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FDA Issues Draft Guidance on Blood Pressure (BP) Response in Clinical Trials

Preparing for new BP guidance

  • Part 1 in a 3-part blog series on recent cardiac safety regulatory developments

New FDA draft guidance on blood pressure response released in May 2018, entitled: Assessment of Pressor Effects of Drugs Guidance for Industry, is intended to help address blood pressure effect in drug development. If not already familiarized with it, now is a good time to do so as the final guidance — expected to be issued in as early as the first quarter of 2019 — carries important implications for drug developers.

The foundation for the draft guidance is that elevated blood pressure is known to increase risk of stroke, heart attack and death. Therefore, the effect of a drug on blood pressure is an important consideration in benefit-risk assessment in drug development.

Although the FDA's draft guidance on BP safety signals is new, the interest by the regulators in defining potential safety concerns with compounds that generate an "off-target" BP response is not. In fact, a number of compounds have specific reference to potential blood pressure effects on their label. One of the key points in the draft guidance is to improve the assessment or measurement of blood pressure in the clinical trial setting.

Blood pressure measurement has gone through some changes, from the use of a mercury manometer and stethoscope to identify the Korotkoff sounds for systolic and diastolic, to the use of automated oscillometric devices in the clinic setting.  Beyond the clinic setting, as noted in the draft guidance, Ambulatory Blood Pressure Monitoring (ABPM) has proven itself as an effective tool in defining both efficacy and safety BP endpoints. Within the research literature you can see the use of automated clinic BP assessment, ABPM and telemonitored home BP monitoring.

The draft guidance, is applicable across all therapeutic indications. And depending on the BP signal, monitoring across different trial phases may be recommended.

In the guidance, the FDA:

  1. Addresses precision of blood pressure measurement in the assessment of effects of a drug in development, and
  2. Recommends systemic characterization of the effect of a drug on blood pressure during drug development.

Key questions for drug developers

The guidance provides a good overview and considerations as to safety and benefit/risk assessment and incorporates rounded insights from regulatory, clinical and scientific perspectives.  It identifies some specific design considerations, which you can find in the bullet points below, as well as some key things worth considering when approaching a compound with a potential BP signal, such as:

  • Should we focus on a normotensive study population or patients with hypertension or other hemodynamic disease states?
  • Is there a need for an intensive BP study in early development to define the potential exposure response BP profile of a compound in development?
  • What BP monitoring options are available to "build the best mouse trap" to define the potential blood pressure signal?
  • Is there a different approach for short-term therapeutic treatments vs. compounds individuals take for an extended period?
  • How should we assess compounds being developed for a pediatric/adolescent population?
  • Can we apply lessons learned from the extensive experience with ECG and QT assessment as a cardiac safety endpoint?

The next step in the draft guidance review process (following the comment period that closed in late July) will be a public meeting to discuss the draft guidance.

If you have a question around BP response that I or one of my colleagues may answer, drop me a line at Jeff.Heilbruan@Bioclinica.com.

Additional Reading

The assessment off-target blood pressure responses in developing compounds has been a topic of discussion within the regulatory and development arena over the last several years. In fact, it was in 2009, when it gained momentum following a presentation led by FDA's Dr. Robert Fiorentino at DIA's Annual Meeting, entitled, "Beyond the QT interval…The use of surrogates in premarket safety and risk/benefit evaluation: Blood Pressure." More recently, in 2013, the Cardiac Safety Research Consortium (CSRC) conducted a think-tank, which produced the white paper, "Assessment of Drug Induced increases in blood pressure during drug development: Report from the Cardiac Safety Research Consortium."

To obtain a copy of one or both of these items, email Jeff.Heilbraun@Bioclinica.com.

In my next blog post, we'll dive deeper into the major implications of the draft FDA guidance on BP safety endpoints, so stay tuned!

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