— Part 2 in a 3-part blog series on cardiac safety regulatory developments

In my last blog, FDA Issues Draft Guidance on Blood Pressure (BP) Response in Clinical Trials, we looked at the FDA’s draft guidance Assessment of Pressor Effects of Drugs Guidance for Industry issued in May 2018.

In this blog post you’ll find answers to commonly asked questions along with additional background and BP safety endpoint considerations to help drug developers prepare for the new FDA BP guidance, which may come as early as first quarter, 2019.

  1. Why is it important to monitor blood pressure as an endpoint in clinical trials?

As a sponsor, it is important to understand the risks associated with a new therapeutic treatment. Within clinical research and practice, blood pressure can be viewed as both an efficacy and safety biomarker. The need for measuring BP to determine if a specific anti-hypertensive therapy is effectively treating hypertension is well recognized. However, there is also a need for determining the ‘off-target’ effects on BP associated with some classes of compounds used for treating a variety of disease states. While BP as an ‘off-target’ safety consideration is not a novel topic within clinical research, the level of risk associated with changes in BP (within a normotensive and probably more importantly a hypertensive population) is now the focal point of the FDA’s draft guidance issued in May, which is expected to be finalized in early 2019.

  1. What are some of the methods and technologies available to sponsors for monitoring blood pressure?

Blood pressure can be evaluated using both invasive and non-invasive methods. Most BP data collected in clinical trials (especially in later phase trials) focus on non-invasive methods, which include both auscultation (listening for Korotkoff sounds) and oscillometric measurements. Recently, there has been a trend toward automated oscillometric measurement (captured based on a standardized and validated algorithm) with the goal of reducing variability that can be introduced by human error/bias when using an aneroid/mercury sphygmanometer and listening for the Korotkoff sounds. A number of recent publications explore the question of whether the clinician or study nurse should be in the room (attended) or not (unattended) during the office blood pressure assessment, which stemmed from the SPRINT and other industry publications study. No matter whether the assessment is attended or unattended it is important to focus on the basics of completing accurate blood pressure assessment. From measuring the individual’s arm and selecting the appropriate sized cuff, to having the individual sit quietly, feet flat on the floor and arm supported, are simple but critical steps in accurate BP assessment.

Blood pressure evaluation can be divided into several different categories depending on the location and technology being applied. In a standard office setting, BP data can be collected using an automated oscillometric BP device or in some cases a stethoscope and the auscultatory method (some of the automated office BP units provide an option to complete a manual BP assessment where the device acts as a manometer) The automated devices can also be set to take a series of readings and generate an average. In an Ambulatory setting as well as within a clinical pharmacology setting, Ambulatory blood pressure monitoring (ABPM) technology can be used to obtain 24-hour readings, scheduled at a pre-defined sequence. As noted in the draft guidance, ABPM is considered a gold standard for defining the circadian blood pressure profile Current BP technology also enables measurements in a home setting. Home BP measurements can be remote telemonitored to a centralized location for patient-independent data capture, with real time data transmission and early visibility into safety trends for sponsors. Each of these technologies has been implemented in clinical trials and the data submitted to the FDA for either efficacy or safety endpoints. In addition to standard, brachial blood pressure assessment there are now devices that also capture additional non-invasive hemodynamic measures associated with central pressure, arterial compliance and pulse wave velocity measures,

Want to know more about BP response, safety endpoints and how to be prepared for the new guidance?

Stay tuned for the third and final installment in this blog series in which we will explore BP assessment in greater detail. We’ll also dive into disease- and therapeutic-specific considerations from a BP perspective. Looking forward to continuing the discussion!

Have a question about the new guidance or BP in research? Want a copy of the paper on SPRINT or another item mentioned here? Email me anytime at Jeff.Heilbraun@Bioclinica.com.