Guidance for Industry and for FDA Reviewers
Recommended Clinical Study
Design for Ventricular Tachycardia
Ablation
Document issued on: May 7, 1999
U.S. Department Of Health And Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Pacing and Electrophysiology Devices Group
Division of Cardiovascular and Respiratory Devices
Office of Device Evaluation
- 1 - Preface
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to
Jun Dong, M.D.  Comments may not be acted upon by the Agency until the document
is next revised or updated.  For questions regarding the use or interpretation of this
guidance contact Jun Dong, M.D. 301-796-6317 or by email at jun.dong@fda.hhs.gov.
Additional Copies
Additional copies are available from the Internet:  
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM077054.pdf.  You may also send and email request to 
dsmica@fda.hhs.gov to receive and electronic copy of the guidance or send a fax to 
301-847-8149 to receive a hard copy.  Please use the document number (2244) to
identify the guidance you are requesting.
- 2 - Introduction
The use of cardiac ablation for the treatment of Ventricular Tachycardia raises many new
questions of safety and effectiveness in comparison to the use of cardiac ablation for the treatment
of Supraventricular Tachycardias.  The following outline has been provided to aid sponsors in
developing a protocol for the treatment of Ventricular Tachycardia. We have given you two study
designs: non-randomized and randomized.   In no way is this outline intended to be all inclusive
of the necessary components for a clinical study.  This outline was based on recommendations
provided to the FDA by Circulatory System Devices Panel members and by comments offered by
clinical investigators.
Note: This guidance document represents the agencys current thinking on clinical
study design for ventricular tachycardia ablation.  It does not create or confer
any rights of or on any person and does not operate to bind FDA or the public.
An alternative approach may be used if such approach satisfies the requirements
of the applicable statute, regulation, or both.
We have further qualified some of our recommendations in the form of italicized
notes, such as this one, which explain the concern or reasoning behind our
recommendation.  If you choose not to follow our recommendations in designing
your study, you should strive to address FDAs underlying concerns.
The remainder of this guidance document is in three parts:
I.  Things to Consider in Designing Your Study
II.  Non-Randomized Study Design Options
III.  Randomized Study Design Options
- 3 - I.  Things to Consider in Designing Your Study
Designing a study to evaluate the safety and efficacy of an ablation system for the
treatment of ventricular tachycardia poses unusual demands for many sponsors.  The desire for
steady and expeditious patient enrollment needs to be balanced against the claims the sponsor
wishes to make for the device and the type of patients they wish to enroll.  Choices made early on
about inclusion criteria may impact which study design can be used or how long the study will
take. Please consider the impact of the following inclusion criteria when designing your study:
Ischemic VT:  For patients with ischemic VT, ablation may not be expected to cure the
patients VT.  In that case, the goal of treatment could be to reduce the frequency of a
patients VT episodes, perhaps accompanied by an improvement in quality of life1.
Therefore, your primary study endpoint of 6-month success should be a reduction in VT
episodes.  These patients are suitable for either a randomized study (preferably with a
marketed ablation system as the control arm) or a non-randomized study where each
patient acts as his or her own control.
Idiopathic VT: For patients with VT in the presence of a structurally normal heart, it
might be more realistic to attempt to rid the patient of VT symptoms for the duration of
the follow-up period.  In that case, your primary endpoint of 6-month success might be an
absence of VT throughout the follow-up period.  However, since the benefit of ablation
is less well-established in these patients, a randomized study design is strongly
encouraged.  The benefit of choosing this type of study is that the follow-up period may
be shortened since patients only need to be followed up to the point that they have their
first VT episode.
Presence of ICD: If a non-randomized study is chosen and patients will act as their own
control, considerable time will be saved if patients are enrolled already having an ICD.
You can use ICD interrogation to establish the baseline frequency of VT episodes rather
than requiring patients to go through an observation period prior to ablation.  You may
consider requiring that patients already have an ICD as part of your inclusion criteria.
High-density VTs: If a non-randomized study is chosen and patients with low density
VTs are included, both the baseline observation period and the follow-up period are
extended in order to capture events.  Therefore, you may consider requiring that patients
have a relatively high density of VTs in order to be enrolled in the study.
                                                       
1 Please consult FDA for advice on designing your clinical study if you intend to use Quality of Life as a primary
endpoint, or if you intend to make labeling claims about Quality of Life.
- 4 - II.  Non-Randomized Study Design Options
 A.  Study Design
These studies are designed to be non-randomized, single arm studies where patients act as
their own control.  The figure below is a flow chart illustrating how patients would
progress through the study.
Patient meets
inclusion/exclusion
criteria?
|
|-----Yes - Patient enrolled
|
Patient undergoes baseline period to
document VT episodes
|
|
Patient has sufficient # of episodes to
continue in study?
|
No.  Discontinued from study.----------- |
(Patients will be factored into |
the analysis under intention-to |
treat) |  Yes
Ablation procedure. Categorize patient as acute
success or failure based on non-inducibility of the
primary VT morphologies
|
|
| --- Next 7 days: Document all adverse
| events.  Major complications
| will contribute to safety
| endpoint.
|
6-month follow-up period.  Document all
recurrences.  Categorize each patient as a
6-month success or failure based on  pre-
determined definition.
- 5 - B.  Entry Criteria and Enrollment
An important point to remember is that patients are enrolled, and count toward
your allotment, if they meet the entry criteria and sign the Informed Consent.  Some
patients may not receive ablation if they then go on to have too few episodes during the
prospective baseline period to allow a statistical comparison between the baseline and the
follow-up period.  Patients should be notified of this possibility in the Informed Consent.
Special consideration should be given to the following inclusion/exclusion criteria:
1.  Specify a frequency of VT episodes that sufficiently characterizes the patient prior to
enrolling in the study.
2.  Specify whether patients will be required to have an ICD prior to enrollment in the
study.
3.  Define the etiology of the patients heart disease (i.e., ischemic VT).
4.  Specify whether patients will be refractory to or intolerant of antiarrhythmic drug
therapy.
 
 
 C.  Study Endpoints
 
 Primary Endpoints
 
 We recommend that you define the terms acute success and 6-month success as they
apply to individual patients.  In addition, state hypotheses for the expected rates of acute
success, 6-month success, and complications.
 
 We recommend:
 Acute Success Rate:
 First, develop a definition of success that can be applied to each patient in the study.
Typically, this would be defined as the acute non-inducibility of clinically relevant VT
morphologies.  Then, hypothesize an overall acute success rate for your study.
 
 Note:  It is important that the clinician identify the clinically-relevant VTs prior
to ablation therapy.  These should include VTs which are responsible for
the patients symptoms and/or are greater than 20 seconds in duration.
 
 Note:  Because this study is intended to support the marketing claims for an
ablation treatment system, success should only refer to successful
ablation with the investigational system.  If patients require additional
- 6 - treatments with non-investigational system components, they should be
considered acute failures.  An exception would be if you were trying to
market your system as an adjunctive treatment to another (marketed)
system.
 
 6-month Success Rate:
 First, categorize each patient as either a 6-month success or failure.  Success can be
defined as either a reduction in VT episodes or an absence of VT episodes at the end of
the 6-month follow-up period.  Then, hypothesize an overall 6-month success rate for
your study.
 
 Note:  Patients should demonstrate a clinically meaningful decrease in VT
episodes at six months to be categorized as a 6-month success.  You
may have different definitions of success and failure for different
categories of patients (for example, requiring an absence of episodes in
patients with a low density of episodes during the baseline).
 
 Note:  Patients should be categorized as 6-month successes or failures regardless
of whether they were acute successes.  We suggest you stratify the VT
recurrence rates for both the acute successes and the acute failures.
 
 Complication Rate: The percentage of patients undergoing an ablation
procedure who sustained at least one major complication.
 
 Note:  While FDA does not distinguish between procedure-related and
device-related complications, we do suggest that you stratify all the
reported complications according to whether they occurred acutely (within
the first week following the ablation procedure) or later.  Please refer to
the Appendix for suggestions on how to distinguish major complications
from minor complications.
 
 
 
 D.  Study Protocol
 
 VT Episode Documentation
 
 If you define 6-month success as a decrease or absence of VT episodes, you should also
prospectively specify the method of counting the number of VT episodes.  This may
include one or more of the following:
 1)   ICD interrogation;
 2)   Event monitoring; and
 3)   ECG from hospital visit.
- 7 -  
 Note: To avoid discrepancies in accuracy of VT counting methods, we
recommend that you use the same data collection methods both pre- and
post-ablation.
 
 Note: Use of ICD interrogation may overcount minor VT episodes.  If an ICD is
used, only count those VT episodes that were greater than 20 seconds in
duration, or of sufficient duration to result in delivery of therapy.
 
 Note: We recommend that you carefully consider ways to reduce the potential
for VT episode reporting bias.  For example, we do not recommend
retrospectively assessing the frequency of VT.  Instead, we believe that
baseline data collection should begin only after a patient has enrolled in
the study.  Also, we do not recommend using patient self-report as a
method for counting VT episodes.
 
 Pre-Ablation Procedures
 
 1) Baseline data collection - quantify the number of VT episodes for six months prior
to ablation.
 2) Echocardiogram for assessment of ventricular ejection fraction and presence of
intraventricular thrombus.
 3) Neurologic examination by a neurologist.
 
 Post-Ablation and Follow-up Recommendations
 
 1) Attempt reinduction of primary VT substrates.
 2) Echocardiogram for assessment of ventricular ejection fraction and presence of
intraventricular thrombus.
 3) Neurologic examination by a neurologist.
 4) Count VT episodes for six months post-ablation.
4)  Perform routine follow-up evaluations (physical exam, ECG) out to at least
six months.  Continue with follow-up phone contact to 12 months.
Repeat Ablations
While it may be desirable to allow patients the opportunity for repeat ablations, it is
important to do so while maintaining the integrity of the study design.  In general, this
means that patients can receive additional repeat ablations once they are categorized as 6-
month failures.  Specifically:
- 8 -   If your definition of 6-month success is absence of VT episodes, then a patient may
receive a second ablation once they experience their first VT episode, provided you
have allowed sufficient follow-up to capture acute adverse events (7 days).
  If your definition of 6-month success is reduction in VT episodes, then a patient may
receive a second ablation once they experience a sufficient number of episodes to
classify them as a 6-month failure.
NOTE: Because this information will appear in your labeling, you should
strive for consistency in offering repeat ablations.  Each investigator
should be encouraged to apply the same criteria in deciding whether
patients should receive a second ablation.
E.  Statistical Analysis
Recommended Statistics
Use descriptive statistics to present demographic data, success rates, complication rates,
and pre- and post-ablation counts of VT episodes.  For success rates and complication
rates, specify the 95% confidence limits for those proportions.  For pre- and post-ablation
counts of VT episodes, specify the medians (or the mean, if you are able to show that the
data are normally distributed).
To compare your observed success rates to your hypothesized success rates, use a test of
a single proportion.
Stratifying 6-month Efficacy by Success vs. Partial Success
As a secondary analysis, you may want to stratify your long-term efficacy results into two
groups: patients who were clearly asymptomatic at follow-up, and patients whose targeted
VTs were eliminated, but who developed new VT morphologies that resulted in
symptomatic episodes during the follow-up period.
- 9 - III.  Randomized Study Design Options
A.  Study Design: Two Options
These studies are designed to be randomized with a concurrent-control where patients
are randomly assigned to receive ablation or a control treatment.  The control
treatment is preferably ablation with a market-approved ablation system.  However, it
could be drugs if you are trying to establish your system as a first-line treatment for
VT (and provided patients are not drug refractory).  There are two choices for
comparing the 6-month outcomes of the two groups:
OPTION 1: Classify each patient as a 6-month success or failure and compare
the proportion of successes between the two groups.  If this option is
chosen, patients in both treatment arms will proceed through the study
as if they were their own control, and the relative proportions of
successes will be compared.  Please follow the recommendations
outlined in the previous section, Non-Randomized Study Design
Options for all patients. You can skip the rest of the recommendations
that follow, however please read the sections on Crossovers and
Statistical Analysis, below.
OPTION 2: Count the number of recurrent episodes during the six-month follow-up
period and compare these values between the two groups.  If this
option is chosen, you will not need a baseline period as patients will not
act as their own controls.  Instead, you will combine the data from
patients in each group and compare the average (or median) recurrence
rates.  In this case, all patients must complete the entire 6-month
follow-up period.
If Option 2 is chosen, the rest of this section applies to your study design:
B.  Entry Criteria
Special consideration should be given to the following inclusion/exclusion criteria:
1) Specify whether patients will be required to have an ICD.
2) Define the etiology of the patients heart disease (i.e., ischemic VT). C.  Study Endpoints
Primary Endpoints
We recommend that you prospectively define endpoints for comparing acute success,
6-month success, and complication rate across the two treatment groups.   Keep in
mind that if you wish to make claims of superiority of your device compared to the
control device, your hypotheses and sample size calculations should reflect this.
Acute Success Rate Comparison:
We recommend that success be defined as the acute non-inducibility of clinically
relevant VT morphologies.  Hypothesize a clinically-relevant difference between the
treatment group and the control group in terms of acute success.  Perform a sample
size calculation on this endpoint.
Note:  It is important that the clinician identify the clinically relevant VTs
prior to ablation therapy.  These should include VTs which are
responsible for the patients symptoms and/or are greater than 20
seconds in duration.
Note:  Because this study is intended to support the marketing claims for an
ablation treatment system, success should only refer to successful
ablation with the investigational system.  If patients require additional
treatments with non-investigational system components, they should be
considered acute failures.  An exception would be if you are trying to
market your system as an adjunctive treatment to another
(marketed) system.
6-month Recurrence Rate Comparison:
Hypothesize a clinically-relevant difference between the treatment group and the
control group in terms of the average number of recurrences in the 6-month follow-up
period.  Perform a sample size calculation on this endpoint.
Note:  We recommend that you prospectively specify the method of counting
the number of VT episodes during the six-month follow-up period.
Complication Rate Comparison:
Hypothesize a clinically-relevant difference between the treatment group and the
control group in terms of the complication rate.  Perform a sample size calculation on
this endpoint.  As with the Non-Randomized Study Design, you complication rate will
be based on the percentage of patients with major complications (see Appendix A).
- 11 - D.  Study Procedure
VT Episode Documentation
Prospectively specify the methods for counting VT episodes, which may include one
or more of the following:
1) ICD interrogation;
2) Event monitoring; and
3) ECG from hospital visit.
Note: If an ICD is used, only count those VT episodes of at least 20 seconds
duration, or of sufficient duration to result in delivery of therapy.
Pre- and Post-Ablation Procedures
Refer to the Non-Randomized Study design for recommendations on procedures for
patients in the ablation arm of the study.
Follow-up Recommendations
Document the number of VT episodes in the six-month period following delivery of
therapy for patients in either arm of the study.
Crossovers and Repeat Ablations
Allowing patients to cross over to the other treatment arm and/or allowing repeat
ablations are options that raise similar issues of study integrity.  In both cases, there is
the potential for losing information about the 6-month efficacy endpoint. As with the
Non-Randomized Study Design, there are ways to minimize this problem:
For Option 1:  Crossovers  Patients randomized to either arm of the study may cross
over to the other arm once they are categorized as 6-month failures,
but no sooner than one week after the initiation of treatment.  If you
choose to incorporate crossovers into your study, you will minimize
further bias by offering this option to patients in either arm.  Repeat
ablations  follow the rules developed in the Non-Randomized Study
(page 7).
For Option 2:   Crossovers  Patients may only cross over to the other treatment arm
once they have completed the full 6-month follow-up period.  Similarly,
repeat ablations should only occur after the patient has completed the
6-month follow-up period.
- 12 - E.  Statistical Analysis
Analysis of Efficacy
For Option 1:  compare the 6-month success rates of the two treatment modalities
using a test for the difference between two proportions.
For Option 2:  compare the two treatment modalities in terms of their overall impact
on VT recurrence. Compare the number of VT episodes in the six-
month follow-up period for patients in both groups, assuming
crossovers were not allowed prior to the six-month follow-up period.
Analysis of Safety
For Option 1 or 2: Compare the complication rates of the two arms of the study using
a test for the difference between two proportions.
- 13 - Appendix A
Definition of Major Complication Rate
Major complication rate:  The percentage of patients treated with the investigational device
who experience any adverse event which occurs within the first week following the
investigational procedure; AND:
  is life-threatening; or
 
  results in permanent impairment of a body function or permanent
damage to a body structure; or
 
  necessitates significant intervention, such as major surgery, to
prevent permanent impairment of a body function or permanent
damage to a body structure; or
 
  requires hospitalization or an extended hospital stay; or
 
  results in moderate transient impairment of a body function or
transient damage to a body structure; or
 
  requires intervention such as medication or cardioversion to prevent
permanent impairment of a body function or damage to a body
structure.
A minor complication would be any event that results in minimal transient
impairment of a body function or damage to a body structure, or which does not
require any intervention other than monitoring.
- 14 -