Guidance for Industry and FDA 
Staff 
 
Clinical Study Designs for 
Catheter Ablation Devices for 
Treatment of Atrial Flutter  
 
 
 
 
Document issued on: August 5, 2008 
 
 
 
For questions regarding this document, contact Randall G. Brockman, M.D. at (240) 276-
4095.  
 
 
 
 
 
 
 
 
       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 
/1678.html.  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 240-276-3151 to receive a hard copy.  
Please use the document number (1678) to identify the guidance you are requesting. 
  Contains Nonbinding Recommendations 
Table of Contents 
 
1.  INTRODUCTION..........................................................................................1 
The Least Burdensome Approach.........................................................................................1 
2. BACKGROUND.............................................................................................2 
3.  SCOPE............................................................................................................3 
4.  STUDY DESIGN............................................................................................4 
A.  Randomized Controlled Trials (RCTs)...........................................................................4 
B.  Alternatives to RCTs.......................................................................................................5 
C.  General Design Considerations.......................................................................................6 
5.  STUDY ENDPOINTS....................................................................................7 
A.  Primary Effectiveness Endpoint - Rhythm.....................................................................7 
B.  Safety Endpoint  Ablation Device/Procedure...............................................................7 
6.  STUDY GROUPS..........................................................................................8 
7.  STATISTICAL CONSIDERATIONS.........................................................9 
8.  SAMPLE SIZE.............................................................................................10 
9.  FOLLOW UP OF STUDY SUBJECTS.....................................................10 
10.  ANTICOAGULATION PARAMETERS................................................10 
11.  INVESTIGATOR SELECTION AND TRAINING...............................11 
12.  DATA COLLECTION FORMS...............................................................11 
13.  STUDY MONITORING...........................................................................11 
 
 
 
  Contains Nonbinding Recommendations 
Guidance for Industry and FDA Staff 
 
Clinical Study Designs for 
Catheter Ablation Devices for 
Treatment of Atrial Flutter  
 
 
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 addresses the use of a randomized clinical trial (RCT) approach in designing 
clinical studies for catheter ablation devices for the treatment of atrial flutter. The first 
several premarket approval (PMA) applications approved for the treatment of atrial flutter 
relied on clinical data from single-arm trials because no devices were approved for treatment 
of atrial flutter.  Recently approved IDE studies and PMA applications have used the option 
of a RCT given the availability of PMA-approved ablation catheters indicated for treatment 
of atrial flutter.  This guidance provides recommendations about the clinical study designs 
that rely on a RCT.  
 
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 
  1 Contains Nonbinding Recommendations 
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:  
http://www.fda.gov/cdrh/modact/leastburdensome.html 
 
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. 
 
2. Background 
Atrial flutter (AFL) is a rapid regular atrial contraction occurring usually at rates between 
250 and 350 beats per minute and thought to be a relatively common arrhythmia .  However, 
the epidemiology of atrial flutter has not been studied as thoroughly as that of atrial 
fibrillation (AF).  In one epidemiologic study, the overall incidence of atrial flutter was 
0.088% (or 88 per 100,000 people).1  Over one-half of these patients also had atrial 
fibrillation.  Atrial flutter alone was seen in 0.037% of the study population. The incidence of 
atrial flutter increased markedly with age, from 5 per 100,000 of those older than 50 years of 
age to 587 per 100,000 for those older than 80 years of age.  Atrial flutter was more than 
twice as common in men compared to women.  The incidence of atrial flutter has been 
reported to be approximately twice that of paroxysmal supraventricular tachycardia.2 
 
Endocardial mapping suggests that typical atrial flutter is based on right atrial macro reentry 
which involves the isthmus between the inferior vena cava (IVC) and the tricuspid annulus 
(TA).  The most common form demonstrates a counterclockwise circuit around the tricuspid 
                                                 
1 Granada J, et al. Incidence and predictors of atrial flutter in the general population. Journal 
of the American College of Cardiology. 2000; 36: 2242-2246. 
2 Orejarena L, et al.  Paroxysmal Supraventricular Tachycardia in the General Population. 
Journal of the American College of Cardiology. 1998; 31: 150-157. 
  2 Contains Nonbinding Recommendations 
valve.3  Current treatments span a spectrum of non-invasive to invasive options and include 
pharmaceutical, catheter-based, and other device-based approaches.  Literature reports of 
early success with catheter ablation4 (initially 4 or 5 mm tip manually deflectable catheters 
using radiofrequency energy and fluoroscopic guidance) have led to the development of non-
traditional ablation catheters and ablation systems (large tip catheters,5 electroanatomic 
mapping systems6,7, remote navigation systems, and alternate energy sources8).   
 
Since 2003, FDA has approved premarket approval (PMA) applications for ablation catheter 
systems indicated for the treatment of atrial flutter.  The first several PMAs relied upon 
clinical data from single-arm trials because no devices were approved for treatment of atrial 
flutter at that time.  Subsequently, recently approved IDE studies and PMA applications have 
reflected a randomized clinical trial (RCT) approach given the availability of PMA-approved 
ablation catheters indicated for treatment of atrial flutter.   
3.  Scope 
For the purpose of this guidance document, FDA defines type I atrial flutter as a 
cavotricuspid dependent, right atrial macro-reentrant arrhythmia.   
 
The product code for this category of device is: 
 
OAD - Cardiac ablation percutaneous catheter, intended for treatment of atrial flutter 
                                                 
3 Saoudi N, et al. A classification of atrial flutter and regular atrial tachycardia according to 
electrophysiological mechanisms and anatomical bases.  European Heart Journal. 2001; 22: 
1162-1182. 
4 Cauchemez B, Haissaguerre M, et al. Electrophysiological Effects of Catheter Ablation of 
Inferior Vena CavaTricuspid Annulus Isthmus in Common Atrial Flutter. Circulation. 1996; 
93: 284-294. 
5 Scavee C, Haissaguerre M, et al. Prospective randomised comparison of irrigated-tip and 
large-tip catheter ablation of cavotricuspid isthmus-dependent atrial flutter.  European Heart 
Journal. 2004; 25; 963969. 
6 Kottkamp H, et al.  Electromagnetic Versus Fluoroscopic Mapping of the Inferior Isthmus 
for Ablation of Typical Atrial Flutter.  Circulation. 2000; 102: 2082-2086. 
7 Willems S, et al. Catheter ablation of atrial flutter guided by electroanatomic mapping 
(CARTO): a randomized comparison to the conventional approach. Journal of 
Cardiovascular Electrophysiology. 2000; 11: 12231230. 
8 Timmermans C, et al. Randomized Study Comparing Radiofrequency Ablation With 
Cryoablation for the Treatment of Atrial Flutter With Emphasis on Pain Perception. 
Circulation. 2003; 107: 1250-1252. 
  3 Contains Nonbinding Recommendations 
 
These devices are class III, requiring PMA approval before marketing (section 513(a) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360c(a)).   
 
Devices excluded from the scope of this guidance include: 
  electrode recording catheters or probes (product code DRF, 870.1220), 
  cardiac ablation percutaneous catheters (product code LPB), and 
  percutaneous catheters intended for treatment of atrial fibrillation (product code 
OAE). 
FDA believes that the devices addressed by this guidance document are significant risk 
devices as defined in 21 CFR 812.3(m).9  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).10 
 
4.  Study Design 
FDA recognizes that there is no unique best design for clinical investigations of devices.  
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 capable of developing data that demonstrates the safety 
and effectiveness of the device for its intended use and patient population. 
A.  Randomized Controlled Trials (RCTs) 
In general, RCTs provide the least burdensome means of providing reasonable assurance of 
the safety and effectiveness of devices for catheter-based ablation of atrial flutter.  It 
                                                 
9 Please refer to Blue Book Memorandum entitled Significant Risk and Nonsignificant Risk 
Medical Device Studies, http://www.fda.gov/cdrh/d861.html. 
10 You should review the statutory definition of applicable clinical trial to determine 
whether your trial must be registered to comply with the law.  See PL 110-85, Section 
801(a), (adding new 42 U.S.C. 282(j)(1)(A)).  http://frwebgate.access.gpo.gov/cgi-
bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf   Information can 
be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more 
information visit the PRS Information Page (http://prsinfo.clinicaltrials.gov). 
  4 Contains Nonbinding Recommendations 
generally is feasible to conduct RCTs for atrial flutter ablation devices.11,12,13  Potential 
advantages to RCT designs include an improved ability to compare effectiveness of the 
investigational device to devices approved for treatment of atrial flutter.  Different patient 
demographics (e.g., a patient with co-morbid conditions versus a patient with only atrial 
flutter) may have different inherent safety and effectiveness profiles.  As a result, it may be 
challenging for a performance-goal study design to account for any differences in patient 
demographics, which may be difficult to control.  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 or control treatments.  Randomization avoids 
systematic differences between groups with respect to known or unknown baseline variables 
that could affect outcome. Inability to eliminate systematic differences between treatment 
groups is a major problem of studies without a concurrent randomized control. 
Randomization also provides a sound basis for statistical inference. 
 
Potential advantages to RCT 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, concomitant cardiopulmonary disease, device design, evolving 
procedural methods and operator experience and may be difficult to evaluate using data from 
an historical control.   
 
B.  Alternatives to RCTs 
Although FDA recommends RCTs, we will consider alternative study designs if they are 
scientifically sound and address the relevant questions.  Regardless of the study design that is 
used, the data to support PMA approval should be of sufficiently high quality to adequately 
demonstrate that an acceptable risk-benefit profile exists and that the device provides a 
reasonable assurance of safety and effectiveness.  In practice, this means that the burden of 
proof may be concurrently greater as the study design departs further from the RCT design 
(e.g., missing data may be less tolerable in a single-arm design).  Alternative study designs 
may include, but are not limited to, reliance on valid non-U.S. data where appropriate for the 
                                                 
11 Kasai A, et al.  Comparison of Effectiveness of an 8-mm Versus a 4-mm Tip Electrode 
Catheter for Radiofrequency Ablation of Typical Atrial Flutter. American Journal of 
Cardiology. 2000; 86: 1029-1032. 
12 Schreieck J, et al. Prospective Randomized Comparison of Closed Cooled-tip Versus 8-
mm-Tip Catheters for Radiofrequency Ablation of Typical Atrial Flutter. Journal of 
Cardiovascular Electrophysiology. 2002: 13: 980-985. 
13 Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With 
Atrial Fibrillation. Journal of the American College of Cardiology. 2006;48:e149-246. 
  5 Contains Nonbinding Recommendations 
intended U.S. patient population (21 CFR 814.15), study designs employing matched 
controls for safety evaluation, and performance goals for safety and/or effectiveness.   
 
There may be other valid study designs that are not discussed in depth in this guidance.  For 
example, an alternate design could include a concurrent, non-randomized control comparing 
a new device to an approved device.  In such a design, it is important to match the subjects 
characteristics of the investigational treatment arm and the concurrent control arm.  Another 
alternate study design could include a single arm trial using established performance goals.  
In this study design, FDA would evaluate the safety and effectiveness strictly based on the 
pre-specified performance goals.  If you propose an alternative study design, we recommend 
that you explain thoroughly the scientific arguments supporting your design.  For example, if 
you elect to use a performance goal approach, the specific literature and rationale justifying 
this approach should be explained in detail.  You should also be aware that FDAs evaluation 
of the claims allowed in labeling will likely be guided, in part, by the design and results of 
the associated clinical trial.   
 
C.  General Design Considerations 
The objective of ablation treatment for atrial flutter is to reduce or eliminate long-term 
recurrence of atrial flutter.  We recommend that chronic success (defined as the absence of 
recurrent atrial flutter at 6 months post-ablation) should be the primary effectiveness 
endpoint.  However, under certain conditions, FDA believes there is sufficient scientific 
evidence to indicate that acute procedural success (defined as the creation of bidirectional 
block at the cavo-tricuspid isthmus) is predictive of chronic success.  We believe acute 
procedural success may be appropriate to serve as a surrogate effectiveness endpoint for 
catheters provided all of the following device characteristics are present: 
  creates endocardial lesions  
  manipulated in the endovascular space 
  a single ablation electrode 
  the energy source is radiofrequency (RF) 
  temperature sensing capability 
  steerable (i.e., catheter has a tip which is manually-deflectable via a thumb-wheel 
or similar mechanism residing on the handle of the catheter) 
  percutaneous placement. 
 
At this time, we believe the surrogate effectiveness endpoint may not be appropriate for 
catheters with alternate energy sources, and novel approaches to navigation and/or steering. 
  6 Contains Nonbinding Recommendations 
 
5.  Study Endpoints 
A.  Primary Effectiveness Endpoint - Rhythm 
As described above, the primary effectiveness endpoint for catheter ablation devices intended 
for the treatment of atrial flutter should be chronic success, which is defined as the absence 
of recurrent atrial flutter at 6 months post-ablation.  For select catheters described in the 
preceding section where sufficient clinical evidence has validated acute procedural success 
as a surrogate for the chronic endpoint, a surrogate endpoint may be appropriate.  Acute 
procedural success should be defined as the creation of bidirectional conduction block across 
the cavo-tricuspid isthmus.4,7,14  Ideally, this assessment should be done in the absence of 
anti-arrhythmic drugs.  If an anti-arrhythmic drug is used in the follow-up period to treat 
atrial flutter, we recommend that the subject be counted as a chronic treatment failure.  If an 
anti-arrhythmic drug is used to treat an arrhythmia other than atrial flutter, and there is no 
evidence of atrial flutter recurrence, the subject may be considered to be a chronic treatment 
success. 
 
The preferred modality for assessing effectiveness is a periodic review of the subjects 
symptoms, along with surveillance rhythm monitoring (Holter monitoring, resting ECG 
recording and/or event monitoring can be considered).  
 
B.  Safety Endpoint  Ablation Device/Procedure 
FDA recommends the safety endpoint be a composite serious adverse event endpoint and, at 
a minimum, include the following:  
  cardiac perforation/tamponade 
  cerebrovascular accident 
  complete heart block 
  death 
  myocardial infarction 
  pulmonary embolism 
                                                 
14 Poty H, Saoudi N, et al. Radiofrequency Catheter Ablation of Atrial Flutter: Further 
Insights Into the Various Types of Isthmus Block: Application to Ablation During Sinus 
Rhythm. Circulation. 1996; 94: 3204-3213. 
  7 Contains Nonbinding Recommendations 
  transient ischemic attack 
  additional risks specific to the device that need to be measured. 
 
We recommend you collect relevant major complication information for 7 days after the 
ablation is performed.  We believe this 7-day period provides an accurate assessment of the 
types and frequencies of safety problems that can occur after ablation and is consistent with 
how safety is assessed for other types of cardiac ablation devices.  FDA recommends that 
you include an independent clinical events committee to evaluate adverse events. (21 CFR 
812.25(b)) 
 
6.  Study Groups 
You should clearly define your study inclusion and exclusion criteria.  Examples of 
appropriate inclusion and exclusion criteria for catheter ablation studies designed to treat 
atrial flutter are listed below. 
 
Suggested Inclusion Criterion 
  Subjects with at least one documented episode of Type I atrial flutter in the six month 
period preceding the date of enrollment in the study and are clinically indicated for 
catheter ablation. 
 
Suggested Exclusion Criteria 
  Any prior right atrial cavo-tricuspid isthmus ablation 
  Subjects who cannot have anti-arrhythmic drugs stopped for at least 5 half-lives prior 
to the procedure (for class I and class III anti-arrhythmic drugs) or for at least 4-6 
months for amiodarone 
  Myocardial infarction within the prior two months 
  Current unstable angina 
  Cardiac surgery within the prior three months 
  Currently documented intracardiac thrombus by transesophageal echocardiography 
  Permanent leads in or through the right atrium 
  Clinically significant tricuspid valve regurgitation or stenosis 
  Uncompensated congestive heart failure 
  Any cerebral ischemic event (including transient ischemic attacks) in the prior six 
months 
  8 Contains Nonbinding Recommendations 
  Clinically significant coagulation disorder 
  Pregnancy 
  Uncontrolled hyperthyroidism 
  Current enrollment in any other clinical investigation 
  Any other significant uncontrolled or unstable medical condition 
  Life expectancy of less than two years. 
 
Exclusion criteria should be designed to minimize the risk of underlying medical conditions 
from having a substantial impact on the evaluation of the safety profile of the device.  
Specific criteria may not be applicable to all devices.  In addition, FDA will evaluate 
scientifically valid justifications for why specific subject populations cited above should not 
be excluded. 
 
7.  Statistical Considerations 
The study design should be clearly described in the protocol.  For example, the treatment 
allocation ratio to the treatment arms, the randomization scheme, and the implementation of 
blinding/masking, if any, should be clearly described for a randomized design.  Safety and 
effectiveness endpoints and their hypotheses both in words and mathematical forms should 
be clearly stated. 
 
Pre-specification of the statistical analysis is a key factor for obtaining consistent and 
convincing evidence of device safety and effectiveness.  Therefore, we recommend that you 
pre-specify: 
  the hypothesis tests used to evaluate the safety and effectiveness endpoints 
  plans for checking any assumptions required for the validity of these tests  
  alternative procedures/tests to be used if the required assumptions are not met 
  a clear study success criterion that indicates which hypotheses must be met in order 
for the study to be considered a success. 
 
The study protocol should clearly define the study population to be analyzed (e.g., intent-to-
treat or per-protocol).  If secondary endpoints and hypotheses for which labeling claims 
(such as presentation of p-values or confidence intervals) are intended, your protocol should 
pre-specify an appropriate testing procedure that for preservation of Type I error in the 
setting of multiple comparisons. 
 
  9 Contains Nonbinding Recommendations 
In addition, FDA recommends that the investigational protocol pre-specify one or more 
methods for handling missing data during data anaylsis. 
 
8.  Sample Size 
We recommend that you provide a relevant statistical justification for any sample size 
calculation.  FDA recommends that sponsors perform both safety endpoint and effectiveness 
endpoint calculations appropriate for the hypotheses and tests specified on these endpoints.  
Generally, the larger sample size should be the one employed in the study. 
 
9.  Follow Up of Study Subjects 
We recommend that you develop standardized monitoring protocols and include, at a 
minimum, a telephone call at 7 days and outpatient follow up visits at thirty days and six 
months.  If acute procedural success is used as a surrogate primary effectiveness endpoint for 
qualified devices, the duration of the study (and thus the final follow-up visit) may be less 
than 6 months.  These visits should typically include documentation of symptoms and 
assessment of cardiac rhythm with a 12 lead electrocardiogram (ECG), or other equivalent 
cardiac rhythm measurement.  When symptoms suggestive of recurrent atrial flutter occur, 
rhythm documentation with transtelephonic event monitoring is recommended. 
 
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 demonstration of 
safety and effectiveness; therefore, the study protocol should be strictly followed without 
omission of post-procedure testing. 
 
10.  Anticoagulation Parameters 
Current guidelines15,16 recommend that the guidelines for atrial fibrillation be extended to 
atrial flutter.  If a subject is likely to be in atrial flutter at the time of the ablation (and 
                                                 
15 Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With 
Atrial Fibrillation. Journal of the American College of Cardiology. 2006;48:e149-246. 
16 Blomstrom-Lundqvist Carina, et al. ACC/AHA/ESC Guidelines for the Management of 
Patients With Supraventricular Arrhythmias*Executive Summary. Circulation. 
2003;108(15):1871-1909. 
  10 Contains Nonbinding Recommendations 
therefore is to undergo termination of the atrial flutter), FDA recommends that he or she 
receive 3 to 4 weeks of therapeutic anticoagulation prior to the ablation.  A reasonable 
alternative could include a pre-procedural trans-esophageal echocardiogram which reveals no 
evidence of left atrial appendage thrombus.  Subjects in atrial flutter at the time of the 
procedure should receive at least 3 to 4 weeks of post-procedural therapeutic anti-
coagulation.  FDA will entertain alternative approaches based on their scientific and clinical 
merit. 
 
11.  Investigator Selection and Training 
FDA recommends that you base your selection of investigators on their scientific training 
and clinical experience, i.e., physicians trained in catheter ablation and board-certified in 
electrophysiology.  However, in situations in which the investigator lacks a thorough 
knowledge of study procedures, you should train the investigator prior to study initiation.  In 
addition, the selection of a study site with site staff trained in study procedures to assist the 
investigator with appropriate data collection and subject follow-up is an important factor in 
determining whether the site is fully qualified to conduct the study. 
 
12.  Data Collection Forms 
FDA recommends that you 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. 
 
13.  Study Monitoring 
In designing your studies with atrial flutter ablation devices, we feel it is essential that you 
develop a comprehensive monitoring plan for these studies.  Sponsors are required to include 
written monitoring procedures in applications for investigational device exemptions (21 CFR 
812.25(e)).  Experience has shown that when sponsors make adequate provisions for 
monitoring studies, and assuring prompt corrections to departures from the investigational 
plan, the quality of the resulting submission is improved.  Therefore, we recommend selecting 
qualified monitors, adherence to the investigational plan and other requirements, and 
investigators compliance with record-keeping and reporting obligations. 
 
 
  11 Contains Nonbinding Recommendations 
 
  12