**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:]{.underline}

> Stimulator, Vagus Nerve

[Device Trade Names:]{.underline}

> **[VNS Therapy[™]{.smallcaps} System]{.underline}**
>
> VNS Therapy[™]{.smallcaps} Pulse Model 102 Generator
>
> VNS Therapy[™]{.smallcaps} Pulse Duo Model 102R Generator
>
> VNS Therapy[™]{.smallcaps} Programming Wand Model 201
>
> VNS Therapy[™]{.smallcaps} Magnet Model 220
>
> VNS Therapy[™]{.smallcaps} Software Model 250
>
> VNS Therapy[™]{.smallcaps} Lead Model 302
>
> VNS Therapy[™]{.smallcaps} Tunneler Model 402
>
> VNS Therapy[™]{.smallcaps} Accessory Pack Model 502

[Applicant\'s Name and Address:]{.underline}

> Cyberonics, Inc.
>
> 100 Cyberonics Boulevard
>
> Cyberonics Building
>
> Houston, Texas 77058 USA
>
> [PMA Number]{.underline}: P970003
>
> [Date of Panel Recommendation]{.underline}: \_\_\_\_\_\_\_\_\_\_\_,
> 2004
>
> [Date of Notice of Approval to the Applicant]{.underline}:
> \_\_\_\_\_\_\_\_\_\_\_, 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.

[]{.mark}

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.

```{=html}
<!-- -->
```
-   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:

    -   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.

    -   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]{.underline}**:

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]{.underline}**:

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[™]{.smallcaps} Pulse Model 102 Generator
>
> VNS Therapy[™]{.smallcaps} Pulse Duo Model 102R Generator
>
> VNS Therapy[™]{.smallcaps} Programming Wand Model 201
>
> VNS Therapy[™]{.smallcaps} Magnet Model 220
>
> VNS Therapy[™]{.smallcaps} Software Model 250
>
> VNS Therapy[™]{.smallcaps} Lead Model 302
>
> VNS Therapy[™]{.smallcaps} Tunneler Model 402
>
> VNS Therapy[™]{.smallcaps} 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[™]{.smallcaps} 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[™]{.smallcaps} Pulse Model 102
generator is used for initial implants and is compatible with the VNS
Therapy[™]{.smallcaps} Lead Model 302. The VNS Therapy[™]{.smallcaps}
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[™]{.smallcaps} 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[™]{.smallcaps} 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[™]{.smallcaps} Programming Wand Model 201

The programming wand is used with the VNS Therapy[™]{.smallcaps}
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[™]{.smallcaps} 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[™]{.smallcaps} 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[™]{.smallcaps} 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]{.underline} to an alternative first-line ADD,
(2) [switching]{.underline} to a second-line ADD (for example, a
tricyclic ADD such as desipramine), (3) [adding]{.underline}
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]{.underline} 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
HRSD~24~ from baseline) and 10 of 34 (29%) subjects were remitters (a
HRSD~24~ 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%).

[]{.mark}

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)

Primary efficacy analysis of the 28-item Hamilton Rating Scale for
Depression (HRSD~28~) 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 HRSD~28~ 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 (HRSD~28~ 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 \# /  | > I  | >  | >    | >    | > D | >    | >     |
| > Investigator     | mpla |  E | D-02 | D-02 | -04 | D-04 |  D-04 |
| >                  | nted | nt | >    | >    | >   | >    | >     |
| > Institution      |      | er | >    | >    | ^e^ | > E  | > 12- |
|                    |      | ed | Eval | 12-M | >   | valu | Month |
|                    |      | >  | uabl | onth | >   | able | >     |
|                    |      | >  | e^c^ | >    |  En |      |  Comp |
|                    |      | D- |      | Comp | rol |      | leter |
|                    |      | 02 |      | lete | led |      |       |
|                    |      | >  |      | r^c^ |     |      |       |
|                    |      |  L |      |      |     |      |       |
|                    |      | T^ |      |      |     |      |       |
|                    |      | a^ |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 040 / Rittberg     | 16   | 16 | 15   | 15   | 15  | 6    | 5     |
|                    |      |    |      |      | *   |      |       |
| University of      |      |    |      |      | *^e |      |       |
| Minnesota          |      |    |      |      | ^** |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 041 / Goodnick     | 10   | 1  | 9    | 7    | 3   | 3    | 1     |
| (Dominguez)^d^     |      | 0^ |      |      |     |      |       |
|                    |      | b^ |      |      |     |      |       |
| U. of Miami School |      |    |      |      |     |      |       |
| of Medicine        |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 042 / Conway       | 10   | 10 | 9    | 7    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| St. Louis U.       |      |    |      |      |     |      |       |
| School of Medicine |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 043 / Carpenter    | 13   | 13 | 12   | 10   | 11  | 8    | 7     |
|                    |      |    |      |      | *   |      |       |
| Brown              |      |    |      |      | *^e |      |       |
| University/Butler  |      |    |      |      | ^** |      |       |
| Hospital           |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 044 / Marangell    | 17   | 17 | 13   | 10   | 12  | 12   | 12    |
|                    |      |    |      |      |     |      |       |
| Baylor College of  |      |    |      |      |     |      |       |
| Medicine           |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 045 / George       | 18   | 18 | 18   | 15   | 13  | 13   | 10    |
|                    |      |    |      |      |     |      |       |
| Medical U. of      |      |    |      |      |     |      |       |
| South Carolina     |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 046 / Ninan        | 13   | 13 | 11   | 10   | 3   | 2    | 2     |
|                    |      |    |      |      | *   |      |       |
| Emory U. School of |      |    |      |      | *^e |      |       |
| Medicine           |      |    |      |      | ^** |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 047 / Burke, W.    | 9    | 9  | 7    | 7    | \-  | \-   | \-    |
| ^d^                |      |    |      |      |     |      |       |
|                    |      |    |      |      |     |      |       |
| U. of Nebraska     |      |    |      |      |     |      |       |
| Medical Center     |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 048 / Barry        | 7    | 7  | 7    | 7    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| Stanford U. School |      |    |      |      |     |      |       |
| of Medicine        |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 049 / Schwartz     | 12   | 12 | 10   | 9    | 11  | 11   | 11    |
|                    |      |    |      |      |     |      |       |
| SUNY Upstate       |      |    |      |      |     |      |       |
| Medical U.         |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 050 / Burke, M.    | 11   | 10 | 9    | 8    | 8   | 8    | 6     |
|                    |      |    |      |      |     |      |       |
| Psychiatric        |      |    |      |      |     |      |       |
| Research Institute |      |    |      |      |     |      |       |
|                    |      |    |      |      |     |      |       |
| (Via Christi)      |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 051 / Rapaport     | 9    | 9  | 7    | 3    | \-  | \-   | \-    |
| (Soliman)          |      |    |      |      |     |      |       |
|                    |      |    |      |      |     |      |       |
| U. of California   |      |    |      |      |     |      |       |
| San Diego MC       |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 052 / Zajecka      | 9    | 9  | 8    | 7    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| Rush               |      |    |      |      |     |      |       |
| Presbyterian-St.   |      |    |      |      |     |      |       |
| Luke's MC          |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 053 / Ginsberg     | 4    | 4  | 3    | 2    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| New York           |      |    |      |      |     |      |       |
| University MC      |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 054 / Moreno       | 13   | 13 | 12   | 12   | 15  | 15   | 14    |
|                    |      |    |      |      |     |      |       |
| University of      |      |    |      |      |     |      |       |
| Arizona HC         |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 055 / Husain       | 8    | 8  | 5    | 4    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| U. of Texas        |      |    |      |      |     |      |       |
| Southwestern MC    |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 056 / Nierenberg   | 9    | 9  | 9    | 9    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| Massachusetts      |      |    |      |      |     |      |       |
| General Hospital   |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 057 / Dunner       | 6    | 6  | 5    | 5    | 17  | 16   | 14    |
|                    |      |    |      |      |     |      |       |
| University of      |      |    |      |      |     |      |       |
| Washington         |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 058 / Howland      | 19   | 19 | 17   | 14   | 14  | 14   | 14    |
|                    |      |    |      |      |     |      |       |
| University of      |      |    |      |      |     |      |       |
| Pittsburgh         |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 059 / Kling        | 19   | 18 | 16   | 13   | 12  | 12   | 12    |
|                    |      |    |      |      |     |      |       |
| University of      |      |    |      |      |     |      |       |
| Maryland           |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 060 / Cooke        | 3    | 3  | 3    | 3    | \-  | \-   | \-    |
|                    |      |    |      |      |     |      |       |
| University of      |      |    |      |      |     |      |       |
| Toronto            |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| 071 / Krystal      | N/A  | \- | \-   | \-   | 4   | 4    | 4     |
|                    |      |    |      |      |     |      |       |
| Duke University    |      |    |      |      |     |      |       |
| Medical Center     |      |    |      |      |     |      |       |
+--------------------+------+----+------+------+-----+------+-------+
| **Totals**         | **2  | *  | **2  | **1  | *   | **1  | **    |
|                    | 35** | *2 | 05** | 77** | *13 | 24** | 112** |
|                    |      | 33 |      |      | 8^e |      |       |
|                    |      | ** |      |      | ^** |      |       |
+--------------------+------+----+------+------+-----+------+-------+

^a^Two subjects withdrew during the acute phase. Four subjects continued
into the long-term phase but did not complete a visit.

^b^Subject 041-184 elected not to continue into the long-term phase;
however, mistakenly completed a visit. The subject was included for
long-term phase analysis.

^c^Withdrawn subjects were included in the intent-to-treat, evaluable
and 12-month completer populations if they met the respective
definitions. ^d^Site 47 was originally involved in the D-04 study,
however the site was closed since no subjects were enrolled. The IRB for
site 41 closed\
the D-04 study when the investigator left the site.

^e^11 subjects only signed informed consents and never provided any
clinical data.

**Figure 1 - D-02 Long-Term Phase Scheme**

Months post implantation (approximately)

-4-6 weeks 0 3 4 5 6 7 8 9 10 11 12 13 14 15

  --- -- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ----
                                                                               

                                                                               
  --- -- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ----

B1 B2 IMP V9 (see long-term visit schedule in Table 8.1.0-2; schedule
differs slightly for treatment and delayed treatment)

Visits

a\) Subject Selection

To be considered for enrollment in the D-02 and D-04 studies, subjects
were required to meet the inclusion/exclusion criteria which were
designed to 1) permit enrollment of subjects with either unipolar or
bipolar depressive disorder in a current MDE; 2) maximize the quantity,
quality, reliability, and comparability of the data collected; and 3)
ensure subject safety. Study entry criteria were similar for both
studies. Most of the differences in the criteria were due to the need
for D-02 subjects to undergo implantation, ie, the D-02 protocol had
more exclusion criteria than D-04 to ensure that only subjects suitable
for the implant surgery would be enrolled. These added criteria would
not be expected to differentially influence the level of treatment
resistance in the two subject groups. Additionally, D-02 subjects were
required to have failed psychotherapy to ensure exposure to this
treatment modality prior to undergoing VNS Therapy surgery.

b\) Inclusion/Exclusion Criteria

D-02: To be eligible for the study, patients were required to be in a
chronic (duration ≥2 years) current major depressive episode (MDE)
and/or have had a history of recurrent MDEs (at least four lifetime
depressive episodes, including the current episode) according to the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV). Additionally, subjects were required to have a HRSD~24~ score
of at least 20 at the acute phase baseline. Continuation criteria
required an HRSD~24~ score [\>]{.underline} 18. Subjects had to have
failed at least two but not more than six mood disorder treatments from
different treatment categories during the current MDE. Treatment failure
was determined by an Antidepressant Resistance Rating (ARR) score ≥3
using the modified version of the Antidepressant Treatment History Form.

D-04: The principal inclusion criteria for the D-04 study were the same
as those for the D-02 study (see above); differences included: 1) D-04
subjects were not required to have a history of treatment with
psychotherapy or to be stable on antidepressants, atypical
anti-psychotics or anticonvulsant medications at least 4 weeks prior to
the baseline visit, (2) D-04 subjects were not limited to receiving five
or fewer antidepressants for treating their current episode, and (3)
D-04 subjects were also not excluded for: pregnancy; history of
myocardial infarction or cardiac arrest; history of cervical fracture
that would make implantation of the VNS Therapy System difficult;
receiving general anesthesia within 30 days of enrollment; having a
demand cardiac pacemaker, implantable defibrillator, or other
implantable stimulator; potential future need for a whole body MRI,
short-wave diathermy, microwave diathermy or ultrasound diathermy; or
relocating to an area distant from the study site (which was
exclusionary for D-02).

Exclusions for both studies included atypical depression or psychotic
symptoms; schizophrenia, schizoaffective disorder, or delusional
disorders; rapid cycling; delirium, dementia, amnestic, or other
cognitive disorders; not having an acceptable clinical response due to
failure with ≥7 antidepressant treatments during the current MDE; recent
suicide attempts (or suicide risk); recent alcohol or substance
dependence or abuse (other than nicotine); subject had other progressive
neurological disease, significant central nervous system (CNS) disease
or injury; current enrollment in another investigational study or
currently using an investigational device; a history of, or evidence of,
significant brain malformation or significant head injury, clinically
apparent cerebral vascular events, or prior brain surgery such as
cingulatomy; or previous implantation with the VNS Therapy System.

**Concomitant Mood Disorder Treatments**

D-04 subjects were allowed to have mood disorder treatments changed
according to the investigator and subject's determination of the best
treatment regimen throughout the course of the study.

For the D-02 study, since the objective was to investigate VNS Therapy,
continuation of stable baseline mood disorder treatments was allowed,
but *changes* to these treatments were not allowed during the acute
phase. Due to the severe treatment-resistant nature of the study
population, changes to the mood disorder treatments were allowed during
the long-term phase, although such changes were discouraged. Subjects
taking antidepressant, atypical antipsychotic, and anticonvulsant
medications were required to receive stable doses for at least 4 weeks
prior to the first baseline visit. If these medications were changed
during this period, Visit B1 and Visit B2 were to be repeated after the
antidepressant medications were stable for a total duration of at least
4 weeks.

Subjects were required to maintain a stable regimen of all
antidepressant, atypical antipsychotic, and anticonvulsant medications
throughout the D-02 acute phase. Additionally, electroconvulsive therapy
(ECT) was not allowed during the acute phase, but was permitted in the
long-term phase.

c\) Study Population

The following figure (Figure 2) and tables (Tables 3 and 4) describe the
population of the D-02 and D-04 studies.

Figure 2\
Protocol D-02 Long-Term Phase Subject Flowchart

Table 3\
D-02 Populations Defined for Long-Term Phase Analysis

+---------+------------------------------------------+----------------+
| **Popul | **Patients Included**                    | **Variables    |
| ation** |                                          | Analyzed**     |
+---------+------------------------------------------+----------------+
| Safety  | All subjects implanted with the VNS      | Patient        |
|         | Therapy System                           | Accounting,    |
|         |                                          | Safety         |
|         |                                          |                |
|         |                                          | **(N = 235)**  |
+---------+------------------------------------------+----------------+
| I       | Subjects were included in the ITT        | Efficacy       |
| ntent-t | population if they were                  |                |
| o-treat |                                          | **(N = 231)**  |
| (ITT)   | -   Implanted, randomized, and met the   |                |
|         |     acute phase continuation criteria    | 4 of 235       |
|         |                                          | implanted      |
|         |                                          | subjects did   |
|         |                                          | not meet acute |
|         |                                          | phase          |
|         |                                          | continuation   |
|         |                                          | criteria       |
+---------+------------------------------------------+----------------+
| Ev      | Subjects were included in the evaluable  | Efficacy       |
| aluable | population if they                       |                |
|         |                                          | **(N=205)**    |
|         | -   Met protocol D-02 inclusion criteria |                |
|         |     1, 2, 3 and 5 and ITT criteria       | Of the 235:    |
|         |                                          |                |
|         | -   Completed two baseline HRSD~24~      | 2 subjects did |
|         |     assessments                          | not enter      |
|         |                                          |                |
|         | -   Received VNS Therapy during the      | the long-term  |
|         |     acute phase (if in the treatment     | phase          |
|         |     group)                               |                |
|         |                                          | 3 subjects did |
|         | -   Had no stimulation after day 35      | not meet acute |
|         |     through acute phase exit (if in the  | continuation   |
|         |     sham-control group \[delayed         | criteria       |
|         |     treatment\])                         |                |
|         |                                          | 4 subjects had |
|         | -   Completed an HRSD~24~ assessment at  | no HRSD~24~    |
|         |     V8 or V9                             | assessments    |
|         |                                          | post-acute     |
|         | -   Had an acute exit HRSD~24~ score of  | phase exit     |
|         |     18 or greater (if in the delayed     |                |
|         |     treatment group)                     | 21             |
|         |                                          | del            |
|         | -   Received VNS Therapy during the      | ayed-treatment |
|         |     long-term phase                      | subjects (one  |
|         |                                          | also did not   |
|         | -   And met at least one of the          | meet acute     |
|         |     following criteria                   | continuation   |
|         |                                          | criteria) did  |
|         | ```{=html}                               | not have an    |
|         | <!-- -->                                 | acute exit     |
|         | ```                                      |                |
|         | -   Completed at least one HRSD~24~      | HRSD~24~       |
|         |     assessment post-acute phase exit     | [\             |
|         |                                          | >]{.underline} |
|         | -   Were considered a treatment failure  | 18             |
|         |     any time during the study            |                |
|         |                                          |                |
|         | The evaluable population is the primary  |                |
|         | population for the comparison of         |                |
|         | efficacy across 12-months for the D-02   |                |
|         | vs D-04 analysis.                        |                |
+---------+------------------------------------------+----------------+
| 1       | Subjects were included in the 12-month   | Efficacy       |
| 2-month | completer population if they             |                |
| co      |                                          | **(N=177)**    |
| mpleter | -   Met criteria for the evaluable       |                |
|         |     population                           | Of the N=205   |
|         |                                          | evaluable      |
|         | -   Received VNS Therapy for at least 12 | group:         |
|         |     months and the device was turned ON  |                |
|         |     for at least 80% of the time within  | 17             |
|         |     the 12 months from initiating VNS    | discontinued   |
|         |     Therapy                              | prior to       |
|         |                                          | one-year       |
|         | -   Completed an HRSD~24~ assessment at  |                |
|         |     11 or 12 months of VNS Therapy       | 6 did not have |
|         |                                          | \>80%          |
|         | The 12-month completer population is the | stimulation    |
|         | primary population for the evaluation of |                |
|         | long-term efficacy in the D-02 Long Term | 5 did not have |
|         | analysis.                                | 11 or 12 month |
|         |                                          | assessments    |
+---------+------------------------------------------+----------------+

Table 4\
D-04 Analysis Populations

+-----------+------------------------------------------+---------------+
| **Pop     | **Subjects Included**                    | **Variables   |
| ulation** |                                          | Analyzed**    |
+-----------+------------------------------------------+---------------+
| Enrolled  | Subjects admitted to the study by the    | A             |
|           | sites via a signed informed consent      | ccountability |
|           | document.                                |               |
|           |                                          | **N = 127**   |
|           |                                          | provided any  |
|           |                                          | data          |
+-----------+------------------------------------------+---------------+
| Evaluable | Subjects were considered evaluable if    | Efficacy      |
|           | they:                                    |               |
|           |                                          | **(N = 124)** |
|           | met Protocol D-04 inclusion criteria #1, |               |
|           | 2, 3 and 5; completed baseline IDS-SR    | 3 of 127 only |
|           | assessment; had baseline HRSD~24~ score  | provided      |
|           | ≥20; and completed at least one IDS-SR   | baseline      |
|           | assessment post-baseline                 |               |
+-----------+------------------------------------------+---------------+
| 12-Month  | Subjects were included in the 12-month   | Efficacy      |
| Completer | completer population if they:            |               |
|           |                                          | **(N=112)**   |
|           | met the criteria for the evaluable       |               |
|           | population; completed a IDS-SR           | 12 of 124 did |
|           | assessment at 12 months post-baseline    | not complete  |
|           |                                          | an IDS-SR at  |
|           | The evaluable population is the primary  | 12-months     |
|           | population for the comparison of         |               |
|           | efficacy across 12-months for the D-02   |               |
|           | vs D-04 analysis                         |               |
+-----------+------------------------------------------+---------------+

The following tables (Tables 5, 6 and 7) describe the subjects enrolled
in the D-02 and D-04 studies.

Table 5\
Baseline Demographic Characteristics Evaluable Populations

Table 6\
Psychiatric History -- Current Episode Diagnosis\
Evaluable Populations

+----------------------------+-----------+-------------+-------------+
| **Parameter**              | **St      | **D-02      | **D-04      |
|                            | atistic** | Study       | Study       |
|                            |           | (N=205)**   | (N=124)**   |
+----------------------------+-----------+-------------+-------------+
| Diagnosis                  | N         | 205         | 124         |
+----------------------------+-----------+-------------+-------------+
| > Unipolar                 | N (%)     | 185 (90)    | 109 (88)    |
+----------------------------+-----------+-------------+-------------+
| > Bipolar                  | N (%)     | 20 (10)     | 15 (12)     |
+----------------------------+-----------+-------------+-------------+

Table 7\
Summary of Baseline Psychiatric Characteristics\
Evaluable Populations

+--------------------------------+-----------+------------+------------+
| **Parameter**                  | **St      | **D-02     | **D-04     |
|                                | atistic** | Study**    | Study**    |
|                                |           |            |            |
|                                |           | *          | *          |
|                                |           | *(N=205)** | *(N=124)** |
+--------------------------------+-----------+------------+------------+
|                                | N         | 205        | 124        |
+--------------------------------+-----------+------------+------------+
| Length of Current MDE (months) | Mean      | 49.9       | 68.6       |
|                                | (S.D.)    | (52.1)     | (91.5)     |
+--------------------------------+-----------+------------+------------+
| Number of Failed Adequate      | Mean (SD) | 3.5 (1.3)  | 3.5 (1.3)  |
| Trials in Current MDE          |           |            |            |
+--------------------------------+-----------+------------+------------+
| Received ECT Lifetime          | N (%)     | 108 (53%)  | 32 (26%)   |
+--------------------------------+-----------+------------+------------+
| Received ECT, Current MDE      | N (%)     | 72 (35%)   | 15 (12%)   |
+--------------------------------+-----------+------------+------------+
| Duration of Illness (yrs)      | Mean      | 25.5       | 25.8       |
|                                | (S.D.)    | (11.9)     | (13.2)     |
+--------------------------------+-----------+------------+------------+
| Number of Lifetime Episode of  | N         | 205        | 124        |
| Depression                     |           |            |            |
+--------------------------------+-----------+------------+------------+
| > 0-2                          | N (%)     | 50 (24)    | 31 (25)    |
+--------------------------------+-----------+------------+------------+
| > 3-5                          | N (%)     | 69 (34)    | 36 (29)    |
+--------------------------------+-----------+------------+------------+
| > 6-10                         | N (%)     | 56 (27)    | 18 (15)    |
+--------------------------------+-----------+------------+------------+
| > \>10                         | N (%)     | 19 (9)     | 32 (26)    |
+--------------------------------+-----------+------------+------------+
| > Unknown                      | N (%)     | 11 (5)     | 7 (6)      |
+--------------------------------+-----------+------------+------------+
| Number of Prior Hospital       | Mean      | 2.7 (5.4)  | 2.1 (2.9)  |
| Admissions For Mood Disorders  | (S.D.)    |            |            |
| in Lifetime                    |           |            |            |
+--------------------------------+-----------+------------+------------+

d\) Safety Data

**Vital Signs and Physical Examination Observations**

The physical and neurological examinations performed at the end of the
acute and long-term phases of D-02 were essentially unchanged from the
baseline examination, revealing no clinically relevant changes. Vital
signs, including blood pressure, heart rate, and respiratory rate were
also assessed at these time points; there were minimal changes in the
vital signs over time. Moreover, the distribution of the changes was
essentially symmetrical (as many increases as decreases). These results
are reassuring and even more remarkable given the fact that many of
these subjects were on multiple medications with known effects on weight
and other vital signs. Additionally, baseline weight showed that many of
these subjects were in the obese category (BMI [\>]{.underline} 30
kg/m^2^), which is typically associated with more medical complications
and vital sign fluctuations.

**[Adverse Reactions, Serious Adverse Events, Discontinuations, and
Device Failures/Replacements]{.underline}**

**Adverse Events**

In the D-02 acute phase all treatment-emergent adverse events were
collected, irrespective of the relationship between the AE and the VNS
device (implantation or stimulation). The majority of these AEs were
mild to moderate.

The majority of implantation related AEs were events that one would
expect with this kind of surgical procedure or manipulation of the neck
area or of the vagus nerve and were no different from what is described
in the FDA-approved VNS Therapy epilepsy labeling. Stimulation-related
AEs were also examined and are reported in the following tables (Tables
8 and 9).

Table 8\
D-02 Acute Phase Incidence of Treatment-Emergent Adverse Events
[\>]{.underline} 5%

At Least Possibly Related to Stimulation

+---------------------------------------+---------------+-------------+
| **Preferred Term**                    | **Treatment** | **Sha       |
|                                       |               | m-control** |
|                                       | **(N=119)**   |             |
|                                       |               | **(N=116)** |
|                                       | **N (%)**     |             |
|                                       |               | **N (%)**   |
+=======================================+===============+=============+
| Incision Pain                         | 6 (5)         | 3 (3)       |
+---------------------------------------+---------------+-------------+
| Neck Pain                             | 19 (16)       | 1 (\<1)     |
+---------------------------------------+---------------+-------------+
| Dysphagia                             | 15 (13)       | 0           |
+---------------------------------------+---------------+-------------+
| Nausea                                | 8 (7)         | 1 (\<1)     |
+---------------------------------------+---------------+-------------+
| Paresthesia                           | 12 (10)       | 3 (3)       |
+---------------------------------------+---------------+-------------+
| Cough Increased                       | 28 (24)       | 2 (2)       |
+---------------------------------------+---------------+-------------+
| Dyspnea                               | 23 (19)       | 2 (2)       |
+---------------------------------------+---------------+-------------+
| Laryngismus                           | 13 (11)       | 0           |
+---------------------------------------+---------------+-------------+
| Pharyngitis                           | 9 (8)         | 1 (\<1)     |
+---------------------------------------+---------------+-------------+
| Voice Alteration                      | 65 (55)       | 3 (3)       |
+---------------------------------------+---------------+-------------+

The seven events identified below as stimulation-related and occurring
at a frequency ≥ 10% in the VNS Therapy group were analyzed further to
determine how long they persisted.

Table 9\
D-02 Acute Phase Duration of Treatment-Emergent Adverse Events\
Related to Stimulation, Treatment Group

  ---------------- ------------- -------------- -------- -------- -------- -------- --------
                                 **Duration in                                      
                                 Days for an                                        
                                 Event to                                           
                                 Resolve^1^**                                       

                                 **1 - 7 Days** **8 - 14 **15 -   **31 -   **60 -   **\>90
                                                Days**   30       60       90       Days**
                                                         Days**   Days**   Days**   

  **N**                          119            119      119      118      118      117

  Body as a Whole  Neck Pain     4              3        5        4        1        3

  Digestive System Dysphagia     0              3        0        2        2        3

  Nervous System   Paresthesia   1              1        2        1        2        3

  Respiratory      Cough         1              7        5        4        1        9
  System           Increase                                                         

                   Dyspnea       5              4        1        5        1        9

                   Laryngismus   1              0        2        3        0        7

                   Voice         1              3        5        2        4        53
                   Alteration                                                       
  ---------------- ------------- -------------- -------- -------- -------- -------- --------

Note: All numbers refer to the number of adverse events.

[^1^Number within each box indicates number of subjects whose event
resolved within the days shown (ie 4 subjects had the event of neck pain
resolved within 7 days)]{.underline}

Note: Adverse events that had start/stop dates during the acute phase
and those adverse events that were ongoing at Visit 9 (with known stop
dates) are listed in this table; adverse events that had a start date at
Visit 9 are not listed in this table.

Note: AEs included in this table are stimulation-related AEs with a
frequency of [\>]{.underline}10% in the treatment group.

Table 10 shows a cohort of subjects who reported adverse events during
the first three months of VNS Therapy [and]{.underline} who also had
follow-up visits during months 9 through 12 (N=209). This table
identifies those events reported by the subjects during the first three
months and follows them over time. Reported events decrease over time.
The largest decreases were noted between the first and second quarters
of stimulation. The most notable exception was voice alteration. During
the first quarter, 135 of 209 subjects (65%) reported voice alteration;
of those 135 subjects, 90 continued to report it during the fourth
quarter of stimulation.

Table 10\
Prevalence of Most Commonly Reported Stimulation-Related Adverse Events\
in SubjectsWho Experience the Event Within the First 3 Months\
of Stimulation in Study D-02, VNS Therapy (N=209)

+-----------------------+-----------+---------+---------+-------------+
|                       | **N**     | **N (%) |         |             |
|                       |           | [Co     |         |             |
|                       | **Re      | ntinuin |         |             |
|                       | porting** | g]{.und |         |             |
|                       |           | erline} |         |             |
|                       | **Event** | to      |         |             |
|                       |           | R       |         |             |
|                       | *         | eport** |         |             |
|                       | *During** |         |         |             |
|                       |           | **Event |         |             |
|                       | **First 3 | During  |         |             |
|                       | Mos.^1^** | Succe   |         |             |
|                       |           | eding** |         |             |
|                       |           |         |         |             |
|                       |           | *       |         |             |
|                       |           | *Quarte |         |             |
|                       |           | rs^2^** |         |             |
+-----------------------+-----------+---------+---------+-------------+
| **Preferred Term**    | **0--3    | **3-6   | **6-9   | **9-12      |
|                       | Mos.**    | Mos.**  | Mos.**  | Mos.**      |
+-----------------------+-----------+---------+---------+-------------+
| Cough Increased       | 55        | 18 (33) | 15 (27) | 11 (20)     |
+-----------------------+-----------+---------+---------+-------------+
| Dysphagia             | 31        | 16 (52) | 10 (32) | 6 (19)      |
+-----------------------+-----------+---------+---------+-------------+
| Dyspnea               | 35        | 22 (63) | 18 (51) | 16 (46)     |
+-----------------------+-----------+---------+---------+-------------+
| Laryngismus           | 23        | 13 (57) | 9 (39)  | 5 (22)      |
+-----------------------+-----------+---------+---------+-------------+
| Nausea                | 13        | 3 (23)  | 1 (8)   | 2 (15)      |
+-----------------------+-----------+---------+---------+-------------+
| Neck Pain             | 38        | 17 (45) | 19 (50) | 16 (42)     |
+-----------------------+-----------+---------+---------+-------------+
| Paresthesia           | 26        | 12 (46) | 6 (23)  | 4 (15)      |
+-----------------------+-----------+---------+---------+-------------+
| Pharyngitis           | 14        | 3 (21)  | 2 (14)  | 2 (14)      |
+-----------------------+-----------+---------+---------+-------------+
| Voice Alteration      | 135       | 115     | 101     | 90 (67)     |
|                       |           | (85)    | (75)    |             |
+-----------------------+-----------+---------+---------+-------------+

> ^1^Entries are the number of subjects who experienced the AEs between
> implantation and 3 months.
>
> ^2^Number of subjects who continued to experience the same adverse
> event between months 3 and 6, months 6 and 9, and months 9 and 12.
>
> Note: Adverse events were coded using the COSTART 5 dictionary.
>
> Note: Subjects were counted only once within each preferred term and
> time interval.
>
> Note: For the intervals between months 3 and 6, months 6 and 9, and
> months 9 and 12, the denominator is the number of subjects who
> experienced that particular adverse event between implantation and 10
> weeks. Note: 3 months, 6 months, 9 months, and 12 months denote
> post-stimulation.
>
> Note: Most commonly reported adverse events are those occurring with a
> frequency greater than 2% during the first quarter of VNS stimulation
> in either the treatment group or the delayed treatment group.

**Serious Adverse Events**

A serious adverse event (SAE) was defined as an event that resulted in
death, was life-threatening, resulted in or prolonged hospitalization,
resulted in a persistent disability, or involved a congenital anomaly.
Pregnancy and cancer were also treated as SAEs. SAEs were identified
without regard to their relationship to treatment. In the acute phase of
study D-02, there were 30 SAEs following implantation. Of these, 11 were
considered to be related to the implant procedure (wound infection,
asystole, bradycardia, abnormal thinking, vocal cord paralysis,
aspiration pneumonia, voice alteration, device site reaction \[2
reports\], acute renal failure and urinary retention). Investigators did
not report any SAE to be related to stimulation. In the long-term phase
of study D-02 through October 10, 2002, there were 96 SAEs. Of these,
only 6 were considered to be at least possibly related to stimulation
(sudden death of unknown cause, syncope \[2 reports\], dizziness, a
manic depressive reaction in a subject with bipolar disorder, and an
incident of worsening depression for which the investigator considered
VNS therapy a possible but unlikely contributor). SAEs reported in the
ongoing D-02 long-term phase through\
May 30, 2003 are described in the Comprehensive VNS Safety Summary,
Depression Experience which is located in \[Section VIII B 3 a)\] of
this report.

In this treatment-resistant subject population, one would expect
episodes of depression requiring hospitalization to occur throughout the
study, of note, there were three SAEs of worsening depression and two
SAE of suicide attempt *prior to* implantation of the VNS device. The
most common SAE in the acute and long-term phases of D-02 was worsening
depression *(regardless of relationship to VNS Therapy; all except one
depression event were reported as not even possibly related to VNS
Therapy)*. During the acute phase of the D-02 study, there were 12
serious adverse event reports of worsened depression, 5 in the treatment
(stimulation) group \[in four of 119 subjects\] and 7 in the Control (no
stimulation) group \[in 7 of 116 subjects\]. However, one of the
treatment-group reports occurred prior to stimulation initiation
(reported during the recovery period after implantation but before
stimulation initiation). These results indicate that worsened depression
rates are similar or somewhat lower in subjects who receive vagus nerve
stimulation as compared to subjects who receive no stimulation.

The 7 reports for the Control group over a 10-week period (all events
occurred between Visit 2 and end of acute study) can be used to
calculate an incidence rate of "worsened depression" in a group of
treatment-resistant subjects who do not have VNS Therapy (the control
group did not receive stimulation). The rate of 7 reports in 116
subjects over the 10-week period (22.3 patient-years) translates into a
rate of 0.314 events per patient-year. This is the amount of worsened
depression events that may be expected to occur in this patient
population without VNS Therapy. Another way to look at the data would be
that if 116 subjects had 7 events over a 10-week period, then they would
be expected to report about 36 events over a 52-week period (7 \* 5.2).
So, the total population of implanted subjects (235) would be expected
to report approximately 73 events (36 \* 235 / 116). These 73 events of
worsened depression would be the *expected* amount in this population
over a one-year period *without* VNS Therapy.

An analysis of the 235 D-02 subjects who received VNS Therapy, analyzing
only the period of time that stimulation was received (months 0-12 after
implantation for the treatment group and months 3-15 after implantation
for the delayed-treatment group) indicates that 63 events were reported.
The 63 events from subjects receiving stimulation are less than the
projected number of events from the population originally not receiving
stimulation.

If patient-years are used for the calculation, the difference is
similar. The 63 events of worsened-depression in the first year of VNS
Therapy in Study D-02 were reported in approximately 215 patient-years
of stimulation (0.293). The rate reported by the sham-treatment group
while receiving no stimulation was 0.314 events per patient-year.
Subjects reported similar or somewhat lower rates of worsened-depression
while receiving VNS Therapy than did subjects not receiving therapy.

Several subjects attempted suicide; they had received VNS stimulation on
the average of 6.4 months with the range from 3 to 11 months of
stimulation. Since suicide is to be expected in this subject population,
suicidal ideation was investigated by examining item 3 of the Hamilton
Rating Depression Scale. In both the acute and the long-term phases,
subjects generally improved their ratings of this item. Comparison of
suicide rates and attempts occurring during all of the depression
studies to the rates in published literature is addressed in Table 20 of
the SAE discussion.

Although two unanticipated adverse device effects (UADEs) were reported,
they were actually associated with medications given during the surgical
implantation procedure and not the device itself.

**Discontinuations**

Table 11 identifies subjects who discontinued during the D-02 acute and
long-term phases. The continuation rate for VNS Therapy after 12 months
of treatment was 90% (211/235) in this study.

**(Acute Phase)**

Two discontinuations occurred during the acute phase. Subject 059-109
successfully committed suicide approximately 6 weeks after the surgical
procedure for VNS Therapy implantation and subject 050-045, the second
discontinuation, had three SAEs after implantation. She was implanted on
11/22/00, began stimulation on 12/7/00, and developed a wound infection
within several weeks of implantation at the incision site in her neck
(then later at the incision site in her chest). The subject had surgery
on 12/20/00 for irrigation, debridement and closure of both wounds. She
was hospitalized on 01/18/01 for device site reaction, which occurred
when the lead wire was visible through her neck incision. Surgery was
performed on the same day (01/18/01) to reposition and secure the lead
wire. Even though the subject was on antibiotics most of the time after
implantation, the incision wound continued to be infected and the device
was explanted on 02/23/01. This subject also was hospitalized for
worsening depression with suicidal ideation on 01/22/01. During the
hospitalization, medications were adjusted and she was discharged on
02/2/01 with major depression but suicidal ideation no longer present.
The subject was discontinued from the study on 02/23/01.

**(Long-Term Phase)**

There were 28 discontinuations during the long-term phase. Six of the 28
subjects discontinued the long-term phase for adverse events, two of
these adverse events were serious adverse events. The six subjects who
had adverse events included subject 041-184 who had the adverse event of
hoarseness, subject 051-155 who had the adverse event of
lightheadedness, subject 055-105 who had the adverse event of post-op
pain, subject 050-150 who had the adverse event of shooting pain down
the left chest and arm area, subject 047-163 who had the SAE of sudden
unexplained death that occurred shortly after Visit 9, and subject
043-091 who had the SAE of worsening depression.

Combining the discontinuations across all phases, 8 (3%) D-02 subjects
discontinued due to adverse events.

Table 11\
Number of Subjects Withdrawn (With Subject ID Numbers)\
as of October 10, 2002

+-----------------------+-----------+-------------------+-------------+
| **Withdrawal**        | **Acute** | **Before 1 Year   | **After 1   |
|                       |           | of Therapy**      | Year of     |
|                       | *         |                   | Therapy**   |
|                       | *([\<]{.u | **(\> 90 -- 365   |             |
|                       | nderline} | Days)**           | **(\> 365   |
|                       | 90        |                   | Days)**     |
|                       | Days)**   |                   |             |
+-----------------------+-----------+-------------------+-------------+
| > Lack of efficacy    | 0         | 11                | 4           |
|                       |           |                   |             |
|                       |           | (042-006,         | (051-080,   |
|                       |           | 043-092, 044-008, | 040-038,    |
|                       |           | 044-055, 044-141, | 043-073,    |
|                       |           | 051-106, 051-264, | 051-028)    |
|                       |           | 058-062, 058-144, |             |
|                       |           | 058-181, 059-241) |             |
+-----------------------+-----------+-------------------+-------------+
| > AE (acute           | 1         | 4                 | 1           |
| > infection,          |           |                   |             |
| > hoarseness,         | (050-045) | (041-184,         | (050-150)   |
| > lightheadedness,    |           | 043-091, 051-155, |             |
| > post-op pain,       |           | 055-105)          |             |
| > arm/chest pain,     |           |                   |             |
| > worsened            |           |                   |             |
| > depression)         |           |                   |             |
+-----------------------+-----------+-------------------+-------------+
| > Death (suicide,     | 1         | 1 (unknown;       | 0           |
| > undetermined)       | (suicide; | 047-163)          |             |
|                       | 059-109)  |                   |             |
+-----------------------+-----------+-------------------+-------------+
| > Other (MRI, subject | 0         | 6                 | 1 (MRI;     |
| > decision likely     |           |                   | 043-014)    |
| > lack of efficacy,   |           | (044-049,         |             |
| > but not officially  |           | 045-236, 049-042, |             |
| > documented as such) |           | 049-067, 053-123, |             |
|                       |           | 059-247)          |             |
+-----------------------+-----------+-------------------+-------------+
| **Total Acute and     | **2**     | **22**            | **6**       |
| Long-Term**           |           |                   |             |
+-----------------------+-----------+-------------------+-------------+

**Device Failures and Replacements**

For the purposes of this study, the reported events related to device
performance were identified as observations or complications. An
observation was defined as an event that was resolved by reprogramming,
wand battery replacement, wand replacement or programming computer
replacement. This category also included those events where no action
was taken for resolution of the event. A complication was defined as a
symptomatic or asymptomatic event with potential adverse affects that
could not be treated or resolved by reprogramming or replacements of the
wand, wand battery or computer.

In this study most of the reported events were observations; the most
common observation was "difficulty communicating." This observation was
easily remedied during the visit at which the investigator was made
aware of the difficulty or shortly thereafter. In the observations that
were thought to be "erratic stimulation," the site had programmed the
parameters incorrectly and in the observation of "no stimulation," the
site had inadvertently set the device to deliver no output current.
There were two instances of complications and both were high lead
impedance, one due to a broken lead and the other did not have high
impedance upon investigation.

Of the 30 withdrawn subjects, 28 had the generator portion of the VNS
Therapy System explanted (subject 047-163's device was removed after
death) and 26 had the lead portion explanted (two leads were left
implanted in subjects whose generator was explanted). One subject
refused explant and the family of a deceased subject (suicide; 059-109)
decided not to have the device explanted.

Two VNS Therapy systems (generator and lead), although removed, were
discarded and never returned to the Sponsor. All 26 returned VNS Therapy
Generators were analyzed by the Sponsor's product analysis department;
24 leads were returned and analyzed. No anomalies were found other than
those thought to be likely associated with the explant procedure (body
fluids on device, scratches on device consistent with manipulation
during removal, etc.). One additional non-implanted generator was
returned for analysis; the lead would not fit into the generator at
implantation.

In summary, the VNS Therapy device system performed according to its
labeling and provided reliable therapy access to subjects.

e\) Effectiveness Data

The primary objective of the D-02 and D-04 comparison was to compare the
changes in depressive symptomatology during 12 months of VNS Therapy
plus usual standard-of-care (D-02 sample) with 12 months of usual
standard-of-care alone (D-04 sample). The primary efficacy analysis
constituted a comparison of the change over time (slope) of the IDS-SR
raw scores for the D-02 versus the D-04 subjects across 12-months with a
repeated measures linear regression model. Because the IDS-SR was rated
at more visits than the HRSD in the D-04 study, it was chosen as the
primary analysis variable for the repeated measures linear regression
comparing D-02 and D-04. A statistically significant difference
(p\<0.001) was demonstrated in the estimated IDS-SR raw scores per month
between the D-02 and D-04 evaluable populations, ie, the average amount
of improvement in the IDS-SR score per month that subjects in D-02
experienced was statistically significantly greater than the improvement
experienced by the subjects in D-04\
(-0.397 estimated average difference per month).

Moreover, the divergence between D-02 and D-04 continued to widen over
time. The difference in D-02 and D-04 IDS-SR total scores increased in
each of the four quarters. The cumulative estimated predicted
differences at the end of each quarter were --1.190, -2.379, -3.569, and
-4.785 points. These finding are based on the raw IDS-SR scores from
equivalent visits that were matched based on duration of stimulation for
D-02 subjects and the time post-baseline for D-04 subjects. The primary
outcome result is presented graphically in the following figure (Figure
3).

Baseline demographic and illness characteristic differences were
controlled in the primary repeated measures linear regression analysis
by incorporating the 5-level grouped propensity score identified in the
two stage propensity adjustment strategy described in the D-02 vs D-04
statistical plan. This 5-level grouped propensity score did not
contribute to the statistical significance of the primary outcome (p =
0.831). Thus, neither the observed baseline demographic and illness
characteristics, or by implication the unobserved differences between
the two groups, contributed to the difference in primary outcome between
the D-02 and D-04 populations.

![](media/image1.wmf)

When the analysis was repeated on the populations representing all
implanted D-02 subjects compared to all D-04 subjects having any data
(D-02 N = 235; D-04 N = 127), the results remained statistically
significant (p \< 0.001).

**Secondary Analyses (D-02 vs D-04 Comparison)**

**IDS-SR 12-Month Results**

For the long-term evaluable population at 12 months, the D-02 subjects
showed a highly statistically significantly greater decrease from
baseline in the average IDS-SR raw scores than did the D-04 subjects
(p\<0.001; ANCOVA). The percentage of D-02 subjects meeting the
"response" criteria (50% or greater decrease in the IDS-SR raw score
between baseline and month 12) was significantly greater than the
percentage of D-04 subjects. Significantly more D-02 subjects met the
criteria for a "complete" response, which corresponds with the concept
of remission (IDS-SR raw score of 14 or less at month 12). The results
are presented below in Table 12. Where "LOCF**"** is discussed, the
reference is made to the last observation carried forward. This analysis
technique uses the last available data point for subsequent time points
where data is missing.

Table 12\
IDS-SR Scores -- D-02/D-04 Comparisons\
Evaluable Observed Populations

+---------------------------+------------+------------+---------------+
|                           | **D-02**   | **D-04**   | **P-Value +** |
+---------------------------+------------+------------+---------------+
| **N**                     | 180        | 112        |               |
+---------------------------+------------+------------+---------------+
| Baseline Average          | 42.4       | 43.8       |               |
|                           |            |            |               |
| Raw Score (RS)            |            |            |               |
+---------------------------+------------+------------+---------------+
| 12 Month Data             |            |            |               |
+---------------------------+------------+------------+---------------+
| > Average RS              | 32.6       | 39.2       |               |
+---------------------------+------------+------------+---------------+
| > Median RS               | 32         | 40         |               |
+---------------------------+------------+------------+---------------+
| > Average Change          | -9.8       | -4.6       | \<0.001\*\*   |
+---------------------------+------------+------------+---------------+
| > LOCF Average Change     | -9.3       | -5.0       | \<0.001\*\*   |
|                           | (N=204)    | (N=124)    |               |
+---------------------------+------------+------------+---------------+
| > Median Change           | -8.5       | -3.5       |               |
+---------------------------+------------+------------+---------------+
| > Avg. % Change           | 23.4       | 8.1        |               |
+---------------------------+------------+------------+---------------+
| > Median % Change         | 20.6       | 7.9        |               |
+---------------------------+------------+------------+---------------+
| Response                  | 22         | 12         | 0.029\*       |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| LOCF Response             | 20 (N=204) | 12 (N=124) | 0.108         |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| Complete Response         | 15         | 4          | 0.006\*\*     |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| LOCF Complete Response    | 13 (N=204) | 3 (N=124)  | 0.007\*\*     |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+

> +Absence of a p-value indicates no statistical test was applied.
>
> \* Significant at \< 0.050 level. \*\* Significant at \< 0.010 level.
> (exact logistic regression)

**Sustained Response**

Since the first D-04 study HRSD assessment after baseline was not
performed until one year, the HRSD was not appropriate for a sustained
response comparison between the D-02 and D-04 studies. Therefore the
IDS-SR, which was collected quarterly in D-04, was used in an
exploratory analysis between the two populations. Using the convention
of Rush, et. al., IDS-SR sustained response was defined as a 50%
improvement or better at the last two measured quarters (for this
analysis 9- and 12-months was chosen).

Based on the above definition, statistically significantly more D-02
subjects (13%) had sustained response than D-04 subjects (4%) \[p =
0.005, evaluable population, exact logistic regression\].

**HRSD~24~ 12-Month Results**

For the long-term evaluable population at 12 months (see Table 13), the
D-02 subjects showed a highly statistically significantly greater
decrease from baseline in the HRSD~24~ scores than did the D-04 subjects
(p=0.006; ANCOVA). The percentage of D-02 subjects meeting the
"response" criteria (50% or greater decrease in the HRSD~24~ score
between baseline and month 12) was significantly greater than the
percentage for the D-04 subjects. More than twice as many of the D-02
subjects met the criteria for a "complete" response (HRSD~24~ of 9 or
less at month 12) than D-04 subjects (17% vs 7%; p = 0.031).

Table 13\
HRSD~24~ Scores -- D-02/D-04 Comparisons\
Evaluable Observed Populations

+---------------------------+------------+------------+---------------+
|                           | **D-02**   | **D-04**   | **P-Value**   |
+---------------------------+------------+------------+---------------+
| **N**                     | 180        | 104^1^     |               |
+---------------------------+------------+------------+---------------+
| Baseline Average          | 27.9       | 27.8       |               |
+---------------------------+------------+------------+---------------+
| 12 Month Data             |            |            |               |
+---------------------------+------------+------------+---------------+
| > Average                 | 19.6       | 22.8       |               |
+---------------------------+------------+------------+---------------+
| > Median                  | 19.5       | 23.5       |               |
+---------------------------+------------+------------+---------------+
| > Average Change          | -8.2       | -4.9       | 0.006\*\*     |
+---------------------------+------------+------------+---------------+
| > LOCF Average Change     | -7.4       | -4.9       | 0.040\*       |
|                           | (N=205)    | (N=104)    |               |
+---------------------------+------------+------------+---------------+
| > Median Change           | -7.5       | -5.0       |               |
+---------------------------+------------+------------+---------------+
| > Avg. % Change           | 29.6       | 16.6       |               |
+---------------------------+------------+------------+---------------+
| > Median % Change         | 28.4       | 15.6       |               |
+---------------------------+------------+------------+---------------+
| Response                  | 30         | 13         | 0.003\*\*     |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| LOCF Response             | 27 (N=205) | 13 (N=104) | 0.011\*       |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| Complete Response         | 17         | 7          | 0.031\*       |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+
| LOCF Complete Response    | 17 (N=205) | 7 (N=104)  | 0.059         |
|                           |            |            |               |
| (% of Subjects)           |            |            |               |
+---------------------------+------------+------------+---------------+

> 1 -- 20 D-04 subjects did not have HRSD's performed at their 12-month
> visit; the 12-month HRSD was added after study initiation and several
> sites did not have IRB approval prior to subjects reaching one-year in
> the study.
>
> +Absence of a p-value indicates no statistical test was applied.
> \*Significant at the 0.050 level. \*\* Significant at the 0.010 level.
> (exact logistic)

Separate analyses for both unipolar and bipolar groups were performed
and found to show identical results for the evaluable, ITT, or 12 month
completer populations. As shown in Figure 4, the unipolar and bipolar
results closely parallel the results seen in the original (combined)
evaluable, ITT and 12 month completer analyses. Because of the decreased
sample size of the subgroups, some statistical power is lost, though
most of the unipolar analyses retain statistical significance due to the
marked difference in one-year outcomes in the comparison between D-02
and D-04. The bipolar group sample size was too small for most of the
outcomes to reach statistical significance, and indeed for many analyses
was too small to perform a valid analysis (e.g. categorical outcomes).

Figure 4\
HRSD~24~ Response by Diagnosis

![](media/image7.wmf)

It should be noted that due to the very small number of bipolar
patients, the full logistic regression model (with 17 covariates) used
to generate the propensity score could not be calculated for the Bipolar
patients.

**CGI-I (Clinical Global Impression -- Improvement)**

Further support for the effect of VNS Therapy is demonstrated by the
results from the CGI-I; three times as many D-02 subjects (37%) were
rated as much improved or very much improved at 12 months than the D-04
subjects (12%; p \< 0.001; LOCF 34% vs. 12%, p \< 0.001; evaluable
population; exact logistic regression). The magnitude of these
differences indicates robust clinical significance in addition to the
statistical significance. The results are shown in the following figure
(Figure 5).

Figure 5\
Clinical Global Impression -- Improvement (CGI-I) at\
12 Months, D-02 and D-04 (Evaluable Population)

![](media/image8.wmf)

**Sustained Response - 12-Month Completer Population**

Figure 6\
D-02 IDS-SR, HRSD~24~ & MADRS Response and Complete Response\
(Long-Term D-02 Evaluable)

![](media/image20.wmf)Note: N's vary depending on observed data for each
assessment at each visit (see Appendix tables); LOCF N's range from 200
to 202, depending on the assessment.

The figure above (Figure 6) demonstrates continuing improvement over
time for the treatment population. To show that individual responders
maintained their response the Sponsor performed a sustained response
analysis. This analysis was developed and analyzed to show whether
subjects were sustaining a response over a period of time rather than
just responding at one point in time. Sustained response is
characteristic of true treatment response whereas transient response is
characteristic of placebo response. Additionally, because of the chronic
and recurrent nature of the illness, sustained response is a more
clinically relevant outcome.

Subjects were assessed over the last four visits of the first year of
VNS Therapy (months 9, 10, 11, and 12) to ascertain which subjects were
sustained responders (defined in the statistical plan as the key
clinical endpoint). Subjects who had at least one visit with a 50% or
greater response and at least an additional two visits with at least a
40% or greater response were classified as sustained responders.

Of 177 subjects in the 12-month completer population (both groups
combined), 47 (27%) were sustained responders. This is a significant
portion of subjects considering the treatment resistant nature of the
population. The importance of this endpoint is magnified by the fact
that this treatment resistant depression population by definition had
shown little response prior to the trial.

**Long Term Clinical Benefit Analyses**

As defined by the statistical plan, subjects were also evaluated
categorically by assigning them into groups according to "clinical
benefit." Clinical benefit was categorized as extraordinary
([\>]{.underline}75% improvement in HRSD~24~), highly meaningful (50% to
\<75%), meaningful (25% to \<50%), minimal (0% to \<25%) and worsened
(less than 0%). This was done to explore if these treatment-resistant
depression (TRD) subjects were receiving benefit that was not fully
reflected in the response rates. This is consistent with studies in many
chronic illnesses that define lower percentages (\<50% improvement) as a
clinically meaningful response (eg schizophrenia, obsessive compulsive
disorder).

This analysis is based on 12-month HRSD~24~ scores; although 177
subjects are in the 12-month completer population, 3 subjects had
11-month scores but not 12-month scores, therefore only 174 subjects are
displayed. Based on this categorization, 30% of subjects in the 12-month
completer group experienced either an extraordinary or a highly
meaningful clinical benefit while an additional 25% had a meaningful
benefit at 12 months of VNS Therapy (56% had at least a meaningful
benefit). This benefit was greater at 12 months compared with 3 months
(Stuart-Maxwell test, p\<0.001)

The clinical benefit categorization can also be analyzed to further
characterize benefit over time. Both those who had early benefit and
those who did not were assessed later (12-months). Of the 56 12-month
completer subjects who had extraordinary, highly meaningful, or
meaningful clinical benefit at 3-months, 41 *(73%) continued to have*
*extraordinary, highly meaningful, or meaningful clinical benefit at
12-months* (see Figure 7). Conversely, *of the 118 subjects who were
without meaningful benefit at 3-months, 56 (47%) had at least meaningful
clinical benefit by 12-months of VNS Therapy* (see Figure 8). This
indicates that a large portion of those who do not benefit early will
eventually receive meaningful clinical benefit. More importantly for a
TRD population, most subjects who have early meaningful clinical benefit
continue to maintain this meaningful benefit at 12-months. As a point of
reference, it is widely recognized that the powerful acute effect of ECT
diminishes over time. A recent ECT study shows that within six months of
achieving remission (HRSD [\<]{.underline} 10), the relapse rate was
64%.[^2]

Figure 7\
12-Month Outcomes of D-02 Subjects with Extraordinary, Highly
Meaningful\
or Meaningful Clinical Benefit At 3-Months (N=56)

![](media/image4.wmf)

Figure 8\
12-Month Outcomes of D-02 Subjects with Minimal or Less Clinical
Benefit\
At 3-Months (N=118)

![](media/image4.wmf)

Responders, Complete Responders, Percent Change, Raw Score, and Percent
Change from 3 Months to 12 Months

The following table (Table 14) presents the proportion of subjects for
the HRSD~24~, IDS-SR, and MADRS achieving response (proportion of
subjects with a 50% or greater improvement in assessment score compared
with the pre-therapy baseline and not a treatment failure), complete
response (subjects with an assessment score below a preset value),
average percent change from baseline, raw score change, and median
percent change from 3 months of therapy. For each of these outcomes at
the 12-month visit, the result for the 12-month completer population was
statistically significant, as were the corresponding last observation
carried forward (LOCF) analyses. As previously discussed, this analysis
technique uses the last available data point for subsequent time points
where data is missing. Note that the LOCF analysis makes little to no
difference in this study, because retention at one year is 90%. Results
across assessments and populations (evaluable and 12-month completer)
were similar, statistically significant, and supportive of a robust
treatment effect.

Table 14\
Responders, Complete Responders & Percent Change (HRSD~24~, IDS-SR,
MADRS)\
12-Month Completer Population in D-02

+------------+--------+--------+--------+---------+--------+--------+
|            | **HRSD |        | *      |         | **M    |        |
|            | ~24~** |        | *IDS-S |         | ADRS** |        |
|            |        |        | R^b^** |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
|            | **12   | **     | **12   | *       | **12   | **     |
|            | -Month | LOCF** | -Month | *LOCF** | -Month | LOCF** |
|            | V      |        | V      |         | V      |        |
|            | isit** |        | isit** |         | isit** |        |
+------------+--------+--------+--------+---------+--------+--------+
| **         |        |        |        |         |        |        |
| Responders |        |        |        |         |        |        |
| -- N (%)** |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| >          | 34/103 | 34/103 | 25/102 | 26/103  | 34/103 | 34/103 |
|  Treatment | (3     | (3     | (25%)  | (25%)   | (3     | (3     |
|            | 3%)^2^ | 3%)^2^ |        |         | 3%)^2^ | 3%)^2^ |
+------------+--------+--------+--------+---------+--------+--------+
| > Delayed  | 18/71  | 18/74  | 13/71  | 13/73   | 22/71  | 22/74  |
| >          | (25%)  | (24%)  | (18%)  | (18%)   | (3     | (30%)  |
|  treatment |        |        |        |         | 1%)^1^ |        |
+------------+--------+--------+--------+---------+--------+--------+
| > All      | 52/174 | 52/177 | 38/173 | 39/176  | 56/174 | 56/177 |
| > 12-Month | ^a^    | (2     | (2     | (       | (3     | (3     |
| >          | (3     | 9%)^3^ | 2%)^1^ | 22%)^1^ | 2%)^3^ | 2%)^3^ |
| Completers | 0%)^3^ |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| *          |        |        |        |         |        |        |
| *Complete- |        |        |        |         |        |        |
| Responders |        |        |        |         |        |        |
| -- N (%)** |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| >          | 19/103 | 19/103 | 16/102 | 16/103  | 25/103 | 25/103 |
|  Treatment | (1     | (1     | (1     | (       | (2     | (2     |
|            | 8%)^2^ | 8%)^2^ | 6%)^1^ | 16%)^1^ | 4%)^2^ | 4%)^2^ |
+------------+--------+--------+--------+---------+--------+--------+
| > Delayed  | 10/71  | 10/74  | 10/71  | 10/73   | 16/71  | 16/74  |
| >          | (14%)  | (14%)  | (14%)  | (14%)   | (23%)  | (22%)  |
|  treatment |        |        |        |         | ^1\ c^ |        |
+------------+--------+--------+--------+---------+--------+--------+
| > All      | 29/174 | 29/177 | 26/173 | 26/176  | 41/174 | 41/177 |
| > 12-Month | (1     | (1     | (1     | (       | (2     | (2     |
| >          | 7%)^2^ | 6%)^2^ | 5%)^2^ | 15%)^2^ | 4%)^3^ | 3%)^3^ |
| Completers |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| **Percent  |        |        |        |         |        |        |
| Change - % |        |        |        |         |        |        |
| (S.D.)**   |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| >          | 31.9%  | 31.9%  | 27.8%  | 28.1%   | 32.9%  | 32.9%  |
|  Treatment | (33.1) | (33.1) | (30.6) | (30.6)  | (36.4) | (36.4) |
|            | ^3^    | ^3^    | ^3^    | ^3^     | ^3^    | ^3^    |
+------------+--------+--------+--------+---------+--------+--------+
| > Delayed  | 26.5%  | 24.8%  | 17.3%  | 16.7%   | 26.3%  | 24.3%  |
| >          | (32.8) | (34.4) | (32.8) | (32.5)  | (38.0) | (39.7) |
|  treatment | ^3^    | ^3^    | ^3^    | ^3^     | ^3^    | ^3^    |
+------------+--------+--------+--------+---------+--------+--------+
| > All      | 29.7%  | 28.9%  | 23.5%  | 23.4%   | 30.2%  | 29.3%  |
| > 12-Month | (33.0) | (33.7) | (31.9) | (31.8)  | (37.1) | (38.0) |
| >          | ^3^    | ^3^    | ^3^    | ^3^     | ^3^    | ^3^    |
| Completers |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| **Raw      |        |        |        |         |        |        |
| Score--**  |        |        |        |         |        |        |
|  (         |        |        |        |         |        |        |
| **         |        |        |        |         |        |        |
| (S.D.)\*** |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| >          | 19.3   | 19.3   | 32.0   | 31.9    | 20.7   | 20.7   |
|  Treatment | (9.5)  | (9.5)  | (15.6) | (15.5)  | (11.4) | (11.4) |
+------------+--------+--------+--------+---------+--------+--------+
| > Delayed  | 19.9   | 20.2   | 33.4   | 33.6    | 21.8   | 22.1   |
| >          | (9.9)  | (9.9)  | (15.1) | (15.0)  | (11.9) | (11.8) |
|  treatment |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| > All      | 19.6   | 19.7   | 32.6   | 32.6    | 21.2   | 21.3   |
| > 12-Month | (9.7)  | (9.7)  | (15.4) | (15.3)  | (11.5) | (11.5) |
| >          |        |        |        |         |        |        |
| Completers |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| **Median % |        |        |        |         |        |        |
| Change 3   |        |        |        |         |        |        |
| Months**   |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| >          | 22.2%  | 22.2%  | 10.6%  | 10.6%   | 20%^3^ | 20     |
|  Treatment | ^2^    | ^2^    |        |         |        | .0%^3^ |
+------------+--------+--------+--------+---------+--------+--------+
| > Delayed  | 15.4%  | 13.1%  | 8      | 8.8%^1^ | 12%    | 12.0%  |
| >          | ^2^    | ^2^    | .6%^1^ |         |        |        |
|  treatment |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+
| > All      | 19.7%  | 19.4%  | 10     | 1       | 17     | 16     |
| > 12-Month | ^3^    | ^3^    | .2%^2^ | 0.3%^2^ | .2%^3^ | .7%^3^ |
| >          |        |        |        |         |        |        |
| Completers |        |        |        |         |        |        |
+------------+--------+--------+--------+---------+--------+--------+

^1^ p\<0.05; ^2^ p\<0.01; ^3^ p\<0.001; Response and Complete Response
used the Exact McNemar's test compared with 3 months; Percent Change
used the paired t-test (change from pre-stimulation baseline); Median
percent change used the Wilcoxon Signed Rank test to determine whether
the median was different from zero.

^a^ -- Three subjects did not have 12-month HRSD~24~ assessments (these
3 did have 11-month assessments).

^b^ -- One subject did not have a baseline IDS-SR assessment while
several others did not have 12-month assessments. This explains the
varying N's when comparing

^c^ -- two delayed treatment subjects did not have 12-month MADRS
assessments.

\* - No statistical testing was performed on the raw values.

**Concomitant Treatments Received**

**ECT**

No subjects received ECT during the acute phase of D-02. A total of 14
subjects (delayed-treatment subjects 042-0238, 043-0015, 043-0245,
044-0033, 044-0055, 050-0032, 051-0106, 059-0241; treatment subjects
041-0192, 050-0125, 053-0035, 055-0119, 056-0218, 059-0095) received ECT
during the D-02 long-term phase through 12 months of VNS Therapy. All 14
subjects were evaluable (7% of the evaluable population), while 8 of the
14 were 12-month completers (5% of the 12-month completer population).
ECT was used more frequently in non-responders and was unlikely to
substantially affect the results. Four subjects were responders, two of
which were complete responders; none of the subjects were sustained
responders (HRSD~24~). Only one of the four responders received ECT in
proximity to the 12-month visit.

A similar percentage of D-04 subjects (7 of 112 subjects - 040-007,
050-003, 057-014, 058-002, 071-001, 071-002, 071-003; 6%) received ECT
through 12-months. Two of the 7 were responders at 12-months.

Therefore, ECT usage was similar, with similar results, in both study
D-02 and D-04.

**Mood Medication Changes (Long-Term Phase & D-02 vs D-04 Comparison)**

Mood medication changes were permitted during the long-term phase; they
are important to analyze in relationship to response. To ascertain mood
medication changes over the course of the long-term phase, an
antidepressant resistance rating (ARR) score was determined for each
medication for each subject. Changes were then assessed by responder or
non-responder classification to ascertain whether responders
([\>]{.underline}50% improvement in HRSD~24~ at 12-months) had more
changes in mood medications than non-responders (\<50% improvement in
HRSD~24~ at 12-months). An additional analysis was performed for
remitters (HRSD~24~ score less than 10) and non-remitters.

More *non-responders* (77%) than responders (56%) added or increased
mood medications during 12-months of VNS Therapy. Additionally, almost
twice as many responders (44%) had no ARR changes or removed or
decreased medications by at least one ARR or were not taking medications
as compared to non-responders (23%). Changes were similar when comparing
complete responders (remitters) with non-complete responders. This
information suggests that medication changes were unlikely to have had a
significant impact on outcomes

[]{.mark}

When compared to D-02, D-04 ARR changes were similar to the
non-responders from D-02. Over 81% of all D-04 subjects added or
increased mood medications by at least one ARR. Only 7% of subjects
reduced or discontinued medications by at least one ARR without any
increase in a corresponding mood medication by at least one ARR. Data
also indicated that the "strength" of changes were similar between D-02
and D-04 subjects.

This information is important for two reasons. First, it internally
validates that the D-04 group was receiving significant medication
changes (which is important for verifying that D-04 is a relevant
reference group for D-02). Secondly, it provides a validation that the
D-02 responders had less medication changes than might typically be
expected. The lower frequency of medication changes among D-02
responders compared to D-04 subjects and D-02 non-responders is strong
evidence that improvement in the D-02 subjects is due to VNS Therapy and
not medication.

**Robustness of the Efficacy Results**

The statistical plan specified that the efficacy analyses would be
performed on an evaluable population using observed data. To further
evaluate the robustness of the results described in the preceding
sections, several additional analyses were performed. These included
statistical testing of an intent-to-treat (ITT) analysis of the primary
efficacy model and last observation carried forward (LOCF) analyses on
the D-02 vs. D-04 secondary analyses. Additionally, the subset of D-02
sites also involved in the D-04 study was analyzed descriptively.
Finally, the primary efficacy analysis was performed with censoring of
the D-02 data for concomitant antidepressant treatment use. The purpose
of these additional analyses was to demonstrate that the superior D-02
outcomes (1) were not altered if all D-02 implanted subjects were
included in the primary analysis, (2) were not altered when missing
observations were accounted for, (3) were not explained solely by
depression improvement in subjects from the D-02 sites that did not
participate in the D-04 study, and (4) were not due to concomitant
antidepressant treatment.

An ITT analysis typically includes all randomized subjects regardless of
whether they receive adequate treatment or continue for an adequate
duration. Therefore this is a conservative approach to analyzing
treatment outcomes that eliminates any potential bias that may arise by
excluding certain subjects from the efficacy analysis. For this
analysis, the four acute continuation criteria failure subjects were not
included as a further conservative approach (response prior to
stimulation initiation). Therefore the ITT analysis included 231 D-02
subjects and 124 D-04 subjects. The ITT analysis results of the primary
efficacy model were statistically significant (p \< 0.001).

An LOCF analysis is a technique often used by statisticians to address
the impact of missing data. It uses the last available observation for
subsequent time points where data are missing. For treatments associated
with an increasing effect over time, LOCF understates the true treatment
effect. LOCF analyses were performed on all D-02/D-04 secondary
comparisons, and statistical significance was maintained for all
comparisons except for the IDS-SR evaluable response rates and HRSD~24~
evaluable complete response rates; in these latter two analyses, the
results approached statistical significance.

Where sites are not identical between two studies, the differential
outcomes among these sites can contribute to biasing the outcome. Since
the D-02 and D-04 studies had some different sites, this was a potential
concern. Therefore results were examined from sites that were only
involved in both the D-02 and D-04 studies. This examination (a response
rate analysis using the HRSD~24~) yielded results similar to the
analysis that included all the sites (27% HRSD~24~ responder rate at
12-months for the D-02 sites that also participated in the D-04 study
vs. 30% for all D-02 sites). A formal statistical analysis was not
performed because the decreased sample size would not ensure adequate
power.

An additional conservative statistical analysis was performed to confirm
the results of the descriptive medication analyses presented above. In
this alternative analysis, D-02 subjects' scores were censored when the
addition of an antidepressant treatment or an increase in an existing
treatment by an ARR level of one or more occurred. The analysis
incorporated additions or changes in either antidepressant drugs or ECT.
In other words, if a D-02 subject added or increased a concomitant
antidepressant treatment, his or her subsequent IDS-SR scores were not
used in this confirmatory repeated measures linear regression analysis.
Instead the subject's last IDS-SR score before the concomitant
antidepressant treatment change was used for subsequent assessment
points (ie, a last-observation-carried-forward approach). Consequently
this analysis removes from the VNS Therapy group outcome any potential
benefit from an addition or increase in concomitant antidepressant
treatment. The approach is asymmetric as no censoring is performed on
the D-04 data. It is an overly conservative approach because it
penalizes VNS Therapy by removing all incremental benefit that is
attributable to VNS Therapy after the censoring time point. Therefore,
it understates the treatment effect of VNS Therapy.

Despite using this very conservative approach, the repeated measures
linear regression analysis of IDS-SR scores was still marginally
statistically significant (p = 0.052). This constitutes very strong
evidence that the superior outcome in the VNS Therapy group is not due
to concomitant antidepressant treatment. The 95% confidence interval
(-0.37 to 0.00 for the D-02/D-04 difference in IDS-SR score per month
where negative values indicate D-02 superiority) shows that the addition
of VNS Therapy alone (ie, without any additions or increases in
concomitant antidepressant treatments) for less than one year of
treatment was virtually always more effective than were *multiple*
medication/ECT additions or increases over a full year of treatment
using any currently available therapeutic option (standard-of-care).

When primary analysis of IDS-SR data are performed looking at only
shared D-02/D-04 study sites (p=.002) or at only unipolar subjects
(p=\<.001), the results continue to be statistically significant.

In summary, several alternative analyses as described above were applied
to the comparisons of the D-02 and D-04 efficacy outcomes. The objective
of these alternative analyses was to determine if applying conservative
statistical approaches to address the potential biases that might be
inherent in the primary and secondary analysis strategies would alter
the statistical significance or the conclusions of the D-02/D-04
comparisons. When the D-02 and D-04 results were compared with the
conservative alternative analyses, the D-02 outcomes almost always
remained statistically significantly superior to the D-04 outcomes. Thus
the robust statistical significance demonstrated in the primary and
secondary analyses was confirmed by more conservative supplemental
analyses.

3\. Comprehensive VNS Safety Summary

a\) Depression Experience

This section provides an integrated summary of safety data from studies
D-01, D-02, and D-03. SAE data are current through a data cutoff date of
05/30/03.

As previously stated, D-04 was a long-term, observational study and no
safety data was collected.

**Disposition of Subjects**

The following table (Table 15) provides an overview of the implantation
and follow-up for each study.

Table 15\
Summary of Subject Disposition

During the three studies, the VNS Therapy System performed according to
its labeling. Most device issues were associated with communication
difficulties and were easily resolved by repositioning the programming
wand or replacing the programming wand batteries. One high lead
impedance occurred requiring replacement of the lead. Analysis of this
lead revealed a lead break due to fatigue at the electrode bifurcation.
It is important to note that overall lead survivability is excellent at
greater than 98.8% at 71 months.

The following table (Table 16) shows acute phase implantation-related
treatment emergent adverse events. The determination whether an event
was related to implantation was made by the investigator. Events
reported at a [\>]{.underline} 5% incidence considered to be possibly,
probably, or definitely related to [implantation]{.underline} were
incision pain, voice alteration, incision site reaction (typically
redness or swelling at the incision site), device site pain, device site
reaction (typically soreness, swelling or tenderness near the generator
site), pharyngitis, dysphagia, hypesthesia, dyspnea, nausea, headache,
neck pain, pain, paresthesia, and increased cough.

These events are all expected during the type of surgical procedure
associated with VNS Therapy implantation, and except for headache are
addressed in the current labeling for VNS Therapy.

+------------------------+------------------------+---------+---------+
| Table 16\              |                        |         |         |
| D-01 and D-02 Acute    |                        |         |         |
| Phase Incidence of     |                        |         |         |
| Treatment-Emergent     |                        |         |         |
| Adverse Events (AEs)\  |                        |         |         |
| Related to             |                        |         |         |
| Implantation           |                        |         |         |
| [\>]{.underline} 5%    |                        |         |         |
+========================+========================+=========+=========+
| **Body System**        | **Preferred Term**     | *       | *       |
|                        |                        | *D-01** | *D-02** |
|                        |                        |         |         |
|                        |                        | **(     | **(N    |
|                        |                        | N=60)** | =235)** |
|                        |                        |         |         |
|                        |                        | **N     | **N     |
|                        |                        | (%)**   | (%)**   |
+------------------------+------------------------+---------+---------+
| **Number of Subjects   |                        | **48    | **208   |
| with at Least One      |                        | (80)**  | (89)**  |
| Adverse Event**        |                        |         |         |
+------------------------+------------------------+---------+---------+
| **Body as a Whole**    | Device Site Pain       | 10      | 54      |
|                        |                        | (17%)   | (23%)   |
+------------------------+------------------------+---------+---------+
|                        | Device Site Reaction   | 4 (7%)  | 33      |
|                        |                        |         | (14%)   |
+------------------------+------------------------+---------+---------+
|                        | Headache               | 5 (8%)  | 18 (8%) |
+------------------------+------------------------+---------+---------+
|                        | Incision Pain          | 10      | 84      |
|                        |                        | (17%)   | (36%)   |
+------------------------+------------------------+---------+---------+
|                        | Neck Pain              | 2 (3%)  | 16 (7%) |
+------------------------+------------------------+---------+---------+
|                        | Pain                   | 7 (12%) | 17 (7%) |
+------------------------+------------------------+---------+---------+
| **Cardiovascular       | **None                 | **-**   | **-**   |
| System**               | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+
| **Digestive System**   | Dyspepsia              | 3 (5%)  |         |
+------------------------+------------------------+---------+---------+
|                        | Dysphagia              | 2 (3%)  | 26      |
|                        |                        |         | (11%)   |
+------------------------+------------------------+---------+---------+
|                        | Nausea                 | 2 (3%)  | 20 (9%) |
+------------------------+------------------------+---------+---------+
| **Endocrine System**   | **None                 | **-**   | **-**   |
|                        | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+
| **Hemic and Lymphatic  | **None                 | **-**   | **-**   |
| System**               | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+
| **Metabolic and        | Healing Abnormal       | 4 (7%)  | 0%      |
| Nutritional            |                        |         |         |
| Disorders**            |                        |         |         |
+------------------------+------------------------+---------+---------+
| **Musculoskeletal      | **None                 | **-**   | **-**   |
| System**               | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+
| **Nervous System**     | Hypesthesia            | 3(5%)   | 25      |
|                        |                        |         | (11%)   |
+------------------------+------------------------+---------+---------+
|                        | Paresthesia            | 0%      | 13 (6%) |
+------------------------+------------------------+---------+---------+
| **Respiratory System** | Cough Increased        | 1 (2%)  | 15 (6%) |
+------------------------+------------------------+---------+---------+
|                        | Dyspnea                | 2 (3%)  | 20 (9%) |
+------------------------+------------------------+---------+---------+
|                        | Pharyngitis            | 1 (2%)  | 31      |
|                        |                        |         | (13%)   |
+------------------------+------------------------+---------+---------+
|                        | Voice Alteration       | 11      | 78      |
|                        |                        | (18%)   | (33%)   |
+------------------------+------------------------+---------+---------+
| **Skin and             | Incision Site Reaction | 6 (10%) | 67      |
| Appendages**           |                        |         | (29%)   |
+------------------------+------------------------+---------+---------+
| **Special Senses**     | **None                 | **-**   | **-**   |
|                        | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+
| **Urogenital**         | **None                 | **-**   | **-**   |
|                        | [\>]{.underline} 5%**  |         |         |
+------------------------+------------------------+---------+---------+

> Note: Percentages are relative to the number of subjects in the safety
> population. Note: Subjects are counted only once within each body
> system and preferred term. Note: Includes all AEs where relationship
> to implantation was recorded as possible, probable, or definite.

The following table (Table 17) shows all events [\>]{.underline} 5% in
the D-01 and D-02 studies reported by investigators during acute phase
treatment as possibly, probably, or definitely related to
[stimulation]{.underline}.

+--------------------------+-----------+----------+---------+---------+
| Table 17\                |           |          |         |         |
| D-01 and D-02 Acute      |           |          |         |         |
| Phase Incidence of       |           |          |         |         |
| Treatment-Emergent       |           |          |         |         |
| Adverse Events\          |           |          |         |         |
| (AEs) Related to         |           |          |         |         |
| Stimulation              |           |          |         |         |
| [\>]{.underline} 5%      |           |          |         |         |
+==========================+===========+==========+=========+=========+
| **Body System**          | **        | **D-01   | **D-02  | **D-02  |
|                          | Preferred | Tre      | Trea    | Sham-co |
|                          | Term**    | atment** | tment** | ntrol** |
|                          |           |          |         |         |
|                          |           | **       | **(N    | **(N    |
|                          |           | (N=60)** | =119)** | =116)** |
|                          |           |          |         |         |
|                          |           | **N      | **N     | **N     |
|                          |           | (%)**    | (%)**   | (%)**   |
+--------------------------+-----------+----------+---------+---------+
| **Number of Subjects     |           | **56     | **100   | **34    |
| with at Least One        |           | (93%)**  | (84%)** | (29%)** |
| Stimulation-Related      |           |          |         |         |
| Adverse Event**          |           |          |         |         |
+--------------------------+-----------+----------+---------+---------+
| **Body as a Whole**      | Headache  | 11(18%)  | 5 (4%)  | 1       |
|                          |           |          |         | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
|                          | Incision  | 0%       | 6 (5%)  | 3 (3%)  |
|                          | Pain      |          |         |         |
+--------------------------+-----------+----------+---------+---------+
|                          | Neck Pain | 13 (22%) | 19      | 1       |
|                          |           |          | (16%)   | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
|                          | Pain      | 9 (15%)  | 4 (3%)  | 2 (2%)  |
+--------------------------+-----------+----------+---------+---------+
|                          | Reaction  | 3 (5%)   | 5 (4%)  | 0%      |
|                          | Un        |          |         |         |
|                          | evaluable |          |         |         |
+--------------------------+-----------+----------+---------+---------+
| **Cardiovascular         | Pa        | 3 (5%)   | 3 (3%)  | 1       |
| System**                 | lpitation |          |         | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
| **Digestive System**     | Dyspepsia | 4 (7%)   | 4 (3%)  | 0%      |
+--------------------------+-----------+----------+---------+---------+
|                          | Dysphagia | 5 (8%)   | 15      | 0%      |
|                          |           |          | (13%)   |         |
+--------------------------+-----------+----------+---------+---------+
|                          | Nausea    | 4 (7%)   | 8 (7%)  | 1       |
|                          |           |          |         | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
| **Metabolic and          |           | **None   | **None  | **None  |
| Nutritional Disorders**  |           | [\>]{.un | [\      | [\      |
|                          |           | derline} | >]{.und | >]{.und |
|                          |           | 5%**     | erline} | erline} |
|                          |           |          | 5%**    | 5%**    |
+--------------------------+-----------+----------+---------+---------+
| **Musculoskeletal        |           | **None   | **None  | **None  |
| System**                 |           | [\>]{.un | [\      | [\      |
|                          |           | derline} | >]{.und | >]{.und |
|                          |           | 5%**     | erline} | erline} |
|                          |           |          | 5%**    | 5%**    |
+--------------------------+-----------+----------+---------+---------+
| **Nervous System**       | Dizziness | 4 (7%)   | 3 (3%)  | 0%      |
+--------------------------+-----------+----------+---------+---------+
|                          | H         | 3 (5%)   | 2 (2%)  | 1       |
|                          | ypertonia |          |         | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
|                          | Insomnia  | 3 (5%)   | 4 (3%)  | 0%      |
+--------------------------+-----------+----------+---------+---------+
|                          | Manic     | 3 (5%)   | 1       | 0%      |
|                          | Reaction  |          | (\<1%)  |         |
+--------------------------+-----------+----------+---------+---------+
|                          | Pa        | 3 (5%)   | 12      | 3 (3%)  |
|                          | resthesia |          | (10%)   |         |
+--------------------------+-----------+----------+---------+---------+
| **Respiratory System**   | Cough     | 10 (17%) | 28      | 2 (2%)  |
|                          | Increased |          | (24%)   |         |
+--------------------------+-----------+----------+---------+---------+
|                          | Dyspnea   | 8 (13%)  | 23      | 2 (2%)  |
|                          |           |          | (19%)   |         |
+--------------------------+-----------+----------+---------+---------+
|                          | La        | 2 (3%)   | 13      | 0       |
|                          | ryngismus |          | (11%)   |         |
+--------------------------+-----------+----------+---------+---------+
|                          | Ph        | 3 (5%)   | 9 (8%)  | 1       |
|                          | aryngitis |          |         | (\<1%)  |
+--------------------------+-----------+----------+---------+---------+
|                          | Voice     | 33 (55%) | 65      | 3 (3%)  |
|                          | A         |          | (55%)   |         |
|                          | lteration |          |         |         |
+--------------------------+-----------+----------+---------+---------+
| **Skin and Appendages**  |           | **None   | **None  | **None  |
|                          |           | [\>]{.un | [\      | [\      |
|                          |           | derline} | >]{.und | >]{.und |
|                          |           | 5%**     | erline} | erline} |
|                          |           |          | 5%**    | 5%**    |
+--------------------------+-----------+----------+---------+---------+
| **Special Senses**       | Ear Pain  | 3 (5%)   | 1 \<    | 0%      |
|                          |           |          | 1%)     |         |
+--------------------------+-----------+----------+---------+---------+
| **Urogenital**           |           | **None   | **None  | **None  |
|                          |           | [\>]{.un | [\      | [\      |
|                          |           | derline} | >]{.und | >]{.und |
|                          |           | 5%**     | erline} | erline} |
|                          |           |          | 5%**    | 5%**    |
+--------------------------+-----------+----------+---------+---------+

Note: Subjects are counted only once within each body system and
preferred term. Note: Includes all AEs where relationship to stimulation
was recorded as possible, probable, or definite. Note: Percentages are
relative to the number of subjects in the safety population.

Duration of event was analyzed in Study D-02. As expected, surgical
events dissipated significantly over the first several weeks after
device implantation. However, hypesthesia and vocal cord paralysis
(events which may involve some nerve damage to either surrounding
sensory nerves in the neck or directly to the vagus nerve) may take much
longer to resolve or be permanent. These events are already adequately
described in labeling (known events from the epilepsy studies).

Stimulation related events also typically dissipate over time. Either by
a quarter analysis of all subjects or by analyzing the cohort of
subjects reporting events during the first 3-months and seeing if events
continue to be reported in those subjects, stimulation related events
dissipate by 25% to 89% over one year. The decrease depends on the
specific AE, and the most common AE of hoarseness (voice alteration)
does show the least amount of decrease over one-year.

**Physical and Neurological Examinations, Vital Signs Assessments, &
Holter Monitor Recordings**

Investigators performed physical and neurological examinations in D-01
and D-02 study subjects at baseline, end of acute phase, and one-year of
VNS Therapy. The post-baseline examinations were essentially
unremarkable except for the presence of healed surgical scars and the
occasional presence of voice alteration. For the D-02 Study, changes
from baseline were plotted graphically for blood pressure, heart rate,
respiratory rate and weight. The changes conformed to a symmetric
distribution suggesting an absence of effect associated with VNS
Therapy.

Holter monitor recordings were obtained as part of the D-01 study. The
recordings did not show any evidence of significant changes after VNS
Therapy was initiated. This agreed with previous findings from the
epilepsy studies. Therefore, in agreement with FDA, no Holter monitoring
was required for the D-02 study.

**Serious Adverse Events (SAE)**

A serious adverse event (SAE) was defined as an event that resulted in
death, life-threatening event, a hospitalization or prolongation of
existing hospitalization, a persistent disability, a congenital anomaly,
and pregnancy or cancer. Important medical events that did not result in
death, were not life threatening, or did not require hospitalization may
have been considered an SAE when, based upon appropriate medical
judgment if they may have jeopardized the subject and may have required
medical or surgical intervention to prevent one of the outcomes listed
above.

*It is important to note that SAE's were determined without regard to
possible relationship to VNS Therapy. Particularly during the long-term
phase the subjects underlying psychiatric and medical conditions and
their concomitant treatments (including antidepressant medications) were
important potential contributors to the SAEs. Most of the SAE's
described during the studies were not considered by the investigator or
Sponsor to be related to VNS Therapy; only SAE's considered related to
VNS Therapy implantation or treatment are included in this summary.*

**Summary Table of SAEs**

The following table (Table 18) lists the overall incidence of serious
adverse events at least possibly related to VNS Therapy by event for
each subject during the acute and long-term phases of studies D-01,
D-02, and D-03 (including events reported during ongoing treatment past
the\
12-month long-term phases).

Table 18\
Summary of Serious Adverse Events at Least Possibly Related\
to VNS Therapy (Safety Population for Each Study)^1^

  -------------------- ------------------------- ---------- ---------- ----------
  **Body System**      **COSTART Term**          **D-01**   **D-02**   **D-03**

  **Study N**                                    60         235        47

  **Body as a Whole**  Overdose or Suicide       2          0          0
                       Attempt                                         

                       Pain (calf of leg)        1 (I)      0          0

                       Sudden Unexplained Death  0          1          0

                       Wound Infection           1 (I)      1 (I)      0

  **Cardiovascular**   Asystole                  0          1 (I)      0

                       Bradycardia               0          1 (I)      0

                       Deep Thrombophlebitis     1 (I)      0          0

                       Myocardial Infarction     1          0          0

                       Syncope                   0          1 (I) +    1
                                                            2^2^       

  **Digestive**        Diarrhea                  1          0          0

                       Esophagitis               1          0          0

                       Hemorrage GI              0          1          0

                       Vomiting                  1          0          0

  **Nervous System**   Agititation               1          0          0

                       Depression                3          1          1

                       Dizziness                 0          1          0

                       Dysphoria                 1          0          0

                       Manic-Depressive Rx       1          1          0

                       Paresthesia               0          1          0

                       Thinking Abnormal         0          1 (I)      0

                       Vocal Cord Paralysis      0          2 (I) +    0
                                                            1^2^       

  **Respiratory        Pulmonary Embolism        0          0          1 (I)
  System**                                                             

                       Aspiration Pneumonia      0          1 (I)      0

                       Voice Alteration          0          1 (I)      0

  **Skin &             Device Site Reaction      0          2 (I)      0
  Appendages**                                                         

  **Urogenital**       Acute Renal Failure       0          1 (I)      0

                       Urinary Retention         0          1 (I)      0

  **TOTALS**                                     **15**     **22**     **3**
  -------------------- ------------------------- ---------- ---------- ----------

^1^Cut-off date is 05/30/03. ^2^ Event for one subject (047-171) also
noted as possibly related to implantation. I = implant

Of the D-01 SAE's reported as at least possibly related to VNS Therapy,
*only one was judged definitely related*; this was the event of wound
infection associated with implantation. All other D-01 events were rated
as "possibly" related. These were events that the investigator could not
rule out as having a possible relationship to stimulation, but were not
necessarily related to stimulation.

Of the D-02 SAE's reported as at least possibly related to VNS Therapy,
*6 events were judged definitely related to implantation* (voice
alteration, vocal cord paralysis, asystole, 2 device site reactions
\[reposition of generator, extrusion of leads\], and wound infection).
The other implantation related events included three probably related to
implantation (acute renal failure, abnormal thinking and urinary
retention) and four possibly related (aspiration pneumonia, bradycardia,
syncope, and vocal cord paralysis). These events are known complications
of surgery in general (infection, urinary retention), or were caused by
medications administered peri-operatively (acute renal failure, abnormal
thinking) or are specific to VNS Therapy surgery (vocal cord paralysis,
asystole/bradycardia).

*No D-02 SAE's were reported as definitely related to stimulation.* One
SAE was reported as probably related (paralysis of the vocal cord) to
stimulation. Eight SAE's were reported as possibly related to
stimulation, since the investigator could not rule out having a possible
relationship to stimulation, although these events were not necessarily
related to stimulation. These events included depression,
manic-depressive reaction, gastrointestinal bleed, paresthesia,
dizziness, sudden unexplained death, and syncope. The syncope and vocal
cord paralysis were also noted as possibly related to implantation,
although the events occurred at least 10 months after implantation.

Of the D-03 SAE's reported at least possibly related to VNS Therapy,
*one event was judged definitely related to implantation* and two were
possibly related to stimulation. An event of pulmonary embolism was
thought definitely related to implantation while the events of
depression and syncope were considered possibly related to stimulation.
An additional D-03 subject experienced vocal cord paralysis associated
with surgery that was not reported as an SAE.

The most common SAE during acute treatment was depression (all studies,
regardless of relationshipt to VNS Therapy). Although more properly
considered a lack of efficacy than an AE, these events were categorized
as SAEs because the subjects required hospitalization, thus triggering
the designation of SAE. Although only a small number (5) of these
worsened depression events were reported as even possibly associated
with VNS Therapy, the SAEs of depression are discussed here for
completeness. Hospitalization for depression was reported in similar
numbers in each D-02 acute phase group (five \[5\] in the treatment
group and seven \[7\] in the sham-control group \[no stimulation\]).
Additionally in D-02, three SAEs of the nine SAEs occurring *prior* to
implantation were for worsened depression/suicidal ideation; another two
of these pre-implantation SAEs were for hospitalization associated with
suicide attempts (subjects 049-042 and 058-129). This information
underscores the severity of this population and that worsened depression
and suicide attempts are expected in this group. There does not appear
to be any relationship to VNS Therapy.

After reviewing the published literature and comparing it to the
combined D-01, D-02, and D-03 studies, it is clear that completed and
attempted suicide rates for subjects receiving adjunctive VNS Therapy
are not greater than for standard-of-care treatment alone. The following
table (19) provides completed and attempted suicide rates for implanted
patients in D-02 and for all patients combined in D-01, D-02, and D-03,
and compares them to rates published by Khan, 2000 in his article which
reviewed an FDA clinical database consisting of 45 studies for all
antidepressants-approved in the US during the years January 1987 to
December 1997. This comparison to Khan is justified due to their large
patient database of about 20,000 patients, coming from the FDA clinical
trials database. Note that the antidepressants included in this review
were from studies of depressed patients (not treatment-resistant).

Table 19\
Suicide Rates and Attempts reported in Khan^1^ review of the FDA
Database\
and in the D-01, D-02 and D-03 Combined Database

+-----------+------+-------+-------+-------+------------+------------+
|           | *    | *     | *     | **Pa  | *          | *          |
|           | *N** | *Inci | *Inci | tient | *Incidence | *Incidence |
|           |      | dence | dence | ye    | of Suicide | of Suicide |
|           |      | of    | of    | ars** | Attempt/** | / patient  |
|           |      | Su    | Suic  |       |            | year**     |
|           |      | icide | ide** |       | **patient  |            |
|           |      | Attem |       |       | year**     |            |
|           |      | pts** | **N   |       |            |            |
|           |      |       | (%)** |       |            |            |
|           |      | **N   |       |       |            |            |
|           |      | (%)** |       |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+
| D-01,     | 342  | 24    | 3     | 689   | 3.5%       | 0.4%       |
| D-02,     |      | (7%)  | (     |       |            |            |
|           |      |       | 0.9%) |       |            |            |
| D-03      |      |       |       |       |            |            |
| combined  |      |       |       |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+
| D-02      | 235  | 11    | 1     | 437   | 2.5%       | 0.2%       |
| total     |      | (5%)  | (     |       |            |            |
|           |      |       | 0.4%) |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+
| Invest    | 12   | 90    | 27    | 3,206 | 2.8%       | 0.8%       |
| igational | ,879 | (     | (     |       |            |            |
| dru       |      | 0.7%) | 0.2%) |       |            |            |
| g-Khan^2^ |      |       |       |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+
| Active    | 3    | 25    | 5     | 729   | 3.4%       | 0.7%       |
| comparato | ,681 | (     | (     |       |            |            |
| r-Khan^3^ |      | 0.7%) | 0.1%) |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+
| Pla       | 3    | 15    | 2     | 556   | 2.7%       | 0.4%       |
| cebo-Khan | ,079 | (     | (0    |       |            |            |
|           |      | 0.5%) | .06%) |       |            |            |
+-----------+------+-------+-------+-------+------------+------------+

^1^Khan, A, Warner HA, Brown, WA, Symptom Reduction and Suicide Risk in
Patients Treated with Placebo in Antidepressant Clinical Trials, Arch
Gen Psychiatry, 57, 2000, 311-317

^2^Investigational drugs included sertraline, paroxetine, nefazodone,
mirtazapine, bupropion

^3^ Comparator drugs included imipramine, amitriptyline and trazodone

This data reflects the serious adverse event data reported to the
Sponsor as of 05/30/03. The terminology of "suicide attempt" includes
those reported as suicide attempt and overdose. The aggregate VNS data
comes from the 342 D-01, D-02 and D-03 subjects with treatment-resistant
depression followed for up to 48 months for a total follow-up of 689
patient years.

**Summary of Deaths**

A total of seven deaths were reported during the D-01, D-02 and D-03
studies after implantation. Six of the seven were reported as not
related to VNS Therapy by the investigators; one death, although
unlikely to be related, was reported as possibly related since the
investigator could not determine the exact cause of death.

**Unanticipated Adverse Device Effects (UADEs)**

There were no unanticipated adverse device effects (UADEs) reported for
the D-01 or D-03 studies. Two D-02 UADEs were reported. The D-02 UADEs
were related to concomitant medications administered during surgery
(device implantation), not due to the device directly.

**Summary and Conclusions**

In general, adverse events were mild to moderate, similar to those
reported in epilepsy, and were typically well-tolerated by subjects as
evidenced by the high continuation rates. Most of the serious adverse
events reported during the D-01, D-02, and D-03 studies were related to
the patients\' underlying illness, comorbid illnesses, medications, or
other intercurrent events and not to VNS Therapy.

Over this year (and longer, as information was available past one-year),
the VNS Therapy System performed according to its labeling. Most device
issues were communication difficulties easily resolved by repositioning
the programming wand or replacing the programming wand batteries. One
high lead impedance occurred requiring replacement; a lead break due to
fatigue at the electrode bifurcation was noted. It is important to note
that overall lead survivability is excellent at greater than 98.8% at 71
months.

Adverse events were similar between studies. The most common implant
related AE's were incision pain, voice alteration, incision site
reaction (typically redness or swelling at the incision site), device
site pain, device site reaction (typically soreness, swelling or
tenderness near the generator site), pharyngitis, dysphagia, and
hypesthesia. The most common stimulation related AEs were voice
alteration, cough increased, dyspnea, neck pain, dysphagia, laryngismus,
and paresthesia. These events are already adequately described in
labeling (known events from the previous epilepsy studies).

Duration of event was analyzed in Study D-02. As expected, surgical
events dissipated significantly over the first several weeks after
device implantation. However, hypesthesia and vocal cord paralysis
(events which may involve some nerve damage to either surrounding
sensory nerves in the neck or directly to the vagus nerve) may take much
longer to resolve or be permanent. These events are already adequately
described in labeling (known events from the epilepsy studies).

Stimulation related events also typically dissipate over time. Either by
a quarter analysis of all subjects or by analyzing the cohort of
subjects reporting events during the first 3-months and seeing if events
continue to be reported in those subjects, stimulation related events
dissipate by 25% to 89% over one year. The decrease depends on the
specific AE, and the most common AE of hoarseness (voice alteration)
does show the least amount of decrease over one-year.

Physical and neurological examinations in D-01 and D-02 study subjects
at baseline, end of acute phase, and one-year of VNS Therapy suggested
an absence of effect associated with VNS Therapy. Holter monitor
recordings were obtained as part of the D-01 study. The recordings did
not show any evidence of significant changes after VNS Therapy was
initiated. This agreed with previous findings from the epilepsy studies.

Only a small number of serious adverse events (SAE's) were reported as
even possibly related to VNS Therapy in Studies D-01, D-02 and D-03. An
even smaller number (8) were felt to be definitely related to VNS
Therapy; all eight were implant surgery related (expected events, such
as infection, vocal cord paralysis, asystole, etc.). The SAEs that were
reported as possibly related to VNS Therapy were typically events that
the investigator could not rule out as having a possible relationship to
stimulation, although these events were also not necessarily related to
stimulation. The only two unanticipated adverse device effects reported
were actually associated with medications administered during implant
surgery.

In summary, the events seen in the depression studies, both typical
adverse events and serious adverse events, were similar to those seen in
epilepsy studies. VNS Therapy is a safe and tolerable therapy (90%
continuation rate at one-year) for patients with treatment resistant
depression.

b\) Epilepsy Experience (E-01 through E-05 and Post Marketing Data)

The epilepsy experience of the VNS Therapy System is relevant to its use
in depression since the surgical implantation is identical and the
therapeutic use (device and its settings) is essentially the same. This
summary provides a discussion of the clinical safety profile of the VNS
Therapy System from the E-01 through E-05 Epilepsy Clinical Studies with
an analysis of the 5 year commercial post-marketing experience including
relevant safety information that was added to the VNS Therapy's labeling
as a result of the post-marketing experience, the commercial marketing
history and other important safety information as it relates to VNS
Therapy System.

A clinical development program involving more than 450 patients in five
clinical protocols examined the efficacy and safety of VNS Therapy for
the treatment of epilepsy. These studies, starting in 1988, led to
commercial approval in July 1997. Today, more than 22,000 people
(\>56,000 patient-years) worldwide have been implanted with Cyberonics'
VNS Therapy System for difficult to control epilepsy.

**VNS Therapy Surgery**

The most common surgical side effects reported during the epilepsy
clinical studies were infection and nerve injury.

Infection is an event that is possible with any surgical procedure. The
percentage of subjects associated with device explant during the
epilepsy clinical studies was 1.1% or 5/454 subjects (These data were
derived from Summary of Safety and Effectiveness for the NCP Vagus Nerve
Stimulation System, Table 13, P970003, Jan. 16, 1998). Following
commercial approval, the percentage of patients experiencing an
infection was 1.47% or 363/24,640 subjects of which 1.01% or 249/24,640
subjects went on to have their device explanted. Compared to other
implantable pulse generators such as cardiac pacemakers, the rates are
very favorable. Adhering to proper operating room technique and using
prophylactic antibiotics can minimize the risk of infection.

Infection is an event that is possible with any surgical procedure. The
rate associated with device explant during the epilepsy clinical studies
(5/454; 1.1% derived from the Summary of Safety and Effectiveness for
the NCP Vagus Nerve Stimulation System, Table 13, P970003, Jan. 16, 1998
-- Attachment A) and during commercial use (total of 363/24,640 = 1.47%;
associated with explant is 249/24,640 = 1.01%) is less than that
reported for similar implantable devices. The risk of infection can be
minimized by adhering to proper operating room technique, and using
prophylactic antibiotics.

Nerve injury is typically associated with either excessive manipulation
of the nerve or blood supply during wound retraction. Nerve injury is
typically manifested by left vocal cord paralysis or left facial
paralysis. The rate of all nerve injuries reported during the epilepsy
clinical studies was approximately 1% while the reported rate during
commercial use is lower (less than 0.5%). These rates are both lower
than nerve injuries reported from carotid endarterectomy (CEA), an
operation in a similar area of the neck as VNS Therapy implantation.

Two other uncommon events associated with surgery that were never
reported during the clinical studies, but were reported during
commercial use included Horner's syndrome and bradycardia/asystole.
Horner's syndrome has been reported after VNS Therapy surgery
(12/24,640; 0.049%; noted as Horner's or ptosis or miosis). Horners
Syndrome is caused by damage or interruption of the sympathetic nerve to
the eye, and is usually noted as a drooping of the eyelid on the same
side of the damage. It is not necessary to treat Horner's syndrome since
it is not painful and does not interfere with vision; depending on the
nerve damage, full recovery may occur. This outcome is reported in the
literature as associated with other neck surgeries, and Cyberonics'
physician's manuals were updated to include this event
(P970003/S004/A004 - submitted 3/9/98).

The other uncommon event associated with surgery is significant
bradycardia or asystole during the first lead testing performed
intraoperatively. No events of this nature were reported during the
epilepsy clinical studies. However, 47 events (0.191% of implants) have
been reported during commercial use. This event appears to be a vagal
response associated with the initial stimulation during surgery.
Patients experiencing bradycardia intraoperatively typically continue
with the implant procedure, although some surgeons have decided not to
implant the device after the event.

Cyberonics' Physician's Manual was updated in PMA Supplement P970003/S48
to recommend that:

##### During the intraoperative Lead Test, physicians should be prepared to follow guidelines consistent with Advanced Cardiac Life Support (ACLS). 

##### Stimulation should not be programmed on until approximately 2 weeks following surgery to allow the wound to heal and allow the nerve time to accommodate to the electrode placement. 

##### If a patient experiences asystole or severe bradycardia (heart rate \< 40 BPM) or clinically significant changes in heart rate during a lead test during the initial implantation, the patient should be placed on a cardiac monitor during initial stimulation.

**Therapeutic Side Effects and Tolerability**

The two randomized, double-blind, controlled studies (E-03 and E-05) are
the most appropriate to use when discussing adverse events. The
following adverse events were found to occur more frequently acutely, in
either High or Low stimulation, than in baseline in at least one of the
two studies (E-03 High Group Rate, E-05 High Group Rate):

Table 20

  ----------------------- ----------------------- -----------------------
  **Event**               **E-03 High Group^1^**  **E-05 High Group^1^**

  Cough                   12.3%                   52.6%

  Dyspepsia               Not reported            21.1%

  Dyspnea                 10.5%                   27.4%

  Infection               3.5%                    14.7%

  Pain                    Not reported            33.7%

  Paresthesia             15.8%                   24.2%

  Throat Pain\*           7.0%                    42.1%

  Voice Alteration /      38.6%                   72.6%
  Hoarseness                                      

  Vomiting                1.8%                    17.9%
  ----------------------- ----------------------- -----------------------

> \* Throat pain includes pain in throat, laryngismus, and pharyngitis
> combined. (derived from Table 10, SS&E)
>
> ^1^ High Group defined as receiving therapeutic stimulation

More than 95% of patients in the epilepsy clinical studies have
continued to receive VNS Therapy for at least one year. This
continuation rate for VNS Therapy is extremely high and indicates that
VNS Therapy is well tolerated. \[This rate is similar to the one-year
continuation rate seen during the depression studies (92% for the D-01
study and 90% for the D-02 study).\]

**Cardiac Holter Safety Data and Mortality Rates**

Holter monitor studies suggest there is no evidence of adverse cardiac
effects associated with left cervical VNS using the VNS Therapy System,
NCP System, and there appears to be no evidence of adverse cardiac
effects associated with left cervical VNS using the NCP VNS Therapy
System in patients 50 years and older.

**Summary**

More than 450 epilepsy study patients and more than 22,000 commercially
implanted have proven that VNS Therapy is safe for its intended use when
used in accordance with its labeling.

There are non-negligible surgical sequelae that are possible with VNS
Therapy surgery, they are typical of those seen with other implantable
devices (infections) or other similar surgeries (nerve damage), and are
adequately described in the labeling and can be minimized through proper
surgical technique and training. Additionally, the rates of these events
seen with VNS Therapy surgery are similar to lower than those reported
in the literature for similar devices and surgeries.

The most common events associated with VNS Therapy, are hoarseness and
coughing, which occur during the actual stimulation (usually 30 seconds
of stimulation every five minutes). Modifying stimulation settings can
reduce these events. High continuation rates at one year support the
overall tolerability of VNS Therapy. Holter monitor studies have
demonstrated no evidence of adverse cardiac effects associated with left
cervical VNS using the VNS Therapy System.

4\. Other Information from Clinical Investigations

a\) Comparison: D-02 vs. ECT Study

Many psychiatrists consider ECT to be the most effective acute therapy
available for the treatment of depression. Owing to poor patient
acceptance and safety concerns (particularly adverse cognitive effects),
however, physicians generally reserve the use of ECT for patients who do
not respond to or cannot tolerate pharmacotherapy, situations in which a
rapid response is deemed desirable, and certain other limited situations
(eg, psychotic depression). These same concerns severely limit the use
of ECT as a maintenance therapy. Consequently while some responders to
an acute course of ECT receive longer-term maintenance ECT, most receive
maintenance pharmacotherapy.

Prudic et al.[^3] recently completed an observational study of the
effectiveness of ECT at seven community hospitals in the New York City
metropolitan region. One of the investigators (Harold Sackeim, Ph.D.) of
that study defined a subset of the study subjects in an attempt to
provide a cohort that was well-matched to the D-02 study subjects. This
provided a unique opportunity to compare the long-term effectiveness of
VNS Therapy plus standard-of-care treatment (ie, the outcomes from study
D-02) with the effectiveness of standard-of-care post-ECT maintenance
treatment (the outcomes in the matched ECT cohort from the Prudic
study).

Dr. Sackeim created the matched ECT cohort by excluding from the full
data set subjects with the following characteristics that would have
excluded the subjects from enrollment in the D-02 study:

1.  Age less than 18 or greater than 72;

2.  Baseline HRSD~24~ score ≤ 19;

3.  Presence of psychotic symptoms;

4.  Diagnosis of schizoaffective disorder.

The resulting matched ECT cohort comprised 172 of the 347 subjects in
the original study population. The matched ECT cohort was similar to the
D-02 long-term phase evaluable population (N=205) in sex distribution
(65% female vs. 64% female, respectively), baseline mean HRSD~24~ score
(31 vs. 28), and mean age (48 years vs. 46 years). The matched ECT
cohort had a greater proportion of subjects with a diagnosis of bipolar
disorder than did the D-02 group (20% vs. 10%, respectively) and an
older mean age of onset of mood disorder (29 years old vs. 22 years old,
respectively). Overall, however, the D-02 group appears to comprise a
more treatment-resistant population than does the matched ECT cohort
because the D-02 group presented with a longer mean current episode
duration than did the matched ECT cohort (50 vs. 11 months,
respectively), a greater proportion of subjects with a history of prior
ECT (53% vs. 32%), more prior hospitalizations for depression (mean of
2.7 vs. 1.5), a longer mean duration of illness (26 years vs. 19 years),
and more failed adequate treatments in the current episode (a mean of
3.5 vs. 1.7).

Dr. Sackeim determined response and remission rates for the matched ECT
cohort. He defined response as a 50% or greater improvement from
baseline in HRSD~24~ score. He defined remission as a 60% or greater
improvement from baseline to a score of 10 or less on the HRSD~24~
rating. (The definition of complete response \[remission\] used in
analyzing the D-02 long-term results was slightly different in that it
used a cutoff score of 9 or less but no percentage change criterion.) In
the matched ECT cohort, 58% of the subjects achieved response and 44% of
the subjects achieved remission following acute treatment with ECT.
Maintenance of remission, however, was poor among these subjects. Six
months following the completion of the acute course of ECT, 41% of the
matched ECT cohort met the criterion for response; only 20% met the
criteria for remission. Thus, response and remission were not maintained
after a successful acute course of treatment with ECT despite the
availability and use of standard antidepressant treatments.

By contrast, response and remission rates, as determined from the
HRSD~24~ ratings, increased from the end of month 3 to the end of month
12 during continuous treatment with VNS Therapy plus standard-of-care
treatment. In the D-02 evaluable population, 14% (29/205) met the
response criterion and 7% (14/205) met the remission criterion after 3
months of treatment. After 12 months of VNS Therapy plus
standard-of-care treatment, 27% (55/205) met the response criterion and
15% (30/205) met the remission criterion. (Note that the D-02 response
and remission rates described above differ from those described earlier,
because the rates described here are derived from a more conservative
analysis that more closely corresponds to the analysis done by Dr.
Sackeim. In the earlier response and remission calculations, the rates
were calculated based only on subjects with actual observations. Here
rates are calculated by dividing the number of subjects meeting the
response or remission criterion by the entire sample of 205.)

Substantial differences in the study designs, analysis methods, and
subject populations of these two studies preclude any definitive
conclusions. Nonetheless, the striking contrast between the *declining*
response and remission rates during post-ECT standard-of-care
maintenance treatment and the *improving* response and remission rates
during maintenance VNS Therapy plus standard-of-care treatment provides
additional supportive evidence of the long-term effectiveness of VNS
Therapy plus standard-of-care treatment.

b\) Mechanism of Action (MOA) Studies

\(1\) Summary of Previous MOA Studies

Understanding the primary and secondary projections of the vagus within
the central nervous system (CNS) can help elucidate the neural
mechanisms underlying the therapeutic effects of VNS as well as some of
its potential side effects. Though no single finding explains the
mechanism of action of VNS, the combination of presently known studies
strongly support the involvement of a widespread array of autonomic,
reticular and limbic structures found in the brainstem and throughout
both hemispheres of the brain (see figure 9 below discussion). The
beneficial effects of VNS most likely occur through its effects on these
systems. The overlap between these systems and the systems associated
with antidepressant effects strongly implies a potential mechanism for
possible VNS induced antidepressant efficacy. By overlapping with brain
areas associated with antidepressant effects or with mood regulation,
and by affecting the neurotransmitters norepinephrine and serotonin
(both strongly associated with antidepressant effects) the potential
paths for possible VNS induced antidepressant effects are clear.

**Figure 9**

\(2\) Summary of Depression Imaging Studies

Neuroimaging studies show that VNS Therapy modulates activity in regions
of the brain believed to be involved in mood regulation. Aspects of
these studies that emphasize the more immediate VNS-induced cerebral
effects report the involvement of areas that are consistent with the
known projections of the vagal nerve such as the prefrontal cortex,
cerebellum, inferior parietal lobe, hypothalamus, and insula. The
studies exploring the effects of VNS treatment over time report the
involvement of brain regions that have been previously reported in
neuroimaging studies of mood regulation and mood disorders. Similar to
previous depression imaging studies, these VNS imaging studies of TRD
patients report the involvement of cortical regions (orbitofrontal,
superior frontal, and parietal cortex), involvement of subcortical
regions (such as the basal ganglia, hypothalamus, and cerebellum), and
involvement of limbic and paralimbic regions (the insula, cingulate,
hippocampus, and possibly the amygdala) that are implicated in a
emerging limbic-cortical model of depression. That vagal projection
areas overlap brain regions implicated in the neural correlates of
emotional regulation further strengthens the likelihood that VNS
directly affects brain regions that are important to mood regulation and
the treatment of mood disorders.

IX. CONCLUSIONS DRAWN FROM STUDIES

Valid scientific evidence is necessary to establish that there is
reasonable assurance the VNS Therapy System is safe and effective for
its use 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 treatment. The clinical investigations under IDE
G980099, combined with the non-significant risk parallel control study
(D-04), provide reasonable assurance that the VNS Therapy System is safe
and effective when used as indicated. Therefore, the clinical trial
results meet the requirement of 21 CFR § 860.7(c) for statistically
valid investigations.

The safety of the VNS System has been demonstrated in the treatment of
epilepsy as well as in clinical trials for the treatment of depression.
The side effects reported during the clinical trials for depression are
almost identical to those reported for the treatment of epilepsy.

The clinical studies conducted for the treatment of depression included
clearly and concisely stated study objectives, endpoints and hypotheses.
Patient eligibility for study enrollment was based upon defined
inclusion and exclusion criteria, providing assurance that the patient
population was well defined and that the patients selected were suitable
for study.

The results from the comparison of depression ratings between D-02 study
subjects (receiving VNS therapy plus standard-of-care treatment) and
D-04 study subjects (receiving only standard-of-care treatment; no VNS
therapy) over 12 months of observation provide valid scientific evidence
of the effectiveness of VNS therapy for the treatment of chronic or
recurrent major depressive episodes resistant to at least two adequate
antidepressant treatments.

The primary efficacy analysis (a repeated measures linear regression
analysis of IDS-SR scores) showed a highly statistically significant
difference (p \< 0.001) in favor of the VNS therapy group.

The secondary efficacy analyses also demonstrated statistically
significant results in favor of the VNS therapy group vs. the
standard-of-care only treatment group. These included the change from
baseline to 12 months in the HRSD-24 score (difference of 3.3 points; p
= 0.006), IDS-SR response rates (22% vs. 12%; p = 0.029), IDS-SR
complete response rates (15% vs. 4%; p = 0.006), IRS-SR sustained
response rate (13% vs. 4%; p = 0.005), HRSD-24 response rates (30% vs.
13%; p = 0.003), and CGI improvement response rates (37% vs. 12%; p \<
0.001).

Alternate statistical analysis techniques using intent-to-treat-analysis
and last-observation-carried forward approaches demonstrated the
robustness of the results described above. Additionally, a subset
analysis limiting the D-02 data to only those investigational sites also
participating in the D-04 study provided further evidence of the
robustness of the primary analysis result.

Extensive analyses of baseline patient and disease characteristics and
concomitant antidepressant treatment use during the 12-month studies
demonstrate that (1) differences between the D-02 and D-04 subjects in
baseline patient and disease characteristics were few and do not account
for the difference in efficacy outcomes between the subject groups and
(2) differences in the use of concomitant antidepressant treatments do
not account for the difference in efficacy outcomes between the D-02 and
the D-04 subject groups.

X.  Panel Recommendation (To be completed by FDA)

On \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, (year), the Neurological Devices
Panel recommended that the Pre-Market Approval Application for the VNS
Therapy System for the treatment of depression be approved subject to
the Sponsor's acceptance of the conditions outlined in the approval
letter of \_\_\_\_\_\_\_\_\_\_\_, (date).

XI. CDRH Decision (To be completed by FDA)

FDA concurred with the recommendations of the Neurological Devices Panel
of \_\_\_\_\_\_\_\_\_\_\_\_, (date), and issued an approvable letter on
\_\_\_\_\_\_\_\_\_\_\_, (date). On \_\_\_\_\_\_\_\_\_\_\_\_\_\_, (date)
Cyberonics submitted amendments to the application as requested by FDA.

XII. Approval Specifications (To be completed by FDA)

Continued approval of the device is contingent upon the submission of
post approval reports to the Food and Drug Administration as described
in the approval order (Attachment \_\_). A copy of the draft final
labeling is attached (Attachment \_\_\_).

[^1]: Krahl S.E., Senanayake S.S., Pekary A.E., Sattin A. Vagus nerve
    stimulation (VNS) is effective in a rat model of depression.
    *Journal of PsychiatricReseach*. Submitted.

[^2]: Prudic J, Olfson M, Marcus SC, Fuller RB, and Sackeim HA. The
    effectiveness of electroconvulsive therapy in community settings.
    *JAMA*. 2003; in press.

[^3]: Prudic J., Olfson M., Marcus S.C., et al. The effectiveness of
    electroconvulsive therapy in community settings. *JAMA*
    2003;290(8):1091-1093.