In the early 1990s, the concept of the central laboratory was developed and implemented by laboratories delivering services to major pharmaceutical companies. The goal was to consolidate the test results and data originating in different clinical sites, which was previously analyzed in local labs. Bringing the samples to one single laboratory would avoid consolidation of biased test results among different laboratories, all of which could be using different analytical platforms, kits, and reference values. 

This concept was first applied to clinical studies conducted in the United States. Soon after, the courier industry started offering solutions for biologic sample transportation, which allowed the central lab concept to be applied globally. 

Later, the concept of the affiliated laboratory was created. The affiliated laboratory covered geographic regions that had difficulties exporting biologic samples. As a consequence, the central laboratory became more global and started to build different types of associations with analytical laboratories in different parts of the world. 

Nowadays, clinical trials are globalized and clinical sites are not just in the backyard anymore. Places that may sound exotic but are rather well prepared for research appear in the site list of Phase II and III studies (like Coquimbo, Chile, and Belém do Pará, Brazil) and perform according to Good Clinical Practice requirements. In parallel, logistics costs and constraints are increasing, especially after September 11th. 

The increased project logistic costs referred to may, in some instances, be higher than the laboratory costs. Also, a considerable number of samples are not able to reach the analytical facility under adequate conditions to be properly analyzed. The patient recall for sample drawing may take up to one week, sometimes more, and represents a delay in the study schedule. Additionally, this recall may negatively affect patient adherence. 

Query solution and clinical site support processes usually are best dealt with by local teams and staff. Differences in language and time zones between central labs and clinical sites may be problematic if dealt with from a distance. 

Additionally, clinical site staff may be responsible for logistical tasks, though that is not exactly in their scope of expertise. These tasks could include sample and invoice preparation, courier processe or dry ice providers. There also are difficulties in shipping lab material to remote sites, which could increase study costs and cause logistic constraints. These logistic constraints usually relate to moving samples and lab kits to central labs in reference countries, generally the United States or Europe, which is forcing trial sponsors to consider new approaches regarding central laboratory services. 

Considering that the analytical equipment and reagents most frequently used are available in several countries in the five continents, a new concept is becoming more popular among the most innovative trial sponsors and global central labs: Partner laboratory harmonization. 

Harmonization is a process led by the global central lab and its partners for specific projects. It aims to integrate comparable results from different laboratories, avoiding possible bias generated by technical differences among them. 

This process allows laboratories to exchange results instead of exchanging samples, thus overcoming obstacles previously mentioned and representing fewer costs and less delays for the sponsor. Furthermore, it is also fair to say that access to new research environments, with new sets of investigators and patient populations, will also be more easily achievable. 

Depending on the level of harmonization that a group of labs decides to implement, they may reach a very close technical comparability and can even be considered as a single entity by the trial sponsor, delivering the same service and results all over the world. Of course, there are different levels of harmonization, which could involve internal and external parameters. 

 In terms of analytical platform harmonization, the first step is to compare the analytical equipment, methodologies, kits, and reagents used in the laboratory test either in general or for the specific trial. If differences are found, they have to be addressed through correlation tests. This will show that the results coming from different equipment can be considered homogeneous and, therefore, can be consolidated in the study databank. 

Differences are found with some frequency particularly for basic hematology and hormone tests. Additionally, the equipment preferences are different in different places, such as the United States and Europe. Also, keep in mind that the global central lab leading the harmonization process usually has more than one platform for the same test, whereas the local lab is less flexible in terms of analytical equipment. 

Several aspects are part of an analytical equipment setup decision. One aspect to consider is technical support and kit availability in the country, which is usually considered by the local laboratory during its clinical laboratory setup phase. Nowadays, the analytical equipment and kit providers frequently have global distribution and are represented in the countries where the clinical trials are conducted. 

A correlation test program can be necessary depending on the tests involved, regardless of differences between the analytical setups. This correlation means the exchange of samples between labs and comparisons of the results to check if the harmonization is consistent and can be demonstrated statistically during the study. The exchange procedure frequency will have to be agreed on by the involved laboratories. 

Finally, there is the virtual central laboratory concept. In short, there is a calibrator that runs together with the trial samples. The calibrator and the sample results are compared, and the result is adjusted based on the calibrator value that is used by all the laboratories participating in the trial. 

 This aspect is important for the data analysis and data management process. It can be a difficult task depending on the population and tests involved. Safety test reference values are easily harmonized because most of them follow international standards. Safety tests are the main analysis done at local labs in order to speed up a project, especially during the screening phase. 

Hematological parameters can be harmonized, provided that the equipment/methodologies are previously discussed among the partner laboratories (because of the different sensitivities among the existing analyzers). Very often, a correlation study is necessary. In addition, there can be differences regarding population aspects such as genetic and nutritional characteristics, among others. 

The way of reporting urinalysis needs to be discussed previously because there might be some differences in reporting qualitative aspects. The reporting conventions are not always the same. For virology tests—despite the fact that reference values are usually qualitative (negative/positive)—the methods' linearity and sensitivity demand an exchange of information among the partner laboratories. And molecular biology test harmonization depends on the protocols used for the result analysis and reporting, especially for genotyping tests. 

In my experience, harmonization is very difficult for coagulation and immunophenotyping tests. Those parameters are highly dependent on population characteristics and reagents used by the laboratories. However, samples for immunophenotyping tests are not stable enough to be transported from one country to another, which means that the protocol and database have to carefully harmonize these parameters. 

Certification, accreditation, and external QC programs.

 The third step requires that all laboratories involved in a project be able to show their national and international certification and accreditation. The most frequently requested are the ISO 9001 certification and CAP accreditation. 

The certifications for environmental protection and sustainability are becoming very popular among the clinical trial sponsor companies. Therefore, ISO 14000 accreditation is a positive certificate for clients and sponsors. 

There are some quality control programs specific to certain areas of the clinical lab (such as the NGSP program for glicated hemoglobin), and these must also be a part of the discussion. 

The requirements from different regulatory agencies also have to be considered, such as 21 CFR part 11 from FDA, which refers to electronic system validation. 

 The fourth step requires that routines, not just the equipment, go through a harmonization process. The stability data in different temperatures need to be checked. Calibration frequencies, preventive equipment maintenance, and repeat thresholds also have to be discussed among participating laboratories. 

Reporting and data transfer format also are easily harmonized, despite the fact that there may be some difficulties with a few tests, such as urinalysis results. 

Today there is a multidisciplinary group of international specialists that are enforcing the adoption of the CDISC protocol as a kind of standard regarding data transfer format. This tends to facilitate the workflow for IT structure, since there are several formats and platforms for transferring the data requested by different sponsors. 

To ensure laboratory routine consistency throughout different partner laboratories, some SOPs will also have to be discussed and incorporated into the lab's SOP list. 

Sponsors want to receive a reliable clean database from a single source and they usually request different types of connectivity. Therefore, the local lab needs to be prepared to cope with different communication strategies. The common point among them is that the local lab will be requested to send the data to the global central lab or to the global data manager. However, how to do this can be a difficult task. 

The easiest way is to allow the local lab's Laboratory Information Management System (LIMS) to transfer the data to the central lab electronically. Other central labs insist on an interface construction between their system and the local lab's. This is not so easy or simple because it represents two different LIMS running at the same lab. Both labs will have to be fed with the same data for production and sample tracking control. 

The global lab will conduct the harmonization process and define what level of harmonization is required. The global lab is the one that will have access to the sponsor's requirement. 

There are some analyses that usually are centralized and will remain under the global central lab's responsibility, such as pharmacokinetics, study endpoints, and global data management, which can be done also by a third-party company. 

The local lab will conduct the trial in its region. In addition to the sample analysis, it will support the clinical sites and take care of the inbound and outbound samples and kit logistics. The data will be transferred to the global data manager according to the global central lab's specifications. 

The local lab performance has an important impact on the relationship between the investigator and the study sponsor. Sometimes, remote project management interferes negatively in this regard because it is not a concern for the global central lab that is managing the clinical trial project with a given principal investigator at his/her clinical site. This is an additional advantage to having a local laboratory supporting the sites. 

At the end of the responsibility chain is the sponsor, who is responsible for the data submitted to the regulatory agencies. Therefore, the local labs have to be prepared to host periodic audits with the sponsor or global central lab's audits. The scope of these audits is usually related to a particular project or can focus on the laboratory and QA processes. 

Some sponsors ask for a qualification visit before starting the harmonization process. This can be a useful procedure that strengthens the level of integration between local and global laboratory service providers. 

Last but not least, the regulatory agencies are also prepared to make inspections at the local labs in order to validate or not validate the data coming from different laboratories. 

As far as sample drawing kits go, it is increasingly difficult to put sample drawing kits shipped directly from the global central labs in place at different clinical sites. Not only are the costs contributing to these difficulties, but so are customs requirements. The major sample drawing material providers are represented globally, allowing the kits to be assembled and dispatched locally. 

However, for some global central labs, the kits are linked to the sample tracking system, which obliges the global central lab to dispatch kits already bar coded. This will cause the local labs to have additional work whenever the sample drawing tubes do not fit the analytical equipment. This issue has to be addressed during the harmonization process discussion. 

Articles

Bonus Article

With globalization of trials comes the difficulties of biologic sample logistics. Enter the centralized/decentralized laboratory model.

The Local Central Lab Model

A number of authors have recently estimated the expenditure in clinical trials for laboratory services to be above $1 billion (€750 million). Such laboratory services include preclinical and clinical lab testing as well as expenses for imaging techniques. It is envisioned that the proportion of this analytical budget spent at central laboratories in contrast to local laboratories will continue growing. 

Whereas CROs expand into geographical regions where running clinical trials at a lower cost is feasible, laboratories are asked to perform more complex—and expensive—methods or to validate new assays specifically for one sponsor. These requirements seem to support the view that central laboratories in the future will be more "central" rather than a build up of lab affiliates in many geographic regions. Complex new methods can only be offered at competitive prices if samples are tested centrally in larger batches. 

Investigators (and sponsors) expect lab results to be reported immediately after the central lab receives the samples. Result reporting within 12 to 24 hours may be easy to achieve for routine testing methods. Interestingly, for more complex and specialized methods, the frequency of running a specific assay in the laboratory directly depends on the number of samples received. The high cost of instrumentation (up to $250,000) and reagents ($1000 for a kit to test approximately 40 samples), in addition to the need for qualified technicians, explains why laboratories need a minimum batch size to offer competitive lab fees to sponsors. 

A small laboratory processing 50 or 100 samples a day may only receive five to 10 samples for a specific immunology method. This imaginary laboratory would only be able to run the immunology assay two to three times a month at a rather high cost per unit. The chances are very high that small laboratories refer their samples to larger laboratories (often hospital-based laboratories with poor quality standards and missing cross-validation data). A central laboratory with the capability to process 5000 or more samples per day may have the advantage of both offering competitive prices and reporting lab results with the shortest delays. 

When looking for a central laboratory, sponsors should therefore find out early on if candidates are not only able to perform the study-specific test panel but, more importantly, if they are able to perform the assays requested on a daily basis to ensure short result-reporting delays. 

The geographic location of the study site is an important factor in the selection process when looking for a central laboratory. From a logistical point of view, it would not be a good idea to select a European central lab for a U.S. only study and then ship all samples over the Atlantic. 

In view of the increasing number of studies with sites on two or more continents, sponsors are faced with the question: How much local and how much central? In contrast to CROs, a central laboratory should work as centralized as possible. 

To be successful, central laboratories may only be global by following one of the following two strategies: 					

Having at least two major laboratories (e.g., in North America and Europe) and a number of smaller administrative subsidiaries

Creating global networks of independent laboratories following the same global SOPs and using the same IT platform and database.

Both strategies require a similar effort in cross validating lab methods at each location in order to continuously monitor data comparability and identify the need for corrective measures. 

Multicontinental studies provide the professionals involved with physical and practical limits. A key aspect for succeeding in such trials is the ability to communicate between different time zones without having to wait for the next day. 

The ideal location of a globally active central laboratory would seem to be Europe, as it would be located in the geographic center between Californian Biotech clusters (eight to nine hours apart, and reachable after 4 p.m. Central European Time [CET]) and Southeast Asia or Australia (six to nine hours apart, and reachable before 10 a.m. CET). A further advantage for Europe is that South Africa is in the same time zone as continental Europe. Instead of sending emails or faxes and waiting until the next day for a response, a European central lab offers synchronic and interactive communication (e.g., via phone), which may ensure the shortest turn-around times. 

In contrast, a company in New York must overcome the time difference of 12 or more hours between them and their clients in New Delhi, Hong Kong or Sidney. Also, the duration of travel flights seems to be shorter for Europeans: A nonstop flight to San Francisco or Beijing takes 11 to 13 hours. A flight from Singapore to New York needs a stop-over and takes 18 to 24 hours. In addition, within Europe most major European cities are within a radius of two to three hours from each other. 

Fortunately, the need for central lab services will continue to grow. Central laboratories will be asked to develop more sophisticated methods and to extend their logistic infrastructure to new geographic regions. 

In view of the reduced number of global central laboratories (less than a dozen) and the significant differences between them, I do not think the approach of having a master services agreement with two to three central laboratories is viable for the future for most sponsors. Smaller laboratories may be good for local studies where the testing portfolio is not too demanding, but they will not have the volume to cope with test panels that are becoming more complex. Larger central laboratories, following either strategy mentioned, may succeed in supporting global studies if they have an established worldwide infrastructure and a solid quality system in place. 

, MD, FFPM, is chief executive officer and co-founder of INTERLAB Central Lab Services–Worldwide GmbH, Munich, Germany, email: 

Viewpoint

Strategies for labs to support global trials and meet the needs of sponsors worldwide.

Centralizing the Laboratory

A major challenge faced by the pharmaceutical industry in the development of new noncardiovascular drugs is evaluating the potential risk for life-threatening ventricular arrhythmias—in particular, Torsade de Pointes (TdP). In the past two decades, several noncardiovascular drugs, after a long and expensive approval process, were found to induce TdP, resulting in their withdrawal from the market and profound negative financial consequences to sponsors. 

A potentially "torsadogenic" drug may initially appear safe when administered to large numbers of patients in a trial if patients at risk, by chance or by design, are excluded from the study population. The proarrhythmic risk may only become manifest after approval, when administered to individuals who have a latent genetic risk or an acquired predisposition due to underlying heart disease, electrolyte abnormalities or concurrent medications adversely affecting the drug's metabolism. On the other hand, a potentially useful and safe drug may be inappropriately withdrawn during early drug testing because of the erroneous impression that the ECG data indicates a potential proarrhythmic risk. 

The many issues concerning drug safety are extremely complex, and the costs of evaluating new drugs are staggering (over $800 million per drug). This article will consider current methodologies for evaluating the risk of new noncardiovascular drugs for TdP and other life-threatening arrhythmias. Limitations in current guidelines will be considered, and recommendations for further study will be reviewed. 

Torsade de Pointes is an unusual but eye-catching and life-threatening polymorphic ventricular tachycardia that has its origin in patients with the hereditary or acquired long QT syndrome (LQTS).

 The onset of TdP is often precipitated by one or more premature ventricular complexes occurring during the prolonged repolarization phase of the preceding beat. Typically, the arrhythmia is short lived, but it can unexpectedly degenerate into ventricular fibrillation leading to syncope and sudden death. 

The characteristic QRS morphology during TdP involves recurring cycles of gradually changing QRS direction around the ECG baseline (see Figure 1). While the mechanism of the arrhythmia is not well understood, it is clear that abnormal dispersion of ventricular repolarization plays an important role in its initiation. Currently, the electrocardiogram is the basic tool for assessing TdP risk, and a prolonged QT interval is almost a necessary prerequisite for making the diagnosis. 

Figure 1.  Onset of Torsade de Pointes in patient with LQTS.			

The prevalence of TdP in the general population is exceedingly rare, somewhere between 1/100,000 and 1/1,000,000. Because it is so uncommon, yet potentially life threatening, the FDA and other regulatory agencies in Europe and Japan have struggled to develop appropriate guidelines for analyzing the ECG data obtained during the evaluation of new drugs. The most recent consensus guidelines were approved by the International Committee on Harmonization (ICH) and published in 2005.

The European Union, Japan, and the United States have adopted these guidelines (ICH E-14), which rely almost entirely on one ECG parameter, the QT interval, and its correction for changes in heart rate. Other reliable and reproducible ECG markers of abnormal repolarization and TdP are also being investigated, but a more definitive marker for abnormal repolarization has yet to be defined. 

Based on the ICH E-14 guidelines, Morganroth discussed the "thorough ECG trial," also known as the "thorough QT/QTc trial" (TQT), for assessing the TdP risk of new drugs undergoing early Phase II testing.

  The TQT is designed to detect small but important drug-induced changes in QT intervals that would identify a drug as potentially dangerous and preclude it from further large and expensive Phase III trials. 

By focusing on QT interval changes, the TQT demands a large number of digitally acquired, 12-lead ECGs to compare manually measured QT/QTc intervals from subjects on placebo with those on active drug treatment. Multiple ECGs are required at baseline and at many time periods after administering either the drug or placebo. ECGs are also obtained during a supra-therapeutic dose of the drug. Depending on the pharmacokinetics of the drug under investigation, a crossover or parallel design study protocol is chosen. Specific criteria are defined for the increase in rate-corrected QT (usually >20ms) from which to conclude that TdP risk is quite high. 

While TdP has been primarily defined as the prototypic arrhythmia in patients with LQTS, it is clear that prolonged QT and QTc have not always predicted the risk of TdP. Drugs such as amiodarone, phenobarbital, and ranolazine lengthen the QT and QTc but do not usually induce TdP, and amiodarone may actually protect patients from dangerous ventricular tachyarrhythmias. It has also been reported recently that abnormally short QT/QTc can have arrhythmogenic risk of its own.

  These factors must be considered when attempting to use prolonged QT and QTc as unequivocal predictors of risk for TdP. 

Although the ICH E-14 guidelines and, in particular the TQT design, are currently being required by various regulatory agencies, there are a number of conceptual and practical implications of this approach. 

Current ECG equipment manufacturers are primarily driven by health care delivery needs including hospitals, clinics, and physician offices, but not by the clinical research environment, which, by comparison, is a minor component of the overall ECG equipment market. Generally, equipment manufacturers follow published ECG signal and processing standards,

  but the overall quality of clinical ECG data in health care delivery can be quite variable and not always reliable for the purpose of making careful, quantitative measurements necessary for clinical drug trials. Issues related to skin preparation, lead placement, and data quality are often overlooked or not corrected immediately, and there is no compelling need for getting it right the first time. 

Sophisticated signal processing methods are only as good as the signals acquired. What is needed in the drug research environment are specially designed clinical trial ECG recorders, Holter monitors, and software that address common quality problems of poor electrode position and contact, baseline drift, sample speed, and recording duration. 

While imperfect, the QT and heart-rate corrected QT (QTc) continue to be the primary ECG focus in drug development for identifying repolarization abnormalities predictive of TdP risk. In fact, the focus on QT has been so entrenched that a new clinical entity has been defined: Drug-induced Long QT Syndrome. 

There are, however, many reasons for QT interval measurements to be imprecise and inaccurate. These include difficulties in identifying the end of the T wave, choice of optimal lead(s) for measuring the QT, U-wave related issues, adjustments for heart rate changes, and intersubject or intrasubject variability. In addition, some drug study protocols require ECG lead II to be used for all QT measurements even when the end of the T wave is better seen in alternative leads, usually V3-5. QT intervals measured in a single lead may not be as accurate as those made from a global composite of all 12 leads. 

The choice of the best formula for heart rate correction (e.g., Bazett, Fridericia, Framingham) is, however, very controversial, and different formulae may lead to different conclusions regarding a drug's TdP risk. Rautaharju provides compelling arguments against adjusting QT for heart rate using power functions of the RR intervals (e.g., Bazett and Fridericia's) because of nonlinear distortions of the normal QT upper limits at heart rate ranges above and below 60 bpm.

  He recommends adjusting QT using a simple linear function of RR interval. In some studies, the heart rate corrected QT is based on individualized QT interval ranges obtained at different heart rate—RR interval bins prior to administering the study drug. 

All the different methods proposed for QT/RR adjustments assume that there is a common physiologic relationship between QT and heart rate that is similar for all individuals. This is clearly not the case. 

While measures of QT and QTc prolongation have been utilized as surrogate indices of disordered repolarization, numerous studies have shown that this is an overly simplistic assumption. Even ignoring the measurement problems stated above, the QT interval is but one of many possible parameters related to ventricular repolarization, and prolonged QT intervals don't necessarily always reflect disorganized repolarization. 

Evidence for electrical heterogeneity in ventricular myocardium has been published by Antzelevitch and colleagues.

  Using arterially perfused animal wedge preparations of ventricular myocardium, these investigators have shown that transmural dispersion of repolarization (TDR) results from differences in action potential duration (APD) in three electrophysiologically distinct cell types found in the epicardium, the endocardium, and the "M" cells of the middle layers. In particular, the M cells have the longest APD and the epicardial cells have the shortest APD. Furthermore, the M cells are more likely to be affected by QT-prolonging drugs, as well as by slow heart rates and other proarrhythmic perturbations. 

In the wedge preparation, voltage gradients between epicardium and M cells define the upslope of the T wave; the T wave peak reflects the end of epicardial cell repolarization; voltage gradients between M cells and endocardial cells define the downslope of the T wave; the end of the T wave occurs when M cell repolarization is complete. The interval between T peak and T end (TpTe) is a measure of TDR in wedge preparation. 

Both animal and clinical studies have concluded that TdP and other ventricular tachyarrhythmias are initiated by local potential gradients within the three cell layers leading to triggered activity from early after-depolarization or re-entrant excitation. Several studies have recently suggested that prolonged TpTe corrected for heart rate might be a better marker for TdP risk than QTc,

  but this measurement has not yet been implemented in the guidelines for studying new drugs. It is also unlikely that TpTe measured on the 12-lead ECG reflects the same information about TDR as found in the simpler animal wedge preparation. 

Other ECG measures of disordered repolarization have been investigated with conflicting results. One of these, QT dispersion, is obtained by subtracting the QT interval from the ECG lead with the shortest QT from the longest QT interval in the 12-lead ECG. Although this parameter has no physiologic basis, it has been studied intensely, and has finally proven to be of minimal value in the evaluation of TdP risk. Rautaharju has been one of the strongest critics of QT dispersion and has essentially signed its death certificate.

T wave alternans (TWA) is a promising technique that has been used in patients with heart disease to stratify their risks for ventricular tachyarrhythmias and sudden death.

  TWA is a measure of microvolt variations in beat-to-beat changes in T wave amplitude using digital signal processing of the 12-lead ECG at rest or during submaximal exercise. Studies have shown that a "negative" TWA test in these patients is associated with a very low risk of life-threatening arrhythmias. Although TWA is useful in selected patient populations, it has not been carefully studied in the setting of new drug evaluations, and it is unlikely to be abnormal in the normal population. 

Finally, detailed analysis of T wave morphology and complexity has been considered potentially useful for studying disorganized repolarization. Specific T wave phenotypes have been reported for the three common types of hereditary LQTS,

  and similar T wave morphologies are also described in the acquired LQTS.

  In both conditions, prolonged QTc and TpTe intervals are associated with unusual T wave morphologies and increased TdP risk. It is not certain how these various T wave parameters can be used to improve the sensitivity and specificity for TdP risk in the study of new drugs. 

The search for valid ECG parameters to assess the risk of TdP and other life-threatening arrhythmias is ongoing. QT and QTc continue to be the most studied ECG parameters in the evaluation of new drug safety, and current guidelines attempt to standardize the process of analyzing and reporting the ECG data. 

Improvements in ECG equipment, computer analyses, patient preparation, and standardized protocols are needed to reduce the enormous costs related to drug development. The unwarranted and premature demise of potentially useful new drugs because of false positive conclusions of adverse repolarization changes continues to be a problem that needs attention. 

, MD, is professor of medicine at the University of Utah School of Medicine, medical director, Intermountain Healthcare ECG services, at LDS Hospital in Salt Lake City, UT, and a member of the VIASYS Clinical Services ECG CorLab Board of Expert Over Readers, email: 

 1. N. El-Sherif and G. Turitto. "Torsade de Pointes," 

 2. ICH E14 Guidelines, "The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (online)," http://

 3. J. Morganroth, "Cardiac Repolarization and the Safety of New Drugs Defined by Electrocardiography," 

 4. E. Schulze-Bahr and G. Breithardt, "Short QT Interval and Short QT Syndromes," 

Journal of Cardiovascular Electrophysiology

 5. P. Kligfield, L.S. Gettes, J.J. Bailey, R. Childers et al., "Recommendations for the Standardization and Interpretation of the Electrocardiogram. Part I: The Electrocardiogram and Its Technology," 

 6. P.M. Rautaharju and Z. Zhang, "Linearly Scaled, Rate-Invariant Normal Limits for QT Interval: Eight Decades of Incorrect Application of Power Functions," 

 7. C. Antzelevitch, "Cellular Basis for the Repolarization Waves of the ECG," 

Annals of the New York Academy of Sciences

 8. I. Topilski, O. Rogowski, R. Rosso, D. Justo et al., "The Morphology of the QT Interval Predicts Torsade de Pointes During Acquired Bradyarrhythmias," 

Journal of the American College of Cardiology

 9. M. Yamaguchi, M. Shimizu, H. Ino, H. Terai et al., "T wave peak-to-end and QT Dispersion in Acquired Long QT Syndrome: A New Index for Arrhythmogenicity," 

10. P.M. Rautaharju, "A Farewell to QT Dispersion. Are the Alternatives Any Better?" 

11. A.F. Osman and M.R. Gold, "T Wave Alternans for Ventricular Arrhythmia Risk Stratification," 

Feature Article

A look at ECG evaluation for drug-related alterations in repolarization and Torsade de Pointes.

Early Accuracy in New Drug Safety Analysis

Over the past decade, the use of medical imaging in clinical trials has become increasingly important in the drive to produce quantifiable and reproducible results that establish efficacy of a given compound. Imaging is a highly specialized arena, and most drug companies have focused on outsourcing to CROs as a way to plan and execute the imaging components of a trial. The goal in choosing a CRO is to concentrate on finding a partner that can deliver reasonably priced services and the desired level of quality within what is often an aggressive time frame. 

Putting aside the differences in scientific approaches to analysis, it may seem that all partners are basically the same—images are acquired, read, and results come back. However, when you start digging more deeply into the scope of a CRO's operations, real differences emerge that may determine how your partner really performs. One key area of differentiation for CROs is how these companies make use of electronic systems to streamline their operations. 

A detailed look at three of the key attributes of an effective platform for image analysis follows, with hard questions for you to ask potential partners.

A company's approach to the quality system regulations imposed by the FDA is an important indicator of its relative maturity within the CRO community. 

Paper and ink approaches to quality records can be effective in extremely small companies but will certainly show signs of strain during times of growth. If your provider relies on screenshots of radiologists' findings stored in a binder on somebody's desk, that company is likely to lose regulatory paperwork that may be critical to your trial. The need to protect such data leads inevitably to the use of an electronic system, but what are the critical features of such a system? 

 Each action that reflects a decision made during a trial should be recorded along with the name of the user who made the action, the date the decision was made, and an electronic signature that validates his or her identity. The audit log should be stored in a protected environment and accessible only to authorized personnel. Tools to view and process the information in the log should be provided. In audit situations, it is necessary to be able to find this information. 

 If the CRO goes out of business, how will you successfully reproduce the results on which your drug relies? It is not enough to simply send system backup tapes to a data storage facility and then hope you can actually do something with the data in the future. At a minimum, some kind of escrow should be in place whereby the code and operations procedures for the CRO's system are stored by a third party with a provision for your company to have full access to these assets in critical situations. Remember, you need the method as well as the results to survive in an audit. 

 The correct use of passwords, biometrics, and other authentication technologies is critical to the protection of data. Systems that store user passwords in plain text, do not encrypt communications or rely on homegrown authentication are simply not secure. In a similar vein, minimum access should be granted by role. If a user has the right to perform image inspection, this does not infer the right to perform RECIST measurements. Access should be granted on the basis of certification by an experienced user. 

 21 CFR Part 11 lays out stringent rules for electronic signatures. Documents that will be managed electronically must comply with these regulations. Note that even if a vendor claims to be keeping paper records, substantive reliance on the electronic system means that they are subject to the provisions of 21 CFR Part 11. 

Efficiency in CRO operations can be measured in cost, speed, and the ability to reduce the size of the subject population  through the application of quantitative methods that decrease statistical variation. An effective platform brings an IT systems approach to operational efficiency through the use of integrated software components. So, what are some approaches a CRO uses to maximize its results and minimize its costs? 

 One of the key benefits of a CRO is the management of sites by experts in the emerging domain. An integrated platform should manage a database of sites and contacts that allows for tracking the site relationship throughout the trial. As the number of sites in a trial increases, tracking this information in Excel spreadsheets becomes extremely inefficient and an automated system is necessary. 

 Imaging trials typically involve huge amounts of data that require tasks such as quality inspection, manipulation, and analysis. Managing the quantity of data that can arrive from several hundred sites requires an advanced electronic system. It is critical that a CRO knows the state of data analysis at all times, understands how the entire trial is progressing, and can provide meaningful management reports when asked. How many subjects have been scanned? Which sites are performing best? These are important questions. 

 There are typically many independent tasks that must be performed on each study under examination. Some of these tasks can be performed concurrently, and each requires a certain level of expertise (or certification). Efficient processing of these tasks requires a workflow-based approach, where the tasks are allocated to the most cost-effective resource to be performed. Some tasks such as registration do not require a radiologist, and using expensive resources in these situations results in inflated costs and longer trial times. In the ideal situation, many of these tasks will be handled by automated computer algorithms. In short, if your CRO relies completely on radiologists to perform all tasks, they will not be able to scale to larger studies in a cost-effective manner. 

Perhaps the most important differentiator in CRO relationships is the ability to communicate meaningful data in real time. 

A successful partner can provide insights into data that you did not expect and will look for ways to provide you with that information in the most effective fashion. This can range from portals into production systems that show real-time data to emails from a project manager containing that report you need right now in the format you need it. Customized reporting that provides meaningful answers to your questions is a critical element of a successful platform. How is your CRO going to provide you with this kind of information on demand? 

 Web-based reporting tools vary from full data mining applications to simple repositories where reports are placed for you to access easily. Since it is unusual for customers to want to spend a significant amount of time building sophisticated queries, a successful CRO will provide the capability to do this for you and then use the electronic delivery capabilities to speed up your access to data. 

 When sending information over the Internet or through email systems, it is critical that your CRO has separate areas for storing information for each of their customers and provides a secure repository for that information (complete with user names and strong passwords). 

Choosing a CRO requires a detailed analysis of the scientific, clinical, and operations capabilities of each vendor. While the majority of focus is placed on the first two elements, the electronic systems used by the CRO should not be ignored. 

If the CRO makes substantive use of an electronic system yet relies on paper records, they may well be in violation of CFR 21 regulations. If they do not protect both the data and method (software) used to derive results, then how will you show reproducibility in the event of a regulatory finding several years down the track? Can they scale to handle your larger trials if they rely only on radiologists with no automation of analysis? What if they change radiologists midway through a trial, and the lack of precision that is inherent in systems without automation leads to differences in analysis? 

These are some of the typical issues that a platform for image-based trials can help you address. 

 is director of software development at VirtualScopics Inc, email: 

 1. 21 CFR Part 11 "Electronic Records, Electronic Signatures," http://

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

The International Handbook of Computer Security

 (Lesson's Professional Publishing, London, 2000). 

A Manager's Guide to the Design and Conduct of Clinical Trials

, 2nd Ed. (Wiley-Liss, Wilmington, DE, 2006). 

Web & Software Development: A Legal Guide

To select the right CRO as an imaging partner, sponsors must first be aware of what to look for.

Elements of a Successful Platform for Image Analysis

Cardiac safety has become the number one reason for drug withdrawals and labeling changes during the past several years. This has resulted in greater regulatory scrutiny for all new compounds and greater concern among pharma companies in regard to the potential effect of their compounds on cardiac safety. 

One of the outcomes of this focus was the ICH E14 document, which provided guidance on the conduct of a dedicated ECG study that many term the "thorough QT (TQT) trial." These trials generally are conducted after proof of concept has been completed and employ digital and centralized ECGs as described in E14. However, although almost all TQT trials are centralized, only 20% to 25% of all other clinical research trials (Phases I through IV) use centralized ECG analyses. 

If a TQT trial shows cardiac safety concerns, regulatory bodies generally require more robust or intense ECG collection in Phase III, and those trials are more commonly centralized and use digital ECGs. However, the majority of trials conducted worldwide still get ECGs the old fashioned way. They are done by local ECG machines with varying algorithms and often collected at the beginning and end of the trial, providing little to no data about the cardiac effects of the chemical entity being studied. 

The reasons for this decentralized approach include a lack of regulatory guidance in this area and the perception that centralization must be more costly. I will discuss these and other issues to demonstrate that ECG centralization has an important place in the drug development process. 

ECGs serve many roles in the research and development process. They generally are required as part of the screening, selection, and enrollment process for study participants; they assist in assessing the cardiac safety of the investigational drug; they provide efficacy data for cardiovascular-related compounds; and they provide indirect benefits to the subject and his or her  physician in diagnosing undetected structural or electrical cardiac diseases, as well as detecting progression of cardiac disease during the course of the clinical trial. 

Currently, most view the main role of ECGs as the tool that best assesses the effect of investigational drugs on the electrical functions of the heart. In particular, ECGs are used to gather information on changes in the QT interval, the best surrogate marker for the possibility that an investigational drug may cause Torsade de Pointes, a life threatening arrhythmia. ECGs also gather information on heart rate effects, atrioventricular conduction, depolarization, and changes in ECG morphology that may indicate pathological cardiac changes. 

This process begins with early phase studies in healthy volunteers and continues into Phase III and Phase IV studies, where subjects are most susceptible to the cardiac effects of agents and where effect modifiers exist that may enhance unknown or minimal cardiac actions of new drugs. 

For those who do not centralize ECG analysis because of a lack of concern about cardiac safety when the drug has no early QT signal or other cardiac issues, it is important to understand that it is difficult to assess all the possible cardiac safety effects of investigational drugs in premarketing clinical trials. Most of the best known recent drug withdrawals and labeling changes have been for drugs that were already being marketed to the public. It would, therefore, make sense to get the best possible data during clinical trials before these drugs make their way to the market with unexpected effects. 

The task of identifying potential cardiac safety effects in clinical trials is difficult enough due to the short duration, narrow patient populations, limited indications, and relatively small size of these studies. The difficulty is further compounded by the fact that very few clinical trials use centralized ECG readings to increase the probability of detecting cardiac effects. This increases the background "noise" in clinical trials due to the different ECG machines at different clinical sites; the different measurement algorithms for QT, QTc, QRS, and PR intervals; and the differing morphology interpretation programs within the ECG machines themselves. 

Add to this the large daily variation in a subject's QT duration (about 60 to 75 msec) and the lack of consistency amongst cardiologists in ECG interpretation, and analyzing data obtained in this manner becomes extremely difficult. 

Decentralized collection and interpretation

The site analyzing the ECG, a decentralized analysis process, is the most common method for ECG interpretation. This is estimated to occur in 75% to 80% of clinical trials (excluding TQT trials) and is, therefore, the most common method of ECG interpretation in clinical research. All queries, data reconciliation, and database issues are the responsibility of the sponsor. 

Most clinical trial sponsors do not consider the consequences of ECG collection in their integrated summary of cardiac safety in filing approval for marketing until late in the process. Therefore, they incur many data problems that would generally be addressed throughout the research process by a central ECG laboratory. These processes include qualifying the ECG equipment at sites, training investigators, generating queries, reconciling data, and performing the actual management of the ECG database and database lock. 

The sites are responsible for performing and acting upon the interpreted ECG, which must be documented in the case report form. This transfer of information can result in transcription errors and other unexpected results due to the investigator's inability to adequately interpret the ECG data. 

From a purely clinical standpoint, Viskin et al.

  did a study to look at the competency of noncardiologists, cardiologists, electrophysiologists, and QT experts in assessing the QT interval measurement in a small sample of ECGs. The findings were striking: Noncardiologists and cardiologists were found to be essentially equal in their inability to assess the length of the QT interval with an accuracy rate of 21% and 22% respectively; electrophysiologists faired better at 62%; and QT experts were correct 96% of the time. 

For the majority of clinical trials being conducted today, whether the investigator interprets the ECG or has a local cardiologist do the work for them, it is highly unlikely that accurate clinical signals will be detected. 

Centralized collection and interpretation

For clinical trial sponsors who have not considered centralizing ECG analysis, I raise the question: Why it is so common to use a central laboratory for blood analysis but not for ECGs? The concerns that led to blood laboratory centralization are the same for ECGs when it comes to data quality and integrity. 

When a sponsor chooses to centralize the ECG process, an ECG core laboratory takes on much of the work that would normally be done by sponsors, CROs, and sites. The use of digital ECG collection allows for a process that expedites the ECG reading process and results in cleaner data that is not subject to interpretation of the handwriting at the investigator site. 

The query process is also enhanced, as some core labs have systems that automatically check for changes in demography and/or missing visits. This will aid the data lock process as the study draws to a close. Additionally, most core labs provide equipment to the sites for the digital collection of ECGs. 

The sites should be provided with equipment that has been tested to assure full function and programmed for the specific demography capture for the study. Importantly, the interpretation algorithm used for all machines in a given study should be the same. This ensures that all sites are working from a common platform and should reduce some of the spurious errors seen when sites use old or poorly constructed equipment. 

Most investigator sites involved in the study of noncardiac drugs do not have the expertise to analyze ECGs. As stated earlier, since most studies are conducted in a decentralized fashion, generally the investigator sites just copy the interval duration measurements (IDMs) directly off the machine's paper print out. Often the machine's morphology interpretation is used with a local cardiologist over-read in some cases. 

As each site will have different machines, the IDMs—which generally consist of the heart rate or R-R interval, the PR interval, the QRS interval, the QT interval, and the calculated QTc—will vary from site to site. In addition, some sites may use different machines on different visits, resulting in varying IDMs on the same subject. Also, it is important to note that not all machines calculate QTc the same way, making comparison across the entire study unscientific. Lastly, the accuracy of the measurements of these algorithms is known to be inaccurate, especially in ECG tracings with abnormal ST-T morphology, which is common in subjects with clinical conditions. 

When a core ECG laboratory is used, the work of the CRAs and data management teams at the sponsor or CRO is diminished due to the query and data cleaning processes employed by the laboratory. In regard to data quality, every IDM is measured by a qualified person and each ECG is seen by a qualified cardiologist, thus ensuring a high degree of consistency. 

Currently, there is no regulatory mandate to centralize ECGs for trials other than what is implied in the E14. However, with the advent of the ECG warehouse (which uses digitally acquired ECGs provided in XML format to allow regulators to more efficiently view and analyze the quality of ECG data submitted), regulators have been asking for most studies in all phases of research to be submitted to the warehouse. 

This is not a prospective requirement at the current time in Phases I through III, but it is a request that trial sponsors are complying with and requires them to collect their ECG data in a centralized fashion for that trial. The submission of the data to the warehouse will serve to expedite regulatory review and will assist the regulatory agency in advancing their knowledge of cardiac safety issues, which could lead to improvements in the current process or to new methods of testing. 

Perhaps the greatest difficulty in changing the current balance of decentralized to centralized ECG collection and interpretation is the concern over cost. 

Unfortunately, most clinical trial sponsors cannot quantify the number of ECGs they do, and even more rarely are they able to estimate the true cost of doing ECGs decentralized versus centralized. The general perception is that they are already paying the site to perform and read the ECGs and that the addition of a centralized ECG reading service is a further expense. 

One approach sponsors can take is to decrease the ECG acquisition fee they pay, as that fee takes into account both the technician time and the use of the investigator's ECG machine. Digitally centralized ECGs require the use of centralized equipment; therefore, technically the investigator is not entitled to reimbursement related to the equipment provided. 

Much of the work done by ECG core laboratories has little to do with the actual reading of the ECGs. Each core laboratory has its own method of measuring IDMs and interpreting ECGs. Clinical trial sponsors should endeavor to understand what approach is being taken before selecting a provider. Often overlooked in the selection process are the systems being used by the core laboratory and the procedures in place to simplify the ECG data acquisition process for the sponsor. 

Sponsors need to assess the ECG core laboratory's ability to manage, ship, and program ECG equipment (logistics); to query data on an ongoing basis; to deliver clean data on time; and to supervise the process with a strong emphasis on project management. Although many sponsors feel that they already have these services "in house," they are certainly not free, and a good ECG core laboratory will serve to decrease the work of CRAs at clinical sites, decrease the work of the study's project manager, and decrease the work of the data management team being used by the sponsor—freeing all for other work. 

Proving to sponsors that improvement in data quality and the reduction of effort on their part and the part of sites is of sufficient value to justify the expense of ECG centralization has been a challenge for core labs. However, at current pricing levels it is a challenge that can be met when sponsors consider all of the costs involved with decentralized ECG collection. 

It is important for sponsors to recognize that the support each core laboratory provides may not be the same. They also need to understand what they are paying for to ensure they are truly getting value for their investment. 

, MD, FACC, is executive vice president and chief medical officer at eResearch Technology, 8th Floor, 30 S. 17th Street, Philadelphia, PA 19103, email: 

1. Viskin et al., "Inaccurate Electrocardiographic Interpretation of Long QT: The Majority of Physicians Cannot Recognize a Long QT When They See One," 

A call to sponsors to rethink the role of ECGs in drug development and the use of central core labs.

Cardiac Safety: The Merits of ECG Centralization

Imaging is widely applied as a biomarker in therapeutic clinical trials. It is commonly used to assess the response to therapeutic interventions. However, the wealth of imaging modalities and techniques applicable for different diseases often make it difficult for the clinical trial manager to choose the technique best suited for the underlying question. 

This article describes the opportunities and challenges for the use of imaging in clinical trials from an imager's perspective—one who has experience as a principal investigator, co-investigator, and core lab scientist. 

The most common use of imaging in clinical trials today is in the evaluation of tumor size. The two most commonly used evaluation criteria are the World Health Organization (WHO)

 criteria and the Response Evaluation Criteria in Solid Tumors (RECIST)

Both assessments are based on the measurement of one or two diameters of selected target lesions. Up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, are identified as target lesions. The sum of the longest diameter for all target lesions is calculated. The response to treatment is classified by the following criteria: 					

The disappearance of all target lesions constitutes complete response.

Partial response is a decrease of at least 30% in the sum of the longest diameters of the target lesions.

An increase of at least 20% is considered progressive disease.

Anything between partial response and progressive disease is labeled stable disease.

These evaluation criteria have been developed to estimate volume changes of lesions in response to therapy. This was necessary because the assessment of the true lesion volume was very time consuming, since the lesions had to be outlined on every slice manually. Therefore, it was not applicable in clinical routine. However, the assessment of diameters also has several drawbacks. 

Its biggest limitation is its inaccuracy. As a result, the assessed changes have to be large in order to be considered truly significant volume changes. For example, a 30% diameter decrease suggesting partial response is equal to a 65% volume decrease. Therefore, the assessment of the true three-dimensional volume of all lesions is a much more sensitive response criteria. 

Computer algorithms have been developed to semi-automatically assess the tumor volume and are used in some clinical trials

  (see Figure 1). These algorithms have to be implemented in clinical routine. For clinical trials, the implementation of such semi-automatic algorithms would mean that tumor response may be detected in a much earlier stage and, therefore, success or failure of a treatment may be shown in a much shorter time frame. This would lower the costs of clinical trials significantly because the need for follow-up examinations would be reduced due to the earlier achievement of study endpoints. 

Figure 1. Images of a male patient with liver metastases from colorectal cancer. The target lesion (arrow) (a) is measured according to WHO criteria by measuring its longest diameter and the according longest orthogonal diameter. A semi-automatic software segmented the tumor three-dimensionally (b), displaying three orthogonal planes.			

The use of imaging in trials shows great promise, but proper application requires early dialogue.

Supplements-10-02-2007