4.         Summary of Safety and Effectiveness Data

Attached is a detailed Summary of Safety and Effectiveness for the VNS Therapy System. The document was prepared in accordance with the Pre-Market Approval (PMA) Manual (1998). A CD ROM containing a soft copy of this document (formatted in Microsoft Word) was submitted with this PMA Supplement and is labeled VNS Therapy System for depression - Summary of Safety and Effectiveness.


Summary of Safety and Effectiveness

 

I.                   GENERAL INFORMATION

                        Device Generic Name:

Stimulator, Vagus Nerve

                        Device Trade Names:

VNS Therapy System

VNS Therapy Pulse Model 102 Generator

VNS Therapy Pulse Duo Model 102R Generator

VNS Therapy Programming Wand Model 201

VNS Therapy Magnet Model 220

VNS Therapy Software Model 250

VNS Therapy Lead Model 302

VNS Therapy Tunneler Model 402

VNS Therapy Accessory Pack Model 502

                        Applicant's Name and Address:

Cyberonics, Inc.

100 Cyberonics Boulevard

Cyberonics Building

Houston, Texas 77058 USA

PMA Number:                                                             P970003

Date of Panel Recommendation:                                    ___________, 2004

Date of Notice of Approval to the Applicant:                 ___________, 2004

 

II.                Indications for Use

The VNS Therapy System is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients over the age of 18 who are experiencing a major depressive episode that has not had an adequate response to two or more adequate antidepressant treatments.

 

 

 

 

III.             CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS

 

A.        Contraindications

 

·       The VNS Therapy System cannot be used in patients after a bilateral or left cervical vagotomy.

 

·       Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (hereafter referred to as diathermy) on patients implanted with a VNS Therapy System. Diagnostic ultrasound is not included in this contraindication.

 

Energy delivered by diathermy may be concentrated into or reflected by implanted products such as the VNS Therapy System. This concentration or reflection of energy may cause heating.

 

Testing indicates that diathermy can cause heating of the VNS Therapy System well above temperatures required for tissue destruction. The heating of the VNS Therapy System resulting from diathermy can cause temporary or permanent nerve or tissue or vascular damage. This damage may result in pain or discomfort, loss of vocal cord function, or even possibly death if there is damage to blood vessels.

 

Because diathermy can concentrate or reflect its energy off any size-implanted object, the hazard of heating is possible when any portion of the VNS Therapy System remains implanted, including just a small portion of the Lead or electrode. Injury or damage can occur during diathermy treatment whether the VNS Therapy System is turned “ON” or “OFF”.

 

Diathermy is further prohibited because it may also damage the VNS Therapy System components resulting in loss of therapy, requiring additional surgery for system explantation and replacement. All risks associated with surgery or loss of therapy (loss of seizure control) would then be applicable.

 

Advise your patients to inform all their health care professionals that they should not be exposed to diathermy treatment.

 


 

B.        Warnings

 

·       The safety and efficacy of the VNS Therapy System has not been established for uses not covered in the “Intended Use/Indications” section of this manual.

 

·       The safety and efficacy of the VNS Therapy System have not been established for stimulation of the right vagus nerve or of any other nerve, muscle, or tissue.

 

·       Note: Use of the Magnet to activate stimulation is not recommended for patients with depression. The Magnet Mode output current should remain at 0.0mA for patients with depression. 

Excessive stimulation at an excess duty cycle (that is, one that occurs when ON time is greater than OFF time) has resulted in degenerative nerve damage in laboratory animals. An excess duty cycle can be produced by continuous or frequent magnet activation (> 8 hours), as determined by animal studies. Cyberonics recommends against stimulation at these combinations of ranges.

 

·       Patients who manipulate the Pulse Generator and Lead through the skin (Twiddler’s Syndrome) may damage or disconnect the Lead from the Pulse Generator and/or possibly cause damage to the vagus nerve.

 

·       Aspiration may result from the increased swallowing difficulties reported by some patients during stimulation. Patients with pre-existing swallowing difficulties are at greater risk for aspiration.

 

·       Device malfunction could cause painful stimulation or direct current stimulation. Either event could cause nerve damage and other associated problems. Patients should be instructed to use the Magnet to stop stimulation if they suspect a malfunction, and then to contact their physician immediately for further evaluation. Prompt surgical intervention may be required if a malfunction occurs.

 

·       Susceptible patients with predisposed dysfunction of cardiac conduction systems (re-entry pathway) have not been studied as part of controlled clinical trials to establish the safety of VNS Therapy System treatment in these patients. Evaluation by a cardiologist is recommended if the family history, patient history, or electrocardiogram suggests an abnormal cardiac conduction pathway. Serum electrolytes, magnesium, and calcium should be documented before implantation. Post-implant electrocardiograms and Holter monitoring are recommended if clinically indicated.

 

·       Patients with obstructive sleep apnea (OSA) may have an increase in apneic events during stimulation. Cyberonics recommends care when treating patients with pre-existing OSA. Lowering stimulus frequency or prolonging OFF time may prevent exacerbation of OSA. 

 

·       Physicians should warn patients that VNS Therapy has not been proven to be a cure for depression.

 

C.        Precautions

 

·       Laryngeal irritation may result from stimulation. Patients who smoke may have an increased risk of laryngeal irritation.

 

·       Dyspnea may result from stimulation. Patients with chronic obstructive pulmonary disease may have an increased risk of dyspnea.

 

·       It is important to follow recommended implantation procedures and intraoperative product testing described in the Physician’s Manual. During the intraoperative Lead Test, infrequent incidents of bradycardia and/or asystole have occurred. If asystole, severe bradycardia (heart rate < 40 bpm), or a clinically significant change in heart rate is encountered during a Lead Test or during initiation of stimulation, physicians should be prepared to follow guidelines consistent with Advance Cardiac Life Support (ACLS).

 

Additionally, postoperative bradycardia can occur among patients with certain underlying cardiac arrhythmias.  If a patient has experienced asystole, severe bradycardia (heart rate < 40 bpm) or a clinically significant change in heart rate during a Lead Test at the time of initial device implantation, the patient should be placed on a cardiac monitor during initiation of stimulation. 

 

The safety of this therapy has not been systematically established for patients experiencing bradycardia or asystole during VNS Therapy System implantation.

 

·       Reversal of lead polarity has been associated with an increased chance of bradycardia in animal studies. It is important to make sure that the lead connector pins are correctly inserted (white marker band/serial number to + connection) into the lead receptacle(s).

 

·       Do not program the VNS Therapy System to an ON or periodic stimulation treatment for at least 14 days after the initial or replacement implantation. Failure to observe this precaution may result in patient discomfort or adverse events.

 

·       Resetting the pulse generator turns the device OFF (output current = 0.0 mA), and all device history information is lost. The device history information should be printed out before resetting.

 

·       Do not use frequencies of 5 Hz or below for long-term stimulation. Because these frequencies generate an electromagnetic trigger signal, their use results in excessive battery depletion of the implanted pulse generator and, therefore, should be used for short periods of time only.

 

·       It is important to follow infection control procedures. Infections related to any implanted device are difficult to treat and may require that the device be explanted. Cyberonics recommends that the patient be given antibiotics preoperatively. The surgeon should ensure that all instruments are sterile prior to the operation.

 

Cyberonics recommends frequent irrigation of both incision sites with generous amounts of bacitracin or equivalent solution prior to closure. (To minimize scarring, these incisions should be closed with cosmetic closure techniques.) Also, antibiotics should be administered postoperatively at the discretion of the physician.

 

·       The VNS Therapy System is indicated for use only in stimulating the left vagus nerve in the neck area inside the carotid sheath.

 

·       The VNS Therapy System is indicated for use only in stimulating the left vagus nerve below where the superior and inferior cervical cardiac branches separate from the vagus nerve.

 

·       Physicians who implant the VNS Therapy System should be experienced performing surgery in the carotid sheath; physicians should be familiar with vagal anatomy, particularly the cardiac branches; and they should be trained in the surgical technique relating to implantation of the VNS Therapy System. See the section “Physician Training/Information” in the Physician’s Manual.

 

·       A neck brace can be used by the patient for the first week to help ensure proper lead stabilization.

 

·       Appropriate physician training is very important:

 

Ř      Prescribing physicians should be experienced in the diagnosis and treatment of depression and should be familiar with the programming and use of the VNS Therapy System.

Ř      Physicians who implant the VNS Therapy System should be experienced performing surgery in the carotid sheath and should be trained in the surgical technique relating to implantation of the VNS Therapy System. (See the “Physician Training/Information” section of the Physician’s Manual.)

 

IV.              Device Description

On July 16, 1997, Cyberonics, Inc. (Cyberonics or Sponsor) received PMA approval for the VNS Therapy™ System (P970003) for the treatment of epilepsy.  The VNS Therapy System used for vagus nerve stimulation (VNS), consists of the implantable VNS Therapy Pulse Generator, the VNS Therapy Lead and the external programming system used to change stimulation settings.  The pulse generator is an implantable, multiprogrammable, pulse generator that delivers electrical signals to the vagus nerve.  The pulse generator is housed in a hermetically sealed titanium case and is powered by a single battery.  Electrical signals are transmitted from the pulse generator to the vagus nerve by the lead.  The lead and the pulse generator make up the implantable portion of the VNS Therapy System.  The external programming system includes a programming wand, the Model 250 Programming Software, and a compatible computer.  The software allows a physician, with the programming wand placed over the implanted pulse generator, to identify, read and change device settings. 

 

The commercially available VNS Therapy Systems were used to conduct the depression pilot and pivotal clinical studies.

 

VNS Therapy System used for the D-01 Study:

The commercially available pulse generator used for the D-01 study was an improved pulse generator from the original Model 100 approved by PMA P970003.  The improved Model 100C (P970003/S04) permitted increased longevity (from 4.9 to 6.36 years) and incorporated an Elective Replacement Indicator (ERI) flag for the user during external programming.  All of the programmable, diagnostic and therapeutic functions remained unchanged.

 

VNS Therapy System used for the D-02 Study:

The commercially available pulse generator used for the D-02 study was the Model 101 (P970003/S22); an improved pulse generator from the original Model 100C Pulse Generator used in the D-01 study.  The improved Model 101 provided patients with a smaller, more comfortable pulse generator.  The Model 100C measured 2 in x .5 in (55 mm x 13.2 mm) and weighed 2 oz (55 g) while the Model 101 measured 2.1 in x 2.1 in x .41 in (54 mm x 54 mm x 10.3 mm) and weighed 1.34 oz (38 g).  All of the programmable, diagnostic and therapeutic functions remained unchanged. 

 

Shortly after all D-02 pivotal study subjects were implanted with the Model 101, further size, weight and human factor improvements unrelated to the study were made to the commercially available VNS Therapy System pulse generator and lead.  These improvements resulted in the single connector, Model 102 Pulse Generator measuring 2.1 in x 0.27 in (52.2 mm x 6.9 mm) and weighing 0.88 oz (25 g), which accommodates a new single connector pin, Model 302 Lead (P970003/S40).  The Model 102R was designed as a replacement for Model 100, Model 100C and Model 101 Generators with dual connector Model 300 leads nearing end of service.  Cyberonics modified the Model 102 Pulse Generator to incorporate the Model 101 header assembly with the dual connectors.  This design change resulted in the Model 102R (P970003/S47).  The Model 102R measures 2.0 in. x 2.3 in. x 0.27 in. (52 mm x 58.4 mm x 6.9 mm) and weighs 0.95 oz. (27 g).  The Model 102R is slimmer, lighter and easier to implant than its dual connector predecessor, the Model 101 Generator.  All of the programmable, diagnostic and therapeutic functions remained unchanged.  The FDA approved these design changes based on the technical data presented in the aforementioned PMA-Supplements, thereby agreeing with Cyberonics that these design improvements do not require additional clinical data to support the change.

 

Thus the clinical data collected to support the safety and effectiveness for the VNS Therapy depression indication using the model 101 and 300 series leads are directly applicable to the currently commercially distributed VNS Therapy™ System which includes the following products:

 

VNS Therapy Pulse Model 102 Generator

VNS Therapy Pulse Duo Model 102R Generator

VNS Therapy Programming Wand Model 201

VNS Therapy Magnet Model 220

VNS TherapySoftware Model 250

VNS Therapy Lead Model 302

VNS Therapy Tunneler Model 402

VNS Therapy Accessory Pack Model 502

 

The pulse generator, a device similar to a cardiac pacemaker, is surgically placed in the left chest.  The lead is then connected to the pulse generator and attached to the left vagus nerve. The VNS Model 402 Tunneler is used during implantation to create a subcutaneous path for the lead and is used in its placement as well.

 

The VNS Therapy System operates when electrical signals are transmitted from the pulse generator to the vagus nerve via the lead.  Peripheral components are used to non-invasively activate, program, and retrieve information from the pulse generator.

 

Patients are provided with magnets that, by placing the magnet over the implanted pulse generator can deactivate (turn OFF) programmed stimulation. Programmed stimulation resumes when the magnet is removed.


A.        VNS Therapy™ Pulse Model 102 and Pulse Duo Model 102R Generators

 

The VNS Therapy Pulse Model 102 and Pulse Duo Model 102R Generators are implantable, multiprogrammable pulse generators that deliver electrical signals to the vagus nerve.  Constant current, capacitively coupled, charge-balanced signals are transmitted from the Generator to the vagus nerve by the lead.  The pulse generator is housed in a hermetically sealed titanium case.  Feedthrough capacitors are used to filter electromagnetic interference from the pulse generator circuitry.  The major components and functions of the pulse generator are as follows: a microprocessor, a voltage regulator, a 76.8 kHz crystal oscillator, one antenna to transmit information and another antenna to receive information, communication circuitry, DC-DC voltage generation and control circuitry, constant current control circuitry, a dual pole magnetic reed switch for manual activation of the pulse generator and for inhibition of the output pulses, and a lithium thionyl chloride cell to provide power for stimulation and circuit operation.  The lithium thionyl chloride battery chemistry has the low impedance and high energy density characteristics required for the rapid pulsing needed in peripheral nerve stimulation, and similar batteries have been previously used in cardiac pacemakers, implantable spinal cord stimulators, and implantable drug pumps. VNS Therapy Pulse Model 102 generator is used for initial implants and is compatible with the VNS TherapyLead Model 302. The VNS Therapy Pulse Duo Model 102R Generator is used for replacing pulse generators nearing end of service that are only compatible with dual connector leads.

 

1.         Therapy

The pulse generator has a number of programmable settings, which allow the physician to optimize the treatment for a patient.  Those settings include pulse width, magnet-activated output current, output current, magnet-activated ON time, signal frequency, magnet-activated pulse width, signal ON time and signal OFF time.   Information on the settings used in the clinical trials is contained in the Physician’s Manual.

 

2.         Diagnostic and Safety Characteristics

The pulse generator has telemetry capability that supplies information about its operating characteristics, such as parameter settings, lead impedance and history of magnet use.  The pulse generator has a number of characteristics to enhance operational reliability and safety, such as electromagnetic interference (EMI) filter capacitors, a series battery resistor to limit temperature rise in the event of short circuit, defibrillation protection diodes, direct current-blocking capacitors on both leads that prevent direct current (DC) from being applied to the patient, a software watchdog timer to prevent continuous stimulation, and protection against voltage dips on the battery that could disrupt microprocessor memory.

 

B.        VNS Therapy Lead Model 302

The lead delivers electrical signals from the pulse generator to the vagus nerve.  The lead has two helical electrodes with a helical anchor tether on one end and on the other end a 3.2-millimeter (mm) connector. The helix of the lead is available in two sizes of inner diameter (2.0‑mm and 3.0‑mm) to allow for appropriate fit on different sized nerves.  The helical design is soft, pliable, and expands or contracts with changes in nerve diameter, which may occur immediately post implant.  These design features allow the 2‑mm inside diameter helical electrode to fit most vagus nerves.  The lead is insulated with silicone rubber and is non-bifurcated. The lead wire is quadrifilar MP-35N, and the electrode is a platinum ribbon.

 

C.        VNS Therapy Tunneler Model 402

The tunneler is designed for use during implantation of the lead. The tunneler consists of 4 basic components: a stainless steel shaft, 2 fluorocarbon polymer sleeves and a stainless steel bullet tip. It is recommended for subcutaneous tunneling of the lead connector from the neck to the chest. The Tunneler is supplied sterile and is for single use only.

 

D.        VNS Therapy Programming Wand Model 201

The programming wand is used with the VNS Therapy Software Model 250 installed on either a compatible handheld or laptop computer to activate, program, reprogram and interrogate the pulse generator. Capabilities of the programming wand include revision of the programmable parameters of the pulse generator, retrieval of telemetry data, and resetting of the pulse generator's microprocessor.

 

E.         VNS Therapy Software Model 250

The programming software is a computer program that permits communication with the implanted pulse generator.  The programming software is menu-driven and uses on-screen messages and prompts to assist the operator in using the system.  Whenever the programming software is initialized, a self-test is automatically run to verify checksum, file lengths, and file names.  The programmed parameters and operational status can be interrogated.  One or more parameters can be programmed at one time, and the programmed values are verified and displayed.  The programming system uses a strict communications protocol designed to minimize the possibility of "phantom" programming (i.e., inadvertent programming via environmental sources of electromagnetic interference or partial programming of a parameter).

 

F.         VNS Therapy Accessory Pack Model 502

The accessory pack contains replacement components for the VNS Therapy System. These components are back-ups for items that may become unusable during routine surgery and include a hex screwdriver, test resistors and lead tie downs. The hex screwdriver can also be used during a pulse generator explantation. These are supplied sterile.

 

G.        VNS Therapy Magnet Model 220

Cyberonics provides patients two magnets—a watch-style magnet and a pager-style magnet.  The pulse generator recognizes a magnetic field so that when a magnet is passed or held over the pulse generator, the magnetic field causes a reed switch within the pulse generator to close. This switch works like a gate: when the magnet closes it, the normal signal (stimulation) cannot pass (the pulse generator is temporarily turned OFF). When the magnet is removed, the switch (gate) opens immediately, and the pulse generator is turned back ON and can stimulate again.  The magnet is placed over the pulse generator to stop stimulation.

 

V.                 Alternative Practices and Procedures

There are currently three major treatment modalities for which there is substantial evidence of effectiveness in the treatment of a major depressive episode: pharmacotherapy with antidepressant drugs (ADDs), specific forms of psychotherapy, and electroconvulsive therapy (ECT).  ADDs are the usual first line treatment for depression.  Clinical trials have demonstrated efficacy for a number of pharmacologic classes of ADDs.  Commonly the initial drug selected is a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac), or another of the newer ADDs such as venlafaxine (Effexor).  Several forms of psychotherapy are used to treat depression.  Among these, there is good evidence for the efficacy of cognitive behavior therapy and interpersonal therapy, but these treatments are used less often than are ADDs.  Phototherapy is an additional treatment option that may be appropriate monotherapy for mild cases of depression that exhibit a marked seasonal pattern.  Physicians usually reserve ECT for treatment-resistant cases or when they determine a rapid response to treatment is desirable.  

 

Many patients do not respond to initial antidepressant treatment.  Currently there are no treatments with an FDA-approved indication specifically for the treatment of such non-responders.  Broadly speaking, physicians generally use one or more of the following strategies to treat patients who do not respond adequately to initial antidepressant treatment: (1) switching to an alternative first-line ADD, (2) switching to a second-line ADD (for example, a tricyclic ADD such as desipramine), (3) adding psychotherapy, a second ADD, or an augmentation agent.  Augmentation agents are drugs that are not generally considered to have significant antidepressant activity when administered alone, but they can enhance the effectiveness of an ADD when they are administered in combination with the ADD.  Augmentation agents include drugs such as lithium, triiodothyronine, or atypical antipsychotic drugs such as olanzapine.  Additional options for treatment-resistant patients, especially for patients who fail on the above alternatives, include monoamine oxidase inhibitors and ECT.  For treatment-resistant cases that exhibit a marked seasonal pattern, adding phototherapy to pharmacotherapy may also be an option.

 

Despite the widespread availability of these treatment modalities, it is estimated that 10% to 20% of patients do not respond to treatment.  Even among patients who do respond, many do not respond completely, ie, they do not achieve symptom remission.  Such partial responders remain at substantial risk for suicide, future recurrences of full syndromic depression, and significant functional impairment.  Moreover, there is little published evidence that any of the treatment strategies described above produces effective long-term control of depression in patients who fail to respond to initial antidepressant treatment.  Furthermore, many treatments used for patients who do not respond at all or only respond partially to the first or second attempt at antidepressant therapy are poorly tolerated and/or are associated with significant toxicity.  For example, tricyclic antidepressant drugs often cause anticholinergic effects and weight gain leading to premature discontinuation of therapy, and they can be lethal in overdose (a significant problem in depressed patients).  Lithium is the augmentation strategy with the best published evidence of efficacy (although there are few published studies documentating long-term effectiveness), but lithium has a narrow therapeutic index that makes it difficult to administer; among the risks associated with lithium are renal and thyroid toxicity.  Monoamine oxidase inhibitors are prone to produce an interaction with certain common foods that results in hypertensive crises.  Even selective serotonin reuptake inhibitors can rarely produce fatal reactions in the form of a serotonin syndrome.  ECT too is associated with significant risks: long-lasting cognitive impairment following ECT significantly limits the acceptability of ECT as a long-term treatment for depression. 

 

VI.              Marketing History

Cyberonics, Inc. was founded in 1987 to design, develop and market medical devices to improve the lives of people touched by epilepsy, depression and other chronic disorders that may prove to be treatable with our patented Vagus Nerve Stimulation Therapy (VNS Therapy™). 

 

To date, more than 22,000 patients in 44 countries have accumulated over 56,000 patient-years of experience using VNS Therapy for the treatment of epilepsy.  The first human implant of the VNS Therapy System occurred in 1988 in a patient with epilepsy.  The FDA approved Cyberonics’ patented VNS Therapy on July 16, 1997 (P970003) for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with medically refractory partial onset seizures. The commercial use of the VNS Therapy System continues to expand as VNS Therapy System has been approved by governmental regulatory bodies around the world as safe and effective for the treatment of epilepsy.  

 

The VNS Therapy System has not been withdrawn from marketing in the U.S. or any other country for any reason related to the safety or effectiveness. 

 

A.        Foreign Marketing History

Since June 1994, the VNS Therapy System has been approved for sale as a treatment for epilepsy in all the member countries of the European Union.  Currently, the VNS Therapy System is commercially distributed in Canada, Argentina, Brazil, Chile, Australia, Austria, Belgium, China, Croatia, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, Ireland, Israel, Italy, S. Korea, Liechtenstein, Luxembourg, Malaysia, New Zealand, The Netherlands, Norway, Poland, Portugal, Saudi Arabia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey and the United Kingdom.

 

In March 2001 Cyberonics received CE Mark Approval to begin commercial distribution of the VNS Therapy System for the treatment of depression in all the member European Community (EC) countries.  Subsequently, in April 2001 Cyberonics received the license to begin commercial distribution of the VNS Therapy System for the treatment of depression in Canada. Approximately 100 patients have received the VNS Therapy System for the treatment of depression outside the United States.

 

As of October 10, 2003 92 patients have received the VNS Therapy System for the treatment of depression in the European Union. Nearly half of these patients have been enrolled in the ongoing European open-label, non-randomized, single-arm, longitudinal depression Post-Marketing Study, D-03. Preliminary effectiveness results showed that at 3 months 14 of 34 (41%) subjects were responders (a 50% or greater decrease in HRSD24 from baseline) and 10 of 34 (29%) subjects were remitters (a HRSD24 score of less than or equal 10). Furthermore, after one year of stimulation, the results showed 7 of 17 (41%) subjects were responders and 5 of 17 (29%) subjects were remitters.  These results are comparable or better than those seen in the pivotal trial D-02 discussed later in this document.  The preliminary adverse event profile in the D-03 study is very similar to the one seen in previous epilepsy studies as well as in the current depression studies presented later in this document: D-01 (Feasibility) and D-02 (Pivotal).

 

The Sponsor has received six (adverse event) complaints from the approximately 50 depression patients that were implanted commercially in Europe but not enrolled in the D-03 Study. 

These events are similar to adverse events reported in the use of the VNS Therapy System for epilepsy and the D-01 and D-02 Clinical Studies for depression.

 

B.        U.S. Marketing History

Since July 1997 the VNS Therapy System has been approved for sale as a treatment for epilepsy in United States.  Two off-label depression implants in the U.S. reported adverse events.  These adverse events are similar to those reported in the use of the VNS Therapy System for epilepsy and the D-01 and D-02 Clinical Studies for depression.

 

VII.           POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

The possible complications of VNS System treatment for chronic or recurrent depression include those related to implantation, those related to performance of the implanted pulse generator, and those related to long-term patient tolerance of the implant. 

 

Except for lead positioning, implantation of the pulse generator is similar to implantation of a cardiac pacemaker. In addition to the normal risks associated with a surgical procedure, complications associated with implantation include, but may not be limited to, skin irritation; pain at the incision site; infection; extrusion or migration of the pulse generator and/or lead; dislodgment, disconnection (lead from pulse generator), breakage (lead), or corrosion of the stimulating lead; hematoma; fluid accumulation; cyst formation; inflammation; and histotoxic reactions.  These phenomena may occur either acutely or chronically and may require device replacement to correct the complication.

 

Complications can include damage to the vagus nerve, either due to surgical trauma, compression by the electrode, or excessive stimulation.  Hoarseness not associated with the stimulation suggests possible nerve irritation which can be investigated immediately.  Persistent hoarseness may be caused by nerve constriction, nerve fatigue, or a pulse generator malfunction.

 

The implant-related events in study D-02 that occurred in 10% or more of subjects were device site pain, device site reaction, incision pain, dysphagia, hypesthesia, pharyngitis, voice alteration and incision site reaction.  Adverse events that the investigators judged were at least possibly stimulation-related and which occurred at a frequency of 10% or greater in the VNS Therapy group in the acute phase (first 3 months) of the D-02 study were neck pain (16%), dysphagia (13%), paresthesia (10%), cough increased (24%), dyspnea (19%), laryngismus (11%), and voice alteration (55%).

 

Intolerable stimulation-related adverse events can generally be reduced or eliminated by a reduction in the output current, frequency, or pulse width.  Most of the reported events were mild to moderate and well tolerated; very few clinical study patients discontinued therapy due to side effects.


VIII.        Summary of Studies

A.        Summary of Non-Clinical Laboratory Studies

1.         Pre-Clinical Laboratory Studies

Pre-clinical laboratory studies previously submitted to FDA in the Original PMA application and its Supplements (P970003) were referenced in this PMA supplement and support the safety of the commercially available VNS Therapy System for the new indication of depression. Therefore, no additional pre-clinical laboratory studies were required to evaluate the safety of VNS Therapy for the treatment of patients with depression.  A summary of these studies can be found in the Summary of Safety and Effectiveness Document for P970003.

 

2.         Pre-Clinical Animal Studies

Pre-clinical animal studies previously submitted to FDA in the Original PMA application and its Supplements (P970003) were referenced in this PMA supplement and support the safety of the commercially available VNS Therapy System for the new indication of depression. Therefore, no additional pre-clinical animal studies were required to evaluate the safety of VNS Therapy for the treatment of patients with depression.  A summary of these studies can be found in the Summary of Safety and Effectiveness Document for P970003.

 

Although no additional animal studies were required to evaluate the safety of VNS Therapy for the treatment of patients with depression, a study studying the effectiveness of VNS in a rat model of depression was performed by Krahl, et al.[1]  Using a validated animal (Wistar Kyoto rat) model for major depression, the authors found that VNS significantly reduced the percentage of time that the rats were immobile in the swim test as compared to the non-stimulated control group (p < 0.05) and further stated that “antidepressant efficacy in [this model] is positively correlated with clinical efficacy.”  Additionally the authors stated, “the antidepressant efficacy of VNS was not statistically different from that obtained with desipramine and electroconvulsive shock (ECS), two standard clinical treatments that are known to be effective” in this animal model. 


3.         Risk Analysis

As a part of the Sponsor’s Design and Development Program, the commercially available VNS Therapy System’s Risk Analysis was re-evaluated for treatment-resistant depression (TRD). Since epilepsy and depression subjects undergo the same implantation procedure using the same commercially available VNS Therapy System, no new surgical risks were identified. The results of this evaluation provide supporting evidence of the safety of the VNS System for the treatment of chronic or recurrent depression.  Since depression is a mood disorder, the Sponsor evaluated the potential risks associated with patients who are implanted with a VNS Therapy System and are having a TRD episode.  The risks associated with this TRD population which are included in the VNS Therapy Risk Analysis include suicide attempt/suicide, manic depressive reaction, anxiety, confusion, overdose, and worsening depression.  These potential risks were determined to be unrelated to the VNS Therapy System and associated to the underlying nature of this severe mood disorder. No design related mitigation solutions could be developed.

B.        Summary of Clinical Investigations

Cyberonics has conducted three depression studies to establish the scientific evidence to support that the VNS Therapy System is safe and effective for its intended use in the treatment of chronic or recurrent treatment-resistant depression.  The first clinical trial conducted was a feasibility trial (D-01); the second clinical study was a randomized, controlled clinical trial with a long-term open-label extension (D-02); and the third trial was an observational study of subjects receiving standard-of-care treatments but not receiving VNS Therapy (D-04).  Baseline demographic and disease characteristics of the D-04 subjects were well matched to the D-02 subjects for comparison.

 

The objective of the feasibility study (D-01) was to assess the safety and efficacy of VNS using the VNS Therapy System in treating subjects with unipolar or bipolar depression.  The objective of the pivotal trial (D-02) was to establish that adjunctive VNS Therapy is a safe and effective long-term therapy for patients with chronic or recurrent treatment-resistant depression.

 

Additional mechanism of action studies of VNS have been performed and are summarized in this section.


 

1.         Feasibility Study D-01

This was an open-label, nonrandomized, single-treatment arm, longitudinal, multicenter, feasibility study of VNS for the treatment of subjects in a treatment-resistant major depressive episode (MDE).  The first subject enrolled in the study on June 25, 1998.  The acute phase was a 12-week (after implantation) phase that was followed by the long-term phase, which continues to be conducted.

 

Seventy-one subjects enrolled in the study, 11 of whom discontinued prior to implantation; therefore, 60 subjects were implanted.  One implanted subject failed to meet continuation criteria until the long-term phase, at which point stimulation was initiated.  Fifty-nine of the 60 subjects completed the acute phase.  All 60 subjects continued into the long-term phase.  Fifty-nine of the 60 subjects (98%) continued after 12 months of VNS Therapy treatment and as of 10/29/02, 52 of the 60 (87%) continued in the study.

 

Table 1 describes the demographic characteristics and psychiatric history of the enrolled subjects.

 

Table 1
Baseline Demographic Characteristics and Psychiatric History
(N=60)

Parameter

Statistic

Result

Age (years)

Mean

46.8

 

 

 

Gender

 

 

Male

N (%)

21 (35)

Female

N (%)

39 (65)

 

 

 

Ethnic Origin

 

 

Caucasian

N (%)

59 (98)

Other

N (%)

1 (2)

 

 

 

Current Diagnosis

 

 

Unipolar

N (%)

44 (73)

Bipolar

N (%)

16 (27)

 

 

 

Length of Current Diagnosis (Years)

Mean

9.9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Primary efficacy analysis of the 28-item Hamilton Rating Scale for Depression (HRSD28) showed 18 (31%) of the 59 observed evaluable subjects responded at acute phase exit (Visit 12), 25 of 55 (45%) responded after one year of VNS Therapy, and 18 of 42 (43%) responded after two years of VNS Therapy, where response was defined as a greater than or equal to 50% reduction of HRSD28 score.  Furthermore, after one year of stimulation, 13 of the 18 acute responders (72%) maintained their response and 12 of the acute non-responders (29%) responded.  Secondary measures of efficacy confirmed the primary efficacy measure.  Of the 30 subjects who had extraordinary, highly meaningful, or meaningful clinical benefit at acute exit, 20 (67%) continued to have the same or better benefit at 12 months and 23 (77%) maintained at least a meaningful clinical benefit at 12 months.  Thirteen of the 25 (52%) subjects who did not have a meaningful or better clinical benefit at acute phase exit had a meaningful or better clinical benefit at 12 months.  Of the subjects included in the evaluable population, 15%, 27% and 21% reached remission (HRSD28 score less than or equal to 10) at acute exit and after 1 and 2 years, respectively, of treatment.  CGI, MADRS, GAF, BDI-II, and IDS-SR scales showed similar improvements at both acute and long-term time points.

 

No subjects died during the acute phase.  One subject died during long-term follow up; this death was not attributed to VNS Therapy (sepsis following colorectal surgery).  A second subject died after she was diagnosed with lung cancer and had her device explanted, following withdrawal from the study.  The most commonly reported adverse events (those reported by more than 10% of subjects) considered at least possibly related to stimulation were voice alteration, neck pain, pain, dyspnea, headache, dysphagia, and increased cough.  The most commonly reported adverse events (reported by more than 10% of subjects) considered at least possibly related to implantation were device site reaction, device site pain, incision pain, neck pain, pain, and voice alteration.  In general, adverse events (AEs) were mild to moderate and well-tolerated and were comparable to the D-02 and epilepsy studies.

 

A total of 16 device observations were reported during the D-01 study; there were no complications noted.  The observations included 6 instances of difficulty communicating, 1 of difficulty completing device diagnosis, 3 of user error, 2 of no stimulation, 3 of painful stimulation and 1 instance where the generator would not deliver the programmed output current of 3.5 mA, but would deliver 2.5 mA.


2.         Pivotal D-02 Acute and Long-Term Study and D-02/D-04 Comparison Study

D-02 consisted of an acute and a long-term phase designed to collect data regarding outcomes of VNS Therapy in subjects with chronic or recurrent treatment-resistant depression.  The first subject enrolled in the study on July 27, 2000.  Clinical (depression assessments), quality of life, and safety data were collected monthly or quarterly during the long-term phase of the study.

 

The acute phase of D-02 was a 12-week (after implantation), double-blind, randomized, parallel-group, sham treatment-controlled, multi-center, pivotal study of adjunctive vagus nerve stimulation (VNS) using the VNS Therapy System in subjects with treatment-resistant depression.  In the acute portion, all subjects in both groups meeting the eligibility criteria for participation in the study were implanted with the VNS Therapy Pulse Generator and VNS Therapy Lead.  After implantation, subjects were randomized to either the treatment (stimulation) group or control (sham) group and results of these two groups were compared.  The VNS Therapy System remained OFF for 2 weeks after implantation to allow for recovery from surgery and to provide an opportunity to assess possible placebo response.  Two weeks after surgery (Visit 2), treatment group subjects had the device turned ON and the output current was adjusted to a comfortable and tolerable level during a 2-week period.  Sham-control group subjects were treated identically; however, the output current of the device (for both normal and magnet current) was set at 0.00 milliamperes (delivering no stimulation - OFF) throughout the acute phase.  Two weeks after device activation, the treatment group subjects’ stimulation parameters were to remain constant and were, therefore, not changed for the remainder of the study (8 weeks).  Stimulation parameters were permitted to be decreased, however, to accommodate for events possibly related to tolerance.  During the acute phase of the study, antidepressant medications were to remain unchanged from baseline.

 

After completion of the acute phase, subjects could continue in an open‑label long-term phase, during which time subjects in the treatment group continued VNS Therapy and stimulation was initiated for subjects in the sham-control group.  Sham-control group subjects followed the same treatment schedule that the treatment group received during the acute phase with 2 weeks of stimulation adjustment followed by 8 weeks of fixed stimulation parameters.  Subjects were seen approximately monthly for the first year of VNS Therapy treatment and then seen quarterly thereafter.

 

D-04 was a long-term, observational, prospective study to collect data regarding depression and health care utilization outcomes during usual standard-of-care treatment for treatment-resistant chronic and/or recurrent depression in people who were in a major depressive episode at the time of admission.  The usual standard-of-care was defined as the treatment strategy the physician and subject chose to follow (standard-of-care).  Clinical (depression assessments), quality of life and economic outcomes were assessed at baseline, 3, 6, 9 and 12 months.  The first subject enrolled in the study on January 17, 2001.  D-04 provides a comparison group to D-02 for the long-term analysis through 12-months.  No safety data were collected in D-04; however, data from efficacy assessments (eg, HRSD) addressed suicidal ideation and worsening depression.  Although serious adverse events were not collected during Study D-04, the health services information form (HSUPC; data reported in the electronic dataset) did capture hospitalizations associated with psychiatric illness (therefore not recorded specifically as worsened depression).  If these data are used as a surrogate, 28 hospitalizations were reported in the D-04 subjects during 118 patient-years of experience for a total rate of 0.237.  VNS Therapy hospitalizations for “worsened depression” compare favorably with this rate.

 

The following table (Table 2) summarizes enrollment at each site and the figure that follows (Figure 1) describes the study scheme for the D-02 and D-04 studies.

 


Table 2
Dispositions of Subjects for D-02 Acute/Long-Term and D-04

Study Site # / Investigator

Institution

Implanted

Entered

D-02 LTa

D-02

Evaluablec

    D-02

12-Month Completerc

 

D-04 e

Enrolled

 

D-04

Evaluable

 

D-04

12-Month Completer

040 / Rittberg

University of Minnesota

16

16

15

15

15 e

6

5

041 / Goodnick (Dominguez)d

U. of Miami School of Medicine

10

10b

9

7

3

3

1

042 / Conway

St. Louis U. School of Medicine

10

10

9

7

-

-

-

043 / Carpenter

Brown University/Butler Hospital

13

13

12

10

11 e

8

7

044 / Marangell

Baylor College of Medicine

17

17

13

10

12

12

12

045 / George

Medical U. of South Carolina

18

18

18

15

13

13

10

046 / Ninan

Emory U. School of Medicine

13

13

11

10

3 e

2

2

047 / Burke, W. d

U. of Nebraska Medical Center

9

9

7

7

-

-

-

048 / Barry

Stanford U. School of  Medicine

7

7

7

7

-

-

-

049 / Schwartz

SUNY Upstate Medical U.

12

12

10

9

11

11

11

050 / Burke, M.

Psychiatric Research Institute

(Via Christi)

11

10

9

8

8

8

6

051 / Rapaport (Soliman)

U. of California San Diego MC

9

9

7

3

-

-

-

052 / Zajecka

Rush Presbyterian-St. Luke’s MC

9

9

8

7

-

-

-

053 / Ginsberg

New York University MC

4

4

3

2

-

-

-

054 / Moreno

University of Arizona HC

13

13

12

12

15

15

14

055 / Husain

U. of Texas Southwestern MC

8

8

5

4

-

-

-

056 / Nierenberg

Massachusetts General Hospital

9

9