IMAGEREADY MR CONDITIONAL PACING SYSTEM AND INGEVITY PACE/SENSE LEAD

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA ## I. GENERAL INFORMATION Device Generic Name: Pulse Generator (PG): Implantable Pacemaker Lead: Steroid-eluting, endocardial, bipolar, pace/sense lead Lead stabilizer accessory Stylet accessories Device Trade Name: ImageReady™ MR Conditional Pacing System, consisting of: ### The following Implantable PGs: - INGENIO™ MRI Pacemaker, Models K175, K176 &amp; K177 - VITALIO™ MRI Pacemaker, Models K275, K276 &amp; K277 - FORMIO™ MRI Pacemaker, Model K279 - ESSENTIO™ MRI Pacemaker, Models L110, L111 &amp; L131 - PROPONENT™ MRI Pacemaker, Models L210, L211 &amp; L231 - ACCOLADE™ MRI Pacemaker, Models L310, L311 &amp; L331 ### INGEVITY™ MRI Pace/Sense Lead: - Models 7731 &amp; 7732 (Passive-fixation, Ventricular straight) - Models 7735 &amp; 7736 (Passive-fixation, Preformed Atrial J) - Models 7740, 7741 &amp; 7742 (Active-fixation, straight) ### Accessories: - Slit Suture Sleeve Accessory, Model 6402 - ZOOM® LATITUDE™ Programming System, Model 3120 - Programmer Software Application, Model 2869 v2.02 - IS-1 Port Plug, Model 7145 Other Leads and Accessories: ### INGEVITY™ Non-MRI Pace/Sense Lead: - Models 7631 &amp; 7632 (Passive-fixation, Ventricular straight) - Models 7635 &amp; 7636 (Passive-fixation, Preformed Atrial J) - Models 7640, 7641 &amp; 7642 (Active-fixation, straight) ### Other Accessories: - Delivery Stylet, Models 5003, 5004, 5005, 5012, 5013, 5014 Device Procode: LWP NVN PMA P150012: FDA Summary of Safety and Effectiveness Data {1} Applicant's Name: Boston Scientific Corporation and Address: 4100 Hamline Avenue North St. Paul, Minnesota 55112-5798 Date of Panel Recommendation: None PMA Number: P150012 Date of Notice of Approval to Applicant: April 25, 2016 ## II. INDICATIONS FOR USE ### II. A. Ingenio and Accolade MRI Pacemaker Device Indications The Ingenio and Accolade MRI pacemakers are indicated for the treatment of the following conditions: - Symptomatic paroxysmal or permanent second- or third-degree AV block - Symptomatic bilateral bundle branch block - Symptomatic paroxysmal or transient sinus node dysfunction with or without associated AV conduction disorders (i.e., sinus bradycardia, sinus arrest, sinoatrial [SA] block) - Bradycardia-tachycardia syndrome, to prevent symptomatic bradycardia or some forms of symptomatic tachyarrhythmias - Neurovascular (vaso-vagal) syndromes or hypersensitive carotid sinus syndromes Adaptive-rate pacing is indicated for patients exhibiting chronotropic incompetence and who may benefit from increased pacing rates concurrent with increases in minute ventilation and/or level of physical activity. Dual-chamber and atrial tracking modes are also indicated for patients who may benefit from maintenance of AV synchrony. Dual chamber modes are specifically indicated for treatment of the following: - Conduction disorders that require restoration of AV synchrony, including varying degrees of AV block - VVI intolerance (i.e., pacemaker syndrome) in the presence of persistent sinus rhythm - Low cardiac output or congestive heart failure secondary to bradycardia ### II. B. INGEVITY™ Pace/Sense Lead and Accessories Intended Use/Indications PMA P150012: FDA Summary of Safety and Effectiveness Data Page 2 of 82 {2} The intended use/indication information listed below is presented as written in the device labeling. ## II.C.1. Passive-fixation Non-MRI Models 7631, 7632, 7635 and 7636 and MRI Models 7731, 7732, 7735 and 7736 This Boston Scientific lead is indicated for use as follows: - Intended for chronic pacing and sensing in the right atrium (Preformed Atrial J) or right ventricle (Straight) when used with a compatible pulse generator. ## II.C.2. Active-fixation Non-MRI Models 7640, 7641, and 7642 and MRI Models 7740, 7741, and 7742 This Boston Scientific lead is indicated for use as follows: - Intended for chronic pacing and sensing in the right atrium and/or right ventricle when used with a compatible pulse generator. ## II.C.3. Slit Suture Sleeve Accessory Model 6402 The intended use of the slit suture sleeve accessory is: - Use to secure and immobilize Boston Scientific INGEVITY™ leads at the venous entry site. ## II.C.4. Delivery Stylet Models 5003, 5004, 5005, 5012, 5013, and 5014 The delivery stylet accessory is indicated for use as follows: - For use with Boston Scientific implantable transvenous leads. ## III. CONTRAINDICATIONS ## III. A. Ingenio and Accolade MRI Pacemaker Device Contraindications These Boston Scientific pacemakers are contraindicated for patients who have a separate implanted cardioverter defibrillator (ICD) with transvenous leads. Use of certain pacing modes and/or features available in Boston Scientific pacemakers is contraindicated for the following patients under the circumstances listed: - Unipolar pacing or use of the MV Sensor with a Subcutaneous Implantable Cardioverter Defibrillator (S-ICD) because it may cause inappropriate therapy or inhibition of appropriate S-ICD therapy; - Minute Ventilation in patients with both unipolar atrial and ventricular leads; PMA P150012: FDA Summary of Safety and Effectiveness Data Page 3 of 82 {3} - Single-chamber atrial pacing in patients with impaired AV nodal conduction; - Atrial tracking modes for patients with chronic refractory atrial tachyarrhythmias (atrial fibrillation or flutter), which might trigger ventricular pacing; - Dual-chamber and single-chamber atrial pacing in patients with chronic refractory atrial tachyarrhythmias; and/or - Asynchronous pacing in the presence (or likelihood) of competition between paced and intrinsic rhythms. ## III. B. INGEVITY™ Lead and Accessories Contraindications ### III.B.1. Passive-fixation Non-MRI Models 7631, 7632, 7635 and 7636 and MRI Models 7731, 7732, 7735 and 7736 Use of this Boston Scientific lead is contraindicated for the following patients: - Patients with a hypersensitivity to a nominal single dose of 0.61 mg dexamethasone acetate - Patients with mechanical tricuspid heart valves ### III.B.2. Active-fixation Non-MRI Models 7640, 7641, and 7642 and MRI Models 7740, 7741, and 7742 Use of this Boston Scientific lead is contraindicated for the following patients: - Patients with a hypersensitivity to a nominal single dose of 0.91 mg dexamethasone acetate - Patients with mechanical tricuspid heart valves ### III.B.3. Slit Suture Sleeve Accessory Model 6402 There are no known contraindications for the slit suture sleeve accessory. ### III.B.4. Delivery Stylet Models 5003, 5004, 5005, 5012, 5013, and 5014 There are no known contraindications for the delivery stylet accessories. ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the ImageReady™ MR Conditional Pacing System labeling, INGENIO™ MRI, VITALIO™ MRI, FORMIO™ MRI, ESSENTIO™ MRI, PROPONENT™ MRI, and ACCOLADE™ MRI pacemaker labeling, and INGEVITY™ lead labeling. PMA P150012: FDA Summary of Safety and Effectiveness Data Page 4 of 82 {4} V. IMAGEREADY SYSTEM MRI CONDITIONS OF USE Based on its use as a system versus an individual device, “Conditions of Use” apply to the ImageReady™ MR Conditional Pacing System (ImageReady System) rather than “Indications for Use.” When used as a system and according to the labeled MRI Conditions of Use, the ImageReady System has been determined to meet the status of MR Conditional per ASTM F2503:2008. The MRI Conditions of Use are as follows: The following Conditions of Use must be met in order for a patient with an ImageReady System to undergo an MRI scan. Adherence to the Conditions of Use must be verified prior to each scan to ensure that the most up-to-date information has been used to assess the patient’s eligibility and readiness for an MR Conditional scan. **Cardiology** 1. Patient is implanted with the ImageReady™ MR Conditional Pacing System⁴ 2. Pulse generator in MRI Protection Mode during scan 3. Bipolar pacing operation or pacing off 4. Patient does not have elevated body temperature or compromised thermoregulation at time of scan 5. Pulse generator implant location restricted to left or right pectoral region 6. At least six (6) weeks have elapsed since implantation and/or any lead revision or surgical modification of the MR Conditional Pacing System 7. No cardiac-related implanted devices, components, or accessories present other than the ImageReady™ MR Conditional Pacing System 8. Pacing threshold ≤ 2.0 V in pace-dependent patients 9. No abandoned leads or pulse generators 10. No evidence of a fractured lead or compromised pulse generator-lead system integrity **Radiology** 1. MRI magnet strength of 1.5 T only - Radio frequency (RF) field of approximately 64 MHz - Spatial gradient no greater than 50 T/m (5,000 G/cm) 2. Horizontal, ¹H proton, closed bore scanners only 3. Specific Absorption Rate (SAR) limits for Normal Operating Mode⁵ or for First Level Controlled Operating Mode⁶ must be observed for the entire active scan session as follows: - Whole body averaged, ≤ 4.0 watts/kilogram (W/Kg) - Head, ≤ 3.2 W/Kg 4. Gradient Field limits: Maximum specified gradient slew rate ≤ 200 T/m/s per axis ⁴ Defined as a Boston Scientific MR Conditional pulse generator and lead(s), with all ports occupied by a lead or port plug. ⁵ As defined in IEC 60601-2-33, 201.3.224, 3rd Edition ⁶ As defined in IEC 60601-2-33, 201.3.208, 3rd Edition PMA P150012: FDA Summary of Safety and Effectiveness Data Page 5 of 82 {5} 5. No local transmit-only coils or local transmit/receive coils placed directly over the pacing system; the use of receive-only coils is not restricted 6. Patient in supine or prone position only 7. The patient must be monitored during the MRI scan by pulse oximetry and/or electrocardiography (ECG) ## VI. DEVICE DESCRIPTION ### VI. A ImageReady System Description The ImageReady™ MR Conditional Pacing System (ImageReady System) has been created specifically as a system for use with MRI scans performed under the Conditions of Use described in Section V. The Ingenio™ MRI or Accolade MRI pacemaker design has minimized use of ferromagnetic materials, which can interact with the fields generated during a typical MRI scan, and the circuits have been designed to tolerate voltages that may be induced during scans. The INGEVITY lead wire has been designed for use with the ImageReady pacemaker specifically to reduce absorption of energy from MR Fields, thus minimizing subsequent heating. The system is designed for full body scan, with no thoracic exclusion zone. The ImageReady System has mitigated risks associated with MRI scans as compared to conventional pacemakers and leads. The implanted system, as opposed to its constituent parts, is determined to have the status of MR Conditional as described in ASTM F2503:2008. Additionally, an MRI Protection Mode has been created for use during the scan. MRI Protection Mode modifies the behavior of the pacemaker and has been designed to accommodate the MRI scanner electromagnetic environment. A Time-out feature can be programmed to allow automatic exit from MRI Protection Mode after a set number of hours chosen by the user. These features have been tested to verify the effectiveness of the designs. Other MRI-related risks are further reduced by adherence to the Conditions of Use for MR Scanning specified in the Technical Guide. ### VI. B Pacemaker Device Description The Ingenio MRI and Accolade MRI pacemakers (see Figure 1 and Figure 2) are multi-programmable and consist of both dual-chamber and single-chamber models, offering adaptive-rate bradycardia therapy as well as various levels of therapeutic and diagnostic/trending functionality based upon the model. Two sensors are available to adapt the pacing rate to the patient's changing metabolic demand. Minute Ventilation responds to change in respiration, and the accelerometer PMA P150012: FDA Summary of Safety and Effectiveness Data Page 6 of 82 {6} responds to patient activity (motion). Rate adaptive models can use either the accelerometer or minute ventilation sensor, or a blend of both accelerometer and minute ventilation.  Figure 1: Images of INGENIO™, VITALIO™ and FORMIO™ MRI Pacemakers    Figure 2: Images of ACCOLADE™, PROPONENT™ and ESSENTIO™ MRI Pacemakers # VI. C Lead and Lead Accessory Device Description # VI.C.1. INGEVITY™ Pace/Sense Lead Description The INGEVITY lead is a steroid-eluting endocardial pace/sense lead intended for implantation into the right atrium and/or right ventricle for chronic pacing and sensing. PMA P150012: FDA Summary of Safety and Effectiveness Data {7} The lead is designed to conduct intrinsic electrical signals from the cardiac tissue to a pulse generator; the IS-1 bipolar connector allows the lead to be used in conjunction with a compatible pulse generator. The six French diameter lead is offered in several lengths. The isodiametric INGEVITY lead body is a co-axial design, that includes single-filar inner and outer coils for improved flex fatigue. An open-lumen conductor coil design enables lead delivery using a stylet. The conductors are separated by both a silicone rubber and polytetrafluoroethylene (PTFE) lining. Both the inner and outer coil are covered in ethylene tetrafluoroethylene (ETFE) for extra insulation protection. The entire lead body is encompassed in a polyurethane outer insulation. The lead is equipped with a radiopaque suture sleeve that is visible under fluoroscopy and is used to secure, immobilize, and protect the lead at the venous entry site after lead placement. The lead electrodes are coated with IROX (iridium oxide) to increase the microscopic surface area. The INGEVITY lead family includes these lead types: - Straight, extendable/retractable fixation (active) models allow for various lead placement possibilities for the tip electrode in the right atrium and/or right ventricle; - Straight, tined fixation (passive) models provide fixation in the apex of the right ventricle; and - Preformed Atrial J-shaped, tined fixation (passive) models provide fixation in the atrial appendage. Some models of the lead are MR Conditional when connected to a Boston Scientific MR Conditional pulse generator as part of the ImageReady™ MR Conditional Pacing System. Photos of the INGEVITY Lead Family are shown in Figure 3 and Figure 4.  Figure 3: INGEVITY™ Pace/Sense Lead Family PMA P150012: FDA Summary of Safety and Effectiveness Data Page 8 of 82 {8}  Figure 4: INGEVITY Lead Family – Distal End Close-up ## VI.C.2. Slit Suture Sleeve Accessory Model 6402 Description The suture sleeve (Figure 5) is a radiopaque, adjustable, tubular reinforcement made of molded silicone rubber, used to secure and protect the lead at the venous entry site after placement. The silicone rubber is mixed with titanium dioxide to color it white and barium sulfate to make it radiopaque. A slit traverses the length of the suture sleeve to facilitate installation over the INGEVITY lead body.  Figure 5: Slit Suture Sleeve Model 6402 ## VI.C.3. Delivery Stylet Models 5003, 5004, 5005, 5012, 5013, and 5014 Stylet models 5003, 5004, 5005, 5012, 5013, and 5014 are separately packaged accessories intended for use with the INGEVITY™ Pace/Sense Leads. They are sterilized with ethylene oxide. The stylet cap is color-coded to visually identify the stylet length, which is also imprinted on the cap. Table 1 provides details of each model's characteristics. PMA P150012: FDA Summary of Safety and Effectiveness Data {9} Table 1: Stylet Descriptions | Stylet Model | Type | Stiffness | Length | Hub/Knob Color | Cap Color | | --- | --- | --- | --- | --- | --- | | 5003 | Straight | Extra Soft | 45 cm | Yellow | White | | 5004 | Straight | Extra Soft | 52 cm | Yellow | Red | | 5005 | Straight | Extra Soft | 59 cm | Yellow | Yellow | | 5012 | Straight Long-tapered | Soft | 45 cm | Green | White | | 5013 | Straight Long-tapered | Soft | 52 cm | Green | Red | | 5014 | Straight Long-tapered | Soft | 59 cm | Green | Yellow | # VII. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of bradycardia. Alternative therapies include the use of other commercially available dual or single chamber adaptive rate pacing systems. Each system has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. # VIII. MARKETING HISTORY INGEVITY Leads, both non-MRI and MRI models, have received CE mark and the MRI models are approved for use with the ImageReady™ MR Conditional Pacing System. European implants began in March 2014. The INGEVITY Leads have not been withdrawn from the market in any country for any reason related to the safety and effectiveness of the system. The non-MRI Ingenio and Accolade models are market approved in the US. Both device families are market approved internationally as well. Likewise, the Ingenio MRI and Accolade MRI models are market approved internationally. With regard to CE Mark, these Ingenio/Accolade MRI models are part of the ImageReady System with either FINELINE II Sterox and Sterox EZ leads, or with INGEVITY MRI leads. The ImageReady System has not been withdrawn from the market in any country for any reason related to the safety and effectiveness of the system. A summary of marketing status is provided in Table 2. PMA P150012: FDA Summary of Safety and Effectiveness Data {10} Table 2: Market Status of ImageReady System, Ingenio and Accolade Pacemakers and INGEVITY Leads | Product | US Market | International Market | | --- | --- | --- | | ImageReady System | FDA Approved *<Date to be filled in by FDA>* | CE Mark authorized for Ingenio/ Accolade MRI models with either FINELINE II Sterox and Sterox EZ leads or with INGEVITY MRI leads. Also approved for Ingenio models with FINELINE II Sterox and Sterox EZ leads in Asia Pacific, Europe (non-CE Countries), Middle East/Africa and South America/Latin America. | | Ingenio non-MRI (Lower Tier) ADVANTIO INGENIO | FDA Approved May 2012 | CE Mark authorized September 2011 Also approved in Asia Pacific, Canada, Europe (non-CE Countries), Middle East/Africa and South America/Latin America | | Ingenio non-MRI (Upper Tier) VITALIO FORMIO | FDA Approved May 2013 | CE Mark authorized January 2013 Also approved in Asia Pacific and Canada | | Ingenio MRI (Lower Tier) ADVANTIO* INGENIO | FDA Approved *<Date to be filled in by FDA>* **ADVANTIO MRI not intended for US Market* | CE Mark authorized July 2012 Also approved in Asia Pacific, Europe (non-CE Countries), Middle East/Africa and South America/Latin America | | Ingenio MRI (Upper Tier) VITALIO FORMIO | FDA Approved *<Date to be filled in by FDA>* | CE Mark authorized January 2013 Also approved in Asia Pacific, Europe (non-CE Countries), Middle East/Africa and South America/Latin America | | Ingenio 2 (Accolade) non-MRI ESSENTIO PROPONENT ACCOLADE | FDA Approved October 2014 | CE Mark authorized September 2014 Also approved in Europe (non-CE Countries) | | Ingenio 2 (Accolade) MRI ESSENTIO PROPONENT ACCOLADE | FDA Approved *<Date to be filled in by FDA>* | CE Mark authorized September 2014 Also approved in Europe (non-CE Countries) | | INGEVITY non-MRI and accessories | FDA Approved *<Date to be filled in by FDA>* | CE Mark authorized February 2014 Also approved in Asia Pacific, Canada and South America/Latin America | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 11 of 82 {11} | Product | US Market | International Market | | --- | --- | --- | | INGEVITY MRI | FDA Approved *<Date to be filled in by FDA>* | CE Mark authorized February 2014 and are approved for use with the ImageReady system Also approved in Asia Pacific, Europe (non-CE Countries), Middle East/Africa and South America/Latin America | ## IX. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. ## IX. A. ImageReady™ MR Conditional Pacing System Potential Adverse Events Potential adverse events differ depending on whether the MRI Conditions of Use are met. For a complete list of potential adverse events, refer to the Physician’s Technical Manual for the pulse generator. MRI scanning of patients when the Conditions of Use are met could result in the following potential adverse events: - Arrhythmia induction - Bradycardia - Patient death - Patient discomfort due to slight movement or heating of the device - Side effects of MRI Protection Mode pacing at elevated fixed rate and increased output including reduced exercise capacity, acceleration of heart failure, and competitive pacing/arrhythmia induction - Syncope MRI scanning of patients when the Conditions of Use are NOT met could result in the following potential adverse events: - Arrhythmia induction - Bradycardia - Damage to the pulse generator and/or leads - Erratic pulse generator behavior - Inappropriate pacing, inhibition of pacing, failure to pace - Increased rate of lead dislodgement (within six weeks of implant or revision of system) - Irregular or intermittent capture or pacing - Pacing threshold changes PMA P150012: FDA Summary of Safety and Effectiveness Data Page 12 of 82 {12} - Patient death - Patient discomfort due to movement or heating of the device - Physical movement of pulse generator and/or leads - Sensing changes - Syncope ## IX. B. Ingenio and Accolade Pacemaker Potential Adverse Events - Air embolism - Allergic reaction - Bleeding - Bradycardia - Cardiac tamponade - Chronic nerve damage - Component failure - Conductor coil fracture - Death - Elevated thresholds - Erosion - Excessive fibrotic tissue growth - Extracardiac stimulation (muscle/nerve stimulation) - Fluid accumulation - Foreign body rejection phenomena - Formation of hematomas or seromas - Heart block - Heart failure following chronic RV apical pacing - Inability to pace - Inappropriate pacing - Incisional pain - Incomplete lead connection with pulse generator - Infection including endocarditis - Lead dislodgment - Lead fracture - Lead insulation breakage or abrasion - Lead perforation - Lead tip deformation and/or breakage - Local tissue reaction - Loss of capture - Myocardial infarction (MI) - Myocardial necrosis - Myocardial trauma (e.g., tissue damage, valve damage) - Myopotential sensing - Oversensing/undersensing PMA P150012: FDA Summary of Safety and Effectiveness Data Page 13 of 82 {13} - Pacemaker-mediated tachycardia (PMT) (Applies to dual-chamber devices only) - Pericardial rub, effusion - Pneumothorax - Pulse generator migration - Shunting current during defibrillation with internal or external paddles - Syncope - Tachyarrhythmias, which include acceleration of arrhythmias and early, recurrent atrial fibrillation - Thrombosis/thromboemboli - Valve damage - Vasovagal response - Venous occlusion - Venous trauma (e.g., perforation, dissection, erosion) - Worsening heart failure For a list of potential adverse events associated with MRI scanning, refer to the MRI Technical Guide (included above in Section IX. A). Patients may develop psychological intolerance to a pulse generator system and may experience the following: - Dependency - Depression - Fear of premature battery depletion - Fear of device malfunction ## IX. C. INGEVITY™ Lead Potential Adverse Events - Air embolism - Allergic reaction - Arterial damage with subsequent stenosis - Bleeding - Bradycardia - Breakage/failure of the implant instruments - Cardiac perforation - Cardiac tamponade - Chronic nerve damage - Component failure - Conductor coil fracture - Death - Electrolyte imbalance/dehydration - Elevated thresholds - Erosion PMA P150012: FDA Summary of Safety and Effectiveness Data Page 14 of 82 {14} - Excessive fibrotic tissue growth - Extracardiac stimulation (muscle/nerve stimulation) - Fluid accumulation - Foreign body rejection phenomena - Formation of hematomas or seromas - Heart block - Hemorrhage - Hemothorax - Inability to pace - Inappropriate therapy (e.g., shocks and antitachycardia pacing [ATP] where applicable, pacing) - Incisional pain - Incomplete lead connection with pulse generator - Infection including endocarditis - Lead dislodgment - Lead fracture - Lead insulation breakage or abrasion - Lead tip deformation and/or breakage - Malignancy or skin burn due to fluoroscopic radiation - Myocardial trauma (e.g., tissue damage, valve damage) - Myopotential sensing - Oversensing/undersensing - Pericardial rub, effusion - Pneumothorax - Pulse generator and/or lead migration - Syncope - Tachyarrhythmias, which include acceleration of arrhythmias and early, recurrent atrial fibrillation - Thrombosis/thromboemboli - Valve damage - Vasovagal response - Venous occlusion - Venous trauma (e.g., perforation, dissection, erosion) For the specific adverse events that occurred in the clinical studies, please see Section X below. ## X. SUMMARY OF PRECLINICAL STUDIES Extensive pre-clinical testing was done to assess the safety and effectiveness of the ImageReady System and INGEVITY™ lead and lead accessories. Pre-clinical test methods included in vitro (bench) testing, in vivo (animal) testing, modeling, MR scanner-based testing and usability testing. PMA P150012: FDA Summary of Safety and Effectiveness Data Page 15 of 82 {15} # X. A. Laboratory Studies A series of non-clinical laboratory studies was conducted on the ImageReady™ MR Conditional Pacing System and the INGEVITY™ lead and is summarized in this section. See Table 3 through Table 5. # X.A.1. Biocompatibility Testing Table 3: Summary of Ingenio and Accolade Pulse Generator Biocompatibility Testing | Biological Effect per ISO 10993-# | Test Method | Test Result | | --- | --- | --- | | ISO 10993-3: 2009 Genotoxicity | Ames Assay | Passed | | | In vitro Mouse Lymphoma | Passed | | | Mouse Micronucleus Assay | Passed | | ISO 10993-3: 2009 Carcinogenicity | As the device is made of well-characterized materials and the results from the ISO 10993-3: 2009 genotoxicity studies demonstrated no mutagenic response, carcinogenicity testing was not conducted. | Not Required | | ISO 10993-3: 2009 Reproductive Toxicity | The pulse generator does not come in direct contact with reproductive tissues, embryo or fetus. Moreover, the device has no known chemicals that have the potential to induce reproductive or developmental toxicity. | Not Required | | ISO 10993-4: 2009 Blood interactions | Body contact is tissue/bone; therefore, Hemolysis- Direct & Indirect, Coagulation (PTT), Complement Activation, In vitro Hemocompatibility and Thrombogenicity are not required. | Not Required | | ISO 10993-5: 2009 In vitro cytotoxicity | Cytotoxicity MEM Elution | Passed | | ISO 10993-6: 2009 Local Implantation Effects | Combined with Chronic Toxicity per ISO 10993-11: 2009 | Passed | | ISO 10993-10: 2010 Irritation and delayed-type hypersensitivity | Intracutaneous reactivity | Passed | | | Guinea pig maximization Sensitization | Passed | | ISO 10993-11: 2009 | Acute Systemic Toxicity | Passed | | | Materials Mediated Rabbit Pyrogen Assay | Passed | PMA P150012: FDA Summary of Safety and Effectiveness Data {16} Table 4: Summary of INGEVITY Lead and Slit Suture Sleeve Biocompatibility Testing | Biological Effect per ISO 10993-# | Test Method | Test Result | | --- | --- | --- | | ISO 10993-3: 2009 Genotoxicity | Ames Assay | Passed | | | In vitro Mouse Lymphoma | Passed | | | Mouse Micronucleus Assay | Passed | | ISO 10993-3: 2009 Carcinogenicity | As the lead is made of well-characterized materials and the results from the ISO 10993-3: 2009 genotoxicity studies demonstrated no mutagenic response, carcinogenicity testing was not conducted. | Not Required | PMA P150012: FDA Summary of Safety and Effectiveness Data {17} PMA P150012: FDA Summary of Safety and Effectiveness Data Page 18 of 82 | Biological Effect per ISO 10993-# | Test Method | Test Result | | --- | --- | --- | | ISO 10993-3: 2009 Reproductive Toxicity | The lead does not come in direct contact with reproductive tissues, embryo or fetus. Moreover, the device has no known chemicals that have the potential to induce reproductive or developmental toxicity. | Not Required | | ISO 10993-4: 2009 Blood interactions | Hemolysis- Direct & Indirect | Passed | | | Coagulation (PTT) | Passed | | | Complement Activation | Passed | | | In vitro Hemocompatibility | Passed | | | Thrombogenicity | Passed | | ISO 10993-5: 2009 In vitro cytotoxicity | Cytotoxicity MEM Elution | Passed | | ISO 10993-6: 2009 Local Implantation Effects | Combined with Chronic Toxicity per ISO 10993-11: 2009 | Passed | | ISO 10993-10: 2009 Irritation and delayed-type hypersensitivity | Intracutaneous reactivity | Passed | | | Guinea pig maximization Sensitization | Passed | | ISO 10993-11: 2009 Systemic Toxicity | Acute Systemic Toxicity | Passed | | | Rabbit Pyrogen Assay | Passed | | | Sub Acute Toxicity 14 Days Intravenous injection | Passed | | | Sub Acute Toxicity 14 Days Intraperitoneal injection | Passed | | | Chronic Systemic Toxicity | Passed | | ISO 10993-13: 2004 Degradation of polymeric materials | No evidence of oxidative or hydrolytic degradation of the polyurethane material used on the lead | Passed | | ISO 10993-14: 2004 Degradation of ceramic materials | The IROX ceramic material has a history of safe clinical use. Per Annex A, section A.2 of ISO10993-9, degradation studies are not required if the probable degradation products are the same substances, in similar quantities, and at a similar rate as devices that have a history of safe clinical use | Not Required | | ISO 10993-15: 2000 Degradation of metals/alloys | No evidence of corrosion / dissolution of metals and alloys from the electrodes and conductor coils | Passed | {18} | Biological Effect per ISO 10993-# | Test Method | Test Result | | --- | --- | --- | | ISO 10993-18: 2005 Chemical characterization | Profile of extractables/leachable chemicals in the lead was conducted. Identified extractables must be the same substances, in similar quantities, and at a similar rate as devices that have a history of safe clinical use. | Successfully Completed | Table 5: Summary of Biocompatibility Testing of Packaging for Lead and Lead Accessories | Test Performed | Test Method | Test Result | | --- | --- | --- | | ISO 10993-5: 2009 In vitro cytotoxicity | Cytotoxicity MEM Elution | Passed | | USP 32, NF 27 Monograph <661> Physicochemical Tests for Plastics | Extraction using purified water | Passed | # X.A.2. Bench Testing Not Related to MRI # Implantable Pulse Generator System Testing Outside the MRI Environment The INGENIOTM MRI, VITALIOTM MRI and FORMIOTM MRI pacemakers use the same platform and design as the commercially available INGENIOTM, VITALIOTM and FORMIOTM (non-MRI) pacemakers. Likewise the ESSENTIOTM MRI, PROPONENTTM MRI and ACCOLADETM MRI pacemakers use the same platform and design as the commercially available ESSENTIOTM, PROPONENTTM and ACCOLADETM (non-MRI) pacemakers. For the purpose of this testing the only difference is the unique MR Conditional X-ray Identification (ID) tag used in the MRI models. Therefore, the bench testing outside of the MRI environment performed on the commercially available non-MRI pacemakers applies to the corresponding MRI pacemakers (by family). A brief summary is provided in Table 6. Table 6: Summary of Bench Testing Outside the MRI Environment for the Ingenio and Accolade Pacemakers | Test Activity | Summary | Results | | --- | --- | --- | | Component Testing on new or modified components | Performed qualifications to ensure component suppliers are capable of providing parts that meet Boston Scientific requirements. | Passed | PMA P150012: FDA Summary of Safety and Effectiveness Data {19} | Test Activity | Summary | Results | | --- | --- | --- | | System Design Testing | Conducted to verify a specific sub-set of system requirements that require end to end testing in the System Requirement Specification (SyRS) and are not otherwise cover by HW (mechanical, electrical and component), SW or FW testing. System under test included PG with PG FW and 2869 PRM SW. | Passed | | Mechanical Testing | Conducted to verify that the PG meets the mechanical design specifications. Mechanical and environmental requirements were tested. | Passed | | Electrical Testing | Conducted to verify that the PG meets the electrical design specifications. | Passed | | PG Software (Firmware) Testing | Conducted to verify the PG FW meets the FW requirements specification. | Passed | | Model 2869 PRM Software Testing | Conducted to verify the Model 2869 PRM SW meets the SW requirements specification. | Passed | | Battery Testing | Conducted to verify that the battery meets design performance requirements. Testing verifies battery performance at stress conditions beyond the limits expected for the device / system. | Passed | | Packaging Testing | Conducted to verify that the packaging system meets all the design requirements after being exposed to challenge conditions (sterilization, climatic conditioning, distribution simulation, aging). | Passed | # Lead and Lead Accessory Testing Outside the MRI Environment The INGEVITY lead is equivalent for testing conducted outside the MRI environment, regardless of lead type between non-MRI and MRI. A brief summary is provided in Table 7. Table 7: Summary of Bench Testing for the INGEVITY™ Lead and Lead Accessories | Test Activity | Summary | Applicable Standards | Results | | --- | --- | --- | --- | | Component Testing on new or modified components used in the INGEVITY leads or lead accessories | Performed qualifications to ensure component suppliers are capable of providing parts that meet Boston Scientific requirements. | Varies by component/material if applicable | Passed | PMA P150012: FDA Summary of Safety and Effectiveness Data {20} | Test Activity | Summary | Applicable Standards | Results | | --- | --- | --- | --- | | Mechanical and Electrical Testing with Shelf Life Testing | Verified the mechanical and electrical performance of the active and passive fixation designs of the INGEVITY family of leads after accelerated and real time aging representing two years of shelf life. | ASTM D4169-09 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Terminal Testing with Shelf Life Testing | Verified the INGEVITY lead terminal mechanical and electrical performance meets the product specification after accelerated and real time aging representing two years of shelf life. | ASTM D4169-09 ISO 5841-3 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Lead Explant Axial Strength Testing with Shelf Life Testing | Verified the explant axial strength performance of the active and passive fixation INGEVITY lead designs after accelerated and real time aging representing two years of shelf life. | ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Packaging and Package Shelf Life Testing | Verified the INGEVITY device packaging meets requirements of package cleanliness, packaging and labeling integrity, packaging and literature materials and sterile tray content, after accelerated and real time aging representing two years of shelf life. | ASTM D4169-09 EN 45502-2-1, 11607-1:2006, ISO 5841-3 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Corrosion Performance Testing | Verified the current induced corrosion performance of the active and passive fixation INGEVITY lead designs. Verify the mechanical, electrical, and corrosion performance of conductor joints at the distal end of the lead after being subjected to an equivalent to 10 years of pacing in an accelerated period in saline. | EN 45502-2-1 and ISO 5841-3 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Steroid Testing | Verified the active and passive fixation INGEVITY leads conform to the steroid requirements in the product specification. | USP <788> ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 21 of 82 {21} PMA P150012: FDA Summary of Safety and Effectiveness Data Page 22 of 82 | Test Activity | Summary | Applicable Standards | Results | | --- | --- | --- | --- | | Lead Distal Section Fatigue Validation Test | Demonstrated the fatigue performance of the conductors in the distal section of the lead in the cyclic bending conditions experienced during 10 years of chronic implant in the right ventricle of the heart. The test demonstrated the distal section of the lead can experience 400 million cycles of intracardiac flexure without conductor fatigue fracture. | ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Lead Body Bell-Mouth Fatigue Mechanical Testing | Demonstrated that the uniform lead body region of the INGEVITY lead can experience 64,000 cycles when exposed to the 6-mm bell-mouth test condition established in the CEN-CENELEC International Standard (EN 45502-2-1 Section 23.5, Test 1) without conductor fatigue fracture. | CEN-CENELEC International Standard (EN 45502-2-1) ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Subcutaneous Lead Body Fatigue Mechanical Testing | Demonstrated that the INGEVITY lead can experience cyclic deflections equivalent to 10 years of subcutaneous flexure without conductor fatigue fracture. | ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Intracardiac Lead Body Fatigue Testing | Demonstrated that the intracardiac region of the INGEVITY lead can experience cyclic deflections equivalent to 10 years of intracardiac flexure without conductor fatigue fracture | ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Terminal Flex Fatigue Testing | Demonstrated the IS-1 conductors in the terminal region of the lead can experience the cyclic test conditions established in the CEN-CENELEC International Standard (EN 45502-2-1 Section 23.5, Test 2), with the exception of the tensile load, which was increased from 100g in the CEN-CENELEC standard to 200g. | CEN-CENELEC International Standard (EN 45502-2-1) ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | {22} | Test Activity | Summary | Applicable Standards | Results | | --- | --- | --- | --- | | Accessory Testing | | | | | Accessory Mechanical/ Electrical and Shelf Life Testing | Verified the slit suture sleeve Model 6402 conforms to the mechanical requirements of handling, retention and lead body protection and meets the requirements of a four year shelf life. | ASTM 4169-09 EN 45502-2 EN 45502-2-1 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Accessory Particulate Testing | Verified the slit suture sleeve Model 6402 conforms to its requirements for product and packaging cleanliness. | ASTM 4169-09 EN 45502-2 EN 45502-2-1 ISO 14708-1: 2000 EN 45502-1: 1997 | Passed | | Accessory Package and Shelf Life Testing | Verified the accessory packaging used for the slit suture sleeve Model 6402 and the stylet accessories performs its intended functions to contain, protect and maintain a sterile barrier for the intended four years of shelf life. Testing also verified the performance of the printed markings of the labeling. | EN ISO 11607-1:2006 | Passed | | Stylet Accessory Shelf Life Testing | Verified the stylet models for use with INGEVITY leads meet the requirement for a four-year shelf life. | None | Passed | X.A.3. Testing Related to MRI This section provides a summary of the pre-clinical evaluation performed to demonstrate safety and effectiveness of the ImageReady™ MR Conditional Pacing System with respect to MRI-environment hazards. The pre-clinical evaluation included MRI scanner testing, bench testing, computer modeling, and animal studies performed by Boston Scientific as guided by ISO/TS 10974, “Assessment of the safety of magnetic resonance imaging for patients with an active implantable medical device.” Boston Scientific’s pre-clinical evaluation was designed to: a) apply exposure levels more severe than typically encountered during clinical MRI scanning; b) provide monitoring and measurement methods sensitive enough to detect any possible device performance anomalies; and c) assess a wide range of system implant and patient anatomy configurations. All evaluations were performed under generalized, conservative conditions for patient and device exposure in 1.5T MRI scanners, including conditions beyond limits typically encountered in clinical practice. An MRI scanner was used where appropriate for system-level testing. Standard test methods and test equipment were used where possible. Custom test systems were developed and used to create higher exposure levels as needed in bench and animal testing. PMA P150012: FDA Summary of Safety and Effectiveness Data Page 23 of 82 {23} The pre-clinical evaluation demonstrates Boston Scientific MR Conditional pacemakers and leads, when used together, meet all product requirements designed to mitigate the risks associated with MRI scans. These results demonstrate the ImageReady System is safe and effective for scans performed in accordance with the labeled Conditions of Use. The following testing related to MRI is summarized in Table 8 through Table 15 below: - Lead and PG Heating - Vibration - Translation Force - Torque - Image Artifact - Unintended Cardiac Stimulation - PG Malfunction ## Lead Heating Table 8: Summary of Lead Heating Testing Related to MRI | Lead Heating | | | --- | --- | | Field Interaction | Radiofrequency | | Mechanism and Source of Hazard | Pacing leads may act as antennae, picking up RF energy. A portion of this energy may be transmitted into the cardiac tissue and converted into heat. | | Clinical Impact | Heating near the lead electrodes may cause thermal tissue injury, which may alter pacing thresholds. | | Evaluation Method | The patient safety risk due to MRI-induced lead heating was evaluated using a combination of bench testing, computer modeling, and animal studies. A computer modeling framework was used to compute the RF power deposited to cardiac tissues in contact with lead electrodes in approximately 0.5 million simulated patient and scanning scenarios. The computer model was developed based on known RF theory and was extensively validated by performing lead heating measurements in an RF coil test system. The 0.5 million simulated scenarios were developed using established electromagnetics simulation methods and are comprised of combinations of human body models, lead implant configurations, and MRI scanner/scanning conditions. Using the computer modeling framework, a worst-case RF power potentially inducible in any patient with INGEVITY MRI leads was determined. An animal study was performed to determine the change in pacing capture threshold as a function of RF power. The worst-case RF power was compared to results of the animal study to assess the risk of clinically significant change in pacing capture threshold caused by MRI-induced lead heating. | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 24 of 82 {24} # PG Heating Table 9: Summary of PG Heating Testing Related to MRI | PG Heating | | | | --- | --- | --- | | Field Interaction | Radiofrequency | Gradient | | Mechanism and Source of Hazard | The PG case concentrates RF electric field into adjacent tissue. | Gradient magnetic fields induce electrical currents in conductive materials of the PG, such as the case and internal components, which are dissipated as heat. | | Clinical Impact | Tissue heating near the PG case may cause patient discomfort or tissue injury. | | | Evaluation Method | The patient safety risk due to MRI-induced PG heating was evaluated through analysis of bench testing and computer modeling. Gradient field induced heating of the PG case was measured in a gradient coil test system. Radiofrequency field induced heating of tissues surrounding the PG was determined using established electromagnetics simulation methods. Both bench testing and computer modeling were performed under worst-case conditions for gradient and RF field exposures. Testing and modeling results were compared to thresholds for tissue damage reported in published literature to assess the risk of clinically significant temperature rise caused by MRI-induced PG heating. | | | Results & Conclusions | Analysis comprised of bench testing and computer modeling indicates patient safety risk due to MRI-induced heating of Ingenio and Accolade PGs is minimal. Testing and modeling demonstrated that heating of and around the pacemaker will not harm surrounding tissues. These results support the safety of the ImageReadyTM MR Conditional Pacing System with regard to the MRI-induced PG heating hazard. | | PMA P150012: FDA Summary of Safety and Effectiveness Data {25} # Vibration Table 10: Summary of Vibration Testing Related to MRI | Vibration | | | --- | --- | | Field Interaction | Static and Gradient | | Mechanism and Source of Hazard | Gradient fields induce electrical currents in the conductive surfaces of pacemaker components. Interaction of these currents with the static magnetic field causes vibration. | | Clinical Impact | Vibration of the PG may cause device malfunction, including loss or alteration of pacing therapy. | | Evaluation Method | Bench testing was performed to evaluate the potential for PG malfunction and damage resulting from MRI-induced vibration. A shaker table based test system was used to apply vibration profiles representative of vibration expected in a pacemaker during MRI scans. Vibration testing was conducted at vibration stress levels above and for durations beyond what a device would reasonably be exposed to during its lifetime. Device functionality testing was performed to ensure normal pacing system operation, including therapy delivery. | | Results & Conclusions | Bench testing confirmed that device malfunction and damage caused by MRI-induced vibration of Ingenio and Accolade PGs are unlikely. No device malfunctions or damage were observed during vibration testing and all devices performed normally after vibration testing. These results support the safety and effectiveness of the ImageReady System with regard to the MRI-induced vibration hazard. | # Translation Force Table 11: Summary of Translation Force Testing Related to MRI | Translation Force | | | --- | --- | | Field Interaction | Static | | Mechanism and Source of Hazard | The static magnetic field will act on any ferromagnetic material in a PG or lead, producing a translation or rotation of the PG or lead. | | Clinical Impact | PG or lead movement may cause patient discomfort, tissue injury, or device dislodgment. | | Evaluation Method | The patient safety risk due to MRI static field induced force was evaluated in bench tests. The MRI induced force exerted on pacemakers and leads was measured using test methods described in ASTM F2052-02, "Standard Test Method For Measurement of Magnetically Induced Displacement Force On Medical Devices in the Magnetic Resonance Environment." | PMA P150012: FDA Summary of Safety and Effectiveness Data {26} # Torque Table 12: Summary of Torque Testing Related to MRI | Torque | | | --- | --- | | Field Interaction | Static | | Mechanism and Source of Hazard | The static magnetic field will act on any ferromagnetic material in a PG or lead, producing a torque of the PG or lead. | | Clinical Impact | PG or lead movement may cause patient discomfort, tissue injury, or device dislodgement. | | Evaluation Method | The patient safety risk due to MRI static field induced torque was evaluated in bench tests. The MRI induced torque exerted on pacemakers and leads was measured using test methods described in ASTM F2213-02, "Standard Test Method for Measurement of Magnetically Induced Torque on Passive Implants in the Magnetic Resonance Environment" | | Results & Conclusions | Bench testing demonstrated that MRI-induced torque on Ingenio and Accolade PGs and INGEVITY MRI leads is minimal. These results support the safety of the ImageReady™ MR Conditional Pacing System with regard to the MRI-induced torque hazard. | # Image Artifact Table 13: Summary of Image Artifact Testing Related to MRI | Image Artifact | | | --- | --- | | Field Interaction | Static, Gradient, and Radiofrequency | | Mechanism and Source of Hazard | The pacing system may interfere with the acquisition of MR data. | | Clinical Impact | Image artifacts may compromise the usefulness of MR images. | | Evaluation Method | MRI scanner testing was performed to evaluate the size of the image artifact produced by the ImageReady System. The image artifact created by pacemakers and leads was measured using test methods described in ASTM F2119-07, "Standard Test Method for Evaluation of MR Image Artifacts from Passive Implants" | PMA P150012: FDA Summary of Safety and Effectiveness Data {27} PMA P150012: FDA Summary of Safety and Effectiveness Data Page 28 of 82 ## Unintended Cardiac Stimulation (UCS) Table 14: Summary of Unintended Cardiac Stimulation Testing Related to MRI | Unintended Cardiac Stimulation | | | | --- | --- | --- | | Field Interaction | Gradient and Radiofrequency | | | Mechanism and Source of Hazard | Gradient: The time varying gradient field will induce a voltage between the pacing lead electrodes and the PG. Current may conduct from the lead electrodes to the heart. | RF: The time varying RF field will induce a voltage along the pacing leads. The PG circuitry may rectify the voltage and conduct a current to the heart. | | Clinical Impact | MRI-induced currents, if large enough, may directly stimulate the heart. | | | Evaluation Method | The patient safety risk due to MRI-induced UCS was evaluated using a combination of bench testing and animal studies. Bench testing was performed to measure currents potentially induced on the pacing system and injected into tissues resulting from: a) rectification of RF pulses; and b) interactions with gradient fields. An animal study was performed to determine the strength-duration relationship for a current stimulus to capture cardiac tissue. The probability that UCS could occur was determined by comparing the statistical distributions of MRI-induced current obtained in bench testing with statistical distributions of capture thresholds obtained in animals. | | | Results & Conclusions | Bench testing and animal study results indicate patient safety risk due to MRI-induced UCS of the ImageReady™ MR Conditional Pacing System is remote. Analysis of the results demonstrated that the probability for MRI-induced unintended stimulation resulting in cardiac tissue capture is exceedingly small. These results support the safety of the ImageReady System with regard to the MRI-induced UCS hazard. | | ## PG Malfunction Table 15: Summary of PG Malfunction Testing Related to MRI | PG Malfunction | | | --- | --- | | Field Interaction | Static, Gradient, and Radiofrequency | | Mechanism and Source of Hazard | The static, gradient, and RF fields may interfere with the electrical operation of the pacing system. | {28} | PG Malfunction | | | --- | --- | | Clinical Impact | MRI-field interactions may cause PG malfunction, including loss or alteration of pacing therapy. | | Evaluation Method | MRI scanner and bench testing were performed to evaluate the potential for PG malfunction and damage resulting from MRI-field interactions. MRI scanner testing was performed to evaluate pacing system operation during and after exposure to the combination of static, radiofrequency, and gradient fields. Bench testing was performed to evaluate pacing system operation during and after independent exposure to static, radiofrequency, and gradient fields. For bench testing, custom electrical injection test systems and a custom gradient coil system were used to apply exposure levels at or above what a device would reasonably be exposed to in clinical scanning scenarios. Device functionality testing was performed to ensure normal pacing system operation, including therapy delivery. | | Results & Conclusions | MRI scanner and bench testing confirmed device malfunction and damage resulting from MRI-field interactions of ImageReady systems are unlikely. MRI scanner testing confirmed normal pacing system operation, including therapy delivery, during and after exposure to the combination of static, radiofrequency, and gradient fields. Bench testing confirmed normal pacing system operation, including therapy delivery, during and after independent exposure to static, radiofrequency, and gradient fields. No device malfunction or damage was observed during testing and all devices performed normally after MRI scanner and bench testing. These results support the safety and effectiveness of the ImageReady System with regard to the MRI-induced malfunction hazard. | X. B. Animal Studies The safety of the INGEVITY™ leads and ImageReady™ MR Conditional Pacing System was evaluated in a series of canine studies (see Table 16); these studies were conducted in accordance with §21 CFR 58 – Good Laboratory Practice (GLP). The results of the studies support the safety of the INGEVITY leads and ImageReady System. System level testing of the Ingenio and Accolade family of pulse generators was done via animal studies conducted in accordance with GLP; these studies were not specific to the MRI versions of Ingenio and Accolade pacemakers and were reviewed by FDA under supplements for existing families of devices. PMA P150012: FDA Summary of Safety and Effectiveness Data {29} Table 16: Summary of GLP Animal Studies | Study Name/Number | Objective | # / Type Animals Test Devices Study Duration | Method | Results | | --- | --- | --- | --- | --- | | Chronic Evaluation of Pacing Capture Threshold (PCT) Change in a Canine Model GLP Study 10-124G | Obtain data to understand the relationship between heating, power dissipation, and Pacing Capture Threshold (PCT) change for the INGEVITY lead family. | • 10 Canines • Test articles consisting of lead outer insulation and distal electrodes with coaxial cable and fiber optic temperature probe • 40 days | Test articles were designed to efficiently transmit RF power to the distal electrodes (actual lead electrode) and allow measurements of PCT, impedance and R-wave amplitudes via the coaxial cable using a pacing system analyzer device. The power dissipation to PCT/temperature change relationship was obtained by measuring changes to PCT and any increases in lead tip-tissue interface temperature that may be caused by delivering RF power to the lead distal electrodes at various power levels. | Sufficient data were collected to establish a relationship between PCT change and RF total dissipated power for the INGEVITY lead family to establish a lead heating performance specification. | PMA P150012: FDA Summary of Safety and Effectiveness Data {30} | Study Name/Number | Objective | # / Type Animals Test Devices Study Duration | Method | Results | | --- | --- | --- | --- | --- | | Passive Fixation Lead Electrical/ Mechanical GLP Study 10-122G | Assess the safety and efficacy of the INGEVITY passive pacing lead system in a canine model over 90 and 180 days post implant. An additional purpose of the study was to gather observational data pertaining to the INGEVITY MRI lead for probability analysis of unintended cardiac stimulation hazard. | • 20 Canines • Model 7632 passive fixation straight lead • Model 7636 passive fixation preformed J lead • 90 days for endpoints and 180 days for observational data | The lead test articles were implanted and connected to a pacemaker. Electrical data (atrial and ventricular pacing voltage threshold, atrial sensing P wave, ventricular sensing R wave) was taken throughout the study to document lead function and radiographs taken to document lead position. Simulated MRI electrical testing was performed on 18 animals to characterize chronic single beat stimulation threshold measurements over the range of gradient and RF field pulse widths for an MR scanner. All animals had a comprehensive necropsy performed, including to inspect and observe gross cardiac changes and to assess the cellular-level tissue biocompatibility response at the implant site. | Under the conditions of this study, the chronic electrical performance endpoints were successfully met and observational data was collected. The study successfully supported safety and efficacy of the INGEVITY passive pacing lead system in a canine model over 90 days post implant and continued to collect observational data up to 180 days post implant. The study successfully collected the single beat stimulation threshold measurements over a range of pulse widths relevant to MR scanners after 90 or 180 days post implant in the canine model. | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 31 of 82 {31} | Study Name/Number | Objective | # / Type Animals Test Devices Study Duration | Method | Results | | --- | --- | --- | --- | --- | | Active Fixation Lead Electrical/ Mechanical GLP Study 10-072G | Assess the safety and efficacy of the INGEVITY active pacing lead system in a canine model over 90 and 180 days post implant. An additional purpose of the study was to gather observational data pertaining to the INGEVITY MRI lead for probability analysis of unintended cardiac stimulation hazard. | • 19 Canines • Model 7642 active fixation straight lead • 90 days for endpoints and 180 days for observational data | The lead test articles were implanted and connected to a pacemaker. Electrical data (atrial and ventricular pacing voltage threshold, atrial sensing P wave, ventricular sensing R wave) was taken throughout the study to document lead function and radiographs taken to document lead position. . Simulated MRI electrical testing was performed on 16 animals to characterize chronic single beat stimulation threshold measurements over the range of gradient and RF field pulse widths for an MR scanner. All animals had a comprehensive necropsy performed, including to inspect and observe gross cardiac changes and to assess the cellular-level tissue biocompatibility response at the implant site. | Under the conditions of this study, the chronic electrical performance endpoints were successfully met and observational data was collected. The study successfully supported safety and efficacy of the INGEVITY Active pacing lead system in a canine model over 90 days post implant and continued to collect observational data up to 180 days post implant. The study successfully collected the single beat stimulation threshold measurements over a range of pulse widths relevant to MR scanners after 90 or 180 days post implant in the canine model. | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 32 of 82 {32} | Study Name/Number | Objective | # / Type Animals Test Devices Study Duration | Method | Results | | --- | --- | --- | --- | --- | | Acute Accessory GLP Study 11-022G | Demonstrate the safety and performance of the INGEVITY active and passive fixation pacing leads with their compatible accessories in an acute setting in an animal model. | • 2 swine • Models 7641 and 7642 active fixation straight leads • Model 7636 passive fixation preformed J lead • Model 7632 passive fixation straight lead • Model 6402 Slit Suture Sleeve • 0.014 inch long tapered straight stylets • 0.013 inch tapered straight stylets • Acute | Standard right atrium (RA) and right ventricle (RV) brady lead implant technique was used for the lead implantation. The lead with stylet was inserted and positioned in the RV chamber, RA chamber or appendage multiple times. A pacing system analyzer (PSA) device was connected to select leads and used to collect electrical data. Fluoroscopy cines were also taken throughout the study to view the lead position and the suture sleeve visibility. Acute repositionability of the lead in the RA and RV and compatibility with accessories were tested in this study. Qualitative data were collected and recorded regarding the ease and general performance of the INGEVITY lead with specified accessories. | Endpoint 1: PASS Demonstration that the INGEVITY active fixation straight leads could withstand five consecutive cycles of positioning in the ventricle in ≤ 18 turns for full extension and retraction. Endpoint 2: PASS Demonstration that the INGEVITY family of leads were successfully compatible with: • Select stylets • Slit suture sleeves • Introducers (6Fr and 9Fr) • Guide wires Data on five observational criteria was collected. | PMA P150012: FDA Summary of Safety and Effectiveness Data Page 33 of 82 {33} | Study Name/Number | Objective | # / Type Animals Test Devices Study Duration | Method | Results | | --- | --- | --- | --- | --- | | Passive and Active Fixation Lead Drug Characterization GLP Studies 10-073G and 10-074G) | Characterize the drug system of the INGEVITY passive fixation and active fixation pacing/sensing leads | • 15 Canines in the passive fixation lead study • 9 Canines in the active fixation lead study • Model 7632 passive fixation straight lead • Model 7636 passive fixation preformed J lead • Model 7642 active fixation straight lead • Up to 90 days | The animals were implanted with the INGEVITY leads and survived until their predetermined endpoints (2, 7, 14, 21, 28, 44, 60 and 90 days). Plasma samples were collected and analyzed at multiple time points throughout the study to measure circulating DX. Endocardial tissue was collected at the location of each lead drug collar during necropsy and subsequently analyzed to measure tissue concentration of DX. Each lead’s drug-containing component was analyzed for residual DXA. Observational data were collected during the in-life phase: • Radiographic or fluoroscopic images • Electrical data at implant and just prior to animal termination • Gross necropsy | An assessment of dexamethasone (DX) drug release following lead implant of the INGEVITY passive and active fixation pacing lead systems in an animal model at prescribed time points through 90 days post implant was completed. Systemic (plasma) dexamethasone (DX) and tissue (endocardium) DX concentrations were measured as well as residual dexamethasone acetate (DXA) in the collars of the explanted leads. The studies provided appropriate characterization data on the drug system of the INGEVITY passive and active fixation pacing/sensing leads (3 samples per time-point), respectively. | X. C. Sterilization PMA P150012: FDA Summary of Safety and Effectiveness Data Page 34 of 82 {34} The Ingenio and Accolade pulse generators, as well as the INGEVITY leads and lead accessories, are sterilized via Ethylene Oxide (EO) in accordance with internal quality control procedures and ANSI/AAMI/ISO 11135:2007 Medical Device – Validation and Routine Control of Ethylene Oxide Sterilization. Residual testing was conducted per ISO 10993-7:2008 Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide Sterilization Residuals. The validated EO sterilization process has demonstrated Sterility Assurance Levels (SAL) of greater than $10^{-6}$. ## XI. SUMMARY OF PRIMARY CLINICAL STUDY FOR THE LEAD The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of implantation of the INGEVITY Active Fixation and Passive Fixation Pace/Sense Leads for the treatment of the conditions listed in Section II.A in the US and internationally under IDE G110227. Data from this clinical study were the basis for the PMA approval decision, along with data from the SAMURAI study under IDE G120076 (see Section XII for details). A summary of the clinical study is presented below. ## A. Study Design – INGEVITY Patients were treated between October 22, 2012 and October 22, 2013. Treatment was defined as implanted or attempted with at least one INGEVITY lead. The database for this PMA reflected data collected through February 17, 2016 and included 1060 patients and 1599 leads. There were 43 US and 34 international investigational sites. The INGEVITY Study is a prospective, single-group, non-randomized, multi-center, global clinical study, utilizing performance goals to demonstrate the safety, performance and effectiveness of the INGEVITY Leads. As a single-group study, there was no control group in the INGEVITY study. The study used a Clinical Events Committee as a group of independent evaluators to adjudicate mortality. The INGEVITY Study has been conducted through the 12-month follow-up endpoints to collect data to support US pre-market approval of the INGEVITY lead family. Data continues to be collected via annual follow-up at 2 through 5 years in support of post-market approval requirements. To appropriately characterize long-term safety performance of this new family of pace/sense leads, the various leads in the INGEVITY lead family are studied in separate "lead cohorts." The right ventricular active fixation lead serves as the primary lead model in the INGEVITY Study, and therefore is studied as lead cohort 1 with a sample size equal to 700 leads evaluable at 12 months. The required sample sizes for the right atrial active fixation lead, the right ventricular passive fixation lead and the right atrial passive fixation lead are 350, 175, and 35 leads, respectively, PMA P150012: FDA Summary of Safety and Effectiveness Data Page 35 of 82 {35} evaluable at 12 months. The following lead cohorts were studied in the INGEVITY Study: - Lead Cohort 1 = Right ventricular active fixation leads - Lead Cohort 2 = Right atrial active fixation leads - Lead Cohort 3 = Right atrial and right ventricular passive fixation leads Subjects were followed in the INGEVITY study based on the date of their INGEVITY Lead implant(s). Follow-up was required at pre-discharge, 1 month, 3 months and 12 months post-implant. Subjects will continue to be followed annually until 5 years post-implant. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the INGEVITY study was limited to patients who met all of the following inclusion criteria: - Willing and capable of providing informed consent; - INGEVITY™ Lead(s) and a Boston Scientific pulse generator must be the initial (de novo) pacing system implants for the patient; - Has a Class I or II indication for implantation of a single (VVI(R) only) or dual chamber pacemaker or CRT-P system according to the American College of Cardiology (ACC)/American Heart Association (AHA)/Hearth Rhythm Society (HRS)⁹, or European Society of Cardiology (ESC)¹⁰ guidelines; - Willing and capable of participating in all testing/visits associated with this clinical study at an approved clinical study center and at the intervals defined by this protocol; and - Age 18 or above, or of legal age to give informed consent specific to state and national law. Patients were not permitted to enroll in the INGEVITY study if they met any of the following exclusion criteria: - Has or has had any pacing or ICD system implants; - Intended to receive an AAI(R) pulse generator; - Known or suspected sensitivity to dexamethasone acetate (DXA); PMA P150012: FDA Summary of Safety and Effectiveness Data Page 36 of 82 ⁹ Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons Circulation 2008;117: e350-e408. ¹⁰ Vardas PE, Auricchio A, Blanc J, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Europace 2007; 9: 959-998. {36} - Has a mechanical tricuspid heart valve; - Enrolled in any other concurrent study, with the exception of local mandatory governmental registries and observational studies/registries that are not in conflict; - Documented permanent or persistent $\mathrm{AF}^{11}$ where the physician intends to implant a dual chamber pulse generator (single chamber VVIR pulse generators are acceptable); - Currently on the active heart transplant list; - Documented life expectancy of less than 12 months; - Women of childbearing potential who are or might be pregnant at the time of study enrollment or INGEVITY™ Lead implant (method of assessment upon physician's discretion); and/or - Currently requiring dialysis. # 2. Follow-up Schedule All patients were scheduled to return for follow-up examinations at pre-discharge (3-72 hours post-implant), 1, 3, 12, 24, 36, 48 and 60-months postoperatively. Preoperative and postoperative evaluations and objective parameters measured are listed in the following table. Adverse events and complications were required per the protocol to be reported at all visits. The key timepoints are shown below in the tables summarizing safety and effectiveness. Table 17: Data Collection Schedule | Procedure/Assessment | Enrollment | Implant | Pre-Discharge | 1 Month | 3 Months | 12 Months | 2, 3, 4, 5 years | Add'l Visits | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Timeframe | ≤ 30 days prior to Implant | Day 0† | 3-72 h† | 30 ± 7 d†Clinic Visit | 91±14 d†Clinic Visit | 365 ± 45 d†Clinic Visit | -2 yr: 730±90 d†-3 yr: 1095±90 d†-4 yr: 1461±90 d†-5 yr: 1826±90 d†Clinic Visit | Not specified | | Informed consent form, including informed consent signature date | X | -- | -- | -- | -- | -- | -- | -- | | Demographics, including age at implant, gender | X | -- | -- | -- | -- | -- | -- | -- | | Physical assessment, including weight and height | X | -- | -- | -- | -- | -- | -- | -- | | Medical history | X | -- | -- | -- | -- | -- | -- | -- | | PSA measurements for all INGEVITY Leads (capture | -- | X | -- | -- | -- | -- | -- | -- | PMA P150012: FDA Summary of Safety and Effectiveness Data {37} | Procedure/Assessment | Enrollment | Implant | Pre-Discharge | 1 Month | 3 Months | 12 Months | 2, 3, 4, 5 years | Add'l Visits | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | thresholds @ 0.5ms) | | | | | | | | | | PA and lateral chest X-ray and/or fluoroscopic image of INGEVITY Lead distal tip fixation | -- | X | | -- | -- | -- | -- | -- | | Implant Questionnaire | -- | X | -- | -- | -- | -- | -- | -- | | Cardiovascular Medications, including updates and changes | X | X | X | X | X | X | X | O | | IPG lead measurements for all INGEVITY Leads (threshold @ 0.5ms through 3-Month Visit) | -- | X | X | X | X | X | X | X (if lead-related AE), else O | | ECG documenting LOC | -- | X | X | X | X | X | X | X (if lead-related AE), else O | | Adverse Event assessment/ reporting | X | X | X | X | X | X | X | X | | Protocol Deviation | X | X | X | X | X | X | X | X | Legend: X = Required; -- = Not required/ Not applicable; O = Optional; h = hours; d = days; ECG = Electrocardiogram; LOC = Loss of Capture; IPG = Implantable Pulse Generator; PSA = Pacing System Analyzer; PA = Posterior-Anterior † Clock starts after end of Implant procedure, day of implant is day 0 and hour 0 is pocket closure The follow-up compliance for all successfully implanted subjects is presented in Table 18. Follow-up is ongoing. Table 18: Follow-Up Visit Compliance (N = 1038 Implanted Subjects) | Visit | Visit Window | Expected Number of Visits* | Completed Number (%) of Visits | Completed Number (%) of Visits in Visit Window | | --- | --- | --- | --- | --- | | Implant | Not applicable | 1038 | 1038 (100%) | 1038 (100%) | | Predischarge | 3-72 hours after implant | 1038 | 1037 (99.9%) | 1035 (99.7%) | | 1 Month Follow-Up | 30 ± 7 days after implant | 1033 | 1015 (98.3%) | 924 (89.4%) | | 3 Month Follow-Up | 91 ± 14 days after implant | 1018 | 1000 (98.2%) | 916 (90.0%) | | 12 Month Follow-Up | 365 ± 45 days after implant | 979 | 948 (96.8%) | 912 (93.2%) | | * Expected number of visits based on the number of subjects actively followed at the time of the opening of the visit window. | | | | | ## 3. Clinical Endpoints ### SAFETY ENDPOINTS With regard to safety, the following endpoints were evaluated for the INGEVITY Leads, to satisfy worldwide regulatory requirements. PMA P150012: FDA Summary of Safety and Effectiveness Data {38} - Safety Endpoint 1: Lead-related Complication-Free Rate from Implant through Three Months Post-Implant - Safety Endpoint 2: Lead-related Complication-Free Rate from Three Months Post-Implant through Twelve Months Post-Implant - Safety Endpoint 3: Hazard of Lead-Related Complications Over Time Lead-related complications are defined as lead-related adverse events resulting in permanent loss of pacing therapy, invasive intervention, injury or death. Lead-related adverse events include, but are not limited to the following, based on the Advanced Industry Guidance for Uniform Reporting of Clinical Performance of Cardiac Rhythm Management of Pulse Generators and Leads, and in accordance with the FDA Guidance: - Cardiac perforation requiring surgical intervention - Cardiac perforation not requiring surgical intervention - Conductor fracture/helix damage - Lead dislodgment - Failure to capture - Oversensing - Failure to sense (undersensing) - Insulation breach - Abnormal pacing impedance - Extracardiac stimulation Lead-related complications associated with attempted INGEVITY Lead implants counted toward the safety endpoints. Lead-related adverse events that are not a complication counted as a complication if intravenous (IV) drug therapy was necessary to treat the event. IV drug therapy that occurred concomitant but unrelated to the lead-related adverse event did not count as a lead-related complication. Complications involving an INGEVITY lead that occurred as a result of a procedure unrelated to that INGEVITY lead did not count toward this safety endpoint. Two examples of this scenario are 1) an INGEVITY lead dislodgment that resulted from an ablation procedure and 2) an RV INGEVITY lead dislodgment that resulted from a repositioning of an RA lead (INGEVITY or market-released). ## EFFECTIVENESS ENDPOINTS With regard to effectiveness, the following endpoints were evaluated for the INGEVITY Leads. These endpoints were analyzed separately by lead fixation type and chamber. - Effectiveness Endpoint 1: Pacing Threshold at 0.5 ms pulse width at Three Months Post-Implant - Effectiveness Endpoint 2: Sensed Amplitude at Three Months Post-Implant - Effectiveness Endpoint 3: Pacing Impedance at Three Months Post-Implant PMA P150012: FDA Summary of Safety and Effectiveness Data Page 39 of 82 {39} SUCCESS/FAILURE CRITERIA With regard to success/failure criteria, the study was required to pass Safety Endpoints 1, 2 and 3 and Effectiveness Endpoints 1, 2 and 3. ## B. Accountability of PMA Cohort At the time of database lock, a total of 1060 subjects were enrolled in the PMA study at 77 at 77 centers, including 603 (56.9%) enrollments at 43 centers in the US and 457 (43.1%) (43.1%) enrollments at 34 centers outside of the US., as shown in Table 19. Table 19: Enrollment Numbers by Country (N = 1060 Enrolled Subjects) | Country | Number (%) of Centers | Number (%) of Subjects | | --- | --- | --- | | United States | 43 (55.8%) | 603 (56.9%) | | Spain | 4 (5.2%) | 88 (8.3%) | | France | 2 (2.6%) | 57 (5.4%) | | Austria | 3 (3.9%) | 45 (4.2%) | | United Kingdom | 3 (3.9%) | 39 (3.7%) | | Germany | 4 (5.2%) | 37 (3.5%) | | Portugal | 2 (2.6%) | 32 (3.0%) | | Denmark | 2 (2.6%) | 26 (2.5%) | | Malaysia | 2 (2.6%) | 25 (2.4%) | | Belgium | 2 (2.6%) | 22 (2.1%) | | Italy | 1 (1.3%) | 21 (2.0%) | | Canada | 3 (3.9%) | 20 (1.9%) | | Sweden | 2 (2.6%) | 16 (1.5%) | | Hong Kong | 1 (1.3%) | 11 (1.0%) | | Thailand | 1 (1.3%) | 10 (0.9%) | | Australia | 2 (2.6%) | 8 (0.8%) | | Total | 77 | 1060 | Of the 1060 enrolled subjects, 1038 were successfully implanted with the INGEVITY leads. Subjects were allowed to contribute both a right atrial and a right ventricular lead to the endpoint analyses. There were 563 subjects that contributed both a right atrial lead and a right ventricular lead to the endpoint analyses, and 473 subjects that contributed one lead to the analysis, either a right atrial or a right ventricular lead. Figure 6 shows the disposition of subjects in the study. A subject could miss a PMA P150012: FDA Summary of Safety and Effectiveness Data {40} follow-up visit, and still contribute data at a subsequent follow-up visit. $91\%$ (962) of patients were under follow-up and therefore available for analysis at the 12 month post-operative visit.  Figure 6: Subject Disposition The last 12-month follow-up visit was performed in November 2014. Results include any visit or event that occurred on or before February 17, 2016. This dataset represents the data submitted in support of the PMA; however, subject follow-up continued beyond this date, with subjects and leads followed for a median of 31 and 32 months, respectively. # DATA CONTRIBUTING TO ENDPOINTS Of the 1060 enrolled subjects, 1599 leads in 1036 subjects were eligible to contribute to endpoint analyses. To be eligible for endpoint analysis the lead must have been the final lead implanted or attempted in a chamber during the initial implantation procedure. Each patient could contribute up to two leads, one per chamber. Table 20 summarizes the data contributing to each of the endpoints. PMA P150012: FDA Summary of Safety and Effectiveness Data {41} Table 20: Summary of Data Contributing to Study Endpoints | | | Included in Endpoint Analysis | | | --- | --- | --- | --- | | Endpoint | Description | Patients | Leads | | Safety Endpoint 1 | Lead-Related Complication-Free Rate through 3 months | 1036 (100%) | 1599 (100%) | | Safety Endpoint 2 | Lead-Related Complication-Free Rate from 3 months through 12 months | 1009 (97%) | 1545 (97%) | | Safety Endpoint 3 | Weibull Shape Parameter for Lead-Related Complications | 1036 (100%) | 1599 (100%) | | Effectiveness Endpoint 1 | Pacing Threshold @ 0.5 ms at 3 months | 982 (95%) | 1482 (93%) | | Effectiveness Endpoint 2 (RA) | Sensed Amplitude at 3 months (RA) | 521 (93%) | 521 (93%) | | Effectiveness Endpoint 2 (RV) | Sensed Amplitude at 3 months (RV) | 914 (88%) | 914 (88%) | | Effectiveness Endpoint 3 | Pacing Impedance at 3 months | 995 (96%) | 1526 (95%) | Statistical analyses were performed and determined that the missing/excluded data were highly unlikely to affect the conclusions from the study. # C. Study Population Demographics and Baseline Parameters Although the study was performed globally, the demographics of the study population are typical for a pace/sense lead study performed in the US. Baseline characteristics, including subject demographics and the primary indication for implant for successfully randomized subjects are summarized in Table 21 and Table 22. Table 21: INGEVITY Subject Demographics | | | | Implanted or Attempted Subjects | | | --- | --- | --- | --- | --- | | Characteristic | Measurement | All Enrolled Subjects (N=1060) | Pacemaker (N=1006) | CRT-P (N=3…