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Commentary |
Cambridge, Massachusetts, USA
Developments in the visualization of molecular events in vivo are progressing at an unprecedented rate, a characteristic of rapidly developing or emergent technologies. The need to target the molecular mechanisms of disease has been the driving force behind this rapid growth in knowledge whilst the bridging of disciplines, such as imaging science, chemistry and biology, in some cases with a good deal of entrepreneurship, has made such technological advances possible. At the vanguard is the field of targeted molecular imaging agents. Targeted molecular imaging agents are now used in biological, medical and pharmaceutical research where they are proving to be powerful tools in the investigation of experimental in vivo systems. It is almost taken for granted that these technologies will translate readily into clinical practice, providing unique molecular information on disease. But will targeted molecular contrast agents reach the clinic and deliver the benefits expected of them? Journals, conferences and societies are now dedicated to molecular imaging and targeted contrast agents. But to make an agent available to widespread clinical use requires regulatory approval from either the Food and Drug Administration (FDA) in the USA or the European Agency for the Evaluation of Medicinal Products (EMEA) in Europe. The main purpose of these agencies is to ensure that safe and efficacious agents reach the market while denying access to agents that do not meet these standards.
In defining targeted molecular imaging agents I am specifically referring to agents that will be used widely in the clinic and be prescribed because of their role in guiding clinical management. This is quite different from how such agents are currently used in, for example, probing cell biology or validating drug targets. Positron emission tomography (PET) tracers are making an impact in drug development and are likely to increase in use, but the widespread translation of these techniques into the clinic is unlikely to occur. Also excluded are the niche applications such agents might have in the manner of in vitro biomarkers [1]. Nevertheless, the medical community has high expectations of targeted molecular imaging. Witness the investment by national, private and business institutions across Europe and the USA. But if targeted contrast agents are increasingly viewed as potentially important clinical biomarkers, the role and value of using these agents remains to be established, and in this commentary I discuss in brief whether there is a realistic prospect of this occurring.
Clinically, molecular imaging has been successfully applied for several decades via radionuclide imaging and, more recently, via modalities such as magnetic resonance [2, 3] and ultrasound. To address whether targeted contrast agents will reach the clinic requires an understanding of the process behind the development of a contrast agent. A contrast agent, despite rarely being administered more than once, is a drug and is treated as such by regulatory authorities. Prior to approval for clinical use, a contrast agent would have been guided through the discovery and development phases by a biotechnology or large pharmaceutical company, often in collaboration with academia. The processes require the coordination and cooperation of multidisciplinary teams. The financial outlay in bringing a contrast agent from the laboratory to the clinic is in the order of $100–150 million. This is a small sum compared with a therapeutic drug whose development costs, depending on the manner in which the data are interpreted, are reported to be on the order of $800 million [4]. However, the time required to develop such a contrast agent is no less than a therapeutic; it takes at least 8–10 years to bring any drug to market. More importantly, diagnostic imaging agents are very unlikely to return the type of profits seen with therapeutic drugs [5]. It is difficult to imagine how molecularly targeted agents are going to bring an equal or greater return than the non-specific imaging agents currently available in the clinic. The cost of targeted imaging agents may therefore be higher than expected, and this effect could be compounded by increasing price controls being imposed on drugs by governments.
Any drug must demonstrate safety and efficacy in order to gain regulatory approval, and much of the drug development process is geared toward achieving this goal. The most recent regulatory review of a MRI agent was that of EPIX Pharmaceuticals, Inc. (Cambridge, MA). An NDA (new drug application) had been filed in December 2003 with the FDA, supported by four phase 3 international multicentre trials. The drug (VasovistTM) is a blood pool agent targeted to human serum albumin, and is intended for use as an MR angiography agent. The FDA's fundamental concern was with the efficacy data. My personal view (the author was the head of imaging at EPIX following the original approvable letter) is that the conflict between the FDA and the company can be distilled to two issues, namely (1) to what level is it reasonable and necessary to deconstruct a clinical experiment (in the manner of a laboratory bench top experiment)? And (2) what is a reasonable level of experimental standardization? These two issues are intimately related and affect how widely applicable the results are in clinical practice. The company unsuccessfully argued that clinical practice at individual sites or the equipment manufacturer's sequence recommendations are a de facto basis of standardization (and showed that the variation in acquisition techniques was in fact very small and did not significantly affect the results). The FDA declined to accept this argument on the grounds that the efficacy results might still be biased in favour of the drug and therefore did not approve the compound (the actual term was "approvable", but the result is that the compound is not approved for use in man in the USA). Further details can be found in the press release section of EPIX's website at www.epixpharma.com.
The role of the FDA is to protect the health of the USA by approving, on a scientific basis, safe and effective drugs. But it also has the clear duty of not withholding beneficial drugs from the public. More often than not there is a fine balance between these two alternatives, especially at a time of heightened public and political scrutiny of the drug development business. The European authorities approved the drug in September 2005 after a 15-month review utilizing the same clinical data submitted to the FDA.
This is not to say that there is a fundamental difference in the goals of EMEA and the FDA. Although organizationally different, EMEA differs little from the FDA with respect to the challenge of evaluating new targeted contrast agents. One fundamental difference is that EMEA's decisions tend to be more reliant on the review of impartial outside experts for the technical assessment of an application. EMEA, for example, has a document analogous to the FDA's guidance document on imaging agents "Points to consider on the evaluation of diagnostic agents". Of note is the European position that "...there are no generally accepted principles for the evaluation of efficacy of diagnostic agents", indicating it is for the sponsor to provide convincing clinical scientific evidence of efficacy.
I remain troubled that the American public has been denied a valuable diagnostic agent. No one will deny the importance of experimental standardization, and standardization is straightforward when dealing with the physical parameters that define radionuclide or X-ray based imaging. Standardization is subtler when dealing with MRA where there is no meaningful standard comparator, and there are several different, but equally representative ways to approach imaging inflowing blood. In the EPIX trials, VasovistTM was compared against blood flow techniques such as time-of-flight and phase contrast angiography. EPIX's argument was that the drug was effective in clinical practice, which is a legitimate means by which to seek approval. Indeed, adopting arbitrary standardized parameters, in the case of flow-sensitive techniques when there is no proven superiority among several approaches, might itself result in unexpected bias. Those in the field of MRA and particularly those who are involved in drug-related studies should oppose where appropriate the unilateral imposition of views that do not take into account the complexities of the modality being studied.
Whatever the merits of this case, this series of events provides insight into the regulatory hurdles to the delivery of a drug/imaging agent to market. Such setbacks are ultimately resolvable, but remain a concern for industry strategists and decision makers who finance investments in research and development (R&D).
The recent review of another MRI contrast agent (Combidex; Advanced Magnetics, Inc., Cambridge, MA; www.advancedmagnetics.com) highlights additional regulatory challenges faced by an imaging agent. Combidex, an iron oxide nanoparticulate, was issued an "approvable" letter by the FDA following review by an advisory committee, but for very different reasons from EPIX. An advisory committee consists of a panel of experts called by the FDA to make a recommendation, usually on one or a small handful of questions that guides the Agency's decision making. Details of the FDA's advisory committee (which sat in April 2005) on the subject can be found at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4095T1.pdf. Bearing in mind that submission for regulatory approval encompasses a substantial body of work including chemistry, manufacturing, toxicity, pre-clinical and clinical data that are typically the sum of 8–10 years of work, Combidex remains unapproved because both the FDA and the independent advisory committee criticised aspects of its safety profile, requesting too broad an indication and in providing limited efficacy data. These two cases as indices of the regulatory climate for imaging agents in man have left a sense of considerable unease in the world of diagnostic imaging agent development.
Efficacy, safety and regulatory issues not withstanding, additional technical issues for consideration in the development of a targeted contrast agent include identifying a target of interest, recognizing its biological significance and assessing the likelihood of discovering and synthesising an agent that will bind specifically to and be at sufficient concentration at the target site to generate a recordable signal. Any of these issues could prove to be as problematic as any regulatory, efficacy or safety issue. But in part, the role of the translational radiologist in collaboration with scientific colleagues will be to navigate and guide those imaging studies that will define the clinical efficacy and relevance of a targeted imaging agent to satisfy both regulators and consumers. These studies will influence whether the commercial argument can be made that will stimulate investment in developing targeted contrast agents. Ultimately, the sales of an agent will be an index of its clinical value. A successful agent will be rapidly assimilated into clinical practice where further refinements in dosage, indication and safety profile will be determined.
Can targeted agents be brought into the clinic, or will they simply remain laboratory tools divorced from clinical application? The answer is, of course, that any efficacious and safe agent can be brought to the clinic, but at what price? More important is the question of whether such agents will make an impact on clinical practice, and this is a more difficult answer to predict. Regulators are not in agreement as to the requirements for demonstrating likely clinical impact before approval. The need for development both in clinical trial designs and in appropriate criteria for regulatory requirements may override any other limiter on the adoption of molecular imaging in the clinic. Indeed it is surprising that the imaging community, despite its resolve to promote molecular imaging, has been almost mute in its response to the current regulatory climate. I strongly encourage the radiological community to give it some thought.
As end-users, radiologists and medical-imaging scientists have influence over contrast agent development. Their technical expertise is sought to guide the practical application of imaging strategies, but the radiological community has limited exposure of the drug development world in terms of the requirements, needs and execution of imaging trials. Imaging experts could become more engaged in the development of new imaging agents, particularly of targeted contrast agents by:
The opportunity is there and need only be taken up by the radiological community. It would be sad if the only legacy of targeted imaging agents were a wealth of good science, but shameful if patients were not to benefit from its findings.
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Acknowledgments |
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The opinions expressed in this manuscript are those of the author and do not necessarily reflect those of other parties or institutions. No financial conflict is declared.
Received for publication April 6, 2006. Revision received July 25, 2006. Accepted for publication July 31, 2006.
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