By Rebecca Mayo, J.D.
A new FDA draft guidance provides recommendations for using animal studies to evaluate organ preservation devices.
Recommendations regarding best practices for utilizing animal studies for the evaluation of organ preservation devices were provided by the FDA in a draft guidance. According to the agency, a shortage of organs available for transplants has driven device makers to use newly developed organ preservation technologies in animal models to evaluate suitability for clinical experience. The FDA acknowledged that the best practices for conducting animal studies to evaluate organ preservation devices are evolving alongside the rapid advancement in such technologies. Therefore, the guidance is only the FDAs initial thoughts on how animal transplant models can be utilized, and the FDA encourages members of industry to submit a pre-submission to obtain feedback for specific protocols (Notice, 84 FR 20152, May 8, 2019).
Scope. The guidance applies to devices intended to preserve human vascularized organs via machine perfusion from the time of organ procurement until transplant. It does not apply to devices intended to preserve organs via cold static storage or human cells, tissues, or cellular or tissue-based products already regulated and the devices utilized to preserve and transport these products.
Study design. The FDA recommends a risk-based approach. The risks inherent to the to the proposed indications for use and other known risks of the device already identified should be considered. Once the risks and their corresponding failure modes are identified, a protocol should be developed with focused objectives and a priori acceptance criteria. The scientific rationales for the chosen acceptance criteria and a rationale for the selection of a particular animal model for the study which includes considerations of anatomical, physiological, and immunological similarities and differences between the animal model and humans should be provided. Since machine perfusion has a higher risk of contamination, bacterial cultures on perfusion samples should be taken at the end of a perfusion. The protocol should also assess whether the device and organ can withstand normal handling as well as turbulence during transport.
Special attention should be paid to the duration of the different phases of the experimental procedures. During the procurement phase, warm ischemia time and cold ischemia time should be specified as part of the animal organ procurement protocol which relent the indications for use of the device. The time to successfully annulate and connect the organ t the device should be evaluated during the preservation phase. The reperfusion phase should include a cold-flush of the organ per standard protocol and the organ should be exposed to a realistic preparation period.
Reperfusion models. New organ preservation technologies has allowed the potential to monitor and assess organs ex vivoprior to transplantation, however there are some limitations that should be taken into consideration. There should be a control group so the relative effects of the injury can be evaluated. Ex vivo reperfusion should be performed under near-physiological conditions. If the device utilized a blood-based perfusate, whole blood should be used. The duration of ex vivoreperfusion should be specified to allow adequate assessment of organ function and viability. A panel of bio markers should be evaluated to assess both organ injury and organ function. Organs should be weight before and after reperfusion to assess the risk of machine perfusion-related edema. Finally, tissue biopsies should be collected from multiple representative regions of the organ before and after reperfusion.
In vivo models rely on the most clinically relevant endpoint, graft survival rather than biomarkers for organ injury and function, however in vivo models introduce many non-device related variables which may affect outcomes and hinder meaningful interpretation of data. Baseline hemodynamics profiles in organ recipients should be collected and immunosuppressants should be provided. The animal studies should be conducted in a highly controlled facility by qualified personnel and standard procedures including antibiotic and immunosuppressant regimens and post-operative monitoring and care should be applied.
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