Non-Clinical Testing Recommendations for Machine Perfusion Devices Used to Preserve Vascularized Human Organs for Transplant
This guidance applies to devices intended to preserve human vascularized organs through machine perfusion (hypothermic or normothermic) from procurement until transplant. It excludes devices for cold static storage and HCT/Ps preservation devices.
What You Need to Know? 👇
What are the key regulatory considerations for organ preservation device animal studies?
FDA recommends a risk-based approach with focused objectives and a priori acceptance criteria. Studies should follow Good Laboratory Practice requirements (21 CFR Part 58) and incorporate The Three R’s principles while generating sufficient data to demonstrate device safety.
How should procedure duration be determined in organ preservation device studies?
Duration should reflect the device’s indications for use. Specify warm and cold ischemia times during procurement, evaluate cannulation time against acceptance criteria during preservation, and consider maximum expected transportation time consistent with intended use.
What are the main differences between ex vivo and in vivo reperfusion models?
Ex vivo models offer controlled environments with detailed monitoring but have limitations in evaluating immune responses. In vivo models provide clinically relevant graft survival endpoints but introduce confounding variables that may affect data interpretation.
When should I submit a Pre-Submission for organ preservation device studies?
FDA encourages Pre-Submissions for all organ preservation device protocols, especially for first-of-its-kind devices, novel perfusion solutions, or when choosing between ex vivo and in vivo models. This helps obtain specific feedback before study initiation.
What biomarkers should be evaluated in organ preservation device studies?
FDA recommends evaluating a panel of molecular, functional, and imaging biomarkers targeting both organ injury and function. Special consideration should be given to endothelial cell injury markers and inflammatory cascade activation indicators.
How can contamination risks be mitigated in machine perfusion studies?
Perform bacterial cultures on perfusate samples at the end of perfusion sessions. Machine perfusion has higher contamination risk than cold static storage due to increased circuit complexity and organ manipulation requiring careful monitoring protocols.
What You Need to Do 👇
Recommended Actions
- Develop a risk-based approach for animal study protocol development
- Define clear study objectives and acceptance criteria
- Select appropriate animal model with scientific justification
- Design protocol considering all three phases (procurement, preservation, reperfusion)
- Implement contamination control measures
- Evaluate device transportability if applicable
- Consider both ex vivo and in vivo models based on study objectives
- Establish appropriate biomarker panel for organ assessment
- Implement proper histopathological evaluation procedures
- Submit Pre-Submission to FDA for feedback on proposed animal studies
- Follow GLP requirements
- Document all procedures and results thoroughly
Key Considerations
Non-clinical testing
- Risk-based approach for developing animal study protocols
- Protocol should have focused objectives and a priori acceptance criteria
- Provide rationale for animal model selection considering anatomical, physiological, and immunological factors
- Evaluate three phases: organ procurement, preservation, and reperfusion
- Specify warm and cold ischemia times reflecting intended use
- Total preservation time should consider expected maximum transportation time
- Assess device transportability if applicable
Biocompatibility
- Perform bacterial cultures on perfusate samples at end of perfusion session
- Evaluate perfusate composition and additives
- Assess organ edema through weight measurements before and after reperfusion
Safety
- Evaluate strategies to mitigate organ injury from mechanical trauma during transport
- Assess reperfusion injury through ex vivo or in vivo models
- Collect tissue biopsies from multiple organ regions before and after reperfusion
- Independent pathologist evaluation focusing on endothelial cell integrity
Other considerations
- Consider using both ex vivo and in vivo models to verify findings
- Follow GLP requirements (21 CFR Part 58)
- Balance ethical principles of The Three R’s with regulatory least burdensome principles
- Submit Pre-Submission to obtain FDA feedback on proposed animal studies
Relevant Guidances 🔗
- Animal Testing for Medical Device Safety and Performance Evaluation
- Jurisdictional Determinations for HCT/P Processing Devices: CBER vs CDRH Assignment
- Good Laboratory Practice (GLP) Requirements for Non-Clinical Laboratory Studies
Related references and norms 📂
- 21 CFR Part 58: Good Laboratory Practice for Nonclinical Laboratory Studies
Original guidance
- Non-Clinical Testing Recommendations for Machine Perfusion Devices Used to Preserve Vascularized Human Organs for Transplant
- HTML / PDF
- Issue date: 2019-05-08
- Last changed date: 2019-05-07
- Status: FINAL
- Official FDA topics: Medical Devices, Gastroenterology-Urology, 510(k), Premarket
- ReguVirta ID: 7c3a981bf8d471a3a4be9e07e9c6cf29