A new final guidance document released on 15 February 2013 by the US Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) is intended to assist sponsors of surgical ablation devices for the treatment of atrial fibrillation (A-fib/AF) generate clinical trials data that will be of greater use to FDA's device review staff.
A-fib is a common form of irregular heartbeat (arrhythmia), often associated with other cardiac problems such as congestive heart failure and stroke. Its incidence increases with age, and is usually treated with pharmaceuticals, including anticoagulants and other drugs intended to moderate heart rhythm.
But in some cases, physicians may also opt to treat patients using a medical device. In one of those procedures, doctors insert a wire into the heart, and radio wave energy is used to restore normal functioning to the heart by selectively destroying tissue to restore the normal communication of electrical signals, thus reducing arrhythmia.
A-fib can also be broken down into a number of subcategories (per FDA's definitions), including:
- Paroxysmal- Two or more A-fib occurrences within 7 days, including those treated pharmacologically or electrically.
- Persistent - A-fib which is sustained beyond seven days but no more than one year.
- Longstanding Persistent - Continuous A-fib of longer than one-year.
- Permanent - Longstanding persistent A-fib for which no treatment is being pursued.
- Lone - A-fib in those younger than the age of 60.
- Continuous - Uninterrupted, continuous A-fib (found during a period of monitoring).
A Nuanced Approach
FDA's final guidance document, Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation, noted that the agency "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, as well as for stand-alone versus concomitant procedures."
Because patients with A-fib exhibit different degrees of severity, as measured using the above definitions, sponsors should take care to evaluate them differently as well, FDA said. For example, a temporary rhythm disturbance is inherently different than an ongoing, persistent case of A-fib. FDA recommends in the guidance that sponsors conduct separate studies for different types of A-fib, and justifications should be provided if this norm is strayed from.
The guidance goes on to explain that while FDA doesn't believe that there's a single "best design" for clinical investigations, there are a number of common elements that ought to be considered.
Randomized controlled trials (RCTs) are preferable because they tend to be least burdensome, but alternative study designs are permissible so long as they account for similar measures of comparability, historical controls and trial performance goals. The latter may prove especially tricky considering the heterogeneous study population, FDA explained.
Study endpoints exhibit many common elements as well, FDA said. A successful trial will be one that demonstrates the meaningfulness and statistical likelihood of a clinical benefit, either in or absent the presence of an antiarrhythmic drug (AAD).
Follow-up should be provided to patients at the 12-month post-surgery mark to determine the long-term effectiveness of the therapy, FDA recommended.
Endpoints and Safety
Though FDA said it didn't believe that a reduction in AF burden was an "optimal primary effectiveness endpoint," it said it recognized that this could come to be justified, particularly during follow-up monitoring. A sustained reduction in A-fib in patients with longstanding persistent A-fib, for example, might be clinically significant. During a trial, however, it is difficult to determine clinical significance of such a development.
Under normal circumstances, however, "FDA recommends freedom from AF/AFL/AT for one year in the absence of Class I or III AADs as the primary effectiveness endpoint" in longstanding persistent and persistent A-fib. For patients with Proximal A-fib, FDA "recommends freedom from AF/AFL/AT for one year in the absence of Class I or III AADs as the primary effectiveness endpoint."
All scenarios should be pre-specified, FDA added. Secondary endpoints may include:
- AF burden reduction
- improvement in symptom scores tracking dyspnea, dizziness, or palpitation
- improvement in QOL
- improvement in exercise tolerance
- improvement in ventricular ejection fraction
- improvement in atrial transport function
- atrial remodeling, assessed by decrease in atrial size
Safety evaluations should also be conducted with an emphasis on those symptoms most likely to occur in A-fib patients, including stroke, heart attack, excessive bleeding, infection, blood clots and damage to non-intended tissue. These should be noted both during the trial and during a one-year follow-up examination of the patient.
Read the entire guidance here.