NEWSLINE to support further development of investigational imaging Imminently Emerging Technologies: agents. We also note that the agency is continuing to ac- An Action Planning Retreat tively work with SNM and the imaging industry in general to increase the availability of investigational imaging agents Henry F. Van Brocklin, PhD for incorporation in multicenter clinical trials. Vice President, SNM MICoE Standardization: As information becomes available on University of California San Francisco molecular imaging agents that provide the greatest value to clinical patient management, SNM will develop, in concert Chaitanya Divgi, MD with its membership and/or the imaging community: University of Pennsylvania

• Guidelines for image acquisition, processing, and quan- * Retreat participants included Sue Abreu, MD, Sue titation so that multicenter trials can produce compara- Abreu Consulting; Eric Agdeppa, PhD, Global Molecular ble results; Imaging Scientists, GE Healthcare; Robert W. Atcher, PhD, • Platform standards for PET tracers and a set of procedures MBA,Vice President-Elect, SNM, Biosciences Division, to determine whether a product meets those standards Los Alamos National Laboratory; Laurence Clarke, PhD, across multiple sites for all types of imaging; and Cancer Imaging Program, National Cancer Institute; Peter • A system to develop protocols and validate outcome S. Conti, MD, PhD, SNM Molecular Imaging Center of measures for oncologic and nononcologic (e.g., infection) Excellence, University of Southern California; Barbara Y. indications, including appropriate phantoms and statisti- Croft, PhD, Cancer Imaging Program, National Cancer cal designs. Institute; Janet Eary, MD, University of Washington Addressing Intellectual Property (IP) Issues: SNM Medical Center; Richard A. Frank, MD, PhD, FFPM, should work with industry and like-minded academic groups, Medical Affairs and Clinical Strategy, GE Healthcare; Kim such as the Biomarkers Consortium, to identify important Gallagher, PhD, GE Healthcare; Peter Herscovitch, MD, compounds and develop models for IP packaging. SNM Brain Imaging Council, NIH Clinical Center; Marybeth Howlett, MEM, SNM MICoE; Ed Jackson, Topics for Future SNM Discussions University of Texas M.D. Anderson Cancer Center; Joel S. Karp, PhD, University of Pennsylvania; Paul E. Kinahan, • Review sections of the FDA Critical Path Initiative PhD, University of Washington; Maxim Y. Kiselev, PhD, related to imaging to develop SNM proposals on IBA Molecular, North America; Peter Martin, PhD, regulation of molecular imaging probes; Molecular Imaging, Philips Medical Systems; Adrian D. • Communicate with the Institute of Medicine (IOM) to Nunn, PhD, Bracco Research USA Inc.; Ron Nutt, PhD, ensure that SNM proposals are aligned with IOM Advanced Biomarkers Technologies; Virginia M. Pappas, recommendations concerning nuclear medicine and CAE, Chief Executive Officer, SNM; Martin G. Pomper, the use of molecular biomarkers; MD, PhD, President, SNM MICoE, Johns Hopkins Medical • Communicate with medical professional organizations Institutions; Harendra D. Rupani, MD, Novartis; Paul to achieve understanding of how best to integrate Shreve, MD, University of Michigan Medical Center; molecular imaging into clinical practice; Albert J. Sinusas, MD, SNM Cardiovascular Council, Yale • Broaden the scope of discussion to encompass mo- University; Mark Soffing, MBA, RPh, BCNP, IBA lecular imaging in general rather than focusing on radio- Molecular, North America; Dan Skovronsky, MD, PhD, tracers; Avid Pharmaceuticals; Thomas H. Tulip, PhD, Chair, SNM • Ensure that the proposals are consistent with the Bench to Bedside Campaign, Corporate Advisory Board, recommendations of the recent National Academy of Bristol-Myers Squibb Medical Imaging; Tal Zaks, PhD, Sciences report, Advancing Nuclear Medicine Through Oncology Translational Medicine and Genetics Program, Innovation; GSK; and George Zubal, PhD, SNM Instrumentation • Engage CMS to develop a mechanism for reimburse- Council, Molecular NeuroImaging LLC. Additional con- ment of new molecular imaging agents; and tributions by David Mankoff, MD, PhD, University of • Initiate discussions with FDA to define new approval Washington Medical Center; George Q. Mills, MBA, MD, pathways for molecular imaging probes. Perceptive Informatics/PAREXEL.

40N THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 2 • February 2008