Guidance for Industry and FDA 
Staff 
Clinical Study Designs for 
Percutaneous Catheter Ablation 
for Treatment of Atrial 
Fibrillation  
Document issued on: January 9, 2004 
For questions regarding this document, contact Felipe Aguel at (301) 796-2467 or by e-mail at 
 felipe.aguel@fda.hhs.gov.  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Cardiac Electrophysiology and Monitoring Branch 
Division of Cardiovascular Devices 
Office of Device Evaluation  Contains Nonbinding Recommendations 
Preface 
Public Comment 
Comments and suggestions may be submitted at any time for Agency consideration to Dockets 
Management Branch, Division of Management Systems and Policy, Office of Human 
Resources and Management Services, Food and Drug Administration, 5630 Fishers Lane, 
Room 1061, (HFA-305), Rockville, MD, 20852.  When submitting comments, please refer to 
the exact title of this guidance document. Comments may not be acted upon by the Agency 
until the document is next revised or updated.   
Additional Copies 
Additional copies are available from the Internet at: 
http://www.fda.gov/cdrh/ode/guidance/1229.pdf , or  to receive this document by fax, call the 
CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a touch-tone 
telephone.  Press 1 to enter the system.  At the second voice prompt, press 1 to order a 
document.  Enter the document number (1229) followed by the pound sign (#).  Follow the 
remaining voice prompts to complete your request.    Contains Nonbinding Recommendations 
Table of Contents 
Introduction...............................................................................................................................1 
Scope.........................................................................................................................................2 
The Least Burdensome Approach.............................................................................................3 
Study Design.............................................................................................................................3 
Study End Points.......................................................................................................................5 
Data Collection Forms..............................................................................................................8 
Study Groups............................................................................................................................8 
Sample Size...............................................................................................................................9 
Patient Follow Up...................................................................................................................10 
Blanking Period......................................................................................................................10 
Anticoagulation.......................................................................................................................10 
Study Monitoring....................................................................................................................11 
References...............................................................................................................................11  Contains Nonbinding Recommendations 
Guidance for Industry and FDA Staff 
Clinical Study Designs for Percutaneous 
Catheter Ablation for Treatment of Atrial 
Fibrillation  
This guidance represents the Food and Drug Administration's (FDA's) current thinking 
on this topic.  It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public.  You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to discuss 
an alternative approach, contact the FDA staff responsible for implementing this 
guidance.  If you cannot identify the appropriate FDA staff, call the appropriate number 
listed on the title page of this guidance.  
Introduction 
Atrial fibrillation (AF) is a complex arrhythmia; its precise mechanisms remain unclear, and 
the clinical presentation, arrhythmia characteristics, and underlying pathophysiology are 
variable.  The arrhythmia has been classified in various ways based on electrocardiography 
(ECG) or clinical criteria.  Because ablation therapies proposed to date for treatment of atrial 
fibrillation are intended to prevent or reduce the recurrence of this arrhythmia, this document 
will use a rhythm classification scheme (Table 1), adapted from the American College of 
Cardiology/American Heart Association/ European Society of Cardiology (ACC/AHA/ESC) 
Guidelines for the Management of Patients with Atrial Fibrillation, based on arrhythmia 
recurrence pattern.1  This general classification scheme may be useful when defining patient 
populations for inclusion in clinical studies and when selecting appropriate methods to 
evaluate treatment effectiveness in the selected patient populations. 
1 Contains Nonbinding Recommendations 
Table 1.  AF Rhythm Classification Scheme 
Classification  AF Episodes 
Paroxysmal self-terminating
not self-terminating but can be cardioverted with drugs or 
Persistent 
electricity 
not self-terminating and the arrhythmia cannot be 
Permanent 
cardioverted or recurs quickly following cardioversion 
Recurrent  two or more documented episodes occur 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidances means that 
something is suggested or recommended, but not required. 
Scope 
This guidance document addresses study design issues associated with catheter ablation 
devices intended for treatment of atrial fibrillation.  These devices (product code, LPB, 
Electrode, Percutaneous, Conduction Tissue Ablation) are class III, requiring premarket 
approval applications before marketing (section 513(a) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 360c(a))).   
FDA believes that the devices addressed by this guidance document are significant risk 
devices as defined in 21 CFR 812.3(m).i  In addition to the requirement of having an FDA-
approved IDE (21 CFR Part 812), sponsors of such studies must comply with the regulations 
governing institutional review boards (21 CFR Part 56) and informed consent (21 CFR Part 
50). 
i Please refer to Blue Book Memorandum entitled SIGNIFICANT RISK AND 
NONSIGNIFICANT RISK MEDICAL DEVICE STUDIES, 
http://www.fda.gov/cdrh/d861.html. 
2 Contains Nonbinding Recommendations 
The Least Burdensome Approach 
The issues identified in this guidance document represent those that we believe should be 
addressed before your device can be marketed.  In developing the guidance, we carefully 
considered the relevant statutory criteria for Agency decision-making.  We also considered 
the burden that may be incurred in your attempt to follow the guidance and address the issues 
we have identified.  We believe that we have considered the least burdensome approach to 
resolving the issues presented in the guidance document.  If, however, you believe that there 
is a less burdensome way to address the issues, you should follow the procedures outlined in 
the A Suggested Approach to Resolving Least Burdensome Issues document.  It is 
available on our Center web page at: https://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM588914.pdf
Study Design 
FDA believes that, in general, randomized, controlled trials reflect the least burdensome 
means of collecting clinical data in support of safety and effectiveness for catheter devices 
intended to treat AF.  In considering alternative study designs, FDA believes that using 
patients as their own control or using a historical control can complicate the demonstration of 
effectiveness in most investigations.  Statistical concerns that underlie this recommendation 
include both general considerations, e.g., regression to the mean, and disease-specific 
considerations, e.g., the clustered, non-random AF recurrence pattern that has been described 
for patients with paroxysmal AF.2,3  Additional considerations that suggest the use of a 
randomized control include the high degree of heterogeneity that exists in the potential 
patient population, in AF disease presentation, in potential ablation technologies, and in 
concomitant medical treatment. 
Although FDA generally recommends a randomized, controlled trial for these reasons, you 
may use an alternative study design if it is scientifically sound and addresses the relevant 
safety and effectiveness questions.  For example, a self-controlled study may be appropriate 
to evaluate treatment effectiveness among patients with truly refractory permanent AF, and a 
study with a sham control arm may be considered for a study involving subjective criteria 
such as perceived symptoms.  FDA recognizes that there is no unique best design in 
catheter ablation investigations, but considers the elements discussed in this document as core 
features of reasonable studies.  As noted earlier, we will consider alternative study designs, 
but we recommend that you explain the scientific arguments supporting your alternative 
design. 
 indications for use
If you conduct a randomized, controlled study, you should select an appropriate control 
therapy.  Selection of this control should depend on the:  
3 Contains Nonbinding Recommendations 
 patient population
  device design considerations.   
Potential control therapies include:  
 best medical therapy with antiarrhythmic drugs 
  therapy with approved medical device(s)   
 patients as own controls 
  sham therapy. 
In the case where sponsors elect to utilize best medical therapy with antiarrhythmic drugs as 
the control therapy, FDA recognizes that drug regimens are tailored to individual 
circumstances and that no unique optimal regimen may exist.  However, FDA recommends 
that any investigation with antiarrhythmic drugs utilize a pre-specified tiered protocol that 
delineates criteria for initial drug selection and for changes in drug therapy. 
Control to a previously approved, atrial fibrillation device therapy may be a particularly 
desirable option because study design, patient enrollment and data analysis may all, 
potentially, be very straightforward.  For example, if a catheter ablation system is approved 
for treatment of AF via pulmonary vein isolation, then it might be both simple and 
appropriate to use a randomized study to compare the safety and effectiveness of a new 
ablation device versus the safety and effectiveness of the previously approved device.   
Sham controlled studies allow the sponsor to evaluate for procedure/placebo effect and to 
mask study subjects.  This type of study design may be most appropriate for studies with 
subjective endpoints such as reduction in patient-reported symptoms, or when the risk level 
for the sham procedure is particularly low.  FDA recognizes that it may be difficult for 
sponsors to develop a clinical study design with a sham control arm that both investigators 
and patients believe is ethical; for this reason, studies involving a sham control arm should be 
carefully designed with due consideration to risks versus benefits. 
Potential advantages to randomized, controlled trial designs extend not only to evaluation of 
device effectiveness but also to evaluation of device safety.  Adverse event rates may be 
affected by factors such as patient characteristics, device design, evolving procedural 
methods and operator experience and may be difficult to evaluate using historical control 
data rather than randomized control data.  For example, multiple case series have suggested 
that catheter ablation to create pulmonary vein isolation for treatment of atrial fibrillation can 
be associated with severe adverse events.2,3,4  In contrast, a recently reported, concurrently 
controlled but non-randomized study suggests that at least one catheter ablation procedure 
4 Contains Nonbinding Recommendations 
used for pulmonary vein isolation may actually reduce the incidence of adverse events when 
compared to medical management.5  
 
Whatever the concurrent control arm selected, FDA believes that several strategies could be 
employed to facilitate patient recruitment.  These include, but are not limited to, 2:1 (or 
other) randomization schemes and crossover study designs that would allow medically 
managed control patients to receive ablation procedures after a pre-specified time (e.g., six 
months in a control arm).  These considerations will allow study sponsors to develop 
reasonable study designs that facilitate assessment of safety and effectiveness by the FDA 
consistent with a least burdensome approach to device regulation. 
Study End Points 
Primary Effectiveness Endpoint 
In the future, it may be feasible to demonstrate that ablation therapies for AF positively 
affect disease outcomes.5  At the current time, it is probably most appropriate to evaluate 
ablation therapy for AF as a palliative therapy and to select endpoints that have the 
potential to clearly demonstrate a reduction in symptoms caused by AF.  
 
Effectiveness endpoints should be clinically meaningful and amenable to robust 
evaluation during a clinical study.  FDA believes that evaluation of reduction of AF 
burden (or reduction in the incidence of AF) is problematic as the primary endpoint for a 
study designed to evaluate therapy for paroxysmal AF.  Measurement of this endpoint 
post-ablation could be strongly influenced by various, non-therapy-related factors.  The 
potential for waning patient compliance with remote monitoring and recording 
procedures would be one concern.  Because recording and reporting of symptomatic 
episodes is subjective, placebo effect could be an important concern during unmasked 
studies.  As noted above, evaluation of AF recurrence can also be influenced by statistical 
concerns or issues related to disease natural history, e.g., the phenomenon of regression 
to the mean and the non-random recurrence pattern reported for paroxysmal AF.2,3  
Finally, evaluation of reduction in paroxysmal AF burden or recurrence may not be an 
optimal primary endpoint because it is difficult to determine or define the percent 
reduction that should be considered clinically significant. 
 
For a primary effectiveness endpoint, FDA recommends the relatively unambiguous 
endpoint of freedom from symptomatic atrial fibrillation at one year.  This outcome 
should be in the absence of antiarrhythmic drug therapy, or, alternatively, using an 
antiarrhythmic drug that was previously ineffective at a given dose.  A one-year follow-
up period both minimizes the confounding effects of the clustered, non-random AF 
  5 Contains Nonbinding Recommendations 
recurrence pattern that was previously discussed and provides sufficient time to evaluate 
adverse events, e.g., pulmonary vein stenosis, that may be manifest or progressive only at 
late time points in some patients.   
 
Depending on the design of the device and the objectives of the study design, the 
following endpoints may also be appropriate: 
  reduction of atrial fibrillation burdenii 
  improvement in exercise tolerance 
  improvement in quality of life 
  improvement in symptom scores tracking dyspnea, dizziness, or 
  palpitations. 
We recommend that you explicitly define acute procedural and chronic procedural 
success, and scenarios indicating treatment failure.  For example, persistence of 
symptoms at six months in a control arm might lead to patient crossover into an 
interventional arm, but should be counted as a treatment failure in the control arm.  
(Indications in labeling should reflect your definition of acute procedural success.) 
 
Published results indicate that current catheter ablation therapies used to treat AF may 
commonly require two or more ablation procedures in order to achieve treatment success 
in a substantial subset of treated patients.6  When you design your study, FDA 
recommends that your study design not define early repeat ablation (e.g., no more than 
two months post-ablation) as a treatment failure.  Conversely, we recommend that you do 
not count any patient who requires more than three ablation procedures as a treatment 
success.  The number of ablation procedures performed on each patient should be 
recorded and reported.  Each repeat ablation should restart the recommended twelve-
month follow-up period.   
Primary Safety Endpoints 
In considering primary safety endpoints, FDA acknowledges that an ablation intervention 
arm and a drug intervention arm may have different safety criteria.   
 
                                                 
ii Experience suggests that technical, clinical, and patient compliance considerations may 
make it difficult to complete a valid determination of change in atrial fibrillation burden 
using external arrhythmia event recorders.  Automatically-triggered, implantable event 
recorders with a high sensitivity and specificity for detection of AF (or similar AF detection 
capabilities incorporated within implantable cardiac pacemakers or implantable cardioverter-
defibrillators) can provide a valid means to evaluate this parameter.2,3  
  6 Contains Nonbinding Recommendations 
Ablation Procedure Safety Endpoint 
For an ablation procedure safety endpoint, FDA recommends for the devices 
addressed in this guidance document, a composite serious adverse event endpoint that 
includes, but need not be limited to, the following:  
  transient ischemic attack 
  cerebrovascular accident 
  major bleeding 
  cardiac tamponade 
  pulmonary vein stenosis 
  pericarditis 
  myocardial infarction 
  diaphragmatic paralysis 
  death. 
 
There may be other safety endpoints specific to a particular device design or energy 
source.  The risk analysis that you perform for your device should provide 
information that will drive the development of these device-specific safety endpoints, 
and you should include them in the study design.  Note that if the ablation procedure 
involves placement of left atrial ablation lesions, FDA recommends assessing 
pulmonary vein stenosis using a baseline imaging evaluation (CT or MRI), with 
assessment at least at, but not limited to, three months and one year for stenosis 
progression.  In addition, FDA recommends yearly imaging for five years for long-
term follow-up, given the current incomplete understanding of the presentation and 
progression of pulmonary vein stenosis.   
 
Composite Serious Adverse Event Endpoint 
For a drug intervention arm, FDA recommends a composite serious adverse event 
endpoint, which includes, but need not be limited to, the following:  
  life-threatening arrhythmia 
  transient ischemic attack 
  cerebrovascular accident 
  anaphylactic reaction 
  pulmonary hypertension (if amiodarone therapy) 
  death. 
 
  7 Contains Nonbinding Recommendations 
For either type of composite safety endpoint (ablation or drug), FDA recommends that 
you incorporate hierarchical or other weighting schemes, as appropriate, for each 
combination of adverse events. 
 
Data Collection Forms 
FDA recommends that sponsors design the case report forms to optimize collection of 
information relevant to the primary safety and efficacy endpoints, minimizing the 
accumulation of data that may be peripheral or irrelevant to the clinical study.  Experience 
has shown that this approach can reduce the total number of data point errors and thereby 
diminish the amount of time and effort needed for the data clean-up process.    
 
Study Groups 
FDA recommends that sponsors design their studies to include patient populations in which 
the proposed therapy is most likely to show benefit.  Study design parameters such as 
inclusion and exclusion criteria and measures of success and failure will likely depend on 
whether the device is intended to treat paroxysmal and/or persistent AF, or permanent AF. 
For paroxysmal or persistent AF, FDA recommends that the study inclusion criteria include 
patients who are highly symptomatic and who have failed treatment with at least one 
antiarrhythmic drug.  Permanent AF patients are less likely to be highly symptomatic but will 
have been in AF for at least six months and failed at least one antiarrhythmic drug.  
 
You should explicitly delineate your inclusion and exclusion criteria.  We recommend that 
you use inclusion and exclusion criteria to precisely define the treated patient population and 
to carefully select a patient population likely to benefit from the proposed therapy.  Evolution 
in device design, procedural methods, and operator experience all may change our 
understanding of which patients are likely to benefit from a proposed procedure completed 
with a specific ablation device.  Examples of inclusion and exclusion criteria that may be 
appropriate for pulmonary vein isolation studies designed to treat paroxysmal AF are listed 
below. 
 
Examples of Inclusion Criteria (Paroxysmal Population) 
 
  Highly symptomatic patients, i.e., >2 discrete atrial fibrillation episodes per 
month for 2 months preceding trial entry and >6 discrete atrial fibrillation 
episodes in the 6-12 months preceding trial entry 
 
  8 Contains Nonbinding Recommendations 
  Absence of structural heart disease as demonstrated by transthoracic 
echocardiogram of all four chambers of the heart 
 
  Failure or intolerance of 1 antiarrhythmic drug 
 
Examples of Exclusion Criteria (Paroxysmal Population) 
 
  Left atrial size 50 mm 
 
  LV ejection fraction <40% 
 
  Current use of amiodarone, or use of amiodarone in the preceding 6 monthsiii 
 
  Known cerebrovascular disease, including history of stroke or transient ischemic 
attack (TIA) 
 
  Previous left heart ablation procedure, either by surgery or by percutaneous 
catheter, for atrial fibrillation 
 
Appropriate inclusion and exclusion criteria for studies involving patients with persistent AF 
might be similar to those suggested above, with the possible exception of the suggested 
frequency of AF recurrence that is specified as an inclusion criterion.  An appropriate 
recurrence rate for patients with frequent persistent AF could be substituted.  
 
Inclusion and exclusion criteria for studies involving patients with permanent AF will also 
likely be similar with the exception of symptoms, left atrial size and, possibly, ejection 
fraction.  You may have additional inclusion and exclusion criteria depending on your study 
design, and your devices indications, design features, and performance characteristics. 
Sample Size 
We recommend that you provide a statistical justification for any sample size calculation.  
FDA recommends that sponsors perform both safety endpoint and effectiveness endpoint 
calculations.  We believe that the safety endpoints will drive sample sizes in the majority of 
cases. 
 
                                                 
iii Because a prolonged time (months) is required to clear amiodarone from cardiac tissue, it 
can be difficult or impossible to effectively withdraw a patient from amiodarone therapy 
within the setting of a clinical study.  Additionally, because of potentially severe side effects 
associated with prolonged amiodarone therapy, we believe it may be inappropriate to define 
arrhythmia suppression achieved by previously effective amiodarone therapy plus ablation as 
a clinical success. 
  9 Contains Nonbinding Recommendations 
Patient Follow Up 
We recommend that you develop standardized monitoring protocols and include outpatient 
follow up visits at, but not limited to, one, three, six and twelve months.  These visits should 
typically include documentation of symptoms and assessment of cardiac rhythm with 12-lead 
electrocardiogram (ECG), Holter monitoring, or other equivalent cardiac rhythm 
measurements.   
 
For any ablation procedures that involve lesions in the left atrium, we recommend that 
imaging studies to assess pulmonary vein stenosis be completed at baseline and at three 
months in all patients.  If an individual patient demonstrates pulmonary vein narrowing at 
three months or has symptoms potentially related to pulmonary vein stenosis (pulmonary 
hypertension) at six or twelve months, we recommend that pulmonary vein imaging studies 
be completed for that patient at six and twelve months.  Your study should specify the extent 
or percentage of narrowing that constitutes stenosis. 
 
The importance of adequate and appropriate follow-up of study subjects cannot be 
overemphasized.  Our experience is that many clinical investigators omit or perform 
incomplete post-procedure testing and evaluations once the procedure has been completed. 
Results obtained from effective follow-up contribute significantly to the review and approval 
process; therefore, the study protocol should be followed as written without omission of post-
procedure testing.  
Blanking Period 
A blanking period is a time interval during which success criteria are not evaluated.  Reports 
in the literature suggest that current left atrial ablation procedures that are used to treat AF 
may not decrease the incidence of AF until four to six weeks following ablation.  You may 
wish to include in the study design a blanking period of at least four weeks during which 
device efficacy by patient monitoring is not assessed as part of the study record.  If a 
blanking period is used, it should restart after any repeat ablation procedure is performed. 
Anticoagulation 
We recommend that you explicitly define and explain post-procedure anticoagulation 
protocols, as currently there is no evidence-based consensus guideline for anticoagulation 
following percutaneous catheter based AF ablation.   
 
  10 Contains Nonbinding Recommendations 
Study Monitoring 
In designing your studies with catheter ablation devices intended for the treatment of AF, we 
recommend that you develop a comprehensive monitoring plan for these studies.  Please note 
that sponsors are required to include written monitoring procedures in applications for 
investigational device exemptions (21 CFR 812.25(e)).  Experience has shown that if sponsors 
make adequate provisions for monitoring studies, quality of the studies and data will follow.  
Therefore, we recommend:  
  selecting qualified monitors 
  ensuring investigator adherence to the investigational plan and other requirements 
  ensuring investigator compliance in regard to recordkeeping and reporting. 
References 
 
1   American College of Cardiology/American Heart Association/European Society of 
Cardiology (ACC/AHA/ESC) Guidelines for the Management of Patients with Atrial 
Fibrillation. J Am Coll Cardiol 2001;38:1266i-lxx. 
2   Chen SA, Hsieh MH, Tai CT, et al.  Initiation of atrial fibrillation by ectopic beats 
originating from the pulmonary veins: Electrophysiological characteristics, 
pharmacological responses, and effects of radiofrequency ablation. Circulation 
1999;100:1879-86. 
3   Robbins IM, Colvin EV, Doyle TP, et al.  Pulmonary vein stenosis after catheter ablation 
of atrial fibrillation. Circulation 1998;98:1769-1775. 
4   Kok LC, Mangrum M, Haines DE, Mounsey P. Cerebrovascular complications 
associated with pulmonary vein ablation. J Cardiovasc Electrophysiol 2002;13:764-767. 
5   Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after 
circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled 
nonrandomized long-term study. J Am Coll Cardiol 2003;42:18597. 
6   Ernst S, Ouyang F, Lober F, et al. Catheter-induced linear lesions in the left atrium in 
patients with atrial fibrillation. J Am Coll Cardiol 2003:42:1271-1282. 
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