Clinical Study Design for Surgical Ablation Devices Used in Treatment of Atrial Fibrillation Under Direct Visualization
This guidance addresses clinical study design for surgical ablation devices intended for the treatment of atrial fibrillation (AF) under direct visualization. It applies to new surgical ablation devices and legally marketed devices seeking a new AF treatment indication. The guidance specifically excludes cardiac ablation devices not used under direct visualization and those delivered intravascularly.
What You Need to Know? 👇
What are the key differences between paroxysmal, persistent, and longstanding persistent atrial fibrillation for surgical ablation studies?
Paroxysmal AF terminates spontaneously within seven days, persistent AF is sustained beyond seven days but ≤1 year, and longstanding persistent AF is continuous for >1 year. Each type requires different study designs, inclusion criteria, and monitoring approaches due to varying procedural complexity and follow-up requirements.
What is the FDA’s preferred study design for surgical ablation devices treating atrial fibrillation?
FDA recommends randomized controlled trials (RCTs) as the first choice, comparing the investigational device to an approved device or therapy. RCTs provide the least burdensome means of developing valid scientific evidence by eliminating systematic differences between treatment groups and providing sound statistical inference.
What constitutes the primary effectiveness endpoint for surgical AF ablation studies?
The primary effectiveness endpoint is freedom from AF/AFL/AT episodes ≥30 seconds duration for one year, evaluated in the absence of Class I or III antiarrhythmic drugs. This should be assessed through periodic Holter monitoring, event recorders, or equivalent cardiac rhythm measurements.
What safety events must be included in the primary safety evaluation for surgical ablation devices?
The composite safety endpoint must include all-cause death, stroke/TIA, myocardial infarction, thromboembolic events, excessive bleeding, deep sternal wound infection, conduction system damage requiring pacemaker, peripheral structure damage (esophagus/phrenic nerve), and pulmonary vein stenosis, with one-year minimum follow-up.
How should pulmonary vein stenosis be evaluated in surgical ablation studies?
Baseline imaging (CT/MRI) followed by assessment at 3-6 months post-procedure is recommended. Stenosis should be categorized as mild (<50%), moderate (50-70%), or severe (≥70%) diameter reduction. Severe stenosis constitutes a major complication requiring independent, masked core laboratory evaluation.
What are the requirements for investigator selection and training in surgical ablation studies?
Investigators must be qualified by training and experience. If lacking electrophysiological expertise, an experienced investigator should assist with conduction block verification. Training on procedures is recommended, and “roll-in” subjects may be included to avoid learning curve bias in endpoint evaluation.
What You Need to Do 👇
Recommended Actions
- Design a randomized controlled trial with 12-month follow-up period
- Develop detailed protocols for:
- Patient selection criteria
- Anticoagulation management
- Follow-up visits and monitoring
- Adverse event reporting
- Establish an independent Clinical Events Committee
- Create investigator training program
- Implement standardized neurological assessments
- Define clear primary effectiveness and safety endpoints
- Develop statistical analysis plan including sample size justification
- Create detailed documentation procedures for all study aspects
- Establish quality monitoring procedures
- Plan for potential post-approval studies with extended follow-up
Key Considerations
Clinical testing
- Randomized controlled trials (RCTs) are recommended as the least burdensome means to develop valid scientific evidence
- 12-month minimum follow-up period required
- Primary effectiveness endpoint should be freedom from AF/AFL/AT for one year without Class I or III antiarrhythmic drugs
- Separate studies recommended for different types of AF (paroxysmal vs persistent)
- Standardized follow-up visits at 30 days, 3, 6, 9 and 12 months
Human Factors
- Investigator selection should be based on qualification and experience
- Training required for investigators lacking thorough knowledge of procedures
- Consider including “roll-in” subjects to avoid learning curve bias
Labelling
- Should identify factors affecting benefit/risk profile:
- Type of AF treated
- Surgical approach used
- Concomitant procedures
- Relevant patient characteristics
Safety
- Primary safety composite endpoint including:
- All-cause death
- Stroke and TIA
- Myocardial infarction
- Thromboembolic events
- Excessive bleeding
- Deep sternal wound infection
- Damage to conduction system requiring pacemaker
- Damage to peripheral structures
- Pulmonary vein stenosis
- Neurological assessment required before and after procedure
- One year safety follow-up recommended
Other considerations
- Clear anticoagulation protocols required
- Antiarrhythmic drug therapy should be discontinued prior to effectiveness evaluation
- Statistical justification needed for sample size calculations
- Independent Clinical Events Committee recommended for adverse events adjudication
Relevant Guidances 🔗
- Design Considerations for Medical Device Pivotal Clinical Studies
- Benefit-Risk Factors in IDE Applications for Medical Device Clinical Investigations
- IDE Clinical Investigation Decision Process and Requirements
- Applying Human Factors Engineering and Usability Engineering to Medical Devices
Related references and norms 📂
- NIH Stroke Scale (NIHSS): Standardized scale for assessment of neurologic deficit
- Modified Rankin Score (MRS): Scale for assessment of stroke disability