FDA Executive Summary

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1 FDA Executive Summary Prepared for the April 17, 2015 meeting of the Neurological Devices Panel Meeting to Discuss Clinical Study Design and Evaluation of Clinical Study Data for the Treatment of Aneurysm Executive Summary Page 1 of 38

2 Table of Contents 1 Introduction and Purpose of Advisory Panel Meeting Aneurysm Overview: Diagnosis, Study Methods, and Treatment Approaches Morphology and Size of Aneurysms Anatomical Locations Perforators Rupture rate Aneurysm Treatment Methods Surgical Clipping Coiling Balloon Assisted Coiling Stent Assisted Coiling (SAC) Flow Diverters Other Treatment Approaches Section Review Long Term Treatment Durability Grading Scales Strengths and Limitations Associated with Randomized Controlled Trials versus Single-Arm Studies with a Performance Goal Randomized Control Trials Performance Goals (PG) Strengths and Limitations of RCTs and Performance Goals Statistical Accounting for Heterogeneity in Aneurysm type, size and location in the Analysis of Safety and Effectiveness Approaches to Patient Subgroups Regulatory Summary of Aneurysm Treatments Approved Indications for Use Premarket Approval (PMA) Submissions Pipeline TM for Uncoilable or Failed Aneurysms (P100018) Humanitarian Device Exemption (HDE) Submissions NeuroForm - Stryker Neurovascular HDE (H020002) CORDIS Enterprise - Codman & Shurtleff HDE (H060001) Low-profile Visualized Intraluminal Support (LVIS ) - MicroVention HDE (H130005) 28 4 Summary Glossary References Executive Summary Page 2 of 38

3 List of Figures Figure 1. Illustration of saccular aneurysms occurring throughout the neurovasculature. The percentages are the relative occurrence rates based on the different locations (Netter 1991) Figure 2. Illustration of (A) Stent Assisted Coiling (combination of endosaccular and endoluminal treatment) and (B) Flow Diversion (solely endoluminal) Figure 3. Overview for some marketing pathways, a few device examples for each pathway, and typical trial designs related to the treatment of aneurysm. HDE and PMA devices have similar requirements during the approval process with an important difference being that a PMA device requires a reasonable assurance of safety and efficacy while and HDE requires that probable benefit outweighs the risk. 510(k) devices have involved both Randomized Control Trials (RCT) and Performance Goal (PG) studies, whereas only PG studies have been used for PMA approval Executive Summary Page 3 of 38

4 List of Tables Table 1. Approved Flow Diverters and SAC systems and Indications for Use Table 2. Summary of location and size information for the aneurysms treated in the PUFS Trial Table 3. Location of aneurysms treated as part of the NeuroForm SSPB (H020002) Table 4. Size of aneurysms treated as part of the NeuroForm SSPB (H020002) Table 5. Serious Device or Procedure-Related Adverse Events of the NeuroForm SSPB (H020002) Table 6. Clinical outcome as part of the NeuroForm SSPB (H020002) Table 7. Location of aneurysms treated as part of the Enterprise SSPB (H060001) Table 8. Adverse events reported for the Enterprise SSPB (H060001) Table 9. Aneurysm occlusion results reported as part of the Enterprise SSPB (H060001) Table 10. Aneurysms location information as part of the LVIS SSPB (H130005) Table 11. Aneurysm size information as part of the LVIS SSPB (H130005) Table 12. Occlusion results as part of the LVIS SSPB (H130005) Executive Summary Page 4 of 38

5 1 Introduction and Purpose of Advisory Panel Meeting A cerebral aneurysm (also known as an intracranial or intracerebral aneurysm) is a weak or thin spot on a blood vessel in the brain that balloons out and fills with blood. The bulging aneurysm can put pressure on nerves or surrounding brain tissue. It may also leak or rupture, spilling blood into the surrounding tissue (called a hemorrhage). Some cerebral aneurysms, particularly those that are very small, may not bleed or cause other problems. Aneurysms have been reported in the literature for several decades (Housepian and Pool 1958; Chason and Hindman 1958; Jellinger 1976) and it is estimated that on average five percent of the population is afflicted (Jellinger 1976). Originally, open surgery was used to treat aneurysms by placing a clip across the neck of the aneurysm to eliminate flow from the parent artery into the aneurysm. In recent years there have been several advancements in the treatment of aneurysms through endovascular means (Johnston et al. 1999; Roy, Milot, and Raymond 2001; Starke et al. 2012). These methods are used as an alternative to open surgical clipping. One device type that has recently been reported in clinical use is flow diversion technology (Berge et al. 2012; Byrne and Szikora 2012; Wakhloo et al. 2015; D Urso et al. 2011). Flow diverters are high mesh density stents that when placed in the parent vessel of an aneurysm, reduce the flow into the aneurysm. This intervention promotes blood stasis in the aneurysm, endothelial growth across the neck, and occlusion of the aneurysm. Flow diverters offer an alternative to other interventional techniques (e.g. traditional coiling and stent-assisted coiling) or surgical clipping (Berge et al. 2012). Alternatively, stentassisted coiling uses aneurysm coils as the primary mechanism for blood stasis. The coil is kept within the aneurysm using a stent that has a lower mesh density in comparison to flow diverters. Under the Premarket Approval (PMA) regulatory pathway, the Covidien Pipeline Embolization Device (PED) flow diverter is approved for endovascular treatment of large or giant wide-neck intracranial aneurysms in the internal carotid artery (ICA) from the petrous to the superior hypophyseal segment. Use of flow diverters in other regions of the brain has not been approved, although published literature has reported its use outside the ICA (Nelson et al. 2011). Under the humanitarian device exemption (HDE) regulation pathway, three stent-assisted coiling (SAC) systems are approved with embolic coils for the treatment of wide neck, intracranial saccular aneurysms arising from a parent vessel with a diameter of > 2mm and < 4.5 mm that are not amenable to treatment with surgical clipping 1. It is important to note the regulatory evidence required for PMA and HDE approvals are different. For example, under PMA, the application must provide reasonable assurance that the device is safe and effective for its intended use. Under HDE the application requires and explanation of why 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. Considering the different regulatory approaches to studying devices, and published literature in this field, identifying the best approach to trial designs and evaluation of clinical study data can be challenging in the development of medical devices for the treatment of aneurysm. Additional concerns of flow diverters 1 Under H020002, an SAC system is approved for wide neck aneurysms are defined as having a neck of > 4mm or a dome-to-neck ratio of < 2mm, Under H060001, an SAC system is approved for use with embolic coils for the treatment of wide-neck, intracranial, saccular or fusiform aneurysms arising from a parent vessel with a diameter of >3 mm and < 4 mm and wide-neck is defined as having a neck width > 4mm or a dome-to-neck ratio of <2. Under H130005, an SAC system is approved for use with bare platinum embolic coils for the treatment of unruptured, wide neck (neck > 4 mm or dome to neck ratio < 2), intracranial, saccular aneurysms arising from a parent vessel with a diameter > 2.5 mm and < 4.5 mm. Executive Summary Page 5 of 38

6 and related technologies can include inadvertent blockage of arterial branches off of the parent vessel especially small perforator arteries proximally and distally with respect to the aneurysm (Lopes et al. 2003; Masuo et al. 2005; Seong, Wakhloo, and Lieber 2007; D Urso et al. 2011) and the potential for long-term damage caused by arterial branch occlusion remains an unknown safety concern. The safety and effectiveness for novel interventional aneurysm treatments is an evolving, innovative product area that involves several factors including aneurysm type (small/medium versus larger/giant), location (anterior versus posterior) and surrounding anatomy (such as perforators), different assessment tools (primary and secondary endpoints), and different clinical trial designs (single arm studies using performance goals or randomized controlled trials). FDA is convening this panel meeting to seek expert opinion on scientific and clinical considerations relating to trial design, assessment measures, outcome measures, as it relates to the evaluation of clinical study data for aneurysm treatment technology and other neurointerventional medical devices. FDA Comment: Medical devices indicated for the treatment of aneurysms have been approved using different regulatory paths, in part based upon the benefit risk profile of the medical device and how it was used to promote public health. FDA is seeking panel input on the comparisons that can be made using different clinical study data for these devices. See Questions 1, 2, 3, 4, 5. 2 Aneurysm Overview: Diagnosis, Study Methods, and Treatment Approaches Intracranial aneurysms occur in the neurovasculature and typically develop at vessel branch points as illustrated in Figure 1. Aneurysms of the anterior neurovasculature can include cavernous ICA aneurysms, ophthalmic artery aneurysms, superior hypophyseal artery aneurysms, posterior communicating artery (PCom) aneurysms, anterior choroidal aneurysms, ICA termination aneurysms, anterior communicating artery (ACom) aneurysms, anterior cerebral artery (ACA) aneurysms, or middle cerebral artery (MCA) aneurysms. Aneurysms of the posterior neurovasculature can include posterior inferior cerebellar artery (PICA) aneurysms, anterior inferior cerebellar artery (AICA) aneurysms, superior cerebellar artery (SCA) aneurysms, basilar apex aneurysms, or posterior cerebral artery (PCA) aneurysms (Greenberg 2010; Winn 2011). Aneurysms may be treated prior to rupture in their unruptured state or after a rupture has occurred, resulting in an intracranial hemorrhage, known as subarachnoid hemorrhage (SAH). 2.1 Morphology and Size of Aneurysms Aneurysms are often classified by their morphology. Aneurysms may be described as saccular (bulging on one side), fusiform (bulging on all sides), pseudoaneurysm (resulting from trauma to the blood vessel wall), or dissecting (a separation of the layers of the arterial wall). The most common types of aneurysms are saccular (sometimes referred to as berry aneurysms) which protrude off of the side of the vessel; fusiform aneurysms which is a dilation of a particular segment of a vessel, and dissecting aneurysms which results from a tear between the inner (intima) and out vessel wall causing blood to collect between layers of the vessel wall. Neck size, the size of the opening that connects the parent artery to the aneurysm body, is also an important descriptor for aneurysms and can dictate treatment options. Aneurysms with a neck > 4 mm in diameter are typically classified as wide-neck (Biondi et al. 2007; Sedat et al. 2009; Huang et al. 2009; Standhardt et al. 2008; Wiebers 2003) and a study conducted by Roy et al. on 125 unruptured aneurysms determined 37.6% of those aneurysms to be wide-neck (Roy, Milot, and Raymond 2001). Such aneurysms can be difficult to treat and are less amenable to coiling or surgical clipping in comparison to aneurysms with smaller necks (Kwon et al. 2005). Executive Summary Page 6 of 38

7 Figure 1. Illustration of saccular aneurysms occurring throughout the neurovasculature. The percentages are the relative occurrence rates based on the different locations (Netter 1991). Although some disagreement exists on the precise size classifications of naturally occurring saccular aneurysms, a general trend can be seen and most studies have defined aneurysm sizes (based on the location of maximum diameter) as follows: Small < 5 mm, Medium 6-10 mm, Large mm, and Giant > 25 mm (Molyneux et al. 2009). The International Study of Unruptured Intracranial Aneurysm (ISUIA) retrospectively studied 1449 patients with angiographically confirmed aneurysms and identified the size distribution of aneurysms to be 47%, 27%, 12%, and 14% for small, medium, large, and giant aneurysms, respectively (Wiebers 1998). The predominant occurrence of small and medium aneurysms has also been confirmed in additional studies (Standhardt et al. 2008). 2.2 Anatomical Locations The initial ISUIA data referenced above determined that of the 1449 aneurysms included in the trial, 207 (14%) were located in the posterior portion of the vasculature. In a 2003 follow-up study, 12% of the 4060 participating patients had aneurysms located in the posterior circulation. The relative occurrence rates between the different locations is also shown in Figure 1 (Netter 1991). The distinction between anatomical locations is noteworthy because the posterior vasculature been shown to be an indicator of poor clinical outcome for both surgery and endovascular treatment of unruptured aneurysms, primarily due to the increased risk of rupture (Wiebers 2003). This difference in patient outcomes based on anatomical location was supported by subsequent studies which determined that the advantage of endovascular over surgical treatment can depend greatly on the location of the aneurysm location in part due to the accessibility of the aneurysm through endovascular means (Molyneux et al. 2005). This investigation was a randomized prospective study where 1070 patients were selected for surgical clipping and 1063 were treated endovascularly. The primary outcome was measured by death or dependence at 1 year (modified Rankin Scale of 3-6). The investigators determined that the risk ratio more strongly favored endovascular treatment in the posterior vasculature as compared to the anterior (risk ratio of 0.89 Executive Summary Page 7 of 38

8 for anterior aneurysms and a risk ratio of 0.39 for posterior, both favoring endovascular treatment) (Molyneux et al. 2005) Perforators Perforators are small branches that emerge from larger vessels which may be responsible for supplying blood to various portions of the brain. While perforators are present in both the anterior and posterior circulations, perforator vessels in the posterior circulation are at particularly high risk for occlusions causing infarction relative to those in the anterior circulation. This discrepancy is likely because of the delicate perfusion and lack of collateral blood supply to brainstem structures. During endosaccular treatment methods such as traditional coiling, perforators typically are unaffected. However, techniques such as stent-assisted coiling, flow diversion, and even surgical clipping can potentially impact the perforators by occluding or damaging these branches (Molyneux et al. 2005). It has been estimated that based on the flow diverter mesh size and the size of the perforator, a flow diverter could reduce the perforator orifice area by 55% (Kulcsár et al. 2010). Perforator occlusion has been discussed in the clinical literature for both flow diverters as well as SAC and has raised concern regarding the safety of such devices (Lopes et al. 2003; Masuo et al. 2005; D Urso et al. 2011). In one case study, ophthalmic artery occlusion was seen on immediate angiography as well as on the 6-month follow up study (Szikora et al. 2010). Other clinical studies that have investigated flow diverters have raised concerns about perforator patency (Kulcsár et al. 2010). Kulcsár et al. (2010) reported the occurrence of a late ischemic event in one patient in the treatment of posterior aneurysms which was attributed to the flow diverter implantation occluding perforators. This study suggests limited use of flow diverters to otherwise untreatable aneurysms due to the potential impact the devices may have a serious impact on perforators (Kulcsár et al. 2010). Conversely, several literature sources de-emphasize the concern for perforator occlusion. A series of in vitro studies have stated that because flow through perforators is driven by pressure, even with 90% coverage of the perforator inlet area, the resulting perforator blood flow may only be reduced by < 10% (Seong, Wakhloo, and Lieber 2007; Appanaboyina et al. 2008; D Urso et al. 2011). FDA Comment: The FDA is seeking the panel s comment on the benefit/risk considerations for medical devices when evaluating different types of aneurysms in different regions of the neurovasculature. FDA is also seeking panel comment on assessing the parent artery and how perforators should be considered with respect to anatomical location and trial design. See FDA Questions 1, 2, Rupture rate Aneurysm rupture rate is another important factor when considering aneurysm treatment options as it can lead to a SAH which can be life threatening. It has been suggested that aneurysms have an average rupture rate of around 1% per year in patients with a diagnosed aneurysms, although that number can vary based on the study (Ishibashi et al. 2009; The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012; Juvela et al. 2013). Of the 1449 patients enrolled in the ISUIA trial, 32 had a confirmed aneurysmal rupture (2.2% of the total number of patients) with 28 of those in the first 7.5 years of follow-up (rupture rate of 0.3% per year) (Wiebers 1998). For the patients in this study with a ruptured aneurysm there was a 66% mortality rate which was the leading cause of death for patients in the study regardless if the death was attributable to the aneurysms underscoring the significances of aneurysm rupture as a major risk to patient health. In a later study comparing conservative management to intervention, 51 patients in the unoperated cohort (3% of the patients) experienced a confirmed rupture during follow-up with 49 of those occurring within the first 5 years of diagnosis (rupture rate of 0.5%) (Wiebers 2003) while Juvela et al. (2013) followed patients for more than 20 years and found an annual incidence rupture rate of 1.1%. Executive Summary Page 8 of 38

9 Rupture rates can be affected by many factors such as a history of prior SAH, location in the posterior circulation, as well as the overall size of the aneurysm (Ishibashi et al. 2009). It has been suggested that rupture rate for patients without a prior history of SAH can be as low as 0.05% in the first year which is 10 times lower than those with a previous SAH (0.5%) (Wiebers 1998). Other studies have confirmed the correlation between increased rupture rates and a prior history of SAH ( The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012). Aneurysms in the ICA, ACom, ACA or MCA that were < 7 mm, 7-12 mm, mm and > 25 mm had rupture rates of 0%, 2.6%, 14.5%, and 40%, respectively at 5 years (Wiebers 2003). Rupture rates of 2.5%, 14.5%, 18.4% and 50% were seen, for the same distribution of size, for aneurysms involving the posterior circulation and posterior communicating artery aneurysms (Wiebers 2003). Size is an additional factor that can have a direct impact on the rupture rate. Several studies have suggested that smaller aneurysms (< 7 mm) rarely rupture with a rupture rate reported at 0.7% and, therefore, may be best treated conservatively ( The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012; Rinkel et al. 1998; Komotar, Mocco, and Solomon 2008). For patients with an unruptured aneurysm without a history of SAH, that rate drops to 0.1% for aneurysms < 7 mm in diameter (Ishibashi et al. 2009; Wiebers 2003). This finding again supports the position that small aneurysms are best treated with conservative management over surgical or interventional methods (Komotar, Mocco, and Solomon 2008). Conversely, it has been seen that larger aneurysms are at a greater risk for rupture. The rupture rate for aneurysms > 25 mm have a reported 6% rupture rate in the first year (Wiebers 1998) with an annual rupture rate as high as 43.1% (Ishibashi et al. 2009). As the aneurysm grows in size the outer wall can begin to thin increasing the likelihood of rupture. As a result, large aneurysms are typically treated soon after discovery. The role of anatomical location and geometry can play an important role in the rupture rate of aneurysms. Aneurysms in the posterior circulation have a rupture rate almost three times that of the aneurysm located in the ICA (Ishibashi et al. 2009; Wermer et al. 2007). Aneurysms with a daughter sac (an irregular protrusion of the wall of the aneurysm) are also at a higher risk for rupture ( The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012). FDA Comment: Aneurysm rupture can result in a subarachnoid hemorrhage which can lead to death. Understanding the risk of rupture is an important factor when designing and evaluating clinical trials for endovascular treatment of aneurysms as it can have a significant impact on patient outcomes. FDA is seeking panel input regarding the benefit/risk ratio related to aneurysm treatment, factoring in the possibility of rupture, as it pertains to aneurysm size, location, safety endpoints and patient follow up. See FDA Questions 1, 4, 7, Aneurysm Treatment Methods While aneurysm occurrence can be relatively common, the treatment methods prescribed have been the subject of controversy for a number of years (Ishibashi et al. 2009; Hetts et al. 2014; Chalouhi et al. 2014; The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012; Komotar, Mocco, and Solomon 2008). With the advent of the less invasive endovascular treatments there has been an increase in the number of unruptured aneurysms that are being treated rather than followed (Wiebers 2003; Komotar, Mocco, and Solomon 2008; Ishibashi et al. 2009; The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort 2012; Hetts et al. 2014; Chalouhi et al. 2014), but a consensus has yet to be reached as to which aneurysms are best treated with which method Surgical Clipping Executive Summary Page 9 of 38

10 Aneurysms, both ruptured and unruptured, may be treated via craniotomy (brain surgery) by surgical clip ligation and microsurgical clips placed on the aneurysm neck in order to remove the aneurysm from the circulation and prevent possible rupture (or if the aneurysm had already ruptured, to prevent re-rupture). Some feel that surgical clipping is still the best option for particular aneurysms types (Cantore et al. 2008). The advantage with this technique is that it can provide immediate aneurysm occlusion and has been shown to provide positive results for patients with large and giant aneurysms (Cantore et al. 2008) and the immediate occlusion reduces the risk of SAH. As part of the International Subarachnoid Aneurysm Trial (ISAT) that compared open surgery to endovascular coiling, clipping was shown to have a lower annual risk of rebleeding in previously ruptured aneurysms, 3.6% and 4.2% for clipping and coiling respectively at 7 year follow up (Molyneux et al. 2005). It has also been shown that clipped aneurysms are 4 times less likely to be retreated than with endovascular treatment (Campi et al. 2007). It is important to note however, that clipped aneurysms are much less likely to have follow-up imaging. While there are some clear benefits to surgical clipping there are also some concerns. There was a higher mortality rate associated with open surgery, 10.7% and 13.8% for traditional coiling and surgical clipping respectively (Molyneux et al. 2009). Patient age has been shown to be a strong indicator of poor surgical outcome (Wiebers 2003). This phenomenon is most easily attributed to the inherent trauma that any open surgical procedure carries. It has also been shown that surgical clipping carries an increased risk of seizures both in the short and long term follow up (Molyneux et al. 2005). Molyneux et al. (2005) showed that 4.1% of surgical patients (compared to 2.5% of the interventional patients) had seizures associated with rebleed after receiving treatment for their aneurysm. Surgical clipping is also not immune to interaction with perforators. While open surgery allows for visualization of perforators that may not be visible on angiography, there still is a risk of unintentionally clipping a perforator which will cause immediate occlusion and could significantly affect a patient s outcome Coiling Endovascular treatment methods offer a less invasive method to treat intracranial aneurysms. For traditional coiling a catheter, typically inserted in the femoral artery, is tracked through the vasculature to the aneurysm where coils are placed inside the body of the aneurysm to promote occlusion. The first endovascular method was performed using detachable embolic coils (Guglielmi, Viñuela, Sepetka, et al. 1991; Guglielmi, Viñuela, Dion, et al. 1991) which were placed through a guide catheter into the aneurysm to promote occlusion. The number of coils used varied depending on the size of the aneurysm. An early trial included 15 patients all of which showed significant benefit from the procedure (Guglielmi, Viñuela, Dion, et al. 1991). Subsequent to this first trial, several larger studies have investigated the benefit of coiling for aneurysm repair (Campi et al. 2007; Standhardt et al. 2008; Cognard et al. 1999). The largest of these investigations was the ISAT which studied 2143 patients treated with either surgical clipping or coiling (Molyneux et al. 2002; Molyneux et al. 2005; Molyneux et al. 2009). This study found that while there was a small increased risk of recurrent bleeding from coiling, 1.0% and 0.3% for coiling and clipping respectively, a decreased risk of death was observed at 5 years for patients treated endovascularly, 10.7% and 13.8% for coiling and clipping (Molyneux et al. 2009). Standhardt et al (2008) retrospectively investigated the treatment of 173 patients with unruptured aneurysms (202 total aneurysms) over a 12 year period, all treated with traditional coiling. Aneurysms in this study were primarily small (<7 mm) and medium (7-12 mm) in size, 43.5% and 37.1% respectively, and were most frequently found in the in the ICA, 43.1%. Of the 202 aneurysms, 57.5% demonstrated complete occlusion following the procedure. This outcome was significantly higher for small sized aneurysms (71.6%). Giant aneurysms (>25 mm) resulted in the poorest initial occlusion rate at 10.5% rising only slightly to 11.8% at follow up. Morbidity and mortality rates for the 173 patients were relatively low, 3.5% and 0.5%, respectively. The most common complication found in this study was thromboembolic events with 3% of these patients suffering a stroke. This study also noted a strong Executive Summary Page 10 of 38

11 dependence on neck size and occlusion rate. Aneurysms with narrow necks had an occlusion rate of 77.1% while the rate for wide-neck aneurysms was 35.8% (Standhardt et al. 2008). These results suggest that not all aneurysms types may be best suited for treatment with traditional coiling. Cognard et al. (1999) performed a prospective study investigating the use of detachable coils in 169 aneurysms. This study focused almost exclusively on smaller aneurysms (<8 mm) with aneurysms most frequently occurring in the ICA (35%). Immediate occlusion was seen in 56% of the aneurysms with that number rising to 79% at follow up. Of the 148 aneurysms that reached complete occlusion, 20 (14%) required retreatment within the first 3-40 months after treatment. This study showed almost no connection between retreatment rate and anatomical location but did show a slight dependence on neck size, with wide-neck (defined the by dome to neck ratio < 2) having a higher probability of requiring retreatment. Although traditional coiling is less invasive than surgical clipping, the possible need for retreatment is another important factor when deciding on a treatment method Balloon Assisted Coiling One of the concerns associated with coiling is the possibility of coils protruding into the arterial lumen and occluding flow in the parent artery. To help mitigate this risk, a procedure referred to as Balloon Assisted Coiling (BAC), also known as the Remodeling Technique (RT), was developed (Moret et al. 1997). During this technique, a balloon is inflated inside the parent artery after a microcatheter used to deliver the coils is placed inside the neck of the aneurysms. The coils are then detached with the balloon inflated to allow the clinician to more tightly pack the aneurysm without the risk of coils protruding into the lumen (Nelson and Levy 2001). Pierot et al. investigated BAC as part of the Analysis of Treatment by Endovascular approach of Non ruptured Aneurysms (ATENA Trial) (Pierot, Spelle, and Vitry 2008). This was a prospective trial that included 649 patients harboring 739 unruptured aneurysms. The majority of these aneurysms (54.5%) were treated with traditional coiling, while (37.3%) were treated using BAC. Of 739 unruptured aneurysms, 91.9% were located in the anterior circulation with only 60 (8.1%) aneurysms in the posterior circulation. Aneurysm size was classified using the following groupings: 1 to 3 mm (17.7%), 4 to 6 mm (41.1%), 7 to 10 mm (29.1%), and 11 to 15 mm (12.0%). Aneurysms greater than 15 mm were listed as part of the exclusion criteria. Postoperative evaluation of aneurysm occlusion (evaluated by a core laboratory) showed that 59.0% had complete occlusion, 21.7% had some neck remnant (i.e. flow still present in a portion of the aneurysm neck) and 19.3% had aneurysm remnant (i.e. flow still present in the dome of the aneurysm). When comparing the number of complications between traditional coiling and BAC, this study showed an increased percentage of patients had thromboembolic complications with coiling as compared to BAC (7.3% compared to 5.5% respectively). While this information helps to support use of the BAC technique for anterior aneurysm, little is known about the efficacy in the posterior portion of the neurovasculature because of the small number of subjects with aneurysms in the posterior neurovasculature. A recent review article discussed some of the differing opinions on the safety and effectiveness of BAC, such as complication rates and thrombus events as well as the treatment of wide-neck aneurysms (neck > 4 mm) (Pierot et al. 2012). One of the studies included in this review indicated there was increased risk of procedure related complications with BAC, 14.1% as opposed to 3.0% seen with traditional coiling (Sluzewski et al. 2006). A more recent study have shown that complication rates are similar, 10.8 % and 11.7% for BAC and traditional coiling respectively (Pierot et al. 2009). Another study showed that the rate of thrombus events is also comparable between these two techniques (14% and 9% for BAC and traditional coiling respectively) (Layton et al. 2007). For treating wide-neck (> 4 mm) aneurysms a retrospective study by Chalouhi et al. found that SAC had higher occlusion rate then BAC, 75.4% versus 50% respectively, as well as a lower retreatment rate, 4.3 % and 15.6 (Chalouhi et al. 2013). The apparent Executive Summary Page 11 of 38

12 A) B) Figure 2. Illustration of (A) Stent Assisted Coiling (combination of endosaccular and endoluminal treatment) and (B) Flow Diversion (solely endoluminal). disagreement between studies using BAC suggests that additional studies are required to fully understand the complete benefit/risk profile associated with BAC Stent Assisted Coiling (SAC) In conjunction with detachable coil technology (see section 2.4.2), SAC utilizes a stent placed across the opening of the aneurysms to aid in coil packing which in turn promotes occlusion, Figure 2A. Similar to BAC, these stents act as a rigid structure that helps prevent protrusion of the coils into the parent vessel. The only SAC systems approved by the FDA (see section 3.3 below) are through the HDE process where the regulatory determination for approval is an assessment of the risks and probable benefits of the device which is different than the evidence required to provide a reasonable assurance that the device is safe and effective for its intended use under the PMA regulatory path. One development in SAC came with the introduction of self-expandable stents (Peluso et al. 2008). Previous stent iterations required the use of a balloon for placement of the stent (similar to the original cardiac stents) which limited use to regions of the neurovasculature that could be accessed using balloon catheters, and the devices had reduced stent flexibility. Self-expanding stents are constructed from nitinol, a shape memory alloy that eliminates the requirement for a balloon, thus improving tractability and removing the risk of rupturing the parent vessel through balloon overexpansion. These stents were also relatively large in diameter which made delivery into some of the smaller vessel in the neurovasculature more difficult. Subsequent device iterations allowed for greater access to new portions of the neurovasculature. Nonetheless, long term follow-up for devices used in these regions remains unavailable and therefore, effectiveness of this technique has not been established. One of the first studies to investigate the use of SAC for the treatment of intracranial aneurysms was Lanzino et al. (1999) which utilized coronary balloon expandable stents in sections of the internal carotid, vertebral, and basilar arteries. Of the 10 patients treated in this study there were no permanent periprocedural complications. Greater than 90 % occlusion was seen in all 8 of the patients treated with both a stent and detachable coils (2 patients were treated with stenting alone). In-stent stenosis was noted on follow up angiography for at least one of the patients. This study demonstrated the technical feasibility of using stents to aid in the coiling of intracranial aneurysms but the authors at the time noted that while immediate results were positive, long term effects were still unknown. In 2004 Benitez et al. demonstrated the use of a specifically designed intracranial microstents (Neurofrom) for use with both ruptured and unruptured wide-necked intracranial aneurysms (Benitez et al. 2004). This study included 48 patients with 49 aneurysms (32 of which were unruptured). Eight of the stent deployments failed. Forty-one aneurysms were stented then coiled, six were treated with stent only, and one aneurysm was coiled and then stented. The mortality rate for this trial was 8.9% with four Executive Summary Page 12 of 38

13 patients (7%) experiencing a thromboembolic event with an overall complication rate of 10.7%. Complete occlusion was reported in 35 (66%) of the patients treated. These early findings suggested that a device could provide possible benefit to a previously under-severed patient population could be achieved. This device was approved by the FDA under HDE in Lee et al. (2005) also performed one of the first studies that investigated the use of SAC specifically for wide-neck intracranial aneurysms. Twenty-two patients harboring 23 aneurysms (16 unruptured) were treated with SAC. These aneurysms were primarily located in the ICA (60%). Immediate occlusion was reported in 43% of the aneurysms studied in this trial. Interestingly, this study reported infrequent in-stent thrombosis even when patients were not given antithrombolytics due to the presence of SAH. The authors also reported no evidence of stent-related thromboembolic complications during the follow up period. While this study again highlights the utilization of SAC for the treatment of wide-neck aneurysms, the authors assert that longer periods of follow-up are required before a better understanding of the safety and efficacy can be reached (Lee et al. 2005). As this technology has been further developed, SAC has been shown to have a lower recurrence rate (i.e. flow returning to the aneurysm dome) compared to coiling alone (Piotin et al. 2010). Clinical outcomes of 1137 patients with 1325 aneurysms were retrospectively analyzed between 2002 and Of these aneurysms 206 (16.5%) were treated with stents while the remaining aneurysms (1109) were treated with coiling alone. A significantly higher recurrence rate was seen in the patients treated with coiling alone versus those treated with stents, 33.5% and 14.9% respectively. A study by Piotin et al. suggested that one factor reducing recurrence rates in SAC is improvements to arterial wall reconstruction at the aneurysm neck (Piotin et al. 2010). This study is affected by the technological development in stent design that occurred over the course of enrollment, which caused variation in the results. Although tighter packing of coils is more difficult with SAC than coiling alone, follow-up results show SAC to have a better long term occlusion rate (Piotin et al. 2010; Biondi et al. 2007; Sedat et al. 2009; Lubicz et al. 2009) Flow Diverters One of the newest developments in the treatment of aneurysms has been flow diversion technology. One flow diverter is approved by FDA (discussed more fully in section 3.2 below). Flow diverters function by reducing the blood flow from the parent artery into the aneurysm. While similar in concept to a stent used for SAC, flow diverters have a significantly higher mesh density preventing flow in the parent artery from entering the aneurysm thus eliminating the need for a coil (Figure 2B) (Seong, Wakhloo, and Lieber 2007; Trager et al. 2009). This reduction in flow is designed to promote blood stasis, endothelial growth across the neck, and occlusion of the aneurysm. Typically when an aneurysm is treated with either coils, stent assisted coils, or surgical clipping, aneurysm occlusion occurs very rapidly which will protect against bleeding or rebleeding (Pierot 2011). Alternatively, Pierot et al. observed complete occlusion in only 49% of patients at 3 months and 95% of patients at 6 months post procedure. Although a portion of the slower occlusion progression may be attributed to the antiplatelet regimen prescribed to patients (Pierot 2011), this progression is slower in flow diverters where the aneurysm is left empty. This latent occlusion has been cited as a potential major safety risk because of the possibility for aneurysm rupture during this time (D Urso et al. 2011). 2 Neuroform Microdelivery Stent System - H was approved on September 11, ApprovedDevices/ucm htm Executive Summary Page 13 of 38

14 One common flow diverter described in the literature is the Pipeline Embolization Device (PED, ev3) 3 One study conducted by Lylyk et al. (2009) on PED included 53 patients harboring 63 aneurysms who were enrolled in this multicenter trial. All of the aneurysms treated were wide-neck which was defined as a dome-to-neck ratio of <2 or a neck size > 4 mm. The majority of the aneurysms included in this study were located along the anterior circulation (87%). Due to the inherent nature of flow diversion which works endoluminally, immediate occlusion was only seen in 5 aneurysms (8%) all of which were < 10 mm in their maximum dimension. At 6-month of follow-up 93% (26 of the 28 available aneurysms, not all patients were available at follow up) had complete occlusion with this percentage rising slightly at 12 months to 94.4% (17 of the 18 available aneurysms). A second study called the Pipeline Embolization Device for the Intracranial Treatment of Aneurysm Trial (PITA) (Nelson et al. 2011) investigated 31 patients harboring 31 aneurysms with all but two located in the anterior circulation. These aneurysms were primarily small, <10 mm (64.5%) and only 2 cases (6.5%) > 25 mm. While PED is intended to be used without adjunctive coiling, 16 of 31 aneurysms included in this trial used coils in addition to the PED. At follow-up (180 days) 93.3% of the aneurysms had been fully occluded with no reported device migrations. Mild in-stent stenosis (25%-50%) was reported in one case. This trial demonstrates the technical feasibility of flow diverters. It should also be noted that this study involved adjunctive coiling, an off-label use in the US; additional testing will be important to demonstrate a reasonable assurance of safety and effectiveness. Byrne et al. reported on early experiences with another flow diverter technology called SILK flow diverter 3 in 70 patients as part of a prospective multicenter study outside the US (OUS) (Byrne et al. 2010). Primarily the patients in this study presented with either wide-neck or fusiform aneurysms (91%). Immediately after treatment only 7 (10%) had complete occlusion of their aneurysm with occlusion rates rising to 49% at follow-up. Follow-up angiography was specified at one month after stoppage of antiplatelet therapy (median of 119 days of follow-up). Similar to early experience with SAC systems, there were 15 reports (21%) of deployment related complications. The morbidity and mortality rates for this trial were 4% and 8% respectively (4 deaths and 2 cases of permanent neurological deficit). As discussed above, these improving angiographic outcomes using flow diverter technology are in contrast to what is typically seen with coiling procedures. As reported earlier, coiling procedures have demonstrated favorable immediate occlusion results but reports also note high recurrence rates especially for large (>10 mm) and wide-neck aneurysms (Raymond et al. 2003; Murayama et al. 2003). The ability of flow diverters to produce endothelial growth across the aneurysm neck is an important factor in providing long term aneurysm occlusion (Pierot 2011). Flow diverters also by design do not typically require manipulation of the aneurysm sack which reduces the risk of rupture (Lylyk et al. 2009). Recently a meta-analysis of the literature was performed that included 29 studies with a total of 1654 aneurysms treated with flow diverters (Brinjikji et al. 2013). This analysis showed that 76% of these aneurysms achieved complete occlusion at 6 months with procedure related morbidity and mortality as low as 5% and 4% respectively. One of the major concerns with flow diverters is the risk of rupture due to the latency of occlusion (D Urso et al. 2011). It has been estimated that the risk for SAH after treatment with a flow diverter could be between 2 and 4% (D Urso et al. 2011; Brinjikji et al. 2013; Briganti et al. 2012) and the rate of SAH and Intraparenchymal hemorrhage decreases after the first 30 days post treatment (Brinjikji et al. 2013). 3 The PED is the only flow diverter approved by the FDA. PED and a second SILK flow diverter technology have received CE mark approval in Europe. Executive Summary Page 14 of 38

15 Although flow diverters are becoming more prevalent, safety and effectiveness data is limited for use in both the anterior circulation and posterior circulation, regions of the brain that are outside the approved labeling of approved devices. The PED device is only indicated for use in ICA from the petrous to the superior hypophyseal segment while the SAC systems (all with HDE approval) are approved for all locations in the neurovasculature. The use of the PED in other regions of the neurovasculature has not been shown to demonstrate a reasonable assurance of safety and effectiveness. In addition, the risk of occluding perforator arteries exists (See Section above). Specifically, occlusion of perforating vessels can lead to infarcts which can significantly impact patient function (Phillips et al. 2012). A study by Phillips et al. investigated 32 posterior aneurysms to evaluate the safety associated with the use of these types of devices (Phillips et al. 2012). This study showed complete occlusion of the target aneurysm in 86% of the patients at 6 months with 100% occlusion seen in those patients followed > 2 years. The authors note that higher clinical perforator infarction in basilar artery compared to the carotid may be seen with the PED. In this study perforator occlusion was seen in 3 patients (14%). While no deaths or poor neurological outcomes were reported, this investigation highlights the fact that flow diverters can produce varying results based on the target aneurysm location and aneurysm location may be a factor in deciding the best course of treatment Other Treatment Approaches Pharmacotherapy may include prescribed drugs that lower your blood pressure or reduce the impact of the heart's contraction and minimizing the risk of a rupture. Another approach may be drug therapies with ongoing observations, and periodic assessment to track the aneurysm status. Additional approaches reported in the literature include the development and use of precipitates, second generation stents of various designs, aneurysm liners, liquid polymers, hydrogels, aneurysm neck protection, and microanastomoses, bioactive manipulations to endovascular devices (Szikora et al. 1996; Jeffree et al. 1999; Kallmes and Fujiwara 2002) Section Review When deciding on a treatment method for aneurysms, there are a number of factors that can be considered such as size, morphology, anatomical location, rupture rate as well as patient age (Ishibashi et al. 2009; Wiebers 2003). A number of treatment strategies exist, each involving specific benefit/risk considerations. Coiling is a less invasive approach than open surgery for treating aneurysms. There is a risk of increased bleeding with coiling versus clipping but the long term mortality rate has been shown to be lower (Molyneux et al. 2009). Not all aneurysms types may be appropriate for coiling as wide-neck aneurysm (> 4 mm) have been shown to have a lower occlusion rate (Standhardt et al. 2008). Balloon assisted coiling is a method to increase the coil packing density without leaving a permanent implant in the parent vessel. Recent studies suggest that complications rates for BAC and traditional coiling are similar. However the disagreement for thrombus events, complication rates, and occlusion rates suggests that this method still requires further evaluation before the associated benefits and risks are better understood. Stent assisted coiling provides another approach to treat wide-neck aneurysms but the impact of stents placed in the neurovasculature is still unknown. Published literature has also stated that longer term follow-up is still required to better understand all of the benefits and risks associated with this device type. Similar to SAC, the effect of flow diverters on the surrounding vasculature (e.g. perforators) is still not completely understood. Understanding the impact of flow diverter technologies in specific sections of the neurovasculature will help to further examine the benefit risk ratio in other areas of the neurovasculature. Executive Summary Page 15 of 38

16 FDA Comment: The current understanding of aneurysms and determining how medical devices should be evaluated is a major focus of this panel meeting. The treatment tools of clipping, coiling, BAC, SAC, and flow diverter technology, as well as approaches to studying different technologies is important to designing the right studies and identifying the most appropriate outcome measures (See Questions 4, 5, 6, 7, 8). 2.5 Long Term Treatment Durability With flow diverters requiring more time to achieve complete occlusion, the duration of patient follow-up is important. The optimal time of follow-up is largely unknown. For patients treated with traditional coiling Raymond et al. (2003) found a strong correlation of initial incomplete treatment, initial aneurysm dome or neck size and rupture status on the subsequent risk of recurrence, and the need for retreatment. They also reported that only 46.9% of recurrences were detected at 6 months after treatment. Recurrences were still being detected as long as 3 years after surgery (Raymond et al. 2003) Other studies have investigated the correlation of aneurysm size and neck size with treatment results. Studies have shown that aneurysm neck size is well-correlated with recanalization which is caused by coiling compaction and can be seen in 8 40% of cases (Zubillaga et al. 1994; Mericle et al. 1998; Cognard et al. 1999; Raymond et al. 2003; Murayama et al. 2003). Zubillaga et al. (1994) suggested that the treatment of wide neck aneurysms with detachable coils should be reserved for patients who are a high surgical risk. Raymond et al (2003) found a strong association between the recurrence rate and both aneurysm dome size (>10 mm) and neck size (> 4 mm) for patients treated with traditional coiling. Of the 160 patients with large aneurysm (>10 mm in diameter), 81 (50.6%) had a recurrence compared to a 21.3% recurrence rate for patients with an aneurysm 3-9 mm in diameter. For the 132 patients with a wide-neck aneurysm (> 4 mm in diameter) 69 (52.3%) had a recurrence compared to 23.7% for patients with a neck size < 4mm. Coiling has also shown a lower rate of death (absolute rate reduction of 7.4%) and does not show any statistically significant difference in rebleed rate compared to surgical clipping even at 5 years of follow up (Molyneux et al. 2005). Some works have even suggested that recurrence of clinical symptoms for patients treated with surgical clipping may take up to 10 years to present (Ebina et al. 1982; Sakaki et al. 1994). In a study looking at long term follow up for stent-assisted coiling 8.3% of patients required retreatment for their original aneurysm (Fargen et al. 2012). This study also showed an increased frequency of retreatment in patients previously diagnosed with a SAH. It has been suggested that lower recurrence rates in SAC patients comes from better arterial wall reconstruction at the neck (Piotin et al. 2010). Long term follow up has also shown that 3.6% of patients treated with SAC suffered a transient ischemic attack (TIA)/stroke in the region around the stent (Shapiro et al. 2012). One important distinction with the current SAC systems is that they have been approved through the HDE process which requires demonstration of probable benefit (as opposed to a reasonable assurance of effectiveness). For some HDE devices such as SAC systems, FDA has accepted shorter-term effectiveness data as evidence of probable benefit and has not required data to demonstrate long term effectiveness. It should also be noted that additional information is still required using SAC, since the basis for approvals were granted under HDE and long term follow up was limited. As discussed previously, flow diverters typically show improving occlusion results as patient follow up increases. However, in a short term follow up (1-30 days), one study using the PED observed 2.5% of giant aneurysms ruptured after treatment and 2.2% of patients died from their hemorrhage (Briganti et al. 2012). Other studies have reported cases of delayed rupture with most cases happening in the first 3 months after the procedure (Kulcsár et al. 2011; Mustafa et al. 2010; Turowski et al. 2010). It has been suggested that late thrombosis of the flow diverter is possible (Fiorella et al. 2010; Klisch et al. 2011). Very late thromobosis (> 1 year) has been seen in multiple studies where flow diverters have been used Executive Summary Page 16 of 38

17 (Fiorella et al. 2010; Klisch et al. 2011). From one of the few studies that has captured long term followup, device occlusion with resultant death has been see as late as 2 years (Fiorella et al. 2010). What is clear from these results is that information on long term follow up remains unclear. Importantly, one distinction between flow diverters and the other devices such as coiling or SAC is the time required for the aneurysms to fully occlude (Byrne et al. 2010). This delayed occlusion may affect the duration of follow up required to assess safety and effectiveness because the aneurysm will continue to change months after the completion of the procedure. FDA Comment: The FDA is seeking the panel s guidance on appropriate follow-up durations for different aneurysm treatment device trials as well as what relevant information should be captured to ensure the long term safety of patients. See FDA Question Grading Scales When reporting aneurysm occlusion, most studies report results using the Raymond scale. This scale can be defined by three grades: (1) complete aneurysmal occlusion, (2) residual neck, and (3) residual aneurysms (Roy, Milot, and Raymond 2001; Raymond et al. 2003). While this has been used for many years, new studies have been published presenting alternative methods. It should also be noted that angiographic results are not definitively tied to a clinical outcome. Meyers et al. (2009) presents a method with 6 different grades given to the aneurysms: Grade 0, complete and total occlusion, Grade 1 > 90% volumetric occlusion, Grade % occlusion, Grade % occlusion, Grade % occlusion and Grade 5 less than 25% occlusion. While the increased number of grades allows for more gradation in the results, it is not without its limitations. Namely, it requires more accurate calculation of the true aneurysm volume. For implementation in a clinical trial, this calculation could be conducted by a core lab to standardize the calculation across study sites which is often included in FDA trials. Another method that was specifically designed for flow diverters was developed by Kamran et al. (2010). This method evaluated both the saccular occlusion as well as the patency of the parent artery. For saccular aneurysms occlusion the grading scale was broken into 5 levels: 0, No change in endoaneurysmal flow, 1, Residual contrast filling greater than 50% of the pretreatment volume, 2, Residual filling less than 50% of the pretreatment volume, 3, Residual filling confined to the neck not to extend beyond the wide of the neck, and 4, No residual filling. To evaluate patency of the parent artery this work proposed 3 levels: A, No change in parent artery diameter, B, Narrowing of the parent artery, and C Parent artery occlusion. It is proposed by Kamran et al. that this two part grading system better describes different possible outcomes from the use of a flow diverter. This study also demonstrated a usability analysis comparing Executive Summary Page 17 of 38

18 two researchers that were asked to apply this method to a series of angiograms. These results showed that in this study agreement was seen between the researchers and consistent consensus was reached. Another method designed for flow diverters investigated both flow modification as well as occlusion (Szikora et al. 2010). This method used 3D reconstructed images derived from rotational angiography before the procedure. These reconstruction images were then evaluated using the following scale: complete stasis (i.e. no contrast material entering the aneurysm), significant flow reduction (if contrast stagnation was seen with in the aneurysm at the late venous phase of the angiographic series), or slow flow (if contrast circulation within the aneurysm became slower but without contrast stagnation into late venous phase images) (Szikora et al. 2010). Because of the specific equipment that is required this type of evaluation may not be possible at all hospitals. While there have been some newly developed methods for measuring aneurysm occlusion they are not without their limitations. The development of methods specifically targeted at aneurysms treated with flow diverters could be helpful to better understand and document the treatment process of these aneurysms. Limitations such as the use of additional equipment may slow the implementation of some of these methods. FDA Comment: While the Raymond scale has been the benchmark for assessing success in aneurysm studies, the FDA is seeking the panel s guidance on whether it is still the most appropriate method to determine aneurysm occlusion, or whether other scales exist that can also assess treatment success. See FDA Questions 6, Strengths and Limitations Associated with Randomized Controlled Trials versus Single-Arm Studies with a Performance Goal Clinical trial designs used to evaluate neurovascular devices can include the Randomized Controlled Trial (RCT), single-arm study where the investigative device is compared to a performance goal (PG), and retrospective review of clinical data sets Randomized Control Trials For an RCT, the investigational device and a control device are randomly assigned to patients to provide a head-to-head comparison. This methodology has been used to compare surgical clipping to coiling (Molyneux et al. 2002; Molyneux et al. 2005; Molyneux et al. 2009). There are no published studies at this time where an RCT was used for aneurysm treatment technology using an endoluminal device Performance Goals (PG) Published studies for SAC or flow diverters have compared the performance of the device to a PG. A PG is a numerical threshold typically determined from prior studies that will be used as the control Strengths and Limitations of RCTs and Performance Goals A number of factors can be involved when comparing RCTs vs PG (Grunkemeier, Jin, and Starr 2006; Devereaux et al. 2005). One benefit of an RCT is that the device is concurrently compared to a control product, using the same pool of patients, whereas the PG is determined based on historical information from patients who might have had much different characteristics than the patients used for the investigative device. Also, with an RCT, because patients are randomized to treatment groups, their individual characteristics are probabilistically balanced across groups. That is, a patient with a particular characteristic is equally likely to be in either group. The result is that patient characteristics tend to be balanced across groups, so that patient characteristics are less likely to cause one treatment group to perform better or worse than the other. The only systematic difference between groups is the treatment Executive Summary Page 18 of 38

19 received. Because of this, RCTs can provide an unbiased assessment of benefits and risks associated with both the device and the proposed indication for use compared to a study using a PG. Conversely, a single-arm study compared to a PG does not directly control for potential confounding covariates such as patient characteristics that differ between the subjects in the study and the patient population from which the PG was obtained. However, there are reasons that RCTs are not used more often for neurovascular device studies. The first concern with performing an RCT is determining a control. As there are currently no endoluminal devices with a known benefit/risk profile for the intradural locations of the neurovasculature (PED has an indication for an extradural section of the ICA) the selection of an appropriate control becomes challenging. An RCT also requires consent of patients to be randomized to either the investigational or control device. Enrollment may be difficult if there is a perceived difference in the potential performance of the two treatments due to a lack of equipoise on the part of either potential subjects or study investigators. An RCT also tends to require an increased number of study subjects because subjects are needed for both groups. This can result in a more time-consuming and costly study (Devereaux et al. 2005). However, while a PG study may require fewer patients, the determination of an appropriate PG is based partly on historical study information which can be limited and may not capture all of the relevant effectiveness or safety concerns for new device designs. FDA Comment: The FDA is seeking panel guidance on whether trials utilizing PGs are as appropriate as RCTs, factoring in the concerns relating to aneurysm morphology, size, and location, or if an RCT is feasible at this time. If an RCT is feasible for the study of aneurysm treatment, the FDA is seeking the panel s guidance on the scientific and clinical considerations factoring into when an RCT study is appropriate. See FDA Questions 4, Statistical Accounting for Heterogeneity in Aneurysm type, size and location in the Analysis of Safety and Effectiveness For many proposed devices indicated to treat aneurysms, the variety of types, sizes and locations of the aneurysm can lead to challenging trial designs. The safety and effectiveness of the device might also be different across the variety of subgroups (e.g., aneurysm morphology, size, and region specificity such as anterior or posterior relevant to treatment risk). For example, the cerebral arteries are more prone to adverse events given their more distal location, potential greater tortuosity, and small sizes (see sections 2.2 and 2.3). FDA is not aware of any consensus regarding what subgroups (anterior versus posterior, perforator rich versus perforator poor, etc.) should be used, and whether those subgroups should be different for different treatment types (flow diverters vs. conventional stents vs. endosaccular devices, etc.). In addition, there are several options for how to account for the variety of subgroups in the overall analysis of safety and effectiveness Approaches to Patient Subgroups One may consider three potential options for analyzing safety and effectiveness across subgroups: 1) Pool all enrolled patients together, 2) Use a hierarchical model that acknowledges several mutually exclusive sub populations, where the analysis of the endpoint in each subpopulation borrows strength from the analyses in the other subpopulations, and 3) Study every size/location/type subgroup separately. Option 1 pools all patients together regardless of the characteristics of their aneurysm. This option is advantageous in that enrollment in a single-arm study is simplified as there will be fewer exclusion criteria regarding size, location and type. The disadvantage to this option is that it will be difficult to determine where the device might work best or not at all. Executive Summary Page 19 of 38

20 The second option is midway between options 1 and 3 (see below). With hierarchical modeling, there are two or more levels in the model where each level contains exchangeable, mutually exclusive groups. For the aneurysm studies, a top level might be aneurysm location (e.g., anterior or posterior) and a lower level might be the patients who have aneurysms at each location. The exchangeability assumption at the lower level is that the patients who have aneurysms within a particular location are not distinguishable enough so that the effectiveness or safety of the device for any one patient is predicted to be better or worse than for another patient. Exchangeability at the location level implies that the safety or effectiveness of the device is not predicted a priori to be better or worse in one location versus another. If exchangeability cannot be assumed at the location level because of a particular factor or factors (such as the possibility of occluding perforators in the perforator rich locations of the neurovasculature), then one might be able to assume partial exchangeability by accounting for the factor using measured covariates. In the case of occluding perforators, one might create four subgroups at the top level: anterior with and without perforators, and posterior with and without perforators. Alternatively, the presence/absence of perforators can be a middle level in between location and patients (creating a 3-level model). Whatever the level structure of the hierarchical model, the subgroups at each level are assumed to have similar outcomes on the endpoint being measured. For example, if the outcome is rupture rate, the model would assume that the anterior and posterior locations have similar rupture rates, and that the perforator rich anterior aneurysms have similar rupture rates (the same for perforator-rich posterior aneurysms). The assumption of exchangeability (similarity on the endpoint of interest) must be determined prior to running the study, and should involve clinical as well as statistical input. If exchangeability can be assumed, then there are several advantages to a hierarchical model. One advantage is that the safety or effectiveness estimate within each subgroup can borrow strength from the estimates in the other subgroups, provided that the estimates are similar enough. That is, to the extent that the variability across subgroups is not greater than the variability of patients within a subgroup, more borrowing of strength occurs so that the precision of each subgroup estimate increases due to borrowing compared to the precision of the subgroup estimate alone (without borrowing). Consequently, a second advantage to a hierarchical model is that if the exchangeable subgroups have similar estimates, the number of subjects needed for sufficient power is often much fewer than if each anatomical subgroup were tested separately. If the chosen subgroups are determined not be exchangeable, then (as mentioned above) one could identify sets of subgroups that can be considered exchangeable (e.g., giant and large aneurysms could be considered similar in rupture rate, and small and medium aneurysms could be considered similar in rupture rate), and restructure the hierarchical model to borrow only among exchangeable subgroups. The third option is to study each subgroup (e.g., each location/size/type combination) separately so that it is clear where the device works or not. This option also has disadvantages because it requires enough subjects for each combination so that appropriate statistical power can be achieved. Powering each subgroup may result in a large sample size such that the study may not be feasible. FDA Comment: The characterization of an aneurysm may be important in terms of either occlusion rate, rupture rate, or rate of general adverse events. Clinical factors such as morphology, size, and location may affect a device s indication for use. The FDA is seeking the panel s guidance on determining which anatomical subgroups are important for device indications and which subgroups are expected to yield similar outcomes on the safety and effectiveness endpoint(s) of interest. See FDA Questions 2, 3, 5, 8. Executive Summary Page 20 of 38

21 Figure 3. Overview for some marketing pathways, a few device examples for each pathway, and typical trial designs related to the treatment of aneurysm. HDE and PMA devices have similar requirements during the approval process with an important difference being that a PMA device requires a reasonable assurance of safety and efficacy while and HDE requires that probable benefit outweighs the risk. 510(k) devices have involved both Randomized Control Trials (RCT) and Performance Goal (PG) studies, whereas only PG studies have been used for PMA approval. 3 Regulatory Summary of Aneurysm Treatments FDA has approved one flow diverter (Pipeline Embolization Device, PED) under PMA and three SAC systems under HDE 4. Since original coiling approvals, due to increased knowledge on the associated risks with these devices and the ability to mitigate these risk, special controls were developed for these devices and they have been down-classified to Class II 5 requiring the submission of a pre-market notification (510(k)) 6. Figure 3 displays some marketing pathways, examples of devices and evidence related to each pathway, as well as trial designs associated with pathways and devices. 4 One of the major differences between an HDE device and a device approved through the PMA process is that the standard for approval of HDE devices is that the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use as opposed to PMA devices that must demonstrate a reasonable assurance of safety and effectiveness 5 Coiling systems are classified as a Class II device by the FDA and are approved via the 510(k) pathway. Originally these devices were considered Class III 6 The 510(k) pathway requires a device to demonstrate substantial equivalence to a currently marketed device in contrast to the assurance of safety and effectiveness in a PMA. Executive Summary Page 21 of 38