Clinical Study Designs for 
Surgical Ablation Devices for 
Treatment of Atrial Fibrillation  
 
Guidance for  
Industry and Food and Drug 
Administration Staff 
 
 
Document issued on: February 15, 2013 
 
The draft of this document was issued on September 14, 2009. 
 
 
For questions regarding this document, contact the Cardiac Electrophysiology Devices 
Branch at 301-796-5631.  
  U.S. Department of Health and Human Services 
  Food and Drug Administration 
Center for Devices and Radiological Health 
 
Cardiac Electrophysiology Devices Branch 
Division of Cardiovascular Devices 
Office of Device Evaluation  Contains Nonbinding Recommendations 
Preface 
 
 
Public Comment 
 
You may submit written comments and suggestions at any time for Agency consideration 
to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, (HFA-305), Rockville, MD, 20852.  Submit electronic comments to 
http://www.regulations.gov.  Identify all comments with the docket number listed in the 
notice of availability that publishes in the Federal Register.  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.  You may also send an e-mail request to 
dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request 
to 301-847-8149 to receive a hard copy.  Please use the document number 1708 to 
identify the guidance you are requesting. 
      Contains Nonbinding Recommendations 
Table of Contents
 
1.  Introduction ................................................................................................................... 1 
2.  Scope ............................................................................................................................. 2 
3.  Terminology .................................................................................................................. 3 
A.  Surgery or Surgical Approach ................................................................................ 4 
B.  Paroxysmal, Persistent, and Longstanding Persistent AF ....................................... 4 
C.  AF as a Rhythm Disturbance versus AF as a Disease ............................................ 5 
4.  Study Design ................................................................................................................. 5 
A.  Randomized Controlled Trials ................................................................................ 5 
B.  Alternative Study Designs ...................................................................................... 6 
Non-Randomized Concurrent Controls.............................................................. 6 
Historical Controls ............................................................................................. 6 
Performance Goals ............................................................................................. 7 
C.  Control Group Considerations ................................................................................ 7 
D.  Ablation Procedure Lesion Sets .............................................................................. 8 
5.  Indications for Use ........................................................................................................ 8 
Other Indications ................................................................................................ 8 
6.  Study Endpoints ............................................................................................................ 9 
A.  Primary Effectiveness Evaluation ........................................................................... 9 
General Recommendations and Considerations................................................. 9 
Longstanding Persistent and Persistent AF: Primary Effectiveness Endpoint 11 
Primary Effectiveness Failure .......................................................................... 11 
B.  Secondary Effectiveness Endpoints ...................................................................... 11 
Atrial Transport Function ................................................................................. 12 
Ventricular Function ........................................................................................ 12 
C.  Primary Safety Evaluation .................................................................................... 12 
Pulmonary Vein Stenosis ................................................................................. 13 
Neurological assessment .................................................................................. 14 
7.  Study Groups .............................................................................................................. 14 
8.  Other Study Design Recommendations ...................................................................... 15 
A.  Anti-Arrhythmic Drug Therapy ....................................................................... 15 
B.  Anticoagulation ................................................................................................ 16 
C.  Non-Inferiority Versus Superiority .................................................................. 16 
Sample Size ...................................................................................................... 16 
D.  Follow-Up of Study Subjects ........................................................................... 16 
E.  Blanking Period ................................................................................................ 17 
F.  Investigator Selection and Training ................................................................. 17 
G.  Study Monitoring ............................................................................................. 18 
 
 
 
 
 
      Contains Nonbinding Recommendations 
 Clinical Study Designs for Surgical Ablation 
Devices for Treatment of Atrial Fibrillation  
 
Guidance for Industry and Food and Drug 
Administration Staff 
 
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. 
1. Introduction 
This guidance provides FDAs recommendations on clinical trial designs for surgical ablation 
devices intended for the treatment of atrial fibrillation (AF).  The recommendations in this 
guidance address clinical studies for new surgical ablation devices intended for treatment of AF, 
as well as for legally marketed surgical ablation devices for which a new indication for treatment 
of AF is sought.  
 
Atrial fibrillation is a complex arrhythmia and its precise mechanisms remain unclear.  Current 
treatments span a spectrum of non-invasive to highly invasive options and include medical and 
surgical variants.  The success of the MAZE procedure1 and its successors has led to the 
development of surgical ablation devices designed to mark cardiac tissue in a manner similar to 
suture lines, thereby disrupting the path of the electrical impulses causing the patients AF.   
 
FDA believes that several important elements of appropriate clinical study design  such as 
inclusion and exclusion criteria and assessment of effectiveness  differ for subjects with 
longstanding persistent AF, persistent AF, and paroxysmal AF (defined in Section 3) as well as 
for stand-alone versus concomitant procedures.  This guidance addresses those differences. 
 
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 
                                                 
1 Cox JL, Schuessler RB, dAgostino Jr HJ et al; The surgical treatment of atrial fibrillation III. Development of a 
definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569-583. 
     
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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. 
2. Scope 
This guidance document addresses clinical study design issues associated with devices intended 
for surgical ablation, under direct visualization, for the treatment for AF as a rhythm disturbance.  
See the Terminology section below for a distinction between AF as a rhythm disturbance 
and AF as a disease.  The scope of this guidance includes: 
Product code OCM - Surgical Cardiac Ablation Device, for Treatment of Atrial Fibrillation, 
Class III 
The scope of this guidance document specifically excludes cardiac ablation devices not intended 
for use under direct visualization, as defined in Section 3.A, and cardiac ablation devices 
delivered intravascularly. 
The following table outlines additional device types that are excluded from the scope of this 
guidance, unless a sponsor seeks to expand the indications of one of the listed devices to include 
treatment of atrial fibrillation, in which case this guidance is applicable to that proposed 
indication.  Although such devices may have a cleared indication of ablation of cardiac tissue, 
FDA notes that these devices may not have been evaluated for treatment of AF as a rhythm 
disturbance. 
Classification  Class  Product  Description 
Regulation  Code 
(21 CFR) 
878.4350  II  GEH  Cryosurgical unit and accessories 
878.4400  II  GEI  Electrosurgical cutting and coagulation 
devices and accessories  
NEY  Microwave ablation system and accessories 
NTB  Ultrasound ablation system and accessories 
OAB  Low energy direct current thermal ablation 
system 
OCL  Surgical device for ablation of cardiac tissue 
878.4810  II  GEX  Powered surgical laser instrument 
none (post- III  LPB  Cardiac ablation percutaneous catheter  
Amendments) 
none (post- III  OAD  Cardiac ablation percutaneous catheter for 
Amendments)  treatment of atrial flutter 
none (post- III  OAE  Percutaneous catheter intended for treatment 
Amendments)  of atrial fibrillation 
 
     
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FDA believes that the devices addressed by this guidance document are significant risk devices 
as defined in Title 21, Code of Federal Regulations (CFR) 812.3(m); for additional information, 
please refer to the Medical Device section of the Information Sheet Guidance for IRBs, Clinical 
Investigators, and Sponsors, which is available at 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformatio
nSheetsandNotices/ucm113709.htm#risk.  In addition to complying with the regulations 
governing institutional review boards (IRBs) (21 CFR part 56) and informed consent (21 CFR 
part 50), sponsors of such studies must obtain FDA and IRB approval of their application for an 
Investigational Device Exemption (IDE) before they may begin any study on an investigational 
device (see section 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 
360j(g); 21 CFR 812.42).   
3. Terminology 
The following terms are defined as described for the purposes of this guidance document. 
Term  Definitions 
Failed electrical cardioversion  An electrical cardioversion is considered a failure 
if it is not able to restore sinus rhythm for 30 
seconds or longer. 
Paroxysmal AF  Recurrent AF (2 episodes) that terminates 
spontaneously within seven days. Episodes of AF 
of  48 hours duration that are terminated with 
electrical or pharmacologic cardioversion should 
also be classified as paroxysmal AF episodes. 
Persistent AF  AF which is sustained beyond seven days but no 
more than one year. Episodes of continuous AF in 
which a decision is made to electrically or 
pharmacologically cardiovert the patient after 
more than 48 hours, but prior to 7 days, should 
also be classified as persistent AF episodes. 
Longstanding Persistent AF  Continuous AF of greater than one-year duration. 
Permanent AF  The term permanent AF is not appropriate in the 
context of patients undergoing catheter or surgical 
ablation of AF, as it refers to a group of patients in 
continuous AF for which a decision has been made 
not to pursue restoration of sinus rhythm by any 
means. 
     
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Lone AF   AF in young individuals (under 60 years of age) 
without clinical or echocardiographic evidence of 
cardiopulmonary disease, including hypertension. 
Continuous AF  Uninterrupted AF presented on all ECG 
monitoring performed during a defined period of 
time. 
 
A.  Surgery or Surgical Approach 
We define surgery or the surgical approach as a clinical procedure carried out under direct 
visualization. This means that the clinician is able to see, either directly or by means of live 
video, the point or area of epicardial and/or endocardial contact between the ablating device 
and the cardiac tissue for all or some of the lesions.  For example, included in this definition 
is open-chest surgery and minimally invasive surgery via thoracoscopy, as long as the 
clinician performs the majority of the ablation lesions under direct visualization.  Specifically 
excluded from this definition are clinical procedures that are performed principally under 
indirect visualization, such as cardiac catheterization, or percutaneous approaches to the 
epicardium via pericardial access carried out under fluoroscopic or echocardiographic 
guidance. The guidance document entitled Clinical Study Designs for Percutaneous Catheter 
Ablation for Treatment of Atrial Fibrillation, which is available at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m072590.htm, addresses study design for catheter ablation as a therapy for AF. 
B.  Paroxysmal, Persistent, and Longstanding Persistent AF 
The table above defines paroxysmal AF, persistent AF, longstanding persistent AF, 
and permanent AF as used in this guidance.  These terms are adopted from the 2012 
HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial 
Fibrillation2 with minimum modifications for the purposes of this guidance document.  It is 
recognized that subjects may have paroxysmal and persistent AF.  A patients AF type 
should be defined as the most frequent type of AF experienced within six months of an 
ablation procedure. 
Paroxysmal AF is by nature episodic and can occur in clusters with temporal gaps between 
recurrences.  This makes the evaluation of therapy effectiveness for paroxysmal AF more 
difficult than for persistent and longstanding persistent AF.  FDA believes that in addition to 
the above definition for longstanding persistent AF, subjects who have failed electrical 
cardioversion may also be considered to have longstanding persistent AF depending on the 
definition used for failed electrical cardioversion.  
                                                 
2 Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and 
Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient 
Management and Follow-up, Definitions, Endpoints, and Research Trial Design. Heart Rhythm 2012;9(4):632-696. 
     
  4  Contains Nonbinding Recommendations 
C.  AF as a Rhythm Disturbance versus AF as a Disease 
AF as a rhythm disturbance should be distinguished from AF as a disease.  AF as a rhythm 
disturbance refers solely to the presence of AF as diagnosed with appropriate 
electrocardiographic techniques.  AF as a disease additionally refers to the functional 
impairments (e.g., congestive heart failure and thromboembolic stroke) caused by an AF 
rhythm.  We refer to elimination of AF as an outcome of treating AF as a rhythm 
disturbance, and cure of AF as an outcome of treating AF as a disease.  We note that the 
recommendations in this guidance only apply to those devices seeking an indication of 
treating AF as a rhythm disturbance but not those for cure of AF as a disease. 
4. Study Design 
FDA recognizes that there is no unique best design for clinical investigations of devices.  
However, the elements discussed in this document embody FDAs current thinking regarding 
appropriate study designs for these devices.  The design, execution, and analysis of any clinical 
trial of a device should be appropriate to develop valid scientific evidence to substantiate the 
safety and effectiveness of the device for its intended use and patient population.  (See 21 CFR 
860.7.) 
A.  Randomized Controlled Trials 
FDA believes that, in general, randomized controlled trials (RCTs) provide the least 
burdensome means of developing valid scientific evidence for surgical ablation devices 
intended for the treatment of AF.  Potential advantages to RCT designs extend to evaluation 
of both device effectiveness and device safety.  Randomization also provides a sound basis 
for statistical inference. 
 
Assurance that subject populations are similar in test and control groups is best attained by 
randomly dividing a single sample population into groups that receive the test treatment (i.e., 
ablation using the study device) or control treatment (i.e., no ablation or ablation using an 
approved device for the indications being sought).  This technique avoids systematic 
differences between groups with respect to known or unknown baseline variables that could 
affect safety and/or effectiveness outcomes.  Variables that may affect the safety profile 
(adverse event rates) and/or effectiveness profile include patient characteristics, concomitant 
cardiopulmonary disease, pre-operative AF duration, left atrial size, ejection fraction, 
concomitant medications, device design, concomitant cardiac surgery, evolving procedural 
methods, and operator experience.  Inability to eliminate systematic differences between 
treatment groups is a major problem of studies without a concurrent randomized control.  
 
Based on these considerations, FDA recommends that the first choice to be considered in 
designing a study should be a RCT, where the control arm consists of treatment with an 
approved device or therapy for the indications that are being sought.  
 
If you conduct a RCT, we recommend that you select an appropriate control therapy or 
control group.  Whether a particular control is appropriate depends on: 
     
  5  Contains Nonbinding Recommendations 
 
  the specific indication for use under study;  
  the intended target patient population;  
  the availability of an approved device for the indications being sought; 
  the device design;  
  an assessment of potential confounding factors; and 
  any concomitant cardiac surgeries.  
 
B.  Alternative Study Designs 
Although we generally recommend RCTs, we will consider alternative study designs that are 
scientifically sound and adequate to answer relevant safety and effectiveness questions.  To 
the extent that your alternative study design departs from the RCT design, we recommend 
you employ rigorous methodology designed to reduce potential sources of bias and other 
confounders.  We also recommend that you thoroughly explain the scientific rationale 
supporting the design in your IDE submission.  We note that if FDA finds that there is reason 
to believe that the risks to the subjects are not outweighed by the anticipated benefits to the 
subjects and the importance of the knowledge to be gained, FDA may disapprove an IDE 
application.  (See 21 CFR 812.30(b)(4).)    
Non-Randomized Concurrent Controls 
A non-randomized concurrent control design is one alternative to a RCT.  Such a study 
would compare data from subjects receiving ablation treatment from the investigational 
device to data from subjects either receiving no ablation treatment or receiving an 
alternative treatment.  (See 21 CFR 860.7(f)(1)(iv)(a), (c).)  However, the comparability of 
the treatment and control groups may be reduced because the benefits of randomization are 
eliminated in such a study.  Potential limitations on comparability include differences in 
patient care across investigational sites and factors that may introduce selection bias such 
as concomitant underlying disease and differences in AF disease.  Thus, non-randomized 
studies should include rigorous steps to closely match subjects in the control group with 
subjects in the treatment group.  Either covariate analysis or propensity score analysis can 
enhance the comparability of the treatment and control arms in such a study.  We 
recommend that you prospectively describe in detail any methods of analysis in your 
clinical protocol. 
Historical Controls 
FDA will consider a study design implementing an historical control that compares data 
from a group of subjects receiving the test treatment with historical data from a group of 
comparable subjects external to the study who received no ablation treatment, but who 
followed an established effective regimen at an earlier time, or who received ablation from 
a device already approved for the indications being sought.  (See 21 CFR 
860.7(f)(1)(iv)(d).)  FDA believes that if an historical control is employed, a thorough 
analysis of the relevant medical literature should be provided in support of your historical 
control choice.  We recognize that, due to the heterogeneity of disease presentation and 
treatment in the target AF patient population and the variety of ablation, drug, and other 
     
  6  Contains Nonbinding Recommendations 
therapies that may be used for treatment of AF, the use of an historical control may 
complicate the collection and analysis of appropriate medical literature.  Whenever 
possible, FDA recommends you use a control cohort for which patient-level data are 
available. 
 
Performance Goals 
If a RCT or a nonrandomized concurrent control design is not possible and if patient-level 
data are not available, FDA recommends that you propose a performance goal supported by 
a thorough analysis of the relevant medical literature. We anticipate significant challenges 
in arriving at an appropriate performance goal due to heterogeneity across published 
studies and rapid progress in the field of AF management. 
C.  Control Group Considerations 
If your study utilizes a randomized or non-randomized concurrent control arm, appropriate 
potential concurrent control therapies may include: 
  ablation therapy with one or more medical devices approved for the indications that are 
being sought; 
  best medical therapy with antiarrhythmic drugs with or without electrical cardioversion. 
Regardless of the concurrent control arm selected, several strategies may be appropriate to 
facilitate subject recruitment.  Appropriate strategies may include use of 2:1 or other 
randomization allocation ratios, and selection of a control arm with therapy by best medical 
management instead of no therapy. 
If you elect to use best medical therapy with antiarrhythmic drugs as the control therapy for 
evaluation of effectiveness, FDA recognizes that drug regimens are tailored to individual 
circumstances and that no unique optimal regimen exists.  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.  
If your study design includes an historical control, we recommend you choose a control 
cohort with characteristics that will maximize the likelihood that your study outcomes will be 
interpretable, such as: 
  patient level data is available for control group 
  ablation lesion set for control group is known 
  duration, method, and rigor of follow-up in study subjects is known 
  surgical approach in control group is equivalent to that in study subjects 
  AF disease and underlying heart disease in control group and study subjects is similar 
  concomitant cardiac surgeries in control group and study subjects are the same. 
     
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D.  Ablation Procedure Lesion Sets 
We recognize that there may not be one set of ablation lesions or ablation lines that are 
generally accepted as being the most effective in treating AF.  You should provide a valid 
justification for your lesion set if it deviates significantly from those widely accepted in the 
field.  Also, we recommend that, to the extent possible, all enrolled subjects have the same 
set of ablation lesions performed.  Any deviations from the protocol-specified lesion set 
should be clearly documented in the case report forms.  In order to maximize consistency in 
terms of lesion sets, we recommend that the protocol include clear instructions regarding a 
pre-specified lesion set and the recommended device used to create each lesion.  Failure to 
adhere to the pre-specified lesion set could make the data difficult to interpret.  
AF ablation performed concomitantly with another surgical procedure has a different 
benefit/risk profile than surgery done solely for the purpose of performing AF ablation.  
When surgical AF ablation is an adjunctive procedure in a patient already indicated for 
cardiac surgery, the additional risk posed by the ablation procedure may be small compared 
to the risks of the primary surgical procedure.  When the sole purpose of the surgery is to 
perform AF ablation, FDA intends to weigh the risk of the surgery and ablation procedure 
against the sole possible benefit of treatment of AF.  In an IDE application for a trial where 
the only purpose of the surgical procedure is ablation for treatment of AF, you should 
provide a sound scientific rationale to support your hypothesis that the benefits of AF 
ablation outweigh the risks of the surgical procedure.  (See 21 CFR 812.30(b)(4).)  In this 
situation, the careful selection of the control population is particularly important to FDAs 
evaluation of your trial design and the study results. 
5. Indications for Use 
We recommend that your study design reflect the proposed intended use and indications for use 
of your ablation device.  We believe that your proposed indications for use should identify 
factors that may affect the benefit/risk profile of your device, such as the type of AF treated, the 
surgical approach used, any concomitant procedures, and relevant patient characteristics. 
Specific aspects of the study design often limit the indications for use of a device upon approval.  
For example: 
  
  if your study includes only subjects with longstanding persistent AF, the corresponding 
indications for use may be limited to the treatment of longstanding persistent AF;   
  if your study design pertains only to ablation concomitant with mitral valve replacement or 
repair surgery, approval of your device may be limited to that specific indication; and  
  if the only surgical procedure used in your study employs a minimally invasive surgical 
approach, your indications may be limited accordingly. 
Other Indications 
Surgical ablation devices have a range of potential indications beyond treatment of AF as a 
rhythm disturbance.  These other indications include improvement in atrial transport 
function, improved ventricular function, reduced risk of stroke, reduced risk of heart failure 
and improved survival.  However, FDA is not aware of any conclusive clinical evidence from 
     
  8  Contains Nonbinding Recommendations 
large randomized clinical trials that surgical AF ablation results in any of these patient 
benefits.  Therefore, FDA does not consider elimination of AF to be an appropriate surrogate 
indicator for these benefits.  As a result, we recommend that clinical studies directly measure 
and support any indications beyond treatment of AF as a rhythm disturbance.  For example, a 
study that demonstrates restoration of atrial contraction, in addition to effective termination 
of AF, may support indications that include improved atrial transport function.  Similarly, a 
study that demonstrates increased left ventricular ejection fraction and improvement in 
ventricular dimensions may support an indication for restoration or maintenance of 
ventricular function.  If you would like to include a labeling claim regarding any of these 
other endpoints, the claim should be based on pre-specified statistical hypotheses.  
Additionally, if you aim to make claims regarding quality of life (QOL) or other subjective 
outcomes, the trial design should account for placebo effect.  While the FDA suggests that 
you test clinically relevant secondary endpoints (e.g., improvement in QOL, exercise 
tolerance), please keep in mind that the claims allowed in the labeling may be limited by 
aspects of the study design (e.g., claims based on subjective endpoints will be problematic in 
an unblinded trial).  
 
Indications that include reduction in the risk of stroke should be supported by a study 
designed to evaluate the risk of stroke either while continuing or following termination of 
anticoagulation therapy. 
 
In summary, you should formulate the indications for use for which you plan to seek 
approval in concert with clinical trial hypotheses that will support the proposed indications 
for use. 
 
6. Study Endpoints 
Clinical studies involving subjects with paroxysmal AF and studies involving subjects with 
persistent forms of AF are likely to be different in terms of procedural complexity as well as ease 
of follow-up.  Clinical studies involving these subjects may also differ in terms of appropriate 
effectiveness endpoints and in terms of appropriate inclusion and exclusion criteria.  Where 
appropriate, the recommendations in this guidance address studies on treatment of paroxysmal 
AF, persistent AF, and longstanding persistent AF separately. 
A.  Primary Effectiveness Evaluation  
General Recommendations and Considerations 
We recommend that you demonstrate that the benefit to subjects from the therapy is both 
clinically meaningful and statistically significant relative to the increased risk associated with 
the use of the ablative device.  We generally recommend you evaluate the primary 
effectiveness in the absence of antiarrhythmic drug (AAD) therapy.  However, an outcome 
evaluated in the presence of an antiarrhythmic drug that was not effective in treating AF prior 
to study enrollment may serve as a primary or secondary effectiveness endpoint.  In either 
case, you should justify your choice of effectiveness endpoint.   
     
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For the primary effectiveness endpoint, FDA recommends you evaluate freedom from AF 
through the minimum follow-up period recommended by relevant medical society guidelines, 
which currently is 12 months.2  We believe that the primary effectiveness endpoint for a 
rhythm disturbance is AF elimination (without iatrogenic arrhythmias) and not necessarily 
the resumption of normal sinus rhythm. Freedom from AF should be defined as freedom 
from AF/atrial flutter (AFL)/atrial tachycardia (AT) episodes of 30 sec duration or longer on 
Holter or event recorder or for the full recording time on a standard 12-lead ECG and in the 
absence of Class I or III AADs.   
FDA believes that reduction in AF burden is not an optimal primary effectiveness endpoint 
due to the absence of justification for an AF burden threshold that would be considered 
clinically significant and the technical challenges in precisely measuring AF burden without 
an implanted device. On the other hand, FDA recognizes that AF burden assessed at various 
points in time during follow-up may provide supplementary information concerning device 
effectiveness. 
Arrhythmia monitoring plays an important role in the assessment of device effectiveness.  
Generally, we recommend periodic Holter monitoring as the preferred modality for assessing 
effectiveness, although other modalities, such as standard 12-lead ECG, trans-telephonic 
recordings, loop recorders, and event recorders may be adequate.  FDA recommends an event 
recorder be made available following the ablation procedure for scheduled and symptom-
driven recordings to capture symptomatic and asymptomatic atrial tachyarrhythmia 
recurrences.  We believe that less direct evaluation modalities, such as reduction in perceived 
symptoms, are not able to demonstrate primary effectiveness due to the subjective nature of 
such modalities and the potential for placebo effect.  Our recommendations for minimum 
arrhythmia monitoring in the follow-up after a surgical ablation procedure are included in 
section 8E of this guidance.  
FDA believes that although single procedure success might not be the basis for the primary 
effectiveness endpoint, it should be reported in surgical AF ablation studies.  
 
We also recommend that you explain the means by which your study design minimizes 
confounding factors, such as the placebo effect.   
Acute Procedural Success 
Your assessment of effectiveness of the device should include a measure of acute procedural 
success.  We believe that a measure of acute procedural success includes completion of the 
protocol-defined ablation lesion set and achievement of conduction block across ablation 
lesions (e.g., PV entrance and/or exit block if PV encircling lesions are created, entrance 
and/or exit block from posterior LA segment if box lesion is used).  Although we do not 
believe acute procedural success is a surrogate for the recommended primary effectiveness 
endpoint, the relationship between acute procedural success and primary effectiveness 
success should be reported and explored because it may provide important data for device 
labeling. 
 
     
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Longstanding Persistent and Persistent AF: Primary Effectiveness Endpoint 
We generally recommend separate studies for different types of AF.  However, if the sponsor 
decides to study persistent and longstanding persistent AF together, the sponsor should 
provide a clinically and scientifically valid justification for this approach.  Additionally, the 
sponsor should pre-specify the minimum proportion of subjects to be enrolled as 
representative of each type of AF studied. 
For both persistent and longstanding persistent AF, FDA recommends freedom from 
AF/AFL/AT for one year in the absence of Class I or III AADs as the primary effectiveness 
endpoint.  The recommendations for minimum ECG monitoring during follow-up for 
persistent and longstanding persistent AF subjects are included in section 8E of this 
guidance.  
Paroxysmal AF: Primary Effectiveness Endpoint 
For paroxysmal AF, FDA recommends freedom from AF/AFL/AT for one year in the 
absence of Class I or III AADs as the primary effectiveness endpoint.  We believe this 
follow-up period minimizes the confounding effects of a clustered, non-random AF 
recurrence pattern.  Please refer to section 8E for the FDA recommendations for minimum 
ECG monitoring during follow-up for paroxysmal AF subjects. 
Primary Effectiveness Failure  
To facilitate determination of primary effectiveness, the FDA recommends that you pre-
specify scenarios that are indicative of primary effectiveness failure.  FDA believes the 
following are examples of scenarios indicative of primary effectiveness failure:  
  Any electrocardiographically documented AF/AFL/AT episode of 30 sec duration or 
longer by Holter, event monitor or rhythm strip; or for the full 10 second recording of a 
standard 12-lead ECG, following any blanking period through the final follow-up visit; 
  The use of Class I or III AADs (or an increased dose of a previously ineffective AAD if 
the sponsor only wants to claim benefit in the presence of a previously ineffective drug) 
following any blanking period through the final follow-up visit; 
  DC cardioversion for AF/AFL/AT following any blanking period through the 12 months 
follow-up visit; 
  Subsequent catheter ablation or surgical treatment for AF/AFL/AT following any 
blanking period through the final follow-up visit; 
  Other scenarios indicative of treatment failure suggested by relevant medical societies. 
B.  Secondary Effectiveness Endpoints 
Depending on the design of the device and its indications for use, appropriate secondary 
effectiveness endpoints may include: 
  AF burden reduction 
  improvement in symptom scores tracking dyspnea, dizziness, or palpitation 
  improvement in QOL  
     
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  improvement in exercise tolerance 
  improvement in ventricular ejection fraction 
  improvement in atrial transport function 
  atrial remodeling, assessed by decrease in atrial size. 
If you intend to present comparisons between groups for a secondary effectiveness endpoint 
in your labeling, your protocol should include a pre-specified hypothesis for each and an 
adjustment for multiplicity, as appropriate.  Your sample size estimation should take these 
secondary endpoint hypotheses into account.  For secondary endpoints subject to placebo 
effect, including exercise tolerance, QOL, and symptom scores, we recommend that you 
design your study to minimize the placebo effect. 
Atrial Transport Function 
Assessment of the return of atrial transport function following AF ablation has been 
reported in the literature, and restoration of atrial transport function has been cited as a 
benefit of the surgical MAZE procedure3 as well as surgical ablation for isolation of the 
pulmonary veins for treatment of AF.4  To date, however, clinical trials have focused 
almost exclusively on elimination of AF as a rhythm disturbance.  FDA believes that 
recovery of atrial transport function may have a positive impact on QOL and on reduction 
of the morbidities associated with AF such as stroke and heart failure.  If you intend to 
assess atrial transport function as part of the study, you should consider coupling this 
assessment with evaluation of morbidity reduction and improvement in QOL.  For 
example, see the scoring method for evaluating and reporting the restoration of atrial 
transport function proposed by Melo et al.5   
Ventricular Function 
Termination of the AF rhythm disturbance and the associated erratic and elevated 
ventricular rates may result in improvement in ventricular function.  If you plan to assess 
ventricular function, your study design should include some means for evaluating 
ventricular function and ventricular dimensions, both pre- and post-procedure.  This may 
include echocardiographic or other imaging evaluations of ventricular dimensions and 
ejection fraction coincident with assessment of rhythm state at the effectiveness evaluation. 
C.  Primary Safety Evaluation 
For primary safety evaluation, FDA recommends a composite safety endpoint consisting of 
serious adverse events including, but not limited to:  
                                                 
3 Yuda S, Nakatani S, Kosakai Y, et al. Long-term follow-up of atrial contraction after the maze procedure in 
patients with mitral valve disease. J Am Coll Cardiol 2001;37(6):1622-7. 
4 Thomas L, Boyd A, Thomas SP, et al. Atrial structural remodeling and restoration of atrial contraction after linear 
ablation for atrial fibrillation. Eur Heart J 2003;24(21):1942-51. 
5 Melo JQ, Neves J, Adragao P et al. When and how to report results of surgery on atrial fibrillation. Eur J 
Cardiothorac Surg. 1997;12(5):739-44. 
     
  12  Contains Nonbinding Recommendations 
  all-cause death 
  stroke and transient ischemic attack (TIA) 
  myocardial infarction (MI) 
  thromboembolic events (pulmonary embolism and peripheral embolism) 
  excessive bleeding 
  deep sternal wound infection/mediastinitis 
  damage to the specialized conduction system requiring permanent pacemaker 
  damage to peripheral structures, such as the esophagus and phrenic nerve 
  pulmonary vein (PV) stenosis. 
  
Depending on the specifics of the surgical approach and the device/safety, there may be other 
appropriate serious adverse events to include.  
In terms of safety and evaluation of adverse events, the investigational plan must include a 
description and analysis of all increased risks to which subjects will be exposed by the 
investigation.  (See 21 CFR 812.25(c).)  The sponsor must immediately conduct an 
evaluation of any unanticipated adverse device effect (UADE) (21 CFR 812.46(b)), and 
ensure that any reviewing IRB and FDA are promptly informed of significant new 
information about an investigation (21 CFR 812.40).  If the sponsor determines that a UADE 
presents an unreasonable risk to subjects, the sponsor must terminate all investigations 
presenting such risk as soon as possible, and not later than five working days after the 
sponsor makes this determination and not later than 15 working days after the sponsor first 
received notice of the UADE (21 CFR 812.46(b)(2)).     
FDA believes that a one year follow-up for safety evaluation provides sufficient time to 
evaluate adverse events such as PV stenosis that may be manifested or progressive only at 
late time points in some subjects.  A shorter follow-up period, e.g., less than one year, may 
be appropriate if using your device under direct visualization does not pose a risk of PV 
stenosis.  If you believe this is the case, you should provide a sound rationale for follow-up 
duration of less than one year. 
Pulmonary Vein Stenosis 
When PV stenosis is identified as a risk associated with your device, we recommend that 
you evaluate PV stenosis using a baseline imaging study (CT or MRI), followed by an 
assessment using the same method within 3 to 6 months of the ablation procedure to screen 
for PV stenosis.  If subjects show evidence of PV stenosis, we recommend additional 
follow-up imaging at twelve months post-procedure to evaluate stenosis progression. 
Consistent with the recommendation from the 2012 HRS/EHRA/ECAS Expert Consensus 
Statement in Surgical and Catheter Ablation of AF,2 FDA recommends that PV stenosis be 
categorized as mild < 50%, moderate 50-70% and severe  70% reduction in the diameter 
of a PV or PV branch; a severe PV stenosis should be considered a major complication and 
thus contribute to the primary safety endpoint.  We also recommend that an independent, 
masked observer in a central core laboratory perform all evaluations of the imaging studies 
done to evaluate PV stenosis. 
     
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Case report forms should include a means for determining whether subjects are 
experiencing symptoms suggestive of PV stenosis. 
We believe subjects in a control arm who are not undergoing ablation are unlikely to 
experience PV stenosis and therefore need not be evaluated by imaging.  A study using a 
surgical ablation procedure that involves direct visualization of the ablation device when 
used in the vicinity of the pulmonary veins need not include assessment of PV stenosis.  If 
you determine that the risk of PV stenosis is minimal and therefore reason that PV 
assessment is not warranted in your study, we recommend that you describe how you made 
this determination and provide a scientific rationale in support of your reasoning.  
Neurological assessment 
Available literature suggests that clinically evident neurological injury as well as 
asymptomatic cerebral embolism may occur in ablation subjects periprocedurally. The 
pathophysiology and clinical significance of asymptomatic cerebral emboli remain unclear, 
but there may be some emboli that are not completely asymptomatic and thus are more 
appropriately categorized as stroke or TIA when adequately investigated.  Therefore, 
subjects undergoing surgical ablation should undergo standardized neurological evaluation 
before and after the ablation procedure.  Moreover, the agency recommends that at least a 
subset of study subjects undergo more specialized neurologic evaluations.  The following 
points should be considered when designing the neurological assessment for the subset of 
patients: 
 
    The number (percentage) of patients in the subset should depend on the type of device, 
the type of trial, and existing pre-clinical and clinical data; 
    The neurological assessments should occur at baseline, prior to discharge, 1 month post 
procedure, and after any neurological event; 
    Clinical tests should include a standardized complete neurological physical 
examination.  Standarized scales for assessment of neurologic deficit (such as the NIH 
Stroke Scale (NIHSS)) and of stroke disability (such as the Modified Rankin Score 
(MRS)) should be considered for those diagnosed with neurological events at the time 
of the event and at 90 days post-event.  Cognitive testing should be considered when 
assessment of global neurologic function is appropriate; 
    The neurological physical examination should be performed by a neurologist.   
Personnel performing other tests should be certified (external certification for NIHSS, 
either internal or external certification for MRS).  The assessors should be independent 
from the study; 
    The use of specialized neuroimaging techniques should be considered when a goal is 
detection of asymptomatic vascular injury; 
7. Study Groups 
FDA recommends that your study include patient populations in which the proposed therapy is 
most likely to show benefit.  Selection of study subjects should carefully balance inclusion of 
subjects with characteristics needed to support a broad indication with exclusion of subjects to 
control for potential confounding factors.  We recommend that your protocol list inclusion and 
     
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exclusion criteria to define precisely the patient population likely to benefit from the proposed 
therapy.  Additionally, your study design should account for prior complications and previous 
treatments of AF.  
The selected inclusion and exclusion criteria should ensure that subjects have a type of AF (i.e., 
paroxysmal, persistent, or longstanding persistent) that is consistent with the devices proposed 
indication for use.  For all types of AF we expect the subjects to have a documented history of 
AF-associated symptoms.  Moreover, we recommend that your protocol specify the minimum 
AF documentation requirement for the type(s) of AF you intend to study.  In this regard, we 
believe you should follow the relevant recommendations from the 2012 HRS/EHRA/ECAS 
Expert Consensus Statement in Surgical and Catheter Ablation of AF.2 
Consistent with ACC/AHA/ESC 2006 Guidelines for the Management of Patients with AF6 and 
HRS/EHRA/ECAS Expert Consensus Statement,2 we recommend that AF ablation trials 
primarily include subjects who have failed or are intolerant to at least one Vaughan-Williams7 
class I or class III AAD.  Depending on the study design, it may also be possible to include 
subjects who have failed only rate control medical therapy.  We also believe that for the purpose 
of interpreting study results, subjects with confounding characteristics should be excluded from 
your study.  For example, subjects with a previous left atrial ablation procedure should be 
excluded from your study, unless that patient population is consistent with the indications you 
are seeking. 
8. Other Study Design Recommendations 
A.  Anti-Arrhythmic Drug Therapy 
We recommend that you evaluate the long-term effectiveness of the ablation procedure in the 
absence of AAD therapy.  That is, if you reinitiate AAD therapy after the procedure, all study 
subjects that receive ablation treatment should discontinue AAD use prior to the end of any 
blanking period.  Alternatively, either as a primary or secondary effectiveness endpoint, it 
may be appropriate to evaluate the effectiveness of ablative therapy in the presence of a 
previously ineffective AAD therapy, as explained above.  FDA considers AAD therapy to 
include primarily Vaughan-Williams7 Class I and Class III agents but not to include rate 
control medical therapy.  FDA does not consider rate control medical therapy to be likely to 
affect AF recurrence and it would be appropriate to continue to administer these agents to 
study subjects consistent with widely accepted medical practice. 
                                                 
6 Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with 
Atrial Fibrillation. Circulation 2006;114:e257-e354.   
7 Vaughan Williams EM. Classification of anti-arrhythmic drugs. Symposium on Cardiac Arrhythmias. 1970;449-
472. 
     
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B.  Anticoagulation 
We recommend that you describe in detail your post-procedure anticoagulation protocols.  
You may elect to design your study with a pre-specified period that requires anticoagulation 
following the ablation procedure.  Beyond such a defined period of required anticoagulation, 
we recommend that your protocol follow the published practice ACC/AHA/ESC 2006 
Guidelines for managing patients with AF.  These guidelines advise treatment with 
anticoagulation therapy according to the patients stroke risk rather than according to the 
presence or type of AF, as advised by the HRS/EHRA/ECAS Expert Consensus Statement.2 
The protocol should clearly specify appropriate monitoring and documentation of 
anticoagulation status during the follow-up phase. 
C.  Non-Inferiority Versus Superiority 
If the control group consists of subjects treated with a legally marketed surgical ablation 
device, the study may be designed to demonstrate non-inferiority or superiority.  If your 
study hypothesis is intended to test non-inferiority, we recommend you provide an 
appropriate clinical justification for the non-inferiority margin that you choose.  If your study 
hypothesis is intended to test superiority, we recommend you demonstrate a statistically 
meaningful benefit/risk profile showing improved benefit, reduced risk, or both.  For non-
inferiority studies, in addition to the non-inferiority margins used to test your study 
hypotheses, we recommend you establish a minimum acceptable performance floor to 
prevent the potential non-inferiority creep after several iterations of trials. 
Sample Size 
We recommend that you provide a statistical justification for any sample size calculation.  
FDA recommends that you take into account all endpoints, primary and secondary, when 
calculating the sample size, especially in the circumstance where you intend to present 
comparisons between groups in your labeling for any secondary effectiveness endpoints.  
This will help to provide statistical robustness for your study endpoints.   We believe that, 
due to low event rates, the primary safety endpoint will likely drive the sample size in most 
studies. 
D.  Follow-Up of Study Subjects 
We recommend that you develop standardized protocols for outpatient follow-up visits to be 
conducted at 30 days, three months, six months, nine months, and twelve months regardless 
of the AF type being studied (i.e. paroxysmal, persistent, or longstanding persistent AF).  
Follow-up visits should typically include documentation of symptoms and assessment of 
cardiac rhythm with 12-lead ECG, Holter monitoring, or other equivalent cardiac rhythm 
measurements.  For paroxysmal AF indications, the minimum following-up screening for 
atrial tachyarrhythmia recurrences should include a 12-lead ECG at each follow-up visit, 
scheduled and symptom-driven event recording from the end of the blanking period to the 
end of follow-up, and a Holter at the end of the follow-up period. For persistent and 
longstanding persistent AF indications, the minimum follow-up screening should include a 
     
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12-lead ECG at each follow-up visit, a Holter every 6 months, and symptom-driven even 
monitoring. For evaluation of PV stenosis, the follow-up visits should include CT or MR 
imaging, as appropriate. 
In addition to the premarket follow-up considerations discussed above, extended, long-term 
post-approval studies may be appropriate for class III (premarket approval) devices to assess 
the stability of the treatment effect and any specific long-term safety and effectiveness 
concerns that arise during the premarket study.  For devices for which post-approval studies 
are anticipated or a possibility, we recommend your study continue to follow subjects every 
six months beyond marketing approval.  In the event that FDA requires a post-approval study 
as a condition of the PMA approval (see 21 CFR 814.82(a)(2)), incorporating this extended 
follow-up in the original pivotal study will allow you to easily convert the premarket study 
into a post-approval study.  This may free you from having to obtain new informed consent 
from study subjects for additional follow-up and having to recruit new subjects.  In such an 
approach, you would obtain subject consent for up to five years of follow-up, but specify a 
one-year follow-up time period for purposes of gathering premarket safety and effectiveness 
data.  Upon approval of your device, subjects who were treated with your device during the 
clinical investigation could be followed for a total of up to five years post-ablation as part of 
a post-market study without the need to seek a new informed consent for the additional 
follow-up period. 
The importance of adequate and appropriate follow-up of study subjects cannot be 
overemphasized.  Complete results obtained from effective follow-up contribute significantly 
to our ability to evaluate your marketing application; therefore, we recommend you make 
every effort to ensure that subjects participate in all scheduled post-procedure testing 
specified in your study protocol.  Since missing data may be an issue at the time of data 
analysis, FDA recommends that the investigational protocol pre-specify one or more methods 
for handling missing data. 
E.  Blanking Period 
A blanking period is a time interval following treatment during which success criteria are not 
counted for purposes of evaluating study endpoints.  Since cardio-thoracic surgery in and of 
itself can provoke transient episodes of AF, and it is believed that these early recurrences are 
not indicative of longer-term success, we recommend that you employ a blanking period of 
three months during which the effectiveness of the device is not evaluated by arrhythmia 
monitoring.  During the blanking period, you should monitor subjects for AF recurrence and 
you should record and document any AF events, but you should not consider recurrence of 
AF during this period as treatment failures.   
F.  Investigator Selection and Training 
Sponsors must select investigators who are qualified by training and experience to investigate 
the device that is the subject of the study (21 CFR 812.43(a)).  If the primary investigator 
does not have experience with electrophysiological techniques, we recommend that an 
investigator who has such expertise participate in the investigational procedure to assist with 
     
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verification of conduction block.  If an investigator or other site staff lack a thorough 
knowledge of the clinical procedures used in your study, we recommend that you provide 
training on the procedures.  It may be appropriate to include a small number of subjects per 
site that will not be included in the endpoint evaluation (sometimes termed roll-in subjects) 
in order to avoid a learning curve bias.  The inclusion of a subject as a roll-in subject 
should be specified prior to treating the subject and prior to subject randomization (if 
applicable). 
G.  Study Monitoring 
Sponsors must ensure proper monitoring of the investigation (21 CFR 812.40), and the 
investigational plan must include the sponsors written procedures for monitoring the 
investigation and the name and address of any monitor.  (See 21 CFR 812.25(e).)  We 
recommend that you select experienced monitors and ensure that investigators adhere to the 
investigational plan.  A sponsor who discovers that an investigator is not complying with the 
investigational plan must promptly either secure compliance or discontinue shipments of the 
device to the investigator and terminate the investigator's participation in the investigation 
(21 CFR 812.46(a)).  We recommend you establish an independent Clinical Events 
Committee comprised of practicing physician of appropriate expertise to adjudicate reported 
adverse events.  In addition, please see the FDAs guidance entitled Oversight of Clinical 
Investigations: A Risk-Based Approach to Monitoring, which is available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM269919.pdf  for recommended approaches to monitoring clinical investigations 
involving FDA-regulated products. 
     
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