The quality of clinical trials is highly dependent upon the ability of clinical investigator sites to perform their responsibilities effectively. As clinical protocols become increasingly more complex and clinical development becomes more global in scope, the ability to fully meet the needs of investigator sites is also becoming a more critical factor in ensuring the successful outcome of clinical trials. 

Understanding and responding to the daily challenges that sites face, as well as their views on the tools they use to communicate about and manage the study, can also foster a better working relationship between the site, study sponsor, CRO, and central laboratory. 

In 2008, ICON Central Laboratories, a global central laboratory provider, surveyed over 9000 investigator sites around the world to obtain more detailed information about the environment in which sites work, the stresses they encounter, and the types of services that might improve the way they manage daily research activities. The survey responses provide interesting trends and insights regarding how study coordinators, in particular, view and/or are affected by: 					

The type of clinical setting in which they work

The balance between rendering patient care and conducting research functions

The most time consuming aspects of the research responsibilities

The means by which they communicate with the study team and central lab

The type of support services provided by their central laboratory

These results offer study sponsors, CROs, and central laboratories guidance in how they can refine their services to better support investigator sites as they fulfill their critical roles in the conduct of clinical trials. 

ICON Central Laboratories' first annual investigator site survey was conducted in May 2008. The survey was disseminated via email to over 9000 sites worldwide using a commercially available Web-based survey software. It included 33 questions, most involved the use of a rating scale as well as "skip logic," which drilled down to additional questions only when previous responses warranted it. The survey also included several open-ended questions to permit elaboration and additional comments. 

Input regarding the survey design was obtained from B2B International, an internationally recognized market research firm with experience in the pharmaceutical industry. The survey was conducted in English only. To improve response rate, responders were entered into a drawing to receive one of 15 iPod nanos. 

The overall response to the survey was 24%, a rate considered quite good given the mode of survey delivery, the nature of follow-up, and the single language (English) in which the survey was provided. The response rate from North American sites, which represented 69% of those surveyed, was 26%. The response rate for sites in the rest of world (ROW) was 19%. The regional distribution of respondents is indicated in Figure 1. 

  Figure 1: Regional Distribution of Sites			

Due to the low response rate in certain countries/regions, it was not possible to perform a comprehensive geographic analysis of the survey responses. However, some differences could be discerned between some regions and countries that could prove useful in both targeting and refining services. 

Respondents were overwhelmingly study coordinators, with 85% describing themselves as serving in that role. For that reason the responses of study coordinators are the focus of this article. Figure 2 displays the distribution of respondents by research role. 

For the survey, as a whole sites were fairly evenly distributed by inpatient, outpatient, and strictly research facilities. However, when analyzed by country/continent, there were some significant differences, notably the percentage of respondents in non-U.S. sites that indicated their setting was a hospital. This trend likely reflects the manner in which health care is delivered from country to country and, in the case of the United States, also reflects the degree to which clinical research has permeated all facets of the health care delivery system. 

One objective of the site survey was to ascertain the work intensity and stress associated with managing research. As one such measure, survey participants were asked the number of clinical investigators for whom they worked. The responses trended bi-modally with a relatively even distribution between site personnel working for only one investigator or for between three and five investigators.  

The number of study subjects seen weekly was also used as a measure of job stress and intensity. The majority of responses fell into two categories: those seeing between four to 10 subjects per week, and those seeing between 11 to 30 subjects per week. However, in the United States, Canada, Africa, India, and Asia, some 20% of respondents indicated that they saw over 30 study subjects per week. 

As another possible indicator of job stress and intensity, participants were asked whether their positions entailed performing non-research related tasks and, if so, what percentage of time was spent on such activities. Almost all coordinators had at least some non-research related functions, although there were some significant geographic differences with respect to the amount of time spent outside of research. Figure 3 reflects some of these regional differences and may offer insight for CRAs as they plan site visits and other interactions involving coordinators. 

On a qualitative level, respondents were asked what they viewed as the most frustrating aspect of the job on the day of a subject visit. One study coordinator reflected the view of many respondents by stating, "I try to plan ahead as much as possible, but when my subject is late the whole day is thrown off and it becomes a real challenge to meet the courier pick-up time." Study coordinators also indicated that even when time pressures were not present, the stress of trying to meet the needs of the study subject was a contributing factor to daily stress. One U.S.-based study coordinator reflected this trend, noting that the job is stressful even "when everything goes off as planned but we have to tell the subject 'you are not eligible for the study.'" 

ICON Central Laboratories was particularly interested in understanding sites' access to and attitudes toward computer assisted services in managing their day-to-day research activities. Virtually all sites, regardless of geography, had good physical access to the Internet, email, and other research-related software. Interestingly, however, the U.S. coordinators indicated the most difficulty in gaining access to a computer in their work areas, with 22% responding that they did not have good access. A distant second was Western Europe, with 8% indicating that access was a problem. Otherwise, coordinators in other regions did not view computer access as an issue. 

With the growing use of EDC to efficiently collect study data, ICON Central Laboratories opted to survey respondents about their experience in using such software, particularly as it relates to capturing lab results. The vast majority of sites (90%) had used EDC in the management of a study and, of those, 40% had used it to capture lab-related information. Those using EDC for lab data collection generally found the software helpful, with 70% indicating it was quite helpful or very helpful to them. 

The survey questions were structured to gain insight into the preferences of respondents based upon how "computer adept" they were. Survey respondents were categorized as "computer adept" if they: 									

Were clinical research coordinators/study coordinators

Used email to communicate with sponsors/CROs daily to weekly

Had easy access or access most of the time to the Internet, where specimen collection is performed

Respondents were categorized as "not computer adept" [only 3% of coordinators were in this category] if they: 					

Used email to communicate with the sponsor/CRO no more than monthly

Had difficulty getting access to the Internet or didn't have access at all in the area where they performed specimen collection.

Prior to conducting the survey, it had been assumed that study coordinators who were more computer adept would tend to favor certain service features. However, that was not the case. The survey data show that coordinators, regardless of computer adeptness, prefer receiving lab reports via fax. In fact, 80% of coordinators rated fax delivery as a good to excellent mode of delivery vs. mailed hard copies, emailed lab reports, and report retrieval via a secure Web site. That number is slightly higher among noncomputer adept coordinators, but not significantly. 

When report delivery preferences were analyzed by geographic location, a significantly different picture emerged. Coordinators in the United States favor fax delivery, with 55% favoring that mode and only 29% opting for email. In all other regions, emailed reports were preferred to fax. In many countries, when those preferring email delivery and access via secure Web site were added together, they represented 50% or more of the respondents. 

The most apparent difference between the two groups related to their preferences for new on-line services. The introduction of more computer intensive services such as a Web-based requisition form, a Web-based investigator manual, the ability to order collection kits and supplies online, and the ability to process shipments via the courier's Web site instead of using preprinted airway bills were viewed more favorably in the "computer adept" group, although both groups expressed fairly high levels of support for such new services. 

Coordinator attitudes toward using computer technology seemed to reflect either one extreme or another. "The less I have to go searching on the Internet for lab reports or anything else, the better," noted one coordinator. While another stated that "using online lab tools would be huge." These polarized responses typified the respondents free text comments in this section of the survey.  

Since investigator meetings serve as an important means for communicating information about lab and other study-related matters, two questions were included in the survey to better understand this area. 

The first question related to whether coordinators had actually attended an investigator meeting and heard the lab presentation. Surprisingly, the percentage responding "yes" to this question varied significantly, depending upon the geographic location of the coordinator, with 74% of U.S. study coordinators having attended such a presentation and only 55% of non-U.S. coordinators indicating such attendance. More investigation is needed to understand why this disparity exists, since such presentations are routinely provided as a part of the central laboratory's service package, regardless of the meeting's location. 

The second question asked respondents to rank the lab-related topics of most importance to them when attending the investigator meeting. The question was posed to determine if regional differences would justify a different approach to such presentations depending on the countries participating in a study. Few regional differences were identified from the responses, with virtually all respondents ranking the explanation of kits, the overview of specimen collection instructions, and contact information as the most important topics to address in the lab's presentation. 

The survey also asked respondents to rate their interest in a variety of services that could be made available to them in the future. Regardless of location, coordinators seemed to have the same priorities for such services, with particularly high interest in online access to requisitions and study-specific lab manuals and the ability to reorder kits and supplies via the computer. 

Articles

Partnerships in Clinical Trials

Results reveal insight into the roles, activities, pressures, and priorities of study coordinators.

Investigator Site Survey

Medical imaging in trials has been used as a measure of efficacy for more than 20 years. While the clinical practice of radiology provides sufficient information for managing individual patients, this practice varies geographically within the United States and globally. It was recognized by FDA that variability in evaluating trial images at the sites necessitated a more standardized and controlled review process, which was described in the agency's 1994 "Points to Consider for Developing Medical Imaging Drug and Biologic Products." 

In this document, recommendations for the blinded independent central review of images (blinded read) from trials for medical imaging contrast agents were outlined. This independent review was meant to improve the quality of imaging data evaluations from clinical trials. The blinded read process used today across therapeutic areas is derived primarily from FDA and diagnostics industry documents and forums. It is this diagnostics-derived blinded read process which was included in FDA—and other regulatory agency's—therapeutic guidance documents. 

In clinical trials of diagnostic imaging agents, a radiologist, not a clinician, is usually the principal/site investigator. In spite of this, it was recognized that standardizing image review, evaluating reader performance, and eliminating bias in the reviews was nearly impossible—even with an identified radiologist investigator performing the reads at each site. In today's therapeutic trials, it is uncommon to have a dedicated radiologist responsible for image interpretation at the site and for signing 1572 forms. At many sites, a nonradiologist reviews the images to select and measure target lesions and completes the imaging section of the case report form (CRF). This is either a nonradiologist physician, or even the site coordinator. While some nonradiologists may believe they can accurately interpret routine CT scans or radiographs, it takes a trained radiologist to evaluate the complexity of imaging effects seen in pathology (edema, hemorrhage, calcification, arterovenous shunting) or to distinguish tumor from nontumor imaging effects in cancers with ill-defined margins. 

Methodology issues have always plagued site reads for oncology and other therapeutic drug trials. A radiologist's clinical interpretation is designed for individual patient management, but rarely meets requirements to enable selection and measurement of lesions and may use nonstandard terminology. Standardized imaging efficacy criteria used in trials (e.g., Response Evaluations in Solid Tumors [RECIST] and others) are neither commonly used in clinical radiology practice, nor are they routinely included in radiology residency training programs. Site reads being performed in oncology studies are also not fully auditable to the extent of blinded reads. Training of blinded readers on trial-specific imaging efficacy criteria occurs routinely and is accepted to have a positive impact on the quality of results. However, training of site readers—radiologists or otherwise—is usually a less rigorous process, not infrequently performed by a CRA or other imaging nonexpert. Because of their relatively uncontrolled nature, the site read process, particularly in oncology clinical trials, is considered by some to be "the wild west." 

There are many factors that influence reader performance, including experience, expertise, evaluation criteria used, viewing hardware/software, reader fatigue, disease process, drug mechanism of action, and design of blinded read. The evaluation of reader performance is viewed as a reflection of the quality of imaging data results from a trial. Intra-reader and inter-reader variability are easily evaluated in blinded reads where CRFs are linked to the image database, measurements made on images directly populate the CRF, and response is automatically derived. However, similar standard methods to evaluate site reader performance in multicenter trials for regulatory submission have yet to be established. 

When two or more readers evaluate the same group of images there exists a potential for disagreement. In the diagnostics blinded reads of the early 1990s, a group of three readers, each of whom evaluated all images, were commonly used. The same process continues to be used in blinded reads of diagnostic studies. In this read design, the performance of readers is compared to a standard of reference and thus sensitivity and specificity can be calculated for each reader with weight given to the two readers with the best performance. 

However, in most therapeutic trials, oncology being an example, there is generally no standard of reference against which the imaging results are compared—that is, there is no established "truth" against which to compare the readers' results. A process for adjudicating differences between readers was established in oncology trials whereby two primary readers each read all images, and a third independent reviewer is asked to review subjects' images when the primary readers disagree. Generally the adjudication reader does not create new measurements, but is asked to agree with either Reader 1 or Reader 2. Thus two readers agree on response in all subjects. 

In more than a decade of widespread use of dual primary readers/single adjudicator blinded read paradigm, it has become understood that there are multiple factors that impact adjudication rates in trials. A few of these factors include imaging modality, disease process, lesion morphologic appearance and its impact on the ability to precisely measure lesions, blinded read study design, efficacy evaluation criteria, image quality, reader training, study population, and many others. Regulatory authorities have never elucidated specific acceptable or nonacceptable adjudication rates, and rates averaging 25% to 40% are routinely observed in oncology registration trials. 

Since there are so many factors that can influence the adjudication rate within a single trial, the adjudication rate cannot be viewed as a direct measure of either overall study quality or a specific measure of reader performance. 

Recently, adjudication rates have come under scrutiny by regulators and others, suggesting that a specific rate in a specific trial may be a negative performance indicator. It has also been suggested that if the adjudication rate is X and the difference between the site read and blinded read results is similar, the blinded reads could be unnecessary. 

On the surface this sounds like a reasonable assumption.  However, due to methodological issues that exist with many site reads for oncology trials—not the least of which being that nonradiologists and even nonphysicians are interpreting images—this assumption cannot be considered correct. Trial results derived from a process in which the methodology is less than optimal cannot be compared to results from a fully auditable and transparent process. 

The blinded read process, however, is not without its own issues. Blinded reads do add additional expense to a clinical development program. All bias is not removed with blinded central image evaluations. Informative censoring can result when a patient progresses according to the site read but not according to the blinded read. However, this can be mitigated using widely-available current technology to perform independent confirmation of disease progression within 24 to 48 hours. But more than 15 years of global regulatory experience, combined with industry/regulatory/academic joint efforts to improve quality in independent image reviews, has built a broad foundation of understanding that results from controlled blinded reads are superior to those from lesser controlled site reads. 

There are some easy-to-implement changes to site reads that would improve the quality of the methodology: 

Identify a single radiologist (a study subinvestigator) at each site to perform evaluations, complete the imaging portion of the CRF, and sign 1572 forms. 

Prospectively train and test the site readers on the study-specific efficacy criteria. 

Monitor site reader performance in an ongoing fashion and implement retraining as needed. 

Implement a regulatory compliant audit trail process. 

More than 15 years ago, industry, FDA, and other regulatory bodies recognized that if image evaluations were to be used as a measure of efficacy, a controlled evaluation process was required. Site reads did not meet this criterion, and not much has changed in the quality of site reads since that time. This is not to say that the quality of site reads, however, cannot improve. But investment of both significant time and expense will be necessary to improve and control the quality of site reads before efficacy of a drug can be based on the site read.  

Viewpoint

Is basing drug efficacy on the site read risky business?

On and Offsite Image Reads

The pharmaceutical industry's recent shift of focus to molecular therapies, genomics, and biomarker discoveries in medical research has increased the need for well-preserved biological samples. This has created substantial value for samples derived from clinical research. 

Today, high-quality tissue, blood, and serum samples derived from clinical trial patients can be used to advance a wide range of medical endeavors. As such, preserving samples to the highest standards has become a critical component in maximizing the value of present day and future clinical research. 

By utilizing today's high-throughput analytical and molecular technology, quality biospecimens are used to detect biomarkers, identify new applications for existing targeted treatments, accelerate drug development, and create biomarker-targeted diagnostics and therapeutics. Temperature control and monitoring during the storage and transportation ensures the efficacy of samples for future analyses. 

To ensure the integrity and long-term viability of clinical samples, pharma and biotech companies will need to develop strategies for the specialized storage and transportation of these samples. Without careful consideration for compliant storage, shipping, data management, and audit trails, researchers risk damaging or losing clinical research samples. This, in turn, has serious time and financial implications on the clinical trial process. 

Consider the consequences if clinical trial samples were to thaw out before reaching the testing lab, rendering the samples useless. This compromise could cost the sponsor hundreds of thousands of dollars to repeat the trial. Moreover, if samples are delayed at customs and don't reach their destinations on time, it could have a ripple effect on the development process by increasing the time it takes to bring a new product to market. This could consequently cost the sponsor millions of dollars, as a day lost in development is a day lost on the market. 

Furthermore, regulatory agencies increasingly require more detailed information for the approval of new drugs. A complete audit trail detailing the sample's history from collection to destruction protects sponsors from clinical trial setbacks that could postpone product launch. 

A lack of planning can prove costly, as these materials represent today's multimillion dollar research investments and tomorrow's multibillion dollar revenue. By developing a strategic sample management plan that takes into account best practices for temperature-controlled storage and logistics, regulatory guidelines, and audit trails, organizations can protect financial investments while streamlining the research processes. 

Similar to other GXP environments, good storage practices require the discipline and attention to critical details, such as regulatory and industry compliance, data management, and quality and risk management. Good storage practices should be described in Standard Operating Procedures (SOPs) to ensure that processes are widely recognized and constantly met by personnel. These SOPs should be incorporated into routine training programs, and should be regularly updated to guarantee compliance to an expanding array of regulatory requirements from a number of entities. 

The U.S. FDA, the Centers for Disease Control, and professional organizations such as the American Association of Tissue Banks, the National Cancer Institute, the American Association of Blood Banks, the International Red Cross, and the International Society for Biological Repositories provide guidelines for biorepositories and human sample banks. Without SOPs that take into consideration these guidelines, staff turnover may jeopardize sample integrity through loss of knowledge that occurs when an employee leaves an organization. 

Additionally, other factors to incorporate into good storage practices include:

			Secure facilities and redundant measures to ensure specimens are kept in compliant conditions at all times when in storage			

				Expert staff that has been trained specifically in sample storage and transportation to ensure all regulatory and custom issues are properly handled			

			Storage technologies capable of monitoring the temperature of samples around the clock in order to provide a complete audit trail			

Business continuity plans and redundant systems to protect sample integrity during emergencies. 

As clinical research continues its migration toward globalization, expanding into regions such as South America, Eastern Europe, and East Asia, the process of transporting human clinical trial samples has become increasingly complex. Regulatory requirements, temperature-control, and worldwide custom concerns have made transporting clinical trial samples a science in itself. As a result, companies should develop a strategy for cold chain management to maintain visibility and control over clinical samples to ensure they are not compromised by temperature deviations while in transit. 

A comprehensive cold chain management plan defines how temperature-sensitive products and biomaterials such as clinical trial samples, active pharmaceutical ingredients, and microbiological and viral samples are packaged, transported, and stored throughout the research and development process. Maintaining the integrity of the cold chain requires logistics and management expertise to ensure that temperature-sensitive samples are constantly monitored and properly packaged so they do not degrade during packing, shipping, processing, and storage. 

From a regulatory perspective, lack of compliance can delay shipments at inspection points or subject drug developers to fines ranging from a few hundred to thousands of dollars. To ensure compliance, mitigate financial risk, and reduce development setbacks, sponsors must take a comprehensive approach to cold chain management in which the process is an integrated component of the organization's overall best practices. 

In order for analysis to be meaningful and accurate, an effective system must be capable of reporting processes through all stages of a sample's shipping, handling, and storage lifecycle. Therefore, inherent in good storage practice is maintaining the associated documentation that provides verification that samples have been stored in appropriate conditions from collection to final retrieval. 

Audit trails are required by various regulatory agencies to help establish that samples have not been compromised while in transit or in storage. Most notably, the FDA and international Current Good Laboratory Practices, Current Good Manufacturing Practices, and Current Good Clinical Practice have regulations that affect various aspects of clinical development including storage, transportation, and electronic documentation. Title 21 CFR Part 11, for example, considers electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures. This rule applies to records in electronic form that are created, modified, maintained, archived, retrieved or transmitted in FDA-regulated industries. 

For a comprehensive audit trail, records must form a complete history of the sample's lifecycle, and include: 					

The type of sample, such as tissue, blood, plasma or other

Who and where the samples were collected from

Storage and shipping conditions of the sample at all times

In addition to audit trails, information management plays a critical role in drug development. Researchers are also analyzing a vast amount of clinical information about patients' health and disease from patient records and clinical trials. This data helps researchers identify patterns and disease sub-types, therefore leading to effective strategies for diagnosing and treating disease in new and efficient ways. Because of this, good storage practices require that samples and their associated data be well-kept and easily accessible if needed. This is truly important, as in many cases the genomic information that accompanies the physical sample is as important as the sample itself. 

To maintain accessibility of archived samples and their data, companies should consider implementing robust, multifaceted laboratory information management systems (LIMS) to help facilitate sample management and data collection. Today's sophisticated LIMS software handles receiving, processing, and storing information generated by lab processes. This ensures that each sample is protected and stored in a compliant manner, while streamlining the process of sample management, making information readily available to certified users of the system. 

Due to the commercial and scientific significance of these samples, materials should not be left to ad hoc processes that may jeopardize the integrity of such valuable property. This is especially true today as the value of such materials is rapidly increasing through discoveries that can be made from ongoing testing. As such, now is the time for organizations to establish a comprehensive management strategy that incorporates and dictates how samples are handled, stored, transported, and documented throughout their entire lifecycle. This ensures the integrity of clinical trial samples, which help accelerate product development and lead to new therapeutics. 

Despite this, companies often overlook the critical step of developing strategies for specialized, long-term storage of biological samples. This could have serious financial ramifications, as biospecimen management, storage, and retrieval have become increasingly important aspects in improving the efficiency of drug development. Due to these factors, it's only a matter of time before researchers and regulatory bodies alike adopt good storage practices universally. The question is, will you be ready? 

, is Global Director of Marketing and Commercial Operations at BioStorage Technologies, 2655 Fortune Circle West, Suites A-B, Indianapolis, IN 46241, email: 

1. S. Cubbler, "The Logistics of a Successful Product Launch," 

http://www.pharmaceuticalcommerce.com/frontEnd/1284Exel_launch_logistics_pharmaceutical_Cubbler.html

2. Key Medicines and Their Performance. Pfizer Annual Review,  

http://www.pfizer.com/investors/financial_reports/annual_reports/key_medicines.jsp

3. National Cancer Institute and Biorepositories—Office of Biorepositories and Biospecimen Research, NCI Cancer Bulletin 6 (9). (May 5, 2009), 

The importance of managing the storage and transportation of clinical trial samples.

Good Storage Practices

Cover

Medical imaging is employed in all phases of new drug development. Imaging can guide the diagnosis, treatment, and management of disease and serve as biomarkers for prognosis, progression, and outcomes. 

Whereas traditional imaging methods are largely directed at obtaining anatomical information, functional (i.e., molecular or mechanistic) imaging quantifies real-time physiologic and metabolic processes at the cellular or molecular level. These novel imaging techniques have become attractive biomarkers in clinical trials. Through early determination of drug efficacy, functional imaging techniques promote efficient decision-making in clinical trials, saving time and money. 

Magnetic Resonance Spectroscopy (MRS) and Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) are functional imaging techniques increasingly used in clinical trials. MRS generates spatially localizable biochemical information from tissues. DCE-MRI is a perfusion-based technique that evaluates tissue vascularity. However, the use of MRS/DCE-MRI imaging endpoints as in vivo biomarkers requires imaging studies to produce reliable quantitative, semi-quantitative, and qualitative results that can be used to assess disease status. 

Ensuring such consistency in multicenter clinical trials that involve imaging is problematic because data acquisition and reconstruction are performed in many different settings and often with different types of instrumentation. 

MRS complements MRI as a noninvasive means for the characterization of tissue metabolism. While MRI uses the signal from hydrogen protons to form anatomic images, MRS uses this information to produce a unique biochemical signature for the metabolite constituents of different tissues. Although proton MRS has been applied in a wide range of biomedical investigations, there is a growing interest in utilizing multinuclear spectroscopy (i.e., 31P and 13C) to extend the clinical applications of MRS even further. Herein, we focus on the applications of proton MRS in clinical trials 

The biochemical profile of a tissue of interest acquired by MRS is called spectrum. MRS spectrum represents a graph of a group of peaks where each peak reflects a chemical compound denoted in parts-per-million (ppm) on the x-axis with concentration indicated by peak height. Computer software programs using analytical methods and mathematical formulas calculate the relative concentration of detected metabolites in healthy and pathological states.

In a typical brain proton spectrum, the water peak appears at 4.7 ppm, while fat peaks appear at 0.9, 1.3, 3.2, and 5.2 ppm. N-acetyl aspartate (NAA) peaks in healthy brain tissue at 2.02 ppm, with a decreased peak in brain pathology. Total choline, an indicator of membrane synthesis and cellular proliferation, peaks at 3.22 ppm. While an increased choline peak is found in most malignant tumors, decreasing choline may reflect changes related to anti-tumoral treatment. MRS has been used to investigate several diseases, including cancer, epilepsy, Alzheimer's, Parkinson's, and Huntington's chorea.

Although its main current application consists of proton MRS in the brain, there is a growing interest in using MRS for understanding disease states in the prostate, liver, muscle, breast, and heart.

  For example, MRS has shown to be an effective tool in Fatty Liver Disease (FLD) evaluation. FLD is the most common cause of chronic liver disease in the United States. Risk factors include obesity, diabetes, alcoholism, and drug toxicity.

  Because liver biopsy, currently the gold standard for measuring liver fat, is invasive, prone to sampling errors, and inappropriate in some settings, MR-based techniques are attractive alternatives for evaluating hepatic fat.

  MRS in particular is a promising functional imaging method commonly utilized in clinical trials involving FLD. 

MRS proved to be a sensitive method for measuring hepatic triglyceride content (HTGC) in 2349 Dallas Heart Study participants.

  Using MRS to measure hepatic fat, a lifestyle intervention study in 50 adults with nonalcoholic FLD (NAFLD) concluded that improved aerobic fitness is an independent predictor of reduced liver fat.

  In a study evaluating a novel method of MRS (i.e., the HISTO sequence), researchers found that the new sequence reliably measured hepatic lipid levels.

A current National Institute of Health study will compare MRS-measured HTGC with liver biopsy results in 70 adults. A Washington University study will analyze the reproducibility of pre- and postprandial HTGC obtained via modified MRS sequence in patients with NAFLD. 

More conventional MR imaging appears to correlate highly with MRS measurements and may be easier to implement in trials. Liver fat fractions determined using a new MRI acquisition sequence correlated highly with MRS results in 37 diabetic adults.

  Another study determined in-phase and out-of-phase MRI for rapid liver fat estimation was as accurate as MRS in 33 diabetic adults at risk for NAFLD.

Clinical trials involving several other diseases, especially various cancers, have utilized MRS. A recent American College of Radiology Imaging Network (ACRIN) trial compared MRI and MRS, as well as the combination of both for prostate cancer detection prior to radical prostatectomy.

  ACRIN is also investigating MRS-measured total choline as a marker of pathologic response in Stage III breast cancer patients who have had an incomplete response to neoadjuvant chemotherapy. 

A randomized ACRIN drug trial (bevacizumab with temozolomide) will use MRS and DCE-MRI to stage adults with recurrent brain cancer (i.e., intracranial glioblastoma or gliosarcoma) then assess agreement between local and central imaging interpretation. The same trial will also evaluate MRS and DCE-MRI as prognostic biomarkers based on serial imaging results. 

Despite promising results in research applications, there are significant challenges to using MRS in a trial. It requires verification of imaging instrument performance, standardization of image acquisition protocols, development of an on-site training program, and development of reliable data management and data mining procedures. While these requirements discourage the routine clinical use of MRS, for certain drug development trials the effort may prove worthwhile. Because measurable anatomical impact of drug therapy lags behind MRS changes, the unique biochemical information from MRS can promote earlier decision-making with respect to the viability of an investigative agent. 

DCE-MRI tracks the diffusion of an intravascularly administered paramagnetic contrast agent (i.e., gadolinium) into the extravascular tissue over time. As the mean contrast agent concentration within a volume of tissue (i.e., a "voxel") increases, its signal intensity increases. Using mathematical algorithms and compartmental modeling, this relative signal increase is converted into a quantitative measure of contrast agent over time. The volume of blood vessels in the voxel, the rate of flow, and the rate of diffusion are the principle determinants of the outcome measure of DCE-MRI, (Ktrans). Because of how rapidly these processes occur, DCE-MRI requires more rapid image acquisition than conventional MRI (i.e., every 2 to 10 seconds vs. 30 seconds to several minutes).

Immature blood vessels seen in cancers are highly permeable to gadolinium-based contrast agents. Because tumors elicit angiogenic factors to spur new blood vessel growth, anti-angiogenic and vascular destructive agents can be effective anti-tumor therapies, particularly in combination with other drugs. 

During vascular-targeted therapy trials, DCE-MRI can measure vascular responsiveness to the study drug. As vascular changes precede tumor shrinkage, DCE-MRI allows earlier assessment of drug efficacy and treatment response than is possible with traditional anatomic measurements.

  Therefore, as the number of anti-angiongenic agents is rapidly growing in various phases of clinical trials, one must conclude that DCE-MRI has a promising future in drug development. 

As a novel imaging approach, DCE-MRI provides insight into the tumor microenvironment (e.g., vessel permeability, perfusion, extracellular-extravascular volume fraction). As such, the technique can define a drug's mechanism of action and measure its pharmacodynamics. Although not yet accepted as a marker for registrational trials, DCE-MRI results ultimately may serve as predictive biomarkers of clinical outcomes, such as treatment response and progression-free survival.

DCE-MRI has been used extensively in oncology trials. A recent prospective study in 13 brain cancer patients with low-grade glioma found that changes on serial DCE-MRI predicted malignant transformation. Increased relative cerebral blood volume on DCE-MRI preceded evidence of malignancy on standard MRI (i.e., contrast enhancement on T1-weighted images).

  A current study at Yale will correlate DCE-MRI and diffusion-weighted MRI results with histopathologic findings and clinical response to radiotherapy in patients with glioblastoma multiforme. 

Researchers also are analyzing DCE-MRI results as predictors of treatment response. One study in head and neck cancer patients at Memorial Sloan-Kettering Cancer Center (MSKCC) will compare DCE-MRI and MRS to clinical markers as predictors of treatment response to neoadjuvant chemotherapy for osteogenic sarcoma and Ewing's sarcoma. In particular, the trial will investigate whether preoperative and/or early treatment DCE-MRI results predict treatment response (i.e., tumor necrosis and disease-free survival) compared to clinical and molecular parameters. An ovarian cancer study at MSKCC is using a novel DCE-MRI analysis method (with and without motion correction) to assess changes in tumor perfusion following anti-angiogenic therapy. 

A National Cancer Institute (NCI) study in breast cancer patients undergoing surgery will evaluate the diagnostic potential of DCE-MRI and MRS compared to conventional findings from mammography, tissue proteomics, and histopathology. A randomized Phase II NCI-sponsored trial in patients with advanced or metastatic colorectal cancer will correlate drug-induced tumor vascular changes with clinical biomarkers to evaluate DCE-MRI as a predictor of response to chemotherapy (FOLFOX alone vs. FOLFOX plus bevacizumab at 5 or 10mg/kg). 

Investigating chemotherapy (FOLFOX plus bevacizumab) response in metastatic colorectal cancer patients, an ACRIN trial will evaluate a new DCE-MRI acquisition method and compare drug-induced tumor vascular changes to clinical indicators of treatment response. 

Several kidney cancer trials using DCE-MRI are underway. A randomized Phase II trial in patients with advanced renal cell carcinoma will use DCE-MRI to assess tumor vascular changes following chemo (bevacizumab alone vs. bevacizumab plus interferon alpha-2a) and correlate them with clinical and imaging outcomes, including change in tumor size and progression-free survival. Another trial involving targeted combination chemotherapy (VEGF, RAF kinase, mTOR, and EGF-R) will also evaluate DCE-MRI results as a biomarker for efficacy. 

Researchers are using DCE-MRI to study prostate cancer. In one study, DCE-MRI parameters are being compared with laboratory markers and histopathologic (biopsy) results in prostate cancer patients. A Washington University study is evaluating the accuracy of prostate cancer detection using different types of MR-based imaging (including DCE-MRI and MRS). The trial will compare pretreatment imaging to histopathological findings in surgical specimens (from radical prostatectomy) and biopsies (obtained during radiotherapy). 

National Taiwan University Hospital is analyzing DCE-MRI results as a biomarker for treatment response in a Phase II study of radiotherapy for locally advanced hepatocellular carcinoma. Pretreatment DCE-MRI will be compared to subsequent imaging studies to correlate tumor perfusion changes with disease progression and other clinical outcomes. 

Successful DCE-MRI integration in a trial requires careful orchestration. Imaging at such rapid rates with existing MRI equipment affects image quality, resolution, and anatomical coverage. When technologists and radiologists are not familiar with DCE-MRI, careful training is essential to obtain high-quality images. Patient selection, the tumor mass chosen as the region of interest (ROI), and imaging plane all affect image quality. Furthermore, to assess exam reproducibility, most protocols include pretreatment test-retest procedures to ensure similar levels of contrast accumulation. While some therapies take days or weeks to reach peak anti-angiogenic effect, others take effect hours after administration. Considering the need for test-retest visits and variable drug timetables, the ideal DCE-MRI schedule differs for each trial.

Mechanistic imaging techniques, including MRS and DCE-MRI, have a promising future as biomarkers in clinical trials. Considerable expertise, precise site training, and strict quality assurance are necessary to design and administer effective protocols using functional imaging. Yet novel imaging methods, which for many conditions and investigative agents may determine drug efficacy faster than standard clinical parameters, can make clinical trials more efficient and cost-effective. 

An established imaging CRO with the capability to provide high-quality functional image quantitation can smoothly integrate novel imaging methods into a clinical trial. A comprehensive approach and standardized operating procedures ensure the normalization of quantitative data across multiple sites. Centralized image management—from acquisition through interpretation—is essential in multicenter trials. The strengths of an imaging CRO pave the way for seamless implementation of functional imaging methods, such as MRS and DCE-MRI, in clinical trials. 

 is Scientific Director at ACR ImageMetrix, 1818 Market Street, Suite 1600, Philadelphia, PA 19103, email: 

1. H. Poptani, "Magnetic Resonance Spectroscopy (MRS) for Measurement of Hepatic Fat," White Paper in library section under Scientific Showcase on Web site 

2. B. Taouli, R. Ehman, S. Reeder, "Advanced MRI Methods for Assessment of Chronic Liver Disease," 

3. F. Hughes Cassidy, T. Yokoo et al., "Fatty Liver Disease: MR Imaging Techniques for the Detection and Quantification of Liver Steatosis," 

4. L. Szczepaniak, P. Nurenberg et al., "Magnetic Resonance Spectroscopy to Measure Hepatic Triglyceride Content: Prevalence of Hepatic Steatosis in the General Population," 

American Journal of Physiology—Endocrinology and Metabolism

5. K. Kantartzis, C. Thamer et al., "High Cardiorespiratory Fitness is an Independent Predictor of the Reduction in Liver Fat During a Lifestyle Intervention in Non-alcoholic Fatty Liver Disease," 

6. N. Pineda, P. Sharma et al., "Measurement of Hepatic Lipid: High-Speed T2-Corrected Multiecho Acquisition at 1H MR Spectroscopy—A Rapid and Accurate Technique," 

7. B. Guiu, J.M. Petit et al., "Quantification of Liver Fat Content: Comparison of Triple-Echo Chemical Shift Gradient-Echo Imaging and in Vivo Proton MR Spectroscopy," 

8. R. Borra, S. Salo et al., "Nonalcoholic Fatty Liver Disease: Rapid Evaluation of Liver Fat Content with In-Phase and Out-of-Phase MR Imaging," 

9. J. Weinreb, J. Blume et al., "Sextant Localization at MR Imaging and MR Spectroscopic Imaging before Prostatectomy: Result of ACRIN Prospective Multi-institutional Clinicopathologic Study," 

10. M. Rosen, "Dynamic Contrast Enhanced MRI (DCE-MRI) in Drug Development," White Paper in library section under Scientific Showcase on Web site 

Novel methods hold promise in making clinical trials more efficient and affordable.

Supplements-01-03-2010

Investigator Site Survey

On and Offsite Image Reads

Good Storage Practices

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Imaging as Biomarkers