Kristin Brooks06.03.09
Clinical Trial Imaging
Innovation, trends and challenges
By Kristin Brooks
Given the demand in drug development for both discovery and development biomarker capabilities, imaging has become an increasingly valuable tool. Pharmaceutical and biopharmaceutical companies are progressively using imaging as an endpoint or surrogate endpoint, as part of their clinical trial designs. This plays into the goals of the FDA’s critical path initiative—using technology, imaging in particular, to enhance and expedite drug development efforts.
Photo courtesy of WorldCare Clinical |
Although certain imaging methods can be expensive, using imaging technology can provide cost savings by reaching earlier go/no-go decisions, in addition to generating clear data of the drug’s efficacy. Growth in imaging services has been strong and technology continues to advance, helping to ease image quality issues, but standardization issues and timeliness of imaging analysis remain obstacles.
Patrick McConville, Ph.D., director of imaging at Charles River Laboratories, and president Rick Taranto and chief medical officer Dr. Richard Walovitch of WorldCare Clinical, address the latest innovations, industry trends, and challenges from their perspectives as providers of clinical trial imaging.
Contract Pharma: Please briefly discuss the goals behind Charles River’s acquisition of MIR Preclinical Services.
Patrick McConville: Last September, Charles River announced the acquisition of MIR, which became part of the company’s newly named Discovery and Imaging Services and provides non-GLP pharmacology services to evaluate the efficacy of compounds. MIR enhances Charles River’s portfolio by offering expertise in key therapeutic areas including oncology, inflammation and cardiovascular disease. The expertise in these disease areas is complemented by comprehensive in vivo imaging capabilities, including magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT) and in vivo optical imaging.
CP: Has decreased preclinical demand had an impact on imaging services?
PM: Imaging, similar to other areas of the drug development process, is not immune to the global economic crisis. However, preclinical imaging has become recognized in recent years as a valuable tool for improving the efficiency and accuracy of the drug discovery and development process. As a result, the pharmaceutical industry is increasingly embracing imaging, as it can offer important and valuable improvements over traditional drug discovery methods. Specifically, imaging methods can provide earlier and more highly predictive and quantitative endpoints, facilitate clinical translation, and increase the power and efficiency of clinical trials.
CP: What are some of the latest innovations and trends in clinical trial imaging?
PM: There are many imaging innovations that help to achieve effective and timely endpoints in clinical trials. Reliable, early indicators have enormous potential for enhancing the predictive power and efficiency of clinical trials. Image-based biomarkers fall into this category, and are increasingly used for exactly this purpose. Examples in anti-cancer drug discovery include dynamic contrast-enhanced magnetic resonance imaging (DCE MRI), diffusion MRI, and FDG and FLT PET. These technologies enable early indicators, since they measure early anti-cancer effects at the cellular level, and unlike traditional methods, do not necessarily rely on much later gross effects (e.g. tumor size changes). The nature of these ‘cell targeted’ biomarkers is that they also allow validation of the drug’s intended target in the clinical trial, something that has facilitated the development of several currently approved targeted therapies.
Dr. Richard Walovitch: We’re seeing a lot of volumetric analysis, which requires 3-D volume or continuous slices of organs, where instead of just looking at height and width, you look at depth as well. We’re seeing a lot of that in CNS studies, as well as changes in criteria for oncology studies. Also positron emission tomography (PET) is getting to be very popular in oncology, where they’re trying to understand the metabolic rate of the tumor tissue, which you can see with positron tracers. That’s another innovation that’s starting to make its way into clinical drug development, as well as dynamic contrast MRI. Those are some of the more innovative ways that we try to understand what’s going on physiologically with diseases. We’re studying those longitudinally with drugs and seeing if the imaging changes over time.
CP: Does innovation in imaging impact cost and efficiency for trials?
PM: Imaging is now a key tool to enable earlier and more effective go/no-go decisions in the drug development process. It also facilitates clinical translation of both new drugs and the methodologies best suited to determine effectiveness. Importantly, imaging provides a noninvasive method to track the progression of a drug in a single subject over a period of time.
For example, diffusion MRI and FDG PET provide quantitative readouts of an anti-cancer drug’s effectiveness in a human patient in weeks, compared with the months that traditional tracking of tumor size can take. At the preclinical level, the readout can occur in hours/days, instead of weeks/months. Not only does this save time, but the nature of these methods also provides information at the cellular, targeted level, increasing predictive power at the same time. Through the use of earlier and more highly predictive image-based biomarkers, clinical trial efficiency is greatly increased. For example, imaging can enable more efficient enrolling and de-enrolling of clinical trial patients, leading to enormous savings in drug development costs for the pharmaceutical company.
Rick Taranto: The opportunity for cost savings, particularly using these imaging endpoints or imaging modalities, is to get a clearer understanding of the impact of therapy being tested, giving sponsors better information to make more qualified earlier-stage decisions. Also, with a drug that’s moving forward in the development process in Phase II or Phase III, it creates the opportunity to shorten the duration of the study. In an oncology program for example, now you’re evaluating progression-free survival as an endpoint, as opposed to overall survival.
CP: From what industry segment do you see the most business arising?
RT: We continue to see that most of the opportunities that WorldCare’s invited to bid on are brought directly to us from sponsors. Imaging, from our experience, seems to be an area that sponsors want to be very engaged in and have complete control of in terms of selection. There are those opportunities that come to us from a CRO involving a smaller trial for a company that may only have a single product and wants to outsource the full management of the trial to a CRO, but most of our contact is with a mix of large pharma, biotech, and is expanding into the medical device side.
CP: What are the standardization issues for clinical trial imaging?
PM: Standardization of imaging protocols has undoubtedly been a major obstacle to broad validation and acceptance of imaging methodology. By the complex nature of imaging protocols, the potential for inconsistencies between protocols running at different sites using different equipment is ever present, and, unfortunately, has led to difficulty in advancing imaging techniques to the point of FDA acceptance, for example. Various bodies have recognized these issues and consortiums have been formed to standardize key imaging protocols, such as diffusion MRI, DCE MRI, and FDG and FLT PET.
CP: What is the typical time it takes from the imaging procedure to reach the recipient?
PM: Image analysis is the predominant bottleneck in both preclinical and clinical. The latest generation imaging systems for MRI, PET, SPECT and CT can generate data much more quickly than an authorized expert can analyze it. Typical times for clinical imaging are a few days to a week or so. This has led to new innovations in the way data is stored and accessed, as well as increased outsourcing of image analysis or image reads, leveraging shift work or work performed by experts in other time zones. At Charles River, we are not only seeing increased demand for image procedure services, but also for image data analysis services.
CP: How far off is the automation of procedure to recipient and image-based adaptive trials?
PM: The use of more highly automated procedures for image analysis has been controversial and has yielded mixed results. Significant enhancements in software capabilities, as well as national and global unification of imaging protocols, are needed if we are ever to move toward automation of image analysis and endpoint determination. Right now, the focus needs to be on acceptance of an expanded suite of imaging procedures and indications for reimbursement as well as FDA acceptance. This will pave the way for improved technology, increased automation and the use of adaptive trials guided by image-based endpoints that will be translatable between clinical and preclinical imaging.