On January 28, 2013, consumer-advocacy group Public Citizen filed a letter “in response” for FDA to reconsider its August 8, 2012 denial of the group’s petition that asked FDA to withdraw its approval for a medical device directed to stent technology. Public Citizen’s original petition urged the withdrawal of approval for and recall of Stryker Corporation’s (“Stryker’s”) Wingspan Stent System with Gateway PTA Balloon Catheter (“Wingspan Stent”), which is used to treat narrowing of the blood vessels in the brain.
In its January 28 letter, Public Citizen claimed that FDA denied the petition based on flawed reasoning. Specifically, Public Citizen argued that FDA’s decision minimized the importance of crucial scientific evidence indicating that the Wingspan Stent is ineffective and, furthermore, that it is more harmful to patients experiencing intracranial narrowing of the blood vessels when compared to alternative forms of treatment. Public Citizen also criticized FDA’s attempt at comprise by narrowing the proposed indication of the stent in response to the scientific data outlined in the petition. Public Citizen argued that such attempts fell far short of being sufficient to ensure the safety of patients that might consider using Stryker’s medical device.
The Wingspan Stent is a class III medical device that comprises a stent with a balloon catheter and, until recently, was indicated for use “in improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with ≥ 50% stenosis [(a narrowing of the blood vessels that supply blood to the brain)] that are accessible to the system.” In simple terms, the device uses a self-expanding tube that is inserted into a blocked artery in the brain with the “goal of increasing blood flow and preventing strokes in patients who have experienced repeat strokes, even after taking medication to prevent blood clotting.”
FDA granted approval to market the product under an application for a Humanitarian Device Exemption (“HDE”). Under an HDE, FDA authorizes the marketing of a humanitarian use device that treats or diagnoses a disease or condition that affects less than 4,000 people in the United States annually. Notably, an HDE application is exempt from the effectiveness requirements of sections 514 and 515 of the Federal Food, Drug, and Cosmetic Act. Thus, an applicant seeking an HDE need not pursue the standard premarket approval steps of demonstrating that its medical device is effective through clinical investigation or through proof of equivalence with an already existing product.
HDE applicants must still establish certain threshold requirements before introducing their products in the marketplace. Applicants need to prove, and FDA must determine, that the proposed device will not expose its intended patients “to an unreasonable or significant risk of illness or injury, and that the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.” Further, FDA must conclude that comparable devices do not exist and that the proposed device would otherwise be unavailable to the public without FDA approval.
FDA granted the original HDE application based on both preclinical and clinical data. The sole clinical study submitted with the application to FDA occurred in 2005 and contained 45 participants (only 44 subjects received the Wingspan Stent). Public Citizen described the study as being “small, prospective, uncontrolled, multicenter, and single-arm[ed].” It took place in 12 academic medical centers throughout Europe and Asia. Each participant had a history of stroke, with their most-recent stroke having occurred more than seven days before they enrolled in the study. Each participant also had recurrent symptoms attributable to stenosis ≥ 50% that were refactory, or resistant, to standard medical therapy.
Among other adverse events that occurred in the study population, the composite ipsilateral stroke–which is a stroke occurring on the side of the brain supplied by the stented intracranial artery–or death rate at 30 days post procedure, the primary safety end point of the study, was 4.5%. Two out of 44 subjects that received the Wingspan Stent had ipsilateral strokes within 30 days of the procedure; one of the two people died as a result of the stroke. After six months post-procedure, another person suffered a stroke. Notably, the study did not include a control group. In other words, it consisted only of individuals that received the Wingspan Stent; no other treatment was used for comparison purposes. Questions about the sufficiency of the clinical trial formed the foundation for Public Citizen’s petition and its follow-up letter to FDA’s denial of its petition.
Public Citizen filed its citizen petition on December 21, 2011, and a supplement to the petition on January 12, 2012. The petition contained two requests to FDA: (1) withdraw HDE approval for the Wingspan Stent; and (2) order Stryker to initiate a class I recall of all unused Wingspan Stents. In the petition, Public Citizen criticized the value of the 2005 HDE clinical study as failing to prove that the Wingspan Stent is safer or more effective than medical therapy alone, which it called the “best alternative treatment option.” It highlighted the fact that the study’s results suggested that treatment with the Wingspan Stent results in strokes and even death in some individuals. Public Citizen also attacked the study for not using as an appropriate control group a group of subjects treated solely with medical therapy, which it defined as including antiplatelet therapy, blood pressure-lowering medication, and management of risk factors. Although it also discussed various other clinical trials involving the Wingspan Stent that supported withdrawal of Stryker’s HDE, Public Citizen focused heavily on a National Institute of Health (“NIH”) study using the medical device that raised concerns about its safety and efficacy.
Public Citizen asked FDA to withdraw its approval for the Wingspan Stent based on the results of the NIH’s Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (“SAMMPRIS”) study. The SAMMPRIS study enrolled 451 subjects, each of who had experienced a recent stroke or a transient ischemic attack (“TIA”) attributed to stenosis of 70-90% in a major intracranial artery. The SAMMPRIS subjects received either stenting with the Wingspan Stent together with aggressive medical management, or aggressive medical management alone. Public Citizen described aggressive medical management as antithrombotic therapy plus management of stroke risk factors. The two studies differed in several ways. Among their differences, the HDE study did not use subjects that had experienced a TIA, and its subjects had stenosis ≥ 50% in a major artery.
The SAMMPRIS study ended prematurely. Subjects that received both a Wingspan Stent together with medical therapy experienced a 30-day stroke or death rate that was much higher than the group receiving only medical therapy. The stroke or death rate was 14.7% in the Wingspan Stent group; the medical management group, however, experienced a stroke or death rate of only 5.8%. The rates beyond the first 30 days remained the same. Stryker and FDA both made public comments stressing the dissimilarities between the SAMMPRIS study’s subjects from those in the HDE study, implying that the SAMMPRIS study provided limited insight into the safety and efficacy of the Wingspan Stent as indicated for use by FDA. Public Citizen’s supplement to its petition responded to and attempted to counter these arguments.
FDA conceded that the “SAMMPRIS study results provide clear, scientifically valid evidence that stenting does not provide a benefit over aggressive medical management for most patients with symptomatic intracranial stenosis.” But despite this statement, FDA reiterated its public comments that “[a] different study population was included in the SAMMPRIS study as compared to the HDE study” and that the “FDA believes that the SAMMPRIS subjects who differed from the population included in the HDE study . . . are not sufficiently comparable to the” HDE study subjects. These SAMMPRIS subjects include those that were not shown to be refactory to medical therapy, had a TIA as their qualifying event, did not have a history of stroke, or had their most recent stroke within 7 days of enrollment in the study. Because of the different population pools, FDA concluded that data between the two studies could not be compared to draw reliable conclusions about the HDE study and its subjects.
FDA noted, however, that the SAMMPRIS results provided it with relevant information about the Wingspan Stent for patients not considered in the HDE study. It therefore adopted a new indication (that Stryker proposed) for the Wingspan Stent. Under the new indication, use of the Wingspan Stent is limited to patients: (1) who are 22-80 years old; (2) who have had two or more strokes, despite use of aggressive medical management; (3) whose most recent stroke occurred more than seven days before the Wingspan Stent treatment is to occur; (4) who have a 70-90% stenosis due to atherosclerosis of an intracranial artery related to recurrent strokes; and (5) who have made good recovery from their past strokes and have a modified Rankin score of 3 or less, where the Rankin scale measures the degree of disability in stroke patients (a lower score indicates less disability).
Public Citizen found FDA’s response to its petition to be inadequate. In its January 28, 2013 letter to FDA, Public Citizen urged FDA to withdraw its approval of the HDE for the Wingspan Stent and to reevaluate the data provided in the petition, which, according to Public Citizen, “overwhelmingly fails to support the FDA’s regulatory decision to allow the Wingspan Stent System to remain on the market–even for patients specified in the new labeling.” Based on its response to Public Citizen’s petition and supplement, it is unlikely that FDA will change course concerning the Wingspan Stent.
FDA has not yet responded to Public Citizen’s most recent attempt to have the Wingspan Stent withdrawn from the marketplace. But a review of the events leading up to the January 28 letter indicate that Public Citizen is determined to remove the product from the market, and that its fight to do so may continue regardless of how FDA responds to the letter.