There is considerable interest in drug safety among multiple stakeholders in the United States, including the Food and Drug Administration (FDA), the National Institutes of Health, the Institute of Medicine (IOM), biopharmaceutical companies, Congress, individual congressional committees, the Supreme Court, patient advocacy groups, the media, and perhaps most importantly, prescribing physicians and their patients.

  Given that no drug is immune from the possibility of causing adverse events in certain genetically and/or environmentally susceptible individuals, an operational definition of "safety" is needed. A useful general definition is found in the FDA's Sentinel Initiative:

Using medical products brings benefits and risks. Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of the benefit expected in a specific population and within the context of alternatives available.  

This definition, which encapsulates the concept of benefit-risk assessment, "one of the important facets of the science of safety,"

 applies very well in the science of cardiac safety. An investigational drug must be found by an agency to have a favorable benefit-risk balance to receive marketing approval. It is the responsibility of sponsors to provide regulatory agencies with the most accurate and thorough safety (and efficacy) data possible at the time of requesting marketing approval, and it is also in their own best interests, as discussed later.  

Between the late 1980s and the early 2000s, a series of high-profile drug marketing withdrawals for cardiac reasons focused regulatory attention on this issue. Of particular relevance is one form of polymorphic ventricular tachycardia, torsades de pointes, that is very rare but can be fatal.

  Several hundred deaths from widely-prescribed drugs for relatively benign conditions (including terfenadine, an antihistamine, for allergies) indicated that the benefit-risk balance for these drugs was unacceptable.

Torsades de pointes is associated with QT interval prolongation as seen on the surface electrocardiogram (ECG). Figure 1 provides a stylistic representation of the QT interval and the phenomenon of QT interval prolongation.  

Figure 1: Stylistic representation of the QT interval and QT interval prolongation.			

Each segment of the ECG can be assigned a length in the time domain. The QT interval represents the total time of cardiac muscle cell depolarization (contraction) and repolarization (returning to the relaxed state such that contraction can occur again). It is defined as the length in the time domain from the onset of the Q-wave to the off-set of the T-wave, measured in milliseconds (msec). Precise categorization of the "normal QT interval" for any individual is impractical since it changes with every heart beat. However, consideration of the typical ranges observed in groups of individuals following a period of supine rest provides some perspective. Since the QT interval is impacted by heart rate, tending to be shorter as heart rate increases, it is typically "corrected for heart rate" by one or more of several mathematical formulas, resulting in QTc data. In this context, the normal distribution of QTc intervals for healthy adult males suggests a range from around 350-460 msec. For healthy adult females, the distribution is similar but falls around a somewhat higher mean, suggesting a range from around 360-470 msec.

Given the association between torsades de pointes and QT prolongation, regulatory agencies in Europe, Canada, Japan, and the United States now require a dedicated trial to assess the impact (if any) of an investigational drug on the QT interval. This trial is called a Thorough QT/QTc (TQT) Study, and is described in the 2005 ICH Guideline E14.

   While assessment of the QT risk of new drugs had certainly been addressed beforehand,

  the adoption of ICH E14 by regulatory agencies formalized clinical cardiac safety assessment.  

The TQT is a rigorously controlled clinical trial. This rigor includes using identical monitoring equipment for each subject to collect multiple digital ECGs, transmitting them to a core ECG laboratory (core lab), and having all QT/QTc measurements for a given study performed at a core ECG lab in a blinded manner by a relatively small number of highly experienced technicians or cardiologists. In addition, the Phase I units conducting these trials must ensure that the subjects in each cohort are treated identically to ensure consistency in conduct. These centralized, standardized processes greatly enhance the quality and integrity of the data.

  The logic here is similar to that behind the use of a single central laboratory (central lab) to analyze biological samples collected at multiple investigational sites. Standardization ensures consistency of many factors that can influence readings, including instrumentation, reference ranges, personnel, environment, and reagents.

  More detailed discussion of the TQT study and torsadogenic liability can be found in many sources.

Moving beyond QT/QTc interval prolongation 

While ICH E14 has made QT/QTc prolongation a high-profile cardiac safety biomarker, it is widely acknowledged to be imperfect, and, by itself, it is not now sufficient for regulatory evaluation of a drug's cardiac safety when requesting marketing approval. Other assessment methodologies include concentration-QT/QTc modeling,

  assessment of additional ECG intervals such as the PR interval and QRS duration, as well as heart rate, and various characteristics of ECG morphology.

  Importantly, as for QT/QTc interval prolongation, all these additional ECG data points benefit considerably from a centralized, standardized analysis strategy.

Current lack of centralization for Phase III data

In stark contrast to the approach mandated for the TQT study, the majority of ECG data from other trials worldwide is still collected and analyzed in a decentralized manner. This fragmented, non-standardized approach to collecting cardiac safety data is characterized by the use of different ECG machines (and/or different vintages of the same machine) at different sites, and the common use of paper print-outs of the ECGs.

  For historical reasons, many machines that calculate QTc values employ the Bazett correction formula, which is arguably the most inaccurate.

 Heterogeneity of equipment and software from different manufacturers introduces inconsistency. Kligfield et al. confirmed this long-held suspicion and concluded that systematic differences in QT measurements between manufacturers are significant and must be considered when used as markers of arrhythmogenic risk.

  Individual printers can introduce errors by distorting the paper as ECGs are being printed. Different physicians at different sites then read these print-outs. While undoubtedly highly qualified in their own medical specialty, not all of these physicians will be highly trained and experienced in cardiac electrophysiology, and in the measurement and interpretation of ECG intervals and waveforms (see also Viskin et al.

Further confounding late stage developmental studies is the extreme difficulty in overcoming the logistical issues involved. These trials typically engage large numbers of subjects over several years, and are therefore conducted in multiple outpatient settings. ECG acquisition characteristically consists of single tracings unaligned to pharmacokinetic peaks. The high degree of QT interval variability in even normal subjects challenges the significance of solo measurements as opposed to mean QT values. Likewise, strategic sampling at peak drug concentrations would increase reliability.   

As disclosed at the end of this article, the authors work for commercial vendors of centralized, standardized, cardiac safety services, and these central labs stand to gain financially should wider adoption of the standardized system occur. That acknowledged, in the authors' collective opinion, employment of the centralized system for ECG data from Phase III trials is in the best interest of patients (the primary consideration) and also in the best interests of sponsors and regulators. No one questions that centralization of biological samples (their analysis at central labs) should be used in Phase III trials. Patients benefit every time optimum quality data are used in drug research, and, in the present context, they are best served when a sponsor utilizes a core lab and presents regulators with ECG data that permit the best possible assessment of the degree (if any) of cardiac risk. If a cardiac risk is identified and the drug's likely benefit is deemed to sufficiently outweigh the cardiac risk, the drug can still be approved. In this case, biopharmaceutical sponsors and regulators will employ risk minimization strategies. These approaches can allow the (possibly very large) majority of potential patients to reap the benefits of the newly approved drug while providing maximum protection to patients for whom a different treatment modality is preferable. 

A major reason that many sponsors do not currently employ centralized approaches in Phase III trials is the misperception that it is considerably more expensive to do so. Therefore, in the absence of a regulatory mandate, they choose to use the decentralized approach. As Furlong

  observed, "It remains a challenge for core labs to fully demonstrate to sponsors the added value brought about by centralization as well as the cost-savings realized through the complete study management process." Some members of our industry have already written on this topic

   but all of us who work at core labs need to do more in this regard.  

With regard to agency guidance, regulators have not yet addressed centralization of cardiac safety in later phase trials. It appears that cardiac safety core laboratories and the biopharmaceutical sponsors they work with will need to continue to explore the benefits that centralization has to offer in order to drive this process forward. One obstacle to this is the extreme focus on QT as a surrogate for cardiac safety. In Phase III trials, for drugs that have no QT changes in a TQT study, the focus should be on morphology rather than QT.  

To these authors, it would seem prudent to use a strategy that is acknowledged to provide higher quality data for a (somewhat) more heterogeneous subject sample as typically employed in a Phase III trial to assess cardiac parameters as carefully as possible. From a workload perspective, reviewing data collected in a centralized manner rather than a decentralized one would not require extra work. To the contrary, higher quality data would potentially decrease the time needed. The downside, therefore, is not readily apparent. In contrast, the upside is clear: Higher quality data would provide greater assurance that potential risks had been looked for as thoroughly as possible in the preapproval data, the only data available at that time (subsequent postmarketing data are always to be considered once available). It is quite conceivable that a risk that would not have been identified with the data acquired from a decentralized approach would indeed be identified in data acquired in the manner advocated in this article, and hence regulators would have the opportunity to protect the public health in the manner they deemed most appropriate in the context of the magnitude of the risk and the magnitude of the drug's likely benefits.  

Additional benefits to the centralized approach

The perception of a cardiac and/or cardiovascular risk being associated with a marketed drug—whether or not the risk is real—attracts enormous mass media attention. In the era of sensationalist, sound-bite coverage, clinical science sadly falls very low on the list of points to be covered in the allotted 30 seconds of television coverage (it can do somewhat better in print coverage). When a cardiac or cardiovascular safety concern is "identified" for a marketed drug, there is frequently a "torrent of recriminations."

 Such recriminations are almost always directed at the biopharmaceutical sponsor, and the costs are considerable, ranging from loss of reputation to a decrease of billions of dollars in market capitalization. However, and perhaps increasingly so, they are targeted at regulatory agencies too. In addition to being in the best interests of patients, the paramount concern, doing everything possible to identify any degree of cardiac risk in preapproval trials is in the best interests of sponsors and regulators. 

The centralized, standardized data collection process employed for TQT studies greatly enhances the quality and integrity of the data acquired and analyzed. Currently, in contrast to this approach, the majority of ECG data from other trials worldwide is still collected and analyzed in a fragmented, non-standardized manner. Many sponsors do not currently employ centralized approaches in Phase III trials because of the pervasive misperception that it is considerably more expensive to do so. Those of us who work at ECG core labs need to do more to increase sponsors' awareness of the added value brought about by adoption of a centralized approach as well as the cost-savings realized through the complete study management process being placed with a core lab. In addition, and moving beyond the vendor, biopharmaceutical sponsors then need to take joint responsibility with us in furthering the science of cardiac safety.  

The authors work for commercial vendors of centralized cardiac safety services. 

,* PhD, is Senior Scientific Director, Cardiac Safety Services, at Quintiles, Durham, NC, e-mail: 

, MD, FACC, is Chief Medical Officer at Cardiocore, Bethesda, MD. 

, PhD, is Chief Scientific Officer at Biomedical Systems, St. Louis, MO. 

, MD, FACC, is  Executive Vice President and Chief Medical Officer at ERT, Philadelphia, PA.

*To whom all correspondence should be addressed.

1. J.R. Turner, "Drug Safety, Medication Safety, Patient Safety: An Overview of Recent FDA Guidances and Initiatives," 

The Sentinel Initiative: A National Strategy for Monitoring Medical Product Safety

3.  F. Dessertenne, "La Tachycardie Ventriculaire A Deux Foyers Opposes Variables," 

Integrated Cardiac Safety: Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance

. (John Wiley & Sons, Hoboken, NJ, 2009). 

5.  T. J. Bunch and M. J. Ackerman, "Cardiac Channelopathies," in 

, 3rd Edition, J. G. Murphy, and M. A. Lloyd, eds. (Mayo Clinical Scientific Press/Informa Healthcare USA, Boca Raton, FL), pp. 335-344. 

The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs

7.  ICH Guideline E14 Implementation Working Group, 

The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs: Questions & Answers

8.  "CPMP: Points to Consider on the Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products," (CPMP/SWP/986/96.). 

9.  J. Morganroth, F. V. Brozovich, J.T. McDonald, and R.A. Jacobs, "Variability of the QT Measurement In Healthy Men: With Implications for Selection of an Abnormal QT Value to Predict Drug Toxicity and Proarrhythmia," 

10. S.E. Steare and J. Morganroth, "A Rational Approach to the Planning and Analysis of Electrocardiogram Safety Data in Clinical Trials," 

International Journal of Pharmaceutical Medicine

11. A. Furlong, "Cardiac Safety: Cost to Trials," 

New Drug Development: An Introduction to Clinical Trials

13. W.S. Redfern, L. Carlsson, A.S. Davis, et al., "Relationships Between Preclinical Cardiac Electrophysiology, Clinical QT Interval Prolongation and Torsade De Pointes For A Broad Range Of Drugs: Evidence for a Provisional Safety Margin in Drug Development," 

14. G.J. Noel, D. B. Goodman, S. Chien, et al., "Measuring the Effects of Supratherapeutic Doses of Levofloxacin on Healthy Volunteers Using Four Methods of QT Correction and Periodic and Continuous ECG Recordings," 

Cardiac Safety of Noncardiac Drugs: Practical Guidelines for Clinical Research and Drug Development

16. C. Strnadova, "The Assessment of QT/QTc Interval Prolongation in Clinical Trials: A Regulatory Perspective," 

17. P. Kligfield, B. Tyl, M. Marek, and P. Maison-Blanche, "Magnitude, Mechanism, and Reproducibility of QT Interval Differences Between Superimposed Global and Individual Lead ECG Complexes,"  

18. C.M. Beasley, Jr, A. Dmitrienko, and M.I. Mitchell, "Design and Analysis Considerations for Thorough QT Studies Employing Conventional (10s, 12-Lead) ECG Recordings," 

Articles

Partnerships in Clinical Trials

Centralized approach for Phase III studies enhances the quality and integrity of collected data.

The Science of Cardiac Safety

If you talk to a clinical cardiologist about cardiac safety, it is highly unlikely that the letters "QT" will ever be uttered. On the other hand, if you speak to someone in the pharmaceutical industry about cardiac safety, it is highly likely that the 

 thing mentioned will be the effect of a drug on cardiac repolarization and how the measurement of the QT interval is essential to characterizing that risk. Although the fundamental rules for measurement of electrocardiogram (ECG) intervals and overall ECG morphology interpretation should be the same whether an ECG is recorded from a patient being evaluated by a healthcare professional or from a healthy subject involved in a clinical drug trial, this is generally not the case.  

In a healthcare setting the physician is generally presented with a patient who is following up for a known medical condition or who has an acute illness. If an ECG is performed, the physician will primarily look for morphologic features that may represent cardiac abnormalities. The interval duration measurements will be examined only briefly, and may lead to the conclusion that first degree AV block or bundle branch block is present, but only an extremely long QT interval is likely to catch the treating physician's attention. In addition, many ECGs are read with hedging terms such as "possible," "consider," "cannot rule out," or "probable" that offer some medical-legal protection.  

Pharmaceutical sponsors of drug research generally utilize ECGs for the following purposes: 					

Screening, selection, and enrollment of study participants.

Assessment and monitoring of cardiac safety of the investigational drug through evaluation of changes in ECG morphology (e.g., infarcts) and interval duration measurements (with emphasis on changes in QTc).

Assessment of the efficacy of the investigational drug or intervention in cardiovascular trials.

In addition to the above, indirect benefits accrue to subjects who enroll in clinical trials. The screening ECG recorded for a clinical trial may be the first ECG ever obtained for a subject, and may lead to the detection of previously undiagnosed structural or electrical cardiac diseases. Serial ECGs performed during a clinical trial may also lead to the recognition of progression of pre-existent cardiac disease that is unrelated to the clinical trial. 

One of the most important, if not the most important, responsibilities of the ECG core laboratory is to determine whether a subject in a clinical trial has developed a new ECG finding while receiving treatment with the investigational drug. The accurate assessment of interval duration measurements, particularly the QT interval, has become one of the most important factors to consider in drug development, and for many it is the only factor that is considered when determining which cardiac safety evaluations will be performed in a clinical program. The International Conference on Harmonization E14 (ICH E14)

  guidelines outline the criteria by which new drugs are assessed for the potential of producing QT prolongation, and define the threshold for QTc prolongation which raise concerns about triggering a potentially lethal arrhythmia known as "torsade de pointes."  

However, there has been very little regulatory guidance, and very little pharmaceutical industry attention paid to the ECG assessment of cardiac safety issues unrelated to QTc prolongation. This trend has continued despite the fact that most of the headline grabbing, drug-related safety issues of the last few years have been due to cardiovascular events unrelated to cardiac repolarization (QTc prolongation). Table 1 illustrates some of these high profile examples.  

Table 1. Most recent drug-related safety issues have been unrelated to cardiac repolarization.			

ECG processing in clinical research includes obtaining, measuring, interpreting, storing, reporting, and analyzing ECG data. Most of these are common features for both research and development as well as clinical practice. However, ECG reading for clinical research does have some important distinguishing characteristics that make the process different from that of clinical practice. 

 Regulatory compliance is not required for clinical ECG interpretation, but is of the utmost importance in clinical trials from which results will be submitted to international regulatory agencies. 

Accurate, reproducible Interval Duration Measurements (IDMs). 

Unlike ECG reading in clinical practice, where small errors in measurement of the PR, QRS, RR, or the QT intervals are unlikely to be of any significance, accurate measurement of IDMs in clinical research is absolutely critical to assess a drug's cardiac safety profile. As stated above, the identification of small changes in the corrected QT interval is currently the cardiac safety issue of greatest concern to drug developers, but is not the focus of this article. 

Highly reproducible, blinded, consistent ECG interpretation.

 While consistent ECG reading is important in clinical ECG analysis, it is critically important for ECG interpretation in clinical research. Consistent interpretation of ECGs, ideally by a core laboratory with a very small number of expert cardiologists, is necessary to avoid the reporting of spurious "changes" in ECG findings. False positive ECG changes that are reported during a study could be falsely attributed to the investigational drug but, instead, would actually be due to inconsistencies in the ECG interpreter's style. A good example would be the interpretation of old myocardial infarction. In clinical practice it is common for cardiologists to use many different terms to report an old myocardial infarction (MI), such as: an MI; a Possible MI; a Probable MI; or some other variation. This is a completely acceptable practice in a clinical setting where the physician interpreting the ECG wants to hedge their interpretation in order to ensure that an important finding is not overlooked. It is, in fact, common practice to err on the side of caution in an attempt to prevent or at least reduce the possibility of medical-legal complications. However, this type of interpretation could wreak havoc in a clinical study database where it would interfere with the detection of new events during drug exposure, and would make it impossible to determine if there was a new event "on drug."  

The appearance of serial ECGs may vary, and Q wave myocardial infarctions may seem more or less evident on serial ECGs due to subtle changes in lead position, subject positioning, or heart rate. In clinical practice, the "appearance" and "disappearance" of Q waves may lead to inconsistent ECG interpretations, but will generally have no effect on patient care. In contrast, during a clinical trial, the spurious report of a new MI which is in fact due to a slight change in ECG axis or lead positioning can have tremendous consequences both for the clinical trial and for the entire drug program. Several examples of ECGs which were nearly identical, but had inconsistent interpretations are presented in Tables 2 and 3. The differences between the ECG core laboratory interpretations and the interpretations of the investigators and the clinical sites are also addressed.  

Table 2. Examples of ECGs which were nearly identical, but had inconsistent interpretations.			

Based on the ECG interpretations provided by the sites, the two clinical research subjects shown in Tables 2 and 3 would both have been characterized as having ECG findings consistent with new myocardial infarction that occurred on treatment. Depending on the study criteria, these subjects could have been sent to a data safety monitoring board for review and/or had more definitive and expensive tests done to determine whether an asymptomatic infarct occurred between study visits. However, the ECG core laboratory's reports of the same subjects' ECGs have shown no abnormalities and no change from baseline, thus abrogating the need for further work up and review. It is very important that ECG interpretation in clinical trials be done consistently, with strict adherence to clear interpretation guidelines, in order to allow for the detection of true drug-related effects. The use of a core ECG laboratory for ECG interpretation is a common mechanism to ensure such consistency.  

Table 3. Subjects would have been classified as having ECG findings consistent with new myocardial infarction that occurred on treatment.			

The focus of this article has been the importance of consistent ECG morphology interpretation, which is best accomplished by ECG centralization. Another article in this supplement addresses the importance of centralization, but it would be remiss to not point out another frequently overlooked benefit of centralization. Centralization of ECG evaluation can prevent situations like the following example. In a "Warning Letter: Investigator Didn't Review Screening ECGs"

  a clinical investigator failed to review the screening electrocardiograms (ECGs) for the majority of the 58 subjects the FDA audited, according to a warning letter. The FDA says it cannot tell how the investigator could have adequately determined that the subjects were eligible for inclusion in the trial "given that the ECGs were not documented as having been reviewed prior to the randomization visit." 

ECG interpretation in clinical research is challenged by the lack of consensus on: 					

The criteria which determine what is a normal vs. abnormal ECG, and what are normal ranges for IDMs.

The clinical relevance of different ECG abnormalities and/or changes (e.g. progressive prolongation of a PR interval in first degree AV block or of the QRS interval with a bundle branch block). 

The relevance of new or worsening findings in normal healthy volunteers vs. patients with pre-existing illness and/or cardiac disease (see clinical relevance section below).

The significance of trivial ECG changes during serial ECG comparisons. For instance, changes in IDMs may be minimal, but may be sufficient to cross a chosen threshold. Example: a normal ECG with a PR interval duration of 199 milliseconds (msec) that becomes abnormal when the PR interval on the next ECG measures 201 msec, resulting in a report of a new abnormality and, if comparisons are requested, a finding of "deterioration" (see comparison to baseline section below).

ECG core labs should have standard criteria for normal IDMs for both adult and pediatric studies, but should also have the flexibility to accommodate sponsor requests for protocol alerts related to either safety or inclusion/exclusion criteria. 

An example of the clinical importance of standardization of interpretation is exhibited in an article by Vijayaraghavan, et al.

  The study included 5,277 patients from 51 hospitals participating in the Canadian ACS Registry who were hospitalized with an acute coronary syndrome (ACS) and had an interpretable initial ECG. Core lab ECG interpretation was blinded to site interpretation and outcomes. Patients with core-lab-defined ST-elevation and cardiac marker elevation (n = 1,202) not classified as ST-elevation by the site were less likely to receive acetylsalicylic acid (ASA) (90% vs. 96%, P <0.0001), heparin (91% vs. 95%, P <0.04), and reperfusion therapy (14% vs. 76%, P <0.0001) than patients for whom there was agreement that ST-elevation was present. After adjusting for other validated prognostic factors, site-unrecognized ST-elevation was independently associated with higher mortality (odds ratio = 2.21; 95% CI, 1.46–3.36; P <0.001). The authors concluded that in patients with ACS, there was only moderate agreement between core lab and site interpretation of the initial ECG. Site-unrecognized ST-elevation myocardial infarction was associated with underutilization of evidence-based therapies and increased one-year mortality. 

In the opinion of the author, it is not appropriate for an ECG core laboratory to determine clinical relevance, as the core laboratory is blinded to all clinical information. It is difficult to determine the clinical relevance of various ECG abnormalities or ECG changes solely based on a single resting ECG tracing. This dilemma is only aided slightly by the addition of serial ECG comparisons. Clinical relevance is just that, a clinical decision—not a decision made in a vacuum or based on the interpretation of a single piece of evidence. The clinical relevance of a particular finding must be judged in the context of the patient's prior history, current symptoms, and physical findings. Therefore, if a determination of the clinical relevance of any particular ECG abnormality is desired, the investigator at the study site should determine that "clinical" information is needed to determine "clinical" significance. 

In addition, the clinical significance of different ECG findings is dissimilar in diverse populations and often cannot be dictated by rules. For example: 					

Flat T waves are generally not felt to be clinically significant, but if a patient is experiencing chest pain at the time the T waves become flat, that would be clinically significant. The core ECG lab would be blinded to any patient symptoms and site reliance on a core laboratory determination that this finding was not significant could have an adverse effect on patient care.

A change in the heart rate from 60 bpm to 90 bpm (both within the normal range) may be clinically more important than a change in the heart rate from 99 bpm to 101 bpm, however the latter example results in a new diagnosis of sinus tachycardia. 

In most cases, clinically relevant ECG abnormalities or ECG changes should be defined as those that required medical attention due to their prognosis or treatment (e.g., new MI, new left bundle branch block (LBBB), or new onset atrial fibrillation). A subclass of this group would include clinically relevant ECG abnormalities that are significant enough to initiate active medical follow-up or that require changes in the subject's management. These changes would be classified as medical or ECG alerts (e.g., acute MI). Serious findings warrant expedited notification of all appropriate medical personnel (including both on-site investigators and safety officers) identified by each study protocol. When faced with these alerts, sites should follow normal and prudent procedures to ensure patient safety, and should not delay appropriate care due to the fact that the patient is in a clinical trial. 

Comparison between serial ECGs recorded during a trial is another area of contention and inconsistency. There is little agreement on which (or how many) ECGs should serve as the baseline comparator for a study, or whether comparisons should be made to baseline ECGs or to subsequent ECGs recorded during a trial. In addition, when multiple baselines are collected it is possible that some may have different morphology determinations. This prompts the question as to which of the baseline ECGs is the "true" comparator, since morphologic findings, unlike interval duration measurements, cannot be mathematically averaged. 

As stated previously, slight changes in a measurement can result in an ECG crossing a pre-defined boundary and can result in a comparison of "deteriorated" or "improved." Some examples are:  									

A small increase in the QRS duration may result in a "deterioration" from incomplete LBBB to complete LBBB. 

A small increase in the PR interval may result in the manifestation of a first degree AV block and thus a "deterioration" in conduction. 

A small decrease in heart rate may result in sinus tachycardia improving to normal sinus rhythm.

These rule related "deteriorations" or "improvements" do not aid the clinical site, the subject, or the collection of the study data, and may simply result in confusion, added expense, and delays. 

Another major problem with performing ECG comparisons arises when ECGs are delivered to the ECG core laboratory out of sequence. If the comparator ECG is not available when later ECGs are evaluated, a comparison cannot be made. If the comparator ECG subsequently becomes available, the interpretation of all subsequent ECGs will need to be revised, resulting in added expense, delay, and potential for errors. 

For these reasons it is preferred not to include comparisons in ECG interpretations during clinical trials. Instead, rely upon the use of clinical alert criteria, which allow for notification of site and sponsor whenever a concern for subject safety arises. The ECG criteria which trigger an alert may be customized depending on the details of the study population, drug being investigated, or needs of the sponsor and sites. 

Diabetes guidance: a shift in regulatory focus? 

There has been a great deal of attention paid to the risk of diabetes medications and their potential to increase the risk of cardiovascular mortality. In December 2008, the FDA issued "Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes"

  which "provides recommendations for the development of drugs and therapeutic biologics regulated within the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. Specifically, this guidance makes recommendations about how to demonstrate that a new antidiabetic therapy to treat type 2 diabetes is not associated with an unacceptable increase in cardiovascular risk." This marks a broadening of regulatory focus on cardiac safety issues to include the evaluation of new drugs for cardiovascular risks unrelated to QTc prolongation. 

The number of subjects needed for a clinical trial to comply with the guidance is quite large and this will result in a major paradigm shift in how diabetes studies are conducted. In the past, the majority of the subjects in Phase II and Phase III diabetes studies were relatively healthy, and the study endpoints were related to the degree of the glucose regulation which was achieved. In contrast, the new guidance calls for the evaluation of clinical endpoints of cardiac risk such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality—known as Major Adverse Cardiovascular Events (MACE) criteria. This requirement for cardiovascular endpoint data will result in larger and longer Phase II and Phase III trials, and will require the inclusion of subjects at high risk for cardiovascular events. Without these higher risk subjects, meeting the new requirement of showing a risk ratio of <1.8, but preferably <1.3, would require sample sizes that would make the conduct of these trials unfeasible due to size and cost. 

How does ECG reading in clinical research compare to a healthcare interpretation?

Cardiac Safety: Beyond QT

In the last decade, cardiac safety concerns have been responsible for more drug withdrawals than any other safety reason. In response, both regulators and drug companies now have a renewed focus on TQT trials, which help assess the cardiac safety of drugs. 

The ICH's E14 Guidance increased the demands on drug developers and made the regulatory process even more complex. Major regulatory agencies around the world, including the FDA, EMA, MHLW (Japan), and Health Canada, require a TQT study not only for new drugs submitted for approval, but also for any change to an approved drug that significantly increases its exposure. In fact, some drugs that were originally approved in the 1960s have recently undergone TQT trials because of changes in dosage.  

To conform with the E14 Guidance, a TQT trial must meet the following criteria:  

Robust enough to detect a 5 millisecond prolongation of the QT interval

Use a positive control to validate the study

If the TQT study is negative, the drug can proceed normally in development. However, if the TQT study is positive, all subsequent studies will need extra ECG monitoring and the drug may be required to include specific instructions on its label, ranging from special dosing instructions to black box warnings. 

TQT studies are an essential element of any drug development program. However, because of their importance to the progression of the drug development program and the cost of conducting the study, TQT studies must be conducted with careful design considerations. 

Some of the important aspects of the design include the number of subjects, timing of the ECGs, and the amount of the drug dosed. The number of subjects required for a TQT study can be simply determined by the variability of the QT measurement and the power needed to achieve the required QT prolongation. However, there are a number of considerations that go into determining the variability. 

The first variability factor is the study design: crossover versus parallel. A crossover design benefits from the reduced variability and increased power of the subjects acting as their own control. Parallel design studies are better suited for drugs with long half-lives, when dosing within a patient population, and for drugs with known period effects.  

A second factor affecting the variability of the study is the number of groups required. In order to complete TQT studies as quickly as possible, many companies split the study into smaller groups conducted at different sites within the same contract research organization (CRO) or among different CROs. Different sites increase the variability in the QT measurement.  

The final factor affecting the variability is the timing of the baseline ECGs. Baseline ECGs should be taken at multiple times throughout the day before dosing; these times of day should correspond to the times of day the ECGs are measured following dosing. In some cases, baseline ECGs are measured for more than one day before dosing. 

In terms of ECG measurement after dosing, the collection of ECGs during the TQT study should be such that the Cmax of the drug is carefully captured, unless there is reason to believe the maximal QT prolongation of the drug will not occur during the Cmax. Taking pharmacokinetic (PK) samples to correspond with the ECG is also recommended, as the exact drug concentration seen during the ECG time points can be determined. Furthermore, the PK samples will facilitate pharmacokinetic/pharmacodynamic (PK/PD) modeling, which may help researchers understand whether or not a drug causes QT prolongation. This understanding may prevent the need to conduct additional studies. 

The dose levels used in a thorough study are very important. The E14 guidance makes it clear that in most cases, the TQT study should not be dosed solely at the therapeutic dose, but also at a higher dose where the exposure of the drug may be similar to that seen after accumulation of the drug or because of drug-drug interactions. Therefore, a TQT study should be conducted as soon as the therapeutic dose and pharmacokinetics of the compound are well known. Ideally, the TQT study would occur as early as possible in the development process, since the result of the TQT study will influence the design of Phase III studies.  

Finally, in most cases, the TQT study is conducted at steady-state, again to maximize the exposure. For drugs with short half-lives, this may not be required. 

The design of TQT studies should begin approximately six months in advance. 

More than six months before dosing. Check investigational new drug application (IND) status. If the initial studies on the drug were conducted in the United States, an IND will already be open. If there is no IND and the TQT studies are to be conducted in the United States, an IND must be filed. Start the evaluation process for selecting a CRO. Site visits are highly recommended, as the physical setup of the clinical pharmacology unit (CPU) is extremely important in TQT studies. 

Six months before dosing. Define the therapeutic and supratherapeutic doses. The therapeutic dose will be defined in a Phase IIa study conducted in patients or in healthy subjects if an appropriate biomarker exists to measure the drugs' pharmacodynamic action. The supratherapeutic dose is "substantial multiples" of the therapeutic dose and is used to represent the "worst-case scenario" that might be seen with accumulation and inhibition. At this point a final decision regarding a CRO can be made.

Three months before dosing. Submit the study design to the FDA for feedback. The FDA has established a fast review process to ensure timely responses. Some CROs can assist with the submission to the FDA and suggest the types of questions to ask the FDA. 

Two months before dosing. Incorporate feedback from the FDA into the study design. Review options for selecting patient populations, if required.

One and a half months before dosing. Submit the final protocol to the institutional review board (IRB) for approval.

The day of dosing. Have a staff member from the sponsor organization observe dosing.

One and a half months following first dose. Complete the clinical component of the TQT. This time frame is variable, as it depends on the number of days of dosing and the washout needed between periods. The ECG readings will begin at the core ECG laboratory. Begin bioanalysis of the PK samples: The samples must be measured even if the PK of the drug is well-known so that any potential effect on the QT interval can be compared to the actual Cmax of the subjects. Also, having the PK data will enable PK/PD modeling. 

Three months after dosing. Receive draft final report for the TQT study from CRO. Following approval, the report is ready to be finalized and submitted to the FDA. As TQT studies are strongly suggested to have positive control arms, it is vital that a 5 millisecond significant difference is seen in this arm.

There are several challenges that can present obstacles when designing TQT trials. It is very important to address and consider these issues in the design stage of a TQT study, and when selecting the CRO to perform it. 

. The E14 Guidance indicates that a positive control arm is desired and asks that one arm of the study be at the therapeutic dose and one arm at a significantly higher, or supratherapeutic, dose. An appropriate range for the supratherapeutic dose is often a dose within 10 times of the therapeutic dose. However, the safety profile of many drugs does not allow a dose of this size. Dosing a study with a supratherapeutic dose that is too high can result in significant adverse events that do not permit subjects to complete the study and would result in the loss of complete data for the dose level. 

Conducting a maximum tolerated dose (MTD) study allows a sponsor to clearly define the dose level that will be tolerated. MTD studies are conducted in a small group of subjects and can be completed quickly. Therefore, the cost of the MTD study can easily be justified when compared to the cost of repeating a TQT study. 

The guidance also states that, "if the concentrations of a drug can be increased by drug-drug or drug-food interactions involving metabolizing enzymes (e.g., CYP3A4, CYP2D6) or transporters (e.g., P-glycoprotein), these effects could be studied under conditions of maximum inhibition." In this case, an understanding of the metabolic pathway and the resulting drug-drug interactions (DDI) are required. If the preclinical data indicate metabolism at one of the key CYP enzymes or transporters, a DDI study will allow determination of how this interaction affects the concentrations of the drug. A dose that results in a similar exposure as that seen with the maximum clinically indicated dose under the interaction should then be used as the supratherapeutic dose. 

. Another pitfall is not taking into account QT/RR hysteresis, which refers to the delay between changes in heart rate and QT interval when designing or conducting studies. QT/RR hysteresis is not corrected by the standard QT correction factors. 

A change in heart rate—due to external factors such as stress or even drug-inducement—can take up to four minutes to result in a change in the QT interval. This lag is not consistent across subjects, ranging from a few seconds to several minutes. 

The TQT trial's clinical pharmacology facility needs to be equipped with staff trained to maintain the most-consistent heart rate possible, so the likelihood of QT/RR hysteresis is minimized and the usual correction factors (e.g., Bazett and Fridericia) can be relied on.  

Experienced CROs will monitor several factors to minimize QT/RR hysteresis, including:   

Timing of blood draws so that they occur after ECG measurement

Reducing the excitement, and therefore subjects' heart rate, from items such as horror movies

Restricting use of computers, cell phones, and other devices

Clearly explaining what is expected of the subjects well in advance of the trial

It is also important to consider the effect the drug or administration of the drug may have on the heart rate. A large number of drugs are known to increase or decrease the heart rate. However, even drugs with no known effect on heart rate can result in a heart rate change if they are intravenously infused with a significant volume of vehicle. By controlling the changes in heart rate, the variability seen in the QT intervals will drop and will result in the need for fewer subjects to maintain sufficient power for the study. 

Insufficient power to detect change in the positive control arm.

 Another challenge is in the calculation of the power of the TQT prolongation study. The positive control arm must have a significant QT prolongation change. It is very important to ensure the number of subjects is sufficient, taking into account the known change in QT of the chosen positive control and the variability expected in the study. 

Factors that can impact variability include proper baseline correction, ECG machines used, and other design elements. Without a good estimate of the variability of the study, it is not possible to provide a good estimate of the sample size. It is critical to work with an experienced clinic and central ECG provider that has a solid understanding of all of the components of the overall variability.  

As in all clinical research, proper study design and first-rate administration of a TQT study are essential. Proper scientific and practical experience is especially important. Even larger pharmaceutical companies can benefit from the design expertise of an experienced CRO. However, for smaller companies that may have limited experience with TQT studies, collaborating with an experienced CRO is essential. In terms of designing a TQT study, theoretical knowledge is not sufficient. It is important to look for a CRO with expertise in the actual performance of TQT studies, as this experience leads to the best possible design for the conduct of a trial. 

 Once the design of the TQT study has been determined, the focus changes to conducting the study itself. 

Here, two aspects are important: the staff and the physical setup of the CPU within the CRO. These two factors help determine the variability in the QT measurements that will be seen in the study. As the variability goes up, the chance of having a significant signal in the positive control arm goes down, unless the subject numbers are increased to compensate. How do these factors affect variability? It is well known that the correction factors for heart rate are far from perfect. Therefore, the best way to reduce the variability introduced by changing heart rate is to not rely on correction factors, but to do everything possible to keep a subject's heart rate consistent throughout each ECG measurement. A good way to maximize staff expertise in conducting TQT studies is to dedicate individuals to these types of studies, ensuring that the experience is concentrated among a select group of key personnel. 

Understanding the critical elements and challenges of cardiac safety trials.

Supplements-11-01-2010

The Science of Cardiac Safety

Cardiac Safety: Beyond QT

The ABCs of Thorough QTs