Feeling the Heat (or Cold) – New Draft Guidance Addresses Requirements for Devices that Produce Thermal Effects

FDA recently issued a draft guidance, Evaluation of Thermal Effects of Medical Devices that Produce Tissue Heating and/or Cooling (link), which describes information to include in a marketing application to support the evaluation of thermal effects of medical devices that produce local, regional, and/or systemic changes in tissue temperature due to their use, either by heating or cooling.

The draft guidance applies to medical devices that heat or cool tissue as an intended or unintended consequence of device use.  Examples of such devices include devices that deliver forms of electromagnetic energy; devices that deliver ultrasound; electroporation devices; devices that produce temperature changes by contact; and devices with components such as batteries, generators, chargers, leads, and electrode contacts that can potentially heat surrounding tissue during use.

To evaluate the thermal effects of a device, the draft guidance recommends that bench testing precede evaluation of thermal effects.  Bench testing should be conducted first to verify the device meets its specifications and to demonstrate that the subsequent data generated are representative of the final finished device’s performance.

An evaluation of thermal effects should include an assessment of tissue effects (e.g., thermal damage, tissue appearance, tissue/organ function) and related spread of thermal energy in the tissue.  These assessments may be performed experimentally (i.e., using phantoms, ex vivo animal tissue models, and/or in vivo animal testing), computationally, and/or clinically.  To determine which type of tissue evaluation is appropriate, the draft guidance recommends the magnitude and distribution of the heating and/or cooling provided by the device be considered in addition to the availability of the appropriate experimental model, noting that use of a phantom model or ex vivo animal tissue model may be appropriate for devices with local tissue temperature changes, but may not be suitable for devices with regional or systemic effects, where impact of blood flow on the development of tissue effects needs to be accounted for.

For ex vivo tissue or in vivo animal testing, the guidance includes discussion of the selection of tissue and test methods, noting that testing should be performed such that the tissue is exposed to the minimum, average, and worst-case temperature-time history.  The draft guidance discusses selection of tissues, tissue test methods, and methods for assessing the thermally affected tissue region(s), including thermal energy spread.  For measuring the thermally affected tissue region(s), the draft guidance recommends use of histological methods or methods evaluating changes in properties, such as electrical, mechanical, and optical properties or properties related to imaging.  For measuring thermal energy spread, the draft guidance discusses probe-based and image-based thermometry.

When in vivo animal testing is needed, tests should follow good laboratory practices and the animal model should be representative of the intended clinical application.  For example, aesthetic devices intended to create fractional effects, where the technical parameters of the subject device are significantly different from the comparator device, should be tested using an animal model.  Notably, this same example is used for a situation in which data from a study in humans may be needed.  The draft guidance notes that histological data from use of the device in tissues of interest in humans or an appropriate animal model should be provided.  While histological data is common in studies of animal models, it is not clear how human histological data should be obtained in a study of an aesthetic device and the draft guidance provides no discussion of this point.

The draft guidance also discusses use of computational evaluation of tissue effects and thermal energy spread, recommending that such evaluations should use computational models of relevant tissues, impose clinically relevant boundary conditions, and be validated to predict tissue effects and thermal energy spread in the intended tissue of interest for the full range of spatio-temporal temperature distribution.

Given the complexity of these studies and the lack of detail regarding the applicability of the guidance to specific devices, seeking a pre-submission may be beneficial to sponsors.  The draft guidance recommends seeking guidance through the pre-submission process to address questions of:

• The use of phantoms, ex vivo tissue, or in vivo animal models.
• Selection of appropriate model parameters for the intended clinical application.
• The induced spatial temperature distribution over time (i.e., “temperature-time history”) needed to support a claimed tissue effect.
• Design of clinical studies, when needed, to support the device’s indications for use.
• Scenarios where the recommendations in the guidance may not apply.
• Evaluation of devices that induce reversible or irreversible electroporation effects, as electroporation-based ablation has been associated with induction of cardiac arrhythmias.

The draft guidance notes that the recommendations reflect current review practices.  While companies that already market devices that produce tissue heating and/or cooling may already be familiar with FDA’s expectations, availability of the guidance should help those with new devices avoid surprises during review of their marketing applications.