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International Clinical Trials

Picture of Perfection

Richard Walovitch and Richard Taranto at WorldCare Clinical give an insight into the imaging CROs in central and eastern Europe, including guidelines and best practices for standardisation of imaging equipment for clinical trials

 

With access to a large pool of patients, lower overall trial costs than in western Europe (WE), and a rapidly improving regulatory process, central and eastern Europe (CEE) has become an increasingly desirable region for conducting clinical trials. The region is experiencing a surge in the number of clinical trials being conducted and the trend is likely to continue, as more countries modernise their infrastructure and equipment, including their imaging offerings, and improve access to clinical facilities with upgraded technology. For pharmaceutical companies looking to conduct trials in CEE, this means a number of new opportunities and challenges to consider.

 

OPPORTUNITY KNOCKS

 

Despite having a population that is less than half that of India or China, CEE represents the largest number of global clinical trial initiations outside North America (NA) and WE (1). In fact, some estimates show that CEE is growing at about twice the rate of WE. In 2008, the estimate of the European clinical trials market was €20.3 billion ($32 billion USD) and was expected to grow 10.6 per cent annually, which would lead to €30.38 billion ($47 billion USD) in 2012. CEE makes up a good portion of this growth, due to having greater access to drug-naïve patients, lower labour costs and other site fees, a higher concentration of patients near sites, and closer relationships between doctors and patients. These factors equate to a dropout rate of less than five per cent compared to 20 per cent in WE, which means that the initial investment to start a trial, such as the submission fees to ethics committees, give access to a much higher number of potential subjects suitable for the trial than in WE.

 

The 25 countries that make up the CEE, which includes Austria, Bulgaria, the Czech Republic, Hungary, Poland, Romania, Turkey, and the 11 former Soviet states that make up the Commonwealth of Independent States (CIS), offer access to a large pool of motivated patients who are interested in participating in clinical trials due to the opportunities afforded by modern therapies and medical equipment, previously unavailable or not readily accessible. Trials in the CEE also provide a patient population with more similar genetics to NA and WE than in the other emerging geographies. Additionally, CEE provides access to patients who are drug-naïve, thus allowing for trials in first line therapies. This has been a major source of patients for first-line therapies in oncology drug development. Large countries like Russia and Ukraine and countries farther east that are just beginning to conduct clinical research offer even greater growth potential (see Table 1) (1,2).

 

 

Trial costs are noticeably lower in the region than in the US or WE, due in part to the fact that many CEE countries are able to recruit large numbers of eligible subjects easily and efficiently. Additionally, most countries in the CEE seek to have biopharmaceutical companies conduct their global clinical trials there and to be recognised as a valuable region to their global drug development programmes (3).

 

The regulatory process in the CEE is also becoming more clearly defined, which means a quicker turnaround on approvals (4). Clinical research in these countries is currently being conducted in accordance with international regulatory standards, and recently Russia and Ukraine have also adopted international regulatory guidelines.

 

With an established arena for conducting clinical trials in place, there has been an increase in the number of countries that biopharmaceutical companies know they can get quality data and access to patients from, but to a generation of experienced professional clinical investigators who remain critical to conducting efficient and high-quality studies.

 

CHALLENGES AHEAD

 

As growth continues in clinical trials in CEE, the use of medical imaging becomes more widespread, now that imaging biomarkers are more frequently accepted as surrogate endpoints in biopharmaceutical trials involving numerous therapeutic areas and disease states. An imaging trial’s success relies heavily on the submission of consistent, accurate and high-quality imaging data, therefore the need for improving infrastructure for imaging facilities and standardising image acquisition and image review is becoming more apparent. This includes a greater emphasis on reader training and testing, since improving the quality of readers can help better stratify patients for treatment, evaluate safety, improve dose selection, and even provide early prognostic information to assess the effectiveness of a particular treatment.

 

Pharmaceutical companies conducting clinical trials exclusively within the CEE region or as part of a global study benefit from identifying a partner that can qualify imaging facilities, standardise image acquisition protocols, manage the collection and QC of imaging data sets and coordinate the central review of images by a panel of trained radiologists.

 

Over the last five years, imaging centres in CEE have gained access to an array of imaging modalities and technologies for use in clinical trials as the number of countries importing imaging equipment in the region has grown consistently year after year (5). However, determining which imaging centres have access to standardised equipment can be difficult to decipher. Imaging CROs have an understanding of a clinical trial’s imaging equipment needs and can assist in determining what equipment is capable of performing specific tests (for example a high-resolution CT for lung imaging in pulmonary drug delivery). Additionally, they can recommend what imaging acquisition parameters are required at a minimum to perform the intended study, allowing sponsors to select the appropriate sites after reviewing test cases.

 

BEST PRACTICES FOR QUALIFYING IMAGING SITES IN CEE

 

Standardising image acquisition entails collecting information about a potential site’s software and hardware equipment for scanning participating study subjects. The wide range of vendors and varying software platforms used across a multi-centre study means that confirming baselines, acceptability and compliance is an important first step before the first patient first visit (FPFV). Experienced imaging CROs can play a key role in reducing a study’s size and duration by ensuring the submission of consistent, accurate and high-quality imaging data. Setting up a standard image acquisition protocol for sites in advance and confirming that the sites can acquire scans that follow the procedures outlined is a critical point in establishing a harmonised imaging data set across sites and time points.

 

Sponsors can easily confirm if consistent techniques were used in scan acquisition and set up an image library by centrally collecting all imaging visits. Making sure that imaging visits occur within the protocol defi ned study window is also important. By proactively notifying sites to remind coordinators that imaging visits are due for a particular subject, imaging CROs help improve compliance. If any issues are detected, they can be followed to resolution to improve the quality of the imaging visits and accuracy of independent assessments.

 

An imaging CRO’s expertise in acquisition protocols can be instrumental in reducing a study’s size and duration. Acting as a partner to the sponsor of the trial, the imaging CRO helps guide sponsors in designing an independent imaging charter for submission to a regulatory agency. This document is typically a part of an image preparation and submission guide, developed before the study begins. Together, these documents specify a standard manner for acquiring, managing and assessing images to ensure that data from multiple imaging sites is collected consistently.

 

During the course of developing an imaging charter, a reader testing methodology should also be defined. Sponsors, together with imaging CROs, should determine which reading model is most relevant to the disease process and phase of research before defi ning the image review process, and establish proper procedures to adequately monitor reader performance throughout the trial and assess overall reader variability at the end of the trial. Guidelines for the identifi cation of test cases, the assessment by blinded readers, and regular analysis and review of reader performance results should also be included as part of the reader testing methodology. By selecting a read process, and by having an understanding of the inherent variability in reads, a sponsor can identify the best ways to monitor (and therefore limit) variability over time.

 

Many different methods can be applied to assess reader performance and improve the precision and accuracy of the data set. Working with statisticians that understand imaging data is critical to employing the right test and to interpreting results appropriately. If the sponsor and CRO are equipped with a valid measure of reader variability, they can investigate the causes of low reader reproducibility and proactively identify potential problem areas to be addressed. Factors such as poor image quality, insufficient reader training, unclear read criteria, and low individual reader performance are common causes, but the efficient use of statistics allows both parties to take the appropriate remediation steps to increase the trial’s chances of success.

 

IDENTIFYING THE RIGHT PARTNER

 

In evaluating the abilities of an imaging CRO, sponsors should consider its operational procedures, access to therapeutic and modality expertise, adherence to stringent quality control processes, trial workflow expertise, and the ability to provide regulatory support. A proven track record in managing images from around the globe for different therapeutic indications, combined with access to radiologists with the relevant therapeutic expertise, is the best indicator of an imaging CRO’s ability to successfully manage and submit an imaging study along with access to practicing board-certified radiologists who are aware of current diagnostic recommendations required for certain trials.

 

CONCLUSION

 

With clinical trial growth in CEE expected to continue, standardisation of imaging equipment will become increasingly important. By working with a partner that can qualify imaging facilities, standardise image acquisition protocols, manage the collection and QC of imaging data sets, and coordinate the central review of images by a panel of trained radiologists, sponsors will be better equipped to submit consistent, accurate and high-quality imaging data to ensure a successful trial outcome.

 

References

 

1.      Central and Eastern Europe: Outsourcing Trends and Growth Opportunities in Clinical Trials, CenterWatch store, centerwatch.com/pdfs/samples/S08633_intro.pdf

 

2.      Cliniminds, Clinical Trials Market in Central and Eastern Europe (CEE), www.cliniminds.eu/CEE.aspx

 

3.      Cantini, Quality of Data from Central and Eastern Europe, www.cromsource.com/fi le/ 200910271444420.8%20Cantini.pdf

 

4.      Virk KP, Clinical Trials in Central and Eastern Europe: The Challenge of Dealing with Multiple Languages and Cultures, The Monitor ACRP, October 2008, www.languageconnections.com/descargas/CLINICAL% 20TRIALS%20IN%20CENTRAL%20&%20EASTERN% 20EUROPE.pdf

 

5.      The Outlook of Medical Devices in Central and Eastern Europe, http://www.espicom.com/Prodcat2.nsf/Product_ID_ Lookup/00000645?OpenDocument

 

 


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Richard Walovitch is the president of WorldCare Clinical (WCC). Richard has a PhD in pharmacology from the University of Illinois Medical Center and a BSc in biology from the University of Illinois. He is an author of more than 100 peer-reviewed publications, mostly in the fi eld of medical imaging. Email: rwalovitch@wcclinical.com

Richard Taranto is Executive Vice President of Business Development at WCC. Since joining WCC in 2002, he has managed multiple clinical imaging trials for biopharmaceutical and medical device companies, including more than 25 Phase 2-5 studies, and developed and implemented management tools to streamline organisational effectiveness. Before coming to WCC, Richard was Senior Project Manager at Perceptive Informatics. He earned a BSc in zoology from the University of Rhode Island and an MBA from Boston College. Email: rtaranto@wcclinical.com

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