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The Food and Drug Administrationand Molecular Imaging Agents:

Potential Challenges andOpportunities

Jennifer A. Henderson, JD, MPHa, Brooke C. Alexander, JDa,John J. Smith, MD, JDab

Molecular imaging, which combines the use of traditional imaging modalities with pharmaceutical and biologicimaging agents, holds considerable promise, particularly in light of recent advances in genomics and newapplications beyond diagnosis toward the earlier detection and characterization of disease, the reliable assess-ment of treatment efficacy, and imaging-link therapeutic applications. Its potential notwithstanding, thecurrent U.S. Food and Drug Administration (FDA) regulatory framework governing imaging agents sets a highbar for marketing approval, which may slow the pace at which molecular imaging becomes routinely available.Understanding the FDA’s regulatory framework, the issues surrounding molecular imaging agents, and poten-tial opportunities will allow the radiology community to more effectively collaborate with the FDA to addressthese regulatory barriers and ensure that the full potential of molecular imaging is realized.

Key Words: Food and Drug Administration, molecular imaging agents

J Am Coll Radiol 2005;2:833-840. Copyright © 2005 American College of Radiology

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NTRODUCTION

olecular imaging is a rapidly evolving field that com-ines the use of traditional imaging modalities such asagnetic resonance imaging (MRI), positron emission

omography, and ultrasound, as well as promising tech-iques such as optical imaging, with pharmaceutical andiologic agents to image physiologic processes in vivo athe molecular level [1]. Although radiologists have beensing the basic techniques of molecular imaging for de-ades, recent advances in genomics, including the se-uencing of the human genome, are moving the field

Center for Integration of Medicine and Innovative Technology, Cambridge,ass.

Hogan & Hartson, LLP, Washington, DC.

*Corresponding author and reprints: Jennifer A. Henderson, JD, MPH,enter for Integration of Medicine and Innovative Technology, 65 Lands-owne Street, Suite 200, Cambridge, MA 02139; e-mail: jahenderson@artners.org.

This work was supported in part by a grant from the Center for Integrationf Medicine and Innovative Technology (CIMIT), a nonprofit consortiumounded by Partners Healthcare System, Massachusetts General Hospital,righam and Women’s Hospital, Massachusetts Institute of Technology andharles Stark Draper Laboratory. CIMIT is funded in part by the U.S. De-artment of the Army (agreement DAMD 17-02-2-0006). The informationn this article does not necessarily reflect the position of the U.S. government,

ind no official endorsement should be inferred.

2005 American College of Radiology091-2182/05/$30.00 ● DOI 10.1016/j.jacr.2005.04.005

eyond existing applications toward the earlier detectionnd characterization of disease, the reliable assessment ofreatment efficacy, and imaging-link therapeutic applica-ions [2]. Molecular imaging’s potential is so pro-ounced that it is thought by many to hold the future ofedical diagnosis and treatment for a wide variety of

onditions [3]. This potential notwithstanding, the cur-ent U.S. Food and Drug Administration (FDA) frame-ork governing the regulation of imaging agents sets aigh bar for marketing approval, a hurdle with the po-ential to slow the pace at which molecular imaging be-omes routinely available to patients in need. Under-tanding the FDA’s regulatory framework and the issuesurrounding molecular imaging agents will allow the ra-iology community to more effectively collaborate withhe FDA to address these regulatory barriers and ensurehat the full potential of molecular imaging is realized.

MAGING AGENTS GENERALLY

edical imaging agents are compounds, drugs, and/oriologics used in conjunction with an imaging modalityo allow for the improved conspicuity of a particularathology or anatomic area of interest. Imaging agentsave typically been used for diagnostic purposes, allow-

ng for the detection and localization of disease, though

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834 Journal of the American College of Radiology/Vol. 2 No. 10 October 2005

here are long-standing exceptions in nuclear medicine,s may be seen with diagnostic and therapeutic uses of31I [4]. There are two general types of imaging agents:ontrast agents and radiopharmaceuticals. Contrastgents, also referred to as imaging enhancers, are intro-uced into the bloodstream or a discrete anatomic spaceo improve the contrast between anatomic structures asisualized by medical imaging equipment and are thenxcreted or metabolized. Examples include such com-only used products as iodinated low-osmolar contrastaterial used in computed tomographic scanning and

adolinium in the setting of MRI. Contrast agents aresed with a broad range of indications and diseases. Ra-iopharmaceuticals, also referred to as probes or tracers,re substances or drugs that have been tagged with radio-uclides, which allows them to be traced, measured, or

maged on the basis of their physiologic interactions witharget organs. In addition to metabolic clearance andegradation, radiopharmaceuticals also undergo radioac-ive decay, a property that facilitates their imaging. Asith contrast agents, there is a wide variety of radiophar-aceuticals clinically used for a broad spectrum of con-

itions, such as Tc-99m methylene diphosphonate forone scanning and Tc-99m sestamibi for cardiac imag-ng.

In the context of medical imaging agents, molecularmaging agents represent the further refinement ofmaging agent technology, technology that can besed with a wide variety of imaging modalities toetter visualize pathology and anatomic structures.olecular imaging agents, which can be both contrast

gents and radiopharmaceuticals, build on the sensi-ivity and specificity of existing technologies, allowinghe visualization of molecular pathways with a highegree of fidelity. In short, these agents allow the

maging and quantification of molecular changes con-ected with specific diseases, possibly before the ap-earance of symptoms, as opposed to visualizing grossnatomic changes or gross metabolic activity [5]. Anxperimental example of a molecular imaging agent isbrin-targeted paramagnetic nanoparticles, which al-

ow the visualization of vulnerable plaque by MRI.he specificity of molecular agents will not be limited

o diagnosis alone but expanded to disease-specificherapeutics, likely linking both diagnosis and treat-ent in the same molecule [1]. Although disease-

pecific and even patient-specific molecular imagingpplications hold great promise in developing person-lized medicine that exploits the tremendous geneticariation that is known to exist between conditionsnd individuals, it necessarily limits the broad clinicalpplication of any one agent, as opposed to the currentandscape of broad clinical use of today’s contrast

gents and radiopharmaceuticals. s

Notwithstanding the great potential of molecular im-ging, the techniques and agents have been difficult toefine, likely affecting the development of the field. Add-

ng to this is a general lack of awareness within the radi-logy community that molecular imaging techniquesnd agents are already being developed and approved forlinical use [6]. A number of nuclear and MRI molecularmaging agents have already been approved by the FDAor marketing, with others currently undergoing clinicalesting, including Zevalin and Bexxar [6,7]. Despite aack of agreement on a concrete definition, various defi-itions have been set forth in the literature [8,9]. Thecademic radiology community has identified the essen-ial elements of molecular imaging generally to include1) highly specific imaging probes with high affinity forheir targets and acceptable biological delivery, 2) iden-ification of suitable targets, 3) appropriate amplificationtrategies, and 4) sensitive and fast imaging systems withigh resolution” [8].

RINGING IMAGING AGENTS TO MARKET

he process of bringing a medical imaging agent to mar-et under the current FDA regulatory paradigm is re-ource intensive, in terms of both the time necessary toatisfy the FDA’s stringent regulatory requirements forew drugs and the cost of research and development thatanges from animal testing to large-scale clinical trials. Inhe case of a radiopharmaceutical, additional regulatoryontrols imposed by the Nuclear Regulatory Commis-ion also add to this long and significantly costly process.or today’s diagnostic imaging agents, the target popu-

ations and possible applications are typically broadnough to justify such substantial investments fromponsors. In contrast, molecular imaging agents tend toave more specific disease targets, translating to more

imited target populations. Today’s regulatory paradigms uniformly applied across the spectrum of imaginggents, meaning that the time and resources necessary toring imaging agents to market remain constant,hether the target market is large or narrow. This creates

ignificant economic constraints on the development ofny molecular imaging agent intended for small popula-ions, a reality with the potential to substantially impedehe progress of molecular imaging.

The Tufts Center for the Study of Drug Develop-ent, a Boston-based academic, nonprofit research

roup affiliated with Tufts University, has reported theverage cost for pharmaceutical companies to develop aew drug at $802 million over the course of 10 to 15ears, a figure that incorporates out-of-pocket discoverynd preclinical development costs, out-of-pocket clinicalosts, attrition rates for clinical phases, overall clinical

uccess rates, and drug development time lines [10].

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Henderson, Alexander, Smith/The FDA and Molecular Imaging Agents 835

ome estimate a lower figure: Merrill Goozner, for exam-le, maintains that a more precise number would bepproximately one-fifth of the $802 million estimate11,12]. In any case, the average pharmaceutical requiresver a decade and hundreds of millions of dollars to reachDA approval [13]. Only 5 of every 5000 potential com-ounds tested will be taken to clinical trials, and only 1 ofhese 5 will be approved for patient use [11].

he Regulatory Framework

he FDA is charged with ensuring that medical productsre safe and effective for the indications that appear onheir agency-approved labeling. In the case of imaginggents, generally considered drugs under today’s regula-ory paradigm, the FDA’s Center for Drug Evaluationnd Research (CDER) is responsible for reviewing drugarketing applications pursuant to the regulatory re-

uirements set forth in the federal Food, Drug, and Cos-etic Act and subsequent amendments [14]. Medical

maging agents with biologic components may also beegulated by the Center for Biologics Evaluation andesearch under the applicable regulations for the market-

ng of biologic products [15].The process of gaining marketing approval for imag-

ng agents, particularly those that lack FDA approval forny indication, is a substantial endeavor for sponsors,equiring multiple phases of animal and human clinicalrial data to establish safety and efficacy. After the iden-ification of a promising compound or agent, the mar-eting approval process begins with preliminary animaltudies to determine metabolic processes and toxicity. Inhe case of satisfactory metabolic and toxicity results fromnimal testing, an investigational new drug approval ap-lication is filed, allowing the sponsor to begin humanlinical testing [16]. On the granting of an application,he first in a series of three phases of human clinical trialss started to assess the safety of the compound in ques-ion. Phase 1 studies involve a very small number ofealthy volunteers and are designed to determine meta-olic and pharmacologic actions, side effects associatedith dose size, and, in some cases, early evidence on

ffectiveness. Phase 2 clinical trials are conducted to ob-ain preliminary data on the effectiveness of the drug forparticular indication. In these studies, several hundredatients with the target disease or condition in questionre typically enrolled. Finally, Phase 3 studies involvingundreds to thousands of patients are intended to gatherhe definitive information about the effectiveness andafety needed to evaluate a drug’s overall benefits andisks. A determination of safety and efficacy thus turns onocumented data from the clinical trials, detailed de-criptions of the composition of the drug, the results ofnimal studies, and how the drug behaves in the body, as

ell as how the drug is manufactured, processed, pack- a

ged, and labeled. Randomized, controlled, double-lind studies are recognized by the FDA as the bench-ark, or “gold standard,” for establishing effectiveness.n the completion of all three phases of clinical trials, the

ponsor files a new drug application (NDA), which doc-ments the drug’s research history from conception toevelopment [17].At the time of NDA submission, the application is

orwarded to the appropriate division. In the case of anDA for a medical imaging agent, review will be under-

aken by the Division of Medical Imaging and Radio-harmaceutical Drug Products, a team consisting ofDER physicians, statisticians, chemists, pharmacolo-ists, and other scientists charged with the review of allDAs for imaging drugs administered in vivo and used

or the diagnosis or monitoring of disease in conjunctionith a variety of imaging modalities [18]. The division

eviews data from animal and human clinical trials, asell as the proposed labeling, and performs risk-benefit

nalyses [19].After the review of the NDA, the FDA may convene

n advisory committee of outside experts to review theafety and efficacy findings contained in the NDA andake a recommendation on the application [17]. Until

ecently, a special advisory committee, the Medical Im-ging Drugs Advisory Committee, was responsible foreviewing all medical imaging agent NDAs. However,fter an agency finding that imaging drugs could be ef-ectively reviewed by existing advisory committees orubcommittees, the Medical Imaging Drugs Advisoryommittee was dissolved in 2002 [20]. It is important toote that the FDA is not bound by committee recom-endations, though it generally follows them. On the

asis of review by an advisory committee, the CDER may1) approve the drug for marketing, (2) issue an “approv-ble” letter contingent on minor changes, or (3) issue anot approvable” letter.

As with all FDA-regulated products, gaining market-ng approval for an imaging agent does not signal the endf regulation, because postmarket mechanisms are appli-able to ensure the continued safety and efficacy of man-factured products. The CDER generally requires man-facturers to provide the FDA with safety updates,

ncluding reports of adverse reactions and importanthanges in frequency or severity of known adverse effects21]. In addition, manufacturers are required to complyith current good manufacturing practices to ensure thatrugs are being produced with high-quality compoundsn a continual basis [22].

egulation of Radiopharmaceuticals

adiopharmaceuticals present unique issues beyond ba-ic contrast agents because of the incorporation of radio-

ctive substances. These imaging agents are governed by

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836 Journal of the American College of Radiology/Vol. 2 No. 10 October 2005

pecific regulations issued in 1999, as well as additionalevels of control by other areas of government [23]. Forxample, the Nuclear Regulatory Commission regulateshe medical uses of radioactive materials under Title 10,art 35, of the Code of Federal Regulations, titled “Med-

cal Use of Byproduct Material,” to address the risks ofxposure to radiation for patients and medical personnel24]. The Nuclear Regulatory Commission licenses facil-ties, authorizes physicians to use radioactive materials,nd develops guidance and regulations for the use ofhese materials. In addition, the Radiation Protectionivision of the Environmental Protection Agency issues

tandards and guidance for waste management, siteleanup, emergency response, technology, and the riskssessment of radioactive materials used in the medicaletting [25].

Pursuant to the Food and Drug Administration Mod-rnization Act of 1997, legislation aimed at improvinghe efficiency of medical product reviews, the FDA wasnstructed to issue regulations for the approval of radio-harmaceuticals [26]. In response, the FDA released anal rule governing radiopharmaceutical drugs and bio-

ogics, “Regulations for In Vivo Radiopharmaceuticalssed for Diagnosis and Monitoring,” in May 1999 [23].he rule applies to radiopharmaceuticals for diagnostic

nd monitoring use, while specifically excluding thera-eutic agents.Under the final rule, an NDA for a radiopharmaceu-

ical is evaluated on the basis of the same factors used inhe evaluation of nonradiopharmacologic imaginggents. Thus, an NDA for a radiopharmaceutical can bepproved only when there are sufficient data showinghat the proposed product is safe for use under the con-itions prescribed, recommended, or suggested in itsroposed labeling [27]. In addition to these standardequirements, the agency also considers the pharmaco-ogic and toxicologic activity of the agent and its esti-

ated absorbed radiation dose in determining safety andffectiveness [28]. The evaluation of the safety and effec-iveness of a radiopharmaceutical is dependent on theroposed indications, of which the rule lists two catego-ies: one for diagnostic radiopharmaceuticals intended torovide disease-specific information and one for diagnos-ic radiopharmaceuticals not intended to provide disease-pecific information [29]. Radiopharmaceutical imaginggents may also have more than one indication, such as aiagnostic and a therapeutic patient management indica-ion, in which case the radiopharmaceutical will be eval-ated taking into account each intended use.In assessing safety under the final rule, the FDA eval-

ates the radiation dose, the pharmacology and toxicol-gy of the radiopharmaceutical, the risks of an incorrectiagnostic determination, the adverse reaction profile of

he drug, the results of human experience with the radio- c

harmaceutical for other uses, and the results of anyrevious human experience with the carrier or ligand ofhe radiopharmaceutical when the same chemical entitys the carrier or ligand has been used in a previouslytudied product [30]. Pharmacology, toxicology, clinicaldverse event, and radiation safety assessment data arelso requested [31]. The FDA may also require newafety data depending on the characteristics of the prod-ct and available information concerning the safety ofhe diagnostic radiopharmaceutical and its carrier or li-and, taken from other studies and uses [32].

In evaluating the effectiveness of radiopharmaceuti-als, the FDA assesses the agents’ ability to provide “use-ul clinical information” related to their proposed indi-ations [33]. A diagnostic radiopharmaceutical mayrovide useful clinical information without being di-ectly effective for the detection or assessment of a diseaser without aiding patient management by, for example,ndirectly helping a physician plan and perform surgery34]. The accuracy and usefulness will be determinedrom a comparison with a “reliable assessment of actuallinical status,” presented by a diagnostic standard, stan-ards of demonstrated accuracy, or in another manneruch as patient follow-up [35].

DA Guidance Applicable to All Imaginggents

he final rule governing the regulation of radiopharma-euticals was welcomed by industry, providing mucheeded clarification of agency expectations for diagnosticadiopharmaceutical applications and bringing with ithe potential to reduce the cost of gaining marketingpproval. Because of the lack of similar guidance foronradiopharmaceutical imaging agents, the FDA ex-anded the general concepts found in the final rule gov-rning radiopharmaceuticals to all imaging agentshrough a series of three related guidance documents,eveloping Medical Imaging Drug and Biological Products,

eleased in June 2004 [36]. Prepared by the CDER’sivision of Medical Imaging and Radiopharmaceuticalrug Products in collaboration with Center for Biologicsvaluation and Research’s Office of Therapeutics Re-

earch and Review, the guidance documents provideonbinding information on how the FDA will interpretnd apply the final rule governing radiopharmaceuticalso all imaging agents, containing advice and recommen-ations to assist sponsors in planning and coordinatinglinical investigations and subsequent premarket submis-ions. It is important to note that these guidance docu-ents do not apply to the development of in vitro diag-

ostic or therapeutic uses of these agents. In fact, theuidance explicitly states that because medical imaginggents are used solely to diagnose and monitor diseases or

onditions, as opposed to treating them, programs for

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edical imaging agent development can be tailored toeflect this. Because they are relatively new and have yeto be fully implemented, the effect of these guidanceocuments on the review and approval of specific agents

s currently unknown.In part 1, “Conducting Safety Assessments,” the FDA

as divided imaging agents into two general categories:1) contrast agents, defined as “medical imaging agent[s]sed to improve the visualization of tissues organs andhysiologic processes by increasing the relative differencef imaging signal intensities in adjacent regions of theody”; and (2) diagnostic radiopharmaceuticals, whichre defined in the same manner as in the final rule: radio-ctive drugs or biologic products containing radionu-lides linked to ligands or carriers and used in nuclearedicine procedures [36].Part 1 also creates a two-tiered classification system foredical imaging agents, with corresponding clinical

afety monitoring and evaluation factors to assist spon-ors in preparing submissions [36]. Imaging agentslaced in group 1 generally require less extensive clinicalafety evaluation than imaging agents placed in group 2.hree general elements are required for an imaging agent

o be placed in group 1. First, the agent should meetither the safety-margin considerations or the clinical-useonsiderations described in the guidance documents.econd, the agent must not be a biologic product. Last,he imaging agent must not predominately emit � or �articles [36]. Generally, imaging agents administered in

ow mass doses are likely to be considered group 1 agents,ompared with agents with higher mass doses. Althoughtandard clinical safety evaluations must be performed inll clinical investigations, group 1 imaging agents mayenefit from reduced human safety monitoring require-ents in subsequent human trials [36]. Any imaging

gent that does not meet the criteria for group 1 place-ent is considered a group 2 agent. Thus, all biologic

roducts are considered group 2 agents until such time asponsors can show a lack of immunogenicity for thosemaging agents [36]. Sponsors of group 2 agents mustubmit information demonstrating serial assessments ofatient symptoms, physical signs, clinical laboratoryests, and other tests and adverse event reports as part ofhe standard clinical safety evaluations. Additional spe-ialized evaluations may be required.

Part 2, “Clinical Indications,” outlines the agency’sxpectations for each phase of clinical trials [37]. Thevailable indications for imaging agents under the agen-y’s guidances are identical to those provided in the finalule governing radiopharmaceuticals: structure delinea-ion; disease or pathology detection or assessment; func-ional, physiologic, or biochemical assessment; and diag-ostic or therapeutic patient management. It is

mportant to note that the guidance provides additional w

etail regarding the agency’s expectations for each spe-ific indication, specifically for the evaluation of safetynd effectiveness [37].

Finally, the third part of the series, “Design, Analysis,nd Interpretation of Clinical Studies,” addresses agencyonsiderations when evaluating the design, analysis, andnterpretation of studies [38]. In clinical efficacy studies,ubjects should be representative of the population inhich the medical imaging agent is intended to be used,

nd the means by which the patients were chosen shoulde included in the protocol and study reports. The FDAill also look for fully blinded image evaluations or image

valuations blinded to outcomes for independent readersesignated as performing the principal image evaluations38].

HALLENGES UNDER THE CURRENTEGULATORY PARADIGM

he tremendous potential of molecular imaging is gen-rating excitement in the radiology community and inhe general medical community. This enthusiasm is tem-ered by the reality that years if not decades of research lieetween today’s technology and broad clinical applica-ion of molecular-based imaging and therapeutics. If andhen these scientific challenges are successfully ad-ressed, today’s imaging agent regulatory paradigmromises to create substantial obstacles that could im-ede the application of molecular imaging to patients ineed.Molecular imaging is the rational progression of med-

cine to meet the challenges posed by considerable varia-ion in disease and response to treatment. By developingmaging diagnostics and therapeutics in a meaningfulay to address the molecular processes responsible forisease, molecular imaging promises increased sensitivitynd specificity, as well as more effective therapy. In es-ence, these molecular techniques move medicine awayrom disease and pathology as a uniform phenomenoncross populations, to a smaller group or even individu-lized process that more accurately reflects the geneticomplexity and uniqueness of individual patients.

This increasingly personalized approach to diagnosisnd treatment potentially offered by molecular imagings an imperfect fit with today’s imaging agent regulatoryaradigm. The FDA currently regulates imaging agentsnder a new drug approval paradigm that dates back tohe early 1960s, an era when little was known about theonsiderable genetic variation in individuals and the dis-ases that afflict them. Consequently, this paradigm wasesigned to ensure safety and effectiveness across largeropulations, reflecting the assumption that a drug thatorked in one individual with a given condition would

ork equally well in another with the same condition.

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838 Journal of the American College of Radiology/Vol. 2 No. 10 October 2005

he result was the rise of extremely expensive, time-onsuming studies that generate large group data, impos-ng regulatory costs that could only be absorbed by drugshat are sold at high cost to large populations.

Accumulated evidence since the inception of theDA’s regulatory paradigm demonstrates a far moreomplex picture of patients and the drugs used to treathem. Genetic differences across sexes, races, and evenndividuals have been convincingly shown to affect theafety and effectiveness of drugs. Despite this evidence,he new drug regulatory paradigm, and with it the regu-ation of medical imaging agents, has remained un-hanged. For example, it is impractical to conduct atandard phase 3 clinical trial, which typically involvesundreds to thousands of patients, on a molecular agentesigned to image a rare subtype of lung cancer that onlyffects a few thousand patients per year nationwide. Evenf it were possible to identify and recruit patients forlinical trials with these relatively small patient popula-ions, it is unrealistic to expect any commercial sponsoro assume the high cost of such studies in the face of amall potential market. All of these issues become moreronounced as patient populations become smaller orven individual.

The mismatch between today’s regulatory frameworknd the potential future of molecular imaging will likelyequire short- and long-term solutions. As a long-termolution, one approach would be to assess the feasibilitynd desirability of an alternative regulatory mechanismor molecular imaging agents, one that continues to en-ure their safety and efficacy but that represents a lessrohibitive obstacle to market and thus a more commer-ially attractive environment for development. However,lthough the current regulatory framework is ill suitedor the ultimate potential of molecular imaging, a com-lete overhaul of the existing regulatory framework orntroduction of a new regulatory pathway for thesegents is likely premature, considering the early stage ofhis field. Recognizing the potential of molecular imag-ng, the most valuable short-term approach may be toxplore solutions that will ease the development and reg-lation of such agents in the near term, one that serves tooster incentives for the development of molecular imag-ng agents in spite of the current framework. As the field

atures and the FDA and the medical community be-ome more familiar with the characteristics of futuregents and their clinical applications, a long-term ap-roach to the reworking of the regulatory frameworkight be revisited.One example of a targeted solution that could provide

framework to foster the development of molecular im-ging agents in the short term is the existing Orphanrug Act. The Orphan Drug Act was signed into law in

he early 1980s to address a general lack of research and r

evelopment of medical products to treat rare conditionsecause of the small market potential and considerableesource requirements [39]. The Orphan Drug Act of-ered incentives to manufacturers for the development ofrugs and biologics used to treat rare diseases and condi-ions, defined as

ny disease or condition which (a) affects less than 200,000 persons inhe U.S. or (b) affects more than 200,000 persons in the U.S. but forhich there is no reasonable expectation that the cost of developing

nd making available in the U.S. a drug for such disease or conditionill be recovered from sales in the U.S. of such drug [40].

Under the act, the major incentive for developers ofrphan products is the guarantee of 7 years of marketxclusivity after FDA approval. Other incentives offeredy the act include tax credits for clinical testing expenses,ormal protocol assistance, and, most important, researchrants. The Office of Orphan Products Development,stablished to identify orphan products and administerhe program, operates a clinical research grants program,hich provides funding to researchers for clinical trials to

ssist in gaining FDA approval of drugs, biologics, med-cal devices, and medical foods for rare diseases and con-itions [41].A similar type of program is offered specifically for

evices under the Humanitarian Use Device paradigm,hich allows the FDA to grant a humanitarian device

xemption [42,43]. Humanitarian device exemptionsere designed to create incentives for manufacturers toevelop devices that are intended to benefit patients inhe treatment and diagnosis of diseases or conditions thatffect fewer than 4000 individuals in the United Stateser year. If qualified, these devices are exempt from ef-ectiveness requirements because of the limited practica-ility of a clinical trial. Pursuant to the regulations, themount charged for the device cannot exceed research,evelopment, fabrication, and distribution costs [44].Beyond the broad incentive issue created by the cur-

ent regulatory framework, the focus of existing agencyuidance and regulations for medical imaging agents isimited to diagnostic applications. Historically, imaginggents have been used primarily to diagnose and monitoriseases and conditions. The three-part series of recentuidance documents discussed above is no exception,ecause their application is limited to imaging agents foriagnostic and monitoring uses with an explicit exclusionor therapeutic uses. In fact, this series of guidances rep-esents the FDA’s effort to allow development programsor imaging agents to be tailored to reflect these limitedpplications. With the introduction of therapeutic appli-ations and targeted agents, additional guidance from thegency will likely be necessary. Presumably, the develop-ent of imaging agents with therapeutic indications will

equire more rigorous data and agency scrutiny in the

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pproval process than required for imaging agents usedor purely diagnostic purposes, translating into moretringent requirements to provide evidence of safety andffectiveness. Moving in this direction, toward additionalequirements and greater resource expenditure to bringargeted or individualized therapeutic imaging agents toarket, will only aggravate the current situation.The challenges of molecular imaging notwithstand-

ng, government, industry, and the academic communityave recognized the potential of this field. New collabo-ative efforts in the form of special programs and part-erships are under way in industry and at the federal

evel, providing a roadmap for future approaches. Onexample specific to imaging agents is the Development oflinical Imaging Drugs and Enhancers program, createdy the National Cancer Institute and designed to offernvestigators access to the preclinical development re-ources of the institute for selected imaging agents [45].ocused on promising agents that are not otherwise likelyo undergo adequate preclinical testing to warrant anND application, the program considers contrast agents,iologic and molecular probes, radiolabeled compounds,nd other agents that may be integral parts of image-arget therapy. The program is intended to assist in pre-linical evaluation to establish proof of principle and torovide access to molecular probes for approved preclin-cal protocols. In addition to this targeted effort, the

ational Cancer Institute also plans to focus much of itsuture nanotechnology research in the area of molecularmaging and early detection.

In the near term, current federal initiatives to fosternnovation and improve the development and transla-ion of innovative medical products to patient care offervaluable opportunity for the radiology community to

pproach these challenges. The U.S. Department ofealth and Human Services is committed to speeding

he development and availability of innovative medicalechnologies via improved coordination and collabora-ion among its constituent agencies including the Na-ional Institutes of Health (NIH), the Centers for Dis-ase Control and Prevention, the FDA and the Centersor Medicare and Medicaid Services, as outlined in aecently released report, Moving Medical Innovations For-ard—New Initiatives from HHS [46]. In addition, two

pecific federal initiatives currently under way, one at theIH and the other at the FDA, should be harnessed by

takeholders to identify and address the challenges ofolecular imaging: the NIH Roadmap for medical re-

earch and the FDA’s Critical Path Initiative. The NIHas identified molecular imaging as a focal point of itstrategic goals, with the specific aim of linking molecularmaging programs, probes, and libraries to accelerate de-elopment of the field and more specific therapies, with

umerous initiatives and programs under way [47]. On

he regulatory front, the FDA has committed to investi-ating opportunities to improve the medical develop-ent process, an initiative through which stakeholder

nvolvement may help shape future regulatory opportu-ities for addressing molecular imaging-specific chal-

enges. The FDA’s recently released guidance in the areaf pharmacogenomics is also indicative of the agency’secognition of movement toward personalized medicine48].

In addition to unique efforts and opportunities at theederal level, industry has begun forming internal andxternal collaborations that aim to advance molecularmaging applications while addressing some of the previ-usly identified obstacles. For example, GE Medical Sys-ems, Philips Medical Systems, and Siemens Medicalolutions have devoted considerable resources to estab-ishing and developing internal research and develop-

ent capabilities based on the future potential of molec-lar imaging, while also partnering with outsideiotechnology, pharmaceutical, and academic institu-ions with the goal of sharing the responsibilities, costs,nd risks associated with research and development inhis area.

ONCLUSION

olecular imaging is a complex, multidisciplinary fieldhat will require significant educational efforts, more spe-ific characterization of the underlying scientific andedical issues, and subsequent regulatory issues to max-

mize the potential of the field. Although a major over-aul of the current regulatory framework is likely prema-ure at this point, unique regulatory approaches orathways geared to address the significant challenges ofolecular imaging may assist in aligning incentives to

oster continued efforts, collaborations, and progressoving forward. The radiology community should seize

urrent opportunities at the federal and private levels todvance the field and maximize the potential of molecu-ar imaging for improved patient care.

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