Draft Guidance for Industry and FDA Staff: Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation

Status: Draft

Date: September 2009

Target Audience
Ablation device manufacturers, clinicians, and other research personnel involved in designing, recruiting, and carrying out clinical studies for ablation devices used for treating atrial fibrillation

Laws and Regulations

  • 21 CFR 878.4350 – GEH Cryosurgical unit and accessories
  • 21 CFR 878.4400 – Electrosurgical cutting and coagulation devices and accessories
  • 21 CFR 878.4810 – Powered surgical laser instrument
  • 21 CFR 878.4810 – Cardiac ablation percutaneous catheter
  • 21 CFR 812.2 – Investigational device exemptions
  • 21 CFR 812.42 – Institutional review board approval
  • 21 CFR part 50 – Informed consent

Summary
Atrial fibrillation is a fairly common disease caused by abnormalities in the electrical system of the heart. Dysrhythmic firings of the electrical impulses that control the contraction and release of the atrium and the ventricles cause an irregular heartbeat and compromised bloodflow in the heart and throughout the body. Atrial fibrillation can be caused by several factors, such as the wear and tear of aging, abnormalities of the heart valves, thyroid disease, and many unknown factors, according to the Society of Thoracic Surgeons.

Atrial fibrillation can be treated with drugs, catheterization, or in more extreme cases by the Maze procedure, becoming more popular since it was first described in the late 1980s. During this open heart procedure, a series of incisions are made in the atrium in order to disrupt the electrical circuits in the heart. The incisions cut the electric pathway so that the electrical impulse can only follow a single path that in most cases will not allow the heart to beat irregularly. The incisions are made with ablation devices that use electricity, extreme cold, microwaves, ultrasound, or a laser to cut the heart tissue.

Rationale

As more medical devices are created to be used in the Maze procedure, as well as related procedures that have evolved from it, the FDA feels that there should be guidance for device manufacturers and clinicians who will be performing pre- and post-marketing clinical studies to establish the safety and effectiveness of these ablation devices. The design of clinical studies should be different for patients with longstanding persistent atrial fibrillation and patients with sudden or recurrent atrial fibrillation, and effectiveness evaluation should reflect the proposed indications for the devices in everyday surgical practice.

The draft guidance addresses randomized control trials, alternative study designs, control group considerations, indications for ablation devices, study endpoints, and evaluation of the effectiveness of these devices.

Recommendations

  1. Randomized controlled trial (RCT) should be the first choice of study design because it is the least burdensome method of gathering scientific evidence and evaluating it. Any RTC should have an appropriate control group based on the type of therapy or indication under study and any other surgical procedures or pre-existing diseases or conditions that patients may have.
  2. Alternative study designs that are not RCTs should be scientifically sound and allow for as little bias and other confounders as possible. Study design should match subjects as closely as possible.
  3. Studies with historical control groups that have already received treatment should include a thorough analysis of the relevant medical literature. Whenever possible, historical data should include patient level data, rather than data from publications.
  4. The study design should reflect the proposed indication for an ablation device such as the type of atrial fibrillation to be treated, the surgical approach used, and any procedures that will be performed at the same time of surgery. The hypothesis of a clinical study should be related to the proposed indication for the device.
  5. Study endpoints for the evaluation of effectiveness should differ depending on the type of atrial fibrillation. For patients with longstanding persistent atrial fibrillation, the primary effectiveness endpoint should be 6 months without atrial fibrillation. For patients with persistant atrial fibrillation, the primary effectiveness endpoint should be 9 months without atrial fibrillation.

Impact
When designing clinical studies for ablation devices for treating atrial fibrillation, it is important that the studies compare “apples to apples.” The people involved in designing these studies will need to make sure that they use rigorous scientific methodology. They will have to make special efforts to gather similar patients into control and treatment groups. For researchers, this may mean conducting a wider search for patients for participation in the studies and conducting the study in multiple investigational sites.

When the control group is based on historical data, the researchers will have to perform an exhaustive literature analysis to support their arguments that the historical data is a valid control group. For evaluating the effectiveness of treatment, the follow up will have to be longer for certain patient groups, such as patients with persistant atrial fibrillation, who will need to be followed for at least 9 months. In the end, the results of the study should reflect how the ablation device will be used if approved and how well the device actually works in specific situations.

For more information on this issue, contact the Kulkarni Law Firm.