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Cardiac Safety Monitoring – Benefits and Risks Assessment and the Regulatory Environment

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Cardiovascular risks associated with drugs across many therapeutic areas have necessitated cardiac safety evaluation during the drug development process.  Over the years, defining cardiac risk has matured from ECG evaluation to detailed regulatory guidance, such as the ICH-E14 (adopted by the FDA, EMA, and PMDA), which details the formal Thorough QT (TQT) study for assessing cardiac safety (ref 1)

Recently at the 4th annual DIA Cardiac Safety Workshop in Japan and the CSRC-HESI-FDA “Workshop on re-channeling the current cardiac risk paradigm” there were clear and open discussions as to the future direction of cardiac safety evaluation, highlighting the dynamic environment of the cardiac safety arena. In addition to developing and assessing new drug induced proarrhythmia models in nonclinical assays and monitoring the ECG QT interval as an endpoint in clinical trials, the industry has also seen an evolving focus on blood pressure as a cardiac safety consideration for defining the level of risk associated with new therapies (ref 2). Cardiac imaging has also gained an increased interest with specific application to oncology drug development and the maturing Cardio-Oncology benefit/risk assessment.

Why Should You Be Aware of Cardiac Safety Monitoring?

Cardiac safety studies have become an integral part of clinical trial safety assessment of new drugs. Up to 45% of drug withdrawals and non-approvals in the U.S. over the last two decades are due to the presence of cardiac side effects in patients (ref 3). Monitoring for cardiotoxicity early in clinical development has the benefit of identifying drugs with potential cardiovascular liability, identifying patients at higher risk, as well as providing opportunities for selecting safer drug administration regimens, thereby minimizing drug liabilities and making clinical trials safer for participants. In particular, cardiac safety studies implemented in the early phases of clinical trials can identify potential risks and red flags early in the process, preventing expensive testing in later phases of trials, late-stage program termination or post-market withdrawal. In fact, it was noted by FDA in a recent public meeting that since the implementation of ICH-E14 in 2005 no drug was withdrawn from the market due to proarrhythmia.

Key Regulations and Initiatives Surrounding Cardiac Safety

Cardiac safety monitoring has drawn considerable attention from regulatory agencies and has led to the establishment of regulatory guidelines by the International Conference on Harmonization (ICH). One of the key guidelines is ICH-E14, ratified by the US Food and Drug Administration (FDA), Health Canada, the European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), which calls for a rigorous evaluation of new drugs for potential repolarization (QT) related cardiotoxicity (ref 1). The cardiometabolic therapeutic area has also come under public scrutiny following high profile drug withdrawals and non-approvals that resulted in the development of the US FDA Guideline for industry on Diabetes Mellitus (Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes) (ref 4), which was recently extended to include weight loss (anti-obesity) drugs. In addition, scientific knowledge, concerns, and trends surrounding cardiac safety are advanced by the Cardiac Safety Research Consortium (CSRC) and the International Cardio Oncology Society (ICOS).

Cardio-Oncology-What Is It?

Cardio-Oncology is a discipline at the interface of cardiology and oncology which focuses on cardiovascular safety monitoring and clinical management of cardiovascular toxicities of oncology drugs during development and post-approval. The field came about in response to the prevalence of cardiotoxicities associated with cancer therapeutics and the need for clearly defined cardiovascular risk management for their development. Cardio-Oncology is primarily concerned with drug-induced direct damage to the myocardial muscle, leading to progressive heart failure and potentially death. Early detection, before an overt clinical heart failure develops, involves serum biomarkers (primarily cardiac troponins), ECG monitoring and imaging assessment of left ventricular ejection fraction (LVEF) using ECHO and MUGA scans. 

Typical Endpoints for Assessing Cardiac Safety

Many existing oncology drugs result in a particular cardiac phenotype known as prolonged QT. As mandated by ICH-E14, sponsors typically perform Thorough QT (TQT) studies using ECG measurements. However, when it comes to oncology drug development, designing and implementing QT studies presents unique challenges, due in part to complex patient populations and narrow therapeutic windows, requiring ‘alternative’ approaches (ref 5). Other modalities and endpoint measurements are also available for assessing the cardiac safety of new drugs. Choices for sponsors include Ambulatory Blood Pressure Monitoring (ABPM) (for measuring hypertension), Echocardiograms and other image-based modalities like MUGA and MRI (for measuring ventricular and valvular function), and serum biomarker levels (for monitoring cardiac injury).

Blood Pressure Endpoints

A particular class of oncology drugs targeting Vascular Endothelial Growth Factor (VEGF) signaling pathway, affects tumor vasculature and is often associated with hypertension. Administration of these drugs often requires careful blood pressure (BP) monitoring. Studies with a BP endpoint can require evaluation over extended periods of time or spanning circadian rhythms. Advances in BP monitoring technology have made it possible to acquire large amounts of patient BP data in a standardized way for careful evaluation of drug side effects. For example, Ambulatory Blood Pressure Monitoring (ABPM) allows for continuous 24 hour monitoring with configurable settings and standardized equipment. Furthermore, using remote telemonitoring, standardized BP measurements defined within a protocol can be done at home, alleviating the need for trial patients to make frequent visits to their physicians as well as providing early insight into blood pressure trends and enhancing patient safety in a real time setting.

To learn more about ABPM as an endpoint in cardiac safety studies, watch my video presentation on the subject or sign up for my complimentary webinar Blood Pressure as a Cardiac Safety Endpoint: Safety, Clinical R&D, and Regulatory Considerations featuring Robert Jordan, Executive Director of Palatin Technologies.

References

  1. Guidance for Industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. U.S. DHHS, FDA. ICH. October 2005. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf
  2. Sager, P., Heilbraun, J., Turner J. R., Gintant, G., Geiger, M. J., Kowey, P. R., Mansoor, G. A., Mendzelevski, B., Michelson, E. L., Stockbridge, N., Weber, M. A., and White, W. B. (2013). Assessment of drug-induced increases in blood pressure during drug development: Report from the Cardiac Safety Research Consortium. American Heart Journal (Vol. 165, Issue 4, Pages 477-488).
  3. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006; 7: 889-908.
  4. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), December 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati....
  5. Braddock, M., Heilbraun, J., and Mendzelevski, B. Cardiovascular safety and hemodynamic considerations in oncology drug development – webinar highlights October 10th 2012. Expert Opinion on Drug Safety.
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Blood Pressure as a Cardiac Safety Endpoint: Safety, Clinical R&D, and Regulatory Considerations

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