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DOI: 10.1148/radiol.2453060737
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(Radiology 2007;245:645-660.)
© RSNA, 2007

Molecular Imaging Series

Regulatory and Reimbursement Challenges for Molecular Imaging1

John M. Hoffman, MD, Sanjiv S. Gambhir, MD, PhD, and Gary J. Kelloff, MD

1 From the Departments of Radiology and Neurology, University of Utah School of Medicine, 2000 Circle of Hope, Suite 2121, Salt Lake City, UT 84112-5550 (J.M.H.); Departments of Radiology and Bioengineering, Bio-X Program, Stanford University, Stanford, Calif (S.S.G.); and Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Md (G.J.K.). Received April 27, 2006; revision requested June 27; revision received October 19; final version accepted December 1. Address correspondence to J.M.H.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
Molecular imaging is being hailed as the next great advance for imaging. Since molecular imaging typically involves the use of specific imaging probes that are treated like drugs, they will require regulatory approval. As with any drug, molecular imaging probes and techniques will also require thorough assessment in clinical trials to show safety and efficacy. The timeline for the regulatory approval will be long and potentially problematic because of the mounting costs of obtaining final regulatory approval. The current article is a detailed review of the regulatory and reimbursement process that will be required for molecular imaging probes and techniques to become a widespread clinical reality. The role of molecular imaging in the therapeutic drug discovery process will also be reviewed, as this is where these exciting new techniques have the potential to revolutionize the drug discovery and development process and, it is hoped, make it less costly. [18F]fluoro-2-deoxy-2-D-glucose positron emission tomography, one of the first molecular imaging techniques to be widely used, will be used as an example to illustrate the process of obtaining eventual reimbursement for widespread clinical use.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
This is the final article in the molecular imaging series; it will provide what will be required to make molecular imaging a widely used clinical reality involving the numerous molecular imaging probes and techniques described in the series of articles. It was our goal to discuss in this series of articles the potential for molecular imaging to become an integral and important part of future clinical radiology practice. Molecular imaging techniques will allow us to assay and identify important and key alterations in molecular pathways, signal transduction, and receptor levels due to disease (1–6). Molecular imaging studies will provide important information for clinicians to elucidate the behavior of many diseases and their response to certain drugs and therapies (7–9). Molecular imaging techniques could be used to individualize and personalize treatments on the basis of a "molecular phenotype" of the disease at the time of diagnosis and throughout the course of therapy. Since many diseases are systemic or localized to areas of the body where it is not practical or safe to obtain tissue for analysis, molecular imaging will be the key integrating technique that will allow the clinician to characterize and monitor therapy noninvasively and over time. There is little question that this personalized approach to therapy could improve patient care, as individuals would receive the most appropriate and targeted therapy rather than ineffective therapies. It is hoped that this will improve outcomes, minimize unnecessary morbidity associated with ineffective therapies, and provide substantial cost savings for total care.

Molecular imaging will also find a particularly important niche in the therapeutic drug discovery and development process (8,10–15) (Fig 1). It is envisioned that molecular imaging will have the potential to shorten the timeline for drug approval and lessen costs by enabling expedient and more direct measurement of drug effects in the body (10). In the recently released The Critical Path to New Medical Products (16), the Food and Drug Administration (FDA) describes how molecular imaging techniques may be useful in the drug discovery process (17). Critical to the use of molecular imaging in the drug discovery and development process will be molecular imaging probes that image specific molecular targets and pathways in vivo (10,13–15). These probes will then enable visualization of the phenotypic expression of key molecular targets associated with the disease process. Molecular imaging probes have the power to display biochemical and physiologic abnormalities that occur early in the disease process, as opposed to the structural changes that eventually occur and are visualized with more standard anatomic imaging techniques.


Figure 1
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  		Figure 1: A timeline of traditional de novo drug discovery and development. It is well known that de novo drug discovery and development is a 10–17-year process from idea to marketed drug (18). The probability of success is lower than 10% (19). ADMET = absorption, distribution, metabolism, excretion, toxicity; EMEA = European Agency for the Evaluation of Medicinal Products, MHLW = Ministry of Health, Labor and Welfare. (Reprinted, with permission, from reference 20.)

 
Molecular imaging biomarkers that help track the physiologic events taking place in vivo will have many potential uses in all phases of the drug development process, from target discovery and validation to the pivotal clinical trials used for therapeutic drug approval. Molecular imaging disease biomarkers have great potential to help define, stratify, and enrich various groups of promising molecularly targeted therapeutic drugs that are undergoing clinical trial testing. Various scenarios can be envisioned and include the use of molecular imaging techniques to noninvasively assist in the identification, characterization, and quantitation of the therapeutic drug target in various patient study populations.

Clinical molecular imaging studies of the labeled drug itself could assist with pharmacokinetic and pharmacodynamic assessments. Molecular imaging studies of the labeled drug could also be invaluable for assessing the target interaction and modulation that might occur with administration of the therapeutic drug in the diseased tissue and the body as a whole. Molecular imaging techniques could be invaluable when they are used in early-phase clinical studies comparing several lead candidate drugs designed to interact with the same target.

Another area where molecular imaging–type biomarkers may have tremendous promise is in accelerating the drug evaluation process by replacing or supplementing time- and labor-intensive dissection, histologic, and pathologic analyses in both preclinical and clinical testing. Noninvasive molecular imaging techniques also have the potential to enable longitudinal preclinical studies in various animal models with greater relevance to the future clinical trials that will be used for therapeutic drug approval. Finally, molecular imaging biomarkers of tumor response, including changes in cellular apoptosis, proliferation, angiogenesis, and oxygenation status, will be invaluable once they are validated as early measurement surrogates of therapeutic efficacy.

As is the case with all imaging procedures, the clinical viability of molecular imaging will require both regulatory approval of the various imaging probes by the FDA and reimbursement from insurance carriers and the Center for Medicare and Medicaid Services (CMS). This will be a long, complicated, and costly process, as there will be a myriad of probes and technologies—all requiring regulatory approval and reimbursement before a substantial effect in terms of the clinical use of molecular imaging techniques will be realized. The reimbursement approval process, at least for Medicare patients, could be as long and difficult as the FDA regulatory approval process that the imaging community experienced with [18F]fluoro-2-deoxy-2-D-glucose (FDG). The FDA approval process and the reimbursement approval processes will be the greatest challenges to confront the radiology and imaging communities in the future.

To fully exploit the promise of molecular imaging will, in most instances, require very specific imaging agents and probes targeted to specific alterations of a particular biologic process in a given disease. This process of developing specific and targeted molecular imaging probes will be analogous to the current drug development process that we are witnessing in the pharmaceutical industry. When a more specific or targeted agent (either a therapeutic or an imaging agent) is developed, there is typically much less of an eventual market for its use due to its limited applicability. This reduced market expectation engenders tremendous reluctance by the pharmaceutical or imaging agent development company to spend the necessary dollars needed to develop and obtain FDA approval for the drug or imaging agent. The drug development process, including that for the development of diagnostic imaging agents, is a very costly process that requires many years from the time of discovery to the final approval of the drug for use in humans. Current estimates are that it takes about 10–17 years and nearly $0.8–$1.7 billion to bring a therapeutic drug to market (17–21). Figure 1 shows the typical pathway and timeline for the drug discovery, development, and approval process. It has been proposed that imaging may assist in speeding this development timeline and pathway (13,15) (Fig 2).


Figure 2
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  		Figure 2: Imaging applications in the drug discovery process. Imaging can be used to affect the drug discovery and development process. (Reprinted, with permission, from reference 15.)

 
Information regarding the costs of developing imaging agents is more difficult to obtain. A recent report by Nunn (22) provides an excellent overview of the issues related to the development of imaging agents and the associated costs. In that report, the costs involved in bringing a new imaging agent to market are determined to be in the range of $100–$150 million. The annual U.S. sales for all imaging agents in 2004 were reportedly on the order of $2.84 billion (22–25) (Table 1). A "blockbuster" imaging agent reportedly has annual worldwide sales of less than $400 million (22–24) (Table 2). Therefore, it may take many years for a company to recoup its cost investments in a new imaging agent that has a market value on the order of $35–$50 million. Since many of the newer molecular imaging agents will be targeted and not have broad markets for sales, the development process may be even slower and more complicated and thus more costly. The reality is that the entire therapeutic drug and imaging agent development and approval process is driven by the economics of development costs and eventual sales. If the market is small, then it may not be economically feasible to bring the therapeutic drug or imaging agent to market.


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  		Table 1. U.S. and Worldwide Imaging Contrast Agent Sales for 1999 and 2004

 

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  		Table 2. Worldwide Sales of Commonly Used Imaging Contrast Agents

 
There is currently a trend in the pharmaceutical industry as it relates to drug discovery and approvals: A continually decreasing number of new drugs are being approved (17) (Fig 3). In addition, the costs involved in drug approval are rising. It is estimated that there has been an increase of approximately 55% in the cost of bringing a drug to market in just the past decade (20,26,27) (Figs 4–6). As would be expected, annual costs for the research and development of imaging agents have also been increasing (22) (Table 3). Pharmaceutical, biotechnology, and medical device approvals by the regulatory agencies appear to be declining at the same time that the costs to develop a small number of drugs, treatments, and devices are rising.


Figure 3
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  		Figure 3: The figure shows the number of submissions of new molecular entities (NMEs)—drugs with a novel chemical structure—and the number of biologics license application (BLAs) submissions to the FDA over a 10-year period. Similar trends have been observed at regulatory agencies worldwide (Challenge and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html) (17).

 

Figure 4
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  		Figure 4: The figure shows 10-year trends in biomedical research spending as reflected by the NIH budget (Budget of the United States government, appendix, FY year 1993–2003) and by pharmaceutical companies' research and development (R&D) investment (PAREXEL's pharmaceutical R&D statistical sourcebook 2002/2003 [26]). From Challenge and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html (17).

 

Figure 5
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  		Figure 5: The growing productivity gap in the biopharmaceutical industry. Despite enormous increases in spending in novel technologies over the last several years, R&D productivity has actually decreased since the mid-1990s, as measured either by the number of new drugs approved per dollar spent or by the number of original investigational new drug (IND) applications received by the U.S. FDA from commercial sources per dollar spent. (Reprinted, with permission, from reference 20.)

 

Figure 6
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  		Figure 6: The figure shows one estimate of the total investment required to "launch" (ie, market) a successful drug in two time periods. Most of the current cost increases are within the "critical path" development phase, between discovery and launch. Source of information from Windhover's in vivo: the business and medicine report, Bain drug economics model, November 2003 (27) and Challenge and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html (17).

 

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  		Table 3. Annual Research and Development Spending and Sales by Amersham and Schering

 
The FDA is keenly aware of these disturbing trends and the issues related to the drug development and regulatory approval process. In 2004, a report from the FDA entitled Challenge and Opportunity on the Critical Path to New Medical Products was published online on the FDA Web site (17). In this document, the FDA provides important information about and an analysis of what they refer to as the "pipeline problem": the recent slow down—instead of the expected acceleration—in the innovative medical therapies that reach patients. In the document, the FDA outlines possible changes that will facilitate the drug development and approval process. These changes are referred to as the "critical path" (16) (Fig 6). This path is that part of the drug development process from preclinical testing to completion of the pivotal phase III trials. The goal is to ensure that promising drugs, including imaging agents, are brought to market in a timely manner at a cost that will ensure the development and eventual approval of the agents. Since molecular imaging probes are treated like drugs by the FDA, except in certain circumstances, they must be subjected to the same development and regulatory approval process. The critical path may prove to be beneficial for decreasing the cost and improving the time to market for molecular imaging probes as well as therapeutic drugs. This will obviously be very important, as these "small-market" probes will become commercially viable only if the costs of development and approval are reasonable for the companies that develop and market diagnostic imaging agents.


   IMAGING AGENT DEVELOPMENT PROCESS
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
The typical development and subsequent regulatory approval process for new imaging agents, including new molecular imaging probes, is dependent on the type of probe and whether it is a radioactive agent or not. For example, many of the currently used molecular imaging probes are radiolabeled compounds that were developed in academic centers. In some instances, these probes are then licensed to companies for further development. The MR imaging agents that would be considered molecular imaging agents are more often developed by companies that specialize in the development of imaging agents and imaging diagnostics. The discovery and development process and subsequent clinical testing of the new molecular imaging agents are often quite different, depending on whether the agent is a radiolabeled compound or not. The radioactively labeled molecular imaging probes are typically administered in tracer quantities (nanomolar or picomolar concentrations). These tracer levels have a much lower propensity to cause pharmacologic effects and thus may have minimal or no known toxicities. MR imaging agents, on the other hand, may require administration at the milligram level to achieve concentrations that enable adequate imaging. The development process, including the need for more extensive toxicology testing, can be quite different owing to differences in the concentration of the imaging agent that is administered.

The nuclear medicine and PET imaging communities have at their disposal certain programs to facilitate testing of new imaging agents in humans, provided that the agent is not a new molecular entity. The typical process for the academic developer of a new radioactively labeled molecular imaging probe is to use the local Radioactive Drug Research Committee (RDRC) program (28) (described later). Once the initial human studies are done under the RDRC process, the investigator will file an investigational new drug (IND) (29) application, or he or she often will find a commercial partner to assist with the development and subsequent IND application preparation and filing. After the IND application is filed, the investigator or more typically the corporate sponsor will perform the appropriate trials (phase I, phase II, and typically two pivotal phase III trials) that will lead to a new drug application (NDA) (30) (Table 4).


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  		Table 4. Phases of Therapeutic and Imaging Agent Trials

 
There are many unique issues related to imaging agents that should be addressed in the various phases of trials but are not actually required in therapeutic drug trials. The FDA has developed three separate guidance documents (31) that explicitly describe the imaging agent development process. These documents are entitled (a) Conducting Safety Assessments (32); (b) Clinical Indications (33); and (c) Design, Analysis, and Interpretation of Clinical Studies (34). All investigators who are involved in the imaging agent discovery and development process should become familiar with the specific information contained in these documents. The detailed information provided in these guidance documents is beyond the scope of this review. However, it is important that several relevant points are understood: The guidance documents describe and elaborate on important differences between various types of imaging agents. Medical imaging agents can be classified into at least two general categories: contrast agents and diagnostic radiopharmaceutical agents. The FDA also makes a distinction, as defined in guidance document 1 (32), between what they refer to as group 1 (nonbiologic) and group 2 (biologic potential for eliciting an immunologic response) medical imaging agents (Table 5).


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  		Table 5. FDA Definitions of Group 1 and Group 2 Medical Imaging Agents

 

   RADIOACTIVE DRUG RESEARCH COMMITTEE
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
As mentioned previously, the FDA allows certain unique applications for the use of radiopharmaceuticals in humans without IND approval. This is due to the low potential for toxicity of radiopharmaceuticals that are typically administered in tracer quantities. One such difference allowed by legislation is the use of the RDRC program (28). This program began when the FDA published a Federal Register notice on July 25, 1975, classifying all radioactive drugs as either new drugs requiring an IND application for investigational use (21 CFR §312) or drugs that are generally recognized as safe and effective when administered under the conditions specified in the RDRC regulations (21 CFR §361.1) (35). The CFR designation refers to specific regulations in law which describes the processes. The RDRC program under 21 CFR 361.1 permits basic research using radioactive drugs in humans without an IND when the drug is administered under certain conditions (Table 6).


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  		Table 6. RDRC Conditions for Radioactive Drug Use

 
Condition 4 explicitly defines the radiation exposure limits that are allowed when using the RDRC process (Table 7). The critically important point is that limits are set for the exposure from a single administration of a radiopharmaceutical as well as from the annual total of all studies performed in a single individual under the RDRC mechanism. For an adult, the limit is 3 rem for whole-body exposure from a single dose and 5 rem for whole-body exposure from the total number of RDRC studies conducted annually. Any individual organ, except those specifically noted in Table 7, can receive up to 5 rem from a single administration and up to 15 rem from the total number of RDRC studies performed in a year. For research subjects younger than 18 years, these values are not to exceed 10% of the dose set forth for adults.


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  		Table 7. Radiation Exposure Limits Allowed Under the RDRC Process

 
Another important aspect of the RDRC process is the composition of the RDRC, which is defined by the FDA. The local RDRC is approved by the FDA through an application process. To establish an RDRC at one's institution, there are certain requirements for committee membership, as outlined in regulation 21 CFR §361.1 (35): An RDRC shall consist of at least five individuals. Each committee shall include the following three individuals: (a) a physician recognized as a specialist in nuclear medicine, (b) a person qualified by training and experience to formulate radioactive drugs, and (c) a person with special competence in radiation safety and radiation dosimetry. The remainder of the committee shall consist of individuals qualified in various disciplines pertinent to the field of nuclear medicine (eg, radiology, internal medicine, clinical pathology, hematology, endocrinology, radiation therapy, radiation physics, radiation biophysics, health physics, and radiopharmacy). The membership shall be sufficiently diverse to permit expert review of the technical and scientific aspects of proposals submitted to the committee. The addition of consultants in other pertinent medical disciplines is encouraged. An RDRC shall be associated with a medical institution operating for care of patients and with sufficient scientific expertise to allow selection of committee members from its faculty or with a committee established by a state authority to provide advice on radiation health matters. Joint committees involving more than one medical institution that have been established to achieve a high level and diversity of experience will be acceptable. The director of the Center for Drug Evaluation and Research may modify any of these requirements in a particular situation in which alternative factors provide substantially the same composition and association.

It must be remembered that the FDA allows the local RDRC to approve and monitor RDRC-approved studies at the local institution without an IND application being filed. The committee is required to submit an annual report to the FDA as part of the procedures for maintaining an active and approved RDRC program. This is again part of the legal requirement, as outlined in regulation 21 CFR §361.1 (35). The annual report must be submitted to the FDA by January 31 of every calendar year. The report must include very specific information, as outlined on the corresponding Web sites (28,35). The institutional RDRC and investigator must maintain very detailed records to be able to complete the annual report, as required by the FDA. Specifically, the investigator must document the amount of radioactivity and the volume of the agents administered to each subject. More complete information about the data required in the annual report can be found on the FDA RDRC (28) and 21 CFR §361.1 (35) Web sites.


   IND PROCESS
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
During the early development of a new drug or imaging agent, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans. For therapeutic drugs, the interest is in finding out if the compound exhibits pharmacologic activity that justifies commercial development. For imaging agents, pharmacologic activity is not a desirable property and the goal is to see that the agent is safe, does not have appreciable pharmacologic activity, and can be imaged with an acceptable target to background or detectable signal. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when it is used in limited early-stage clinical studies. These are the phase I and II trials described earlier.

The FDA's role in the development of a new drug begins when the drug's sponsor (the investigator or more typically the manufacturer or potential marketer), having screened the new molecule for pharmacologic activity and acute toxicity potential in animals, seeks to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system as overseen by the FDA. There are three distinct types of INDs. The first is what is known as an investigator-initiated IND, the second is called an emergency-use IND, and the third is called a treatment IND or, more commonly, a "compassionate-use" IND (Table 8).


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  		Table 8. Types of INDs

 
The IND application must contain information in three broad areas: (a) animal pharmacology and toxicology studies, (b) manufacturing information, and (c) clinical protocol and investigator information (Table 9). The FDA provides Web sites that detail the specific information required for the IND application submission and the format in which to submit the application (29,36).


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  		Table 9. IND Requirements

 
The IND application should follow the request for the information in the format and order that the FDA requests. This allows an easier review of the information by the FDA (Table 10). One can also refer to the specific code of federal regulation 21 CFR §312.23, where detailed information regarding the IND application components and the data that should be included is provided (36). Various forms such as form 1571 (37), which is the IND application itself (submitted by the sponsor, often a company or an academic institution), and form 1572 (38), which is the statement of the investigator (typically the physician sponsor), can be downloaded from the FDA Web site (29). Once the IND application is submitted, the sponsor must wait 30 calendar days before initiating any clinical trial. During this time, the FDA has an opportunity to evaluate the IND for safety to ensure that research subjects will not be exposed to unreasonable risk. If there is no response from the FDA in the form of requests for clarification or additional information, then the trial can commence after the 30-day waiting period. As with the RDRC mechanism, annual reports to the FDA are also required, and these must also include detailed information. The annual report format is also well defined for an IND application, as mandated in the Code of Federal Regulations. Specific information regarding the annual report can be found at the FDA IND annual report Web site (39). It is beyond the scope of this article to describe all of the specific information that is required for an IND application submission. One should consult the FDA or its IND process Web site for up-to-date information (29).


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  		Table 10. Detailed Components of IND Application

 

   EXPLORATORY IND
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
REIMBURSEMENT PROCESS
 CONCLUSION
 References
 
In January of 2006, the FDA published its final guidelines for what it is calling an exploratory IND (40). This guidance document is intended to clarify what preclinical and clinical approaches—as well as chemistry, manufacturing, and controls information—should be considered when planning exploratory studies in humans, including studies of closely related drugs or therapeutic biologic products, under an IND application. The FDA believes that the existing regulations allow a great deal of flexibility in the amount of data that need to be submitted with an IND application, depending on the goals of the proposed investigation, the specific human testing proposed, and the expected risks. The FDA believes that investigators have not taken full advantage of this flexibility and often provide more supporting information with the IND application submission than is actually required by regulation. A typical exploratory IND study would involve a clinical trial conducted early in phase I with very limited human exposure and no therapeutic or diagnostic intent (eg, screening and microdosing studies). This type of exploratory IND study should be less complicated and expensive to perform, as less animal toxicity data typically will be required.

As mentioned previously, the FDA's report, Challenge and Opportunity on the Critical Path to New Medical Products (17), delineates many of the issues related to the problems of increasing costs and time required for drug development and eventual approval. The exploratory IND protocol has the potential to reduce the time and resources expended on candidate products that may not succeed. New tools such as the exploratory IND approach are needed to distinguish earlier in the process between those candidate products that hold promise and those that do not. The exploratory IND protocol allows an early phase I exploratory approach that is consistent with regulatory requirements while maintaining needed human subject protection.

Another critical aspect of this new approach is that it involves fewer resources than is customary, such as in toxicology testing, and thus enables investigators and sponsors to move ahead more efficiently with the development of promising candidate products. This particular mechanism, while still requiring an IND application, involves fewer potential risks than do traditional phase I studies performed to look for dose-limiting toxicities. Limited exploratory IND investigations in humans can be initiated with less or different preclinical toxicity data compared with the data required for traditional IND studies. The mechanism will also allow the sponsor to (a) determine whether a mechanism of action defined in the experimental systems can also be observed in humans (eg, a binding property or inhibition of an enzyme), (b) provide important information on pharmacokinetics, (c) improve selection of the most promising lead product from a group of candidate products designed to interact with a particular therapeutic target in humans on the basis of pharmacokinetic or pharmacodynamic properties, and (d) explore a product's biodistribution characteristics by using various imaging technologies. The goal of this new mechanism is to help reduce the number of human subjects and resources, including the amount of candidate product, needed to identify promising drugs. Since the exploratory IND mechanism is new, it will be critical for interested parties to monitor the process and determine if it actually facilitates more "first in man" studies.


   REIMBURSEMENT PROCESS
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
CONCLUSION
 References
 
To make any diagnostic test clinically useful and before it will be widely utilized, it obviously must be approved by the FDA; however, it is just as important that the test costs be reimbursed by CMS, Medicaid, or private insurance carriers. Clinical implementation of molecular imaging techniques and technologies will be a true challenge, particularly in light of mounting health care costs. Although molecular imaging may hold great promise for improving the care of patients with many different diseases, reimbursement for molecular imaging test costs will be crucial for the eventual widespread clinical utilization of these procedures. It is unfortunate that these potentially very promising imaging techniques are showing great promise at a very difficult time for the American health care system. In the future, molecular imaging techniques such as PET, optical imaging, and newer MR imaging examinations will undoubtedly be the topic of much debate among both the government and the private sector amid continuing escalations in health care costs. Imaging costs, as well as prescription drug costs, have been cited as entities responsible for the substantial increases in medical costs both in federally funded programs, such as Medicare and Medicaid, and for private insurers (41,42). It is important for all radiologists and imagers to understand the process whereby the technologies that they routinely use in their practice are assessed for reimbursement and payment. Almost all insurers and the federal government use similar processes to assess diagnostic techniques and technologies for reimbursement and payment. The CMS is the federal agency within the Department of Health and Human Services that makes all decisions regarding Medicare coverage and sets reimbursement rates.

The Medicare and Medicaid programs were signed into law on July 30, 1965, by then-president Lyndon B. Johnson. The signing ceremony took place in Independence, Missouri at the Truman Library. President Johnson held the ceremony there to honor President Truman's leadership in implementing health care insurance, which he first proposed in 1945. The most important legislative change to Medicare since the initial law went into effect in 1965 was the Medicare Modernization Act, which was signed into law on December 8, 2003, by President George W. Bush. This historic legislation added an outpatient prescription drug benefit to Medicare and generated many other important changes, including enhanced benefits and choices. Like any large organizational agency of the federal government, the CMS has a mission, a vision, and goals that are clearly defined (43).

In brief, the CMS is responsible for ensuring the health care security of its beneficiaries, which now include nearly 42 million Americans on Medicare. State and federal Medicaid recipients total about 44.7 million participants. The number of Medicare recipients is expected to increase to nearly 79 million by year 2030. The annual Medicare and Medicaid budget is very large. In fiscal year 2005, for example, the CMS total expenses for Medicare were nearly $329.8 billion, with state and federal expenses for Medicaid totaling about $309.4 billion (44).

For the purposes of this discussion and for simplicity, one part of the CMS infrastructure makes coverage decisions and another part sets the actual reimbursement rates. In the past, the process of obtaining a coverage decision, which then allows for reimbursement, was perceived to be long, complicated, and costly; was not always successful; and most often was not transparent to those trying to obtain coverage decisions (45–47). Much like the FDA, however, the CMS is now taking steps to make this process more transparent and to render decisions in a timelier manner. Most coverage decisions are based on an assessment of the technology with evidenced-based data. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 required that the secretary of the Department of Health and Human Services make available to the public the factors that are considered in making national coverage determinations of whether an item or service is reasonable and necessary. To facilitate this process, the CMS produced guidance documents (48–51) similar to those used by the FDA. These documents give the public—particularly individuals or organizations that might request a national coverage determination—detailed information on the national coverage determination process and related evaluation and decision-making factors. Also, like the guidance documents produced by the FDA, the CMS guidance documents are meant to serve as an overview of the process and "does not create or confer any rights for or on any person and do not operate to bind CMS or the public" (48–50).

Most practicing radiologists are probably familiar with the very long process that took place so that costs for rubidium PET, ammonia PET, and FDG PET performed for oncology, dementia, epilepsy, and cardiac indications could be reimbursed (52,53). It took thousands of man years of effort by many people in the imaging community to make this possible. This effort resulted in a special supplement to The Journal of Nuclear Medicine being published in 2001 (54). The document is a detailed tabulation of literature on FDG PET in oncology (1993 to June 2000), cardiology (1986 to June 2000), and neurology (1980 to June 2000). The published document is a subset of the original document formally submitted to the CMS in July 2000 to request expanded Medicare reimbursement for FDG PET. The process for MR spectroscopy cost reimbursement, on the other hand, has been unsuccessful on two separate occasions. The initial decision of noncoverage for MR spectroscopy as a broad indication came in 1994. In 2002, there was a more focused request for reconsideration of the noncoverage determination. This time, the request was more specific in terms of the indications for the MR spectroscopic examination to be reimbursed, which included (a) differentiation of cerebral tumor versus abscess or other infectious or inflammatory processes and (b) differentiation of cerebral tumor versus radiation necrosis. On January 29, 2004, the CMS posted a decision: It had determined that the evidence was not adequate to conclude that MR spectroscopy was reasonable and necessary for the diagnosis of brain tumors; therefore, the current national noncoverage determination would continue (55).

On January 28, 2005, the CMS set forth another very important coverage memorandum regarding the use of FDG PET for all other cancers previously not approved for coverage and reimbursement. The date of the coverage memorandum implementation was April 18, 2005. At that time, the CMS made it possible to receive reimbursement for the use of FDG PET for imaging of all other malignancies; however, certain criteria had to be met. It was their decision that additional scientific data were required to make a final coverage decision. The CMS defined this process as "coverage with evidence development" (56). The specific mechanism and process are also described in a guidance document (57).

For cancer indications listed as eligible for "coverage with evidence development," the CMS determined that the evidence was sufficient to conclude that an FDG PET scan is reasonable and necessary only when the provider is participating in, and patients are enrolled in, either a registry- or CMS-approved clinical trial. The specific language provided by the CMS follows: "one of the following types of prospective clinical studies that are designed to collect additional information at the time of the scan to assist in patient management" (52) must be performed to receive reimbursement. Specifically, these studies include (a) clinical trials of FDG PET that meet the requirements of FDA category B investigational device exemption (42 CFR §405.201) and (b) FDG PET clinical studies designed to collect additional information at the time of scanning to assist in patient treatment. Qualifying clinical studies must ensure that specific hypotheses are addressed, appropriate data elements are collected, hospitals and providers are qualified to perform PET and interpret the results, participating hospitals and providers accurately report data on all the enrolled patients who are not included in other qualifying trials through adequate auditing mechanisms, and all patient confidentiality, privacy, and other federal laws are followed (52).

PET imaging communities, including the Academy of Molecular Imaging and the American College of Radiology, joined forces to develop a centralized process for assisting the radiology community in meeting the criteria for expanded CMS reimbursement of FDG PET studies. This infrastructure is known as the National Oncologic PET Registry (58). Describing the specifics of the registration process is beyond the scope of this article, but one can visit the referenced Web site (58) to gain familiarity with the process, rules, and regulations pertaining to reimbursement for those oncology indications that previously were not approved or reimbursed by the CMS. A unique aspect of the registry is the ability to perform treatment monitoring by using FDG PET. Before the PET registry was developed, the only cancer for which response monitoring had been approved was breast cancer. Now FDG PET can be used to monitor response to therapy. To avoid any confusion as to what is meant by response monitoring, the CMS has provided a definition that should be used: "the use of PET to monitor tumor response to treatment during the planned course of therapy (ie, when a change in therapy is anticipated)" (52). Two excellent Web sites (52,53) provide an up-to-date summary of the current CMS-approved oncologic uses of FDG PET. These Web sites detail the covered indications, the indications for which a noncoverage determination has been made, and the indications for which the coverage with evidence development process can be used.

Acquiring Medicare approval for FDG PET performed for the assessment of patients with dementia has also been a long and complex process. In January 2005, the CMS finally issued a national coverage determination. Medicare decided to cover FDG PET examinations performed (a) for differential diagnosis of frontotemporal dementia and Alzheimer disease under specific requirements or (b) for use in a CMS-approved practical clinical trial focused on the utility of FDG PET for the diagnosis or treatment of dementia-causing neurodegenerative diseases. The CMS concluded that "an FDG-PET scan is considered reasonable and necessary in patients with a recent diagnosis of dementia and documented cognitive decline of at least 6 months, who meet diagnostic criteria for both AD and FTD. These patients have been evaluated for specific alternate neurodegenerative diseases or other causative factors, but the cause of the clinical symptoms remains uncertain" (59).

The CMS mandated specific additional requirements (Table 11) for the differentiation of frontotemporal dementia versus Alzheimer disease. For the scenario in which a CMS-approved practical clinical trial is proposed, the specific protocol must demonstrate the utility of FDG PET for the diagnosis and treatment of neurodegenerative dementia-causing diseases. In this situation, the CMS concluded that an FDG PET scan was considered reasonable and necessary in patients with mild cognitive impairment or early dementia only in the context of an approved clinical trial that involves patient safeguards and protections to ensure proper acquisition, use, and evaluation of the FDG PET scan. The clinical trial must compare patients who do with those who do not undergo FDG PET and have as its goal the monitoring, evaluation, and improvement of clinical outcomes.


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  		Table 11. Specific Requirements for Medicare Reimbursement for FDG PET in Patients with Dementia

 

   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
References
 
This final article in the Molecular Imaging series is meant to provide an overview of the regulatory and reimbursement process for imaging agents and devices. As mentioned previously, as new technologies and techniques such as molecular imaging become available, the processes to obtain regulatory approval of the imaging agent by the FDA and, just as important, approval for reimbursement by the CMS must be closely adhered to. Many lessons have been learned from the imaging community's experience with FDG and PET. This knowledge and experience gained by the imaging community, together with the more open and transparent processes of both the FDA and the CMS to facilitate development and approval for new technologies, are encouraging. There are many challenges ahead, but as many in the imaging community have envisioned, we are just beginning to offer capabilities to improve the health and welfare of patients with many diseases with use of molecular imaging.


   FOOTNOTES
 

Abbreviations: CMS = Center for Medicare and Medicaid Services • FDA = Food and Drug Administration • FDG = [18F]fluoro-2-deoxy-2-D-glucose • IND = investigational new drug • RDRC = Radioactive Drug Research Committee

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 IMAGING AGENT DEVELOPMENT...
 RADIOACTIVE DRUG RESEARCH...
 IND PROCESS
 EXPLORATORY IND
 REIMBURSEMENT PROCESS
 CONCLUSION
 References
 

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