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European Pharmaceutical Contractor

In Search of Innovation

Alan Copa of Cetero Research outlines the importance of working with a CRO that has experience of TQT studies in order to keep trials on time and in budget

The ICH’s E14 guidance regarding TQT trials has led to major regulatory agencies around the world, including the FDA, EMA, MHLW (Japan) and Health Canada, requiring a TQT study for all new drugs submitted for approval, as well as for any approved drug for which dosage or other factors are changed. As a result, some drugs that have been used safely for more than 50 years are now required to undergo TQT trials.

These regulatory demands put added pressure on drug developers who may already feel that their resources are stretched thin and that they are being asked to do more with less. However, there are some approaches that can be used to improve the accuracy of TQT trial data, while keeping trial costs under control.

NEW APPROACHES IN TQT TRIALS

Adding Exercise to TQT trials
Most TQT trials are focused on making sure subjects remain as calm as possible. Clinical pharmacology units (CPUs) take steps to avoid any changes in heart rate, including timing blood draws so that they occur after ECG measurement; limiting the activity of subjects; reducing the excitement, and therefore subjects’ heart rate, from stimuli, such as movies; and restricting use of computers, cell phones and other devices. However, sometimes the compounds being tested are known to increase heart rate. How is it possible to get an accurate baseline QT measurement and still take this side effect into account? One solution is to include exercise as part of the trial.

Some CPUs use treadmills to mimic the increased heart rate levels that the compound is known to cause. One possible study design is to conduct a baseline treadmill test the day before initiating dosing with the study product to cover the range of heart rate anticipated while on the drug. This baseline data is amassed the day before. For example, if the study is scheduled to start at 0900, the baseline test may be done at 0800 the day before to avoid any variations that collecting data at a different part of the day might have.

If the anticipated heart rate on study product is 90 to 100 beats per minute (bpm), the goal of the treadmill test is to achieve a heart rate of 90 to 100bpm in all of the subjects. Once a heart rate of more than 100bpm is achieved, the test stops. The H-12 electrocardiogram (ECG) collects consistent and reliable data that will be used in the analysis. In addition, the core lab will extract triplicate ECGs for a range of more than 80 to 90bpm and a range of more than 90 to 100bpm. The data is then used to calculate subject specific QTcI to be used when evaluating the QT data while on study product. This approach provides more accurate correction factors, and thus better data for evaluating the real-world applications of a compound as the regulatory process moves forward.

Conducting Pilot Studies
The E14 guidance suggests that the TQT trial includes not only a therapeutic dose, but also a supratherapeutic dose that may be significantly higher. This higher dose can mimic exposure to the drug that would be seen after accumulation of the drug or because of drug-drug interactions. A TQT study should be conducted as soon as the therapeutic dose and pharmacokinetics of the compound are well-known. Ideally, the TQT trial would occur as early as possible in the development process, since the result of the TQT study may influence the design of Phase III studies.

There may be disadvantages to using an entire cohort to determine if the supratherapeutic dose will be tolerated. One solution is to conduct a pilot study with approximately eight to 10 subjects to determine the supratherapeutic dose for testing in the TQT study, which can include more than 200 subjects. The pilot study is set up much like single ascending dose (SAD) and multiple ascending dose (MAD) studies in earlystage clinical trials. The single dose or multiple dose design is dependent on the product to be tested. By establishing the supratherapeutic dose in a smaller group, the pilot study approach ensures the safety of the subjects and that the dose will be tolerated. The tolerability of the supratherapeutic dose is critical for the TQT trial so that subjects do not need to be replaced or a cohort does not need to be repeated secondary to an intolerable dose. This helps keep the trial on schedule and on budget.

Using Unique Delivery Methods
Like oral drugs, topical drugs also must undergo TQT trials. However, topical drugs can provide unique challenges. It can be extremely difficult to administer a supratherapeutic dose of a drug topically. One way to solve this problem is to administer the same drug orally for the TQT trial in order to achieve the higher dose levels. Of course, this should only be done if the drug has already been approved for oral administration. However, as more biopharmaceutical companies look toward the use of patches for delivering everything from birth control to anti-smoking agents, more and more drugs will be making the transition from oral to topical delivery.

Being flexible and able to develop new approaches and applications is a vital skill in clinical research. Changing delivery methods is one example of this type of thinking in action.

CRITICAL ELEMENTS OF TQT DESIGN

Even with new innovative approaches, there are certain elements of TQT trials that must always be taken into account in study design. These factors include the number of subjects and timing of the ECGs. The number of subjects required for a TQT study can be simply determined by the variability of the QT measurement and the power needed based on the estimated QT change. However, a number of considerations are part of determining the variability.

One aspect affecting the variability of the study is the number of groups required. While many organisations want to complete TQT studies as quickly as possible, it is important to keep study groups together. One trial split into several smaller groups and conducted at different sites may increase the variability in the QT measurement. It is important to look for a contract research organisation (CRO) with a facility large enough to conduct the entire study as one group.

Another variability factor is the study design: parallel versus crossover. Parallel design studies work best with drugs that have long half-lives or when dosing within a patient population. In crossover studies, subjects receive a sequence of different treatments, however, this is beneficial because there is less variability and the subjects serve as their own control.

The third issue affecting the variability is the timing of the baseline ECGs. Baseline ECGs should be taken at multiple times throughout the day before dosing, corresponding to the times of day that 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 captured carefully, unless there is reason to believe the maximal QT prolongation of the drug will not occur during this period. 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) modelling, which may help researchers identify whether or not a drug causes QT prolongation. This understanding may prevent the need to conduct additional studies.

SELECTING A CRO

With the complexity involved in TQT studies, selecting a good partner is essential. For smaller companies that may have limited experience with TQT studies, collaborating with an experienced CRO is critical. CROs can also offer value to larger organisations. 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 to conduct a trial. Critical questions to ask your CRO include:

  • How many TQT trials have you conducted?
  • How recently were these trials performed?
  • How many TQT subjects have you dosed?
  • What is the largest single study you have done?
  • What size groups can you support?
  • What is your recent extended duration TQT study experience?
  • How many participants are in your TQT trial database?
  • What is your dropout rate for TQT trials?
  • With how many core laboratories do you have strategic alliances?
  • Do you offer other services, including data management, pharmacokinetics, statistics and medical writing?

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 control variability. 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 a 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 maximise 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.

When thinking about using CRO staff and study management, questions to consider include:

  • Are your clinical teams trained on H12, H12+, telemetry and standard 12-lead ECGs?
  • How many pharmacists and pharmacy technicians do you have on staff?
  • What percentage of studies has had a positive moxifloxacin arm?
  • How are holter monitors managed?

The physical setup of the CPU also plays a role in the changes seen in the subject’s heart rate and, therefore, the variability of the study. A well-designed CPU is set up so that all subjects can be monitored closely during the study. Furthermore, the subjects should be able to remain comfortably supine throughout the ECG measurements – comfortable hospital beds, cleanliness and lighting are all critical.

The most important aspect of the CPU is the group size that it can handle. The typical TQT study requires a large number of subjects. If the CPU can only handle small groups, many different groups will be needed. Not only will the dosing of multiple groups delay the programme, but it will also increase the cost.

CONCLUSION

TQT trials are required in the regulatory process in many countries. However, innovations and best practices can improve the efficiency of these trials and help keep them on time and in budget. An experienced CRO can provide sponsors with studies that offer the most accurate data and the best use of resources.


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Alan Copa is President, Clinical Operations Services for Cetero Research’s Fargo, North Dakota facility. He has more than 17 years of CRO experience in a variety of clinical research roles including hands-on experience as a clinical study coordinator, director of pharmacy and director of clinical research. Alan has a PharmD from the University of Minnesota College of Pharmacy, Minneapolis, Minnesota, and a Fellowship from Cardiovascular Research/Critical Care United Hospital, St Paul, Minnesota, US.
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