|Abbott's Absorb bioresorbable stent--Courtesy of Abbott|
One of the most anticipated FDA panel meetings in years will commence in Gaithersburg, MD, on March 15, that of Abbott's ($ABT) Absorb BVS bioresorbable stent. The stent is a paradigm-shifting device, and the data show noninferiority to Abbott's current standard-of-care Xience drug-eluting stent.
But those who peek beyond the top-line statistical analysis (such as the experts one the panel) quickly notice that the device performs worse than the Xience on a number of safety metrics--but not by enough to miss its statistical noninferiority endpoint. And the FDA states that the clinical benefits associated with the device over current generation drug-eluting stents remain to be demonstrated in clinical studies.
The agency does not have to follow the vote of the committee on the device's safety, efficacy and risk/reward profile (which determines whether the group recommends approval), but usually does. Because the data appears borderline, the FDA's final decision will be closely watched as a sign of its regulatory stance going forward and willingness to tolerate uncertainty (especially if the panel vote is close), particularly in the case of devices that represent the first in one in their class, such as the Absorb.
It achieved a CE mark in 2010, and is used widely abroad, with India and Brazil accounting for slightly more than half its 2014 revenue of $132 million, according to Global Data (which projects U.S. revenues of $96 million by 2017, assuming approval).
It therefore represents a failure of the FDA's device arm (CDRH) to meet its stated goal of being the first agency in the world to improve innovative devices. And while there are questions about the device's safety and efficacy, its novelty is not in doubt.
If approved, the Absorb would be the first fully bioresorbable stent in the U.S. Unlike metal drug-eluting stents that stay in the body permanently, bioresorbable drug-eluting stents are designed to degrade into natural materials and be absorbed by the body within two years.
The reams of data being considered and debated has proved complicated and does not provide a straightforward answer to the question of the whether the device should be approved. The panel discussion will surely get quite technical.
Luckily, the FDA's list of discussion questions to be asked to the panel members provides a succinct and understandable overview of the main factors being considered by the agency.
The panel questions
The first question is a standard evaluation of the device's safety and effectiveness, while subsequent questions raise concerns about patient selection and the device's nonperformance against the Xience in patients with diabetes.
In general, supposed benefits of drug-eluting stents include a reduction in restenosis, or renarrowing of the arteries, which results from the body's inflammation response to foreign materials; a continued increase in the size of the coronary artery in the months following the surgery; and the return of vasomotion, or the vessel's reversion to its original, prediseased state.
Although the FDA says those advantages have to be proved, the end-point is one of noninferiority to the Xience, not superiority.
The device met its target end-point in its 2,008-patient statistical endpoint of a noninferior target-lesion failure rate at one year. The actual TLF rate was 7.8%, compared to 6.1% for the Xience, not large enough to definitively prove noninferiority.
And the FDA points out in the list of discussion questions that the Absorb also performed worse than the Xience on rates of cardiac death, target vessel myocardial infarction and definite or probable stent thrombosis (the formation of a blood clot in the treated vessel).
The agency also points out that the difference between the two devices was greater in patients with diabetes, and those with vessels with a diameter of less than 2.25 millimeters. The panelists will comment on the clinical significance of the under performance in patients with small vessels, and Abbott's proposed labeling, which advises against implantation of the Absorb in patients with a vessel size less than 2.5 millimeters.
The experts will also be asked whether the duration of follow-up (one-year) in the main pivotal trial is sufficient, and whether Abbott's they agree with recommendation of postdilation with a compliant angioplasty balloon in spite of a lack of trial evidence that patients fare better when the additional step is performed.
Also up for discussion will be device's labeling and postapproval study.
To approve or not approve?
It's worth noting that Dr. Jeffrey Shuren (the head of FDA's device arm) has said that the first iteration of a paradigm shifting device (such as a bioresorbable stent) is often a bit underwhelming. But its approval is often needed to ensure patients can benefit from subsequent improvements down the line.
And the FDA points out in its executive summary of the Absorb's PMA application that the transition to drug-eluting stents wasn't perfectly smooth either. They originally demonstrated high rates of stent thrombosis, but adjustments were made to device and design and clinical practice, which brought the rates down.
Still, the Absorb has to overcome a fair share of skepticism from the medical community, as evidenced by a critical editorial in the New England Journal of Medicine, which said that the clinical relevance of the finding of statistical noninferiority to the Xience is open to question.
If the agency's questions reveal that the panelists doubt true noninferiority, the basis for the Absorb's approval will be endangered.
- read the March 15 meeting's literature